Evidence Report/Technology Assessment 

Number 152 

Cardiac Resynchronization Therapy and Implantable 

Cardiac Defibrillators in Left Ventricular 

Systolic Dysfunction 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0023

Prepared by: 

University of Alberta Evidence-based Practice Center, Edmonton, AB, Canada 

Investigators 

Finlay A. McAlister, M.D., M.S. 

Justin Ezekowitz, M.B.B.Ch., M.S. 

Donna M. Dryden, Ph.D. 

Nicola Hooton, M.P.H. 

Ben Vandermeer, M.S. 

Carol Friesen, M.A., M.L.I.S. 

Carol Spooner, B.Sc.N., M.S. 

Brian H. Rowe, M.D., M.S. 

AHRQ Publication No. 07-E009 

June 2007
This report is based on research conducted by the University of Alberta Evidence-based Practice 

Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), 

Rockville, MD (Contract No. 290-02-0023). The findings and conclusions in this document are 

those of the author(s), who are responsible for its contents, and do not necessarily represent the 

views of AHRQ. No statement in this report should be construed as an official position of AHRQ 

or of the U.S. Department of Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and others 

make informed decisions about the provision of health care services. This report is intended as a 

reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 
ii 

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

McAlister FA, Ezekowitz J, Dryden DM, Hooton N, Vandermeer B, Friesen C, Spooner C, 

Rowe BH. Cardiac Resynchronization Therapy and Implantable Cardiac Defibrillators in Left 

Ventricular Systolic Dysfunction. Evidence Report/Technology Assessment No. 152 (Prepared 

by the University of Alberta Evidence-based Practice Center under Contract No. 290-02-0023). 

AHRQ Publication No. 07-E009. Rockville, MD: Agency for Healthcare Research and Quality. 

June 2007.

None of the investigators has any affiliations or financial involvement that conflicts 

with the material presented in this report. 
iii 

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

 We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, Ph.D., R.N. 

Director, EPC Program 

Agency for Healthcare Research and Quality 

Mary Nix, M.S., M.T.(ASCP)S.B.B. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 
iv 

Acknowledgments 

We are grateful to members of the technical expert panel, Dr. Gillian Sanders (Department of 

Medicine, Duke University, Durham, NC), Dr. Mark Hlatky (Department of Health Research 

and Policy, Stanford University, Palo Alto), Dr. Richard Page (Division of Cardiology, 

University of Washington School of Medicine, Seattle), Dr. William Abraham (Division of 

Cardiovascular Medicine, Ohio State University, Columbus), and Mary Nix (AHRQ), who 

provided direction for the scope and content of the review. We also thank the external reviewers 

who submitted written comments on earlier drafts of this report: Dr. David Atkins (AHRQ), Dr. 

Eric Fain (St. Jude Medical Inc.), Dr. Martin Fromer (Centre Hospitalier Universtaire Vaudois, 

Lausanne), Dr. Gordon Moe (University of Toronto), Dr. Robert Rea (Mayo Clinic College of 

Medicine, Rochester, MN), Dr. John Spertus (University of Missouri—Kansas), Mr. Bob 

Thompson (Medtronic Inc.), and Dr. Clyde Yancy (Baylor Heart and Vascular Institute, Dallas). 

The authors wish to thank Dr. W.T. Abraham, Dr. C. Leclerq, and Dr. S. Cazeau for 

providing further information about their studies. 

The investigators acknowledge the following financial support: Dr. McAlister is a Population 

Health Scholar supported by the Alberta Heritage Foundation for Medical Research, a New 

Investigator of the Canadian Institutes of Health Research (CIHR), and holds the Merck 

Frosst/Aventis Chair in Patient Health Management at the University of Alberta, Edmonton. Dr. 

Ezekowitz is supported by CIHR. Dr. Rowe is supported by the CIHR as a Canada Research 

Chair in Emergency Airway Diseases (Ottawa, Canada). He is also supported by the Faculty of 

Medicine and Dentistry, University of Alberta, Edmonton and the Capital Health Authority, 

Edmonton. 
v 

Structured Abstract 

Objectives: To determine the efficacy, effectiveness, and safety of cardiac resynchronization 

therapy (CRT) and/or implantable cardioverter defibrillators (ICD) in patients with left 

ventricular systolic dysfunction (LVSD). 

Data Sources: A systematic and comprehensive literature search was conducted to identify 

randomized controlled trials (RCTs) evaluating efficacy and observational studies evaluating 

effectiveness or safety of CRT and/or ICD in patients with LVSD. 

Review Methods: Study selection, quality assessment, and data extraction were completed by 

several investigators in duplicate and independently. Random-effects models were used for 

analyses. 

Results: From 11,340 citations, we identified 14 RCTs (4,420 patients) for the CRT efficacy 

review, 106 studies (9,209 patients) for the CRT effectiveness review, 89 studies (9,677 patients) 

for the CRT safety review, 12 RCTs (8,516 patients) for the ICD efficacy review, 48 studies 

(15,097 patients) for the ICD effectiveness review, and 49 studies (12,592 patients) for the ICD 

safety review—all studies enrolled only patients with LVSD. An additional 12 studies (68,848 

patients) were included for an analysis of peri-implant outcomes for all patients with ICD (i.e., 

not only LVSD patients).

All patients in the CRT studies had LVSD (mean LVEF from 21 to 30 percent) and 

prolonged QRS duration (mean from 155 to 209 msec), and 91 percent had New York Heart 

Association (NYHA) class III or IV symptoms. In patients with LVSD and heart failure 

symptoms, CRT improved ejection fraction (weighted mean difference 3.0 percent [95% CI, 0.9 

to 5.1]), quality of life (weighted mean reduction in Minnesota Living with Heart Failure 

Questionnaire 8.0 points [95% CI, 5.6 to 10.4 points]), and function (59 percent of CRT 

recipients vs. 37 percent of controls improved by at least one NYHA class in the RCTs and 

between 63 percent and 82 percent of CRT recipients improved by at least one NYHA class in 

observational studies). The proportion of patients hospitalized for HF was reduced by 37 percent 

(95% CI, 7 to 57 percent) and all-cause mortality was reduced by 22 percent (95% CI, 9 to 33 

percent; NNT=29 over 6 months). Implant success rate was 93 percent, 0.3 percent of patients 

with LVSD died during implantation. Over a median 11-month followup, 6.6 percent of CRT 

devices exhibited lead problems and 5 percent malfunctioned. 

In patients with LVSD, ICD reduced all-cause mortality by 20 percent (95% CI, 10 to 29 

percent; NNT=20 over 35 months). ICD implant success rate was 99 percent and peri-implant 

deaths occurred in 1.2 percent of LVSD patients and 1.3 percent of all implantees. The frequency 

of post-implantation complications in LVSD patients per 100 patient years included 1.4 (95% CI, 

1.2 to 1.6) device malfunctions, 1.5 (95% CI, 1.3 to 1.8) lead problems, 0.6 (95% CI, 0.5 to 0.8) 

implant site infections, and 19.1 (95% CI, 16.5 to 22.0) inappropriate discharges in RCT 

participants and 4.7 (95% CI, 4.3 to 5.1) inappropriate discharges in patients enrolled in 

observational studies. 

Conclusions: ICD and CRT reduce all-cause mortality in patients with LVSD meeting RCT 

entry criteria. The incremental benefit of CRT plus ICD over CRT alone in patients with LVSD 
vi 

remains uncertain. None of the trials reported differences in the efficacy of CRT or ICD across 

patient subgroups, nor did our meta-regression detect any subgroup effects; however, subgroup 

analyses and meta-regression using aggregate trial data are post-hoc analyses and were 

underpowered to detect such effects. Examination of individual patient trial data is urgently 

needed to define which clinical subgroups are most likely to benefit from these devices. 
vii 

Contents 

Executive Summary........................................................................................................................ 1 

Evidence Report............................................................................................................................ 13 

Chapter 1. Introduction ................................................................................................................ 15 

Background............................................................................................................................. 15 

Study Questions ...................................................................................................................... 17 

Chapter 2. Methods...................................................................................................................... 19 

Literature Search..................................................................................................................... 19 

Selection and Inclusion........................................................................................................... 19 

Quality Assessments ............................................................................................................... 21 

Efficacy Review...................................................................................................................... 21 

 Effectiveness and Safety Review.......................................................................................21 

Data Extraction ....................................................................................................................... 22 

Data Analysis.......................................................................................................................... 22 

 Efficacy Review.................................................................................................................22 

 Effectiveness Review.........................................................................................................23 

 Safety Review ....................................................................................................................23 

Chapter 3. Results ........................................................................................................................ 25 

Literature Search..................................................................................................................... 25 

 CRT Alone or Combined CRT-ICD Devices ................................................................... 25 

 ICD Alone..........................................................................................................................26 

Description of Included Studies: Efficacy Review................................................................. 28 

 CRT Alone or Combined CRT-ICD Devices ....................................................................28 

 ICD Alone..........................................................................................................................32 

Description of Included Studies: Effectiveness Review......................................................... 35 

 CRT Alone or Combined CRT-ICD Devices ................................................................... 35 

 ICD Alone......................................................................................................................... 36 

Description of Included Studies: Safety Review .................................................................... 37 

 CRT Alone or Combined CRT-ICD Devices ................................................................... 37 

 ICD Alone......................................................................................................................... 38 

Methodological Quality of Included Studies: Efficacy Review ............................................. 40 

 CRT Alone or Combined CRT-ICD Devices ....................................................................40 

 ICD Alone..........................................................................................................................40 

Methodological Quality of Included Studies: Effectiveness and Safety Reviews.................. 41 

 CRT Alone or Combined CRT-ICD Devices ....................................................................41 

 ICD Alone..........................................................................................................................41 

 Safety Review for Peri-Implant Complications of ICD Alone..........................................42 

Quantitative Results: Efficacy Review ................................................................................. 120

 CRT Alone...................................................................................................................... 120 

 Combined CRT-ICD Devices..........................................................................................124 
viii 

 ICD Alone........................................................................................................................124 

Quantitative Results: Effectiveness Review ......................................................................... 126 

 CRT Alone.......................................................................................................................126 

 Combined CRT-ICD Devices..........................................................................................128 

 ICD Alone........................................................................................................................128 

 Mortality Comparison Across Devices and Study Types................................................129 

Quantitative Results: Safety Review .................................................................................... 129 

 CRT Alone.......................................................................................................................129 

 Combined CRT-ICD Devices..........................................................................................130 

 ICD Alone........................................................................................................................130 

Chapter 4. Discussion ................................................................................................................ 167 

Benefits of CRT (CRT Efficacy/Effectiveness) ................................................................... 167 

Caveats for CRT Efficacy/Effectiveness Data...................................................................... 169 

Safety of CRT ....................................................................................................................... 171 

Cost-Effectiveness of CRT ................................................................................................... 171

 Proportion of HF Patients Likely To Be Eligible for CRT....................................................172 

Benefits of ICD (ICD Efficacy/Effectiveness) ..................................................................... 172 

Caveats for ICD Efficacy/Effectiveness Data....................................................................... 174 

Safety of ICD ........................................................................................................................ 175 

Cost-Effectiveness of ICD .................................................................................................... 176 

Implications of Our Findings................................................................................................ 176

 The Challenge for Health Outcome Investigators ...........................................................177 

 The Challenge for Health Care Administrators and Funders...........................................177 

 The Challenge for Trialists and Device Manufacturers...................................................178 

References and Included Studies ................................................................................................ 181 

Figures 

Figure 1. Treatment of systolic heart failure (Adapted from Canadian Cardiovascular 

Society Guidelines)..................................................................................................... 15 

Figure 2. Flow diagram of study retrieval and selection for CRT alone or combined 

CRT-ICD devices........................................................................................................ 25 

Figure 3. Flow diagram of study retrieval and selection for ICD alone..................................... 27 

Figure 4. Metagraph of all-cause mortality: CRT alone .......................................................... 146 

Figure 5. Metagraph of mortality due to progressive heart failure: CRT alone....................... 147 

Figure 6. Metagraph of mortality due to sudden cardiac death: CRT alone ............................ 148 

Figure 7. Metagraph of mortality due to noncardiac death: CRT alone................................... 149 

Figure 8. Metagraph of heart failure hospitalizations: CRT alone........................................... 150 

Figure 9. Metagraph of 6-minute walk test: CRT alone........................................................... 151 

Figure 10. Metagraph of improvement in NYHA functional class: CRT alone........................ 152 

Figure 11. Metagraph of quality of life (MLHFI): CRT alone.................................................. 153 

Figure 12. Metagraph of left ventricular ejection fraction: CRT alone ..................................... 154 

Figure 13. Metagraph of all-cause mortality: CRT alone or combined CRT-ICD Devices...... 155 

Figure 14. Funnel plot for all-cause mortality: CRT alone........................................................ 156 
ix 

Figure 15. Metagraph of all-cause mortality: ICD alone........................................................... 157 

Figure 16. Metagraph of death due to progressive heart failure: ICD alone ............................. 158 

Figure 17. Metagraph of mortality due to sudden cardiac death: ICD alone............................. 159 

Figure 18. Metagraph of mortality due to non-cardiac death: ICD alone.................................. 160 

Figure 19. Metagraph of heart failure hospitalizations: ICD alone ........................................... 161 

Figure 20. Summary results for all-cause mortality: ICD alone, stratified by primary or 

secondary prevention ................................................................................................ 162 

Figure 21. Funnel plot for all-cause mortality: ICD alone......................................................... 163 

Figure 22. Scatter plot of all-cause mortality vs. length of followup: CRT alone..................... 164 

Figure 23. Scatter plot of all-cause mortality vs. length of followup: ICD alone...................... 165 

Figure 24. Scatter plot of all-cause mortality vs. length of followup: combined 

CRT-ICD Devices..................................................................................................... 166 

Tables 

Table 1. Summary of evidence for devices in patients with left ventricular 

systolic dysfunction .................................................................................................... 10 

Table 2. Inclusion and exclusion criteria for efficacy review................................................... 20 

Table 3. Inclusion and exclusion criteria for effectiveness and safety review ......................... 21 

Table 4. Description of studies in the efficacy review: CRT alone or combined 

CRT-ICD devices........................................................................................................ 43 

Table 5. Baseline characteristics of patients in trials included in the efficacy review: 

CRT alone or combined CRT-ICD devices................................................................ 46 

Table 6. Description of studies included in the efficacy review: ICD alone ............................ 48 

Table 7. Baseline characteristics of patients in trials included in the efficacy review: 

ICD alone.................................................................................................................... 51

Table 8. Description of studies in the effectiveness and safety reviews: 

CRT alone or combined CRT-ICD devices................................................................ 54 

Table 9. Baseline characteristics of patients in studies included in the effectiveness 

or safety reviews: CRT alone or combined CRT-ICD devices................................... 77 

Table 10. Description of studies included in the effectiveness and safety reviews: ICD........... 86 

Table 11. Baseline characteristics of patients in trials included in the effectiveness 

and safety reviews: ICD............................................................................................ 100 

Table 12. Description of additional studies included in the ICD safety review 

for peri-implant complications only.......................................................................... 107 

Table 13. Baseline characteristics of patients in additional studies included in the ICD 

safety review for peri-implant complications only ................................................... 109 

Table 14. Methodological quality of randomized trials included in the efficacy review: 

CRT alone or combined CRT-ICD devices.............................................................. 111 

Table 15. Methodological quality of randomized trials included in the efficacy 

review: ICD............................................................................................................... 112 

Table 16. Methodological quality assessment of included studies in the effectiveness 

and safety reviews: CRT alone or combined CRT-ICD devices .............................. 113 

Table 17. Methodological quality assessment of included studies in the effectiveness 

and safety reviews: ICD alone .................................................................................. 117 
x 

Table 18. Methodological quality assessment of additional studies included in the 

ICD safety review for peri-implant complications only ........................................... 119 

Table 19. Univariate meta-regression subgroup analyses: CRT............................................... 123 

Table 20. Univariate meta-regression subgroup analyses: ICD alone...................................... 125 

Table 21. Response rates reported in observational studies: CRT alone or combined 

CRT-ICD devices...................................................................................................... 127 

Table 22. Peri- and post-implantation risks: CRT alone........................................................... 132 

Table 23. Peri- and post-implantation risks: combined CRT-ICD Devices ............................. 137 

Table 24. Peri- and post-implantation risks: ICD alone............................................................ 141 

Table 25. Peri- and post-implantation risks with ICD in studies that were not restricted 

to patients with left ventricular systolic dysfunction ................................................ 145 

Appendixes 

Appendix A: Exact String Searches 

Appendix B: Sample Data Extraction Form 

Appendix C: Primary Publications and Associated Publications of Included Studies 

Appendix D: List of Excluded Studies 

Appendix E: Technical Expert Panel and Peer Reviewers 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/defib/defib.pdf 

1 

Executive Summary 

Introduction 

Cardiac resynchronization therapy (CRT) refers to atrial-synchronized biventricular pacing 

(i.e., pacing the right atrium, right ventricle, and left ventricle). CRT improves the electrical 

dyssynchrony found in many patients with heart failure (HF) and thereby can improve 

mechanical dyssynchrony leading to increased left ventricular filling time, reduced mitral 

regurgitation, and reduced septal dyskinesis.1,2 Implantable cardioverter defibrillators (ICD) have 

at least one lead which resides in the right ventricle dedicated to pacing and/or defibrillating 

lethal cardiac arrhythmias. More advanced ICD (dual-chamber devices) have leads in the right 

atrium and right ventricle to help discriminate arrhythmic events and have the potential to be 

programmed to provide dual chamber pacing (e.g., DDD pacing mode). 

Although earlier systematic reviews of CRT and ICD did report benefits from both therapies 

when evaluated individually in patients with HF, questions remained. For one, as these earlier 

systematic reviews focused on randomized efficacy trials, the generalizability of their results to 

clinical practice were uncertain (particularly with respect to potential adverse effects). Second, 

neither of the earlier reviews (which focused on individual devices) was able to clarify the 

incremental benefits conferred by combined CRT-ICD devices over CRT alone or ICD alone 

devices, nor were these earlier reviews able to define which patient groups would benefit most 

from which devices. Finally, a number of large trials have been published since the earlier 

systematic reviews were performed and their impact on the pooled evidence base required 

assessment. 

Study Questions 

1. In adult patients with symptomatic or asymptomatic LV systolic dysfunction, what is the 

efficacy and effectiveness of CRT alone, ICD alone, or combined CRT-ICD devices 

compared to usual medical therapy? 

2. In adult patients with symptomatic or asymptomatic LV systolic dysfunction, what is the 

efficacy and effectiveness of single-chamber ICD compared to that of dual-chamber ICD? 

3. In adult patients with symptomatic or asymptomatic LV systolic dysfunction, how safe is 

CRT alone, ICD alone, or combined CRT-ICD devices? 

4. Which patients would benefit from ICD alone, CRT alone, or combined CRT-ICD devices? 

Methods 

Literature Search 

We systematically searched various electronic databases (including trial registries and the 

website of the U.S. Food and Drug Administration), the reference lists of relevant reviews and 

identified studies, and contacted authors of included studies as well as device manufacturers: 

Medtronic Inc. (Minneapolis, MN), Boston Scientific (formerly Guidant Corp., Indianapolis, 
2 

IN), and St. Jude Medical Inc. (St. Paul, MN). The search was not limited by language or 

publication status and is considered current to November 14, 2006. A full list of search strategies 

and search terms (adapted for each database) and search results are included in Appendix A* of 

the main report. 

Selection and Inclusion 

To address efficacy, we analyzed randomized controlled trials (RCTs) that compared active 

CRT, active ICD, or combined CRT-ICD devices with either placebo pacing, univentricular 

(right-sided) pacing, or drug therapy alone. To address effectiveness, we evaluated studies with 

contemporaneous comparison arms (e.g., cohort studies, RCTs, or controlled non-randomized 

trials). To address safety, we included evidence from both RCTs and observational studies 

(including those without contemporaneous control arms, such as case series and registry data). 

For assessing efficacy or effectiveness, we selected those studies that enrolled greater than 25 

participants with LV systolic dysfunction (LVEF ≤ 35 percent), whether they had HF symptoms 

or not, followed participants for at least 2 weeks, and reported at least one of the following 

outcomes of interest: mortality (all-cause, cardiac, HF, sudden cardiac death), quality of life, 

functional class (NYHA), 6-minute walk test, hospitalization (all-cause or HF), or LVEF. For 

assessing safety, we selected studies that enrolled greater than 25 participants with LV systolic 

dysfunction (LVEF ≤ 35 percent), whether they had HF symptoms or not, followed participants 

for at least 2 weeks, and reported at least one of the following outcomes of interest: implant 

success rates, peri-, or post-implantation risks with either device. On the advice of our expert 

panel, we also examined safety outcomes in all patients receiving ICDs (i.e., not just those with 

definite LV systolic dysfunction). 

Data Extraction and Analysis 

Study selection, quality assessment, and data extraction were completed by several 

investigators in duplicate, independently, and blinded; random-effects models were used for 

analyses in Review Manager 4.2.5 (The Cochrane Collaboration, Copenhagen, DK). Only period 

one data were extracted from crossover studies. For dichotomous results (e.g., HF 

hospitalizations), we calculated relative risks (RR) and for continuous variables (e.g., 6-minute 

walk test) we calculated weighted mean difference (WMD) for the pooled estimates. All results 

were reported with 95 percent confidence intervals (CI). Statistical heterogeneity was quantified 

using the I-squared (I2

) statistic.3 Relevant direct subgroup comparisons were summarized, 

including effects of CRT in patients with more severe HF symptoms (New York Heart 

Association [NYHA] Class III or IV). Meta-regression was used to examine the relation between 

a variety of covariates classified at the study level (e.g., percent of enrolled subjects with atrial 

fibrillation) and the efficacy of CRT, ICD, and combined CRT- ICD devices. 

 

*

 Appendixes cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/defibtp.htm 
3 

Results 

Literature Search (Figures 2 and 3 in Evidence Report) 

From 11,340 citations, we identified 14 RCTs4-17 (4,420 patients) for the CRT efficacy 

review, 106 studies for the CRT effectiveness review17-122 (9,209 patients from 2 controlled but 

non-randomized trials and 104 observational studies—13 retrospective and 91 prospective), and 

89 studies for the CRT safety review,4-17 2 clinical trials, and 73 observational 

studies17,20,22,26,27,29-33,35,36,39,41,42,44-46,49,50,52,53,55-58,60,63-70,73,76,78,80,82,83,85-87,89,91-94,97,98,100,102-

106,108,109,111-113,117,118,123-132 (9,677 patients, 14 randomized trials, 2 controlled trials, and 73 

observational studies—10 retrospective and 63 prospective). We identified 12 RCTs11,133-143

(8,516 patients) for the ICD efficacy review, 48 studies for the ICD effectiveness review144-191

(15,097 patients from 3 RCTs and 45 observational studies—25 retrospective and 20 

prospective), and 49 studies for the ICD safety review,11,133-136,138-145,147,148,152,155-

159,161,162,164,165,169,171,176,178-181,184,186-189,191-202 (12,592 patients from 11 RCTs, 6 RCTs without 

efficacy outcomes, and 32 observational studies—17 retrospective and 15 prospective). An 

additional 12 studies (68,848 patients) were included in our secondary analysis of peri-implant 

safety with ICD for all patients (i.e., not restricted to patients with LV systolic dysfunction).203-

214 

Description of Included Patients (Tables 5, 7, 9, and 11 in 

Evidence Report) 

CRT. All patients in the CRT studies had LV systolic dysfunction (mean LVEF ranged from 21 

to 30 percent), prolonged QRS duration (mean QRS ranged between 155 msec and 209 msec, 

with 64 percent of trial participants exhibiting a left bundle branch block), and HF symptoms (79 

percent were NYHA class III functional status at baseline, 12 percent were NYHA class IV, and 

9 percent were NYHA class II). The mean age of patients was 65.4 ± 10.8 years, 72 percent were 

male, and patients with atrial fibrillation constituted 5 percent of all trial participants. Of the 

patients in the intervention arms, 1,310 (47%) received CRT alone and 1,474 (53%) received a 

combined CRT-ICD device. Eleven of the trials (n = 2,166 patients) randomized patients after 

successful CRT implantation; 3 trials (n = 2,439 patients) randomized patients before attempted 

CRT implantation. Median follow-up in these trials was 6 months, with the longest follow-up 

duration being 29 months. 

ICD. All patients in the ICD studies had LV systolic dysfunction (mean LVEF ranged from 21 

to 28 percent in the primary prevention trials and from 32 to 46 percent in the secondary 

prevention trials) and the majority had HF symptoms (50 percent had NYHA class II symptoms 

at baseline, 36 percent NYHA class III symptoms, and 3 percent NYHA Class IV)—11 percent 

of trial participants were defined as NYHA class I at baseline. The mean age of enrolled patients 

was 60.8 ± 4.2 years and 74 percent were male. All but three of the primary prevention trials 

specified other electrocardiographic entry criteria to identify high-risk patients, such as a history 

of nonsustained ventricular tachycardia,137,138 elevated heart rate or reduced heart rate variability, 

or abnormal signal-averaged ECG. Although devices were specified to be single-chamber ICD in 
4 

all but two trials, protocol adherence to single-chamber vs. dual-chamber ICD was not reported 

in any trial. 

Efficacy, Effectiveness, and Safety of CRT 

Efficacy of CRT (Figures 4 to 14 and Table 19 in Evidence Report). CRT improved ejection 

fraction (WMD = 3.0 percent; 95% CI, 0.9 to 5.1 percent), quality of life (weighted mean 

reduction in Minnesota Living with Heart Failure Questionnaire 8.0 points [95% CI, 5.6 to 10.4 

points]), and function (59 percent of CRT recipients vs. 37 percent of controls improved by at 

least one NYHA class) in trial participants. The proportion of patients hospitalized for HF was 

reduced by 37 percent (95% CI, 7 to 57 percent) and all-cause mortality was reduced by 22 

percent (95% CI, 9 to 33 percent; Number Needed to Treat to prevent one death over 6 months = 

29), driven largely by reductions in progressive HF deaths (RR = 0.64; 95% CI, 0.49 to 0.84). 

Within the CRT trials, there was no consistent pattern of definitive differences in effects for 

different subgroups. Isolated trials reported greater effects in patients with longer QRS 

duration,12 patients with septal coronary sinus leads implanted outside of the anterolateral 

region,215 and patients with nonischemic disease,216 but these findings were either based on small 

numbers of patients or not confirmed in other studies.9,11,15 None of the CRT trials, however, 

were powered to detect subgroup effects of small to moderate magnitude. In univariate metaregressions using trial-level data, no single factor was associated with the magnitude of CRT 

mortality benefit. Three factors suggestive of less severe HF—presence of an ICD in both 

controls and CRT patients, NYHA class II at baseline, and higher LVEF—were significantly 

associated with smaller CRT effects on HF hospitalizations (see Table 19 in main report). These 

analyses, however, are also underpowered to detect subgroup differences in the efficacy of CRT. 

The efficacy of combination CRT-ICD devices and CRT-only devices appeared similar, 

based on meta-regression of aggregate trial data and indirect comparisons (i.e., comparisons 

between trials with different comparators but similar control groups). However, in the absence of 

head-to-head trials comparing the two devices, this conclusion should not be considered 

definitive. Two of the treatment arms of the COMPANION trial11 provide the only opportunity 

to compare combined CRT-ICD devices vs. CRT alone devices within the same trial, but this 

was not a primary pre-specified aim of this trial. Although the mortality benefits were slightly 

greater with the CRT-ICD device (hazard ratio [HR] = 0.64; 95% CI, 0.48 to 0.86) than with 

CRT alone (HR = 0.76; 95% CI, 0.58 to 1.01), this difference was not statistically significant 

(p=0.13) and HF hospitalizations did not differ between patients receiving the combined CRTICD device compared to those receiving the CRT alone device. 11 In the highest risk subgroup of 

COMPANION (NYHA class IV patients), the time to death analysis did not demonstrate any 

benefit of the CRT-ICD device over the CRT alone device (HR = 1.27; 95% CI 0.68 to 2.37).6

 

Effectiveness of CRT (Figures 4 to 14, Figures 22 and 24, and Table 21 in Evidence 

Report). Survival during follow-up was similar in the randomized trials and the observational 

studies for patients who received CRT devices. The pooled effectiveness estimates from the 

observational studies were consistent with our findings from the efficacy trials. For example, in 

the RCTs, 59 percent of patients implanted with a CRT device improved by at least one NYHA 

class and in the observational studies between 63 and 82 percent of CRT recipients improved by 

at least one NYHA class. No covariates were consistently shown across studies to predict CRT 

response. Only one observational study compared outcomes in patients with CRT to outcomes in 
5 

contemporaneous controls without CRT – their findings of improved LVEF (WMD = 4.6 

percent; 95% CI, 2.9 to 6.3 percent) and lower mortality rates (RR = 0.64; 95% CI, 0.26 to 1.56) 

in the CRT arm were consistent in magnitude to the findings from our meta-analysis of the CRT 

trials. 

Safety of CRT (Tables 22 and 23 in Evidence Report). Implant success rate was 93 percent 

(95% CI, 92.2 to 93.7 percent) and peri-implant deaths occurred in 0.3 percent (95% CI, 0.1 to 

0.6 percent) of individuals, with no appreciable differences either between those receiving CRT 

alone or combined CRT-ICD devices, or between participants in RCTs and observational studies. 

Over a median 11-month follow-up, lead problems occurred in 6.6 percent (95% CI, 5.6 to 7.4 

percent) of CRT devices and 5 percent (95% CI, 4 to 7 percent) of these devices malfunctioned. 

Frequencies were similar in the RCTs and observational studies, and combined CRT-ICD 

devices demonstrated similar frequencies of device malfunction (5 percent; 95% CI, 4 to 6 

percent) and lead problems (5.9 percent; 95% CI, 5 to 6.9 percent). 

Efficacy, Effectiveness, and Safety of ICD 

Efficacy of ICD (Figures 15 to 21 and Table 20 in Evidence Report). ICDs reduced all-cause 

mortality in patients with LV systolic dysfunction by 20 percent (95% CI, 10 to 29 percent; NNT 

= 20 over a median follow-up of 35 months but with significant heterogeneity between trials), 

due largely to a 54 percent reduction in sudden cardiac deaths (95% CI, 37 to 63 percent, with no 

appreciable heterogeneity between trials). In the two trials which reported such outcomes, ICDs 

did not demonstrate an appreciable impact on functional status or morbidity; however, 

insufficient studies have reported functional or quality of life outcomes with ICD to draw 

definitive conclusions. ICDs were equally beneficial in reducing all-cause mortality in both 

primary prevention trials (RR = 0.81; 95% CI, 0.69 to 0.95) and secondary prevention trials (RR 

= 0.77; 95% CI, 0.65 to 0.91) (see Figure 20 [p-value for comparison = 0.56]), although the 

absolute benefits were greater in the secondary prevention trials due to the higher baseline risk in 

those patients. 

Only the SCD-HeFT trial reported a significant subgroup effect (greater benefits in patients 

with NYHA class II symptoms vs. NYHA class III symptoms at baseline – p<0.001); however, 

these trials were not powered to detect such subgroup effects. In a series of univariate metaregression analyses using trial-level data, none of the covariates we examined explained the 

heterogeneity of treatment effect on all-cause mortality. Of note, none of these RCTs compared 

single chamber with dual chamber ICDs directly. Although the Dual Chamber and Atrial 

Tachyarrhythmias Adverse Events Study140 reported fewer inappropriate shocks with dualchamber ICD than with standard single right ventricular lead ICD, a secondary post-hoc analysis 

of the MADIT-II Trial comparing the 404 patients who received a single-chamber ICD with the 

313 patients who received a dual-chamber ICD (the choice of which was left to the discretion of 

attending physicians and not randomized) revealed that dual-chamber ICD were associated with 

non-significant trends to higher rates of death (HR = 1.27; 95% CI, 0.76-2.12) or HF 

hospitalization (HR = 1.27; 95% CI, 0.87-1.86). 

Effectiveness of ICD (Figures 15 to 21 and Figure 23 in Evidence Report). Survival during 

follow-up was similar in the randomized trials and the observational studies for patients who 

received ICD devices. The pooled effectiveness estimate from controlled observational studies, 
6 

however, suggested a greater benefit from ICD on all-cause mortality (RR = 0.54; 95% CI 0.43 

to 0.68) than that reported in the RCTs. The fact that the controlled observational studies also 

demonstrated a benefit of ICDs on non-cardiac death (RR = 0.74; 95% CI, 0.65 to 0.85; Figure 

18) suggests that selection bias (clinicians preferentially selecting healthier patients for ICD 

insertion) may explain the exaggerated mortality benefit seen in observational studies. 

Between three-quarters and two-thirds of ICD recipients never received any therapeutic ICD 

discharges in the observational studies – this is consistent with the RCTs demonstrating that 

between 5 and 12 percent of trial participants receive a therapeutic ICD discharge per year.217

Safety of ICD (Table 24 in Evidence Report). ICD implant success rate was 99 percent (95% 

CI, 98.8 to 99.3 percent) and peri-implant deaths occurred in 1.2 percent (95% CI, 09 to 1.5 

percent) of individuals (1.7 percent [1.2 to 2.4 percent] of RCT participants vs. 0.8 percent [0.5 

to 1.2 percent] of subjects in observational studies). We also examined peri-implant deaths and 

success rates for 12 studies (68,848 patients) that enrolled all patients undergoing ICD implant 

(i.e., not just those patients with LV systolic dysfunction). The frequencies were similar to those 

reported in the studies restricted to patients with LV systolic dysfunction: implant success rate of 

98.6 percent (95% CI, 98.3 to 98.9 percent) and peri-implant death rate of 1.3 percent (95% CI, 

1.2 to 1.4 percent). The frequency of post-implantation complications per 100 patient-years of 

follow-up included 1.4 (95% CI, 1.2 to 1.6) device malfunctions, 1.5 (95% CI, 1.3 to 1.8) lead 

problems, 0.6 (95% CI, 0.5 to 0.8) implant site infections, and 19.1 (95% CI, 16.5 to 22.0) 

inappropriate discharges in RCT participants and 4.7 (95% CI, 4.3 to 5.1) inappropriate 

discharges in patients enrolled in observational studies. 

Implications of Findings 

Table 1 summarizes the conclusions which are possible given the currently available 

evidence for therapeutic devices in patients with LV systolic dysfunction. 

CRT. There is high quality evidence that CRT improves ventricular function and remodelling, 

symptoms, and exercise capacity, while also reducing HF hospitalizations and death in patients 

comparable to those enrolled in the trials: (1) NYHA class III or IV HF despite optimal medical 

management, (2) LVEF ≤ 35 percent, (3) sinus rhythm, and (4) ventricular dyssynchrony (i.e., 

prolonged QRS duration). Although the mortality reduction with CRT was evident by six months 

in these trials, a long-term extension of the CARE-HF Trial confirmed that over 3 years of 

follow-up the relative benefits of CRT were stable (i.e., constant HR) and as such the absolute 

magnitude of benefit increased over time (thus, although our meta-analysis demonstrates that one 

death will be prevented within 6 months for every 23 trial patients receiving CRT, the CARE-HF 

follow-up data suggest that one death would be prevented over 2 years for every 13 CRT 

recipients, and one death prevented over 3 years for every 9 CRT recipients.218 

The magnitude of these benefits are similar to those reported for angiotensin converting 

enzyme inhibitors, beta-blockers, and aldosterone antagonists in recent trials.219-223 Balanced 

against these benefits, the peri-procedural risks of CRT appear modest: peri-implantation 

mortality was less than 1 percent (similar to the frequency reported for patients undergoing 

implantation of conventional dual-chamber pacemakers).224 In contrast to isolated reports raising 

concerns about a potential excess risk of ventricular arrhythmias or sudden deaths in patients 

receiving CRT,225 pooled results from multiple RCTs revealed no significant risk of sudden 
7 

death (RR = 1.07; 95% CI, 0.79 to 1.46) or noncardiac death (RR = 0.81; 95% CI, 0.43 to 1.52) 

in recipients of a CRT device. 

Implantation of a biventricular CRT pacemaker (in particular the LV lead) can be technically 

challenging, even in experienced hands. Our review identified an implantation failure rate of 7 

percent; given that these results came from RCTs and early cohort studies that tend to be 

reported by acknowledged experts in the field, this estimate may be conservative. Further, as the 

estimates of safety outcomes with CRT are derived from only a few thousand patients, they 

should not be considered definitive. Given the recent experiences with ICD recalls and FDA 

advisories, it seems prudent to recommend that all patients with LV systolic dysfunction who 

have either a CRT or an ICD device implanted be entered into a registry and followed for longterm risks and benefits (and this would also permit evaluations to define patient, device, or 

operator characteristics which impact on the benefit:safety ratio of CRT devices). 

CRT does not always restore mechanical synchrony, even when lead placement is felt to be 

successful—while 59 percent of CRT recipients in these RCTs improved by at least one NYHA 

class, 41 percent did not.226 In patients outside of RCTs, the rates of nonresponse to CRT have 

varied widely: from 20 to 28 percent in those studies using a functional status definition for 

response (an improvement of at least one in NYHA Class) and between 32 to 45 percent in 

studies employing an echocardiographic definition (most commonly a decrease of at least 15 

percent in left ventricular end-systolic volume).227 Studies to define which patients are most 

likely to benefit from CRT (such as the ongoing Predictors of Response to Cardiac 

Resynchronization Therapy Study)228 and which positions in the ventricular wall are most 

appropriate for implantation of the pacing leads are clear research priorities. 226,229

ICD. There is also high quality evidence that ICD reduces all-cause mortality in patients with 

LVEF ≤ 35 percent and NYHA class II and III symptoms. The relative reduction in all-cause 

mortality—20 percent—equates to preventing one death over 35 months for every 20 patients 

receiving an ICD. Neither functional status nor morbidity outcomes are improved by ICDs in the 

existing RCTs. Our analyses of observational studies with contemporaneous control groups 

confirmed that the benefits of ICD extend beyond the trial setting. 

Trial eligibility criteria are commonly cited as a means by which to identify patients who will 

benefit from an ICD; however, identifying particular patient groups who are at increased risk for 

sudden cardiac death and thus most likely to benefit from an ICD is vitally important.230,231 Twoquarters to two-thirds of ICD recipients in the reviewed trials never received any therapeutic ICD 

discharges;217 even in those who received an appropriate discharge, the benefits were offset over 

time by deaths due to progressive HF;232 and less than a quarter of cardiac arrest victims have a 

LVEF < 30 percent prior to their event.233 Although our meta-regression analyses did not reveal 

any statistically significant differences in the subgroups we examined, these analyses were post 

hoc and underpowered due to the small number of trials. A meta-analysis of individual patient 

data would be necessary to appropriately examine this issue. The establishment of the ICD 

Registry by the American College of Cardiology National Cardiovascular Data Registry (ACCNCDR) in conjunction with the Heart Rhythm Society is also an important initiative which will 

permit the collection of comprehensive data on ICD implants and long-term outcomes. This data 

should help to identify whether particular patient subgroups derive more or less benefit than the 

average results reported in this report and whether specific devices or programming parameters 

are associated with better or worse outcomes.234
8 

Combined CRT-ICD Devices. Our analyses indicate that the mortality benefits from CRT and 

ICD appeared to be independent (i.e. CRT provided mortality benefits whether or not an ICD 

was present, and ICD provided mortality benefits whether or not CRT was present) – this is 

consistent with our understanding of their distinct physiological mechanisms and their effects on 

different cardiac endpoints. This should not be taken to mean that the benefits of each device 

were additive, however. Indeed, the COMPANION Trial suggests that any incremental benefits 

with the combined device may be smaller than expected given the apparently independent 

mortality benefits with each component of the device; however, this comparison was not prespecified or adequately powered in the COMPANION Trial and further studies are required to 

define the incremental benefits of the combined device. 

Recommendations for Future Research: 

A number of areas of uncertainty remain with respect to CRT and ICD therapy in patients 

with left ventricular systolic dysfunction, some of which are the subject of ongoing trials (for 

details, see “Implications of our Findings” on page 176 of the full Evidence Report): 

1. Further information is still needed on the real world safety and effectiveness of CRT and/or 

ICD, since much of the data presented here comes from trials or selected cohorts, including 

trials which enrolled patients only after successful implantation of the device. These studies 

may overestimate the potential benefit:safety ratio from CRT and/or ICD. Although our 

review improves on previous reviews by including observational study data, expanding the 

prospective ACC-NCDR Registry to include CRT as well as ICD would add important “real 

world” estimates of benefits and risks with both of these devices. 

2. Better information is needed on the effects of CRT, ICD, and combined CRT-ICD devices 

over longer time frames and in patient subgroups largely excluded from the trials conducted 

to date (such as those with atrial fibrillation, chronic kidney disease, or less symptomatic 

degrees of HF). In addition, registry data may help compare effectiveness and safety of 

single-vs. dual-chamber ICD-devices and track changes in complication rates as device 

implanters, the tools for implantation, and the sophistication of the devices change over time.

3. Collation of individual patient data from the available trials should be a priority to allow 

exploration for differential subgroup effects. In the words of one editorialist, “it is the entry 

criterion and not the group actually studied that has driven practice guidelines.”235 

4. The incremental benefit of combined CRT- ICD devices over ICD alone is uncertain and is 

the subject of ongoing trials. The incremental benefit of combined CRT-ICD devices over 

CRT alone is also uncertain yet is not to our knowledge currently being tested in any 

randomized trials. Given the changing epidemiology of HF mortality (i.e., due to disease 

modifying agents such as ACE inhibitors and beta-blockers, patients are now more likely to 

die of progressive HF than sudden death),236 the incremental benefits of ICD therapy in a 

patient who has a CRT device may be smaller than suggested from the ICD trial data in this 

report. A trial targeting those patients who currently do not qualify for ICD therapy—for 

example, patients with LVEF in the range of 30 to 40 percent or patients with NYHA class 

IV symptoms—might require over 1,300 patients per arm followed for 3 years to establish 
9 

(or refute) a clear marginal benefit of combined devices over CRT alone. Given the markedly 

higher costs for combined CRT-ICD devices and the rapidly expanding population of HF 

patients eligible for such devices, such a trial is nonetheless justified. 
10

Table 1. Summary of evidence for devices in patients with left ventricular systolic dysfunction* 

Other characteristics 

Device Symptom 

status 

ECG criteria 

Quantity of 

evidence for that 

patient subgroup 

Quality of evidence Magnitude of effect (95% CI) 

NYHA class 

III or IV 

QRS > 120 

msec and sinus rhythm 

13 RCTs, 3,481 

patients 

High (multiple RCTs with 

homogeneous results) 

Reduced mortality: RR = 0.78 (0.67 to Reduced HF hospitalizations: RR = 0.5

(0.41 to 0.64) 

NYHA class 

II 

QRS > 120 

msec and sinus rhythm 

5 RCTs, 344 

patients 

Moderate (one small 

RCT PLUS post-hoc meta-regression of aggregate trial data from 14 RCTs, but few patients in these RCTs had NYHA Class II) 

Ongoing RCTs: 

REVERSE, RAFT 

No significant effect on mortality (RR = 

95% CI 0.17 to 8.26 in the one RCT

In meta-regression, proportion of patie

with Class II symptoms was not significantly associated with reductiomortality (p = 0.76) 

Effect on hospitalization may be smalle

Class II HF than Class III/IV (in metaregression, proportion of patients wiClass II symptoms significantly assowith reduction in hospitalization (p = 

NYHA class 

III or IV 

QRS > 120 

msec and bradyarrhythmia or atrial fibrillation 

3 RCTs, 191 

patients 

Low (post-hoc metaregression of 

aggregate trial data from 14 RCTs) 

Ongoing RCTs: Trip HF, 

RAFT, APAF, BLOCK HF 

No significant association in meta-regr

between proportion of patients with fibrillation and reduction in mortality hospitalizations (p = 0.73 and 0.58, respectively)

NYHA class 

III or IV 

QRS 

duration < 120 msec; any rhythm 

5 studies, 120 

patients 

Low (secondary 

analyses of small observational studies) 

Improvements in symptoms and LV 

remodelling not significantly differenbetween patients with narrow QRS apatients with wide QRS in any of the studies 

CRT alone 

NYHA class I Any QRS 

duration; any rhythm 

None No published evidence 

Ongoing RCT: 

REVERSE 

Not applicable 

CRT = cardiac resynchronization therapy; HF = heart failure; ICD = implantable cardiac defibrillator; LV = left ventricular; msec = micro

York Heart Association; RCT = randomized control trial *Note that other considerations may outweigh the trial evidence in some situations (e.g., the patient who wishes to be “do not resuscita

on the effects of either CRT or ICD in patients with advanced age or severe comorbidities (such as end-stage renal disease). 
11

Table 1. Summary of evidence for devices in patients with left ventricular systolic dysfunction (continued) 

Device 

Other characteristics Quantity of 

evidence for that 

patient subgroup 

Quality of evidence Magnitude of effect (95% CI) 

NYHA class 

III or IV 

QRS > 120 

msec and sinus rhythm 

1 RCT, 903 

patients in relevant comparison arms 

Moderate (one 

large RCT) Ongoing RCTs: 

DECREASE, RAFT

Reduced mortality: hazard ra

0.64 (0.48 to 0.86) Reduced mortality or all-cause hospita

hazard ratio = 0.80 (0.68 to 0.95) 

Combined CRT-ICD device (vs. no device) 

All other patient subgroups None No published evidence 

Ongoing RCTs: MADITCRT, RAFT 

Not applicable 

NYHA class 

III or IV 

QRS > 120 

msec and sinus rhythm 

1 RCT, 1,212 

patients in relevant comparison arms 

Moderate (one large 

RCT, but this comparison was not a priori specified or adequately powered) 

No significant effect on mortality (RR = 

95% CI, 0.66 to 1.05) and no significeffect on time to death in NYHA classubgroup (hazard ratio = 1.27; 95% to 2.37) 

Combined CRT-ICD device (vs. CRT alone) 

All other patient subgroups None No published evidence Not applicable 

Secondary prevention in 

patients with history of ventricular fibrillation or tachycardia 

3 RCTs, 1,963 

patients 

High (multiple RCTs with 

homogeneous results) 

Reduced mortality: RR = 0.77 (0.65 to 

Primary prevention in NYHA 

class II or III patients 

9 RCTs, 5,636 

patients 

High (multiple RCTs with 

homogeneous results) 

Reduced mortality: RR = 0.81 (0.69 to No significant effect on HF hospitalizat

1.10 (0.76 to 1.59) 

ICD alone 

Primary prevention in NYHA 

class I patients 

6 RCTs, 721 

patients 

Low (post-hoc metaregression using 

aggregate trial data from 12 RCTs) 

No significant association in meta-regre

between proportion of patients with Csymptoms and reduction in mortality (p = 0.13) 

 Primary prevention in NYHA 

class IV patients 

1 RCT, 217 

patients 

Moderate (within-RCT 

comparison, but not primary aim of RCT, PLUS post-hoc metaregression using aggregate trial data from 12 RCTs) 

Mortality hazard ratio = 1.27 (0.68 to 2.

CRT-ICD vs. CRT alone arms in the IV patients in the COMPANION TrialPLUS p = 0.62 for mortality metaregression comparing impact of ICD NYHA class IV patients vs. impact in II or III patients 

Evidence Report

15

Chapter 1. Introduction 

The American College of Cardiology (ACC), the American Heart Association (AHA), and 

the Heart Rhythm Society (HRS) commissioned this report to review the current evidence about 

the efficacy, safety, and effectiveness of implantable cardioverter defibrillators (ICD), cardiac 

resynchronization therapy (CRT), and combined CRT-ICD devices in patients with heart failure 

(HF) or asymptomatic left ventricular (LV) systolic dysfunction. 

Background 

Heart failure (HF) leads to significant morbidity and mortality; in 2001 it accounted for 

almost one million hospitalizations in the United States (as the most responsible diagnosis) and 

$29.6 billion in direct and indirect costs.237 HF is the fastest growing cardiovascular diagnosis in 

North America: the community prevalence is estimated at 0.4 percent to 2.4 percent in adults,237-

240 with the annual incidence approaching 10 cases/1,000 in people over 65 years of age.237

Indeed, the lifetime risk of developing HF is estimated at 20 percent in North America.241

Despite many advances in diagnosis and therapy over the past two decades, HF still carries a 

poor prognosis.237,242 The functional status of patients with HF is described using the New York 

Heart Association (NYHA) Classification system: NYHA Class I patients are those who are 

asymptomatic; NYHA Class II patients are those who develop symptoms (dyspnea or fatigue) 

with moderate exertion (climbing two flights of stairs or walking two blocks); NYHA Class II 

patients are symptomatic with mild exertion (climbing one flight of stairs or walking one block); 

and NYHA Class IV patients are symptomatic at rest. 

HF is a clinical syndrome characterized by specific symptoms and is accompanied in most 

cases by a decreased ejection fraction (“left ventricular systolic dysfunction”).243 A plethora of 

randomized trials over the past 2 decades have established a variety of treatment options for 

systolic heart failure, as outlined in schematic form below.243,244

Figure 1. Treatment of systolic heart failure (Adapted from Canadian Cardiovascular Society Guidelines244) 

 

 ACEI

+ 

beta-blocker 

Titrate to target doses

Prescribe ARB 

Prescribe ARB 

Consider nitrate/hydralazine 

 If LVEF < 40% 

For all symptomatic patients: 

• Education 

• Aggressive risk factor 

 reduction 

• Lifestyle modifications 

• Salt/fluid vigilance 

• Tailored diuretic Rx 

Clinically stable

NYHA class III

NYHA Class IIIb-IV

Persistent symptoms 

Continue Rx

Add ARB

Digoxin +/- nitrates 

Combination diuretics 

Spironolactone 

Intolerance 

Intolerance 
16

In general, management of HF involves a combination of nonpharmacological (e.g., lifestyle 

modification, education, smoking cessation) and pharmacological approaches. Pharmacological 

treatment of HF involves a combination of the use of vasodilators (e.g., nitrates), neurohormonal agents (e.g., angiotensin-receptor blocker [ARB] and angiotensin-converting enzyme 

[ACE] inhibitors), beta-blockers, diuretics (e.g., furosemide, spironolactone) and inotropes (e.g., 

digoxin). In special cases, such as atrial fibrillation, cardiac rate control and/or antiarrhythmic 

therapy may also be warranted. Prevention of complications such as cardiac embolism (using 

ASA, warfarin, or both) and infectious diseases (through immunization) are also warranted in 

this patient group. Finally, due to the complexity of the disease, multidisciplinary approaches to 

management, including specialized heart function clinics, are strongly encouraged. 

Despite evidence-based care using optimal combinations of the nonpharmacologic and 

pharmacologic approaches summarized above, rates of morbidity and mortality remain high and 

quality of life is poor for many patients with systolic HF. Attempts to reduce mortality in HF are 

directed at the two main causes of cardiac death in these patients: sudden cardiac death 

(electrical failure) and progressive heart failure (mechanical failure).245 Sudden cardiac death 

accounts for more deaths than progressive heart failure in patients with NYHA Class I or II 

symptom status. On the other hand, progressive heart failure is the predominant cause of death in 

those with NYHA Class III or IV symptoms.246 It is important to emphasize that not all therapies 

that improve functional outcomes (such as symptoms, quality of life, ejection fraction, and other 

hemodynamic measurements) in HF patients confer survival benefits.247 Thus, it is essential that 

any novel therapies for patients with HF be evaluated for their impact on hospitalization and/or 

death. 

Clearly, there is a need for additional treatment strategies in HF that can improve function, 

diminish symptoms, reduce hospitalizations, and increase survival. Recently, attention has 

focused on the potential for cardiac resynchronization therapy (CRT)—atrial-synchronized 

biventricular pacing (i.e., pacing the right atrium, right ventricle, and left ventricle)—to reduce 

the mechanical dyssynchrony common in patients with left ventricular systolic dysfunction, and 

thereby improve left ventricular filling time, reduce mitral regurgitation, and reduce septalposterior wall dyskinesis.1,2 An earlier systematic review of the clinical trials of CRT established 

that, in selected patients with advanced HF and mechanical LV dyssynchrony, CRT improves 

quality of life, NYHA class, 6-minute walk test results, and reduces both hospitalizations and allcause mortality (produced primarily by a 40 percent reduction in progressive HF deaths).248

However, the previous systematic review had two important weaknesses: (1) it was unable to 

clarify the relative survival benefits conferred by CRT alone vs. combined CRT-ICD devices 

given the relative paucity of data at that time, and (2) it was based on efficacy data derived from 

randomized controlled trials conducted on highly select patients (NYHA III/IV symptoms, sinus 

rhythm, LVEF < 35 percent, QRS ≥ 120 msec, and on optimal medical therapy) seen at largevolume hospitals by clinicians experienced in CRT device implantation and monitoring.249 Thus, 

this earlier systematic review needed to be updated to (1) incorporate randomized efficacy trials 

published in the subsequent 3 years, (2) expand the analyses beyond randomized trial evidence to 

examine the safety and effectiveness of CRT devices when they are used in clinical practice 

(which may possibly differ from the effect estimates reported in trial participants and settings), 

and (3) clarify the incremental benefits conferred by combined CRT-ICD devices over CRT 

alone or ICD alone (which could not be properly evaluated before due to a paucity of evidence at 

that time) and to define the patient groups most appropriate to receive a CRT device. 
17

ICDs are devices consisting of at least one lead which resides in the right ventricle dedicated 

to pacing and/or defibrillating lethal cardiac arrhythmias. More advanced ICDs (dual-chamber 

devices) consist of leads in the right atrium and right ventricle and have the potential to be 

programmed as a dual-chamber pacemaker (e.g., DDD pacing mode) and for the atrial lead to 

help discriminate arrhythmic events. ICDs do not improve functional outcomes in patients with 

HF; however, they do confer a substantial mortality benefit (through the prevention of sudden 

cardiac death) in patients who have a history of ventricular arrhythmias or who are at high risk 

for ventricular ectopy due to the severity of their left ventricular dysfunction.250 Since an earlier 

systematic review of ICDs proving the benefits of these devices in the secondary prevention of 

ventricular arrhythmia deaths in high risk patients, a number of large trials have evaluated the 

effects of ICDs for primary prevention in patients with symptomatic or asymptomatic left 

ventricular systolic dysfunction but without known ventricular arrhythmias. As with the CRT 

review, there are issues concerning the impact of ICDs when used in clinical practice compared 

with their impact in the optimal settings and highly select participants involved in efficacy trials. 

Thus, there is a need to (1) update the earlier meta-analysis to incorporate randomized efficacy 

trials published in the subsequent 4 years, and (2) expand our analyses to examine the safety and 

effectiveness of ICDs when they are used in clinical practice. 

The issue of device effectiveness and safety in clinical practice is particularly important as 

the rates of implantation for CRTs and ICDs are increasing exponentially. In 2001, 48,127 ICDs 

were implanted in the United States, of which only two percent were combined CRT-ICD 

devices.251 However, in 2005 over 156,000 ICDs were implanted in the United States, with 42 

percent being combined CRT-ICD (Merril Lynch Industry Model Book, May 2006).

This review will examine the evidence for the efficacy, effectiveness, and safety of CRT 

alone, ICD alone, or combined CRT-ICD in patients with LV systolic dysfunction and will 

attempt to define the potential role of CRT and/or ICD in managing these patients. 

Study Questions

1. In adult patients with symptomatic or asymptomatic LV systolic dysfunction, what is the 

efficacy and effectiveness of CRT alone, ICD alone, or combined CRT-ICD devices 

compared to usual medical therapy? 

2. In adult patients with symptomatic or asymptomatic LV systolic dysfunction, what is the 

efficacy and effectiveness of single-chamber ICD compared to that of dual-chamber ICD? 

3. In adult patients with symptomatic or asymptomatic LV systolic dysfunction, how safe is 

CRT alone, ICD alone, or combined CRT-ICD devices? 

4. Which patients would benefit from ICD alone, CRT alone, or combined CRT-ICD devices?

19

Chapter 2. Methods 

Literature Search 

We systematically searched the following 17 electronic resources: MEDLINE®, Ovid 

MEDLINE® In-Process & Other Non-Indexed Citations, Cochrane Central Register of 

Controlled Trials (which contains the Cochrane Heart Group’s Trial Registry; this group hand 

searches journals pertinent to its content area and adds relevant trials to the registry), Cochrane 

Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), 

Health Technology Assessment Database (HTA), EMBASE, Science Citation Index Expanded 

(via Web of Science®), International Pharmaceutical Abstracts, PubMed®, National Library of 

Medicine (NLM) Gateway, OCLC Proceedings First and Papers First, CRISP (Computer 

Retrieval of Information on Scientific Projects), The National Research Register (UK), 

Australian Clinical Trials Registry, ClinicalTrials.gov, and Current Controlled Trials. We also 

searched for relevant reports from the U.S. Food and Drug Administration and for abstracts from 

the annual Heart Rhythm Society meetings. The reference lists of relevant reviews and included 

studies were reviewed, and authors of included studies were contacted for additional citations 

and information. Finally, additional unpublished data (including individual patient data) were 

sought from the following CRT and ICD manufacturers: Medtronic Inc. (Minneapolis, MN), 

Guidant Corporation (Indianapolis, IN), and St. Jude Medical Inc. (St. Paul, MN). The search 

was not limited by language of publication or publication status and is considered current up to 

November 14, 2006. 

The search terms were adapted from the search strategies used in two previous reviews248,250

and included “biventricular pacing,” “biventricular pacer,” “biventricular stimulation,” “BiV,” 

“artificial cardiac pacing,” “chronic cardiac failure resynchronization therapy,” “single chamber 

pacing,” “dual chamber pacing,” “cardiac resynchronization,” “Medtronic,” “InSync,” “ELA 

medical,” “Guidant,” “St. Jude,” “implantable defibrillators,” “AICD,” “ICD,” “single chamber 

ICD,” “dual chamber ICD,” “congestive heart failure,” “CHF,” “chronic heart failure,” and 

“heart diseases.” Along with the terms for randomized controlled trials (RCTs), the following 

terms were used to refine the search for evidence: “controlled clinical trial,” “meta-analysis,” 

“multi-center trial,” “safety,” “risk,” “adverse effects,” or “adverse symptoms,” “side effects,” 

“harm,” “contraindications,” “causation,” “causality,” “predict,” “complications,” “inappropriate 

shocks” or “inappropriate pacing,” “bleeding,” “hemorrhage,” and “infection.” 

The complete search strategies (adapted for each database) and search results are 

included in Appendix A*. 

Selection and Inclusion 

To address efficacy questions, we limited our analyses to randomized controlled trials 

(RCTs). To address effectiveness questions, our inclusion criteria were expanded to include nonRCTs that used contemporaneous comparison arms (e.g., cohort studies). To address safety 

questions, we included evidence from both RCTs and non-RCTs (including study designs 

 

*

 Appendixes cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/defibtp.htm 
20

without contemporaneous control arms, such as case series, registry data, etc.) since adverse

events are uncommon and uncommonly reported in RCTs (which generally have short followup 

durations). 

To assess efficacy and effectiveness of CRT, ICD, and combined CRT-ICD devices, we 

selected studies that enrolled greater than 25 participants with a left ventricular ejection fraction 

(LVEF) ≤ 35 percent, followed patients for at least 2 weeks, and reported at least one outcome of 

interest: mortality (all-cause, cardiac, HF, sudden cardiac death), quality of life, NYHA 

functional class, 6-minute walk test, hospitalization (all-cause or HF), or LVEF. To assess the 

safety of CRT alone or with ICD, we selected studies that enrolled greater than 25 participants 

with LVEF ≤ 35 percent, followed patients for at least 2 weeks, and reported at least one 

outcome of interest: implant success rates, or peri-, and post-implantation risks. To assess the 

safety of ICD, we selected studies that enrolled greater than 25 participants with LVEF ≤ 35 

percent, followed patients for at least 2 weeks, and reported at least one outcome of interest:

implant success rates, or peri-, and post-implantation risks. After reviewing our draft report, the 

Technical Expert Panel suggested that we also examine the implant success rates and periimplant safety of ICD in all patients (not just those patients with LV systolic dysfunction). 

Although we recognize that many of these patients would have symptomatic HF or 

asymptomatic LV systolic dysfunction, we decided to analyze peri-implant safety of ICD for all 

patients, but to report the results for patients known to have LV systolic dysfunction as a 

subgroup analysis. 

Table 2. Inclusion and exclusion criteria for efficacy review 

Study design Include: RCT (parallel or crossover) > 2 weeks duration. 

Exclude: non-RCTs, acute physiological studies and studies that do not involve human subjects. 

Participants ICD alone: Include patients with asymptomatic LV systolic dysfunction or symptomatic HF and 

LVEF ≤ 35%. 

CRT alone or combined CRT-ICD devices: Include patients with symptomatic HF (NYHA Class 

II-IV) while receiving stable optimal drug therapy, LVEF ≤ 35%, and prolonged QRS. 

Studies with < 25 participants were excluded. 

Interventions Treatment with active CRT, active ICD, or combined CRT-ICD compared to either placebo pacing, 

or uni-ventricular (right-sided) pacing, or drug therapy alone. Studies comparing combined 

CRT-ICD to ICD alone were also included. 

Outcomes Mortality (all-cause, cardiac, HF, sudden cardiac death), quality of life, NYHA functional class, 

6-minute walk test, morbidity (including all-cause or HF hospitalization, ED visit), and LVEF. 

ED = emergency department; HF = heart failure; LV = left ventricular; LVEF = left ventricular ejection fraction; NYHA = New 

York Heart Association; = RCT = randomized controlled trial 
21

Table 3. Inclusion and exclusion criteria for effectiveness and safety review 

Study design Include: RCT (parallel or crossover) or non-RCT (e.g., registry data, prospective 

cohort, case series, FDA document, etc.) > 2 weeks duration. 

Exclude: acute physiological studies and studies not involving human subjects. 

Participants ICD alone: Include patients with asymptomatic LV systolic dysfunction or 

symptomatic HF and LVEF ≤ 35% (but for peri-implant success rates and 

complications, include all ICD patients). 

CRT alone or combined CRT-ICD devices: Include patients with symptomatic HF 

(NYHA Class II-IV) while receiving stable optimal drug therapy, LVEF ≤ 35%, and 

prolonged QRS. 

Studies with < 25 participants were excluded. 

Interventions Treatment with active CRT, active ICD, or combined CRT-ICD. 

Comparison group not necessary. 

Outcomes Effectiveness: Mortality (all-cause, cardiac, HF, sudden cardiac death), quality of life, 

NYHA functional class, 6-minute walk test, morbidity (including all-cause or HF 

hospitalization, ED visit), LVEF. 

Safety: Successful implant rate, risks during implantation (death, lead misplacement, 

device-related malfunctions, procedural complications, implant tools, heart function, 

and patient complaints), risks following implantation (mechanical malfunction, lead 

dislodgment, infection, pain), and battery longevity. For ICD devices, data on 

inappropriate delivery of therapy, need for additional medication, and need for 

hospitalization for HF. 

ED = emergency department; HF = heart failure; LV = left ventricular; LVEF = left ventricular ejection fraction; NYHA = New 

York Heart Association; RCT = randomized controlled trial 

Quality Assessments 

Efficacy Review 

The methodological quality of RCTs was assessed independently by two reviewers using two 

quality assessment methods without being blinded to authors, setting, or results. First, allocation 

concealment was assessed as adequate, inadequate, or unclear using the Cochrane approach.252

Second, a five-point scoring system validated by Jadad253 was used to assess randomization, 

double blinding, and reporting of withdrawals and dropouts. In addition, the funding source and 

whether authors reported the use of intention-to-treat analysis were noted. Decision rules 

regarding the application of the tool were developed a priori and discrepancies were resolved 

through discussion between the two reviewers.

Effectiveness and Safety Review 

The methodological quality of RCTs was assessed as outlined above. The quality of 

observational studies included in the effectiveness and safety review were assessed 

independently by two reviewers using a validated checklist developed by Downs and Black.254

The checklist includes 28 questions evaluating five criteria: reporting (10 questions, total score 

11), external validity (three questions, total score 3), internal validity—bias (seven questions, 

total score 7), internal validity—confounding (six questions, total score 6) and power (two 

questions, total score 2). Decision rules regarding the application of the tool were developed a 

priori and discrepancies in quality assessment were resolved through discussion between the two 

reviewers. 
22

Data Extraction 

Data were extracted using standardized forms and entered into an Excel (Microsoft Corp., 

Redmond, WA) spreadsheet. Data were extracted by one reviewer (DD, NH, or CS) and checked 

for accuracy and completeness by a second (BV). Extracted data included the outcomes 

described in Tables 2 and 3, study characteristics, inclusion/exclusion criteria, baseline drug use, 

characteristics of participants, and procedural data. 

Data Analysis

Efficacy Review 

The following data assumptions were made and imputations performed to transform reported 

data into the form required for this review. Standard errors (SE) were converted into standard 

deviations (SD). Graph extraction was performed using CorelDRAW® 9.0 (Corel Corp., Ottawa, 

Canada). Means were approximated by medians, and 95 percent empirical intervals were used to 

calculate approximate SDs. Change from baseline data were used wherever possible for 

continuous data; however, since correlations between baseline and endpoint data were never 

reported, a correlation of 0.5 was assumed255 to calculate the appropriate standard deviation for 

change from baseline data. Change from baseline and endpoint data were combined; both entities 

estimate differences between treatment groups. When provided, efficacy results were extracted 

rather than intention-to-treat results. 

Numerical results were meta-analyzed primarily in Review Manager version 4.2.5 (The 

Cochrane Collaboration, Copenhagen, Denmark). For dichotomous results (e.g., CHF 

hospitalizations), the review reported relative risks (RR) for each individual study as well as a 

pooled result among those studies that could be combined. For continuous variables (e.g., 6-

minute walk test) mean differences were calculated for separate studies and the weighted mean 

difference (WMD) was calculated for the pooled estimate. All results were reported with 95 

percent confidence intervals (CIs) where possible. 

Due to the differences expected between studies (particularly in control group therapies), we 

decided a priori to combine results primarily using random effects models.256 Statistical 

heterogeneity was quantified and appropriated using the I-squared (I2

) statistic.3 This statistic can 

be roughly interpreted as the percentage of total variance in the meta-analysis that is due to 

between-study variation. Inclusion of studies with active control arms was assessed in sensitivity 

analyses. Relevant direct subgroup comparisons were summarized, including effects of CRT in 

patients with more severe heart failure symptoms (NYHA Class III or IV). ICDs were considered 

in an indirect subgroup comparison using meta-regression. Any other reasons for heterogeneity 

were also explored using meta-regression. 

Estimates of carryover effect were extracted from crossover designs. Only period one data 

were used for irreversible outcomes (i.e., death and CHF hospitalizations). Standard errors for 

crossover WMD were calculated according to Curtin.257 

For our primary outcome, all-cause mortality, we tested for publication bias visually using 

the funnel plot and quantitatively using the rank correlation test,258 the graphical test,259 and the 

trim and fill method.260 Meta-regression and publication bias calculations were performed using 

STATA 7.0 (StataCorp., College Station, TX). 
23

Effectiveness Review 

The procedures used for the analysis of efficacy were also used to test for effectiveness, 

although we did not test for publication bias in observational studies. In addition, mortality rates 

for both RCTs and observational studies were plotted against followup time and a regression 

coefficient was computed for each of the three groups (CRT alone, ICD Alone, and CRT+ICD).

Safety Review 

Quantitative results were meta-analyzed primarily in S-PLUS® 6.0 (Insightful Corp., Seattle, 

WA). Risks were simply pooled and all results were reported with 95% CIs. Statistical 

heterogeneity was assessed using the Chi-square test; p<0.10 was considered heterogeneous.261

Also, heterogeneity was quantified and appropriated using the I2

 statistic.3 The exclusion of 

NYHA class II data and studies with active control arms was assessed in sensitivity analyses; 

however, these are not reported here. The possibility that reports may have been less judicious in 

reporting adverse events was considered. Sensitivity analyses were performed where studies 

(RCT or cohort) did not report a particular risk (e.g., death); zero adverse events were assumed 

for these studies. In addition, some implantation risks were reported by event and not by patient. 

This nonindependence was small and was not expected to affect the results importantly. 

Which HF Patients Would Benefit From CRT, ICD, or Combined CRT-ICD Devices? 

Within-trial subgroup reports and meta-regression across trials were used to examine the relation 

between a variety of covariates and the efficacy of CRT, ICD, and combined CRT-ICD devices. 

Individual patient data was requested from each device manufacturer; however, insufficient data 

were available to perform an individual patient data meta-analysis by January 9, 2007. 

25

Chapter 3. Results 

Literature Search 

CRT Alone or Combined CRT-ICD Devices 

Of 7,110 initial references retrieved from electronic databases and 48 references identified by 

hand searching reference lists in published studies or by contacting content experts (including 

primary study authors), we included 128 unique articles (reporting data from 130 studies). 

Fourteen RCTs4-17 were included for the efficacy review, 106 studies17-122 (2 clinical trials, 104 

observational studies) for the effectiveness review, and 89 studies (14 RCTs,4-17 2 clinical 

trials,39,73 and 73 observational studies17,20,22,26,27,29-33,35,36,41,42,44-46,49,50,52,53,55-58,60,63-70,76,78,80,82,83,85-

87,89,91-94,97,98,100,102-106,108,109,111-113,117,118,123-132) for the safety review (Figure 2). Many of the 

studies were included in more than one of the efficacy, safety, and effectiveness reviews. 

Additional data to those reported in the journal publications or conference presentations were 

provided by the investigators from four trials4-6,10 and are included in these analyses.

Figure 2. Flow diagram of study retrieval and selection for CRT alone or combined CRT-ICD devices 

Initial independent 

references from all 

databases 

N = 7,110 

Citations with potential relevance 

N = 530 

First screening of titles and abstracts 

using general criteria 

Met inclusion criteria (N = 14) 

RCT = 14

Met inclusion criteria (N = 

89) 

Controlled clinical trial = 2 

RCT = 14 

Retrospective cohort = 9 

(plus Registry data = 1) 

Prospective cohort = 63 

Second screening with 

specific criteria 

Reference lists, author’s lists, conference 

presentations N = 48 

Efficacy review Safety review 

Met inclusion criteria (N = 

106) 

Controlled clinical trial = 2 

Retrospective cohort = 13 

Prospective cohort = 91 

Effectiveness review 

128 unique articles containing 130 studies 
26

Many of the included trials were associated with multiple publications that either expanded 

on the main results or reported secondary outcomes not included in the primary report. In such 

cases, only the primary report for each trial was included; however, data on secondary outcomes 

were extracted if they were only reported in these secondary publications. Appendix C*

 identifies 

the associated multiple publications for each included study (there were 49 in total).

There were three main reasons for excluding studies from the CRT review on the second 

detailed screening: (1) the intervention studied was not CRT (48 studies); (2) the article was a 

review, protocol, editorial, or did not present primary data (139 studies); or (3) the study did not 

report required outcomes (134 studies), leaving 32 studies which were excluded for other reasons 

(including small sample size). The list of excluded studies and reasons for exclusion are 

identified in Appendix D*

.

ICD Alone 

Of 4,151 initial references retrieved from electronic databases and 31 references identified by 

hand searching reference lists in published studies or by contacting content experts (including 

primary study authors), we included 82 unique studies. Twelve RCTs11,133-143 were accepted for 

the efficacy review, 48 studies144-191 (3 trials, 45 observational studies) were accepted for the 

effectiveness review, and 49 studies (11 efficacy studies,11,133-136,138-143 38 observational 

studies144,145,147,148,152,155-159,161,162,164,165,169,171,176,178-181,184,186-189,191-202) for the safety review 

(Figure 3). An additional 12 studies (68,848 patients) were included in our secondary analysis of 

peri-implant safety with ICD for all patients (i.e., not restricted to only those patients with LV 

systolic dysfunction).203-214

 

*

 Appendixes cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/defibtp.htm 
27

Figure 3. Flow diagram of study retrieval and selection for ICD alone 

Many of the included trials were associated with multiple publications that either expanded 

on the main results or reported secondary outcomes not included in the primary report. In such 

cases, only the primary report for each trial was included; however, data on secondary outcomes 

were extracted if they were only reported in these secondary publications. Appendix C*

 identifies 

the associated multiple publications for each included study (there were three in total). 

There were three main reasons for exclusion of studies from the ICD review on the second 

detailed screening: (1) the population did not have LVSD (61 studies); (2) the article was a 

review, protocol, editorial, or did not present primary data (105 studies); or (3) the study did not 

report required outcomes (64 studies), leaving 14 studies which were excluded for other reasons 

(including small sample size). The list of excluded studies and reasons for exclusion are 

identified in Appendix D*

. 

 

*

 Appendixes cited in this report are provided electronically at http://www.ahrq.gov/clinic/tp/defibtp.htm 

Initial independent 

references from all 

databases 

N = 4,151 

Citations with potential relevance 

N = 329 

First screening of titles and abstracts 

using general criteria 

Met inclusion criteria 

(N = 12) 

RCT = 12 

Met inclusion criteria for 

LVSD analysis (N = 49) 

RCT = 11 

Trials (non-efficacy) = 6 

Prospective cohort = 15 

Retrospective cohort = 16 

Case control = 1 

Met inclusion criteria for 

peri-implant analysis of all 

ICD implants (n = 12) 

Second screening with 

specific criteria 

Reference lists, author’s lists, conference 

presentations N = 31 

Efficacy review Safety review Effectiveness review 

Met inclusion criteria 

(N = 48) 

Trials (non-efficacy) = 3 

Prospective cohort = 20 

Retrospective cohort = 

24 

Case control = 1 

82 unique 

studies
28

Description of Included Studies: Efficacy Review 

CRT Alone or Combined CRT-ICD Devices

Fourteen randomized trials met the inclusion criteria for the efficacy review and are listed 

below: 

1. The MIRACLE (Multicenter InSync Randomized Clinical Evaluation) Trial4

2. The MUSTIC-SR (Multisite Stimulation in Cardiomyopathies Sinus Rhythm) Trial5

3. The MIRACLE ICD (Multicenter InSync Randomized Clinical Evaluation ICD) Trial6 

4. The MUSTIC-AF (Multisite Stimulation in Cardiomyopathies Atrial Fibrillation) Trial7

5. The PATH-CHF (Pacing Therapies for Congestive Heart Failure) Trial8

6. The CONTAK-CD Trial9

7. The RD-CHF Trial10 

8. The COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in 

Chronic Heart Failure) Trial11

9. The PATH-CHF II (Pacing Therapies for Congestive Heart Failure II) Trial12

10. The HOBIPACE (Homburg Biventricular Pacing Evaluation) Trial13

11. The MIRACLE ICD II (Multicenter InSync Randomized Clinical Evaluation ICD II) 

Trial14

12. The CARE-HF (Cardiac Resynchronization-Heart Failure) Trial15

13. The VecTOR (Ventricular Resynchronization Therapy Randomized) Trial16

14. The RHYTHM ICD (Resynchronization for Hemodynamic Treatment for Heart Failure 

Management) Trial17

Publication Status. Eleven of these trials have been published, and 3 three were located from 

other sources as mentioned in Figure 2. Seven of the trials were conducted in North America, 

and the other seven were conducted in Europe. Characteristics of the trials are summarized in 

Table 4. 

Trial Participants (Table 5). In total, 4,892 patients were enrolled in these trials and 4,420 

(90.3 percent) were randomized to receive CRT (n = 2,703) or control (n = 1,717). Of the 

patients in the intervention arms, 1,310 (48 percent) received CRT alone and 1,393 (52 percent) 

received a CRT-ICD device. The majority of those who were enrolled but not randomized had 

failed implant attempts. The mean age of enrolled patients (in the 11 studies4-9,13,14,16 that 

reported patient age) was 65.4±10.8 years and 72 percent were male (in the 12 studies that 

reported patient gender4-9,11-16). Approximately 79 percent of trial participants were considered 

NYHA class III at baseline (range 0 to 100 percent), and 12 percent were classified as NYHA 

class IV at baseline (range 0 to 67 percent). Five trials included patients with NYHA class II 

symptoms (range 6 to 33 percent in four trials9,16,17 and 100 percent in the fourth trial14)—

approximately 9 percent of all trial participants were judged to be NYHA Class II at baseline. 

Five trials specified a 6-minute walk test result of less than 450 meters as an inclusion 

criterion.4,5,7,16,17 The physical exam findings at baseline were similar among trials with systolic 

blood pressure (range 110 to 118 mm Hg), diastolic blood pressure (range 67 to 70 mm Hg), and 

heart rate (range 69 to 80 bpm) all similar to other trials in heart failure. No trial specifically 
29

recruited patients based on the etiology of their heart failure, although patients with 

uncorrectable valvular disorders and hypertrophic or restrictive cardiomyopathy were excluded 

from all trials. In the six trials that evaluated CRT-ICDs, the majority of patients had ischemic 

etiology (~59 percent);6,9,11,12,14,17 in the other trials, ischemic etiology ranged from 37 percent5

 to 

55 percent.4

Left Ventricular Ejection Fraction. Although PATH-CHF8

 did not specify LVEF in entry 

criteria, 11 trials enrolled patients with LVEF < 35 percent, 1 trial12 enrolled those patients with 

LVEF < 30 percent, and 1 trial13 specified LVEF < 40 percent as an entry criterion. The mean 

ejection fractions were similar in all trials, and ranged from 21 to 30 percent. Nine trials also 

specified a left ventricular end diastolic diameter: ≥ 55 mm in four trials4,6,14,16 and ≥ 60 mm in 

the other four trials.5,7,11,13 The reported mean left ventricular end diastolic diameters for the 

trials were similar (66 to 75 mm). 

QRS Width. QRS width was a criterion for all but one of the trials, with five trials specifying ≥

120 msec, 8,9,11,12,15 three trials ≥ 130 msec,4,6,14 one trial > 140 msec,16 two trials > 150 msec,5,17

one trial > 180 msec,10 and one trial > 200 msec.7 Twelve of the 14 trials had a mean QRS 

between 155 msec and 175 msec, with the MUSTIC-AF trial having a mean QRS of 209 msec 

and RD-CHF having a mean QRS of 206 msec. Left bundle branch block was present in most 

patients (mean 64 percent; range 0 to 100 percent). 

Rhythm. Nine trials4,5,8,9,11,12,15-17 were restricted to patients in normal sinus rhythm, one was 

restricted to patients with atrial fibrillation,7

 and patients with atrial fibrillation constituted 

between 14 and 52 percent of trial participants in the three trials6,10,13 that enrolled patients with 

or without atrial fibrillation (5 percent of all trial participants had atrial fibrillation). One trial14

made no mention of whether or not patients with atrial fibrillation were included. Only one trial13

recruited patients with symptomatic bradycardia and an indication for traditional RV pacing, and 

two trials8,11 required a prolonged PR interval > 150 msec for inclusion (four trials reported PR 

intervals that ranged from 195 to 215 msec). 

In the four trials testing combined CRT-ICD against ICD alone,6,9,14,17 there was a general 

requirement that study patients meet indications for ICD placement. (Note that although 34 of 

the 86 patients in PATH-CHF II had a combined CRT-ICD device, results for this subgroup were 

not reported separately.) Although it was not specified by which ICD criteria patients were 

evaluated, the indications in MIRACLE ICD6

 and CONTAK-CD9 were consistent with the 

AHA/ACC guidelines for secondary prevention at the time of enrollment.262 

Medications. Medication use was specified in all but three trials.8,10,16 ACE inhibitors were 

required or were taken by the vast majority of participants in all trials, beta-blockers were 

required in three trials,4,11,13 and spironolactone was required in one trial.11 Baseline medication 

use in the efficacy review trials is detailed in Table 5. Three trials reported that approximately 

one-third of trial participants used amiodarone,5,8,13 and between 24 and 38 percent of patients in 

three other trials6,14,17 were on non-beta-blocker anti-arrhythmic agents. Digoxin was used in 43 

to 76 percent of patients, with four of the five largest trials having at least 75 percent of their 

patients on digoxin.4,6,9,11,15 
30

Design. Nine of the trials employed a parallel study design.4,6,9,11,14-17 One of these had planned 

a crossover period but was required to change its protocol mid-study and excluded crossover data 

from its analysis;9

 five others completed a crossover design.5,7,8,12,13 The duration of treatment 

was 4 weeks in PATH-CHF;8

 3 months per phase in MUSTIC AF,7 MUSTIC SR,5 PATH-CHF 

II,12 and HOBIPACE;13 6 months in MIRACLE,4

 MIRACLE ICD,6 MIRACLE ICD II,14

VecTOR,16 andRHYTHM ICD;17 12 months in the COMPANION11 trial; and a mean of 29 

months in the CARE-HF trial.15 Thirteen of the 14 trials used a transvenous approach for 

placement of the epicardial leads (54 patients in CONTAK-CD9 required a transthoracic 

approach), while PATH-CHF8

 used a transthoracic approach (in PATH-CHF II12 61 of 86 

patients implanted with devices had this done transthoracically and 25 had transvenous implants 

performed). 

Timing of Randomization. Eleven of the trials (n = 2,166 patients) randomized patients after 

successful CRT implantation; 3 trials (n = 2,439 patients) randomized patients before attempted 

CRT implantation.11,15,16 We explored the influence of randomization timing on efficacy results 

in meta-regression analysis as discussed later in this document. 

Description of Each Trial. 

Parallel-Arm trials. The MIRACLE trial4

 enrolled 453 patients (NYHA Class III or IV); 228 

were randomized to CRT “on,” 225 to CRT “off” after device implantation and the primary 

outcomes were quality of life, 6-minute walk test, and NYHA class. 

The MIRACLE-ICD trial6 randomized 369 patients with NYHA Class III/IV symptoms at 

baseline: 187 to CRT “on” and 182 to CRT “off” after device implantation. All patients in 

MIRACLE-ICD6 received an ICD and the primary outcomes were quality of life, 6-minute walk 

test, and NYHA class. 

CONTAK-CD9

 was a two-part trial with an initial pilot crossover involving two 3-month 

phases and a parallel design study with 6-month followup in the second part. The primary 

outcome was progression of heart failure (all-cause mortality, HF hospitalization, and ventricular 

tachycardia/fibrillation requiring ICD intervention). As with MIRACLE-ICD, all patients in 

CONTAK-CD were implanted with a device with ICD capabilities and were randomized to CRT 

“on” or “off” after device implantation. The primary outcome was a composite of all-cause 

mortality, HF hospitalizations, and ventricular arrhythmias requiring device intervention. 

COMPANION11 was a three-arm, parallel-group trial that compared optimal 

pharmacological therapy (n = 308), CRT alone (n = 617), and combined CRT-ICD (n = 595) 

randomized in a 1:2:2 manner before device implantation. The primary outcome was a composite 

of all-cause mortality and all-cause hospitalization (including emergency department [ED] 

presentations or unscheduled office visits requiring >4 hours of intravenous vasoactive or 

inotropic drugs). 

The MIRACLE ICD II trial14 randomized 186 patients with an indication for an ICD and 

NYHA class II symptoms to CRT “on” or “off” after device implantation (all patients in both 

groups had the ICD function turned on). The primary outcome was change in peak VO2 from 

baseline and a variety of functional assessments were collected. 

The CARE-HF trial15 randomized 813 patients (NYHA Class III or IV) to either medical 

therapy plus CRT (n = 409) or medical therapy alone (n = 404); randomization was before 
31

device implantation. The primary outcome was a composite of all-cause death or unplanned 

hospitalization for major cardiovascular event. 

The VecTOR trial16 randomized 106 patients to either CRT “on” or “off” for 6 months, then 

all patients received CRT “on”—the outcomes were presented at 6 months (before all patients 

were crossed into the “on” arm). Randomization in VecTOR was conducted before device 

implantation. 

The RHYTHM ICD Trial17 randomized 183 patients after device implantation to having the 

CRT function on their device on or off (all patients in both groups had the ICD function turned 

on). 

Crossover Trials. In MUSTIC SR,5 67 patients were enrolled and implantation attempted, 

followed by 8 to 12 weeks of observation; 58 patients were then randomized into a 3-month 

crossover of either CRT “on” or “off” phases after device implantation (Phase 1: n = 29, Phase 2: 

n = 29). 

In MUSTIC AF,7

 64 patients were enrolled and implantation attempted, followed by 8 to 12 

weeks of observation; 43 were then randomized into a 3-month crossover of CRT “on” or “off” 

phases after device implantation (Phase 1: n = 25, Phase 2: n = 18). Both trials used the 6-minute 

walk test as the primary outcome. Neither trial used a washout period between phases and neither 

detected a carryover effect. 

PATH-CHF8

 was a 4-week crossover study in which 42 patients were enrolled and 

implantation attempted; 41 patients were then randomized to CRT “on” or “off” in two phases 

after device implantation with a 4-week washout period between the two phases (Phase 1: n = 

24, Phase 2: n = 17). The primary endpoint was peak oxygen uptake on a maximal exercise test. 

This trial did detect a carryover effect. 

PATH-CHF II12 was a 6-month crossover study in which 86 patients had a CRT device 

implanted (34 of whom had a device with ICD capabilities) and were randomized to LV pacing 

lead “on” or “off” in two phases after device implantation without a washout phase. The primary 

endpoint was change in exercise capacity. 

HOBIPACE13 was a 3-month crossover study in which 33 patients with indications for a 

conventional pacemaker had a CRT device implanted and were randomized to biventricular 

pacing or RV pacing in two phases after device implantation and medication optimization, 

without a washout phase.

Subgroup Analyses. Subgroup analyses were reported in seven of these trials,4,6,9,11-13,15

although three trials11,12,15 reported that their subgroups were specified a priori and only two12,15

stratified their randomization by subgroups. The subgroups reported in each trial were: 

• MIRACLE: beta-blockers, ischemic etiology, LVEF, left or right bundle branch block, QRS 

duration, sex, age; 

• MUSTIC-SR: none reported; 

• MIRACLE ICD: beta-blocker, underlying heart disease (ischemic vs nonischemic), 

morphology of the QRS complex (left vs right bundle branch block), QRS duration; 

• MUSTIC AF: none reported; 

• PATH-CHF: none reported; 

• CONTAK-CD: beta-blockers, ischemic etiology, LVEF, left or right bundle branch block, 

QRS duration, sex, age; 

• RD-CHF: none reported; 
32

• COMPANION: age, sex, ischemic etiology, NYHA, LVEF, LVEDD, QRS, LBBB, heart 

rate, systolic BP, diastolic BP, ACE inhibitor, beta-blocker, loop diuretic, spironolactone 

• PATH-CHF II: QRS duration; 

• HOBIPACE: atrial fibrillation, bundle branch block pattern, site of LV lead placement 

• MIRACLE ICD II: none reported; 

• CARE-HF: Age, sex, NYHA, dilated cardiomyopathy, systolic blood pressure, brain 

natriuretic peptide, LVEF, end-systolic volume index, QRS, IMD, glomerular filtration rate, 

medication; 

• VecTOR: none reported; and 

• RHYTHM ICD: none reported 

Subgroup effects were tested using appropriate statistical methods (i.e., treatment*subgroup 

interaction (or heterogeneity) test) in 3 of these trials.9,11,15 The MIRACLE trial presented 

subgroup-stratified analyses but didn’t report an interaction test. The 3 most frequently 

examined subgroups (and number of trials doing so) were QRS duration (6 trials), bundle branch 

block pattern (5 trials), and ischemic etiology (5 trials). 

ICD Alone 

Twelve randomized trials11,133-143 met the inclusion criteria for the efficacy review and are 

listed below: 

Primary Prevention Trials (i.e., trial participants did not have history of ventricular fibrillation 

or ventricular tachycardia requiring resuscitation): 

1. MADIT (Multicenter Automatic Defibrillator Implantation Trial)133

2. The CABG Patch (Coronary Artery Bypass Graft Patch) Trial134

3. MADIT II (Multicenter Automatic Defibrillator Implantation Trial II)135

4. The CAT (Cardiomyopathy) Trial136

5. AMIOVIRT (Amiodarone vs. Implantable Defibrillator Randomized Trial)137

6. The DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) 

Trial138

7. DINAMIT (Defibrillator in Acute Myocardial Infarction Trial)139

8. SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) 140

9. The COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in 

Chronic Heart Failure) Trial11

Secondary Prevention Trials (i.e., in patients with history of ventricular fibrillation or 

ventricular tachycardia requiring resuscitation): 

1. The AVID (Antiarrhythmics Vs. Defibrillators) Trial141

2. The CIDS (Canadian Implantable Defibrillator Study) Trial142

3. The CASH (Cardiac Arrest Study Hamburg) Trial143
33

Publication Status. All of these trials have been published, and supplemental data were located 

from other sources as mentioned in Figure 2. Characteristics of the trials are summarized in 

Table 6. 

Trial Participants (Table 7). In total, 8,516 patients were randomized in these trials to receive 

ICD (n = 4,301) or control (n = 4,215). The mean age of enrolled patients was 60.8 ± 4.2 years 

and 74 percent were male. The majority of trial participants had HF symptoms (in the trials that 

reported baseline functional class, 50 percent had NYHA class II symptoms at baseline, 36 

percent NYHA class III symptoms, and 3 percent Class IV functional status). Seven trials 

enrolled asymptomatic patients (i.e., those with NYHA class I HF), and this percent ranged from 

13 to 37 percent in these trials such that 11 percent of all ICD trial participants with left 

ventricular systolic dysfunction did not have HF symptoms at baseline.142 Most trials excluded 

Class IV patients. Four trials enrolled patients that had an ischemic etiology for their left 

ventricular dysfunction,133-135,139 3 trials enrolled patients with a non-ischemic dilated 

cardiomyopathy136-138 and 5 trials included either etiology.11,140-143 Of note, patients with other 

indications for defibrillators were not enrolled in these trials, nor were patients with acute 

myocarditis, hypertrophic/ restrictive/or constrictive cardiomyopathy, or arrhythmogenic right 

ventricular dysplasia. 

Left Ventricular Ejection Fraction. Although all trials enrolled patients with left ventricular 

systolic dysfunction (mean LVEF ranged from 21 percent to 28 percent in the primary 

prevention trials and from 32% to 46% in the secondary prevention trials), they used different 

entry criteria for ejection fraction: ≤30 percent;135,136 ≤35 percent,11,133,134,137-140; and ≤40 

percent.141 Two trials did not specify an ejection fraction in their eligibility criteria but their 

mean ejection fractions were 34 percent142 and 46 percent.143

ECG Criteria. Of the primary prevention trials, all but 3 trials specified other 

electrocardiographic entry criteria to identify high risk patients.135,136,140 The other “primary 

prevention” trials identified higher risk patients for study using non-sustained ventricular 

tachycardia,133,137,138 elevated heart rate or reduced heart rate variability,139 or abnormal signalaveraged ECG134 as markers of increased risk. 

Medications. Baseline medication use varied substantially, in part due to the range of years in 

which the trials were initiated and completed (Table 7). One trial enrolled the first patient before 

1990,143 5 trials between 1990 and 1995, 133,134,136,141,142 5 trials between 1996 and 2000,135,137-140

and in one trial it was unclear.11 Baseline beta-blocker use varied between trials (4 to 87 percent), 

as did digoxin use (20 to 86 percent) and angiotensin-converting enzyme inhibitor use (42 to 96 

percent). 

Design. All trials employed a parallel study design and all randomized patients prior to 

implantation of the ICD. ICDs were compared to usual care,133-136,138,139 amiodarone 

alone,137,141,142 amiodarone or placebo, 140 and amiodarone or metoprolol.143 In the 

COMPANION trial, 2 of the 3 study arms (CRT vs. optimal medical therapy) were used in the 

CRT review while data from the combined CRT-ICD and CRT alone arms were used in the ICD 

analyses.11 In the trials in which amiodarone was not a comparator, amiodarone use ranged from 
34

4 to 13 percent, with 84 percent of patients in the MADIT trial being placed on non-trial antiarrhythmic agents. 

Type of ICD. The type of devices used for the trials were unspecified137, epicardial or 

endocardial,133,141-143 epicardial only134 or endocardial only.11,135,136,138-140 Devices were specified 

to be single-chamber ICD in all but the COMPANION and MADIT-II trials, but protocol 

adherence to a single-chamber device was not reported in any trial.11,135 The MADIT-II Trial 

subsequently reported that 44% of intervention arm devices were in fact dual-chamber ICD in a 

second publication.263

Description of Each Trial: 

Primary Prevention Trials. MADIT randomized 196 patients with a prior myocardial 

infarction and NYHA I-III to either an ICD (n = 95) or usual care (n = 101).133

CABG Patch enrolled 900 patients with ischemic cardiomyopathy undergoing CABG and 

abnormal signal-averaged ECG to either an ICD (n = 446) or usual care (n = 454).134

MADIT II enrolled 1,232 patients with a prior myocardial infarction >1 month prior and 

NYHA I-III to an ICD (n = 742) or usual care (n = 490) in a 3:2 manner.135

The Cardiomyopathy Trial (CAT) enrolled 104 patients with a dilated cardiomyopathy ≤9 

months in duration to an ICD (n = 50) or usual care (n = 54).136

AMIOVIRT randomized 103 patients with non-ischemic cardiomyopathy with non-sustained 

VT, to either amiodarone (n = 52) or an ICD (n = 51).137

DEFINITE enrolled 458 patients with a non-ischemic dilated cardiomyopathy and NSVT to 

an ICD (n = 229) or usual care (n = 229).138

DINAMIT randomized 674 patients between 6 and 40 days post-MI with impaired 

autonomic function to an ICD (n = 332) or usual care (n = 342).139

SCD-HeFT enrolled 2,521 patients with either ischemic or non-ischemic NYHA II-III heart 

failure to an ICD (n = 829), amiodarone (n = 845) or placebo (n = 847). 140

COMPANION (described in full in the CRT trial section above) enrolled 1,520 patients 

randomized to optimal medical therapy (n = 308), CRT alone (n = 617) or CRT-ICD (n = 595).11

Secondary Prevention Trials. The AVID trial enrolled 1,016 patients (resuscitated after nearfatal VF, sustained VT with syncope or sustained VT with LVEF < 40 percent) randomized to an 

ICD (n = 507) or drug therapy (n = 509), mainly amiodarone.141

CIDS randomized 659 patients resuscitated from a cardiac arrest, or with ventricular 

tachycardia or fibrillation to either an ICD (n = 328) or amiodarone (n = 331).142

CASH randomized patients resuscitated from a cardiac arrest to one of four arms (ICD, 

amiodarone, metoprolol, or propafenone) in a 1:1:1:1 manner.143 The propafenone arm was 

stopped early due to increased harm, and the remaining 288 patients were randomized to an ICD 

(n = 99), amiodarone (n = 92), or metoprolol (n = 97). 

Subgroup Analyses. Subgroup analyses were reported in 11 of these trials - 9 trials reported 

that their subgroups were specified a priori and 6 stratified their randomization by subgroups. 

The subgroups reported in each trial were: 
35

Primary Prevention Trials: 

• MADIT: age, sex, cardiac history (including NYHA class, treatment for VT, CHF, 

hypertension, IDDM, smoking, CABG, angioplasty, pacemaker), interval since MI, 

pulmonary edema, urea, cholesterol, LBBB, LVEF, NSVT, EP study results; 

• CABG Patch: ischemic etiology, heart failure, diabetes, NYHA class, sex, age, LVEF, QRS, 

angiotensin-converting enzyme inhibitors, beta-blocker, class I or III antiarrhythmics; 

• MADIT II: ischemic etiology, NYHA class, sex, age, LVEF, QRS, LBBB, time from MI, 

diabetes, hypertension, atrial fibrillation, type of ICD, urea; 

• CAT: ischemic etiology, NYHA, sex, age, LVEF, LVEDD, LVESD, QRS, rhythm, Q-T 

interval, Holter findings, EP study findings, medications; 

• AMIOVIRT: none reported; 

• DEFINITE: amiodarone, age, sex, LVEF, QRS, NYHA, atrial fibrillation; 

• COMPANION: age, sex, ischemic etiology, NYHA class, LVEF, LVEDD, QRS, LBBB, 

heart rate, systolic BP, diastolic BP, ACE inhibitor, beta-blocker, loop diuretic, 

spironolactone; 

• DINAMIT: ischemic etiology, diabetes, NYHA class, sex, age, LVEF, QRS, atrial 

fibrillation, NSVT, heart rate, SDRR, reperfusion method; and 

• SCD-HeFT: ischemic etiology, NYHA class, sex, age, race, LVEF, QRS, 6-minute walk test, 

beta-blocker, diabetes. 

Secondary Prevention Trials: 

• AVID: age, LVEF, etiology, qualifying arrhythmia, beta-blockers, heart failure, 

revascularization, atrial fibrillation; 

• CIDS: age, sex, index arrhythmia, LVEF, NYHA class, etiology; and 

• CASH: LVEF, NYHA class, ischemic etiology 

Subgroup effects were tested using appropriate statistical methods (i.e., treatment x subgroup 

interaction or heterogeneity tests) in all but two of these trials.137,139 Six trials presented the 

results of their subgroup analysis in the primary manuscript.11 The three most frequently 

examined subgroups were LVEF (tested in 11 trials), NYHA class (examined in 10 trials, and 

age (examined in 10 trials).138,140,141,143

Description of Included Studies: Effectiveness Review 

CRT Alone or Combined CRT-ICD Devices 

In addition to the 14 RCTs, an additional 106 studies met the inclusion criteria for the review 

of effectiveness of CRT alone or combined CRT-ICD devices (Table 8). Forty-two of these 

studies met the inclusion criteria for the review of effectiveness but not safety. The 106 studies 

included two controlled clinical trials (CCTs), 91 prospective cohort studies, and 13 retrospective 

cohort studies. Sixty of these studies looked at CRT alone; the other 46 looked at a mix of 

patients receiving CRT alone and a combined CRT-ICD device. Sixty-eight studies reported that 

devices were implanted transvenously, two transthoracically,56,97 and five used a mixture of 
36

approaches.12,63,73,84,86 Medtronic Inc., Guidant Corp., ELA Medical, St. Jude Medical Inc., or 

Biotronik manufactured all implanted devices; the models and leads varied among and within 

trials. 

Study Participants (Table 9). In total, 9,846 patients were enrolled; of these, 9,209 patients 

received CRT alone or combined CRT-ICD devices. The mean age was 66 ± 11 years, and 78 

percent were male. The majority of participants had NYHA class III (range 0 to100 percent 

within studies), or NYHA class IV (range 0 to 87 percent within studies) symptoms at baseline 

(Table 9). Nineteen studies included patients with NYHA class II symptoms (range 0 to 100 

percent).8,12,20,26,32,36,40,48,69,74,83,84,98-100,109,114,121,130 One study included patients with NYHA class 

I.20 No studies specifically based inclusion on the etiology of HF of the patients. Patients with 

correctable valvular disorders, hypertrophic or restrictive cardiomyopathy, unstable angina, or 

acute myocarditis were excluded from these studies. 

Left Ventricular Ejection Fraction. Sixty-three studies limited inclusion to patients with an 

ejection fraction ≤ 35 percent, 3 of which enrolled patients with LVEF < 30 percent,47,50,71 17 

enrolled patients with LVEF < 40 percent, and 26 did not specify this criterion. The mean 

ejection fraction ranged from 17 percent to 35.6 percent in these studies. Thirteen studies 

specified a left ventricular end diastolic dimension inclusion criterion of ≥55 

mm,19,34,40,48,51,60,65,69,70,83,104,112,114 and eleven studies specified a left ventricular diastolic 

dimension ≥60 mm in their eligibility criteria.21,43,45,46,58,67,68,73,87,113,115

QRS Duration. QRS width was a criterion for 81 studies, with 1 specifying ≥ 110 msec, 33 

specifying ≥ 120 msec, 22 studies ≥ 130 msec, 11 studies ≥ 140 msec, and 13 studies > 150 

msec. One study compared a 120-to-150 msec group to a ≥ 150 group.120 Fifty studies reported a 

mean QRS between 140 msec and 180 msec, and 15 ranged from 181 msec to 206 msec. 

Medications. Concomitant medication use was not specified in 22 of the 106 studies included in 

our effectiveness review. ACE inhibitors and/or an angiotensin-receptor blocker use ranged from 

12 percent to 100 percent and beta-blockers use ranged from 35 percent to 100 percent. Diuretic 

use ranged from 76 percent to 100 percent, and spironolactone use ranged from 25 percent to 100 

percent in the studies that reported the use of these medications (55 studies and 32 studies, 

respectively). Importantly, use of amiodarone ranged from 14 percent to 79 percent (although 

amiodarone usage rates were only reported in 20 studies). In 34 studies reporting digoxin use, 

between 0 percent and 95 percent of participants were on digoxin. 

ICD Alone 

In addition to the 12 RCTs, there were 48 additional studies that met the inclusion criteria for 

the review of effectiveness of ICD (Table 10). Twenty-one of these studies met the inclusion 

criteria for the review of effectiveness but not safety. The 48 additional studies included five 

parallel RCTs that did not report efficacy endpoints of interest, 20 prospective cohort studies, 22 

retrospective cohort studies, and one case control study.180 Thirteen studies reported that devices 

were implanted transvenously,145,147,162,163,165,169,173,174,181,184,187,189,193 and five used a combination 

of transvenous, endocardial or epicardial approaches.144,155,171,185,188
37

Study Participants (Table 11). In total, 25,111 patients were enrolled in these studies of ICD 

effectiveness; of these, 15,097 patients received ICD. Some patients were excluded or withdrew 

due to unsuccessful implants, death, heart transplantation, or miscellaneous reasons. The mean 

age was 62.6 ± 13.2 years, 79 percent were male. Most studies included patients with NYHA 

class II symptoms (range 0 to 95 percent within studies) and NYHA class III symptoms (range 9 

to 100 percent within studies). Fifteen studies reported including patients in NYHA class IV, 

with a range between 2 percent and 33 percent (Table 

11).144,148,155,157,158,161,165,170,172,173,175,179,185,187,190 Two studies required patients to be survivors of 

sudden cardiac death,146,157 and eight studies required patients to have other high risk features. 

147,148,176,183,186,191,193 Eighteen studies did not state exclusion criteria. Ischemic etiology was 

present in approximately 70 percent of patients (range 0 to 100 percent). 

Left Ventricular Ejection Fraction. Ejection fraction was a criterion for 10 studies, with 5 

studies specifying LVEF < 35 percent,146,148,154,176,191 3 specifying LVEF < 40 percent,151,162,189

and 2 specifying LVEF < 45 percent.145,149 The remaining studies did not specify an entry 

criterion. The mean ejection fraction ranged from 19 to 46 percent. 

Medications. Concomitant medication use was not reported in 16 studies. ACE inhibitors were 

reported in 23 studies (range 55 to 95 percent), beta-blockers were reported in 33 studies (range 

10 to 89 percent), and spironolactone was reported in three studies (5 to 36 percent). Thirty-two 

studies reported the use of antiarrhythmic drugs, including amiodarone (range 10 to 61 percent). 

Description of Included Studies: Safety Review 

CRT Alone or Combined CRT-ICD Devices 

Fourteen randomized trials and 75 additional studies met the inclusion criteria for the review 

of safety of CRT (Table 8). The 75 additional studies included 2 controlled but not randomized 

trials,39,73 one registry study, 9 retrospective cohort studies,26,44,63,68,102,109,123,128,129 and 63 

prospective cohort studies. Sixty-five studies reported that devices were implanted 

transvenously, two transthoracically,85,97 and six using both approaches.9,12,56,63,66,73 Medtronic 

Inc., Guidant Corp., ELA Medical Inc, St. Jude Medical Inc., or Biotronik manufactured all 

implanted devices; the models and leads varied among and within trials. 

Study Participants (Table 9). In total, 12,471 patients were enrolled; of these, 9,677 patients 

received CRT alone or combined CRT-ICD device. The mean age was 66 ± 10 years, and 77 

percent were male. Approximately 80 percent of these study participants had NYHA class III 

symptoms at baseline (range 13 to100 percent), and 11 percent were NYHA class IV (range 0 to 

100 percent) (Table 9). Twenty-two studies included patients with NYHA class II symptoms 

(range 4 to 50 percent).9,12,16,17,20,26,32,33,36,48,49,57,69,83,86,98,100,104,109,130,264 Five studies included 

patients with NYHA class I.16,17,32,86 No studies specifically based inclusion on the etiology of 

HF, although patients with correctable valvular disorders, hypertrophic or restrictive 

cardiomyopathy, unstable angina, or acute myocarditis were excluded from these studies. 
38

Left Ventricular Ejection Fraction. Fifty-five studies limited inclusion to patients with an 

ejection fraction < 35 percent. Three of these enrolled patients with LVEF < 30 percent,12,50,128

nine enrolled patients with LVEF < 40 percent,13,31,35,57,98,104,111,113,119 and 24 did not specify this 

criterion.8,10,20,26,27,44,49,52,53,56,63,64,76,85-87,91,100,108,123,125,126,130,264 The mean ejection fraction ranged 

from 19 percent to 36 percent in these studies. Twenty-five studies specified a left ventricular 

end diastolic dimension inclusion criterion of ≥55 mm,4,6,14,16,60,65,69,70,83,104,112 or ≥60 

mm.5,7,13,45,46,58,66-68,73,87,113,129,131 One study specified ≥33 indexed to height.15

QRS Duration. QRS width was a criterion for 72 studies, with 1 study specifying ≥ 110 msec,57

28 ≥ 120 msec,7-9,11,12,15,22,29-32,35,42,67,69,73,78,80,82,87,103,106,109,112,117,125,126,129 18 ≥ 130 msec, 

4,6,14,17,49,50,60,64,65,70,83,92-94,102,104,111,132 9 ≥ 140 msec,16,33,55,56,85,89,98,119,124 15 > 150 

msec,5,17,36,39,45,46,58,68,91,105,108,113,128,130,131 and 1 > 200 msec.66 Forty-seven studies reported a 

mean QRS between 142 msec and 187 msec, and 15 ranged from 181 msec to 206 

msec.27,41,45,46,56,66-68,73,85,86,93,98,99,131

Rhythm. Ten studies were restricted to patients in normal sinus rhythm,5,8,11,12,89,104,113,128,130,131 

but one was restricted to patients with atrial fibrillation.7 In the others, 6 percent to 90 percent of 

patients had atrial fibrillation. 

Medications. Concomitant medication use was not specified in 30 of the 89 studies included in 

our safety review. ACE inhibitors and/or an angiotensin-receptor blocker use ranged from 62 

percent to 100 percent, beta-blockers use ranged from 35 percent to 88 percent, loop diuretic use 

from 43 percent to 100 percent, and spironolactone use ranged from 32 percent to 59 percent. 

Importantly, use of amiodarone ranged from 14 percent to 79 percent (in the 13 studies reporting 

amiodarone usage rates). In 17 studies reporting digoxin use, between 0 percent to 95 percent of 

participants were on digoxin. 

ICD Alone 

Forty-nine studies met the inclusion criteria for the review of safety of ICD (Table 10). 

Eleven of the 12 trials included in the efficacy review were eligible: Strickberger et al. did not 

include any safety outcomes.137 The 38 additional studies included 6 trials that did not report 

efficacy endpoints of interest and were treated as cohort studies,156,176,192-194,200 15 prospective 

cohort studies,144,145,147,148,152,155,160,165,178,187,188,196,198,199,201 16 retrospective cohort 

studies,157,158,161,162,164,169,171,179,181,184,186,189,191,195,197,202 and 1 case control study.180 Ten studies 

reported that devices were implanted transvenously,135,136,145,156,162,165,184,189,192,197 two used both 

transvenous and transthoracic approaches,133,142 and six used a combination of transvenous, 

endocardial or epicardial approaches.134,143,144,147,171,188

Study Participants (Table 11). In total, 22,044 patients were enrolled in the studies of ICD 

safety; of these, 12,592 patients received ICD. Some patients were excluded or withdrew due to 

unsuccessful implants, death, heart transplantation, or miscellaneous reasons. The mean patient 

age was 61.4 ± 11.9 years and 80 percent were male. Approximately 50 percent of each study 

population was NYHA class II (range 16 to 70 percent) and 38 percent were NYHA class III 

(range 9 to 100 percent). Ten studies reported including patients in NYHA class IV, with a range 

between 2 and 18 percent (Table 11).11,133,135,142,144,148,155,157,179,202 Six studies required patients to 
39

be survivors of sudden cardiac death,141-144,156,157 and 13 studies required patients to have other 

high-risk features.135,139,148,155,156,161,176,183,186,191-193,201 Twenty-one studies did not state exclusion 

criteria.144,146-148,150,152,155,157,158,160,163-166,169,178,179,187,189,195,196 Ischemic etiology was present in 

approximately 55 percent of patients (range 0 to 100 percent). 

Left Ventricular Ejection Fraction. Ejection fraction was a criterion for 19 studies, with 3 

studies specifying an ejection fraction of < 30 percent,135,136,191 11 specifying LVEF < 35 

percent,11,133,134,138-140,146,148,176,189,195 three specifying LVEF < 40 percent,141,162,193 and one 

specifying LVEF < 45 percent.145 The mean ejection fraction ranged from 19 to 46 percent. 

Medications. Concomitant medication use was not reported in 14 studies. ACE inhibitors were 

reported in 25 studies (range 42 to 98 percent), beta-blockers were reported in 31 studies (range 

4 to 89 percent), and spironolactone was reported in two studies (5 and 14 percent). Thirty 

studies reported the use of antiarrhythmic drugs, including amiodarone (range 2 to 96 percent). 

Additional Studies of all ICD Implants (i.e., studies not restricted to patients with left 

ventricular systolic dysfunction). Twelve additional ICD studies that did not meet the 

inclusion criterion of a mean baseline LVEF ≤ 35 percent were examined for implantation 

success rates and peri-implant safety data after input from the Technical Expert Panel who 

reviewed our initial draft report (Table 12).203-214 Five were randomized (two parallel, three 

crossover), two each were retrospective or prospective cohorts, and three involved registry data. 

Implant techniques varied and included transvenous, thoracotomy, pectoral, subpectoral, 

abdominal, epicordial and nonthoracic approaches. In total, 68,930 patients were enrolled in 

these 12 studies of ICD safety; of these, 68,848 received ICD (Table 13). The mean age across 

studies was 61 years, and approximately 80 percent were male. Half of the studies reported 

baseline NYHA class: approximately 35 percent of each study population was in NYHA class I 

(range 19 to 100 percent): 54 percent were NYHA class II (range 39 to 62 percent) and 19 

percent were NYHA class III (range 13 to 24 percent). Two studies reported patients in NYHA 

class IV (0.09 and 1 percent).208,211 One author reported 23 percent of the population was greater 

than NYHA class II.212 None of these studies required patients to be survivors of sudden cardiac 

death, but one only included patients who had suffered Sudden Unexplained Death Syndrome210

though otherwise apparently healthy. Ischemic etiology was present in approximately 66 percent 

of patients (median 71; range 0 to 100 percent). Ejection fraction was not a criterion for 

enrolment into these studies; however, 66 percent of studies reported a baseline LVEF that 

ranged from an average of 36 ± 12.4 to 66 ± 10.3 percent. Concomitant medication use was not 

reported in two studies. ACE inhibitors were reported in one study (88 percent), beta-blockers 

were reported in five (range 24 to 44.3 percent), Sotalol in four (range 5-8 percent), amiodarone 

in six (0 to 39 percent) and other antiarrhythmic therapy in four studies (range 3.1 to 79 percent). 
40

Methodological Quality of Included Studies: Efficacy Review 

CRT Alone or Combined CRT-ICD Devices 

As a measure of methodological quality for the included trials, the Jadad253 score (maximum 

5 points) was 5 for one trial,4

 4 for three trials,6,8,14 3 for four trials,5,7,16,17 2 for five trials,9,11-13,15

and 1 for the remaining study10 (Table 14).

All trials were described as randomized; however, the description of randomization detail 

varied. Three were adequately randomized4,5,7 and the rest were unclear. Two reported clear 

concealment of allocation4,14 and the remaining trials were unclear. Six trials were double-blind 

(patient and the outcome assessor blinded), 4,6,8,14,16,17 four were single-blind,5,7,12,13 and four 

were not blinded.9-11,15 In CONTAK CD,9 MIRACLE,4 MIRACLE ICD,6 and CARE-HF,15 the 

independent events committee was blinded to the trial arm the patient was in; no information was 

available for COMPANION.11 Three trials randomized patients before device implantation,11,15,16 

while all other trials randomized patients after their device was successfully implanted. An 

intention-to-treat statistical analysis was specified in all trials, and MIRACLE4 and PATH-CHF8

performed an intention-to-treat analysis. Withdrawals and dropouts were clearly described in all 

trials. Unscheduled crossovers occurred in 0 to 9 percent of the patients in these trials and the 

number of patients were generally balanced between study arms. Withdrawals ranged from 0 to 3 

percent for the cardiac resynchronization group and from 0 to 2.5 percent for the control groups. 

Industry sponsored 12 of the 14 trials; 2 also received funding from government sources.5,7

Guidant Corp. sponsored four,8,9,11,12 Medtronic Inc. sponsored six,4-7,14,15 ELA Medical Inc. 

funded two,5,7 and St. Jude Medical Inc. funded two.16,17 Kindermann did not receive industry 

funding.13 Funding for RD-CHF10 is not known. 

ICD Alone

As a measure of methodological quality for the included trials, the Jadad253 score was 3 for 

three trials,134,139,140 2 for six trials,11,133,135,137,138,142 and 1 for the remaining three (Table 

15).136,141,143 All trials were described as randomized; however, the description of randomization 

detail varied. Four described their randomization methods adequately,133,134,139,142 and the rest 

were unclear. Three reported clear concealment of allocation,134,136,139 and the rest were unclear. 

One ICD trial was double-blind; 140 however, in five trials the independent events committee was 

blinded to the trial arm the patient was in,136-139,142 and in seven trials blinding was unclear.11,133-

135,140-142 An intention-to-treat statistical analysis was specified and performed in all trials. 

Withdrawals and dropouts were clearly described in all but five trials.133,136,141-143 Unscheduled 

crossovers occurred in 0 to 22 percent of the patients in these trials and were generally balanced 

between study arms. Withdrawals ranged from 0 to 6 percent for the ICD group and from 0 to 32 

percent for the control groups. Allocation concealment was unclear for all but three 

trials.134,136,139

Industry sponsored 10 of the 12 trials; 4 also received funding from institute or foundation 

sources134,140-142 and 3 from pharmaceutical companies. 140,142,143 Guidant Corp. sponsored 

seven,11,133-137,143 Medtronic Inc. sponsored one140 and St. Jude Medical Inc. funded two.138,139
41

Methodological Quality of Included Studies: 

Effectiveness and Safety Reviews 

CRT Alone or Combined CRT-ICD Devices 

Overall, the studies were rated as having “good” quality on the Downs and Black254 scoring 

system. Fourteen studies were described as randomized (described in Table 14) and the 

remaining 113 were observational studies.(Table 16). Reporting ranged from fair to good with 51 

percent rating 10 or 11 out of 11, the rest ranging from scores of 3 to 9. External validity 

assessment posed some problems because authors did not report the source population for 

patients or the proportion of eligible patients selected for inclusion, nor compare the distribution 

of main confounding factors with the source population. For this review we defined the source 

population as those with symptomatic HF. Since this procedure can only be performed in 

specialized centers, we determined that all facilities were representative of patients in usual 

practice. Internal validity concerning assessment of bias ranged from scores of 0 to 7 out of 7 

(median = 5); the lack of blinding was the main shortfall. Internal validity assessments 

concerning confounding ranged from scores of 0 to 5 out of 6 (median = 4), with 17 studies 

scoring 2 or less. This is in part due to the studies having no randomization component. Many 

authors did not state the period of time over which patients were recruited or the source of 

patients. Three studies included a power calculation,36,83,125 and 102 out of 113 had sufficient 

sample sizes to determine a clinically important effect. 

Most studies did not report funding, but the majority of those that did received funding from 

industry.17,25,27,36,40,42,49,52,59,61,65,70,77,83,106,116,118 Sixteen received funding from either government 

or foundations.20,28,30-32,36,44,51,62,64,93,108,114,115,122,128

ICD Alone

Overall, the studies were rated as having “good” quality on the Downs and Black scoring 

system. Twelve studies were described as randomized (Table 15) and the remaining 57 were 

observational studies (Table 17). Reporting was generally good with 37 of 57 scoring 10 or 11 

out of 11, the rest scoring from 4 to 9. External validity assessment posed some problems 

because authors did not report the source population for patients or the proportion of eligible 

patients selected for inclusion, nor did they compare the distribution of main confounding factors 

with the source population. For this review we defined the source population as those with left 

ventricular dysfunction. Since this procedure is mainly performed in specialized centers, we 

determined that the facilities were representative. Internal validity concerning assessment of bias 

ranged from scores of 0 to 7 out of 7 (median = 5); the lack of blinding was the main shortfall. 

Internal validity assessments concerning confounding ranged between scores of 0 to 6 out of 6 

(median = 4), with four studies receiving scores of 2 or less.146,173,186,199 Seven studies included a 

power calculation.151,156,175,192-194,200

Most studies did not report on funding. Thirteen reported sponsorship funding from industry, 

151,154,156,160,175-177,185,187,190,193,194,198 and three reported government funding in addition to 

industry.154,175,177 Two received funds from foundations.147,161
42

Safety Review for Peri-Implant Complications of ICD Alone

These 12 observational studies were rated as having “good” quality on the Downs and Black 

scoring system. Reporting was generally good with eight studies scoring 10 or 11 out of 11, the 

rest ranging from 5 to 9 (Table 18). External validity assessment posed some problems because 

authors did not report the source population for patients or the proportion of eligible patients 

selected for inclusion, nor did they compare the distribution of main confounding factors with 

the source population. For this review, we defined the source population as those having an ICD 

implanted for any reason, such that not all had left ventricular systolic dysfunction. Since this 

procedure is mainly performed in specialized centers, we determined that the facilities were 

representative. Internal validity concerning assessment of bias ranged from 3 to 6 out of 7 

(median = 5); the lack of blinding was the main shortfall. Internal validity assessments 

concerning confounding ranged between scores of 1 to 4 out of 6 (median = 4), with two 

receiving scores of 2 or less.208,209 Two studies included a power calculation,205,210 and six (50%) 

had sufficient sample sizes to determine a clinically important effect.156,175,192,193,200

Half of the studies did not report on funding. Three reported sponsorship funding from 

industry,204,205,213 one reported government funding,209 two received funds from 

foundations.210,212
43

Table 4. Description of studies in the efficacy review: CRT alone or combined CRT-ICD devices 

 Participants 

Author 

Year 

Trial Name 

Country 

Design 

Duration 

Control 

Number 

enrolled 

Number 

excluded 

Number 

randomized 

Number in 

treatment* 

Number in 

Control* 

Number of 

withdrawals Device Method of implant Au

pr

out

CRT alone Abraham4 2002 MIRACLE 

United States, Canada  (45 sites) 

RCT  parallel 6 mo. 

Pacer  inactive 

571 NR 453 228 225 Treatment 

1 

Control 

8 

Medtronic 

InSync®

8040 

Transvenous 

NYHA

6MW

Cazeau5

2001 MUSTIC-SR 

Europe  (15 sites) 

RCT  cross-  over 3 mo. 

Pacer  inactive 

67 3 58 29 29 Treatment 

4 

Control 

3 

ELA ChorumTM

7336, Medtronic InSync®

8040 

Transvenous 

6MWT 

Leclercq7

2002a MUSTIC-AF 

Europe  (15 sites) 

RCT  cross-  over 3 mo. 

RV pacing 64 10 43 25 18 Treatment 

1 

Control 

2 

NR Transvenous 

6MWT 

Auricchio82002a PATH-CHF 

Germany, 

Netherlands 

 (5 sites) 

RCT  cross-  over 1 mo. 

Univentric-  ular  pacing  (4 RV,  36 LV) 

42 1 41 24 17 Treatment 

2 

Control 

5 

Guidant 

Vigor®, 

Discovery®

Transthoracic 

O2 uppeak O2 upanaerthresh6MWT 

CHF = congestive heart failure; CRT = cardiac resynchronization therapy; CRT+ICD = CRT with implanted cardioverter defibrillator; LV = 

ventricular ejection fraction; NA = not applicable; NR = not reported; NYHA = New York Heart Association class; O2 = oxygen; OPT = op

= quality of life; RCT = randomized controlled trial; RV = right ventricular; 6MWT = 6-minute walk test; VO2 max = maximal oxygen consu

VT = ventricular tachycardia *The intervention that patients in crossover studies received in the first period 
44

Table 4. Description of studies in the efficacy review: CRT alone or combined CRT-ICD devices (continued) 

Participants 

Author 

Year 

Trial Name 

Country 

Design 

Duration 

Control 

Number 

enrolled 

Number 

excluded 

Number 

randomized 

Number in 

treatment* 

Number in 

Control* 

Number of 

withdrawals Device Method of implant Au

pr

out

Leclercq102003 RD-CHF 

France  (NR) 

RCT  cross-  over 3 mo. 

RV pacing 56 NR 44 22 22 Treatment 

NR 

Control 

NR 

NR Transvenous 

CHF h

pita

Kindermann13 2006 HOBIPACE 

Germany  (1 site) 

RCT  cross-  over 3 mo. 

RV pacing 33 1 32 15 15 Treatment 

0 

Control 

1 

NR Transvenous 

LV en

voluLVEO2

con

Cleland15

2005 CARE-HF 

Europe  (82 sites) 

RCT  parallel 1, 3, 6, 9,  12,18  mo.,  then  every 6  mo. 

OPT NR NR 813 409 404 Treatment 

14 

Control 

14 

Medtronic 

InSync®, 

InSync® III 

Transvenous 

Comp

caumounphostion majeve

St. Jude16

2005 VecTOR 

United States, 

Canada 

 (41 sites) 

RCT  parallel 6 mo. 

Pacer inactive 

144 0 106 59 47 Treatment 

1 

Control 

2 

St. Jude 

Medical Frontier®5508 

NR 

Peak 

Combined CRT-ICD Young6 2003 MIRACLEICD 

United States, 

Canada 

 (53 sites) 

RCT (post  implant)  parallel 6 mo. 

CRT off + ICD on 

639 270 369 187 182 Treatment 

6 

Control 

5 

Medtronic 

InSync® ICD 

Transvenous 

NYHA

6M
45

Table 4. Description of studies in the efficacy review: CRT alone or combined CRT-ICD devices (continued) 

Participants 

Author 

Year 

Trial Name 

Country 

Design 

Duration 

Control 

Number 

enrolled 

Number 

excluded 

Number 

randomized 

Number in 

treatment* 

Number in 

Control* 

Number of 

withdrawals Device Method of implant Au

pr

out

Higgins92003 CONTAK-CD 

United States  (47 sites) 

RCT Phase I  period 1  cross-  over 3  mo.;  Phase II  parallel  6 mo. 

CRT off + ICD on 

581 15 490 245 245 Treatment 

3 

Control 

1 

Guidant 

Contak® CD 

1823 

Transvenous, 

transthoracic 

Morta

hostionreqdevthe

Abraham142004 MIRACLEICD II 

United States  (53 sites) 

RCT  parallel 6 mo. 

CRT off + ICD on 

222 36 186 85 101 Treatment 

3 

Control 

3 

Medtronic 

InSync® ICD 

7272 

NR 

Peak 

St. Jude17

2004a RHYTHM ICD 

United States  (49 sites) 

RCT  parallel 12 mo. 

CRT off + ICD on 

205 1 179 119 59 Treatment 

3 

Control 

0 

St. Jude 

Medical EpicTM HF 

ICD 

NR 

Comp

CRT alone and combined CRT-ICD Bristow11

2004 COMPANION 

United States  (128 sites) 

RCT  parallel  3 arms 15 mo. 

OPT NR NR 1,520 CRT 

= 

617; 

CRT+

ICD = 

595 

308 Treatment 

37 

Control 

42 

Guidant 

Contak® TR models 1241, 4510-4513, Contak® CD 1823 

Transvenous 

All-ca

mohostion 

Auricchio12

2003 PATH-CHF II 

Germany, 

Netherlands 

 (9 sites) 

RCT  cross-  over 3 mo. 

Pacer inactive 

101 NR 86 43 43 Treatment 

5 

Control 

9 

Guidant 

(various models) 

Transvenous, 

thoracotomy 

Exerc

cappea

VO6MW
46

Table 5. Baseline characteristics of patients in trials included in the efficacy review: CRT alone or combined CRT-ICD devices

Author NYHA class Other measures 

Year 

Trial name Study group Males, n (%) Mean age, yr. mean ± SD Ischemic % II, % III, % IV, % 

Atrial 

fibrillation, 

n (%) 

QRS interval, 

msec 

mean ± SD 

CRT alone Abraham CRT 155 (68) 64 ± 11 50 0 90 10 0 167 ± 21 

4 2002 

MIRACLE Control 153 (68) 65 ± 11 58 0 91 9 0 165 ± 20 

CRT first 19 (66) 64 ± 11 NR 0 100 0 NR 172 ± 22 Control first 24 (83) 64 ± 8 NR 0 100 0 NR 175 ± 19 

Cazeau52001MUSTIC-SR 

All 43 (74) 64 ± 9 37 0 100 0 NR 174 ± 20 CRT first 21 (84) 65 ± 9 NR 0 100 0 25 (100) 209 ± 21 Control first 14 (78) 66 ± 9 NR 0 100 0 18 (100) 208 ± 12 

Leclercq72002aMUSTIC-AF 

All 35 (81) 65 ± 8 43 0 100 0 43 (100) 209 ± 18 CRT first 11 (46) 59 ± 7 42 0 88 13 NR 174 ± 30 Control first 10 (59) 60 ± 5 6 0 82 18 NR 178 ± 34 

Auricchio82002a PATH-CHF 

All 21 (50) 60 ± 7 29 0 86 14 NR 175 ± 32 

Leclercq102003 RD-CHF 

CRT NR 73 ± 8 NR 0 III or IV = 100 23 (52) 206 ± 26 

Kindermann13 2006 HOBIPACE 

All 23 (77) 69.6 ± 8.1 17 0 III or IV = 100 12 (37) 174 ± 42 OPT 293 (73) 66 median 

IQR 59-72 

144 0 377 27 0 160 median 

IQR 152-180 

Cleland 

15

2005 CARE-HF CRT+OPT 304 (74) 67 median 

IQR 60-73 

165 0 386 23 0 160 median 

IQR 152-180 

CRT = cardiac resynchronization therapy; ICD = implanted cardioverter defibrillator; IQR = interquartile range; OPT = optimal pharmacolreported 
47

Table 5. Baseline characteristics of patients in trials included in the efficacy review: CRT alone or combined CRT-ICD devices 

Author NYHA class Other measures 

Year 

Trial name Study group Males, n (%) Mean age, yr. mean ± SD Ischemic % II, % III, % IV, % 

Atrial 

fibrillation, 

n (%) 

QRS interval, 

msec 

mean ± SD 

St. Jude16

2005 VecTOR 

All 66 

(62.5) 

67.1 ± 9.7 NR 29 65 6 NR ≥ 140 

Combined CRT-ICDYoung CRT III/IV 142 (76) 67 ± 11 64 0 88 12 NR 165 ± 22 

6 2001

MIRACLE-ICD Control III/IV 141 (78) 68 ± 9 76 0 89 11 NR 162 ± 22 Higgins CRT II-IV 210 (85) 66 ± 11 67 32 60 8 NR 160 ± 27 

9 2003

CONTAK-CD Control II-IV 211 (83) 66 ± 11 70 33 57 10 NR 156 ± 26 Abraham CRT/ICD on 75 (88) 63 ± 12.8 55 100 0 0 NR 166 ± 25 

14 2004 

MIRACLE ICD II Control CRT off 91 (90) 63.1 ± 12.1 58 100 0 0 NR 165 ± 23 St. Jude CRT on NR NR NR 5 87 7 0 169 ± 16 

17 

2004a RHYTHM ICD Control CRT off NR NR NR 7 85 5 0 167 ± 15 CRT alone and combined CRT-ICD

CRT+OPT 415 (67) 67 54 0 87 13 NR 160 CRT+ICD+OPT 401 (67) 66 55 0 86 14 NR 160 

Bristow112004 COMPANION 

OPT 213 (69) 68 59 0 82 18 NR 158 All 57 (66) 60 ± 9 38 II or III = 33 67 16 155 ± 20 Inactive first 27 (63) 58 ± 8 33 II or III = 28 72 7 157 ± 23 

Auricchio12

2003 PATH-CHF II 

Active first 30 (70) 61 ± 9 44 II or III = 37 63 26 154 ± 18 
48

Table 6. Description of studies included in the efficacy review: ICD alone 

 Partcipants 

Author 

Year 

Study name 

Country 

Design Duration Type of outcomes

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

i

Primary prevention Moss133

1996 MADIT 

United States, 

Germany, Italy 

RCT parallel 27mo. Efficacy, safety 

ICD OPT 253 196 95 101 18 Gu

Tra

tra

Bigger134

1997 CABG-Patch 

United States, 

Germany 

RCT parallel 32 mo. Efficacy, safety 

CABG+ ICD 

CABG + usual care 

1,055 900 446 454 70 Gu

Epi

Moss135

2002 MADIT II 

United States, 

Europe 

RCT parallel 20 mo. Efficacy, safety 

ICD OPT NR 1,232 742 490 3 NR 

Tra

Bänsch136

2002 CAT 

Germany RCT parallel 

66 mo. Efficacy, safety 

ICD Usual care 104 104 50 54 0 Gu

V

PP

Tra

DER = defibrillation energy requirement; EPS = electrophysiological study; ICD = implanted cardioverter defibrillator; LV = left ventricular

ejection fraction; NA = not applicable; NR = not reported; OPT = optimal pharmacological therapy; QOL = quality of life; RCT = randomiz

ventricular; VO2 max = maximal oxygen consumption; VA = ventricular arrhythmia; VF = ventricular fibrillation; VT = ventricular tachycard
49

Table 6. Description of studies included in the efficacy review: ICD alone (continued) 

 Partcipants 

Author 

Year 

Study name 

Country 

Design Duration Type of outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

i

Strickberger1372003 AMIOVIRT 

United States RCT parallel 

2 yr. Efficacy 

ICD Amiodarone NR 103 51 52 NR NR 

Tra

Bristow11

2004 COMPANION 

United States RCT parallel 

3 arms 

15 mo. Efficacy, safety 

ICD+CRT CRT 

OPT NR 1,520 CRT 

 = 

617; 

CRT+

ICD 

 = 

595 

308 Treatment 

 = 37 

Control 

 = 42 

Gui

C

T144CC

Tra

Kadish138

2004 DEFINITE 

United States, 

Israel 

RCT parallel 29 mo. Efficacy, safety 

ICD Single chamber 

OPT NR 458 229 229 6 St J

NR 

Hohnloser139

2004 DINAMIT 

Europe, 

Canada, United States 

RCT parallel 30 mo. Efficacy, safety 

ICD Single chamber 

OPT NR 674 332 342 24 St J

NR 

Bardy140 2005 SCD-HeFT 

United States, 

Canada 

RCT parallel 

3 arms 

46 mo. 

(median) 

Efficacy, safety 

ICD single chamber 

Amiodarone, 

placebo 

NR 2,521 829 Amiodarone 

 = 845, 

Placebo 

 = 847 

50 Me

7

NR 
50

Table 6. Description of studies included in the efficacy review: ICD alone (continued) 

 Partcipants 

Author 

Year 

Study name 

Country 

Design Duration Type of outcomes

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

i

Secondary prevention 

Antiarrhythmics vs. Implantable Defibrillators (AVID) Investigators141

1997 AVID 

United States RCT parallel 

18 mo. Efficacy, safety 

ICD Amiodarone 

or Sotalol 

1,885 1,016 505 509 2 Gu

MVSIn

Traepic

Connolly1422000 CIDS 

Canada RCT parallel 

35 mo. Efficacy, safety 

ICD Amiodarone NR 659 328 331 NR NR 

Tra

tho

Kuck1432000 CASH 

Germany RCT parallel 

3 arms 

57 mo. Efficacy, safety 

ICD Metoprolol 

Amiodarone 

293 288 99 Metoprol 

 = 97, 

Amiodarone 

 = 92 

NR Gui

V

AVAVPVPVM

Epi

eia
51

Table 7. Baseline characteristics of patients in trials included in the efficacy review: ICD alone 

Author NYHA class Other measures 

Year 

Trial name Study group Males n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % 

Atrial 

fibrillation, 

% 

QRS 

interval, 

msec 

mean ± SD

 , % 

Primary prevention 

Moss ICD 87 (92) 62 ± 9 34 II or III = 63 0 NR NR 27 ± 7 

133

1996 MADIT CMT 93 (92) 64 ± 9 29 II or III = 67 0 NR NR 25 ± 7 

CABG+ICD 386 

(86.5) 

64 ± 9 100 II or III = 71 NR NR 71% ≥ 100 

msec 

Bigger 27 ± 6 

134 

1997 CABG PATCH 

CABG 373 

(82.2) 

63 ± 9 100 II or III = 74 NR NR 74% 

≥100 msec

27 ± 6 

ICD 623 (84) 64 ± 10 100 35 25 5 9 50% ≥120 msec 23 ± 5 

Moss135 2002 

MADIT II CMT 417 (85) 65 ± 10 100 34 23 4 8 51% ≥120 msec 23 ± 6 

All 83 (79.8) 52 ± 11 0 65.3 34.6 0 15.76 108 ± 29 24 ± 7 ICD 43 (86) 52 ± 12 0 66.7 33.3 0 20.4 102 ± 29 24 ± 6 

Bänsch136 

2002 CAT 

Control 40 (74) 52 ± 10 0 64.1 35.8 0 11.3 114 ± 29 25 ± 8 

All 72 (69.9) 59 ± 11 0 64 19.4 0 NR NR 22 ± 9 ICD 34 (67) 58 ± 11 0 64 16 0 NR NR 22 ± 10 

Strickberger137 2003 

AMIOVIRT 

Amiodarone 38 (74) 60 ± 12 0 63 24 0 NR NR 23 ± 8 CRT + OPT 413 (67) Median 

67 

54 Exc 87 13 NR ≥120 msec Median 

20 

CRT+ICD +OPT 

399 (67) Median 

66 

55 Exc 86 14 NR ≥120 msec Median 

22 

Bristow11 2004 COMPANION 

OPT only 213 (69) Median 

68 

59 Exc 82 18 NR ≥120 msec Median 

22 

CRT = cardiac resyncrhonization therapy; ICD = implanted cardioverter defibrillator; NR = not reported; OPT optimal pharmac

therapy 
52

Table 7. Baseline characteristics of patients in trials included in the efficacy review: ICD alone (continued) 

Author NYHA class Other measures 

Year 

Trial name Study group Males n (%) Age, yr. Mean ± SD Ischemic, % II, % III, % IV, % 

Atrial 

fibrillation, 

% 

QRS 

interval, 

msec 

mean ± SD

LVEF, % 

All 326 

(71.2) 

58 

range 20-84 

0 57.4 21 0 24.5 115.1 

range 

78-196 

21.4 

range 

 7-35 

ICD 166 

(72.5) 

58 

range 20-84 

0 54.2 20.5 0 22.7 114.7 

range 

78-196 

20.9 

range 

7-35 

Kadish138 

2004 DEFINITE 

Control 160 

(69.9) 

58 

range 22-

79 

0 60.7 21.4 0 26.2 115.5 

range 

79-192 

21.8 

range 10-35 

ICD 252 

(75.9) 

61.5 ± 

10.9 

Hohnloser 100 NR NR 0 NR 107 ± 24 28 ± 5 

139 

2004 DINAMIT 

Control 262 

(76.6) 

62.1 ± 

10.6 

100 NR NR 0 NR 105 ± 23 28 ± 5 

ICD 

639 (76) 60 

Median 

IQR 

52-69 

52 71 29 0 16 NR 25 

median 

Amiodarone 

639 (77) 60 

Median 

IQR 

52-68 

50 70 30 0 17 NR 25 

median 

Bardy140 2005 SCD-HeFT 

Placebo 

655 (77) 59.7 

Median 

IQR 

51-68 

53 68 32 0 14 NR 25 

median 
53

Table 7. Baseline characteristics of patients in trials included in the efficacy review: ICD alone (continued) 

Author NYHA class Other measures 

Year 

Trial name Study group Males n (%) Age, yr. Mean ± SD Ischemic, % II, % III, % IV, % 

Atrial 

fibrillation, 

% 

QRS 

interval, 

msec 

mean ± SD

LVEF, % 

Secondary prevention 

ICD 395 (78) 65 ± 11 81 I or II = 48 7 0 21 116 ± 26 32 ± 13 

AVID Investigators141

1997 

AVID 

Antiarrhythmics 412 (81) 65 ± 10 81 I or II = 48 12 0 26 117 ± 26 31 ± 13 ICD 280 (85.4) 63.3 ± 9.2 82.2 I or II = 37.8 III or IV = 11.0 NR NR 34.3 ± 14.5 Connolly 

142 2000 

CIDS Amiodarone 277 (83.7) 63.8 ± 9.9 82.9 I or II = 39.9 III or IV = 10.6 NR NR 33.3 ± 14.1 Kuck ICD 78 (79) 58 ± 11 73 59 18 0 NR NR 46 ± 19 

143 2000 

CASH Antiarrhythm- ics 152 (80) 57.5 ± 10 73.5 56 16 0 NR NR 46 ± 17 
54

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Met

im

CRT aloneAbraham4

2002 MIRACLE 

United States, 

Canada 

RCT parallel 6 mo. Efficacy, safety 

CRT Pacer 

inactive 

571 453 228 225 9 Medtron

InSyn

Transve

Achilli18

2003 

Italy Prospective 

cohort 

6 mo. Effectiveness 

CRT NA 52 NA 52 NA 0 NR 

Transve

Adamson19

2004 InSync III 

United States Prospective 

cohort 

12 mo. Effectiveness 

CRT NA 397 NA 288 NA 0 Medtron

InSyn

8042 

NR 

Albertsen20

2005 

Denmark Prospective 

cohort 

16.7 mo. Effectiveness, 

safety 

CRT NA 120 NA 114 NA 0 Guidan

MedtInSyn

8042 

NR 

Ansalone23

2002 

Italy Prospective 

cohort 

1 mo. Effectiveness 

CRT NA 31 NA 31 NA 0 NR 

CCT = controlled clinical trial; CHR = congestive heart failure; CRT = cardiac resynchronization therapy; CRT+ICD = CRT with implanted ventricular; LVEF = left ventricular ejection fraction; NA = not applicable; NR = not reported; NYHA = New York Heart Association class; 

pharmacological therapy; QOL = quality of life; RCT = randomized control trial; RV = right ventricular; 6MWT = 6-minute walk test; VO2 m

VT = ventricular tachycardia *The intervention that patients in crossover studies received in the first period 
55

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Aranda24

2005 

United States Retrospective 

cohort 

6 mo. Effectiveness 

CRT NA 60 NA 52 NA 0 NR 

Auricchio8 2002a PATH-CHF 

Germany, 

Netherlands 

RCT crossover 1 mo. Efficacy, safety 

CRT Univentric- 

 ular  pacing  (4 RV,  36 LV) 

42 41 24 17 7 Guidant 

Disco

Transth

Auricchio25 2002b 

Germany Retrospective 

cohort 

3 mo. Effectiveness 

CRT NA 135 NA 50 NA 0 NR 

Transve

thorac

Baker27

2002 

United States Prospective 

cohort 

18 mo. Effectiveness, 

safety 

CRT NA 60 NA 60 NA 6 NR 

Transve

Bax282003 

Netherlands Prospective 

cohort 

6 mo. Effectiveness 

CRT NA 25 NA 25 NA 0 NR 

Bleeker30

2005a 

Netherlands Prospective 

cohort 

6 mo. Effectiveness,  safety 

CRT NA 170 NA 170 NA NR Guidant 

TR, C

CD; MInSynInSyn

Transve

Bleeker31

2005b 

Netherlands Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT NA 56 NA 56 NA 0 Contak® 

CD 

Transve
56

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Bleeker32

2006 

Netherlands Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT NA 100 NA 100 NA 0 Guidant 

TR, R

TR2/1MedtrInSyn

Marqu

Sentry 

Transve

Bonanno34 2004 

Italy Prospective 

cohort 

8.2 mo. Effectiveness 

CRT NA 37 NA 37 NA Medtron

InSyn

8042, ICD® 

Transve

Bordachar35

2004 

France Prospective 

cohort 

3 mo. Effectiveness, 

safety 

CRT NA 41 NA 41 NA 0 Medtron

InSyn

Transve

Boriani38

2006c 

Italy Prospective 

cohort 

3 mo. Effectiveness 

CRT NA 32 NA 32 NA 0 NR 

Braunschweig40

2005 

Europe Prospective 

cohort 

3 mo. Effectiveness 

CRT NA 56 NA 56 NA 0 Medtron

InSyn

8042 

Transve

Cazeau5

2001 MUSTIC-SR 

Europe RCT crossover 

3 mo. Efficacy, safety 

CRT Pacer 

inactive 

67 58 29 29 7 ELA Ch

7336; MedtrInSyn

Transve
57

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Cazeau41

2003 

France Prospective 

cohort 

NR Effectiveness, 

safety 

CRT NA 66 NA 66 NA 0 NR 

Transve

Chalil422006 

United Kingdom 

Prospective 

cohort 

2.2 yr Effectiveness, 

safety 

CRT NA 75 NA 75 NA 0 Medtron

InSyn

8042, 

8040, Sigma 

Transve

Chan43

2003 

Italy, Canada Prospective 

cohort 

3 mo. Effectiveness 

CRT NA 95 NA 95 NA 0 NR 

Cleland15

2005 CARE-HF 

Europe RCT parallel1, 

3, 6, 9, 12, 18 mo., then every 6 mo. 

Efficacy, safety 

CRT OPT NR 813 409 404 64 Medtron

InSynInSyn

Transve

Daubert461998 

France Prospective 

cohort 

10.2 mo. Effectiveness, 

safety 

CRT NA 47 NA 47 NA 10 ELA Ch

RM 7Choru

Transve

de Cock124 2004 

Netherlands Prospective 

cohort 

3 mo. Safety 

CRT NA 103 NA 103 NA 0 NR 

De Martino125

2004 

Italy Prospective 

cohort 

< 1 mo. Safety 

CRT NA 34 34 34 NA 0 NR 

Transve
58

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

De Martino126

2005 

Italy Prospective 

cohort 

< 1 mo. Safety 

CRT NA 83 83 83 NA NR NR 

Dixon50

2004 

United Kingdom 

Prospective 

cohort 

12 mo. Effectiveness,  safety 

CRT NA 27 NA 27 NA 0 NR 

Galvao56

2002 

Brazil Prospective 

cohort 

5 mo. Effectiveness, 

safety 

CRT NA 28 NA 28 NA 0 NR 

Transve

minithorac

Gras58

2002 InSync 

Europe, 

Canada 

Prospective 

cohort 

up to 1 yr. Effectiveness, 

safety 

CRT NA 117 NA 103 NA NR Medtron

InSyn

Transve

Hua60

2006 

China Prospective 

cohort 

7 days Effectiveness, 

safety 

CRT NA 142 NA 142 NA 0 Medtron

 2188  4189  4193

ELA UBiotronSt Jud

Kautzner128

2004 

Czechoslovakia Retrospective 

cohort 

24 mo. Safety 

CRT NA 138 NA 138 NA 0 NR 

Transve
59

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Kies62

2006 

Netherlands Retrospective 

cohort 

6 mo. Effectiveness 

CRT NA 74 NA 74 NA 0 InSync® 

MedtroContak

TR/ReGuidan

Transve

Kindermann13 2006 HOBIPACE 

Germany RCT crossover 

3 mo. Efficacy, safety 

CRT RV pacing 33 32 15 15 1 CRT (tri

dual c

Transve

Koos632004 

Germany Retrospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT NA 81 NA 52 NA 7 NR 

Transve

thorac

Leclercq662000 

Europe 

(15 sites) 

Prospective 

cohort 

1, 2, 6 mo., 

then every 6 mo. 

Effectiveness, 

safety 

CRT NA 37 NA 37 NA 0 Medtron

(variomode

Transve

transt

Leclercq7 2002a MUSTIC-AF 

France RCT crossover 

3 mo. Efficacy, safety 

CRT RV pacing 64 43 25 18 5 NR 

Transve

Leclercq67 2002b 

France Prospective 

cohort 

1, 3, 6, then 

every 6 mo. 

Effectiveness, 

safety 

CRT NA NR NA 125 NA NR NR 

Transve

Leclercq102003 RD-CHF 

France RCT crossover 

3 mo. Efficacy, safety 

CRT RV pacing 56 44 22 22 NR NR 

Transve
60

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Lecoq68

2005 

France Retrospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT NA 158 NA 139 NA 0 ELA Ch

MSP; Conta

MedtrInSyn

Transve

Leon70

2005 

United States Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT NA 422 NA 359 NA InSync® 

MedtronTransve

Lindner71

2005 

Germany Prospective 

cohort 

4 mo. Effectiveness 

CRT NA NR NA 42 NA 0 NR 

Macioce72

2005 

Italy Prospective 

cohort 

6 mo. Effectiveness 

CRT NA 30 NA 30 NA 0 Guidant 

TR CMedtrInSyn

Transve

Mangiavacchi74

2006 

Italy Prospective 

cohort 

1 yr. Effectiveness 

CRT NA 156 NA 156 NA NR 

Marai752006 

Isreal Prospective 

cohort 

3 mo. Effectiveness 

CRT NA 98 NA 98 NA 0 NR 

Transve

Mascioli76

2002 

Italy Prospective 

cohort 

36 mo. Effectiveness, 

safety 

CRT NA 96 NA 68 NA 0 NR 

Transve
61

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Mele77

2006 

Italy Prospective 

cohort 

6 mo. Effectiveness 

CRT NA 37 NA 37 NA 1 Easytra

Guida

Transve

Molhoek782002 

Netherlands Prospective 

cohort 

up to 2 yr. Effectiveness, 

safety 

CRT NA 40 NA 40 NA 0 Guidant 

TR, C

CD; MInSyn

Transve

Mortensen83

2004 InSync III 

Europe, 

Canada 

Prospective 

cohort 

3 mo. Effectiveness, 

safety 

CRT NA 198 NA 189 NA 15 Medtron

InSyn

8042 

Transve

Nagele85

2001 

Germany Prospective 

cohort 

8 mo. Effectiveness, 

safety 

CRT NA 32 NA 32 NA 0 Biotroni

DR; EChoru

MST; Conta

Transve

Niu872006 

China Prospective 

cohort 

1.7 yr Effectiveness, 

safety 

CRT NA 117 NA 111 NA 6 Medtron

InSyn

8042 

Transve

O’Donnell89

2005 

Australia Prospective 

cohort 

9 mo Effectiveness, 

safety 

CRT NA 63 NA 40 NA 0 Medtron

InSynIII,InS

Marqu

Transve

Oliva902005 

Italy Prospective 

cohort 

20 mo. Effectiveness 

CRT NA 258 NA 258 NA 0 NR 
62

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Ollitrault91

2003 

France Prospective 

cohort 

15 mo. Effectiveness, 

safety 

CRT NA 62 NA 62 NA 0 NR 

Penicka932004 

Belgium Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT NA 55 NA 49 NA 0 Guidant 

TR, C

CD 

Transve

Porciani95

2006a 

Italy Prospective 

cohort 

6 mo. Effectiveness 

CRT NA 30 NA 30 NA 0 Medtron

InSynnt Co

CHFD 

Transve

Porciani96

2006b 

Italy Prospective 

cohort 

1 yr Effectiveness 

CRT NA 65 NA 65 NA 0 NR 

Puglisi97

2004 

Italy Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT NA 315 NA 315 NA 0 NR 

Transve

Thora

Reuter992000 

France Prospective 

cohort 

8 mo. Effectiveness 

CRT NA 47 NA 47 NA 0 NR 

Transve

Ricci1012002 

Italy Prospective 

cohort 

8.8 mo. Effectiveness 

CRT NA 48 NA 48 NA NR Medtron

Transve
63

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

RomeyerBouchard131

2005 

France Prospective 

cohort 

8 mo. Safety 

CRT NA 103 NA 99 (CRT 

= 94, 

CRT+ICD 

= 5) 

NA 0 Medtron

InSyn

InSynInSynMarqu

InSyn

Transve

Sawhney105

2004 

United States Prospective 

cohort 

3 mo. Effectiveness, 

safety 

CRT NA 40 NA 40 NA NR NR 

Transve

Schuchert1322004 

Germany, 

United Kingdom 

Prospective 

cohort 

24 mo. Safety 

CRT NA 102 NA 102 NA 0 St. Jude 

Affinit

Fronti

Transve

Sogaard107

2002 

Denmark Prospective 

cohort 

12 mo. Effectiveness 

CRT NA 25 NA 25 NA 0 Medtron

InSyn

Transve

Stahlberg108

2005 

Sweden Prospective 

cohort 

36 mo. Effectiveness, 

safety 

CRT NA 40 NA 40 NA 0 ELA Ch

TalenMedtrInSynTheraSt. JuMedicFronti

Affinit

Transve

St. Jude16

2005 VecTOR 

United States, Canada 

RCT parallel 6 mo. Efficacy, safety 

CRT Pacer 

inactive 

144 106 59 47 3 St. Jude 

Fronti

NR 
64

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Taieb1092002 

France Retrospective 

cohort 

16.7 mo. Effectiveness,  safety 

CRT NA 50 NA 50 NA 0 NR 

Transve

Tedrow110

2006 

United States Retrospective 

cohort 

4 yr Effectiveness 

CRT NA 75 NA 75 NA 0 NR 

Toussaint113

2003 

France Prospective 

cohort 

20 mo. Effectiveness, 

safety 

CRT NA 34 NA 34 NA 0 NR 

Transve

Witte116

2006 

Canada Prospective 

cohort 

4 mo. Effectiveness 

CRT NA 71 NA 71 NA o NR 

Transve

Yu1182002a 

Hong Kong Prospective 

cohort 

4 mo. Effectiveness, 

safety 

CRT NA 25 NA 25 NA 0 Guidant 

TR, C

CD; MInSyn

Transve

Yu1192002b 

Hong Kong Prospective 

cohort 

3 mo. Effectiveness 

CRT NA 30 NA 30 NA 0 Guidant 

TR 12MedtrInSyn

Transve

Yu1212005 

Hong Kong Prospective 

cohort 

24 mo. Effectiveness 

CRT NA 141 NA 141 NA 2 NR 

Transve
65

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Zhang122

2006 

Switzerland Prospective 

cohort 

3 mo. Effectiveness 

CRT NA 50 NA 50 NA 0 Medtron

InSyn

InSyn

InSyn

GuidaConta

Conta

NR 

Combined CRT-ICD Abraham142004 MIRACLE-ICD II 

United States RCT parallel 

6 mo. Efficacy, safety 

CRT on + ICD on 

CRT off + ICD on 

222 186 85 101 6 Medtron

InSy

7272 

NR 

Boriani36

2006a 

Europe Prospective 

cohort 

6 mo Effectiveness 

CRT+ICD NA 127 NA 121 NA 3 St..Jude 

V-339 

CRT-

NR 

Chugh1232005 

United States Retrospective 

cohort 

≤3 yr. Safety 

CRT+ICD NA 77 NA 77 NA 0 Guidant 

CD 18MedtrGem Marqu

Transve

Gasparini127

2005 

Italy Prospective 

cohort 

2 mo. Safety 

CRT+ICD NA 194 NA 194 NA NR 

Transve
66

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Higgins92003 CONTAK-CD 

United States RCT 

Phase I period 

1 of X-over 3 mo.; phase II parallel 6 mo. 

Efficacy, safety 

CRT+ICD CRT off + 

ICD on 

581 490 245 245 4 Guidant 

CD 18

Transve

transt

Kuhlkamp65

2002 

Germany Prospective 

cohort 

3 mo. Effectiveness, 

safety 

CRT+ICD NA 84 NA 81 NA NR Medtron

InSyn

Transve

Murphy84

2006 

United States Prospective 

cohort 

6 mo. Effectiveness 

CRT+ICD NA 54 NA 54 NA 0 NR 

Transve

epica

Ritter102

2006 

Germany Retrospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT+ICD NA 48 NA 48 NA 0 Guidant 

Renew

Transve

Saxon106

2006 

United States Prospective 

cohort 

9 mo Effectiveness, 

safety 

CRT+ICD NA 170 NA 168 NA 0 Guidant 

Renew

Transve

St. Jude17

2004a RHYTHM ICD 

United States RCT parallel 

12 mo. Efficacy, safety 

CRT+ICD CRT off + 

ICD on 

205 179 119 59 3 St. Jude 

EpicTM 

NR 
67

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

St. Jude17

2004b RHYTHM ICD QuickSite 

United States Prospective 

cohort 

NR Effectiveness,  safety 

CRT+ICD NA 162 NA 162 NA NR St. Jude 

Quick

ModeLV leaICD/Csystem 

NR 

Theuns112

2005 

Netherlands Prospective 

cohort 

21 mo. Effectiveness, 

safety 

CRT+ICD NA 86 NA 86 NA NR Guidant 

CD, Renew

RenewMedtrInSyn

7279; Medic

HF 

NR 

Young62003 MIRACLE-ICD 

United States, 

Canada (53 sites) 

RCT (post 

implant) parallel 

6 mo. Efficacy, safety 

CRT+ICD Pacer 

inactive 

639 369 187 182 11 Medtron

InSyn

Transve

Ypenburg117

2006 

Netherlands Prospective 

cohort 2 yr Effectiveness, 

safety 

CRT+ICD NA 195 NA 191 NA 3 CONTA

RENEWAVT Guidant Transve
68

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

CRT alone or combined CRT-ICD Alonso211999 

France Retrospective 

cohort 

12 mo. Effectiveness 

CRT, CRT+ICD 

NA 26 NA 26 (CRT 

= 20, 

CRT+ICD 

= 6) 

NA 0 NR 

Transve

Ammann222004 

Switzerland Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 47 NA 43 (CRT 

= 19, 

CRT+ICD 

= 24) 

NA 0 NR 

Transve

Auricchio12

2003 PATH-CHF II 

Germany, 

Netherlands 

RCT crossover 3 mo. Efficacy, safety 

CRT, CRT+ICD 

Pacer inactive 

101 86 43 43 14 NR 

Transve

thorac

Azizi26

2006 

Germany Retrospective 

cohort 

6 yr. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 244 NA 244 NA 0 Biotroni

MedicGuidaMedtrJude Vitatro

Transve

Bax292004 

Netherlands Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 85 NA 85 (CRT 

= 37, 

CRT+ICD 

= 48) 

NA 0 Guidant 

TR, CCD, CRenew

MedtrInSyn

InSyn

Transve

Bocchiardo332000 

Italy Prospective 

cohort 

22 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 51 NA 48 NA 0 Guidant 

CD; MInSyn

Transve
69

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Boriani37

2006b 

Italy (InSync ICD Registry) 

Prospective 

cohort 

4.yr. Effectiveness 

CRT, CRT+ICD 

NA 421 NA CRT = 

227CRTICD = 

194 

NA 0 Medtron

InSync®NR 

Braun39

2005 

Germany CCT 

24 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

ODT 124 NA 65 (CRT 

= 38, 

CRT+ICD 

= 27 

57 0 Biotroni

DeikoGuidaConta

ContaMedtrInSyn

InSyn

Transve

Bristow11

2004 COMPANION 

United States RCT parallel, 3 

arms 

15 mo. Efficacy, safety 

CRT + OPT, CRT+ICD + OPT 

OPT NR 1,520 CRT = 

617CRTICD = 

595 

308 159 Guidant 

TR 124510-Conta

1823 

Transve

Cowburn442005 

Canada Retrospective 

cohort 

3 yr. Effectiveness, safety 

CRT, CRT+ICD 

NA 68 NA 68 NA 0 NR 

Transve

Da Costa45

2006 

France Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 71 NA 67 NA 0 Medtron

InSyn

InSyn

InSynInSyn

Marqu
70

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Davis472005 

Canada Retrospective 

cohort 

36 mo. Effectiveness 

CRT, CRT+ICD 

NA 85 NA 85 (CRT 

= 67, 

CRT+ICD 

= 18) 

NA NR Guidant 

TR 12MedtrInSyn

8042 

Transve

De Sisti48

2005 

France Retrospective 

cohort 6 mo. Effectiveness 

CRT, CRT+ICD 

NA 102 NA 102 NA 0 Various 

Transve

Diaz-Infante49

2005 

Spain Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 197 NA 143 (CRT 

= 90, 

CRT+ICD 

= 53) 

NA 0 NR 

Transve

Duncan51

2006 

United Kingdom 

Retrospective 

cohort 

6 mo. Effectiveness 

CRT or CRT+ICD 

NA 39 NA 39 NA 0 Guidant 

TR CConta

CHFDRenewMedtrInSyn

8040, ICD 7

NR 

Ellery522005 

Austria, Brazil, 

France, Germany, Hungary, Italy, Netherlands, United Kingdom 

Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 96 NA 85 (CRT 

= 71, 

CRT+ICD 

= 14) 

NA NR NR 
71

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Ermis532004 

United States Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

CRT 158 NA 126 (CRT 

= 62, 

CRT+ICD 

= 64) 

NA 0 NR 

Fung542005 

Hong Kong Prospective 

cohort 

36 mo. Effectiveness 

CRT, CRT+ICD 

NA 53 NA 36 36 0 Guidant 

TR MInSyn

InSyn

Transve

Gaita55

2000 

Italy Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

 96 NA 96 (CRT 

= 29, 

CRT+ICD 

= 67) 

NA 0 NR 

Gasparini572003a 

Italy Prospective 

cohort 

11 mo. 

(median) 

Effectiveness, 

safety 

CRT, CRT+ICD 

NA 159 NA 158 (CRT 

= 102 

CRT+ICD 

= 56) 

NA 0 NR 

Hernandez59 2004 

Spain Prospective 

cohort 

10 mo. Effectiveness 

CRT, CRT+ICD 

NA 28 NA 28 (CRT 

= 16, 

CRT+ICD 

= 12) 

NA 0 NR 

Transve

Kies61

2005 

Netherlands Prospective 

cohort 

18 mo. Effectiveness 

CRT, CRT+ICD 

NA 97 NA 97 (CRT 

= 45, 

CRT+ICD 

= 52) 

NA 0 Guidant 

TR, C

Renew

CD; MInSyn

InSyn

Transve
72

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Krahn64

2002 

Canada Prospective 

cohort 

1, 3, 6 mo., 

then every 6 mo. 

Effectiveness, safety 

CRT, CRT+ICD 

NA 45 NA 40 NA NR Guidant 

TM, C

CD; MInSyn

pacemICD 

Transve

Lenom692005 

France Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 36 NA 36 

(CRT = 

28, 

CRT+ICD 

= 7) 

NA 2 Guidant 

TR 12Conta

MedtrInSyn

Renew

InSyn

Transve

LewickaNowak129

2005 

Poland Retrospective 

cohort 

48 mo. Safety 

CRT, CRT+ICD 

NA 92 NA 92 

(CRT = 

70, 

CRT+ICD 

= 20) 

NA 0 Biotroni

LV 41

NR 

Mair73

2005 

Germany, 

Belgium 

CCT 16.4 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 86 NA 86 (CRT 

= 53, 

CRT+ICD 

= 33) 

NA 0 Guidant 

TR Re

Conta

MedtrInSyn

8042, ICD, I

Marqu

7289 

Transve

epica
73

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Molhoek79 2004a 

Netherlands Prospective 

cohort 

6 mo. Effectiveness 

CRT, CRT+ICD 

NA NR NA 60 (CRT 

= 32, 

CRT+ICD 

= 28) 

NA 0 Guidant 

TR, C

Renew

CD; MInSyn

InSyn

Transve

Molhoek80 2004b 

Netherlands Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 74 NA 74 (CRT 

= 40, 

CRT+ICD 

= 34) 

NA 0 Guidant 

TR, C

CD, C

Renew

MedtrInSyn

InSyn

Transve

Molhoek81 2004c 

Netherlands Prospective 

cohort 

6 mo. Effectiveness 

CRT, CRT+ICD 

NA 61 NA 61 (CRT 

= 33, 

CRT+ICD 

= 28) 

NA 0 Guidant 

TR, C

®CD; 

MedtrInSyn

InSyn

Transve

Molhoek822005 

Netherlands Prospective 

cohort 

up to 3 yr. Effectiveness, 

safety 

CRT, CRT+ICD 

NA NR NA 125 (CRT 

= 42, 

CRT+ICD 

= 83) 

NA 0 Guidant 

TR, C

CD; MInSynInSyn

Transve

Navia86

2005 

United States Prospective 

cohort 

9 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 41 NA 41 (CRT 

= 13, 

CRT+ICD 

= 28) 

NA 0 NR 

Minithor

endos
74

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Notabartolo88

2004 

United States Prospective 

cohort 

3 mo. Effectiveness 

CRT, CRT+ICD 

NA 66 NA 49 NA 12 Guidant 

H135MedtrInSyn

InSyn

Transve

Pappone92

2003 

Italy Prospective 

cohort 

28 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

 135 NA 135 (CRT 

= 47, 

CRT+ICD 

= 88) 

NA 0 NR 

Pitzalis94

2005 

Italy Prospective 

cohort 

14 mo. (median) Effectiveness, 

safety 

CRT, CRT+ICD 

NA 72 NA 72 (CRT 

= 42, 

CRT+ICD 

= 30) 

NA 12 Guidant 

TR CConta

CHFDContaRenew

MedtrInSyn

InSynInSynMarqu

Jude EpicTM 

339 

Transve

Pürerfellner130

2000a 

Europe Retrospective 

cohort 

6 mo Safety 

CRT, CRT+ICD 

NA 47 NA 47 NA 0 Guidant 

TR, H

Transve

Pürerfellner130

2000b 

Europe Registry data 

6 mo Safety 

CRT, CRT+ICD 

NA 150 NA 150 NA 0 Guidant 

TR, H

Transve
75

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Purnode982004 

France Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 43 NA 43 (CRT 

= 37, 

CRT+ICD 

= 6) 

NA 0 ELA Ch

7336; Conta

ContaRenew

H135MedtrInSyn

InSynSt. JuMedicTrilog

Affinit

Transve

Reuter100

2002 

France Prospective 

cohort 

12 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 102 NA 102 (CRT 

= 93, 

CRT+ICD 

= 9) 

NA 11 ELA Ch

7336 MedtrInSynInSyn

Transve

Rossillo103

2004 

United States, 

Italy 

Prospective 

cohort 

18 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 244 NA 233 (CRT 

= 68, 

CRT+ICD 

= 165) 

NA 0 NR 

Salukhe104

2005 

United 

Kingdom 

Prospective 

cohort 

6 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 43 NA 40 (CRT 

= 20, 

CRT+ICD 

= 20) 

NA 0 NR 
76

Table 8. Description of studies in the effectiveness and safety reviews: CRT alone or combined CRT-ICD devices (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment* 

Number in 

control* 

 Number of 

withdrawals De

Meth

imp

Teo1112003 

Singapore, 

Indonesia, Thailand 

Prospective 

cohort 

up to 28 mo. Effectiveness, 

safety 

CRT, CRT+ICD 

NA 29 NA 29 (CRT 

= 24, 

CRT+ICD 

= 5) 

NA 0 Guidant 

TR, CMedtrInSyn

InSyn

Transve

Vidal1142006 

Spain Prospective 

cohort 12 mo. Effectiveness 

CRT, CRT+ICD 

NA 64 NA 64 NA 0 Contak® 

Conta

RenewRenewGuida

Waggoner115

2006 

United States Prospective 

cohort Effectiveness 

CRT, CRT+ICD 

NA 57 NA 57 NA 0 NR 

Transve

Yu1202004 

Hong Kong Prospective 

cohort 

3 mo. Effectiveness 

CRT, CRT+ICD 

NA NR NA 58 (CRT 

= 54, 

CRT+ICD 

= 4) 

NA 0 Guidant 

CD, C

TR; MInSyn

InSynInSyn

Transve
77

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) Age, yr. Mean ± SD Ischemic % II, % III, % IV, % Atrial fibrillation 

% 

QRS inter

msec 

mean ± S

CRT alone Abraham CRT 155 (68) 64 ± 11 50 0 90 10 0 167 ± 2

4

2002 MIRACLE Control 153 (68) 65 ± 11 58 0 91 9 NR 165 ± 2Achilli182003 

All 31 (60) 69.6 ± 9 40 0 III or IV = 100 0 152.6 ± 3

Adamson192004 InSync III 

All 169 (58.7) 65.8 ± 11.3 47 0 96 4 0 164.9 ± 2

Albertsen20 2005 

All 94 (78.3) 62 (4-8) 52 22 69 8 NR NR 

Ansalone232002 

All NR NR 0 0 III or IV = 100 NR 160.3 ± 2

Aranda242005 

All 30 (58) 63 ± 10 52 NR NR NR NR NR 

Auricchio8 2002a PATH-CHF 

All 21 (50) 60 ± 7 29 0 86 14 0 175 ± 3

Auricchio25 2002b 

All 33 (66) 60 ± 9 40 II or III = 32 67 0 163 ± 2

Baker272002 

All 50 (83) 70 ± 12 57 0 57 43 NR NR 

Bax282003 

All 22 (88) 62 ± 9 44 0 76 24 NR 185 ± 3< 70 80 (78) 59 ± 9 48 0 81 19 NR 175 ± 2> 70 57(84) 76 ± 4 66 0 85 15 NR 171 ± 2

Bleeker302005a 

All 137 (80.6) 66 ± 11 55 0 83 17 NR 173 ± 2

CRT = cardiac resynchronization therapy; ICD = implanted cardioverter defibrillator; IQR = interquartile range; NR = not reported 
78

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

Bleeker312005b 

All 44 (78.6) 64 ± 11 52 0 89 11 13 176 ± 3NYHA II 47 (94) 65 ± 10 58 100 0 0 16 160 ± 3NYHA III-IV 41 (82) 66 ± 11 56 0 86 14 12 168 ± 2

Bleeker322006 

All 88 (88) 65.5 ± 10.5 57 50 43 7 14 164 ± 2

Bonanno342004 

All 32 (86.5) 73 ± 7 51 0 III or IV = 100 30 189.1 ± 3

Bordachar352004 

All 33 (80) 69 ± 6.5 56 0 III or IV = 100 0 170 ± 3

Boriani382006c 

All 22 (68.8) 65 median 

(61-74) 

53 0 87.5 12.5 NR 168 med

(142-18

Braunschweig402005 

All 46 (82.1) 65 ± 11 55 20 66 14 0 170 ± 2

Cazeau52001 MUSTIC-SR 

All 50 (75) 63 ± 10 37 0 100 0 NR 1764 ± 

Cazeau412003 

All NR NR 35 0 86 14 27 182 ± 3

Chalil422006 

All 58 (77) 67.8 ± 12.1 71 0 61 39 25 156.9 ± 2

Chan432003 

All 49 (78) 68.8 47 0 III or IV = 100 NR 182 ± 3OPT 293 (73) 66 median 

(59-72) 

36 0 93 7 0 160 median

152-18

Cleland152005 CARE-HF CRT + OPT 39 (74) 67 median 

(60-73) 

40 0 94 6 0 160 median

152-18

Daubert461998 

All 42 (91) 68 ± 9 53 0 13 87 NR 187 ± 2

De Martino1252004 

All NR NR NR 0 III or IV = 100 NR ≥ 120 m

De Martino1262005 

All NR 61.5 ± 6.5 50 0 III or IV = 100 NR ≥ 120 m
79

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

Dixon502004 

All 24 (89) 64 ± 9 52 0 III or IV = 100 NR 177 ± 2

Galvao562002 

All 23 (82.1) 58.5 

(36, 84) 

46 0 43 57 NR 187 ± 18

Gras582002 

All 81 (78.6) 67 ± 10 48 0 68 32 NR 178 ± 2

Hua602006 

All 91 (64) 60 ± NR 31 0 III or IV = 100 NR 146.7 ± N

Kautzner1282004 

All 116 (84) 61 ± 8 NR 0 III or IV = 100 NR ≥150m

Kies622006 

All 67 (90.5) 68 ± 8 43 0 82 18 100 176 ± 

Kindermann13 2006 HOBIPACE 

All 23 (77) 69.6 ± 8.1 57 NR NR NR 37 174 ± 4

Koos632004 

All 52 (64.2) 65.4 ± 12.3 47 NR NR NR NR 165.8 ± 2

Leclercq662000 

All 34 (92) 67.4 ± 7.2 38 0 70 30 41 181 ± 2

Leclercq7 2002a MUSTIC-AF 

All 35 (81) 65 ± 8 43 0 100 0 100 209 ± 1

Leclercq67 2002b 

All 81 (79) 67 ± 11 47 0 70 30 NR 177.9 ± 2

Leclercq102003 RD-CHF 

All NR 73 ± 8 NR 0 III or IV = 100 23 206 ± 2

Lecoq682005 

All 113 (81) 68 ± 9 35 0 69 31 32 188 ± 2

Leon702005 

All 211 (58.8) 65.8 ± 10.8 46.2 0 91.6 8.4 89.7 163.9 ± 2

Lindner712005 

All NR 62 ± 8.4 26 0 100 0 2 185.1 ± 1

Macioce722005 

All 26 (86.7) 74.1 ± 6.1 47 0 III or IV = 100 NR 140 ± 1
80

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

Mangiavacchi742006 

All 116 (74.4) 65.6 ± 8.9 48.7 16.8 III or IV = 83.2 NR 171.7 ± 2

Marai752006 

All 84 (85.7) 69.8 ± 9.0 89.8 0 III or IV = 100 19.4 173.2 ± 

Mascioli762002 

All 53 (77.9) 68 ± 8 51 NR NR NR 9 177 ± 3

Mele772006 

All 27 (73) 68 ± 8 43 0 86 14 0 161 ± 2

Mortensen832004 

All 137 (72.5) 66.3 ± 10.6 42 18 68 14 NR 176.3 ± 2

Nagele852001 

All 24 (75) 60 ± 10 47 NR NR NR NR 185 ± 3

Niu872006 

All 86 (73.5) 53 ± NR NR 0 III-IV = 100 NR 141.8 ± N

O’Donnell892005 

All NR NR NR NR NR NR 0 NR 

Oliva902005 

All 213 (82) 62 ± 10 40 NR NR NR NR 171 ± 3

Ollitrault912003 

All 50 (81) 71 ± 10 NR 0 III or IV = 100 NR > 150 

Porciani952006a 

All 28 (93.3) 73.7 ± 6.3 46.7 0 III or IV = 100 NR 140 ± 

Porciani962006b 

All 51 (78) 73 ± 8 47.7 0 III or IV = 100 0 170 ± 

Puglisi972004 

All 262 (83) 63 ± 10 40 0 85 15 NR 178 ± 3

Reuter992000 

All 38 (81) 64 ± 11 NR 8 47 47 40 173 ± 1

Ricci1012002 

All 40 (83.3) 68 ± 8 40 0 III or IV = 100 15 154 ± 2

RomeyerBouchard1312005 

All 86 (83.5) 71 ± 10 34 0 69 31 13 185 ± 2

Sawhney1052004 

All 28 (70) 59.8 ± 12.1 45 0 III or IV = 100 0 176 ± 2
81

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

Schuchert1322004 

All 71 (70) 67 ± 10 27 0 67 33 12 148.2 ± 1

Sogaard1072002 

All 22 (88) 61.2 ± 10 55 0 55 45 NR 189 ± 2

Stahlberg1082005 

All 38 (95) 65 ± 10 65 0 88 12 30 173 ± 2

St. Jude162005 VecTOR 

All 90 (62.5) 67.1 ± 9.7 NR 29 65 6 NR ≥140 

Taieb1092002 

All 33 (66) 71.4 ± 9.9 32 4 74 22 12 > 150 ± 

Tedrow1102006 

All 53 (70.7) 65.5 ± 12.5 46.6 NR 73.3 9.3 50.1 171.1 ± 4

Toussaint1132003 

All 31 (91.2) 64.5 ± 11 53 0 III or IV = 100 NR 179 ± 1

Witte116

2006 

All NR 68.4 ± 17.7 52 NR NR NR 28 188.3 ± 3

Yu1192002b 

All 21(70) 62 ± 14 40 0 60 40 NR 159.1 ± 2

Yu1212005 

All 103 (73) 64 ± 11 48 9 75 16 NR 156.1 ± 3

Zhang122

2006 

All 36 (72) 66 ± 11 48 0 80 20 NR 151 ± 2

Combined CRT-ICD Abraham CRT/ICD on 75 (88) 63 ± 12.8 55 100 0 0 NR 166 ± 2

14

2004 MIRACLE-ICD II 

Control CRT off 

91 (90) 63.1 ± 12.1 58 100 0 0 NR 165 ± 2

Boriani362006a 

CRT+ICD 100 (82.6) 67 ± 8.6 63 0.8 92.6 6.6 NR 175 ± 2

Chugh1232005 

CRT + ICD 52 (67.5) 61 ± 11 56 NR NR NR 29 168 ± 2

de Cock1242004 

All NR NR NR 0 III or IV = 100 NR ≥140m
82

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

Gasparini1272005 

All 177 (91) 65.2 ± 8.5 70 Mean = 3.0 ± 0.5 NR 164 ± 

Higgins92003 CONTAK-CD 

All 176 (77.5) 66 ± 11 68 13 72 15 0 158 ± 2

Kuhlkamp652002 

All 74 (91) 63.8 ± 8.8 57 32 59 9 6 170 ± 3

Murphy842006 

All 43 (80) 61 

22-85 

54 6 87 7 9 157 ± 

Ritter1022006 

All 32 (66.7) 71 ± 8 89.6 0 III or IV = 100 0 162 ± 2

Saxon1062006 

All 142 (85) 70.7 ± 10.3 78 0 88 13 23 150 ± 2

St. Jude172004a RHYTHM ICD 

All NR NR NR 6 87 6 0 168 ± 1

St. Jude172004b RHYTHM ICD Quicksite®

All 132 (82) 68.8 ± 9.9 78 0 92 8 NR 166 ± 2

Theuns1122005 

All 66 (77) 61 ± 10 59 26 74 0 27 174 ± 3

Young CRT III-IV 142 (75.9) 66.6 ± 11.3 64 0 88 12 NR 165 ± 2

6

2003 MIRACLE-ICD Control III-IV 141 (77.5) 67.6 ± 9.2 76 0 89 11 NR 162 ± 2Ypenburg1172006 

All 153 (79) 64 ± 11 56 0 III or IV = 100 28 163 ± 
83

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

CRT or combined CRT-ICD Alonso21 1999 

All 24 (92.3) 66 ± 7 35 0 69 31 23 178 ± 2

Ammann222004 

All 36 (83.7) 65 ± 10 47 0 III or IV = 100 16 172 med

IQR 158-

All 57 (66.3) 60 ± 9 38 II or III = 33 67 16 155 ± 2Inactive first 27 (62.8) 58 ± 8 33 II or III = 28 72 7 157 ± 2

Auricchio122003 PATH-CHF II 

Active first 30 (69.8) 61 ± 9 44 II or III = 37 63 26 154 ± 1

Azizi26

2006 

All 200 (82) 64 ± 12 44 10 68 22 29 NR 

Bax292004 

All 64 (75.3) 66 ± 12 55 0 80 20 0 178 ± 3

Bocchiardo332000 

All 45 (94) 63 ± 7 52 25 65 10 NR NR 

Boriani372006b 

All 383 (91) 65 ± 9 69 23 66 11 NR 168 ± 3

Braun OPT 40 (67.8) 63 ± 9 70 0 93 7 0 175 ± 2

39

2005 CRT and CRT 

+ ICD 

45 (69.2) 65 ± 11 74 0 90 10 0 172 ± 1

CRT + OPT 415 (67) 67 54 0 87 13 NR 160 CRT + ICD + OPT 

401 (67) 66 55 0 86 14 NR 160 

Bristow112004 COMPANION 

OPT 213 (69) 68 59 0 82 18 NR 158 

Cowburn442005 

All NR 67 ± 12 66 0 III or IV 

= 100 

NR NR NR 

Da Costa45

2006 

All 56 (83.6) 70 ± 10 34.3 0 59.7 40.3 26.9 190 ± 2

Davis472005 

All 75 (88) 66 ± 9 72 5 84 12 NR 168 ± 2
84

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

De Sisti48

2006 

All 86 (84.3) 68 ± 10 51 13.7 65.7 20.6 28.4 187 ± 

Diaz-Infante492005 

All 113 (79) 68.3 ± 7 34 17 80 3 23 165 ± 2

Duncan512006 

All 30 (77) 65 ± 10 59 0 95 5 0 154 ± 7

Ellery522005 

All 73 (76) 68 ± 9 38 0 83 17 NR 163 ± 3

Ermis532004 

All 96 (76.1) 69 ± 11.5 56 NR III or IV = 87 NR NR 

Fung CRT 26 (72.2) 66.0 ± 10.4 36 NR NR NR 100 NR 

54

2005 Control 26 (72.2) 65.2 ± 8.1 33 NR NR NR 0 NR Gaita552000 

All 88 (92) 66 ± 8 NR II, III or IV = 100 NR > 140 m

Gasparini572003a 

All 121 (76.6) 65 ± 9 47 19 III or IV = 81 NR 173.7 ± 2

Hernandez592004 

All 21 (75) 66 ± 9 39 0 III or IV = 100 29 168 ± 2

Kies612005 

All 75 (77.3) 63.3 ± 10.6 62 0 84 16 NR 175.0 ± 2

Krahn642002 

All 37 (82) 65.3 ± 10.3 69 7 76 18 33 166 ± 2

Lenom692005 

All 25 (69) 76 ± 10 67 6 78 2 11 177 ± 2

Lewicka-Nowak1292005 

All 73 62.6 ± 9.6 52 NR NR NR 16 170 ± 2

Mair732005 

All NR 63.9 ± 9.8 31 II or III 

= 8 

III or IV = 92 NR 182 ± 2

Molhoek782002 

All 31(78) 64 ± 10 48 0 III or IV = 100 NR 120-240 m

Molhoek792004a 

All 51 (85) 65 ± 9 48 0 80 20 50 192.5 ± 2

Molhoek80 2004b 

All 57 (77) 64.5 ± 10.5 46 0 85 15 NR 176.6 ± 2
85

Table 9. Baseline characteristics of patients in studies included in the effectiveness or safety reviews: CRT alone or comdevices (continued) 

NYHA class Other mea

Author 

Year 

Trial Name 

Study group Males n (%) 

Age, yr. 

Mean ± SD

or median. 

(IQR) 

Ischemic, 

% II, % III, % IV, % 

Atrial 

fibrillation,

% 

QRS inte

msec 

mean ± S

median (

Molhoek812004c 

All 47 (77) 64 ± 11 46 0 84 16 NR 177 ± 3

Molhoek822005 

All 93 (74) 64 ± 10 54 0 89 11 10 176 ± 2

Navia862005 

All 31 (76) 68 ± 10 51 37 39 2 NR 186 ± 2

Notabartolo882004 

All 39 (80) 66 ± 10 69 0 III or IV = 100 16 158 ± 3

Pappone922003 

All 102 (76) 64 ± 11 43 0 III or IV = 100 4 153 ± 1

Penicka932004 

All NR 71.3 ± 10.4 47 NR NR NR NR 181.5 ± 3

Pitzalis942005 

All 32 (53.3) 62 ± 10 22 0 100 0 NR 171 ± 2

Purerfellner1302000a 

All 31 (67) 70 ± 10 NR NR NR NR 98 NR 

Purerfellner1302000b 

All 117 (78) 64 ± 10 30 8 70 21 NR 165 ± 

Purnode982004 

All 31(72) 67 ± 11 53 7 72 21 79 182 ± 2

Reuter1002002 

All 87 (85.3) 64 ± 11 NR 8 62 30 19 184 ± 3

Rossillo1032004 

All 170 (73) 66.2 ± 5.8 61 0 89 11 NR 169.4 ± 3

Salukhe1042005 

All 32 (80) 65 ± 10.5 58 10 83 7 NR 156.4 ± 1

Teo1112003 

All 26 (90) 59.6 ± 12.8 62 0 III or IV = 100 NR 161 ± 2

Vidal1142006 

All 52 (81) 70 ± 8 48 24 65 11 NR 176 ± 2

Waggoner1152006 

All 43 (75) 61 ± 12 33 III or IV = 100 0 180 ± 2

Yu1182002a 

All 18 (72) 65 ± 12 36 0 44 56 NR 162 ± 3

Yu1202004 

All 38 (66) 66.1 ± 11.6 41 0 74 26 NR 154.3 ± 2
86

Table 10. Description of studies included in the effectiveness and safety reviews: ICD 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

 enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals Dev

Meth

imp

Alter144 2005 

Germany Prospective 

cohort 

46 mo. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 440 NA 440 NA 0 Guidant

Medtr

Transve

epica

Antiarrhythmics vs. Implantable Defibrillators (AVID) Investigators141 1997 AVID 

United States 

RCT parallel 18 mo. Efficacy, safety 

ICD Secondary 

Amiodarone, Sotalol 

1,885 1,016 505 509 2 Guidant

MedtrVentrSulzeInterm

Transve

epica

Backenkohler145 2005 

Germany Prospective 

cohort 

4 yr. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 245 NA 245 NA 0 NR 

Transve

Bansch136 2002 CAT 

Germany RCT parallel 

66 mo. Efficacy, safety 

ICD Primary 

Usual care 104 104 50 54 0 Guidant 

Venta

P3, PCPI 

Transve

DER = defibrillation energy requirement; EPS = electrophysiological study; ICD = implanted cardioverter defibrillator; LV = left ventricular; 

ejection fraction; NA = not applicable; NR = not reported; OPT = optimal pharmacological therapy; QOL = quality of life; RCT = randomize

ventricular; VO2 max = maximal oxygen consumption; VA = ventricular arrhythmia; VF = ventricular fibrillation; VT = ventricular tachycard
87

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Bardy140 2005 SCD-HeFT 

United States, 

Canada 

RCT parallel, 

3 arms 

46 mo. 

(median) 

Efficacy 

ICD Primary 

Amiodarone 

placebo 

NR 2521 829 Amiodaron

e = 

845, 

place

bo = 

847 

50 Medt

72

NR 

Bigger134 1997 CABG-Patch 

United States, 

Germany 

RCT parallel 

32 mo. 

Efficacy, safety 

CABG + ICD Primary 

CABG + 

usual care 

1,055 900 446 454 70 Guid

Ep

Blangy146 2003 

France Retrospective 

cohort 

25 mo. 

Effectiveness 

ICD Primary 

NA 283 NA 144 

LVEF < 

35% 

NA 0 NR 

BodeSchnurbus147 2003 

Germany Prospective 

cohort 

24 mo. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 603 NA 165 NA 0 Biotro

PhGuP2Mi

Me7272PluVe10Co

TeGuAT

Tran

ep
88

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Bokhari148

2004 CIDS 

Canada Prospective 

cohort 

up to 11 yr. Effectiveness, 

safety 

ICD Secondary 

Amiodarone 120 120 120 NA 0 NR 

Bristow11 2004 COMPANION 

USA RCT parallel 

(OPT vs OPT+CRT vs OPT+CRT+ICD Efficacy, safety 

OPT+CRT or OPT+CRT+ ICD Primary 

OPT 1520 1520 CRT = 

617 

CRT+ICD = 

595 

308 159 Guid

ContContTran

Bruch149

2006 

Germany Prospective 

cohort 

1 yr. Effectiveness 

ICD Primary and 

secondary 

NA 98 NA 98 NA 0 NR 

Brunckhorst150 2004 

Germany Prospective 

cohort 

12 mo. Effectiveness 

ICD Primary 

NA 104 NA 104 NA 0 St Ju

GuidMedtNR 
89

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Buxton151

1999 MUSTT 

United States, Canada 

RCT parallel 

(antiarrythmic vs. no antiarrythmic therapy) 

39 mo. (median)Effectiveness 

OPT + EP 

guided therapy (antiarrhythmic drug therapy or ICD if drug therapy failed) 

Primary 

OPT 2,202 704 351 353 NR NR 

Capoferri152 2004 

Switzerland Prospective 

cohort 

20 mo. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 100 NA 100 NA 0 NR 

Carlsson192 2003 

Germany RCT (pooled 

analysis) 

NR Safety 

ICD Secondary 

NA 96 NA 96 NA 0 Guid

Ve

Mi

Ve

VePrVePrVeIII MeGeGe

Tran

Chan153 United States Prospective 

cohort 

5 yr. Effectiveness 

ICD Primary and 

secondary 

NA 6,996 NA 1,442 5,554 0 NR 
90

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Chan154 United States 

(7 centers) 

Prospective cohort 27 ± 12 mo. Effectiveness 

ICD Primary 

NA 395 NA 395 NA 0 NR 

Connolly142 2000 CIDS 

Canada RCT parallel 

35 mo. Efficacy, safety 

ICD Secondary 

Amiodarone NR 659 328 331 NR NR 

Tran

tho

Cuesta155 2003 

Spain Prospective 

cohort 

30 mo. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 120 NA 120 NA 0 NR 

Abdotrans

Dorian193 2004a ASTRID Investigators 

Canada RCT parallel 

12 mo. Effectiveness, 

safety 

ICD Primary 

NA 149 149 149 NA 0 Guid

Ve

1818

Tran

Dorian156 2004b SHIELD Investigators 

United States, 

Canada, Germany, United Kingdom, Poland, France, Spain, Netherlands, Belgium, Italy 

RCT parallel 

(placebo arm only) 

12 mo. Safety 

ICD + 

placebo 

Primary and 

secondary 

NA 214 214 214 NA 2 NR 
91

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Dubner157 2005 

Argentina, 

Uruguay, Brazil, Mexico, Chile, Cuba, Venezuela 

Retrospective 

cohort 

27 mo. Effectiveness, 

safety 

ICD Secondary 

NA 770 NA 770 NA 0 Biotro

NR 

Duray1582005 

Germany Retrospective 

cohort 

2.2 ± 1.5 yr Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 375 NA 375 NA 0 NR 

Elhendy159 2005 

United States Prospective 

cohort 

2.8 yr. Effectiveness 

ICD Primary and 

secondary 

NA 90 NA 90 NA 0 NR 

Ellenbogen160 2003 

United States Prospective 

cohort 

68.6 mo. Effectiveness, 

safety 

ICD NR 

NA 74 NA 74 NA 0 Medt

7272

NR 

Ermis161 2003 

United States Retrospective 

cohort 

15 mo. Effectiveness, 

safety 

ICD Primary and 

secondary 

OPT 310 NA 59 251 0 NR 

Evonich162 2004 

United States Retrospective 

cohort 

6 yr. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 153 NA 153 NA 0 NR 

Tranv
92

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Friedman194 2006 

United States RCT parallel 

6 mo. Safety 

ICD dual 

chamber 

Primary and 

secondary 

ICD ventricular only 

pacing 

400 400 201 199 51 St. Ju

Me

Gatzoulis163 2005 

Greece Prospective 

cohort 

33 mo. Effectiveness 

ICD Primary and 

secondary 

NA 169 NA 169 NA 0 NR 

Tranv

Greenberg164 2002 

Israel Retrospective 

cohort 

2.6 yr. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 732 NA 732 NA 0 NR 

Grimm165 2002 

Germany Prospective 

cohort 

35 mo. Effectiveness, 

safety 

ICD Primary 

NA 101 NA 101 NA 0 Guid

Ve

Mi

MiPri

Ve

Me72727272

Tran
93

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Grimm1952006 

Germany Retrospective 

cohort 

3.2 ± 2.3 yr Safety 

ICD Primary 

NA 93 NA 93 NA 0 Medt

722029/30/74/7GuidMini/takAVContTran

Ho166 2005 

United States Retrospective 

cohort 

4.4 yr. Effectiveness 

ICD Primary and 

secondary 

NA 360 NA 360 NA 0 NR 

Hohnloser139 2004 DINAMIT 

Europe, Canada, United States 

RCT parallel 30 mo. Efficacy, safety 

ICD Primary 

OPT NR 674 332 342 24 NR 

Hreybe1962006 

United States Prospective 

cohort 

4 yr. Safety 

ICD Primary and 

secondary 

NA 230 NA 230 NA 0 NR 

Kadish138 2004 DEFINITE 

United States, Israel 

RCT parallel 29 mo. Efficacy, safety 

ICD Primary 

OPT NR 458 229 229 6 NR 

Koplan167

2006 

United States Retrospective 

cohort 

3.3 yrs Effectiveness 

ICD Primary and 

secondary 

NA 348 NA 348 NA 0 NR 
94

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Kuck143 2000 CASH 

Germany RCT parallel 

3 arms 

57 mo. Efficacy, safety 

ICD Secondary 

Metoprolol, 

amiodarone 

293 288 99 Metoprolol 

 = 97, 

Amiodarone 

= 92 

NR Guid

Ve

AIDVeAICVeVePRVe

TM

Epica

en

Lampert168 2004 

United States Retrospective 

cohort 

2.5 yr Effectiveness 

ICD Primary and secondary 

NA 650 NA 399 NA 0 Guid

an

NR 

Leosdottir169

2006 

Iceland Retrospective 

cohort 

10 yr Effectiveness, 

safety 

ICD Secondary 

NA 62 NA 62 NA 0 NR 

Tran

Lickfett197 2004 

Germany Retrospective 

cohort 

47 mo. Safety 

ICD NR 

NA 105 NA 105 NA 0 NR 

Tran

Moss133 1996 MADIT 

United States, Germany, Italy 

RCT parallel 27 mo. Efficacy, safety 

ICD Primary 

OPT 253 196 95 101 18 Guid

Tran

tra

Moss135 2002 MADIT II 

United States, Europe 

RCT parallel 20 mo. Efficacy, safety 

ICD Primary 

OPT NR 1,232 742 490 3 NR 

Tran

Nazarian170

2005 

United States Retrospective 

cohort 

3 yr. 

Effectiveness 

ICD Primary and 

secondary 

NA 94 NA 94 NA 0 NR 
95

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Niehaus198 2003 

Germany Retrospective 

cohort 

12 mo. Safety 

ICD Secondary 

NA 25 NA 25 NA 0 NR 

Tranv

Noseworthy171 2004 

Canada Retrospective 

cohort 

7 yr. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 637 NA 212 NA 0 NR 

Tranv

ep

Parkash1722006 

United States Retrospective 

cohort 

3.2 yr. Effectiveness 

ICD Primary and 

secondary 

NA 469 NA 469 NA 0 NR 

Pires173 2002 

United States Retrospective 

cohort 

24 mo. Effectiveness 

ICD Primary and 

secondary 

NA 2,030 NA 2,030 NA 0 Angs

Co

MDDR 

Tran

Pires174

2006 

United States Retrospective 

cohort 

22 ± 14 mo. Effectiveness 

ICD NR 

NA 861 NA 861 NA 26 Medt

GuJudMeBio

Tran

Raitt175 2005 

United States RCT (placebo 

arm only) 

10 yr. Effectiveness 

ICD Primary 

NA NR 100 100 NA 26 NR 
96

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Raviele176 2005 BEST ICD 

Italy RCT (analyzed 

as prospective cohort) 

24 mo. Effectiveness, 

safety 

EPC guided 

or ICD 

Secondary 

OPT 143 138 79 59 0 NR 

Robin177

2006 

United States Retrospective 

cohort 

11 yr. Effectiveness 

ICD Primary 

NA 585 NA 585 NA 0 NR 

Russo178 2003 

United States Prospective 

cohort 

15.7mo. Effectiveness, 

safety 

ICD Primary 

NA 51 NA 51 NA 0 NR 

Saba179 2003 

United States Retrospective 

cohort 

4 yr. Effectiveness, 

safety 

ICD Primary and 

secondary 

NA 35 NA 35 NA 0 NR 

Saeed199 2003 

United States Prospective 

cohort 

8.4 mo. Safety 

ICD NR 

NA 229 NA 48 NA 0 Guid

Ve

1818

NR 

Sanchez180 2005 

United States Case-control 

NR Effectiveness, 

safety 

ICD Primary and 

secondary 

OPT 102 NA 19 32 0 NR 

Sanchez181

2006 

United States Retrospective 

cohort 

22 ± 14 mo. Effectiveness, 

safety 

ICD Primary 

NA 123 NA 123 NA 0 NR 

Tran
97

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Schaer1822006 

Switzerland Prospective 

cohort 

18 m0. Effectiveness 

ICD Primary and 

secondary 

NA 58 NA 58 NA 0 NR 

Sears183 2004 

United States Prospective 

cohort 

14.3 mo. Effectiveness 

ICD Primary 

NA 88 NA 88 NA 0 NR 

Takahashi184 2002 

United States Retrospective 

cohort 

12 mo. Effectiveness, 

safety 

ICD NR 

NA 178 NA 178 NA 0 Guid

Ve

TM, 

AVMeMiGeDRVeAn

Co

Pro

Tranv

Tandri185

2006 

United States Retrospective 

cohort 

23 yr. Effectiveness 

ICD Primary and 

secondary 

NA 1382 NA 1382 NA 0 NR 

Thor

abtraen

Telfer186 2002 

United States Retrospective 

cohort 

2.2 yr. Effectiveness, 

safety 

ICD Primary 

NA 379 NA 29 NA 2 NR 
98

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Theuns200 2004 

Netherlands RCT parallel 

12 mo. Safety 

ICD Primary and 

secondary 

ICD NR 60 NA 0 Biotro

acGuPri

NR 

Theuns187

2005b 

Netherlands Prospective 

cohort 

5 yr. Effectiveness, safety 

ICD Primary and 

secondary 

NA 127 NA 127 NA 0 Biotro

GuidELA MedtTran

Theuns201 2005a 

Netherlands Prospective 

cohort 

4 yr. Safety 

ICD Primary and 

secondary 

NA 326 NA 260 NA 0 Biotro

PhTaBe

T; 

ELA 

IV, 

Guid

IV, 

CDRe

ReII; 

Medt

7272

Tran

Tiroke202 2003 

Germany Retrospective 

cohort 

5 yr. Safety 

ICD NR 

NR 149 NA 149 NA NR NR 
99

Table 10. Description of studies included in the effectiveness and safety reviews: ICD (continued) 

 Participants 

Author 

Year 

Trial name 

Study 

location 

Design 

Duration 

Type of 

outcomes 

Treatment 

Primary vs. 

secondary 

prevention 

Control 

Number 

enrolled 

Number 

randomized 

Number in 

treatment 

Number in 

control 

Number of 

withdrawals D

Me

im

Trappe188 2002 

Germany Prospective 

cohort 28 mo. Effectiveness, 

safety 

ICD NR 

NA 410 NA 410 NA 0 NR 

Epica

notho

Wase189 2004 

United States Retrospective 

cohort 4 yr. Effectiveness, 

safety 

ICD Primary and secondary 

NA 256 95 93 NA 0 NR 

Tran

Wilkoff1902006 

United States RCT parallel 

12 mo. Effectiveness 

ICD 

EMPIRIC 

Primary and 

secondary 

ICD TAILORED 900 900 455 455 0 Medt

Zecchin191 2004 

Italy Retrospective 

cohort 

24 mo. Effectiveness, 

safety 

ICD Primary and secondary 

NA 54 NA 54 NA 0 Biotro

Be

GuVe

Mi

II-IPri

PriVit

Re

MeJewATDeSt. Me

VeCo

NR 
100

Table 11. Baseline characteristics of patients in trials included in the effectiveness and safety reviews: ICD 

Author NYHA class Other measu

Year 

Trial Name 

Study group Males, n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % Atrial fibrillation, % QRS interval

msec mean ± S

Alter144 2005 

ICD 357 (81.1) 58 ± 14 48 49 37.3 2 NR NR 

ICD 395 (78) 65 ± 11 81 I or II = 

48 

Anti-arrhythmics 7 0 21 116 ± 26 vs. Implantable Defibrillators141

1997 AVID 

Antiarrhythmics 412 (81) 65 ± 10 81 I or II = 

48 

12 0 26 117 ± 26 

All participants 196 (80) 62.8 ± 0.8 75.1 NR NR NR 15.9 NR 

Secondary 

prevention 

157 (78) 63 ± 11 73.8 NR NR NR 16 52% ≥ 12

msec 

Backenkohler145 2005 

Primary 

prevention 

39 (91) 62 ± 10 81 NR NR NR 14 49% ≥ 12

msec 

All participants 83 (79.8) 52 ± 11 0 65.3 34.6 0 15.7 108 ± 29 

ICD 43 (86) 52 ± 12 0 66.7 33.3 0 20.4 102 ± 29 

Bänsch136 2002 CAT Control 40 (74.1) 52 ± 10 0 64.1 35.8 0 11.3 114 ± 29 Bardy140 2005 SCD-HeFT 

ICD 639 (77) 60.1 

median 

IQR 51.9-

69.2 

52 57.4 21.0 Exc 16 NR 

 Amiodarone 639 (76) 60.4 

median 

IQR 61.7-

68.3 

50 54.2 21.5 Exc 17 NR 

 Placebo 655 (77) 59.7 

median 

IQR 51.2-

67.8 

53 60.7 21.4 Exc 14 NR 

ICD = implanted cardioverter defibrillator; IQR = interquartile range; NR = not reported 
101

Table 11. Baseline characteristics of patients in trials included in the effectiveness and safety reviews: ICD (continued) 

 NYHA class Other measures 

Author 

Year 

Trial Name Study group Males, n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % Atrial fibrillation, % QRS interval, msec mean ± SD 

CABG+ICD 386 

(86.5) 

64 ± 9 100 II or III = 71 0 NR 71% ≥100 

msec 

Bigger 

134 

1997 CABG-Patch CABG 373 

(82.2) 

63 ± 9 100 II or III = 74 0 NR 74% ≥ 100 

msec 

Blangy146 2003 

Participants 

with LVEF 

≤35% 

124 

(86.1) 

60.5 ± 

11.9 

72.9 NR NR NR 18 NR 

BodeSchnurbus147 2003 

All participants 132 (80) 61.8 ± 9.7 72.7 0 100 0 NR 85% < 150 

msec 

ICD 50 (83) 64 ± 9.2 80 I or II 

= 95 

III or IV = 5 NR NR 

Bokhari148 2004 CIDS Amiodarone 50 (83) 64 ± 8.7 80 I or II 

= 95 

III or IV = 5 NR NR 

CRT + OPT 413 

(67) 

Median 

67 

54 Exc 87 13 NR ≥ 120 msec M

CRT+ICD +OPT 399 

(67) 

Median 

66 

55 Exc 86 14 NR ≥ 120 msec M

Bristow11

2004 COMPANION 

OPT only 213 

(69) 

Median 

68 

59 Exc 82 18 NR ≥ 120 msec M

Bruch149

2006 

All participants 67 (80) 60 ± 12 74 2.7 ± 0.5 0 153 ± 39 

Brunckhorst150 2004 

All participants 97 

(93.3) 

67 ± 10 100 NR NR NR NR 383 ± 195 

EPAntiarrhythmics 316 (90) 67 median IQR 60-72 96 39 24 0 NR NR 3

I

Buxton151 1999 MUSTT No 

Antiarrhythmics 

318 (90) 66 median 

IQR 58-72 

93 38 25 0 NR NR 2

I

Secondary 

prevention 

Capoferri NR 55 ± 13 70 NR NR NR NR NR 

152 

2004 

Primary 

prevention 

NR 49 ± 15 67 NR NR NR NR NR 
102

Table 11. Baseline characteristics of patients in trials included in the effectiveness and safety reviews: ICD (continued) 

 NYHA class Other measures 

Author 

Year 

Trial Name Study group Males, n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % Atrial fibrillation, % QRS interval, msec mean ± SD 

All participants NR 53 ± 13.9 69 NR NR NR NR NR 

Carlsson192 2003 

All participants 86 (90) 61 ± 10.3 67.7 NR NR NR NR NR 

Chan ICD NR 66.2 100 NR NR NR NR NR 

153

Control NR 68.6 100 NR NR NR NR NR 

Chan154 ICD 339 (86) 66 ± 9.9 100 NR NR NR 0 39% > 

120ms 

2

ICD 280 

(85.4) 

63.3 ± 9.2 82.2 I or II 

= 37.8 

III or IV = 11 NR NR 

Connolly142 2000 CIDS Amiodarone 277 

(83.7) 

63.8 ± 9.9 82.9 I or II 

= 39.9 

III or IV = 10.6 NR NR 

Cuesta155 2003 All participants 115 

(95.8) 

63.3 ± 9 66.7 NR III or IV = 22.5 NR NR 

Dorian1932004a ASTRID Investigators 

All participants 124 

(83.2) 

60 ± 13 71.1 51.7 9.5 0 10.7 NR 

Dorian156 2004b SHIELD Investigators 

Placebo group 199 (93) 62 ± 12 NR 43 9 Exc NR NR 

Dubner157 2005 

All participants 578 (75) 60 ± 13 39.7 I or II 

= 81 

III or IV = 19 NR NR 

Duray158

2005 

All participants 309 (82) 63.6 ± 10 84 43.5 III or IV = 23.5 NR NR 

Elhendy159 2005 

ICD 63 (70) 65 ± 13 48.9 NR NR NR 15.6 NR 

Ellenbogen160 2003 

ICD 58 

(78.4) 

62 ± 16 65 NR NR NR NR NR 
103

Table 11. Baseline characteristics of patients in trials included in the effectiveness and safety reviews: ICD (continued) 

 NYHA class Other measures 

Author 

Year 

Trial Name Study group Males, n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % Atrial fibrillation, % QRS interval, msec mean ± SD 

All participants 231 

(74.5) 

49.3 ± 

11.9 

45.2 15.8 58.4 18.7 NR NR 

ICD 40 

(67.8) 

51.1 ± 9.9 44.1 13.6 61 25.4 NR NR 1

Ermis161 2003 

No ICD 191 

(76.1) 

48.9 ± 

12.3 

45.4 16.3 57.8 17.1 NR NR 2

Evonich162 2004 

All participants 122 

(79.7) 

65.6 ± 

12.6 

64.4 34 44 0 NR NR 

ICD (dual chamber) 

163 (81) 64.3 ± 

11.3 

Friedman 81 NR NR NR 18 NR 

194 

2006 

ICD 

(ventricular only) 

156 (78) 65.1 ± 

11.3 

81 NR NR NR 20 NR 

All participants 142 (84) 59.9 ± 

12.5 

60 NR NR NR NR NR 3

Primary 

prevention 

18 (100) 57 ± 18 78 NR NR NR NR NR 

Gatzoulis163 2005 

Secondary 

prevention 

124 

(82.1) 

61 ± 12 58 NR NR NR NR NR 

Greenberg164 2002 

All participants 630 (86) 62.6 ± 

12.4 

79 NR NR NR NR NR 

Grimm165 2002 

All participants 82 (81) 51 ± 14 NR 61 35 0 21 NR 

Grimm195

2006 

All participants 83 (89) 56 ± 13 34.4 38 58 4 22 ± 7 NR 

Ho166 2005 

ICD 288 (80) 62 ± 13 68 NR NR NR 23 NR 

ICD 252 

(75.9) 

61.5 ± 

10.9 

Hohnloser 100 95 40 Exc NR 107 ± 24 

139 

2004 DINAMIT CMT 262 

(76.6) 

62.1 ± 

10.6 

100 98 49 Exc NR 105 ± 23 

Hreybe196

2006 

All participants 181(79) 63 ± 14 75 NR III or IV = 45 17 123 ± 34 
104

Table 11. Baseline characteristics of patients in trials included in the effectiveness and safety reviews: ICD (continued) 

 NYHA class Other measures 

Author 

Year 

Trial Name Study group Males, n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % Atrial fibrillation, % QRS interval, msec mean ± SD 

All participants 326 

(71.2) 

58.3 

range 

20.3 - 83.9 

0 57 21 Exc 24.5 115.1 

range 

78-196 

ICD 166 

(72.5) 

58.4 

range 

20.3-83.9 

0 54 21 Exc 22.7 114.7 

range 

78-196 

Kadish138 2004 DEFINITE 

Control 160 

(69.9) 

58.1 

range 

21.8-78.7 

0 61 21 Exc 26.2 115 

range 

79-192 

Koplan167

2006 

All participants 285 (82) 70 ± 8 80.6 NR NR NR NR 51% > 

120ms 

Kuck ICD 78 (79) 58 ± 11 73 59 18 0 NR NR 

143 

2000 CASH Antarrhythmics 152 (80) 57.5 ± 10 74 59 18 0 NR NR Lampert168 2004 

All participants 340 (85) 67.4 

SE ± 1.3 

100 NR NR NR NR > 120 = 24% 

Leosdottir169

2006 

All participants 44 (71) 58 ± 14 62 NR NR NR NR NR 4

Lickfett197

2004 

All participants 87 (83) NR 65 NR NR NR NR NR 

Moss ICD 87 (92) 62 ± 9 34 II or III = 63 0 NR NR 

133 

1996 MADIT CMT 93 (92) 64 ± 9 29 II or III = 67 0 NR NR 

ICD 623 (84) 64 ± 10 100 35 25 5 9 ≥ 120 = 

50% 

Moss 

135 

2002 MADIT II Conventional 

treatment 

417 (85) 65 ± 10 100 34 23 4 8 ≥ 120 = 

51% 

Nazarian170

2005 

All participants 69(73) 55 ± 11 45 20 35 33 27 NR 

Niehaus198 2003 

All participants 20 (80) 60.8 ± 12 72 NR NR NR 28 NR 
105

Table 11. Baseline characteristics of patients in trials included in the effectiveness and safety reviews: ICD (continued) 

 NYHA class Other measures 

Author 

Year 

Trial Name Study group Males, n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % Atrial fibrillation, % QRS interval, msec mean ± SD 

Noseworthy171 2004 

All participants 169 (80) 74.9 ± 4.4 80 I or II 

 = 

90.1 

NR NR NR NR 

Parkash1722006 

All participants 356 (76) 65 ± 15 62 ≤ II = 

81 

III or IV = 19 31 NR 

Pires173 2002 

ICD 1654 

(81.5) 

64.4 ± 

12.4 

78 55 III or IV = 19 NR NR 

Piers174

2006 

All participants 641 (77) 65.4 ± 

12.7 

57 NR NR NR NR NR 

Raitt175 2005 

ICD 

(placebo arm) 

86 (86) 62 ± 13 71 14 50 8 NR NR 

Raviele176 2005 BEST-ICD 

All participants 98 (71) 66.5 ± 9.6 100 NR NR Exc 22 > 114 

msec 

3

Robin177

2006 

All participants 462 (79) 63 ± 15 60 NR NR NR 10 NR 

Russo178 2003 

All participants 41 (92) 70 ± 9 

range 41-98 

100 NR NR NR NR NR 

ICD 29 

(82.9) 

Saba 51 ± 12 20 Exc III or IV = 100 17 NR 2

179 

2003 

Control 114 

(71.7) 

51 ± 12 73 Exc III or IV = 100 26 NR 2

Saeed199 2003 

All participants 38 (79) 64 ± 12 63 42 23 0 NR NR 

Sanchez ICD 15 (79) 60 ± 16 47 NR NR Exc NR NR 

180 

2005 Conventional 

therapy 

26 (81) 61 ± 13 59 NR NR Exc NR NR 

Sanchez181

2006 

All participants 93 (89) 66.7 ± 9.3 100 NR NR NR NR 119 ± 12 2

Schaer1822006 

All participants 50 (86) 56.4 ± 

12.7 

0 NR NR NR NR NR 
106

Table 11. Baseline characteristics of patients in trials included in the effectiveness and safety reviews: ICD (continued) 

 NYHA class Other measures 

Author 

Year 

Trial Name Study group Males, n (%) Age, yr. mean ± SD Ischemic, % II, % III, % IV, % Atrial fibrillation, % QRS interval, msec mean ± SD 

Sears183 2004 

All participants 73 (83) 65 ± 13 69 NR NR NR NR NR 

All 72 (70) 59 ± 11 0 64 19 0 NR NR 

ICD 34 (67) 58 ± 11 0 64 16 0 NR NR 

Strickberger137 2003 AMIOVIRT 

Amiodarone 38 (74) 60 ± 12 0 63 24 0 NR NR 

Takahashi184 2002 

All participants 144 (81) 64 61 NR NR NR NR NR 

Tandri185

2006 

All participants 1050 

(76) 

62 ± 11 72 38 III or IV = 23 NR NR 

Telfer186 2002 

ICD 26 (96) 59 ± 13 NR NR NR NR NR NR 

ICD-single 24 (83) 57 ± 17 72 NR NR NR 27.6 NR 

ICD-dual 23 (74) 61 ± 10 84 NR NR NR 22.6 NR 

Theuns200 2004 

All participants 47 (78) 59 ± 14 78 NR NR NR 25 NR 3

Theuns201 2005a 

All participants 216 (83) 60 ± 13 71 NR NR NR 29 NR 

Theuns187

2005b 

All participants 105 (83) 59 ± 11 72 ≤II = 

72 

III or IV = 28 0 NR 

Tiroke202 2003 

All participants 136 

(91.3) 

62 

range 51-72 

77 42 38 2 NR NR 

Trappe188 2002 

All participants 368 

(89.8) 

57 ± 11 NR I or II 

 = 12 

II = 37 

II or III 

 = 29 

III = 22 

0 NR NR 

Wase189

2004 

ICD 66 (71) 66.5 ± 

12.2 

NR NR NR NR NR NR 2

Wilkoff190

2006 

All participants 731 

(81.2) 

65 ± 12.6 69.4 ≤II = 

47 

III or IV = 14.5 0 NR 

Zecchin191

2004 

All participants 43 

(79.6) 

52.5 ± 

17.2 

0 I or II 

 = 76 

NR NR NR NR 2
107

Table 12. Description of additional studies included in the ICD safety review for peri-implant complications only  Participants 

Author 

Year 

Study location 

Design 

Duration 

Intervention Treatment 

(n) 

Control 

(n) 

Device 

Method of 

implant 

Data or patient source 

Al-khatib204

2005 

United States 

Retrospective 

cohort 

Registry data 2 yr. 9 mo. 

ICD 9,854 NA Defender III, 

 IV ELA Medical 

20% of Part B Medicare files & 100% MEDPAR files January 1999-September 2001 

Bänsch205

2004 

Germany RCT 

 crossover 

1 yr. 

Dual-chamber vs. singlechamber ICD 

102 NA NR Multiple centers in 

Germany 

Boriani206

2003 

Italy RCT 

crossover 

6 mo. 

ICD-atrial enhancements on v. off 

89 NA Guidant 

NR 

Multiple centers in Euroand Canada 

Brockes207

2002 

Switzerland 

Retrospective 

cohort 

5 yr. 

ICD 130 NA NR 

Thoracotomy, 

subxiphoid, transvenous 

One center 

Gradaus208 2003 

Germany Retrospective 

cohort 

Registry data 2yr. 10 mo. 

ICD 3,344 NA NR 

Transvenous 

European Registry of Implantable Defibrillator(EURID) 

Hlatky209

2002 

United States 

Retrospective 

cohort 

Registry data 9 yr. 

ICD 22,565 NA NR Health Care Finance 

Administration for Medicare Beneficiaries files Jan. 1984-Sept. 1995; California Statewide Health Plannand Development hospidischarge database, 1991-1995 

Nademanee210 Thailand, 

United States 

RCT 

parallel 

3 yr. 

ICD vs. propanalol 

47 Not 

included 

NR Guidant Transvenous 

NR 

ICD = implanted cardioverter defibrillator; MEDPAR = Medicare Provider Analysis and Review; NA = not applicable; NR = not reported; R

controlled trial 
108

Table 12. Description of additional studies included in the ICD safety review for peri-implant complications only (continued) 

 Participants 

Author 

Year 

Study location 

Design 

Duration 

Intervention Treatment 

(n) 

Control 

(n) 

Device 

Method of implant 

Data or patient sour

Reynolds203

2006 

United States 

Retrospective 

cohort 

1 yr. 

ICD 30,984 NA NR MEDPAR files fiscal y

2003 

Rosenqvist211 1998 

Europe Prospective 

cohort 

4 mo. 

ICD 778 NA Medtronic 7219 C 

& D Pectoral or 

abdominal 

63 European centers 

Schläpfer212 2002 

Switzerland 

Prospective 

cohort 

63 ± 30 mo. 

ICD vs. amiodarone 

41 Not 

included 

NR 

Epicardial, nonthoracotomy 

One center 

Vollmann213 2003 

Europe, United States, Canada 

RCT 

parallel 

1 year 

ICD Singlechamber vs. dual-chamber 

542 NA 

combined groups 

Medtronic 6942 or 6944 Pectoral 

48 centers 

Wiegand214 2004 

Germany Retrospective 

cohort 

12 yr. 

ICD 372 Not 

included 

NR Sub-pectoral 

Single center 
109

Table 13. Baseline characteristics of patients in additional studies included in the ICD safety review for peri-implant complic

NYHA class Other measures 

Author 

Year 

Trial name 

Study Group Males, n (%) Mean age, yr. mean ± SD Ischemic, % I% II, % III, % IV, % Atrial fibrillation

% 

LVEF, 

mean ± SD 

Al-khatib204

2005 

ICD 7,724 

(78.4) 

NR NR NR NR NR NR NR NR IC

Bänsch205 

2004 

ICD NR NR 82.4 24.5 58.8 16.6 0 NR 37.5 ± 13.5 S

mcy

Boriani206 

2003 

ICD 69 (77.5) 64.1 ± 

12.5 

60 32 60 NR NR 100 46 ± 16 H

pp

Brockes207 2002 

ICD 115 

(88.5) 

61 ± 11 100 NR NR NR NR NR 36 ± 12 C

IC

Gradaus208

2003 

ICD 2,682 

(80.2) 

61.1 ± 12.1 

64.6 19.3 54.3 20.9 1.1 NR 70.6% > 30 IC

re2

Hlatky209

2002 

ICD 18,255 

(80.9) 

71.5 ± NR 6 NR NR NR NR NR NR ≥

(ire

Nademanee2102003 DEBUT 

ICD 45 (95.7) 40.9 ± 11 NR 100 0 0 0 NR 66.1 ± 10.3 S

p

Reynolds2032006 

ICD 24,401 

(78.8) 

NR NR NR NR NR NR NR NR IC

oIC

Rosenqvist211 1998 

ICD 635 

(81.6) 

58 ± 13 58 22.6 53.3 23.1 0.9 NR 39 ± 17 P

o

AF = atrial fibrillation; AT = atrial tachycardia; CAD = coronary artery disease; CRT = cardiac resychronization therapy; EURID = EuroImplantable Defibrillators; ICD = implanted cardioverter defibrillator; ICD9 = International Classification of Diseases, 9th Revision; MI = 

NR = not reported, SUDS = Sudden Unexplained Death Syndrome, VF = ventricular fibrillation; VT = ventricular tachycardia, 
110

Table 13. Baseline characteristics of patients in additional studies included in the ICD safety review for peri-implant complic

NYHA class Other measures 

Author 

Year 

Trial name 

Study Group Males, n (%) Mean age, yr. mean ± SD Ischemic, % I% II, % III, % IV, % Atrial fibrillation

% 

LVEF, 

mean ± SD 

Schläpfer212 2002 

ICD 78 (93) 60 ± 10 NR NR NR III or IV = 23 NR 36 ± 11 A

firV

Vollmann213 2003 

ICD 452 

(83.4) 

64.8 ± 10.9 

79 NR NR NR NR NR 35.5 ± 14.4 In

ICw

Wiegand214 2004 

ICD 306 

(82.3) 

62.5 ± 11 71 NR NR NR NR 28 NR P

grere
111

Table 14. Methodological quality of randomized trials included in the efficacy review: CRT alone or combined CRdevices 

Randomization Double-blinding Author Year 

Trial name Stated Method described Stated Method described 

Description of 

withdrawals/ 

dropouts 

Jadad 

score 

A

co

Abraham 20024 MIRACLE Yes Adequate Yes Adequate Adequate 5 CleCazeau 20015MUSTIC-SR Yes Adequate No NR Adequate 3 UnYoung 20036 MIRACLE-ICD Yes Unclear Yes Adequate Adequate 4 UnLeclercq 20027 MUSTIC-AF Yes Adequate No NR Adequate 3 UnAuricchio 20028 PATH-CHF Yes Unclear Yes Adequate Adequate 4 UnHiggins9 2003CONTAK-CD Yes Unclear No NR Adequate 2 UnLeclercq10 2003 

RD-CHF Yes NA No NA NA 1 NA 

Bristow11 2004 

COMPANION Yes Unclear No NR Adequate 2 Un

Auricchio12 2003 

PATH-CHF II Yes Unclear No NR Adequate 2 Un

Kindermann13 2006 

HOBIPACE Yes Unclear No NR Adequate 2 Un

Abraham14 2004MIRACLE ICD II Yes Unclear Yes Adequate Adequate 4 CleCleland15 2005CARE-HF Yes Unclear No NR Adequate 2 UnSt. Jude16 2005VecTOR Yes Unclear Yes Unclear Adequate 3 UnSt. Jude17 2004aRHYTHM ICD Yes Unclear Yes Unclear Adequate 3 UnNA = not available; NR = not reported 
112

Table 15. Methodological quality of randomized trials included in the efficacy review: ICD 

Randomization Double blinding Author Year 

Trial name Stated Method described Stated Method described 

Description of 

withdrawals/ 

dropouts 

Jadad 

score 

All

con

Moss133 1996 

MADIT 

Yes Clear No NR Unclear 2 Uncle

Bigger134 1997 

CABG-Patch 

Yes Clear No NR Adequate 3 Adeq

Moss135 2002 

MADIT II 

Yes Unclear No NR Adequate 2 Uncle

Bänsch136 2002 

CAT 

Yes Unclear No NR Unclear 1 Adeq

Strickberger137 2003 

AMIOVIRT 

Yes Unclear No NR Adequate 2 Uncle

Kadish138 2004 

DEFINITE 

Yes Unclear No NR Adequate 2 Uncle

Bristow11 2004 

COMPANION 

Yes Unclear No NR Adequate 2 Uncle

Hohnloser139 2004 

DINAMIT 

Yes Clear No NR Adequate 3 Adeq

Bardy140 2005 

SCD-HeFT 

Yes Unclear Yes NR Adequate 3 Uncle

AVID Investigators141

1997 AVID 

Yes Unclear No NR Unclear 1 Uncle

Connolly142 2000 CIDS 

Yes Clear No NR Unclear 2 Uncle

Kuck143 2000 CASH 

Yes Unclear No NR Unclear 1 Uncle

NR = not reported 
113

Table 16. Methodological quality assessment of included studies in the effectiveness and safety reviews: CRT alone or co

ICD devices Downs and Black quality score 

Author Year Reporting External validity Internal validity (bias) Internal validity (confounding) Power Overall 

 Maximum 11 Maximum 3 Maximum 7 Maximum 6 Maximum 2 Maximum 29 

Achilli18 2003 11 3 6 4 1 25 Adamson19 2004 11 1 5 3 1 21 Albertsen20 2005 11 3 5 3 1 23 Alonso21 1999 10 3 5 4 1 23 Ammann22 2004 10 3 5 4 1 23 Ansalone23 2002 6 1 5 2 1 15 Aranda24 2005 9 3 5 4 1 22 Auricchio25 2002b 10 1 5 3 1 20 Azizi 26 2006 8 3 5 3 1 20 Baker27 2002 11 1 4 4 1 21 Bax28 2003 8 2 5 3 1 19 Bax29 2004 9 3 6 4 1 23 Bleeker30 2005a 9 3 6 4 1 23 Bleeker31 2005b 10 3 6 3 1 23 Bleeker32 2006 9 3 6 4 1 23 Bocchiardo33 2000 8 1 3 4 1 17 Bonanno34 2004 10 1 4 4 0 19 Bordachar35 2004 11 2 5 4 1 23 Boriani36 2006a 11 2 5 5 2 25 Boriani37 2006b 9 3 5 4 1 22 Boriani38 2006c 10 2 5 4 1 22 Braun39 2005 10 2 5 4 1 22 Braunschweig40

2005 

9 1 5 2 1 18 

Cazeau41 2003 6 0 3 3 1 13 Chalil42 2006 10 3 5 4 1 23 Chan43 2003 7 2 5 4 1 19 Chugh123 2005 10 3 4 4 1 22 Cowburn44 2005 8 3 4 4 1 20 Da Costa45 2006 11 1 6 4 1 23 Daubert46 1998 11 1 4 3 1 20 Davis47 2005 10 3 5 4 1 23 NR = not reported 
114

Table 16. Methodological quality assessment of included studies in the effectiveness and safety reviews: CRT alone or coICD devices (continued) Downs and Black quality score 

Author Year Reporting External validity Internal validity (bias) Internal validity (confounding) Power Overall 

 Maximum 11 Maximum 3 Maximum 7 Maximum 6 Maximum 2 Maximum 29 

de Cock124 2004 4 3 5 3 1 16 NDe Martino125 2004 9 3 5 5 2 24 NDe Martino126 2005 10 3 5 4 1 23 NDe Sisti48 2005 11 1 5 2 1 20 NDiaz-Infante49 2005 11 3 5 4 1 24 PDixon50 2004 10 1 5 4 1 21 NDuncan51 2006 10 1 6 3 1 21 IEllery52 2005 8 1 4 2 1 16 PErmis53 2004 11 3 5 4 1 24 NFung54 2005 10 3 5 4 1 23 NGaita55 2000 8 2 4 4 1 19 NGalvao56 2002 10 3 5 4 1 23 NGasparini57 2003a 9 2 5 2 1 19 NGasparini127 2005 10 3 5 3 0 21 NGras58 2002 9 1 5 1 1 17 NHernandez59 2004 8 1 3 1 0 13 PHua60 2006 8 1 5 2 1 17 NKautzner128 2004 10 2 5 4 1 22 GKies128 2005 9 3 5 4 1 22 PKies62 2006 9 3 5 2 1 20 FKoos63 2004 11 1 5 4 1 22 NKrahn64 2002 10 3 5 4 0 22 FKuhlkamp65 2002 11 1 5 3 0 20 PLeclercq66 2000 10 2 5 2 0 19 NLecoq68 2005 10 2 4 4 1 21 NLenom69 2005 5 0 2 0 0 7 NLeon70 2005 11 1 5 3 1 21 PLindner71 2005 9 2 5 4 1 21 NMacioce72 2005 9 1 5 1 1 17 NMair73 2005 10 1 4 4 1 20 NMangiavacchi74

2006 

9 1 5 3 1 19 N

Marai75 2006 9 3 5 1 1 19 NMascioli76 2002 8 2 5 4 1 20 NMele77 2006 10 1 6 2 1 20 P
115

Table 16. Methodological quality assessment of included studies in the effectiveness and safety reviews: CRT alone or coICD devices (continued) Downs and Black quality score 

Author Year Reporting External validity Internal validity (bias) Internal validity (confounding) Power Overall 

 Maximum 11 Maximum 3 Maximum 7 Maximum 6 Maximum 2 Maximum 29 

Molhoek78 2002 10 2 5 3 1 21 NMolhoek79 2004a 9 3 5 4 1 22 NMolhoek80 2004b 9 3 5 4 1 22 NMolhoek81 2004 9 3 5 4 0 21 NMolhoek82 2005 10 1 5 3 1 20 NMortensen83 2004 10 1 5 4 2 22 PMurphy84 2006 9 1 5 4 1 20 NNavia86 2005 11 3 5 4 1 24 NNiu87 2006 5 3 5 1 1 15 NNotabartolo88 2004 10 3 5 4 1 23 NO'Donnell89 2005 7 3 6 4 1 21 NOliva90 2005 7 1 2 1 1 12 NOllitrault91 2003 7 1 4 0 1 13 NPappone92 2003 10 3 5 4 1 23 NPenicka93 2004 10 3 6 4 1 24 FPitzalis94 2005 9 3 5 4 1 22 NPorciani95 2006a 9 1 5 3 1 19 NPorciani96 2006b 8 3 5 3 1 20 NPuglisi97 2004 11 3 5 3 1 23 NPurerfellner130 2000 7 2 5 3 1 23 NPurnode98 2004 4 1 2 0 1 8 NReuter99 2000 9 1 5 2 1 18 NReuter100 2002 11 3 5 3 1 23 NRicci101 2002 8 1 3 2 1 15 NRitter102 2006 10 1 5 4 1 21 NRomeyerBouchard131 2005 10 1 5 1 0 17 NRossillo103 2004 10 3 5 3 1 22 NSalukhe104 2005 10 3 7 4 1 25 NSawhney105 2004 11 2 6 5 1 25 NSaxon106 2006 10 1 5 2 0 18 PSchuchert132 2004 10 1 5 4 1 21 NSogaard107 2002 9 3 5 4 1 22 NStahlberg108 2005 11 3 5 4 1 24 FSt Jude17 2004 11 2 5 4 0 22 PTaieb109 2002 3 0 0 1 1 5 N
116

Table 16. Methodological quality assessment of included studies in the effectiveness and safety reviews: CRT alone or coICD devices (continued) Downs and Black quality score 

Author Year Reporting External validity Internal validity (bias) Internal validity (confounding) Power Overall 

 Maximum 11 Maximum 3 Maximum 7 Maximum 6 Maximum 2 Maximum 29 

Tedrow110 2006 9 3 5 4 1 22 NTeo111 2003 10 3 4 3 1 21 NTheuns112 2005 9 1 5 2 1 18 NToussaint113 2003 10 3 5 4 1 23 NVidal114 2006 9 1 6 3 1 20 S

o

Waggoner115 2006 8 1 5 4 1 19 GWitte116 2006 8 1 6 3 1 19 PYpenburg117 2006 11 3 5 4 1 24 NYu118 2002 9 3 5 3 1 21 PYu119 2003 10 1 5 4 1 21 NYu120 2004 9 1 5 4 1 20 NYu121 2005 10 1 6 3 1 21 NZhang122 2006 10 1 5 2 1 19 L

IS
117

Table 17. Methodological quality assessment of included studies in the effectiveness and safety reviews: ICD alone 

 Downs and Black quality score 

Author Year Reporting External validity Internal validity (bias) Internal validity (confounding) Power Overall 

 Maximum 11 Maximum 3 Maximum 7 Maximum 6 Maximum 2 Maximum 29 

Alter144 2005 10 3 4 4 1 22 Backenkohler145

2005 

10 3 5 4 1 23 

Blangy146 2003 4 0 2 0 1 7 Bode-Schnurbus147

2004 

10 3 5 4 1 23 

Bokhari148 2004 10 2 5 5 1 23 Bruch149 2006 8 3 6 4 1 22 Brunckhorst150

2004 

0 2 0 0 0 2 

Buxton151 1999 10 3 6 5 2 26 Capoferri152 2004 9 2 5 4 1 21 Carlsson192 2003 10 3 5 5 2 25 Chan153 2005 8 3 5 4 1 21 Chan154 2006 10 3 5 3 1 22 Cuesta155 2003 10 3 5 4 0 22 Dorian193 2004a 11 2 7 6 2 28 Dorian156 2004b 11 2 7 5 2 27 Dubner157 2005 10 3 5 4 1 23 Duray158 2005 10 3 5 4 1 23 Elhendy159 2005 11 3 5 4 1 24 Ellenbogen160 2003 10 1 5 4 0 20 Ermis161 2003 10 3 5 4 1 23 Evonich162 2004 11 3 5 4 1 24 Friedman194 2006 10 1 6 6 2 25 Gatzoulis163 2005 10 3 5 4 1 23 Greenberg164 2002 9 3 5 4 1 22 Grimm165 2002 11 1 5 4 1 22 Grimm195 2006 10 1 5 3 1 20 Ho166 2005 10 3 5 4 1 23 NR = not reported 
118

Table 17. Methodological quality assessment of included studies in the effectiveness and safety reviews: ICD alone (con

 Downs and Black quality score 

Author Year Reporting External validity Internal validity (bias) Internal validity (confounding) Power Overall 

 Maximum 11 Maximum 3 Maximum 7 Maximum 6 Maximum 2 Maximum 29 

Hreybe196 2006 9 3 5 4 1 22 Koplan167 2006 9 3 5 4 1 22 Lampert168 2004 9 3 5 4 1 22 Leosdottir169 2006 9 3 5 4 1 22 Lickfett197 2004 11 3 4 3 1 22 Nazarian170 2005 7 3 5 4 1 20 Niehaus198 2003 10 1 5 3 1 20 Noseworthy171

2004 

11 3 5 4 1 24 

Parkash172 2006 9 3 5 4 1 22 Pires173 2002 9 1 5 2 1 18 Pires174 2006 10 3 5 4 1 23 Raitt175 2005 10 2 7 5 2 26 Raviele176 2005 10 2 5 5 1 23 Robin177 2006 10 2 5 4 1 22 Russo178 2003 7 2 5 4 0 18 Saba179 2003 10 3 5 4 1 23 Saeed199 2003 11 2 4 2 1 20 Sanchez180 2005 8 3 5 4 1 21 Sanchez181 2006 11 3 6 4 1 25 Schaer182 2006 7 3 5 4 1 20 Sears183 2004 6 1 4 3 1 15 Takahashi184 2002 11 3 4 4 1 23 Tandri185 2006 10 3 5 4 1 23 Telfer186 2002 10 1 5 2 0 18 Theuns200 2004 9 3 4 6 2 24 Theuns201 2005a 10 2 5 4 1 22 Theuns187 2005b 9 3 5 4 1 22 Wase189 2004 9 3 5 4 1 22 Wilkoff190 2006 10 3 6 6 2 27 Zecchin191 2004 10 1 5 3 1 20 
119

Table 18. Methodological quality assessment of additional studies included in the ICD safety review for peri-implant compDowns and Black quality score Author Year Reporting External validity Internal validity (bias) Internal validity (confounding) Power Overall F Maximum 11 Maximum 3 Maximum 7 Maximum 6 Maximum 2 Maximum 29 

Al-Khatib204 2005 10 3 5 3 1 22 PBänsch205 2004 9 1 6 4 2 22 PBoriani206 2003 10 2 5 3 0 20 NBrockes207 2002 9 1 5 3 0 18 NGradaus208 2003 9 3 5 2 1 20 NHlatky209 2002 5 3 3 1 0 12 GNademanee210 2003 10 1 5 4 2 22 FReynolds203 2006 10 3 5 4 1 23 NRosenqvist211 1998 10 1 5 3 0 19 NSchlapfer212 2002 11 3 5 4 1 24 FVollmann213 2003 11 1 5 4 1 22 PWiegand214 2004 11 3 5 4 1 24 NNR = not reported 
120

Quantitative Results: Efficacy Review 

CRT Alone 

All-Cause Mortality. Based on data pooled from all 14 RCTs (n = 544 deaths/3,825 patients), 

CRT alone significantly reduced all-cause mortality (RR = 0.78; 95% CI, 0.67 to 0.91, Figure 4). 

There was negligible statistical heterogeneity among trials (I2

 = 0 percent). The results were 

identical when the analysis was restricted to trials which enrolled only those patients with NYHA 

class III or IV symptoms (n = 498 deaths/2,778 patients, RR = 0.78; 95% CI, 0.67 to 0.91; I2 = 0 

percent). All-cause mortality in the control patients with symptomatic heart failure (NYHA class 

II-IV) was 15 percent and the number needed to treat (NNT) to prevent one death was 29 over a 

median followup of 6 months in patients with symptomatic heart failure. All-cause mortality in 

the control patients with NYHA class III or IV symptoms was 20 percent and the NNT to 

prevent one death was 23 over a median followup of 3 months. Although no differences were 

detected in all-cause mortality (RR = 0.86; 95% CI, 0.54 to 1.39) in the four trials6,9,14,17 that 

included an ICD in both the experimental and control arms (i.e., combined CRT-ICD vs. ICD 

alone), this analysis is based on just 88 deaths in 1,224 patients. Thus, while the data from the 

other 10 trials comparing CRT alone vs. medical therapy conclusively demonstrated reduced 

mortality (RR = 0.77; 95% CI, 0.66 to 0.91) with CRT, the difference between the pooled effect 

estimates from the CRT+ICD vs. ICD alone trials and the pooled effect estimates from the CRT 

alone vs. medical therapy trials was not statistically significant (p = 0.67), 

Progressive Heart Failure Mortality. Eight trials reported progressive heart failure mortality 

in NYHA class II to IV patients (n = 203 deaths/3,004 patients); CRT alone conferred a 

statistically significant reduction in this endpoint (RR = 0.64; 95% CI, 0.49 to 0.84) with 

negligible heterogeneity (I2 = 0 percent; Figure 5). Restricting this analysis to patients with 

NYHA class III or IV symptoms provided similar results (n = 103 deaths/1,408 patients, RR = 

0.56; 95% CI, 0.38 to 82; I2 = 0 percent). In the two trials which tested combined CRT-ICD vs. 

ICD alone and reported this outcome, the benefits of CRT were similar (n = 13 deaths/671 

patients, RR = 0.44; 95% CI, 0.14 to 1.42; p = 0.53 for comparison with non-ICD trials). 

Sudden Cardiac Death. Using data pooled from the 11 trials that reported this outcome, the 

incidence of sudden cardiac death (n = 165 deaths/3503 patients) was no different between CRT 

recipient and control groups (RR = 1.07; 95% CI, 0.79 to 1.46; Figure 6). This result 

demonstrated no statistical heterogeneity (I2

 = 0 percent) and was similar if restricted to trials of 

6 months or longer (RR = 1.02; 95% CI, 0.75 to 1.40; I2

 = 0 percent) or if restricted to patients 

with NYHA class III or IV symptoms (n = 85 deaths/1,452 patients, RR = 0.91; 95% CI, 0.60 to 

1.38, I2

 = 0 percent). Although results were slightly more favorable toward control for the three 

trials which tested combined CRT-ICD vs. ICD alone and reported this outcome, they were still 

nonsignificant (RR = 1.45; 95% CI, 0.43 to 4.91; p = 0.62 for comparison with non-ICD trials).

Noncardiac Death. Pooled data from the six trials (n = 40/1,738 patients) reporting this 

outcome did not demonstrate any significant differences in noncardiac deaths between patients 

with CRT alone vs. controls (RR = 0.81; 95% CI, 0.43 to 1.52; Figure 7). This result was not 

statistically heterogeneous (I2

 = 0 percent). 
121

Heart Failure Hospitalizations. Pooled results from the seven trials that reported HF 

hospitalizations demonstrated a significant reduction in the number of patients hospitalized at 

least once for HF (n = 514/2,270 patients, RR = 0.63; 95% CI, 0.43 to 0.93; Figure 8) in favor of 

CRT alone compared to control. This result was substantially heterogeneous (I2

 = 74 percent). 

Restricting the analysis to patients with more advanced HF (those with NYHA class III or IV 

symptoms) revealed greater reductions (n = 280 hospitalized for HF/1,411 patients, RR = 0.51; 

95% CI, 0.41 to 0.64) and was statistically homogeneous (I2

 = 0 percent). However, no benefits 

were seen in the two combined CRT-ICD vs. ICD trials which reported this outcome (RR = 1.00; 

95% CI, 0.80 to 1.24; p < 0.0001 for comparison with non-ICD trials), and the presence of an 

ICD in both arms of these studies seemed to be the main cause of the heterogeneity present in 

this outcome for the seven CRT trials. 

6-minute Walk Test. CRT was associated with an improved 6-minute walk test distance 

(WMD = 24m; 95% CI, 13m to 35m; Figure 9) compared to controls, although there was 

substantial heterogeneity in this estimate (I2 = 53 percent). This improvement was similar in 

those patients with more advanced HF, i.e., NYHA class III or IV symptoms (WMD = 32m; 

95% CI, 13 to 51; I2 = 64 percent). The magnitude of change for the 6-minute walk test of 24m is 

difficult to interpret in light of other trials that have shown a weak correlation between this and 

other functional testing (e.g., NYHA class, LVEF, VO2 max.). Importantly, the change in 6-

minute walk test is highly dependent on age and less so on NYHA class.265 Subgrouping by the 

presence of an ICD showed that those trials without an ICD (WMD = 31m; 95% CI, 16m to 

46m; I2 = 56 percent) showed greater improvement than those with an ICD (WMD = 12m; 95% 

CI, 0m to 25m; I2 = 0 percent). However, the difference was not statistically significant (p = 0.06) 

and did not explain all the heterogeneity as the ICD group still contained substantial 

heterogeneity. 

New York Heart Association Functional Class. Functional class data from three studies were 

combined in a meta-analysis (although 10 studies reported NYHA class at baseline and at 

conclusion of followup, only three reported it in a format which permitted pooling of data across 

studies). Combining these three studies showed improvements in NYHA class in 59 percent of 

CRT patients and 37 percent of controls (CRT was associated with a 1.55 times increased chance 

of improving at least one NYHA class; 95% CI, 1.25 to 1.92; Figure 10). This result was 

heterogeneous (I2 = 59 percent). In patients with NYHA class III or IV symptoms, the relative 

risk of improving at least one NYHA class was greater (RR = 1.69; 95% CI, 1.47 to 1.94) and 

demonstrated less heterogeneity (I2

 = 0 percent). The data from MIRACLE-ICD6 were not 

reported in a format that permitted pooling with the other three trials; however, the median 

NYHA Class for both groups was III at baseline and was II in the CRT group vs. III in the 

control group at the end of the study. This improvement in NYHA Class was significant (p = 

0.01) and favored CRT; the specific statistical test used was not reported. Although the data from 

CARE-HF15 were not reported in a format that permitted pooling with the other trials, the 

CARE-HF investigators documented statistically significantly improved NYHA class 90 days 

after randomization in patients receiving CRT alone compared to controls (mean NYHA class 

2.7 vs. 2.1, p < 0.001). This was also true for the PATH-CHF II, HOBIPACE, and RHYTHMICD trials (mean changes of 0.25, 0.6, and 0.2 respectively in favor of CRT).12,13,17 Only the 

PATH-CHF Trial8

 (which also could not be combined with the other trials due to the manner in 

which the data were reported) failed to identify a difference between treatment arms; however, 
122

both arms demonstrated significant improvements from baseline and the sample was 

underpowered to detect a difference. 

Quality of Life. Quality of life was measured by the Minnesota Living With Heart Failure 

Instrument266-268 for 11 trials; pooled results showed a significant improvement in favor of CRT 

(WMD = –8.0 points; 95% CI, -10.4 to -5.6 points; Figure 11). Although this result demonstrated 

substantial heterogeneity (I2

 = 61 percent), the results were consistent in direction across studies. 

Restricting the analysis to only those patients with NYHA class III or IV symptoms slightly 

increased the difference between the CRT and control groups (WMD = –8.6 points; 95% CI, –

12.1 to –5.1 points; I2

 = 73 percent). Subgrouping by presence of ICD also did not explain the 

heterogeneity as the no ICD group (WMD = -8.1 points; 95% CI, -11.2 to -5.0) and ICD group 

(WMD = -7.8 points; 95% CI, -12.1 to -3.5) were nearly identical. These differences are 

clinically significant since the minimal clinically important difference for the Minnesota Living 

with Heart Failure Questionnaire has been established to be 5 points.266-268

Left Ventricular Ejection Fraction. Ejection fraction significantly improved in the CRT alone 

arm compared to the control arm in the 5 trials in which it was reported (WMD = 3.0 percent; 

95% CI, 0.9 to 5.1 percent; I

2

 = 75 percent; Figure 12). 

Sensitivity Analyses. Many a priori subgroup and sensitivity analyses (including examining any 

interactions between the effects of CRT in patients with different etiologies of heart failure, or by 

ethnic background, gender, age, comorbidities, and baseline medication use) could not be 

performed due to our inability to obtain individual patient-level data from these trials. None of 

the CRT trials reported definitive subgroup effects. For example, although the PATH CHF II 

Investigators12 reported significantly larger improvements in exercise capacity in patients with 

QRS duration > 150 msec at baseline than those with shorter QRS width, this was based on only 

16 patients; similarly, the report from the HOBIPACE Investigators13 that the functional 

improvements with CRT were greater in those patients with septal coronary sinus leads outside 

of the anterolateral region was based on 17 patients. Further, while a post hoc analysis of the 

MIRACLE trial suggested that patients with an ischemic etiology demonstrated less 

improvements in LVEF and ventricular volumes with CRT than those patients with nonischemic 

disease,216 mortality benefits with CRT did not differ between ischemic and nonischemic patients 

in the COMPANION, CARE-HF, or CONTAK CD Trials (i.e., those trials which specifically 

examined for this interaction in analyses specified a priori).9

 However, it should be noted that 

these trials were not powered to detect such subgroup effects.11,15

A series of univariate meta-regressions on our three most important outcomes (all-cause 

mortality, HF hospitalizations, and quality of life as assessed by the Minnesota Living With 

Heart Failure Instrument) revealed that while no factors influenced the all-cause mortality 

results, several factors (presence of an ICD in both controls and CRT patients, NYHA class II at 

baseline, and higher LVEF) were significantly associated with a reduced magnitude of beneficial 

effects from CRT (see table below). It should be noted that these analyses are based on aggregate 

level data from a small number of relatively homogenous trials.
123

Table 19. Univariate meta-regression subgroup analyses: CRT 

Covariate 

All-cause 

mortality 

(p-values) 

Heart failure 

hospitalizations 

(p-values) 

Quality of life 

(p-values) 

Presence of ICD 0.68 0.001 0.93 

Length of followup 0.28 0.17 0.14 

Ischemic etiology (%) 0.71 0.54 0.12 

NYHA class IV (%) 0.85 0.26 0.55 

NYHA class II (%) 0.76 0.003 0.31 

Mean age (years) 0.27 0.78 0.02 

Mean LVEF (%) 0.42 0.004 0.72 

Randomization after 

implantation 

0.50 0.07 0.14 

The COMPANION trial11 provides the only direct comparison between combined CRT-ICD 

vs. CRT alone devices. Although this was not a primary pre-specified comparison within this 

trial (which was designed to compare both arms against optimal medical therapy alone), the chisquare test for all-cause mortality was not significant [p = 0.13] and the reductions in HF 

hospitalizations were similar in the combined CRT-ICD vs. CRT alone arms.269 

When the data were pooled for all-cause mortality from the four trials6,9,14,17 that included an 

ICD in both the experimental and control arms (i.e., combined CRT-ICD vs. ICD alone), no 

differences were detected (RR = 0.86; 95% CI, 0.54 to 1.39), but this analysis is based on just 

88 deaths in 1,224 patients. On the other hand, pooling data from the other 10 trials comparing 

CRT alone vs. medical therapy demonstrated reduced mortality (RR = 0.77; 95% CI, 0.66 to 

0.91) with CRT (Figure 13). However, this difference between the pooled effect estimates from 

the combined CRT-ICD vs. ICD alone trials and the pooled effect estimates from the CRT alone 

vs. medical therapy trials was not statistically significant (p = 0.67), supporting the assertion 

arising from the COMPANION trial data that the benefits of CRT (at least on all-cause 

mortality) are not appreciably altered by addition of an ICD. However, using the same metaregression model revealed that CRT appeared to have less impact on HF hospitalizations when it 

was added to patients with an ICD (RR = 1.00; 95% CI, 0.80 to 1.24 in the 2 trials [234 of 859 

patients hospitalized] comparing combined CRT-ICD devices with ICD alone) than when CRT 

was compared to patients treated with medical therapy alone (RR = 0.51, 95% CI 0.41 to 0.64 in 

the five non-ICD trials reporting this outcome [280 of 1411 patients hospitalized]); p < 0.0001 

for comparison between those trials with/without ICD in both arms of the trial. 

Publication Bias. Publication bias was examined for our primary outcome, all cause mortality. 

The funnel plot (Figure 14) did appear somewhat asymmetric indicating possible publication 

bias. Both Begg’s rank correlation test (p = 0.06) and Egger’s test (p = 0.06) just failed to 

achieve statistical significance. Using the trim and fill correction added four studies to our metaanalysis, but the new estimate was largely unchanged from the original (RR = 0.77, 95% CI, 0.62 

to 0.92). Interestingly, the bias indicated in all of these tests was that studies which favoured 

CRT were less likely to be published — the opposite of what one usually would expect in funnel 
124

plot asymmetry. This would imply that if publication bias truly did exist, the true relative risk 

reduction with CRT could be even greater than that observed. 

Combined CRT-ICD Devices 

Only one trial compared combined CRT-ICD to medical therapy alone.11 Its effect on allcause mortality was statistically significant (hazard ratio = 0.64; 95% CI, 0.48 to 0.86), and 

although larger than the effect size reported for the CRT alone vs. medical therapy comparison 

(hazard ratio = 0.76; 95% CI, 0.58 to 1.01), this difference was not statistically significant (p = 

0.13). The effects of the combined CRT-ICD device in COMPANION for nonmortality 

outcomes were similar to the results reported in those trials which compared CRT alone vs. 

medical therapy: statistically significant improvements were seen in six minute walk test (Mean 

Difference = 45m; 95% CI, 27 to 63), NYHA functional class (RR = 1.49; 95% CI, 1.23 to 1.81, 

for improving at least one NYHA class), and quality of life (Mean difference = -14 points; 95% 

CI, -18 to -10, on the Minnesota Living with Heart Failure Instrument). 

ICD Alone 

All-Cause Mortality. Based on data pooled from all 12 randomized controlled trials (1851 

deaths in 8,516 patients), ICD alone significantly reduced all-cause mortality (RR = 0.80; 95% 

CI, 0.71 to 0.90; Figure 15 in patients with left ventricular systolic dysfunction). All-cause 

mortality in the control patients with left ventricular systolic dysfunction was 25 percent, so the 

NNT to prevent one death was 20 over a median followup of 35 months in these patients. There 

was moderate statistical heterogeneity among trials (I2 = 44 percent). The results were similar 

(but more homogeneous) when the analysis was restricted to patients with NYHA Class II or III 

symptoms (RR = 0.77; 95% CI, 0.65 to 0.90; I2

 = 0 percent). All-cause mortality in the control 

patients with left ventricular systolic dysfunction and NYHA class II or III symptoms was 29 

percent and the NNT to prevent one death was 15 over a median followup of 72 months in these 

patients. 

Mode of Death Analysis. Unlike the CRT trials (in which the majority of trials classified deaths 

into those due to progressive heart failure mortality vs. sudden cardiac death vs. non-cardiac 

death), the ICD trials focused almost exclusively on all-cause mortality and sudden cardiac 

death. Two trials reported progressive heart failure mortality and the data was not conclusive (n 

= 125 deaths/1668 patients; RR = 0.99; 95% CI, 0.70 to 1.38; I2

 = 0 percent ) (Figure 16). Ten 

ICD trials reported rates of sudden cardiac death and confirmed the benefits of ICD for this 

outcome (n = 414 deaths/5608 patients; RR = 0.46; 95% CI, 0.37 to 0.57; Figure 17). This result 

was not statistically heterogeneous (I2

 = 0 percent). All studies enrolled patients with NYHA 

class I to III, thus without individual patient data no sub-analysis by NYHA class could be 

performed. Pooled data from 8 trials reporting non-cardiac deaths did not demonstrate any 

significant differences between patients with ICD compared to controls (n = 183/4304 patients; 

RR = 1.27; 95% CI, 0.95 to 1.69; Figure 18). This result was not statistically heterogeneous (I2

 = 

0 percent). 

Heart Failure Hospitalizations. Pooled results from the two trials that reported HF 

hospitalizations suggested no difference between ICD and control, but was not conclusive due to 
125

the small number of events (810 of 2,248 patients hospitalized for HF; RR = 1.10; 95% CI, 0.76 

to 1.59; Figure 19). 

6-Minute Walk Test. One study comparing ICD to control had data on 6-minute walk test. ICD 

patients did not appear to walk further than control patients, although the data was not conclusive 

(MD = 6 m; 95% CI, -8 m to 19 m).11 

New York Heart Association Functional Class. One study reported data on NYHA functional 

class and there was no statistically significant difference between ICD and control patients 

during followup (RR = 0.93; 95% CI, 0.84 to 1.04).11 

Quality of Life. Quality of life as measured by the Minnesota Living with Heart Failure 

Instrument was reported in one trial and there was no significant difference between ICD and 

control (MD = -1.0 points; 95% CI, -4.5 to 2.5).11 One other trial used a generic quality of life 

score and found no difference between ICD and control.137

Sensitivity Analyses. Many a priori subgroup and sensitivity analyses (including examining any 

interactions between the effects of ICD in patients with different etiologies of HF, or by ethnic 

background, gender, age, comorbidities, NYHA class, and baseline medication use) could not be 

performed due to our inability to obtain individual patient-level data from these trials. Although 

only one trial reported a significant subgroup effect (the SCD-HeFT Investigators140 reported that 

the mortality benefits of ICD were greater in patients with NYHA class II symptoms than those 

with NYHA class III symptoms at baseline – p<0.001), it should be noted that these trials were 

not powered to detect such subgroup effects. A series of univariate meta-regression sensitivity 

analyses on the primary outcome (all-cause mortality) were performed. As shown in the table 

below, none of the covariates we examined contributed to the moderate heterogeneity observed 

in our meta-analysis of all-cause mortality. As with our meta-regressions with the CRT trials, it 

should be noted these analyses are based on aggregate level data from a small number of 

relatively homogenous trials. There were too few studies reporting HF hospitalizations or any of 

the other secondary outcomes to do meta-regressions on those outcomes. 

Table 20. Univariate meta-regression subgroup analyses: ICD alone 

Covariate All-cause mortality 

(p-values) 

Presence of CRT 0.92 

Length of followup 0.90 

Ischemic etiology (%) 0.46 

NYHA class IV (%) 0.62 

NYHA class II (%) 0.81 

NYHA Class I (%) 0.13 

Mean age (years) 0.995 

Mean QRS interval (msec) 0.82 

Mean LVEF (%) 0.84 

Secondary vs. primary prevention 0.56 
126

Although the single trial that included CRT in the two study arms for its comparison of ICD 

vs. control failed to achieve statistical significance for all-cause mortality (RR = 0.83; 95% CI, 

0.66 to 1.05), the point estimate was almost identical to that reported in the remainder of the 

studies which did not contain CRT in either arm (RR = 0.79; 95% CI, 0.69 to 0.91). The 

difference between this single trial and the other CRT trials was not statistically significant (p = 

0.93), supporting the assertion that the benefits of ICD on all-cause mortality are not appreciably 

altered by addition of a CRT. ICDs were equally beneficial in reducing all-cause mortality in 

both primary prevention trials (RR = 0.81; 95% CI, 0.69 to 0.95) and secondary prevention trials 

(RR = 0.77; 95% CI, 0.65 to 0.91)—see Figure 20 (p-value for comparison = 0.59). 

Publication Bias. There was no indication of any publication bias for our primary outcome (allcause mortality) when comparing ICD to control. The funnel plot did not appear asymmetric 

(Figure 21), and Begg’s rank correlation test (p = 0.54), Egger’s regression test (p = 0.81) and 

Duval’s trim and fill (no studies added) all indicated that there was little possibility that 

publication bias influenced these results. 

Quantitative Results: Effectiveness Review 

CRT Alone 

All-Cause Mortality. As shown in Figure 22, mortality over time was similar in the randomized 

trials and the observational studies for patients who received CRT devices. One observational 

study had contemporaneous control group permitting calculation of a relative risk for all-cause 

mortality and mode of death analyses—the effectiveness point estimates were almost identical to 

the efficacy estimates, although none were statistically significant due to the small number of 

events (all-cause mortality RR = 0.64; 95% CI, 0.26 to 1.56; Figure 4; progressive HF mortality 

RR = 0.68; 95% CI, 0.16 to 2.92; Figure 5; and sudden cardiac death RR = 0.61; 95% CI, 0.18 to 

2.04; Figure 6). 

Left Ventricular Ejection Fraction. The effectiveness estimate from the one controlled 

observational study that reported this outcome was consistent with our findings in the efficacy 

trials (WMD = 4.6 percent; 95% CI, 2.68 to 6.34 percent; Figure 12). 

Other Endpoints. No controlled observational studies reported non-cardiac deaths, heart failure 

hospitalizations, New York Heart Association functional class, 6-minute walk test results, or 

quality of life assessments. 

Nonresponse Rates. As outlined in Table 21, 22 studies reported on response rates in CRT 

recipients. Since the definitions varied between studies, these data were not meta-analyzed. The 

reported response rates varied between 63 percent and 82 percent in those studies using 

definitions of response based on functional status and between 55 percent and 69 percent in those 

studies employing echocardiographic definitions for response. Various parameters have been 

reported in some of these studies to predict response to CRT, but no factors were found to be 

independent predictors consistently across studies (Table 21). Without access to individual 
127

patient data from these studies it was not possible to perform multivariate analyses to define 

predictors of response in the pooled data. 

Table 21. Response rates reported in observational studies: CRT alone or combined CRT-ICD devices 

Author 

Year Definition of responder Followup Sample size 

Proportion of 

responders, % 

Independent 

predictors of 

positive response 

Functional definition of response 

CRT alone

Bleeker30 

2005a 

Improved ≥1 NYHA class 6 mo. 170 78 Analysis by age < 70 vs. 

≥ 70 yrs. (NS) 

Chan43 

2003 

6MWT increased 10% 3 mo. 63 67 Not done 

Lecoq68 

2004 

Alive, no CHF 

hospitalizations, improved 

≥1 NYHA class or > 10% 

increase VO2 max during 

6MWT 

6 mo. 139 72 ∆ QRS (step of 20 msec) 

Lenom69 

2005 

Improved NYHA class 6 mo. 36 71 Not done 

Molhoek82 

2005 

Improved ≥1 NYHA class 6 mo. 74 68 Analysis by etiology (NS) 

Sawhney105 

2004 

Improved ≥1 NYHA class 3 mo. 40 63 Acute response to CRT 

by aortic Doppler VTI 

Stahlberg108 

2005 

Alive, no CHF 

hospitalizations, improved 

≥1 NYHA class and/or 

10% increase in 6MWT 

distance 

6 mo. 35 66 Not done 

Combined CRT-ICD 

Alonso21 

1999 

Alive, improved ≥1 NYHA 

class, 10% increase in 

peak VO2 

6 mo. 26 73 Not done 

Bax29 2004 Improved ≥1 NYHA class, 

improved 6MWT ≥25% 

6 mo. 85 74 Baseline LV 

dyssynchrony of ≥ 65ms 

DiazInfante49 

2005 

Alive, no heart transplant, 

10% increase in 6MWT 

6 mo. 143 80 Etiology, mitral 

regurgitation, LVEDD 

< 75mm 

Hernandez59 

2004 

Improved 6MWT ≥10% 6 mo. 28 79 BNP level, etiology, 

baseline NYHA 

Kies61 2005 Improved ≥1 NYHA class 6 mo. 97 74 Analysis by diabetes 

mellitus vs. no diabetes 

mellitus (NS) 

Molhoek79 

2004a 

Improved ≥1 NYHA class 6 mo. 60 72 Not done 

Molhoek80 

2004b 

Improved ≥1 NYHA class 6 mo. 117 78 NYHA = III vs. IV 

Molhoek81 

2004c 

Improved ≥1 NYHA class 6 mo. 61 74 Analysis by baseline QRS 

(NS) 

Reuter100 

2002 

Improved NYHA class 

associated with improved 

QOL score 

12 mo. 102 82 Etiology, cardiac output 

Echocardiographic definition of response 

 CRT alone 

Bax28 2003 Absolute Increase in LVEF 

≥ 5% 

6 mo. 25 68 Septal to lateral delay 

Penicka93 

2004 

Relative Increase in LVEF 

≥ 25% 

6 mo. 49 55 Tissue doppler imaging 

derived indices of 

asynchrony 
128

Table 21. Response rates reported in observational studies: CRT alone or combined CRT-ICD devices 

(continued)

Author 

Year Definition of responder Followup Sample size 

Proportion of 

responders, % 

Independent 

predictors of 

positive response 

Yu118 2002a LV reverse modeling 

(reduction in LV endsystolic volume > 10%) 

3-6 mo. 141 62 Reduced LVESV ≥9.5% 

(significant predictor of allcause mortality) 

Multiple definitions of response

 CRT alone

Mascioli76 

2002 

Improved ≥ 1 NYHA class, 

LVEF increased by ≥ 10% 

6 mo. 68 69 Analysis performed but 

none found 

Yu120 2004 LV reverse modeling 

(reduction in LV endsystolic volume > 15%) 

3 mo. 30 57 Systolic dyssynchrony by 

tissue doppler imaging 

 Combined CRT-ICD

Notabartolo88 

2004 

2 of 3: Improved ≥ 1 

NYHA class; > 50 meter 

increase in 6MWT; 

decrease QOL score = 15 

pts; or reduction in LV 

end-systolic volume >15% 

3 mo. 49 Echocardiographic 

response 

 = 59 

clinical 

response 

 = 75 

PVD predicted 

echocardiographic 

response; 

no significant predictors of 

clinical response 

CRT = cardiac resynchronization therapy; CRT+ICD = CRT with implanted cardioverter defibrillator; LV = left 

ventricular; LVEF = left ventrular ejection fraction; NS = not significant; NYHA = New York Heart Association class; 

QOL = Quality of life; 6MWT = 6-minute walk test; VO2 max = maximal oxygen consumption 

Combined CRT-ICD Devices 

There were no controlled effectiveness studies which compared combined CRT-ICD to 

contemporaneous controls. 

ICD Alone 

All-Cause Mortality. The benefit of ICD on all-cause mortality was greater in the 11 

observational studies with contemporaneous control groups than in the RCTs (Figure 15). The 

pooled relative risk was 0.54 (95% CI, 0.43 to 0.68), although heterogeneity was substantial (I2 = 

60 percent). As shown in Figure 23, mortality over time was similar in the randomized trials and 

the observational studies for patients who received ICD devices. 

Progressive Heart Failure Mortality. Three observational controlled studies reported this 

outcome, although the result was not significant (RR = 1.15; 95% CI, 0.50 to 2.66; I2

 = 30 

percent). 

Sudden Cardiac Death. The effectiveness estimate derived from eight observational studies 

with control groups was greater than the estimate from the RCTs (RR = 0.33; 95% CI, 0.23 to 

0.46; I2

 = 0 percent; Figure 17). 

Non-Cardiac Death. The effectiveness estimate derived from the eight observational studies 

with control groups revealed a benefit in favor of ICD (RR = 0.74; 95% CI, 0.65 to 0.85; I2 = 0 

percent; Figure 18). This unexpected result suggests that clinicians do select healthier patients for 

ICD insertion since ICD alone should not impact noncardiac deaths. 
129

No controlled observational studies reported HF hospitalizations, quality of life, or changes 

in NYHA functional class or 6-minute walk test with ICD. 

Mortality Comparison Across Devices and Study Types

We evaluated all-cause mortality vs. length of followup in all studies that followed patients 

with CRT alone, ICD alone, or combined CRT-ICD. Mortality increased as length of followup 

increased; however, we were interested in differences in rates of increase in each of the three 

groups. A weighted regression was performed for each group. The plots, along with best fitting 

regression line, are represented in Figures 22, 23, and 24. 

The CRT studies had an increase in mortality of approximately 5.9 percent with each 

followup year. This was slightly higher for the combined CRT-ICD device group with a per 

annum increase of 6.2 percent. However, the ICD alone group had the smallest increase in 

annual mortality at 3.7 percent. It should be noted that the ICD studies tended to be much longer 

in duration than the CRT studies and this may have skewed these results. 

 

Quantitative Results: Safety Review 

CRT Alone 

Fifty-four studies (n = 6,123 patients) reported data which permitted us to examine the safety 

of CRT. Table 22 reports peri-implantation and post-implantation risks from individual studies 

as well as pooled results for CRT alone devices. During data pooling, studies that did not report 

any data for particular outcomes were excluded. 

Peri-Implantation Risks. Twenty-four studies reported data on deaths while undergoing 

implantation of a biventricular pacemaker. There were 8 deaths in 2,571 patients (pooled risk = 

0.3 percent, 95% CI, 0.1 to 0.6 percent). Implants of devices were successful in 93 percent (95% 

CI, 92.2 to 93.7 percent) of attempts in 4,625 patients from 41 studies. Twenty-one studies that 

reported on peri-implantation mechanical complications showed a frequency of 4.3 percent (95% 

CI, 3.6 to 5.1 percent) in 3,139 patients. Of note, implant success rates and peri-implantation 

risks were no different in the CRT RCTs as in the observational studies conducted in non-trial 

settings. 

Post-Implantation Risks. Post-implant mechanical malfunction was reported to be 4.0 percent 

(95% CI 3.0 to 5.2 percent) over a median followup of 12 months in 9 studies (1,316 patients), 

with no appreciable difference between the frequencies reported in observational studies vs. 

RCTs (Table 17). The device malfunction frequency was 5.4 percent (95% CI, 4.2 to 6.7 percent) 

over a median followup of 6 months in 20 studies (1,339 patients), post-implant lead problems 

were reported in 6.6 percent (95% CI, 5.8 to 7.4 percent) of patients over a median followup of 

11 months in 32 studies (3,649 patients), and post-implant infections occurred in 1.8 percent 

(95% CI, 1.3 to 2.5 percent) of patients as reported in 16 studies (2,088 patients)—none of these 

outcomes differed between the CRT RCTs and the observational studies. The frequency of postimplant arrythmias attributed to the CRT device occurred in a far higher proportion of patients in 
130

the CRT RCTs (12 percent; 95% CI, 9.5 to 14.9 percent) than in the observational studies (5.4 

percent; 95% CI, 2.4 to 10.4 percent), likely reflecting the closer followup in RCTs. 

Combined CRT-ICD Devices 

Thirty-six studies (5,199 patients) reported data which permitted the examination of the 

safety of combined CRT-ICD. Table 21 report peri-implantation and post-implantation risks 

from individual studies as well as pooled results. During data pooling, studies that did not report 

any data for particular outcomes were excluded. 

Peri-Implantation Risks. Twenty studies reported data on deaths while undergoing 

implantation of a CRT and ICD: there were 13 deaths in 2,731 patients (pooled risk = 0.5 

percent; 95% CI, 0.2 to 0.8 percent). Implants of devices were successful in 93.7 percent (95% 

CI, 92.9 to 94.4 percent) of attempts in 4,163 patients from 28 studies. Ten studies that reported 

on peri-implantation mechanical complications showed a frequency of 4.6 percent (95% CI, 3.7 

to 5.6 percent) in 1,889 patients. Of note, implant success rates and peri-implantation risks were 

no different in the combined CRT-ICD RCTs as in the observational studies of these devices 

conducted in non-trial settings (Table 21). 

Post-Implantation Risks. Post-implant mechanical malfunction was reported in 4.6 percent 

(95% CI, 3.5 to 6.0 percent) of patients from five studies (n = 1,102 patients), the device 

malfunction frequency was 5.0 percent (95% CI, 4.0 to 6.3 percent) over 12 months in nine 

studies (1,411 patients), and the frequency of post-implant infections was 1.1 percent (95% CI, 

0.7 to 1.7 percent) over 12 months in 10 studies (1,791 patients)—none of these outcomes 

differed between the combined CRT-ICD RCTs and the observational studies. Post-implant lead 

problems were reported in 9.8 percent (95% CI, 8.2 to 11.6 percent) of RCT participants 

compared to 5.7 percent (95% CI, 4.8 to 6.8 percent) of patients in observational studies, again 

likely reflecting closer scrutiny in the RCT setting or a publication bias in the observational data. 

While post-implant arrythmias occurred in 6.4 percent (95% CI, 4.6 to 8.7 percent) of patients in 

two studies (609 patients) which recorded this outcome, inappropriate shocks occurred in 6.0 

percent (95% CI, 4.8 to 7.5 percent) of patients over 12 months in the nine studies (1,210 

patients) which evaluated this outcome. 

ICD Alone 

As previously described, 49 studies were used to examine the safety of ICD alone. Table 22 

reports peri-implantation and post-implantation risks from individual studies as well as pooled 

results. During data pooling, studies that did not report any data for particular outcomes were 

excluded. 

Peri-Implantation Risks. Twenty-eight studies reported data on deaths while undergoing 

implantation of an ICD: there were 59 deaths in 4,902 patients (pooled risk 1.2 percent, 95% CI, 

0.9 to 1.5 percent). Implants of devices were successful in 99.0 percent (95% CI, 98.8 to 99.3 

percent) of attempts in 6,189 patients from 24 studies. Eighteen studies that reported on periimplantation mechanical complications showed a frequency of 5.3 percent (95% CI, 4.6 to 6.2 

percent) in 3,299 patients. Of note, implantation success rates were significantly lower and peri-
131

implantation death rates were significantly higher in the ICD RCTs compared to the 

observational studies. This difference likely reflects closer scrutiny in the RCT setting or a 

publication bias in the observational data. 

We also examined peri-implant deaths and success rates for studies that enrolled all patients 

undergoing ICD implant, not just those patients with left ventricular systolic dysfunction. Ten 

studies (34,956 patients) demonstrated a peri-implant death rate of 1.3 percent (95% CI, 1.2 to 

1.4 percent). Seven studies (4,940 patients) reported an implant success rate of 98.6 percent 

(95% CI, 98.3, 98.9). Both of these frequencies (for implant success and peri-implant death) 

were very similar to the rates reported in studies restricted to patients with left ventricular 

systolic dysfunction. 

Post-Implantation Risks. Implantation mechanical malfunction was reported in 18 studies 

representing 3,299 patients. The malfunction frequency was 5.3 percent (95% CI, 4.6 to 6.2 

percent). The frequency of post-implant mechanical malfunction from 9 studies (2,190 patients) 

was 2.0 percent (95% CI, 1.5 to 2.7 percent; 0.6 per 100 patient-years [95% CI 0.5 to 0.8]) and 

the frequency of post-implant device malfunction from 10 studies (2,569 patients) was 5.8 

percent (95% CI, 4.9 to 6.7 percent; 1.4 per 100 patient-years [95% CI 1.2 to 1.6])—both 

frequencies were similar in RCTs as in observational studies. Post-implant lead problems were 

reported in 16 studies (3,713 patients) and although the pooled rate was 4.3 percent (95% CI, 3.7 

to 5.0 percent; 1.5 per 100 patient-years [95% CI 1.3 to 1.8] ), the rate was far lower in RCT data 

(1.7 percent, 95% CI 1.2 to 2.3 percent) compared to observational data (8.7 percent, 95% CI 7.3 

to 10.3 percent). The frequency of post-implant infections was 1.8 percent (95% CI, 1.4 to 2.2 

percent; 0.6 per 100 patient-years [95% CI 0.5 to 0.8]) as reported in 17 studies of 4,232 patients, 

but was lower in observational studies (1.1 percent, 95% CI, 0.6 to 1.7 percent) than RCTs (2.3 

percent, 95% CI 1.7 to 2.9 percent). The different direction for these two outcomes (one more 

frequent in RCTs, the other more frequent in observational studies) raises the possibility that lead 

infections may have been classified as “lead problems” in some studies but “lead infections” in 

other studies. The frequency of inappropriate shocks was substantially higher in RCT 

participants—38.8 percent, 95% CI, 33.9 to 43.7 percent, or 19.1 per 100 patient years [95% CI, 

16.5 to 22.0] over 24 months of followup vs. 16.3 percent, 95% CI, 15.0 to 17.7 percent, or 4.7 

per 100 patient-years [95% CI, 4.3 to 5.1] over 24 months of followup in the observational 

studies (pooled 5.8 per 100 patient-years [95% CI, 5.4 to 6.2]). 
132

Table 22. Peri- and post-implantation risks: CRT alone 

Trial name, Author 

Study year n/N Simple pool 

risk, % [95% CI] 

Peri-implant deaths: RCT 

COMPANION11 2004 2/699 0.3 [0.0, 1.0] 

MUSTIC-AF7 2002 0/59 0.0 [0.0, 5.0] 

MUSTIC-SR5 2001 1/58 1.7 [0.0, 9.2] 

PATH-CHF8 2002a 0/41 0.0 [0.0, 7.0] 

Sub-Total: 3/857 0.4 [0.1, 1.0] 

Peri-implant deaths: Observational studies 

Bleeker31 2005b 0/56 0.0 [0.0, 5.2] 

Bordachar35 2004 0/41 0.0 [0.0, 7.0] 

Cazeau41 2003 0/66 0.0 [0.0, 4.4] 

Daubert46 1998 0/47 0.0 [0.0, 6.2] 

De Martino125 2004 0/34 0.0 [0.0, 8.4] 

Galvao56 2002 3/28 10.7 [2.3, 28.2] 

Kautzner128 2004 0/46 0.0 [0.0, 6.3] 

Koos63 2004 0/81 0.0 [0.0, 3.6] 

Leclercq67 2002b 0/139 0.0 [0.0, 2.1] 

Lecoq68 2005 0/158 0.0 [0.0, 1.9] 

Leon70 2005 1/422 0.2 [0.0, 1.3] 

Mair73 2005 0/80 0.0 [0.0, 3.7] 

Molhoek79 2004a 0/74 0.0 [0.0, 4.0] 

Nagele85 2001 0/32 0.0 [0.0, 8.9] 

Niu87 2006 0/117 0.0 [0.0, 2.5] 

Ollitrault91 2003 0/62 0.0 [0.0, 4.7] 

Penicka93 2004 1/55 1.8 [0.0, 9.7] 

Schuchert132 2004 0/102 0.0 [0.0, 2.9] 

Stahlberg108 2005 0/40 0.0 [0.0, 7.2] 

Toussaint113 2003 0/34 0.0 [0.0, 8.4] 

Sub Total 5/1714 0.3 [0.1, 0.7] 

Total [N=24] 8/2571 0.3 [0.1, 0.6] 

Implant success rate: RCT 

COMPANION11 2004 617/699 88.3 [85.6, 90.6] 

MIRACLE4 2002 528/571 92.5 [90.0, 94.5] 

MUSTIC-AF7 2002 54/59 91.5 [81.3, 97.2] 

MUSTIC-SR5 2001 58/64 90.6 [80.7, 96.5] 

PATH-CHF8 2002a 41/41 100.0 [93.0, 100.0] 

PATH-CHF II12 2003 86/89 96.6 [90.5, 99.3] 

Sub-Total: 1384/1523 90.9 [89.3, 92.3] 

Implant success rate: Observational studies 

Albertsen20 2005 120/120 100.0 [97.5, 100.0] 

Baker27 2002 54/60 90.0 [79.5, 96.2] 

Bleeker30 2005a 170/170 100.0 [98.3, 100.0] 

Bleeker31 2005b 56/56 100.0 [94.8, 100.0] 

Bleeker32 2006 100/100 100.0 [97.0, 100.0] 

Bordachar35 2004 41/41 100.0 [93.0, 100.0] 

Daubert46 1998 35/47 74.5 [59.7, 86.1] 

De Martino126 2005 82/83 98.8 [93.5, 100.0] 

De Martino125 2004 30/34 88.2 [72.5, 96.7] 

Dixon50 2004 27/27 100.0 [89.5, 100.0] 

Galvao56 2002 28/28 100.0 [89.9, 100.0] 

Gras58 2002 125/139 89.9 [83.7, 94.4] 

RCT=randomized control trial 
133

Table 22. Peri- and post-implantation risks: CRT alone (continued) 

Trial name, Author 

Study year n/N 

Simple pool 

risk, % [95% CI] 

Implant success rate: Observational studies (continued) 

Hua60 2006 142/149 95.3 [90.6, 98.1] 

Kautzner128 2004 42/46 91.3 [79.2, 97.6] 

Leclercq67 2002b 125/139 89.9 [83.7, 94.4] 

Lecoq68 2005 139/158 88.0 [81.9, 92.6] 

Leon70 2005 397/422 94.1 [91.4, 96.1] 

Lewika-Nowak1292005 80/92 87.0 [78.3, 93.1] 

Mair73 2005 80/80 100.0 [96.3, 100.0] 

Mascioli762002 95/96 99.0 [94.3, 100.0] 

Molhoek80 2004b 74/74 100.0 [96.0, 100.0] 

Molhoek78 2002 40/40 100.0 [92.8, 100.0] 

Mortensen83 2004 189/198 95.5 [91.5, 97.9] 

Nagele85 2001 28/32 87.5 [71.0, 96.5] 

Niu87 2006 111/117 94.9 [89.2, 98.1] 

O'Donnell89 2005 58/63 92.1 [82.4, 97.4] 

Ollitrault91 2003 38/62 61.3 [48.1, 73.4] 

Penicka93 2004 53/55 96.4 [87.5, 99.6] 

Romeyer-Bouchard131 2005 99/103 96.1 [90.4, 98.9] 

Sawhney105 2004 40/40 100.0 [92.8, 100.0] 

Schuchert132 2004 96/102 94.1 [87.6, 97.8] 

Stahlberg108 2005 35/40 87.5 [73.2, 95.8] 

Tousaint1132003 34/34 100.0 [91.6, 100.0] 

Yu119 2002b 30/30 100.0 [90.5, 100.0] 

Yu118 2002a 25/25 100.0 [88.7, 100.0] 

Sub-Total: 2918/3102 94.1 [93.2, 94.9] 

Total [N=41] 4302/4625 93.0 [92.2, 93.7] 

Implantation mechanical complication: RCT 

CARE-HF15 2005 16/409 3.9 [2.3, 6.3] 

COMPANION11 2004 12/617 1.9 [1.0, 3.4] 

PATH CHF II12 2003 6/98 6.1 [2.3, 12.9] 

Sub-Total: 34/1124 3.0 [2.1, 4.2] 

Implantation mechanical complication: Observational studies 

Albertsen202005 2/120 1.7 [0.2, 5.9] 

Baker27 2002 1/60 1.7 [0.0, 8.9] 

de Cock124 2004 7/103 6.8 [2.8, 13.5] 

De Martino126 2005 4/83 4.8 [1.3, 11.9] 

De Martino125 2004 4/34 11.8 [3.3, 27.5] 

Dixon50 2004 0/27 0.0 [0.0, 10.5] 

Kautzner128 2004 9/46 19.6 [9.4, 33.9] 

Koos63 2004 3/81 3.7 [0.8, 10.4] 

Lecoq68 2005 2/102 2.0 [0.2, 6.9] 

Lenom69 2005 1/36 2.8 [0.1, 14.5] 

Leon70 2005 28/422 6.6 [4.5, 9.4] 

Mortensen83 2004 3/189 1.6 [0.3, 4.6] 

Nagele85 2001 7/32 21.9 [9.3, 40.0] 

Niu87 2006 9/117 7.7 [3.6, 14.1] 

Puglisi97 2004 10/315 3.2 [1.5, 5.8] 

Purnode98 2004 1/43 2.3 [0.1, 12.3] 

Romeyer-Bouchard131 2005 1/103 1.0 [0.0, 5.3] 

Schuchert132 2004 10/102 9.8 [4.8, 17.3] 

Sub Total 102/2015 5.1 [4.1, 6.1] 

Total [N=21] 136/3139 4.3 [3.6, 5.1] 
134

Table 22. Peri- and post-implantation risks: CRT alone (continued) 

Trial name, Author 

Study year n/N 

Simple pool 

risk, % [95% CI] 

Post-implant mechanical malfunction: RCT 

CARE-HF15 2005 8/409 2.0 [0.8, 3.8] 

MUSTIC-AF7 2002 2/54 3.7 [0.5, 12.7] 

MUSTIC-SR5 2001 2/58 3.4 [0.4, 11.9] 

Sub-Total 12/521 2.3 [1.2, 4.0] 

Post-implant mechanical malfunction: Observational studies 

Dixon50 2004 0/27 0.0 [0.0, 10.5] 

Gras58 2002 4/103 3.9 [1.1, 9.6] 

Koos63 2004 1/81 1.2 [0.0, 6.7] 

Leclercq66 2000 3/37 8.1 [1.7, 21.9] 

Leclercq67 2002b 25/125 20.0 [13.4, 28.1] 

 Leon70 2005 8/422 1.9 [0.8, 3.7] 

Sub Total 41/795 5.2 [3.7, 6.9] 

Total [N=9] 53/1316 4.0 [3.0, 5.2] 

Post-implant device malfunction: RCT 

MUSTIC-SR5 2001 2/67 3.0 [0.4, 10.4] 

VECTOR16 2005 11/120 9.2 [4.7, 15.8] 

Kindermann13 2006 1/30 3.3 [0.1, 17.2] 

Sub-Total: 14/217 6.5 [3.6, 10.6] 

Post-implant device malfunction: Observational studies 

Albertsen20 2005 11/120 9.2 [4.7, 15.8] 

Bordachar35 2004 1/41 2.4 [0.1, 12.9] 

Braun39 2005 1/65 1.5 [0.0, 8.3] 

Chalil42 2006 0/75 0.0 [0.0, 3.9] 

Dixon50 2004 0/27 0.0 [0.0, 10.5] 

Galvao56 2002 3/28 10.7 [2.3, 28.2] 

Kautzner128 2004 2/46 4.3 [0.5, 14.8] 

Lecoq68 2005 18/102 17.6 [10.8, 26.4] 

Lenom69 2005 1/36 2.8 [0.1, 14.5] 

Lewicka-Nowak129 2005 2/92 2.2 [0.3, 7.6] 

Mortensen83 2004 2/189 1.1 [0.1, 3.8] 

Ollitrault91 2003 2/62 3.2 [0.4, 11.2] 

Penicka93 2004 1/55 1.8 [0.0, 9.7] 

Purnode98 2004 1/43 2.3 [0.1, 12.3] 

Romeyer-Bouchard131 2005 1/10 10.0 [0.3, 44.5] 

Schuchert132 2004 8/96 8.3 [3.7, 15.8] 

Stahlberg1082005 4/35 11.4 [3.2, 26.7] 

Sub Total 58/1122 5.2 [3.9, 6.6] 

Total [N=20] 72/1339 5.4 [4.2, 6.7] 

Post-implant lead problems: RCT 

CARE-HF15 2005 24/409 5.9 [3.8, 8.6] 

MIRACLE4 2002 30/524 5.7 [3.9, 8.1] 

MUSTIC-AF7 2002 5/54 9.3 [3.1, 20.3] 

MUSTIC-SR5 2001 8/67 11.9 [5.3, 22.2] 

VECTOR16 2005 8/120 6.7 [2.9, 12.7] 

Kindermann13 2006 2/30 6.7 [0.8, 22.1] 

Sub-Total: 77/1204 6.4 [5.1, 7.9] 

Post-implant lead problems: Observational studies 

Albertsen20 2005 6/120 5.0 [1.9, 10.6] 

Baker27 2002 1/60 1.7 [0.0, 8.9] 

Braun39 2005 1/65 1.5 [0.0, 8.3] 

Chalil42 2006 5/75 6.7 [2.2, 14.9] 

Dixon50 2004 0/27 0.0 [0.0, 10.5] 

Galvao56 2002 1/28 3.6 [0.1, 18.3] 
135

Table 22. Peri- and post-implantation risks: CRT alone (continued) 

Trial name, Author 

Study year n/N 

Simple pool 

risk, % [95% CI] 

Gras58 2002 10/103 9.7 [4.8, 17.1] 

Kautzner128 2004 5/46 10.9 [3.6, 23.6] 

Koos63 2004 18/81 22.2 [13.7, 32.8] 

Leclercq66 2000 2/37 5.4 [0.7, 18.2] 

Leclercq67 2002b 15/125 12.0 [6.9, 19.0] 

Lecoq68 2005 7/102 6.9 [2.8, 13.6] 

Lenom69 2005 1/36 2.8 [0.1, 14.5] 

Leon70 2005 22/422 5.2 [3.3, 7.8] 

Lewicka-Nowak129 2005 12/92 13.0 [6.9, 21.7] 

Molhoek78 2002 3/40 7.5 [1.6, 20.4] 

Mortensen83 2004 12/189 6.3 [3.3, 10.8] 

Nagele85 2001 2/32 6.3 [0.8, 20.8] 

Niu87 2006 2/117 1.7 [0.2, 6.0] 

Ollitrault91 2003 2/62 3.2 [0.4, 11.2] 

Puglisi97 2004 12/315 3.8 [2.0, 6.6] 

Purnode98 2004 1/43 2.3 [0.1, 12.3] 

Romeyer-Bouchard131 2005 7/103 6.8 [2.8, 13.5] 

Sawhney105 2004 2/40 5.0 [0.6, 16.9] 

Stahlberg108 2005 4/35 11.4 [3.2, 26.7] 

Taieb109 2002 10/50 20.0 [10.0, 33.7] 

Sub Total 163/2445 6.7 [5.7, 7.7] 

Total [N=32] 240/3649 6.6 [5.8, 7.4] 

Post-implant infections: RCT 

MIRACLE4 2002 7/524 1.3 [0.5, 2.7] 

Sub-Total: 7/524 1.3 [0.5, 2.7] 

Post-implant infections: Observational studies 

Albertsen20 2005 3/120 2.5 [0.5, 7.1] 

Baker27 2002 3/60 5.0 [1.0, 13.9] 

Daubert46 1998 0/47 0.0 [0.0, 6.2] 

Dixon50 2004 0/26 0.0 [0.0, 10.9] 

Galvao56 2002 1/28 3.6 [0.1, 18.3] 

Gras58 2002 2/103 1.9 [0.2, 6.8] 

Koos63 2004 0/79 0.0 [0.0, 3.7] 

Leclercq67 2002b 15/125 12.0 [6.9, 19.0] 

Leon70 2005 3/422 0.7 [0.1, 2.1] 

Lewicka-Nowak129 2005 1/92 1.1 [0.0, 5.9] 

Mortensen83 2004 0/189 0.0 [0.0, 1.6] 

Ollitrault91 2003 1/38 2.6 [0.1, 13.8] 

Romeyer-Bouchard131 2005 1/99 1.0 [0.0, 5.5] 

Schuchert132 2004 0/102 0.0 [0.0, 2.9] 

Toussaint113 2003 1/34 2.9 [0.1, 15.3] 

Sub Total 31/1564 2.0 [1.4, 2.8] 

Total [N=16] 38/2088 1.8 [1.3, 2.5] 

Post-implant arrhythmias: RCT 

CARE-HF15 2005 64/409 15.6 [12.3, 19.5] 

MUSTIC-AF7 2002 1/54 1.9 [0.0, 9.9] 

PATH-CHF8 2002a 4/41 9.8 [2.7, 23.1] 

PATH-CHF II12 2003 2/86 2.3 [0.3, 8.1] 

Sub-Total: 71/590 12.0 [9.5, 14.9] 
136

Table 22. Peri- and post-implantation risks: CRT alone (continued) 

Trial name, Author 

Study year n/N 

Simple pool 

risk, % [95% CI] 

Post-implant arrhythmias: Observational studies 

Dixon50 2004 0/27 0.0 [0.0, 10.5] 

Koos63 2004 7/81 8.6 [3.5, 17.0] 

Molhoek78 2002 1/40 2.5 [0.1, 13.2] 

Sub Total 8/148 5.4 [2.4, 10.4] 

Total [N=7] 79/738 10.7 [8.6, 13.2] 
137

Table 23. Peri- and post-implantation risks: combined CRT-ICD devices 

Study, Author 

Year n/N Simple pool risk, % [95% CI] 

Peri-implant deaths: RCT 

COMPANION11 2004 3/595 0.5 [0.1, 1.5] 

CONTAK-CD9 2003 2/490 0.4 [0.0, 1.5] 

Sub-Total 5/1085 0.5 [0.1, 1.1] 

Peri-implant deaths: Observational studies 

Ammann22 2004 0/43 0.0 [0.0, 6.7] 

Azizi26 2006 0/244 0.0 [0.0, 1.2] 

Bax29 2004 0/85 0.0 [0.0, 3.5] 

Bocchiardo33 2000 0/48 0.0 [0.0, 6.1] 

Cowburn44 2005 0/68 0.0 [0.0, 4.3] 

Da Costa45 2006 0/67 0.0 [0.0, 4.4] 

de Sisti48 2005 0/102 0.0 [0.0, 2.9] 

Diaz-Infante49 2005 2/147 1.4 [0.2, 4.8] 

Ellery52 2005 0/85 0.0 [0.0, 3.5] 

Ermis53 2004 0/62 0.0 [0.0, 4.7] 

Molhoek81 2004c 0/61 0.0 [0.0, 4.8] 

Navia86 2005 0/41 0.0 [0.0, 7.0] 

Pitzalis94 2005 0/63 0.0 [0.0, 4.6] 

Reuter100 2002 0/102 0.0 [0.0, 2.9] 

Salukhe104 2005 0/40 0.0 [0.0, 7.2] 

Saxon106 2006 5/168 3.0 [1.0, 6.8] 

Teo111 2003 0/29 0.0 [0.0, 9.8] 

 Ypenburg117 2006 1/191 0.5 [0.0, 2.9] 

Sub Total 8/1646 0.5 [0.2, 1.0] 

Total [N=20] 13/2731 0.5 [0.3, 0.8] 

Implant success rate: RCT 

COMPANION11 2004 541/595 90.9 [88.3, 93.1] 

CONTAK-CD9 2003 501/501 100.0 [99.4, 100.0] 

MIRACLE-ICD6 2003 379/429 88.3 [84.9, 91.2] 

Sub-Total 1421/1525 93.2 [91.8, 94.4] 

Implant success rate: Observational studies 

Ammann22 2004 43/47 91.5 [79.6, 97.6] 

Azizi26 2006 240/244 98.4 [95.9, 99.6] 

Bax29 2004 85/85 100.0 [96.5, 100.0] 

Bocchiardo33 2000 48/51 94.1 [83.8, 98.8] 

Boriani36 2006a 118/127 92.9 [87.0, 96.7] 

Cowburn44 2005 63/68 92.6 [83.7, 97.6] 

Da Costa45 2006 68/71 95.8 [88.1, 99.1] 

Diaz-Infante49 2005 147/177 83.1 [76.7, 88.3] 

Ellery52 2005 85/96 88.5 [80.4, 94.1] 

Ermis53 2004 126/158 79.7 [72.6, 85.7] 

Gasparini57 2003a 158/159 99.4 [96.5, 100.0] 

Krahn64 2002 40/45 88.9 [75.9, 96.3] 

Kuhlkamp270 2002 81/84 96.4 [89.9, 99.3] 

Molhoek82 2005 125/125 100.0 [97.6, 100.0] 

Molhoek81 2004c 61/61 100.0 [95.2, 100.0] 

Navia86 2005 41/41 100.0 [93.0, 100.0] 

Pitzalis94 2005 63/65 96.9 [89.3, 99.6] 

Pürerfellner130 2000a 36/44 81.8 [67.3, 91.8] 

Pürerfellner130 2000b 135/150 90.0 [84.0, 94.3] 
138

Table 23. Peri- and post-implnantation risks: combined CRT-ICD 

(continued) 

Study, Author 

Year n/N Simple pool 

risk, % [95% CI] 

Reuter100 2002 89/102 87.3 [79.2, 93.0] 

Ritter102 2006 48/48 100.0 [93.9, 100.0] 

Rossillo103 2004 233/244 95.5 [92.1, 97.7] 

Salukhe104 2005 40/40 100.0 [92.8, 100.0] 

Teo111 2003 29/29 100.0 [90.2, 100.0] 

Theuns112 2005 86/86 100.0 [96.6, 100.0] 

 Ypenburg117 2006 191/191 100.0 [98.4, 100.0] 

Sub-Total: 2479/2638 94.0 [93.0, 94.9] 

Total [N=28] 3900/4163 93.7 [92.9, 94.4] 

 

Implantation mechanical complication: RCT 

COMPANION11 2004 10/595 1.7 [0.8, 3.1] 

MIRACLE ICD II14 2004 6/210 2.9 [1.1, 6.1] 

RHYTHM-ICD17 2005 33/205 16.1 [11.3, 21.9] 

Sub-Total: 49/1010 4.9 [3.6, 6.4] 

Implantation mechanical complication: Observational studies 

Ammann22 2004 1/47 2.1 [0.1, 11.3] 

Azizi26 2006 13/285 4.6 [2.5, 7.7] 

Boriani36 2006a 3/121 2.5 [0.5, 7.1] 

Pürerfellner130 2000a 2/44 4.5 [0.6, 15.5] 

RHYTHM ICD17 2005 8/162 4.9 [2.2, 9.5] 

Teo111 2003 1/29 3.4 [0.1, 17.8] 

 Ypenburg117 2006 9/191 4.7 [2.2, 8.8] 

Sub Total 37/879 4.2 [3.0, 5.8] 

Total [N=10] 86/1889 4.6 [3.7, 5.6] 

Post-implant mechanical malfunction: RCT 

CONTAK-CD9 2003 22/448 4.9 [3.1, 7.3] 

MIRACLE-ICD6 2003 25/364 6.9 [4.5, 10.0] 

Sub-Total: 47/812 5.8 [4.3, 7.6] 

Post-implant mechanical malfunction: Observational studies 

Kuhlkamp270 2002 1/84 1.2 [0.0, 6.5] 

Pürerfellner130 2000a 1/44 2.3 [0.1, 12.0] 

RHYTHM ICD17 2005 2/162 1.2 [0.1, 4.4] 

Sub Total 4/290 1.4 [0.4, 3.5] 

Total [N=5] 51/1102 4.6 [3.5, 6.0] 

Post-implant device malfunction: RCT 

RHYTHM-ICD17 2005 20/205 9.8 [6.1, 14.7] 

Sub-Total: 20/205 9.8 [6.1, 14.7] 

Post-implant device malfunction: Observational studies 

Azizi26 2006 5/285 1.8 [0.6, 4.0] 

Bocchiardo33 2000 2/42 4.8 [0.6, 16.2] 

Boriani36 2006a 8/121 6.6 [2.9, 12.6] 

Ellery52 2005 7/95 7.4 [3.0, 14.6] 

Gasparini57 2003a 2/142 1.4 [0.2, 5.0] 

RHYTHM ICD17 2005 25/162 15.4 [10.2, 21.9] 

Saxon106 2006 1/168 0.6 [0.0, 3.3] 

Ypenburg117 2006 1/191 0.5 [0.0, 2.9] 

Sub Total 51/1206 4.2 [3.2, 5.5] 

Total [N=9] 71/1411 5.0 [4.0, 6.3] 
139

Table 23. Peri- and post-implnantation risks: combined CRT-ICD 

(continued) 

Study, Author 

Year n/N Simple pool 

risk, % [95% CI] 

Post-implant lead problems: RCT 

CONTAK-CD9 2003 31/448 6.9 [4.7, 9.7] 

MIRACLE ICD6 2003 46/364 12.6 [9.4, 16.5] 

MIRACLE ICD II14 2004 19/191 9.9 [6.1, 15.1] 

RHYTHM ICD17 2005 22/205 10.7 [6.8, 15.8] 

Sub-Total: 118/1208 9.8 [8.2, 11.6] 

Post-implant lead problems: Observational studies 

Ammann22 2004 3/47 6.4 [1.3, 17.5] 

Azizi26 2006 13/285 4.6 [2.5, 7.7] 

Bocchiardo33 2000 3/42 7.1 [1.5, 19.5] 

Boriani36 2006a 31/121 25.6 [18.1, 34.4] 

Cowburn44 2005 4/68 5.9 [1.6, 14.4] 

Da Costa45 2006 3/67 4.5 [0.9, 12.5] 

Diaz-Infante49 2005 2/177 1.1 [0.1, 4.0] 

Ellery52 2005 5/95 5.3 [1.7, 11.9] 

Ermis53 2004 1/126 0.8 [0.0, 4.3] 

RHYTHM ICD17 2005 4/162 2.5 [0.7, 6.2] 

Gasparini127 2005 5/194 2.6 [0.8, 5.9] 

Krahn64 2002 4/40 10.0 [2.8, 23.7] 

Kuhlkamp270 2002 7/84 8.3 [3.4, 16.4] 

Molhoek82 2005 10/117 8.5 [4.2, 15.2] 

Pürerfellner130 2005a 4/44 9.1 [2.5, 21.7] 

Pürerfellner130 2005b 1/150 0.7 [0.0, 3.7] 

Reuter100 2002 4/91 4.4 [1.2, 10.9] 

Ritter102 2006 7/48 14.6 [6.1, 27.8] 

Salukhe104 2005 2/40 5.0 [0.6, 16.9] 

Saxon106 2006 11/168 6.5 [3.3, 11.4] 

Teo111 2003 2/29 6.9 [0.8, 22.8] 

Sub Total 126/2195 5.7 [4.8, 6.8] 

Total [N=25] 244/3403 7.2 [6.3, 8.1] 

Post-implant infections: RCT 

CONTAK CD9 (Knight 2004) 5/443 1.1 [0.4, 2.6] 

MIRACLE-ICD6 2003 2/364 0.5 [0.1, 2.0] 

Sub-Total: 7/807 0.9 [0.3, 1.8] 

Post-implant infections: Observational studies 

Azizi26 2006 2/285 0.7 [0.1, 2.5] 

Cowburn44 2005 1/68 1.5 [0.0, 7.9] 

Da Costa45 2006 1/67 1.5 [0.0, 8.0] 

Ellery52 2005 0/85 0.0 [0.0, 3.5] 

Kuhlkamp270 2002 2/84 2.4 [0.3, 8.3] 

Molhoek82 2005 0/125 0.0 [0.0, 2.4] 

Reuter100 2002 0/102 0.0 [0.0, 2.9] 

 Saxon106 2006 7/168 4.2 [1.7, 8.4] 

Sub Total 13/984 1.3 [0.7, 2.2] 

Total [N=10] 20/1791 1.1 [0.7, 1.7] 

Post-implant arrhythmias: RCT 

CONTAK-CD9 2003 36/245 14.7 [10.5, 19.8] 

MIRACLE-ICD6 2003 3/364 0.8 [0.2, 2.4] 

Total [N=2] 39/609 6.4 [4.6, 8.7] 
140

Table 23. Peri- and post-implnantation risks: combined CRT-ICD 

(continued) 

Study, Author 

Year n/N Simple pool 

risk, % [95% CI] 

Inappropriate shocks: RCT 

RHYTHM ICD17 2005 10/205 4.9 [2.4, 8.8] 

Sub-Total: 10/205 4.9 [2.4, 8.8] 

Inappropriate shocks: Observational studies 

Bocchiardo33 2000 6/42 14.3 [5.4, 28.5] 

Boriani36 2006 4/121 3.3 [0.9, 8.2] 

Chugh123 2005 12/77 15.6 [8.3, 25.6] 

Ermis53 2004 3/62 4.8 [1.0, 13.5] 

RHYTHM ICD17 2005 1/162 0.6 [0.0, 3.4] 

Gaita55 2000 4/96 4.2 [1.1, 10.3] 

Saxon106 2006 1/168 0.6 [0.0, 3.3] 

Theuns112 2005 18/86 20.9 [12.9, 31.0] 

Sub Total 63/1005 6.3 [4.9, 7.9] 

Total [N=9] 73/1210 6.0 [4.8, 7.5] 
141

Table 24. Peri- and post-implantation risks: ICD alone 

Study, Author 

Year n/N Simple pool 

risk,% [95% CI] 

Peri-implant deaths: RCT 

AVID141 1997 4/492 0.8 [0.2, 2.1] 

CABG-Patch134 1997 24/434 5.5 [3.6, 8.1] 

CASH143 2000 5/99 5.1 [1.7, 11.4] 

CAT136 2002 0/50 0.0 [0.0, 5.8] 

CIDS142 1999 2/310 0.6 [0.1, 2.3] 

DEFINITE138 2004 0/229 0.0 [0.0, 1.3] 

DINAMIT139 2004 0/310 0.0 [0.0, 1.0] 

MADIT133 1996 0/90 0.0 [0.0, 3.3] 

Sub-Total: 35/2014 1.7 [1.2, 2.4] 

Peri-implant deaths: Observational studies 

Alter144 2005 1/440 0.2 [0.0, 1.3] 

Backenkohler145 2005 0/245 0.0 [0.0, 1.2] 

Bode-Schnurbus147 2003 5/165 3.0 [1.0, 6.9] 

Bokhari148 2004 0/60 0.0 [0.0, 4.9] 

Carlsson192 2003 0/96 0.0 [0.0, 3.1] 

Cuesta155 2003 0/120 0.0 [0.0, 2.5] 

Duray158 2005 0/375 0.0 [0.0, 0.8] 

Ermis161 2003 0/59 0.0 [0.0, 5.0] 

Evonich162 2004 0/153 0.0 [0.0, 1.9] 

Grimm165 2002 0/101 0.0 [0.0, 2.9] 

Leosdottir169 2006 1/62 1.6 [0.0, 8.7] 

Niehaus198 2003 0/25 0.0 [0.0, 11.3] 

Noseworthy171 2004 0/209 0.0 [0.0, 1.4] 

Raviele176 2005 0/24 0.0 [0.0, 11.7] 

Russo178 2003 0/51 0.0 [0.0, 5.7] 

Takahashi184 2002 0/178 0.0 [0.0, 1.7] 

Telfer186 2002 0/22 0.0 [0.0, 12.7] 

Theuns187 2005b 0/127 0.0 [0.0, 2.3] 

Trappe188 2002 12/410 2.9 [1.5, 5.1] 

Wase189 2004 5/93 5.4 [1.8, 12.1] 

Sub Total 24/3015 0.8 [0.5, 1.2] 

Total [N=28] 59/5029 1.2 [0.9, 1.5] 

Implant success rate: RCT 

AVID141 1997 488/492 99.2 [97.9, 99.8] 

CABG-Patch134 1997 434/446 97.3 [95.3, 98.6] 

CASH143 2000 99/99 100.0 [97.0, 100.0] 

CIDS142 2000 310/328 94.5 [91.5, 96.7] 

DEFINITE138 2004 227/229 99.1 [96.9, 99.9] 

DINAMIT139 2004 310/332 93.4 [90.1, 95.8] 

Dorian193 2004a 149/149 100.0 [98.0, 100.0] 

MADIT133 1996 90/90 100.0 [96.7, 100.0] 

MADIT II135 2002 739/739 100.0 [99.6, 100.0] 

SCD-HeFT140 2005 811/812 99.9 [99.3, 100.0] 

Sub-Total: 3657/3716 98.4 [98.0, 98.8] 

Implant success rate: Observational studies 

Alter144 2005 440/440 100.0 [99.3, 100.0] 

Bode-Schnurbus147 2003 165/165 100.0 [98.2, 100.0] 

Bokhari148 2004 60/60 100.0 [95.1, 100.0] 

Capoferri152 2004 100/100 100.0 [97.0, 100.0] 

RCT=randomized control trial 
142

Table 24. Peri- and post-implantation risks: ICD alone (continued) 

Study, Author 

Year n/N Simple pool 

risk, % [95% CI] 

Implant success rate: Observational studies (continued) 

Carlsson192 2003 96/96 100.0 [96.9, 100.0] 

Cuesta155 2003 120//120 100.0 [97.5, 100.0] 

Dubner157 2005 761/761 100.0 [99.6, 100.0] 

Duray158 2005 375/375 100.0 [99.2, 100.0] 

Ermis161 2003 59/59 100.0 [95.0, 100.0] 

Niehaus198 2003 25/25 100.0 [88.7, 100.0] 

Raviele176 2005 24/24 100.0 [88.3, 100.0] 

Russo178 2003 51/51 100.0 [94.3, 100.0] 

Sanchez180 2005 19/19 100.0 [85.4, 100.0] 

Takahashi184 2002 178/178 100.0 [98.3, 100.0] 

Sub-Total: 2473/2473 100.0 [99.9, 100.0] 

Total [N=24] 6130/6189 99.0 [98.8, 99.3] 

Implantation mechanical complication: RCT 

AVID141 1997 28/507 5.5 [3.7, 7.9] 

CASH143 2000 11/99 11.1 [5.7, 19.0] 

DEFINITE138 2004 3/227 1.3 [0.3, 3.8] 

MADIT133 1996 5/95 5.3 [1.7, 11.9] 

SCD-HeFT140 2005 41/812 5.0 [3.6, 6.8] 

Sub-Total: 88/1740 5.1 [4.1, 6.2] 

Implantation mechanical complication: Observational studies 

Alter144 2005 26/440 5.9 [3.9, 8.5] 

Bokhari148 2004 3/60 5.0 [1.0, 13.9] 

Carlsson192 2003 0/96 0.0 [0.0, 3.1] 

Cuesta155 2003 8/120 6.7 [2.9, 12.7] 

Evonich162 2004 17/153 11.1 [6.6, 17.2] 

Grimm165 2002 2/101 2.0 [0.2, 7.0] 

Leosdottir169 2006 13/62 21.0 [11.7, 33.2] 

Noseworthy171 2004 12/212 5.7 [3.0, 9.7] 

Raviele176 2005 0/24 0.0 [0.0, 11.7] 

Russo178 2003 1/51 2.0 [0.0, 10.4] 

Saba179 2003 0/35 0.0 [0.0, 8.2] 

Takahashi184 2002 6/178 3.4 [1.2, 7.2] 

Telfer186 2002 0/27 0.0 [0.0, 10.5] 

Sub Total 88/1559 5.6 [4.6, 6.9] 

Total [N=18] 176/3299 5.3 [4.6, 6.2] 

Post-implant mechanical malfunction: RCT 

CAT136 2002 4/104 3.8 [1.1, 9.6] 

DEFINITE138 2004 3/227 1.3 [0.3, 3.8] 

Friedman194 2006 4/400 1.0 [0.3, 2.5] 

Sub-Total: 11/731 1.5 [0.8, 2.7] 

Post-implant mechanical malfunction: Observational studies 

Alter144 2005 2/440 0.5 [0.1, 1.6] 

Duray158 2005 22/375 5.9 [3.7, 8.7] 

Evonich162 2004 4/153 2.6 [0.7, 6.6] 

Grimm165 2002 2/101 2.0 [0.2, 7.0] 

Noseworthy171 2004 1/212 0.5 [0.0, 2.6] 

 

Post-implant mechanical malfunction: Observational studies 

Takahashi184 2002 2/178 1.1 [0.1, 4.0] 

Sub Total 33/1459 2.3 [1.6, 3.2] 

Total [N=9] 44/2190 2.0 [1.5, 2.7] 
143

Table 24. Peri- and post-implantation risks: ICD alone (continued) 

Study, Author 

Year n/N Simple pool 

risk, % [95% CI] 

Post-implant device malfunction: RCT 

CASH143 2000 5/99 5.1 [1.7, 11.4] 

CAT136 2002 8/104 7.7 [3.4, 14.6] 

CIDS142 2000 2/328 0.6 [0.1, 2.2] 

MADIT133 1996 3/95 3.2 [0.7, 9.0] 

SCD-HeFT140 2005 73/812 9.0 [7.1, 11.2] 

Sub-Total: 91/1438 6.3 [5.1, 7.7] 

Post-implant device malfunction: Observational studies 

Alter144 2005 26/440 5.9 [3.9, 8.5] 

Duray158 2005 15/375 4.0 [2.3, 6.5] 

Evonich162 2004 9/153 5.9 [2.7, 10.9] 

Grimm165 2002 4/101 4.0 [1.1, 9.8] 

 Leosdottir169 2006 3/62 4.8 [1.0, 13.5] 

Sub Total 57/1131 5.0 [3.8, 6.5] 

Total [N=10] 148/2569 5.8 [4.9, 6.7] 

Post-implant lead problems: RCT 

AVID141 1997 3/507 0.6 [0.1, 1.7] 

CASH143 2000 3/99 3.0 [0.6, 8.6] 

CIDS142 2000 8/328 2.4 [1.1, 4.7] 

DEFINITE138 2004 6/227 2.6 [1.0, 5.7] 

Friedman194 2006 5/400 1.3 [0.4, 2.9] 

MADIT II135 2002 13/742 1.8 [0.9, 3.0] 

 Sub-Total 38/2303 1.7 [1.2, 2.3] 

Post-implant lead problems: Observational 

Alter144 2005 52/440 11.8 [9.0, 15.2] 

Bokhari148 2004 18/60 30.0 [18.8, 43.2] 

Ellenbogen160 2003 19/74 25.7 [16.2, 37.2] 

Evonich162 2004 2/153 1.3 [0.2, 4.6] 

Grimm165 2002 8/101 7.9 [3.5, 15.0] 

Leosdottir169 2006 10/62 16.1 [8.0, 27.7] 

Niehaus198 2003 1/25 4.0 [0.1, 20.4] 

Noseworthy171 2004 1/212 0.5 [0.0, 2.6] 

Sanchez181 2006 1/105 1.0 [0.0, 5.2] 

Takahashi184 2002 11/178 6.2 [3.1, 10.8] 

 Sub-Total 123/1410 8.7 [7.3, 10.3] 

 Total [N=16] 161/3713 4.3 [3.7, 5.0] 

Post-implant infections: RCT 

AVID141 1997 10/492 2.0 [1.0, 3.7] 

CABG-Patch134 1997 19/434 4.4 [2.7, 6.8] 

CASH143 2000 3/99 3.0 [0.6, 8.6] 

CIDS142 2000 15/310 4.8 [2.7, 7.9] 

DEFINITE138 2004 1/229 0.4 [0.0, 2.4] 

Dorian193 2004a 3/141 2.1 [0.4, 6.1] 

MADIT133 1996 2/90 2.2 [0.3, 7.8] 

MADIT II135 2002 5/739 0.7 [0.2, 1.6] 

Sub-Total: 58/2534 2.3 [1.7, 2.9] 

Post-implant infections: Observational studies 

Alter144 2005 2/440 0.5 [0.1, 1.6] 

Bokhari148 2004 3/60 5.0 [1.0, 13.9] 

Cuesta155 2003 2/120 1.7 [0.2, 5.9] 

Duray158 2005 1/375 0.3 [0.0, 1.5] 

Evonich162 2004 4/153 2.6 [0.7, 6.6] 

Grimm165 2002 0/101 0.0 [0.0, 2.9] 

Leosdottir169 2006 1/62 1.6 [0.0, 8.7] 
144

Table 24. Peri- and post-implantation risks: ICD alone (continued) 

Study, Author 

Year n/N Simple pool 

risk, % [95% CI] 

Noseworthy171 2004 2/209 1.0 [0.1, 3.4] 

Takahashi184 2002 3/178 1.7 [0.3, 4.8] 

Sub Total 18/1698 1.1 [0.6, 1.7] 

Total [N=17] 76/4232 1.8 [1.4, 2.2] 

Inappropriate shocks: RCT 

AVID141 1997 106/171 62.0 [54.3, 69.3] 

DEFINITE138 2004 49/229 21.4 [16.3, 27.3] 

Sub-Total: 155/400 38.8 [33.9, 43.7] 

Inappropriate shocks: Observational studies 

Alter144 2005 54/440 12.3 [9.4, 15.7] 

Backenkohler145 2005 6/245 2.4 [0.9, 5.3] 

Bokhari148 2004 30/44 68.2 [52.4, 81.4] 

Capoferri152 2004 19/90 21.1 [13.2, 31.0] 

Dorian193 2004a 51/141 36.2 [28.3, 44.7] 

Dorian156 2004b 57/212 26.9 [21.0, 33.4] 

Ermis161 2003 4/17 23.5 [6.8, 49.9] 

Evonich162 2004 37/153 24.2 [17.6, 31.8] 

Grimm165 2002 16/101 15.8 [9.3, 24.4] 

Grimm195 2006 8/93 8.6 [3.8, 16.2] 

Hreybe196 2006 32/230 13.9 [9.7, 19.1] 

Leosdottir169 2006 10/62 16.1 [8.0, 27.7] 

Niehaus198 2003 2/25 8.0 [1.0, 26.0] 

Noseworthy171 2004 1/212 0.5 [0.0, 2.6] 

Raviele176 2005 4/24 16.7 [4.7, 37.4] 

Russo178 2003 5/51 9.8 [3.3, 21.4] 

Saeed199 2003 5/48 10.4 [3.5, 22.7] 

Sanchez180 2005 4/17 23.5 [6.8, 49.9] 

Sanchez181 2006 7/105 6.7 [2.7, 13.3] 

Takahashi184 2002 3/176 1.7 [0.4, 4.9] 

Telfer186 2002 7/22 31.8 [13.9, 54.9] 

Theuns200 2004 37/98 37.8 [28.2, 48.1] 

Theuns201 2005a 18/60 30.0 [18.8, 43.2] 

Tiroke202 2003 38/149 25.5 [18.7, 33.3] 

Zecchin191 2004 11/46 23.9 [12.6, 38.8] 

Sub Total 466/2861 16.3 [15.0, 17.7] 

Total [N=27] 621/3261 19.0 [17.7, 20.4] 
145

Table 25. Peri- and post-implantation risks with ICD in studies that were 

not restricted to patients with left ventricular systolic dysfunction 

Trial name, Author 

Study year n/N Simple pool 

risk, % [95% CI] 

Peri-implant deaths: RCT 

Bansch205 2004 0/50 0.0 [0.0, 5.8] 

Boriani206 2003 0/89 0.0 [0.0, 3.3] 

Nademanee210 2003 0/47 0.0 [0.0, 6.2] 

Vollman213 2003 0/539 0.0 [0.0, 0.6] 

Sub-Total: 0/725 0.0 [0.0, 0.4] 

Peri-implant deaths: Observational studies 

Al-Khatib204 2005 237/9854 2.4 [2.1, 2.7] 

Brockes207 2002 3/76 3.9 [0.8, 11.1] 

Reynolds203 2006 208/23110 0.9 [0.8, 1.0] 

Rosenqvist211 1998 6/778 0.8 [0.3, 1.7] 

Schlapfer212 2002 0/41 0.0 [0.0, 7.0] 

Wiegand214 2004 0/372 0.0 [0.0, 0.8] 

Sub Total 454/34231 1.3 [1.2, 1.5] 

Total [N=10] 454/34956 1.3 [1.2, 1.4] 

Implant success rate: RCT 

Bansch205 2004 102/102 100.0 [97.1, 100.0] 

Boriani206 2003 88/89 98.9 [93.9, 100.0] 

Nademanee210 2003 47/47 100.0 [93.8, 100.0] 

Vollman213 2003 529/539 98.1 [96.6, 99.1] 

Sub-Total: 766/777 98.6 [97.5, 99.3] 

Implant success rate: Observational studies 

Gradaus208 2003 3294/3344 98.5 [98.0, 98.9] 

Rosenqvist211 1998 772/778 99.2 [98.3, 99.7] 

Schapfer212 2002 41/41 100.0 [93.0, 100.0] 

Sub Total 4107/4163 98.7 [98.3, 99.0] 

 Total [N=7] 4873/4940 98.6 [98.3, 98.9] 
146

Figure 4. Metagraph of all-cause mortality: CRT alone 
147

Figure 5. Metagraph of mortality due to progressive heart failure: CRT alone
148

Figure 6. Metagraph of mortality due to sudden cardiac death: CRT alone 
149

Figure 7. Metagraph of mortality due to noncardiac death: CRT alone
150

Figure 8. Metagraph of heart failure hospitalizations: CRT alone

. 
151

Figure 9. Metagraph of 6-minute walk test: CRT alone
152

Figure 10. Metagraph of improvement in NYHA functional class: CRT alone
153

Figure 11. Metagraph of quality of life (MLHFI): CRT alone 

MLHFI = Minnesota Living with Heart Failure Instrument 
154

Figure 12. Metagraph of left ventricular ejection fraction: CRT alone 
155

Figure 13. Metagraph of all-cause mortality: CRT alone or combined CRT-ICD devices
156

Figure 14. Funnel plot for all-cause mortality: CRT alone 
157

Figure 15. Metagraph of all-cause mortality: ICD alone
158

Figure 16. Metagraph of death due to progressive heart failure: ICD alone 
159

Figure 17. Metagraph of mortality due to sudden cardiac death: ICD alone 
160

Figure 18. Metagraph of mortality due to non-cardiac death: ICD alone
161

Figure 19. Metagraph of heart failure hospitalizations: ICD alone
162

Figure 20. Summary results for all-cause mortality: ICD alone, stratified by primary or secondary prevention
163

Figure 21. Funnel plot for all-cause mortality: ICD alone 
164

Figure 22. Scatter plot of all-cause mortality vs. length of followup: CRT alone 

0 12 24 36

followup (months)

0

10

20

30

40

% deaths

Legend: Square = RCT; Circle = prospective cohort; Triangle = retrospective cohort 

Size of plotting character is proportional to square root of sample size of study
165

Figure 23. Scatter plot of all-cause mortality vs. length of followup: ICD alone

0 12 24 36 48 60 72 84 96 108 120 132

followup (months)

0

10

20

30

40

% deaths

Legend: Square = RCT; Circle = prospective cohort; Triangle = retrospective cohort 

Size of plotting character is proportional to square root of sample size of study
166

Figure 24. Scatter plot of all-cause mortality vs. length of followup: combined CRT-ICD devices

0 12 24 36

followup (months)

0

10

20

30

40

% deaths

Legend: Square = RCT; Circle = prospective cohort; Triangle = retrospective cohort 

Size of plotting character is proportional to square root of sample size of study
167

Chapter 4. Discussion 

Benefits of CRT (CRT Efficacy/Effectiveness) 

Using a comprehensive search strategy and concerted efforts to avoid publication and 

selection bias, this systematic review identified all of the available efficacy and effectiveness 

evidence on CRT therapy. Overall, our review reveals that CRT is both efficacious and effective 

when added to optimal medical therapy in certain HF patients. That is, in patients with LVEF ≤

35 percent, prolonged QRS duration, and symptomatic HF despite optimal medical therapy, CRT 

reduced all-cause mortality by 22 percent (largely driven by a 36 percent reduction in 

progressive heart failure deaths) and HF hospitalizations by 37 percent while significantly 

improving LVEF (an absolute improvement of 3 percent), quality of life (by almost 8 points on 

the MLWHF score), and functional status (CRT recipients were 55 percent more likely to 

improve by at least one NYHA symptom class than non-recipients and were able to walk over 24 

meters longer on the 6-minute walk test) in RCTs. As expected, the benefits of CRT were even 

more marked in patients with more severe HF (NYHA class III or IV): relative risk reductions 

were 22 percent for all-cause mortality, 44 percent for progressive heart failure deaths, and 49 

percent for HF hospitalizations. While there was far less effectiveness data than efficacy data for 

CRT, those observational studies with contemporaneous controls that we identified reported 

reductions in all-cause mortality and improvements in 6-minute walk tests and LVEF with CRT 

which are consistent with the results of the RCTs. 

The magnitude of these benefits are similar to those reported for angiotensin converting 

enzyme inhibitors, beta-blockers, and aldosterone antagonists in recent trials219-223 and translate 

into a NNT of 31 patients with symptomatic HF (or 14 with NYHA class III or IV symptoms) to 

prevent one death over 6 months. Balanced against these benefits, the immediate risks of CRT 

appear modest: peri-implantation mortality rates were less than 1 percent (similar to rates 

reported for patients undergoing implantation of conventional dual-chamber pacemakers).224

Although earlier reports raised concerns about a potentially higher risk of non-HF outcomes in 

patients with CRT (particularly an excess of ventricular arrythmias or sudden deaths),225 pooling 

the data from all of the RCTs currently available did not reveal any excess risk of sudden death 

(RR = 1.07; 95% CI, 0.79 to 1.46) or noncardiac death (RR = 0.81; 95% CI, 0.43 to 1.52) in 

recipients of a CRT device. Moreover, an analysis of ventricular arrhythmia frequency in 

patients with ICD who were randomized to CRT “on” or “off” in the MIRACLE-ICD Trial did 

not reveal any significant differences (26 percent vs. 22 percent, p>0.2).6

However, implantation of a biventricular CRT pacemaker (in particular the left ventricular 

lead) is technically challenging, even in experienced hands (our systematic review identified an 

implantation failure rate of 7 percent, even under the optimal conditions inherent in RCTs and 

early cohort studies which tend to be reported by acknowledged experts in the field). 

Furthermore, even in the “ideal patient” (i.e., trial participants), nearly 10 percent of devices 

malfunctioned and 7 percent of patients had post-implant lead problems (most frequently with 

the left-ventricular lead) over a median followup of 11 months. While we found that 

implantation success rates and the frequency of peri-implantation adverse events were no 

different in the CRT RCTs as in the observational studies conducted in non-trial settings, and in 

patients implanted with combined CRT-ICD devices as CRT alone devices, these conclusions 

are based on studies reporting data from less than 7,000 patients and thus should not be 
168

considered definitive. Further, it should be noted that the implant success rates and frequency of 

complications we found in the published literature may not reflect current rates in clinical 

practice since the experience of device implanters, the tools for implantation, and the 

sophistication of these devices change over time. This emphasizes the importance of ongoing 

surveillance programs for these devices, and as discussed under “The Challenge for Health Care 

Administrators and Funders” on page 177 of the Evidence Report, we believe there is a need to 

expand the recently established American College of Cardiology National Cardiovascular Data 

Registry (ACC-NCDR) to collect comprehensive data on CRT devices as well as ICD devices, 

and to include implants in all patients, not just Medicare beneficiaries. Given the recent 

experiences with ICD recalls and FDA advisories, it seems prudent to recommend that all 

patients with left ventricular systolic dysfunction who have either a CRT or an ICD device 

implanted be entered into a registry and followed for long-term risks and benefits. 

The degree of heterogeneity within and between trials in the proportion of patients exhibiting 

functional improvements with CRT highlights an important issue with CRT. Although these 

trials enrolled similar patient populations and implanted similar (and in many cases identical) 

devices, 59 percent of CRT recipients improved by at least one NYHA class while 41 percent did 

not. Clearly, CRT does not always restore mechanical synchrony, even when lead placement is 

felt to be successful.226 While studies to define which patients are most likely to benefit from 

CRT and which positions in the ventricular wall are most appropriate for implantation of the 

pacing leads are clear research priorities,226,229,229 our examination of subgroup analyses in these 

trials was unable to identify any particular subgroups who are more (or less) likely to derive 

benefit from CRT. In nontrial participants, the rates of nonresponse to CRT have varied even 

more widely. Determining the true rate of nonresponse in clinical practice is hampered by the 

lack of a universally accepted definition for “response.” The most frequently cited definitions 

either rely on functional status (an improvement of at least one in NYHA class) or 

echocardiographic assessments of remodelling (most commonly a decrease of at least 15 percent 

in left ventricular end-systolic volume).227 Complicating matters is the fact that patients may 

demonstrate a response clinically but not echocardiographically, or vice versa (for example, there 

was only 76 percent agreement in one study which conducted both assessments as to whether 

patients were classified as responders/nonresponders under both definitions).271 Examining only 

those studies employing either of these definitions reveals that CRT non-response rates (after 

successful device implantation) range from 20 to 28 percent in those studies using a functional 

status definition but in studies employing the more objective echocardiographic remodelling 

definition CRT nonresponse rates range from 32 to 45 percent. 

A variety of reasons have been advanced for the relatively high rates of nonresponse with 

CRT therapy.227 For one, the optimal pacing site in the left ventricle (i.e., the most delayed site 

on the left ventricular free wall) is not consistent between patients and thus it is not surprising 

that inserting leads in the same place in all individuals will have varying impacts.272 Second, it 

has been suggested that the etiology of HF is an important predictor of CRT responsiveness: 

however, although some studies have suggested that patients with ischemic cardiomyopathy 

exhibit less echocardiographic benefit from CRT than patients with idiopathic dilated 

cardiomyopathy,4,273 this has not translated into appreciable differences between the two groups 

in clinical outcomes in the RCTs conducted to date.11,15 Third, the most frequently cited reason 

for the relatively high rates of nonresponse with CRT therapy is that electrical dyssynchrony on 

the electrocardiogram does not always translate into mechanical dyssynchrony—a fact proven in 

several studies.227,274,275 Indeed, some authors have estimated that up to a quarter of all HF 
169

patients with QRS width < 120 msec may have sufficient mechanical dyssynchrony to 

potentially benefit from CRT.276-278 As a result, attention has focused on improving the 

assessment of mechanical dyssynchrony in HF patients with new echocardiographic techniques 

(such as Tissue Doppler Imaging) and the ongoing Predictors of Response to Cardiac 

Resynchronization Therapy (PROSPECT) Study is an attempt to prospectively test and validate 

which of the various echocardiographic indices will best identify those patients most likely to 

respond to CRT.228

An important question about CRT, as with any new therapy, is whether efficacy proven in 

trials translates into effectiveness when applied in clinical practice. This is of particular concern 

for novel therapies which either (1) have been tested in a selected spectrum of patients or (2) 

depend on specialized technical expertise. Both caveats apply to CRT. Thus, while the trials 

proving the efficacy of CRT enrolled relatively young subjects (mean age 65 years), 72 percent 

of whom were male, population-based cohort data279-282 demonstrate that HF patients in clinical 

practice are almost a decade older than trial participants and have a substantially greater burden 

of comorbid illnesses. The impact of CRT in these patients (particularly given the higher periimplantation risks) is unknown. In addition, it bears emphasizing that only selected cases and 

experienced providers participated in these trials. Consequently, it is plausible that the efficacy 

and safety rates observed in these trials may not be applicable in usual clinical practice. In 

particular, recent analyses of Medicare files have confirmed that in the United States these 

devices are being implanted in older patients with more comorbidities203 than the participants in 

the RCTs reviewed in this report; in addition, CRT devices are being implanted by less 

experienced providers working in institutions with lower implant volumes204 than those centers 

that participated in the trials we have reviewed herein. This again emphasizes the importance of 

the prospective national device registry which the Centers for Medicare and Medicaid Services 

has established (https://www.accncdr.com/webncdr/ICD/Default_ssl.aspx) since any 

nonselective uptake of CRT beyond the highly specialized settings in which it was shown to be 

beneficial in these trials would be expected to attenuate its risk/benefit ratio and undermine its 

cost-effectiveness ratios.

In addition to providing “real world” estimates of complication rates, ongoing surveillance is 

required to assess (1) the effects of CRT on mortality and morbidity (including functional status 

and 6-minute walk distances) over longer timeframes than these RCTs have reported, (2) the 

effects of CRT in patient subgroups excluded from the trials conducted to date (such as those 

with atrial fibrillation, chronic kidney disease, or less symptomatic HF), (3) to what extent the 

reductions in HF hospitalizations seen in these trials with CRT may be offset by increased 

admissions for pacemaker revisions, and (4) to track changes in complication rates as device 

implanters, the tools for implantation, and the sophistication of the devices change over time. 

Caveats for CRT Efficacy/Effectiveness Data 

It should be recognized that few participants in these trials had bradyarrhythmias or atrial 

fibrillation. As such, the role of CRT in such patients is unknown (despite promising reports 

from the small HOBIPACE trial13 and registry data283) and is an important area for further study, 

particularly since almost one-third of patients with HF have atrial fibrillation or indications for 

conventional pacemakers.279 Similarly, since less than one-tenth of CRT trial participants had a 

right bundle branch block pattern on their enrolment electrocardiograms, it remains a subject of 

debate whether to extrapolate the CRT trial findings published thus far to HF patients with right 
170

bundle branch block patterns (although a recent study suggested that the degree of left 

ventricular activation delay and the pattern of activation was similar in patients with right or left 

bundle branch blocks).280,284 In a similar vein, the benefits of CRT in patients with less 

symptomatic HF (NYHA class I or II symptoms) are uncertain due to a relative paucity of trial 

data and awaits further study, despite promising data in subgroup analyses from the CRT trials 

and observational studies.32

While none of the trials that examined subgroup effects reported differences in the efficacy 

of CRT across subgroups, and our meta-regression was unable to detect any statistically 

significant differences in the subgroups we examined (ischemic vs. nonischemic etiology, age 

strata, duration of followup), our meta-regression did reveal that studies with a higher proportion 

of NYHA class II patients and higher mean LVEF at baseline, and studies with ICD in both the 

control and CRT arms, found less beneficial effects of CRT on heart failure hospitalizations (but 

no differences in the survival benefits apparent with CRT). However, it should be emphasized 

that these subgroup analyses were underpowered (both within trials and between trials). Thus, 

individual patient data is essential to appropriately examine this issue. We have been involved in 

discussions with all manufacturers of CRT devices to provide individual patient data for this 

review; however, no individual patient data was available by January 9, 2007. Examination of 

the trial data for differential subgroup effects should be an urgent research priority in this field, 

particularly since, in the words of one editorialist, “it is the entry criterion and not the group 

actually studied that has driven practice guidelines.”235 For example, there are no data on the 

impact of CRT (with or without ICD) in different strata of baseline LVEF (for example, 10 to 20 

percent vs. 20 to 30 percent vs. 31 to 35 percent) and thus CRT is currently advocated for 

patients who would have met trial eligibility criteria, even though the mean LVEF in the 

randomized trials proving the efficacy of these devices was substantially lower than the LVEF 

required for trial entry. In the same vein, the degree of heterogeneity within and between trials in 

the proportion of patients exhibiting functional improvements with CRT highlights the need for 

detailed subgroup analyses. Although these trials enrolled similar patient populations and 

implanted similar (and in many cases identical) devices, 59 percent of CRT recipients improved 

by at least one NYHA class while 41 percent did not. Clearly, CRT does not always restore 

mechanical synchrony, even when lead placement is felt to be successful.226 Moreover, studies to 

define which patients are most likely to benefit from CRT and which positions in the ventricular 

wall are most appropriate for implantation of the pacing leads are clear research priorities.226,235

Another limitation of these RCTs is that randomization occurred after implantation of the 

device in all but three trials. This design, similar to the run-in period used in some 

pharmaceutical trials, does not affect the internal validity of the trials since the randomly 

assigned groups should still be balanced for unmeasured confounders. However, it does affect 

the tests of statistical significance (as it causes narrower confidence intervals and increases the 

chance of type 1 errors) and does impact the generalizability of the results as patients who could 

not tolerate the procedure or in whom implantation was unsuccessful would not have been 

included in the final trial data. As a result, these trials likely overestimate the potential benefits 

and underestimate adverse events from cardiac resynchronization—although the univariate metaregression did not demonstrate statistical significance on this factor (p = 0.18), this analysis was 

underpowered due to the small number of studies. This further emphasizes the importance of 

ongoing surveillance registries to track device effectiveness and complication rates (particularly 

given the marked paucity of data on the efficacy or complication rates with cardiac 

resynchronization therapy beyond one year).285
171

Mode of death analyses should always be viewed as hypothesis generating exercises given 

the well-documented uncertainties around the sub-classification of deaths, particularly in 

classifying cardiac deaths as being due to sudden arrhythmic events versus progressive HF.286

Finally, it is uncertain whether, and to what extent, the use of newer techniques to detect 

electro-mechanical dyssynchrony, such as Tissue Doppler Imaging rather than the current criteria 

based on QRS and LVEF, to select patients for CRT in the future will impact on the 

effectiveness and safety of these devices.226

Safety of CRT 

It is well known that trials under-estimate complication rates from both medical and surgical 

interventions due to their selection criteria, relatively short followup time-frames, and close 

monitoring of patients (and providers).251 Although our analysis of peri- and post-implantation 

risks revealed similar frequencies in the RCT data and the observational data at this point in 

time, it should be recognized that this is based on sample sizes of only a few thousand patients 

and reports of device implantations appearing early in the literature are most likely to come from 

larger institutions/more experienced investigators with early experience and competence with 

these devices. Regardless, our analysis demonstrated that CRT implantation was successful 

approximately 93 percent of the time and the peri-implantation risks included a 0.3 percent 

chance of peri-implantation death and a 4 to 5 percent chance of mechanical complication at the 

time of implantation—these rates were almost identical for CRT alone or combined CRT-ICD 

devices. Both types of devices exhibited a 7 percent frequency of post-implant lead problems, a 5 

percent frequency of device malfunction, and a 1 to 2 percent frequency of post-implant 

infections) over a median followup of 6 months. However, it should be recognized that all of the 

published evidence thus far is relatively short-term and based on relatively few patients. This 

further emphasizes the importance of ongoing surveillance registries to track complication rates 

and costs (including costs and complications of failed implantation attempts) over the long-term. 

Cost-Effectiveness of CRT 

Numerous decision analytic studies have explored the cost-effectiveness of CRT therapy. In 

an earlier AHRQ report (a Markov Model with a lifetime horizon, but based on data from the 

relatively short-term trials published to that point in time—most of which reported outcome data 

only within the first 3 months after CRT activation), a median incremental cost of US$107,800 

per QALY with CRT vs. medical therapy was reported.287 However, three subsequent cost-utility 

analyses which have incorporated more recently published trials with substantially longer 

followup durations have reported markedly lower incremental costs per QALY gained for CRT 

devices: US$19,600 in an analysis of the COMPANION trial data,288 £19,319 in an analysis 

employing the CARE-HF trial data,289 and £16,598 in a Markov decision analytic model with a 

lifetime horizon developed for the NHS Research and Development Health Technology 

Assessment Programme from a meta-analysis of the five longest CRT trials.290 However, even 

these analyses found that the incremental cost-effectiveness of CRT-ICD over CRT alone was 

markedly higher ($171,538 per QALY in the United States and £34,664 in the United Kingdom) 

since the benefit of CRT-ICD over CRT is marginal, but at a much higher cost (for example, 

initial implant costs are $20,500 in the United States for CRT devices, but $29,500 in the United 
172

States for CRT-ICD devices and followup costs over 7 years are $39,400 vs. $52,700).288 In the 

words of one editorialist, although CRT alone devices are clearly cost-effective in patients 

similar to those enrolled in the trials, pending further trial data comparing CRT-ICD devices with 

CRT alone devices (see “Implications of our findings” section below), “the question of which 

device is most cost effective for patients with heart failure remains open.”291 

Proportion of HF Patients Likely To Be Eligible for CRT 

Approximately 1 to 3 percent of all patients discharged alive after their index hospitalization 

for HF280,292 and 15 to 20 percent of patients seen in specialized heart failure clinics280,293,294 meet 

CRT trial eligibility criteria (LVEF ≤ 35 percent, QRS ≥ 120 msec, sinus rhythm, and NYHA 

class III or IV symptoms despite treatment with ACE inhibitor/angiotensin receptor blocker and 

beta-blocker). Of these patients, approximately one half also meet trial eligibility criteria for an 

ICD.295 Since clinicians tend to overestimate the severity of functional impairment in heart 

failure,226 and the NYHA classification system demonstrates substantial inter-rater variability,296

it is possible that even fewer patients would require CRT if an objective functional assessment 

(such as 6 minute walk test distance < 450 m) were included in the evaluation. 

Benefits of ICD (ICD Efficacy/Effectiveness) 

Using a comprehensive search strategy and concerted efforts to avoid publication and 

selection bias, this systematic review identified all of the available efficacy and effectiveness 

evidence on ICD therapy in patients with left ventricular systolic dysfunction. Overall, our 

review reveals that ICD is both efficacious and effective when added to optimal medical therapy 

in patients with LVEF ≤ 35 percent, regardless of whether they have HF symptoms or not. In the 

randomized trials, ICD reduced all-cause mortality by 20 percent (largely driven by a 54 percent 

reduction in sudden cardiac deaths) and, given the control mortality rate of 24 percent, this 

relative risk reduction translates into a NNT of 20 to prevent one death over 35 months. The 

relative benefits were similar in the primary prevention and secondary prevention trials (19 

percent relative risk reduction vs. 23 percent relative risk reduction, respectively), although given 

the differences in absolute risk (23 percent all-cause mortality in the primary prevention trials vs. 

30 percent all-cause mortality in the secondary prevention trials) the NNTs to prevent one death 

were different: 23 in the primary prevention trials vs. 15 in the secondary prevention trials. The 

benefits of ICD outside of the trial setting were confirmed in our analyses of observational 

studies with contemporaneous control groups. 

Although ICD did not appear to be associated with an increase in HF symptoms or 

deteriorations in functional status or quality of life in trial participants, these analyses are 

certainly not definitive given the lack of reporting of these endpoints in most of the trials 

published to date. For example, HF events were reported in just two trials (one of which135 did 

report a statistically significant excess risk of HF hospitalizations in ICD recipients: RR = 1.34; 

95% CI, 1.04 to 1.73). A secondary analysis of data from the same trial has confirmed that it was 

those ICD recipients who were saved from sudden death by ICD shocks (as compared to those 

patients who had an ICD implanted but never received any shocks) who were most likely to 

subsequently be hospitalized for HF (hazard ratio 1.90 for first HF hospitalization and 1.74 for 

recurrent HF hospitalizations) and a factor predicting increased risk of subsequent HF was a 
173

QRS interval ≥ 120 msec.297 This finding may reflect the fact that sicker patients are those most 

likely to have ventricular arrythmias; however, it serves to highlight a subgroup of ICD eligible 

patients (those with symptomatic HF and QRS interval ≥ 120 msec, as well as the LVEF ≤ 35 

percent currently advocated in the ACC/AHA/ESC guidelines)298 who should be considered for a 

combined CRT-ICD device rather than an ICD alone. 

Another factor which clinicians and their patients must weigh in the decision about ICD 

implantation is their quality of life. Due to a paucity of data in the trials conducted thus far, this 

did not feature in our systematic review; however, there is some evidence that while quality of 

life improves in some patients after ICD implantation, it declines in others, especially those who 

experience frequent ICD firings.299 Indeed, it has been reported that ICD recipients not 

infrequently demonstrate substantial anxiety and can develop a psychological dependence on 

their device.300 Not unexpectedly, patient anxiety and psychologic distress scores are 

significantly and substantially higher after an ICD shock.301 Further, it has been shown that 

device recalls also substantially increase psychological distress in patients and their families,302

an increasingly relevant factor given analyses of FDA Enforcement Reports demonstrating 

marked increases in device advisories and recall rates over time (as devices get smaller and more 

complicated).303 Indeed, there have been 29 FDA advisories affecting nearly 337,000 ICDs since 

1990—a figure which does not include the 62,000 Guidant ICDs recalled voluntarily by the 

company in June 2005.304

Akin to the situation with CRT (in which between one-quarter and one-half of patients may 

not respond to the device), three-quarters to two-thirds of ICD recipients never received any 

therapeutic ICD discharges in these trials (therapeutic ICD discharges ranged from 5 percent to 

12 percent of patients per year in the trials included in this review).217 In fact, based on analyses 

from MADIT-II demonstrating 50 percent mortality rates within 2 years of an appropriate ICD 

firing,230 it has been estimated that 10 percent of those who receive an ICD for primary 

prevention will receive an appropriate shock and survive at least 1 year.217 Moreover, registry 

data has demonstrated that less than one-quarter of cardiac arrest victims have a LVEF < 30 

percent prior to their event.233 While this clearly has implications for the cost-effectiveness of 

this therapy (see “Cost-Effectiveness of ICD” below) and resource distribution, it also serves to 

highlight the urgent research need to develop and validate tools which will permit adequate risk 

stratification to distinguish those patients who are at increased risk for sudden cardiac death and 

likely to benefit from an ICD from those patients unlikely to benefit. 

Thus, while the MADIT-II and SCD-HeFT trial eligibility criteria are commonly cited as a 

means by which to identify patients who would potentially benefit from an ICD, the 

identification of particular patient groups who are more or less likely to benefit from an ICD is 

vitally important.230,231 Although our meta-regression analyses did not reveal any statistically 

significant differences in the sub-groups we examined (ischemic vs. non-ischemic etiology, 

patient age, duration of followup, presence of CRT or not, the use of concomitant medications, 

QRS width, or mean LVEF in the randomized trials—recognizing that since these trials enrolled 

patients within a narrow LVEF range its potential predictive ability would have been markedly 

reduced), it should be emphasized that these analyses were underpowered due to the small 

number of trials and a meta-analysis of individual patient data would be necessary to 

appropriately examine this issue. Indeed, the establishment of the ICD Registry by the ACCNCDR in collaboration with the Heart Rhythm Society is an important initiative which will 

permit the collection of comprehensive data on ICD implants and long-term patient outcomes. 

This should help to identify whether particular patient subgroups derive more or less benefit than 
174

the averages reported in this report and whether specific devices or programming parameters are 

associated with better or worse outcomes.234

Regardless, the current evidence base does provide some guidance in the selection of 

candidates for a primary prevention ICD. For example, as ICD was not associated with a 

mortality benefit in the DINAMIT trial (in which ICD implants were performed within 40 days 

of an acute myocardial infarction)139 or in MADIT-II patients enrolled within 6 months of 

coronary revascularization (HR = 1.19; p = 0.76),305 it seems reasonable to infer that ICD 

implantation should be delayed for a period of time after acute coronary events (and the 40 day 

window specified in the ACC/AHA/ESC 2006 guidelines298 is supported by the literature). Other 

risk stratification tools, such as microvolt T-wave alternans, have been suggested as potential 

means to identify high and low risk groups and have now been formally tested in prospective 

observational cohorts306 and modelling suggests use of this test to identify those most likely to 

benefit from ICD may enhance the cost-effectiveness of ICD therapy.307 Indeed, CMS approved 

reimbursement for this test in 2006 to identify patients at increased risk who may derive most 

benefit from an ICD within the existing guidelines.

Although the effectiveness analyses suggest that the benefits of ICD demonstrated in the 

RCTs are achievable in clinical practice, the same cautions raised about the CRT randomized 

trial data apply to the ICD randomized trial data, namely that (1) the trials proving the efficacy of 

ICD enrolled relatively young and comparatively healthy subjects (while recent analyses in the 

United States suggest that ICD recipients in clinical practice are older and have a higher comorbidity burden),203 and (2) only experienced ICD implanters from high volume institutions 

participated in these trials (while recent analyses in the United States suggest that ICD implants 

are most commonly performed by less experienced providers working in institutions with lower 

implant volumes).204 This again emphasizes the importance of the ACC-NCDR registry for 

surveillance of outcomes with ICD implantation over time since any nonselective uptake of ICD 

beyond the highly specialized settings in which it was shown to be beneficial in these trials may 

well attenuate its risk/benefit ratio and undermine its cost-effectiveness ratios. 

Caveats for ICD Efficacy/Effectiveness Data 

In addition to the caveats listed above with respect to our inability to identify patient groups 

most likely to benefit from ICD with aggregate trial data, our analysis is also limited by a paucity 

of data on more complex dual-chamber ICD devices capable of antitachycardia pacing. 

Antitachycardia pacing offers another method by which ICD could prevent sudden cardiac death, 

conserve battery life, prevent a reduction in quality of life, and limit the number of inappropriate 

shocks patients receive.308 This device is not without risk, however, since antitachycardia pacing 

can accelerate ventricular tachycardia into ventricular fibrillation requiring a shock.308

While early reports suggested that dual-chamber (i.e., right atrium and right ventricle) pacing 

could improve symptoms in patients with advanced heart failure,309 theoretically at least there is 

a risk of inducing ventricular dyssynchrony with right ventricular pacing. Although three 

studies194,310,311 have failed to demonstrate a significant benefit with the addition of an additional 

atrial lead to the right ventricular ICD lead, and one study suggested that dual-chamber ICD may 

exacerbate heart failure in patients without an indication for dual-chamber pacing,312 one study201

did report a 47 percent improvement in the odds of detecting supraventricular tachycardias, thus 

averting potentially inappropriate shocks. Adding to the confusion, while one trial suggested 

potential harm with an increase in the composite endpoint of mortality and HF hospitalization 
175

with dual-chamber pacing compared to backup ventricular pacing in ICD patients with left 

ventricular dysfunction and without an indication for dual-chamber pacing,313 the Dual Chamber 

and Atrial Tachyarrhythmias Adverse Events (DATAS) Study314 reported fewer inappropriate 

shocks with dual-chamber ICD than with standard single right ventricular lead ICD. Importantly, 

the DATAS Trial used different settings with a longer AV delay in order to minimize pacing, 

and indeed the rate at which the right ventricular lead had to pace was halved, highlighting the 

need for clarity about both the device to be tested and the settings in a larger randomized trial to 

settle this issue. A secondary post hoc analysis of the MADIT-II Trial comparing the 404 

patients who received a single-chamber ICD with the 313 patients who received a dual-chamber 

ICD demonstrated a higher risk of death or heart failure hospitalization with dual-chamber 

ICD.263 However, the choice of single vs. dual-chamber was not randomized in this trial but left 

to the discretion of the attending physician and those patients who received dual-chamber ICD 

were older, had more advanced heart failure symptoms, and more comorbidities. As a result, 

after adjustment the Cox proportional hazards regression revealed that dual-chamber ICD were 

associated with trends to higher rates of death (hazard ratio 1.27, 95% CI 0.76-2.12) or HF 

hospitalization (hazard ratio 1.27, 95% CI 0.87-1.86) which were not statistically significant. 

Thus, although dual-chamber ICD therapy is promising, it must be tested against single-chamber 

ICD in appropriately powered RCTs before definitive conclusions can be drawn. In the 

meantime, although the most recent guidelines for ICD and the prevention of sudden cardiac 

death are silent on the indications for dual-chamber devices,298 we believe it prudent to restrict 

the use of dual-chamber ICD to those patients who require an ICD and have conventional 

indications for dual-chamber pacing (such as chronotropic incompetence, sick sinus syndrome, 

or AV conduction abnormalities).315

Safety of ICD 

Although ICD alone devices are clearly easier to implant than CRT capable devices (implant 

success rates of 99 percent vs. 93 percent), rates of peri-implant deaths and/or mechanical 

complications did not differ appreciably between the CRT or ICD devices. As outlined earlier in 

our report, implantation success rates were significantly lower (98 percent vs. 100 percent), periimplantation death rates were significantly higher (1.7 percent vs. 0.8 percent), and inappropriate 

ICD discharge rates were substantially higher (39 percent vs. 16 percent over 24 months) in the 

ICD RCTs compared to the observational studies, likely reflecting closer scrutiny in the 

randomized trial setting or publication bias in the observational data. 

In addition to the data we report from our systematic review of randomized trials and 

observational studies, it is important to acknowledge that it is difficult to estimate the true 

incidence of ICD (or indeed CRT) device failures since the observed failure rates are likely to be 

an underestimate due to under-reporting and the tendency to attribute patient deaths to the 

underlying disease process rather than unrecognized device malfunction. While there have 

already been 29 FDA advisories affecting nearly 337,000 ICDs since 1990 (and that doesn’t 

include lead advisories, which are more frequent, or the 62,000 ICDs Guidant recalled 

voluntarily in June 2005),304 analyses of FDA Enforcement Reports over the past decade 

demonstrated marked increases in device recall rates over time (as devices get smaller and more 

complicated). Currently, ICD recall rates are as high as 16.4 per 100 person years—54 percent 

for hardware malfunctions (electrical/circuitry malfunctions, battery/capacitor malfunctions, 

problems with hermetic seals, defective crystals, defective headers) and 41 percent for firmware 
176

malfunctions (integral device computer programming).303 It has been estimated that almost threequarters of all ICD advisories result in device replacements and the resultant increases in 

monitoring, outpatient visits, hospitalizations, and use of hospital resources to replace recalled 

devices cost over US$90 million per year.303 

Although there is inadequate long-term data to reliably define battery lifetime and the 

costs/risks of ICD replacement in patients with reduced LV systolic function, cost-effectiveness 

analyses commonly use a 5-year period as the average anticipated interval when ICD generators 

would need to be replaced in their models (based on observational data).316 However, this is 

clearly an over-simplification since the generator life of an ICD will depend on whether it is 

single or dual chamber, the various parameters it is set to, and the frequency of discharges. 

Cost-Effectiveness of ICD 

The cost-effectiveness of ICD in patients with left ventricular dysfunction has recently been 

analyzed in four decision analyses. In an analysis incorporating data from eight of the trials 

included in our analysis, the incremental cost-effectiveness of ICD compared to medical therapy 

alone ranged between US$34,000 to US$70,200 per QALY gained over a lifetime horizon as 

long as the ICD was assumed to retain its effectiveness for at least 7 years.317 Using data from 

the SCD-HeFT trial the incremental cost-effectiveness ratio for ICD was estimated to be 

US$41,530 per QALY, but was also sensitive to long-term survival and only remained attractive 

if the ICD prolonged life for at least 8 years.318 On the other hand, an analysis using data from 

the MADIT-II Trial demonstrated a far less favourable incremental cost-effectiveness ratio for 

ICD of US$235,000 per life-year saved during the 3.5 years of the trial.319 Modelling the benefits 

and costs over a longer time frame (12 years) yielded lower incremental cost-effectiveness ratios 

of US$78,600 to US$114,000 per life-year saved. Finally, a modelling study based on up to 15 

years of cost and survival data from the Duke University Medical Center revealed costeffectiveness ratios ranging from US$367,200 per life-year gained when a 3-year time horizon 

was examined to US$67,800 per life-year gained over a 15-year time horizon for patients within 

the Duke databases who would have been eligible for the MADIT-II study.320 Thus, as the costs 

of ICD implantation are high initially but lower during followup, the results of ICD costeffectiveness analyses are very sensitive to the time horizon used. Regardless, none of these 

analyses have taken into account the cost of device recalls to the healthcare system —whilst the 

device and replacement costs may be covered, the number of days lost from work, lower work 

productivity for spouses and family members and the delay for other patients waiting for 

appropriate and cost-effective therapy (e.g., a regular pacemaker) is sure to increase these 

estimates. As pointed out by the editorialist for one of these cost-effectiveness analyses, we need 

to strive “to identify the right patients at the right time for ICD implantation to deliver enough 

bangs for the bucks.”217 

Implications of Our Findings 

Over the past decade, device therapy options have emerged as promising adjuncts to optimal 

medical therapy for patients with heart failure—CRT and ICD are the two that hold the most 

promise for the greatest proportion of heart failure patients. Although the evidence base 
177

underpinning these therapies has evolved rapidly and fulfilled much of this promise, there remain 

some areas of uncertainty. 

Our findings allow us to summarize the areas of certainty as follows. CRT is a proven 

efficacious (and cost effective) therapy for patients with (1) NYHA class III or IV symptomatic 

HF despite optimal medical management, (2) LVEF ≤ 35 percent, (3) sinus rhythm, and (4) 

ventricular dyssynchrony (i.e., prolonged QRS duration) which improves ventricular function 

and remodelling, symptoms, and exercise capacity, while also reducing HF hospitalizations and 

death. ICD is also a proven efficacious (and cost effective) therapy for patients with LVEF ≤ 35 

percent and predominantly NYHA class II and III symptoms which reduces sudden cardiac 

deaths (and all-cause mortality) without appreciably impacting on functional status or morbidity 

outcomes. 

However, despite this apparent clarity, a number of areas of uncertainty surround CRT and/or 

ICD therapy in patients with left ventricular systolic dysfunction. This report will end with 3 

challenges to address the key grey areas in the current evidence base—one for health outcome 

investigators, one for administrators and health care funders, and one for trialists and device 

manufacturers. 

The Challenge for Health Outcome Investigators 

While the expected benefits with either CRT and/or ICD should be greater (and the costeffectiveness ratios lower) in higher risk patients, a clear research need that this systematic 

review highlights is the current paucity of risk stratification tools to accurately identify those 

patients with left ventricular systolic dysfunction who are most likely to benefit from either (or 

both) of these devices. 

The Challenge for Health Care Administrators and Funders 

The recently established ACC-NCDR will permit the collection of comprehensive data on 

ICD and combined CRT-ICD implants and outcomes in Medicare beneficiaries. While this 

registry will help to define the long-term benefits, risks, and costs of these devices and help to 

clarify whether particular patient subgroups derive more or less benefit from these devices than 

the averages reported in this report, we believe there is a need for this registry to be expanded. 

For example, inclusion of data on all implants (i.e., in all patients, not just those in the over 65 

year old age group that comprises Medicare beneficiaries) and collection of data on patients who 

receive CRT alone devices should be considered. Given the recent experiences with ICD recalls 

and FDA advisories, it seems prudent to recommend that all patients with left ventricular systolic 

dysfunction who have either a CRT or an ICD device implanted be entered into a registry and 

followed for long-term risks and benefits, particularly in light of the small sample sizes of 

current studies reporting on CRT safety. In addition, we believe that the impact of these devices 

on outcomes other than mortality or hospitalizations (such as functional status and 6-minute walk 

distances over longer timeframes than these RCTs have reported) would be important to collect 

as such information would usefully inform clinical and policy decision making. 
178

The Challenge for Trialists and Device Manufacturers 

Trialists and device manufacturers are to be congratulated for a plethora of ongoing studies 

designed to address a number of questions about CRT and/or ICD therapy which we raised 

earlier in our discussion under the “Caveats with efficacy/effectiveness data” for these devices. 

For example, the REVERSE (Resynchronization reverses Remodeling in Systolic left 

vEntricular dysfunction) Trial321 is evaluating the efficacy of CRT alone in patients with NYHA 

class I or II symptoms while the MADIT CRT (Multicenter Automatic Defibrillator Implantation 

Trial with Cardiac Resynchronization Therapy) Trial322 is comparing combined CRT-ICD to 

ICD alone in patients with NYHA class I or II symptoms—a subgroup of HF patients who have 

been under-represented in the trials thus far. Similarly, the Trip HF (Triple resynchronization in 

paced Heart Failure patients - NCT00187265 on clinicaltrials.gov) and APAF (Assessment of 

cardiac resynchronization therapy in patients undergoing “Ablate and Pace” therapy for 

permanent Atrial Fibrillation—NCT00111527 on clinicaltrials.gov) Trials will provide much 

needed data on the efficacy and safety of CRT in patients with atrial fibrillation—another patient 

subgroup under-represented in CRT trials thus far. Furthermore, the BLOCK HF (Biventricular 

Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block–

NCT00267098 on clinicaltrials.gov) Trial will to provide data necessary to determine the 

efficacy and safety of CRT in patients with atrioventricular block. Although our analyses suggest 

that the efficacy of CRT is not altered by the presence of an ICD, two ongoing trials (The 

Resynchronization/Defibrillation for Advanced Heart Failure [RAFT] Trial–NCT00251251 on 

clinicaltrials.gov - and The Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: 

Assessment of Safety and Effectiveness in Heart Failure [DECREASE-HF]236 Trials) will 

provide further detail to solidify the evidence base and resolve the question of the incremental 

benefits of combined CRT-ICD devices over ICD alone in patients with more symptomatic left 

ventricular dysfunction (i.e., NYHA class III and IV). 

A key area of residual uncertainty regarding device therapy in left ventricular systolic 

dysfunction is the incremental benefit of combined CRT-ICD devices over CRT alone. As others 

have pointed out, “the effects of these devices may not be additive.”291 While trials are ongoing 

(as detailed above) to evaluate the incremental benefit of combined CRT-ICD devices over ICD 

alone devices, we challenge device manufacturers and trialists to also test the incremental 

benefits of combined CRT-ICD devices over CRT alone devices. Although some may argue that 

CRT alone devices have been superseded by combined CRT-ICD devices, we would argue that 

the incremental benefits of combined CRT-ICD devices over CRT alone devices are still 

unknown (due to a paucity of trial data comparing these two devices head-to-head in patients 

with left ventricular systolic dysfunction). The indirect comparisons we described (between two 

arms of the COMPANION trial and the meta-regression across trials as discussed on page 123 of 

this report) certainly cannot be considered definitive evidence. Indeed, given the changing 

epidemiology of HF mortality (i.e., HF patients who are living longer due to disease modifying 

agents such as ACE inhibitors, beta-blockers, and spironolactone and multidisciplinary HF 

management clinics are now far more likely to die of progressive HF than sudden death than they 

were even a decade ago),323 we believe that the incremental benefits of ICD therapy in a patient 

who has a CRT device may well be substantially less than anticipated from the ICD trial data 

presented in this report. Clearly, any such trial would need to target those patients who currently 

fail to qualify for ICD therapy, for example, patients with LVEF in the range of 30 to 40 percent 

and/or patients with greater degrees of LV systolic dysfunction and more heart failure symptoms 
179

(NYHA class IV). It has been estimated that such a trial would require over 1,300 patients per 

arm followed for 3 years. To quote Dr. Daubert, “who will undertake such a study?”324 Given the 

markedly higher costs for combined CRT-ICD devices than CRT alone devices and the rapidly 

expanding population of HF patients eligible for such devices, perhaps this question is better 

framed “how can we not undertake such a study?

181

References and Included Studies

1. Leclercq C, Cazeau S, Le Breton H, et al. Acute 

hemodynamic effects of biventricular DDD 

pacing in patients with end-stage heart failure. J 

Am Coll Cardiol 1998;32(7):1825-31. 

2. Nelson GS, Berger RD, Fetics BJ, et al. Left 

ventricular or biventricular pacing improves 

cardiac function at diminished energy cost in 

patients with dilated cardiomyopathy and left 

bundle-branch block. Circulation 

2000;102(25):3053-9. 

3. Higgins JP, Thompson SG. Quantifying 

heterogeneity in a meta-analysis. Stat Med 

2002;21(11):1539-58. 

4. Abraham WT, Fisher WG, Smith AL, et al. 

Cardiac resynchronization in chronic heart 

failure. N Engl J Med 2002;346(24):1845-53. 

5. Cazeau S, Leclercq C, Lavergne T, et al. Effects 

of multisite biventricular pacing in patients with 

heart failure and intraventricular conduction 

delay (MUSTIC SR). N Engl J Med 

2001;344(12):873-80. 

6. Young JB, Abraham WT, Smith AL, et al. 

Combined cardiac resynchronization and 

implantable cardioversion defibrillation in 

advanced chronic heart failure: the MIRACLE 

ICD Trial. JAMA 2003;289(20):2685-94. 

7. Leclercq C, Walker S, Linde C, et al. 

Comparative effects of permanent biventricular 

and right-univentricular pacing in heart failure 

patients with chronic atrial fibrillation (MUSTIC 

AF). Eur Heart J 2002a;23(22):1780-7. 

8. Auricchio A, Stellbrink C, Sack S, et al. Longterm clinical effect of hemodynamically 

optimized cardiac resynchronization therapy in 

patients with heart failure and ventricular 

conduction delay (PATH CHF Trial). J Am Coll 

Cardiol 2002a;39(12):2026-33. 

9. Higgins SL, Hummel JD, Niazi IK, et al. Cardiac 

resynchronization therapy for the treatment of 

heart failure in patients with intraventricular 

conduction delay and malignant ventricular 

tachyarrhythmias. J Am Coll Cardiol 

2003;42(8):1454-9. 

10. Leclercq C, Cazeau S, Lellouche D. Upgrading 

from right ventricular pacing to biventricular 

pacing in previously paced patients with 

advanced heart failure: a randomized controlled 

study (RD-CHF). European Society of 

Cardiology Congress; Aug 30-Sep 3; Vienna, 

Austria. 2003. 

11. Bristow MR, Saxon LA, Boehmer J, et al. 

Cardiac-resynchronization therapy with or 

without an implantable defibrillator in advanced 

chronic heart failure. N Engl J Med 

2004;350(21):2140-50. 

12. Auricchio A, Stellbrink C, Butter C, et al. 

Clinical efficacy of cardiac resynchronization 

therapy using left ventricular pacing in heart 

failure patients stratified by severity of 

ventricular conduction delay. J Am Coll Cardiol 

2003;42(12):2109-16. 

13. Kindermann M, Hennen B, Jung J, et al. 

Biventricular versus conventional right 

ventricular stimulation for patients with standard 

pacing indication and left ventricular 

dysfunction: the Homburg Biventricular Pacing 

Evaluation (HOBIPACE). J Am Coll Cardiol 

2006;47(10):1927-37. 

14. Abraham WT, Young JB, Leon AR, et al. Effects 

of cardiac resynchronization on disease 

progression in patients with left ventricular 

systolic dysfunction, an indication for an 

implantable cardioverter-defibrillator, and mildly 

symptomatic chronic heart failure. Circulation 

2004;110(18):2864-8. 

15. Cleland JGF, Daubert JC, Erdmann E, et al. The 

effect of cardiac resynchronization on morbidity 

and mortality in heart failure. N Engl J Med 

2005;352(15):1539-49. 

16. U.S. Food and Drug Administration. St. Jude 

Medical FrontierTM model 5508L and FrontierTM 

II model 5586 cardiac resynchronization therapy 

pacemakers (CRT-P) supported on the model 

3510 programmer platforms with the model 

3307, v4.8m programmer software: part 2 - 

summary of safety and effectiveness [VecTOR] 

[Web Page]. 2005; Available at http://www.fda. 

gov/cdrh/pdf3/p030035s003b.pdf. (Accessed 25 

September 2006). 
182

17. U.S. Food and Drug Administration. St. Jude 

Medical® EpicTM HF System including the 

EpicTM HF Model V-338 cardiac 

resynchronization therapy defibrillator, the 

AesculaTM LV model 1055K lead, the 

QuickSiteTM LV model 1056K lead, and the 

model 3307, v4.5m programmer software: part 2 

- summary of safety and effectiveness 

[RHYTHM ICD] [Web Page]. 2005; Available 

at http://www.fda.gov/cdrh/pdf3/P030054b.pdf. 

(Accessed 25 September 2006). 

18. Achilli A, Sassara M, Ficili S, et al. Long-term 

effectiveness of cardiac resynchronization 

therapy in patients with refractory heart failure 

and "narrow" QRS. J Am Coll Cardiol 

2003;42(12):2117-24. 

19. Adamson PB, Smith AL, Abraham WT, et al. 

Continuous autonomic assessment in patients 

with symptomatic heart failure: prognostic value 

of heart rate variability measured by an 

implanted cardiac resynchronization device. 

Circulation 2004;110(16):2389-94. 

20. Albertsen AE, Nielsen JC, Pedersen AK, et al. 

Left ventricular lead performance in cardiac 

resynchronization therapy: impact of lead 

localization and complications. Pacing Clin 

Electrophysiol 2005;28(6):483-8. 

21. Alonso C, Leclercq C, Victor F, et al. 

Electrocardiographic predictive factors of longterm clinical improvement with multisite 

biventricular pacing in advanced heart failure. 

Am J Cardiol 1999;84(12):1417-21. 

22. Ammann P, Kiencke S, Schaer B, et al. Cardiac 

resynchronization in severe heart failure and left 

bundle branch block: a single center experience. 

Swiss Med Wkly 2004;134(19-20):277-82. 

23. Ansalone G, Giannantoni P, Ricci R, et al. 

Doppler myocardial imaging to evaluate the 

effectiveness of pacing sites in patients receiving 

biventricular pacing. J Am Coll Cardiol 

2002;39(3):489-99. 

24. Aranda JM Jr, Woo GW, Conti JB, et al. Use of 

cardiac resynchronization therapy to optimize 

beta-blocker therapy in patients with heart failure 

and prolonged QRS duration. Am J Cardiol 

2005;95(7):889-91. 

25. Auricchio A, Kloss M, Trautmann SI, et al. 

Exercise performance following cardiac 

resynchronization therapy in patients with heart 

failure and ventricular conduction delay. Am J 

Cardiol 2002b;89(2):198-203. 

26. Azizi M, Castel MA, Behrens S, et al. 

Experience with coronary sinus lead 

implantations for cardiac resynchronization 

therapy in 244 patients. Herzschrittmacherther 

Elektrophysiol 2006;17(1):13-8. 

27. Baker CM, Christopher TJ, Smith PF, et al. 

Addition of a left ventricular lead to 

conventional pacing systems in patients with 

congestive heart failure: feasibility, safety, and 

early results in 60 consecutive patients. Pacing 

Clin Electrophysiol 2002;25(8):1166-71. 

28. Bax JJ, Marwick TH, Molhoek SG, et al. Left 

ventricular dyssynchrony predicts benefit of 

cardiac resynchronization therapy in patients 

with end-stage heart failure before pacemaker 

implantation. Am J Cardiol 2003;92(10):1238-

40. 

29. Bax JJ, Bleeker GB, Marwick TH, et al. Left 

ventricular dyssynchrony predicts response and 

prognosis after cardiac resynchronization 

therapy. J Am Coll Cardiol 2004;44(9):1834-40. 

30. Bleeker GB, Schalij MJ, Molhoek SG, et al. 

Comparison of effectiveness of cardiac 

resynchronization therapy in patients <70 versus 

> or =70 years of age. Am J Cardiol 

2005a;96(3):420-2. 

31. Bleeker GB, Schalij MJ, Nihoyannopoulos P, et 

al. Left ventricular dyssynchrony predicts right 

ventricular remodeling after cardiac 

resynchronization therapy. J Am Coll Cardiol 

2005b;46(12):2264-9. 

32. Bleeker GB, Schalij MJ, Holman ER, et al. 

Cardiac resynchronization therapy in patients 

with systolic left ventricular dysfunction and 

symptoms of mild heart failure secondary to 

ischemic or nonischemic cardiomyopathy. Am J 

Cardiol 2006;98(2):230-5. 

33. Bocchiardo M, Padeletti L, Gasparini M, et al. 

Biventricular pacing in patients candidate to an 

ICD. Eur Heart J 2000;2(Suppl J):J36-J40. 
183

34. Bonanno C, Ometto R, Pasinato S, et al. Effects 

of cardiac resynchronization therapy on disease 

progression in patients with congestive heart 

failure. Ital Heart J 2004;5(5):364-70. 

35. Bordachar P, Lafitte S, Reuter S, et al. 

Echocardiographic parameters of ventricular 

dyssynchrony validation in patients with heart 

failure using sequential biventricular pacing. J 

Am Coll Cardiol 2004;44(11):2157-65. 

36. Boriani G, Muller CP, Seidl KH, et al. 

Randomized comparison of simultaneous 

biventricular stimulation versus optimized 

interventricular delay in cardiac 

resynchronization therapy. The 

Resynchronization for the HemodYnamic 

Treatment for Heart Failure Management II 

implantable cardioverter defibrillator (RHYTHM 

II ICD) study. Am Heart J 2006a;151(5):1050-8. 

37. Boriani G, Gasparini M, Lunati M, et al. 

Characteristics of ventricular tachyarrhythmias 

occurring in ischemic versus nonischemic 

patients implanted with a biventricular 

cardioverter-defibrillator for primary or 

secondary prevention of sudden death. Am Heart 

J 2006b;152(3):527.e1-11. 

38. Boriani G, Regoli F, Saporito D, et al. 

Neurohormones and inflammatory mediators in 

patients with heart failure undergoing cardiac 

resynchronization therapy: time courses and 

prediction of response. Peptides 

2006c;27(7):1776-86. 

39. Braun MU, Rauwolf T, Zerm T, et al. Long term 

biventricular resynchronisation therapy in 

advanced heart failure: effect on neurohormones. 

Heart 2005;91(5):601-5. 

40. Braunschweig F, Mortensen PT, Gras D, et al. 

Monitoring of physical activity and heart rate 

variability in patients with chronic heart failure 

using cardiac resynchronization devices. Am J 

Cardiol 2005;95(9):1104-7. 

41. Cazeau S, Jauvert G, Alonso C, et al. 

Echographic modelling of cardiac asynchronism: 

prospective evaluation before and after multisite 

stimulation [in French]. Arch Mal Coeur Vaiss 

2003;96(6):659-64. 

42. Chalil S, Yousef ZR, Muyhaldeen SA, et al. 

Pacing-induced increase in QT dispersion 

predicts sudden cardiac death following cardiac 

resynchronization therapy. J Am Coll Cardiol 

2006;47(12):2486-92. 

43. Chan KL, Tang AS, Achilli A, et al. Functional 

and echocardiographic improvement following 

multisite biventricular pacing for congestive 

heart failure. Can J Cardiol 2003;19(4):387-90. 

44. Cowburn PJ, Patel H, Pipes RR, et al. Contrast 

nephropathy post cardiac resynchronization 

therapy: an under-recognized complication with 

important morbidity. Eur J Heart Fail 

2005;17(5):899-903. 

45. Da Costa A, Thevenin J, Roche F, et al. 

Prospective validation of stress 

echocardiography as an identifier of cardiac 

resynchronization therapy responders. Heart 

Rhythm 2006;3(4):406-13. 

46. Daubert JC, Ritter P, Le Breton H, et al. 

Permanent left ventricular pacing with 

transvenous leads inserted into the coronary 

veins. Pacing Clin Electrophysiol 1998;21(1 Pt 

2):239-45. 

47. Davis DR, Krahn AD, Tang AS, et al. Long-term 

outcome of cardiac resynchronization therapy in 

patients with severe congestive heart failure. Can 

J Cardiol 2005;21(5):413-7. 

48. de Sisti A, Toussaint JF, Lavergne T, et al. 

Determinants of mortality in patients undergoing 

cardiac resynchronization therapy: baseline 

clinical, echocardiographic, and 

angioscintigraphic evaluation prior to 

resynchronization. Pacing Clin Electrophysiol 

2005;28(12):1260-70. 

49. Diaz-Infante E, Mont L, Leal J, et al. Predictors 

of lack of response to resynchronization therapy. 

Am J Cardiol 2005;95(12):1436-40. 

50. Dixon LJ, Murtagh JG, Richardson SG, et al. 

Reduction in hospitalization rates following 

cardiac resynchronisation therapy in cardiac 

failure: experience from a single centre. 

Europace 2004;6(6):586-9. 
184

51. Duncan AM, Lim E, Clague J, et al. Comparison 

of segmental and global markers of 

dyssynchrony in predicting clinical response to 

cardiac resynchronization. Eur Heart J 

2006;27(20):2426-32. 

52. Ellery S, Paul V, Prenner G, et al. A new 

endocardial "over-the-wire" or stylet-driven left 

ventricular lead: first clinical experience. Pacing 

Clin Electrophysiol 2005;28(Suppl 1):S31-S35. 

53. Ermis C, Lurie KG, Zhu AX, et al. Biventricular 

implantable cardioverter defibrillators improve 

survival compared with biventricular pacing 

alone in patients with severe left ventricular 

dysfunction. J Cardiovasc Electrophysiol 

2004;15(8):862-6. 

54. Fung JW, Yu CM, Chan JY, et al. Effects of 

cardiac resynchronization therapy on incidence 

of atrial fibrillation in patients with poor left 

ventricular systolic function. Am J Cardiol 

2005;96(5):728-31. 

55. Gaita F, Bocchiardo M, Porciani MC, et al. 

Should stimulation therapy for congestive heart 

failure be combined with defibrillation backup? 

Am J Cardiol 2000;86(9A):165K-58K. 

56. Galvao SS, Barcellos CM, Vasconcelos JT, et al. 

Ventricular resynchronization through 

biventricular cardiac pacing for the treatment of 

refractory heart failure in dilated 

cardiomyopathy. Arq Bras Cardiol 

2002;78(1):39-50. 

57. Gasparini M, Mantica M, Galimberti P, et al. 

Beneficial effects of biventricular pacing in 

patients with a "narrow" QRS. Pacing Clin 

Electrophysiol 2003a;26(1 Pt 2):169-74. 

58. Gras D, Leclercq C, Tang AS, et al. Cardiac 

resynchronization therapy in advanced heart 

failure the multicenter InSync clinical study. Eur 

J Heart Fail 2002;4(3):311-20. 

59. Hernandez Madrid A, Miguelanez Diaz M, 

Escobar Cervantes C, et al. Usefulness of brain 

natriuretic peptide to evaluate patients with heart 

failure treated with cardiac resynchronization [in 

Spanish]. Rev Esp Cardiol 2004;57(4):299-305. 

60. Hua W, Niu HX, Wang FZ, et al. Short-term 

effect of cardiac resynchronization therapy in 

patients with ischaemic or nonischaemic 

cardiomyopathy. Chin Med J 

2006;119(18):1507-10. 

61. Kies P, Bax JJ, Molhoek SG, et al. Comparison 

of effectiveness of cardiac resynchronization 

therapy in patients with versus without diabetes 

mellitus. Am J Cardiol 2005;96(1):108-11. 

62. Kies P, Leclercq C, Bleeker GB, et al. Cardiac 

resynchronisation therapy in chronic atrial 

fibrillation: impact on left atrial size and reversal 

to sinus rhythm. Heart 2006;92(4):490-4. 

63. Koos R, Sinha AM, Markus K, et al. Comparison 

of left ventricular lead placement via the 

coronary venous approach versus lateral 

thoracotomy in patients receiving cardiac 

resynchronization therapy. Am J Cardiol 

2004;94(1):59-63. 

64. Krahn AD, Snell L, Yee R, et al. Biventricular 

pacing improves quality of life and exercise 

tolerance in patients with heart failure and 

intraventricular conduction delay. Can J Cardiol 

2002;18(4):380-7. 

65. Kuhlkamp V, InSync 7272 ICD World Wide 

Investigators. Initial experience with an 

implantable cardioverter-defibrillator 

incorporating cardiac resynchronization therapy. 

J Am Coll Cardiol 2002;39(5):790-7. 

66. Leclercq C, Victor F, Alonso C, et al. 

Comparative effects of permanent biventricular 

pacing for refractory heart failure in patients with 

stable sinus rhythm or chronic atrial fibrillation. 

Am J Cardiol 2000;85(9):1154-6. 

67. Leclercq C, Alonso C, Revault F, et al. Mediumterm results of multisite biventricular stimulation 

in severe cardiac failure [in French]. Arch Mal 

Coeur Vaiss 2002b;95(4):253-9. 

68. Lecoq G, Leclercq C, Leray E, et al. Clinical and 

electrocardiographic predictors of a positive 

response to cardiac resynchronization therapy in 

advanced heart failure. Eur Heart J 

2005;26(11):1094-100. 
185

69. Lenom V, Materne P, Hoffer E, et al. Clinical 

value of cardiac resynchronization therapy in 

patients with congestive heart failure [in Fench]. 

Rev Med Liege 2005;60(2):101-8. 

70. Leon AR, Abraham WT, Brozena S, et al. 

Cardiac resynchronization with sequential 

biventricular pacing for the treatment of 

moderate-to-severe heart failure. J Am Coll 

Cardiol 2005;46(12):2298-304. 

71. Lindner O, Vogt J, Kammeier A, et al. Effect of 

cardiac resynchronization therapy on global and 

regional oxygen consumption and myocardial 

blood flow in patients with non-ischaemic and 

ischaemic cardiomyopathy. Eur Heart J 

2005;26(1):70-6. 

72. Macioce R, Cappelli F, Demarchi G, et al. 

Resynchronization of mitral valve annular 

segments reduces functional mitral regurgitation 

in cardiac resynchronization therapy. Minerva 

Cardioangiol 2005;53(4):329-33. 

73. Mair H, Sachweh J, Meuris B, et al. Surgical 

epicardial left ventricular lead versus coronary 

sinus lead placement in biventricular pacing. Eur 

J Cardiothorac Surg 2005;27(2):235-42. 

74. Mangiavacchi M, Gasparini M, Faletra F, et al. 

Clinical predictors of marked improvement in 

left ventricular performance after cardiac 

resynchronization therapy in patients with 

chronic heart failure. Am Heart J 

2006;151(2):477.e1-477.e6. 

75. Marai I, Gurevitz O, Carasso S, et al. 

Improvement of congestive heart failure by 

upgrading of conventional to resynchronization 

pacemakers. Pacing Clin Electrophysiol 

2006;29(8):880-4. 

76. Mascioli G, Curnis A, Bontempi L, et al. 

Biventricular pacing for patients with severe 

congestive heart failure: a single center 

experience. Ital Heart J 2002;3(10):598-602. 

77. Mele D, Pasanisi G, Capasso F, et al. Left 

intraventricular myocardial deformation 

dyssynchrony identifies responders to cardiac 

resynchronization therapy in patients with heart 

failure. Eur Heart J 2006;27(9):1070-8. 

78. Molhoek SG, Bax JJ, van Erven L, et al. 

Effectiveness of resynchronization therapy in 

patients with end-stage heart failure. Am J 

Cardiol 2002;90(4):379-83. 

79. Molhoek SG, Bax JJ, Bleeker GB, et al. 

Comparison of response to cardiac 

resynchronization therapy in patients with sinus 

rhythm versus chronic atrial fibrillation. Am J 

Cardiol 2004a;94(12):1506-9. 

80. Molhoek SG, Bax JJ, van Erven L, et al. 

Comparison of benefits from cardiac 

resynchronization therapy in patients with 

ischemic cardiomyopathy versus idiopathic 

dilated cardiomyopathy. Am J Cardiol 

2004b;93(7):860-3. 

81. Molhoek SG, van Erven L, Bootsma M, et al. 

QRS duration and shortening to predict clinical 

response to cardiac resynchronization therapy in 

patients with end-stage heart failure. Pacing Clin 

Electrophysiol 2004c;27(3):308-13. 

82. Molhoek SG, Bax JJ, Bleeker GB, et al. Longterm follow-up of cardiac resynchronization 

therapy in patients with end-stage heart failure. J 

Cardiovasc Electrophysiol 2005;16(7):701-7. 

83. Mortensen PT, Sogaard P, Mansour H, et al. 

Sequential biventricular pacing: evaluation of 

safety and efficacy. Pacing Clin Electrophysiol 

2004;27(3):339-45. 

84. Murphy RT, Sigurdsson G, Mulamalla S, et al. 

Tissue synchronization imaging and optimal left 

ventricular pacing site in cardiac 

resynchronization therapy. Am J Cardiol 

2006;97(11):1615-21. 

85. Nagele H, Schmidt E, Petersen B, et al. 

Experience with biventricular pacing in severe 

heart failure [in German]. Herzschrittmacher 

2001;21(2):53-61. 

86. Navia JL, Atik FA, Grimm RA, et al. Minimally 

invasive left ventricular epicardial lead 

placement: surgical techniques for heart failure 

resynchronization therapy. Ann Thorac Surg 

2005;79(5):1536-44. 

87. Niu HX, Hua W, Wang FZ, et al. Complications 

of cardiac resynchronization therapy in patients 

with congestive heart failure. Chin Med J 

2006;119(6):449-53. 
186

88. Notabartolo D, Merlino JD, Smith AL, et al. 

Usefulness of the peak velocity difference by 

tissue Doppler imaging technique as an effective 

predictor of response to cardiac 

resynchronization therapy. Am J Cardiol 

2004;94(6):817-20. 

89. O'Donnell D, Nadurata V, Hamer A, et al. Longterm variations in optimal programming of 

cardiac resynchronization therapy devices. 

Pacing Clin Electrophysiol 2005;28(Suppl 

1):S24-S26. 

90. Oliva F, Frigerio M, Lunati M, et al. Benefits of 

Cardiac Resynchronization Therapy (CRT) in 

patients with advanced congestive heart failure 

listed for heart transplant [abstract]. Meeting and 

scientific sessions of the 25th anniversary 

meeting of the International Society for Heart 

and Lung Transplantation: 2005 Apr 25; 

Philadelphia, PA. J Heart Lung Transplant 

2005;24(2 Suppl):S84-S85. 

91. Ollitrault J, Ritter P, Mabo P, et al. Long-term 

experience with a preshaped left ventricular 

pacing lead. Pacing Clin Electrophysiol 

2003;26(1 Pt 2):185-8. 

92. Pappone C, Vicedomini G, Augello G, et al. 

Combining electrical therapies for advanced 

heart failure: the Milan experience with 

biventricular pacing-defibrillation backup 

combination for primary prevention of sudden 

cardiac death. Am J Cardiol 2003;91(9A):74F80F. 

93. Penicka M, Bartunek J, De Bruyne B, et al. 

Improvement of left ventricular function after 

cardiac resynchronization therapy is predicted by 

tissue Doppler imaging echocardiography. 

Circulation 2004;109(8):978-83. 

94. Pitzalis MV, Iacoviello M, Romito R, et al. 

Ventricular asynchrony predicts a better outcome 

in patients with chronic heart failure receiving 

cardiac resynchronization therapy. J Am Coll 

Cardiol 2005;45(1):65-9. 

95. Porciani MC, Macioce R, Demarchi G, et al. 

Effects of cardiac resynchronization therapy on 

the mechanisms underlying functional mitral 

regurgitation in congestive heart failure. Eur J 

Echocardiog 2006a;7(1):31-9. 

96. Porciani MC, Valsecchi S, Demarchi G, et al. 

Evolution and prognostic significance of 

diastolic filling pattern in cardiac 

resynchronization therapy. Int J Cardiol 

2006b;112(3):322-8. 

97. Puglisi A, Lunati M, Marullo AG, et al. 

Limited thoracotomy as a second choice 

alternative to transvenous implant for cardiac 

resynchronisation therapy delivery. Eur Heart 

J 2004;25(12):1063-9. 

98. Purnode P, Blommaert D, Eucher P, et al. 

Biventricular pacing and heart failure [in 

French]. Louv Med 2004;123(1):18-27. 

99. Reuter S, Garrigue S, Bordachar P, et al. 

Intermediate-term results of biventricular 

pacing in heart failure: correlation between 

clinical and hemodynamic data. Pacing Clin 

Electrophysiol 2000;23(11 Pt 2):1713-7. 

100. Reuter S, Garrigue S, Barold SS, et al. 

Comparison of characteristics in responders 

versus nonresponders with biventricular 

pacing for drug-resistant congestive heart 

failure. Am J Cardiol 2002;89(3):346-50. 

101. Ricci R, Pignalberi C, Ansalone G, et al. Early 

and late QRS morphology and width in 

biventricular pacing: relationship to lead site 

and electrical remodeling. J Interv Card 

Electrophysiol 2002;6(3):279-85. 

102. Ritter O, Koller ML, Fey B, et al. Progression 

of heart failure in right univentricular pacing 

compared to biventricular pacing. Int J Cardiol 

2006;110(3):359-65. 

103. Rossillo A, Verma A, Saad EB, et al. Impact 

of coronary sinus lead position on 

biventricular pacing: mortality and 

echocardiographic evaluation during long-term 

follow-up. J Cardiovasc Electrophysiol 

2004;15(10):1120-5. 

104. Salukhe TV, Francis DP, Clague JR, et al. 

Chronic heart failure patients with restrictive 

LV filling pattern have significantly less 

benefit from cardiac resynchronization therapy 

than patients with late LV filling pattern. Int J 

Cardiol 2005;100(1):5-12. 
187

105. Sawhney NS, Waggoner AD, Garhwal S. 

Randomized prospective trial of 

atrioventricular delay programming for cardiac 

resynchronization therapy. Heart Rhythm 

2004;1(5):562-7. 

106. Saxon LA, Greenfield RA, Crandall BG, et al. 

Results of the multicenter RENEWAL 3 AVT 

clinical study of cardiac resynchronization 

defibrillator therapy in patients with 

paroxysmal atrial fibrillation. J Cardiovasc 

Electrophysiol 2006;17(5):520-5. 

107. Sogaard P, Egeblad H, Kim WY, et al. Tissue 

Doppler imaging predicts improved systolic 

performance and reversed left ventricular 

remodeling during long-term cardiac 

resynchronization therapy. J Am Coll Cardiol 

2002;40(4):723-30. 

108. Stahlberg M, Braunschweig F, Gadler F, et al. 

Three year outcome of cardiac 

resynchronization therapy: a single center 

evaluation. Pacing Clin Electrophysiol 

2005;28(10):1013-7. 

109. Taieb J, Moudni F, Benchaa T, et al. 

Resynchronization of the failing heart by 

pacing [in French]. Ann Cardiol Angeiol 

(Paris) 2002;51(5):289-95. 

110. Tedrow UB, Kramer DB, Stevenson LW, et al. 

Relation of Right Ventricular Peak Systolic 

Pressure to Major Adverse Events in Patients 

Undergoing Cardiac Resynchronization 

Therapy. Am J Cardiol 2006;97(12):1737-40. 

111. Teo WS, Kam R, Hsu LF. Treatment of heart 

failure - role of biventricular pacing for heart 

failure not responding well to drug therapy. 

Singapore Med J 2003;44(3):114-22. 

112. Theuns DA, Thornton AS, Klootwijk AP, et 

al. Outcome in patients with an ICD 

incorporating cardiac resynchronisation 

therapy: differences between primary and 

secondary prophylaxis. Eur J Heart Fail 

2005;17(6):1027-32. 

113. Toussaint JF, Lavergne T, Kerrou K, et al. 

Basal asynchrony and resynchronization with 

biventricular pacing predict long-term 

improvement of LV function in heart failure 

patients. Pacing Clin Electrophysiol 

2003;26(9):1815-23. 

114. Vidal B, Sitges M, Marigliano A, et al. 

Relation of response to cardiac 

resynchronization therapy to left ventricular 

reverse remodeling. Am J Cardiol 

2006;97(6):876-81. 

115. Waggoner AD, Rovner A, de las Fuentes L, et 

al. Clinical outcomes after cardiac 

resynchronization therapy: importance of left 

ventricular diastolic function and origin of 

heart failure. J Am Soc Echocard 

2006;19(3):307-13. 

116. Witte KKA, Pipes RR, Nanthakumar K, et al. 

Biventricular Pacemaker Upgrade in 

Previously Paced Heart Failure PatientsImprovements in Ventricular Dyssynchrony. J 

Card Fail 2006;12(3):199-204. 

117. Ypenburg C, van Erven L, Bleeker GB, et al. 

Benefit of combined resynchronization and 

defibrillator therapy in heart failure patients 

with and without ventricular arrhythmias. J 

Am Coll Cardiol 2006;48(3):464-70. 

118. Yu CM, Chau E, Sanderson JE, et al. Tissue 

Doppler echocardiographic evidence of 

reverse remodeling and improved 

synchronicity by simultaneously delaying 

regional contraction after biventricular pacing 

therapy in heart failure. Circulation 

2002a;105(4):438-45. 

119. Yu CM, Fung WH, Lin H, et al. Predictors of 

left ventricular reverse remodeling after 

cardiac resynchronization therapy for heart 

failure secondary to idiopathic dilated or 

ischemic cardiomyopathy. Am J Cardiol 

2002b;91(6):684-8. 

120. Yu CM, Fung JW, Chan CK, et al. 

Comparison of efficacy of reverse remodeling 

and clinical improvement for relatively narrow 

and wide QRS complexes after cardiac 

resynchronization therapy for heart failure. J 

Cardiovasc Electrophysiol 2004;15(9):1058-

65. 

121. Yu CM, Bleeker GB, Fung JW, et al. Left 

ventricular reverse remodeling but not clinical 

improvement predicts long-term survival after 

cardiac resynchronization therapy. Circulation 

2005;112(11):1580-6. 
188

122. Zhang Q, Fung J-H, Auricchio A, et al. 

Differential change in left ventricular mass 

and regional wall thickness after cardiac 

resynchronization therapy for heart failure. 

Eur Heart J 2006;27(12):1423-30. 

123. Chugh A, Scharf C, Hall B, et al. Prevalence 

and management of inappropriate detection 

and therapies in patients with first-generation 

biventricular pacemaker-defibrillators. Pacing 

Clin Electrophysiol 2005;28(1):44-50. 

124. de Cock CC, van Campen CM, Visser CA. 

Major dissection of the coronary sinus and its 

tributaries during lead implantation for 

biventricular stimulation: angiographic followup. Europace 2004;6(1):43-7. 

125. De Martino G, Sanna T, Dello Russo A, et al. 

A randomized comparison of alternative 

techniques to achieve coronary sinus 

cannulation during biventricular implantation 

procedures. J Interv Card Electrophysiol 

2004;10(3):227-30. 

126. De Martino G, Messano L, Santamaria M, et 

al. A randomized evaluation of different 

approaches to coronary sinus venography 

during biventricular pacemaker implants. 

Europace 2005;7(1):73-6. 

127. Gasparini M, Galimberti P, Regoli F, et al. 

Delayed defibrillation testing in patients 

implanted with biventricular ICD (CRT-D): a 

reliable and safe approach. J Cardiovasc 

Electrophysiol 2005;16(12):1279-83. 

128. Kautzner J, Riedlbauchova L, Cihak R, et al. 

Technical aspects of implantation of LV lead 

for cardiac resynchronization therapy in 

chronic heart failure. Pacing Clin 

Electrophysiol 2004;27(6 Pt 1):783-90. 

129. Lewicka-Nowak E, Sterlinski M, DabrowskaKugacka A, et al. Complications of permanent 

biventricular pacing in patients with advanced 

heart failure [in Polish]. Folia Cardiol 

2005;12(5):343-53. 

130. Purerfellner H, Nesser HJ, Winter S, et al. 

Transvenous left ventricular lead implantation 

with the EASYTRAK lead system: the 

European experience. Am J Cardiol 

2000;86(9A):157K-64K. 

131. Romeyer-Bouchard C, Da Costa A, 

Abdellaoui L, et al. Simplified cardiac 

resynchronization implantation technique 

involving right access and a triple-guide/single 

introducer approach. Heart Rhythm 

2005;2(7):714-9. 

132. Schuchert A, Seidl K, Pfeiffer D, et al. Twoyear performance of a preshaped lead for left 

ventricular stimulation. Pacing Clin 

Electrophysiol 2004;27(12):1610-4. 

133. Moss AJ, Hall WJ, Cannom DS, et al. 

Improved survival with an implanted 

defibrillator in patients with coronary disease 

at high risk for ventricular arrhythmia. 

Multicenter Automatic Defibrillator 

Implantation Trial Investigators. N Engl J Med 

1996;335(26):1933-40. 

134. Bigger JT Jr. Prophylactic use of implanted 

cardiac defibrillators in patients at high risk for 

ventricular arrhythmias after coronary-artery 

bypass graft surgery. Coronary Artery Bypass 

Graft (CABG) Patch Trial Investigators. N 

Engl J Med 1997;337(22):1569-75. 

135. Moss AJ, Zareba W, Hall WJ, et al. 

Prophylactic implantation of a defibrillator in 

patients with myocardial infarction and 

reduced ejection fraction. N Engl J Med 

2002;346(12):877-83. 

136. Bansch D, Antz M, Boczor S, et al. Primary 

prevention of sudden cardiac death in 

idiopathic dilated cardiomyopathy: the 

Cardiomyopathy Trial (CAT). Circulation 

2002;105(12):1453-8. 

137. Strickberger SA, Hummel JD, Bartlett TG, et 

al. Amiodarone versus implantable 

cardioverter-defibrillator: randomized trial in 

patients with nonischemic dilated 

cardiomyopathy and asymptomatic 

nonsustained ventricular tachycardia—

AMIOVIRT. J Am Coll Cardiol 

2003;41(10):1707-12. 

138. Kadish A, Dyer A, Daubert JP, et al. 

Prophylactic defibrillator implantation in 

patients with nonischemic dilated 

cardiomyopathy. N Engl J Med 

2004;350(21):2151-8. 
189

139. Hohnloser SH, Kuck KH, Dorian P, et al. 

Prophylactic use of an implantable 

cardioverter-defibrillator after acute 

myocardial infarction. N Engl J Med 

2004;351(24):2481-8. 

140. Bardy GH, Lee KL, Mark DB, et al. 

Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N 

Engl J Med 2005;352(3):225-37. 

141. AVID investigators. A comparison of 

antiarrhythmic-drug therapy with implantable 

defibrillators in patients resuscitated from 

near-fatal ventricular arrhythmias. The 

Antiarrhythmics versus Implantable 

Defibrillators (AVID) Investigators. N Engl J 

Med 1997;337(22):1576-83. 

142. Connolly SJ, Gent M, Roberts RS, et al. 

Canadian implantable defibrillator study 

(CIDS): a randomized trial of the implantable 

cardioverter defibrillator against amiodarone. 

Circulation 2000;101(11):1297-302. 

143. Kuck KH, Cappato R, Siebels J, et al. 

Randomized comparison of antiarrhythmic 

drug therapy with implantable defibrillators in 

patients resuscitated from cardiac arrest: the 

Cardiac Arrest Study Hamburg (CASH). 

Circulation 2000;102(7):748-54. 

144. Alter P, Waldhans S, Plachta E, et al. 

Complications of implantable cardioverter 

defibrillator therapy in 440 consecutive 

patients. Pacing Clin Electrophysiol 

2005;28(9):926-32. 

145. Backenkohler U, Erdogan A, Steen-Mueller 

MK, et al. Long-term incidence of malignant 

ventricular arrhythmia and shock therapy in 

patients with primary defibrillator 

implantation does not differ from event rates 

in patients treated for survived cardiac arrest. J 

Cardiovasc Electrophysiol 2005;16(5):478-82. 

146. Blangy H, Sadoul N, de Chillou C, et al. 

Characteristics and causes of death in 283 

patients with implanted defibrillators {in 

French]. Arch Mal Coeur Vaiss 2003;96(1):7-

14. 

147. Bode-Schnurbus L, Bocker D, Block M, et al. 

QRS duration: a simple marker for predicting 

cardiac mortality in ICD patients with heart 

failure. Heart 2003;89(10):1157-62. 

148. Bokhari F, Newman D, Greene M, et al. Longterm comparison of the implantable 

cardioverter defibrillator versus amiodarone: 

eleven-year follow-up of a subset of patients in 

the Canadian Implantable Defibrillator Study 

(CIDS). Circulation 2004;110(2):112-6. 

149. Bruch C, Gotzmann M, Sindermann J, et al. 

Prognostic value of a restrictive mitral filling 

pattern in patients with systolic heart failure 

and an implantable cardioverter-defibrillator. 

Am J Cardiol 2006;97(5):676-80. 

150. Brunckhorst C, Binggeli C, Hellermann JP, et 

al. ICD therapy in patients with coronary 

artery disease—incidence of adequate 

interventions [in Germn]. Ther Umsch 

2004;61(4):271-8. 

151. Buxton AE, Lee KL, Fisher JD, et al. A 

randomized study of the prevention of sudden 

death in patients with coronary artery disease. 

Multicenter Unsustained Tachycardia Trial 

Investigators. N Engl J Med 

1999;341(25):1882-90. 

152. Capoferri M, Schwick N, Tanner H, et al. 

Incidence of arrhythmic events in patients with 

implantable cardioverter-defibrillator for 

primary and secondary prevention of sudden 

cardiac death. Swiss Med Wkly 2004;134(11-

12):154-8. 

153. Chan PS, Hayward RA. Mortality reduction by 

implantable cardioverter-defibrillators in highrisk patients with heart failure, ischemic heart 

disease, and new-onset ventricular arrhythmia: 

an effectiveness study. J Am Coll Cardiol 

2005;45(9):1474-81. 

154. Chan PS, Chow T, Kereiakes D, et al. 

Effectiveness of implantable cardioverterdefibrillators in patients with ischemic heart 

disease and left ventricular dysfunction. Arch 

Intern Med 2006;166(20):2228-33. 

155. Cuesta A, Mont L, Rogel U, et al. Comparison 

of effectiveness of implantable cardioverter 

defibrillator in patients with idiopathic dilated 

cardiomyopathy versus those with proved 

coronary heart disease. Am J Cardiol 

2003;92(10):1227-30. 
190

156. Dorian P, Philippon F, Thibault B, et al. 

Randomized controlled study of detection 

enhancements versus rate-only detection to 

prevent inappropriate therapy in a dualchamber implantable cardioverter-defibrillator. 

Heart Rhythm 2004b;1(5):540-7. 

157. Dubner S, Valero E, Pesce R, et al. A Latin 

American registry of implantable cardioverter 

defibrillators: the ICD-LABOR study. Ann 

Noninvasive Electrocardiol 2005;10(4):420-8. 

158. Duray G, Richter S, Manegold J, et al. 

Efficacy and safety of ICD therapy in a 

population of elderly patients treated with 

optimal background medication. J Interv Card 

Electrophysiol 2005;14(3):169-73. 

159. Elhendy A, Chapman S, Porter TR, et al. 

Association of myocardial ischemia with 

mortality and implantable cardioverterdefibrillator therapy in patients with coronary 

artery disease at risk of arrhythmic death. J 

Am Coll Cardiol 2005;46(9):1721-6. 

160. Ellenbogen KA, Wood MA, Shepard RK, et 

al. Detection and management of an 

implantable cardioverter defibrillator lead 

failure: incidence and clinical implications. J 

Am Coll Cardiol 2003;41(1):73-80. 

161. Ermis C, Zadeii G, Zhu AX, et al. Improved 

survival of cardiac transplantation candidates 

with implantable cardioverter defibrillator 

therapy: role of beta-blocker or amiodarone 

treatment. J Cardiovasc Electrophysiol 

2003;14(6):578-83. 

162. Evonich RF, Maheshwari A, Gardiner JC, et 

al. Implantable cardioverter defibrillator 

therapy in patients with ischemic or nonischemic cardiomyopathy and nonsustained 

ventricular tachycardia. J Interv Card 

Electrophysiol 2004;11(1):59-65. 

163. Gatzoulis KA, Andrikopoulos GK, 

Apostolopoulos T, et al. Electrical storm is an 

independent predictor of adverse long-term 

outcome in the era of implantable defibrillator 

therapy. Europace 2005;7(2):184-92. 

164. Greenberg D, Katz A, Epstein M, et al. 

Implantable cardioverter defibrillators in 

Israel: utilization and implantation trends. Int J 

Cardiol 2002;82(1):17-23. 

165. Grimm W, Hoffman JJ, Muller HH, et al. 

Implantable defibrillator event rates in patients 

with idiopathic dilated cardiomyopathy, 

nonsustained ventricular tachycardia on Holter 

and a left ventricular ejection fraction below 

30%. J Am Coll Cardiol 2002;39(5):780-7. 

166. Ho AT, Pai SM, Timothy P, et al. Effect of 

concomitant antiarrhythmic therapy on 

survival in patients with implantable 

cardioverter defibrillators. Pacing Clin 

Electrophysiol 2005;28(7):647-53. 

167. Koplan BA, Epstein LM, Albert CM, et al. 

Survival in octogenarians receiving 

implantable defibrillators. Am Heart J 

2006;152(4):714-9. 

168. Lampert R, McPherson CA, Clancy JF, et al. 

Gender differences in ventricular arrhythmia 

recurrence in patients with coronary artery 

disease and implantable cardioverterdefibrillators. J Am Coll Cardiol 

2004;43(12):2293-9. 

169. Leosdottir M, Reimarsdottir G, Gottskalksson 

G, et al. The use of implantable cardioverter 

defibrillators in Iceland: a retrospective 

population based study. BMC Cardiovascasc 

Disorders 2006 ;6:22. 

170. Nazarian S, Maisel WH, Miles JS, et al. 

Impact of implantable cardioverter 

defibrillators on survival and recurrent 

hospitalization in advanced heart failure. Am 

Heart J 2005;150(5):955-60. 

171. Noseworthy PA, Lashevsky I, Dorian P, et al. 

Feasibility of implantable cardioverter 

defibrillator use in elderly patients: a case 

series of octogenarians. Pacing Clin 

Electrophysiol 2004;27(3):373-8. 

172. Parkash R, Stevenson WG, Epstein LM, et al. 

Predicting early mortality after implantable 

defibrillator implantation: a clinical risk score 

for optimal patient selection. Am Heart J 

2006;151(2):397-403. 

173. Pires LA, Sethuraman B, Guduguntla VD, et 

al. Outcome of women versus men with 

ventricular tachyarrhythmias treated with the 

implantable cardioverter defibrillator. J 

Cardiovasc Electrophysiol 2002 ;13(6):563-8. 
191

174. Pires LA, Johnson KM. Intraoperative testing 

of the implantable cardioverter-defibrillator: 

how much is enough? J Cardiovasc 

Electrophysiol 2006;17(2):140-5. 

175. Raitt MH, Connor WE, Morris C, et al. Fish 

oil supplementation and risk of ventricular 

tachycardia and ventricular fibrillation in 

patients with implantable defibrillators: a 

randomized controlled trial. JAMA 

2005;293(23):2884-91. 

176. Raviele A, Bongiorni MG, Brignole M, et al. 

Early EPS/ICD strategy in survivors of acute 

myocardial infarction with severe left 

ventricular dysfunction on optimal betablocker treatment. The BEta-blocker STrategy 

plus ICD trial. Europace 2005;7(4):327-37. 

177. Robin J, Weinberg K, Tiongson J, et al. Renal 

dialysis as a risk factor for appropriate 

therapies and mortality in implantable 

cardioverter-defibrillator recipients. Heart 

Rhythm 2006;3(10):1196-201. 

178. Russo AM, Nayak H, Verdino R, et al. 

Implantable cardioverter defibrillator events in 

patients with asymptomatic nonsustained 

ventricular tachycardia: is device implantation 

justified? Pacing Clin Electrophysiol 

2003;26(12):2289-95. 

179. Saba S, Atiga WL, Barrington W, et al. 

Selected patients listed for cardiac 

transplantation may benefit from defibrillator 

implantation regardless of an established 

indication. J Heart Lung Transplant 

2003;22(4):411-8. 

180. Sanchez JM, Katsiyiannis WT, Gage BF, et al. 

Implantable cardioverter-defibrillator therapy 

improves long-term survival in patients with 

unexplained syncope, cardiomyopathy, and a 

negative electrophysiologic study. Heart 

Rhythm 2005;2(4):367-73; discussion 374-

375. 

181. Sanchez JM, Greenberg SL, Chen J, et al. 

Smokers are at markedly increased risk of 

appropriate defibrillator shocks in a primary 

prevention population. Heart Rhythm 

2006;3(4):443-9. 

182. Schaer BA, Ammann P, Sticherling C, et al. 

Prophylactic implantable cardioverter 

defibrillator therapy in dilated 

cardiomyopathy: impact of left ventricular 

function. Int J Cardiol 2006;108(1):26-30. 

183. Sears SF, Serber ER, Lewis TS, et al. Do 

positive health expectations and optimism 

relate to quality-of-life outcomes for the 

patient with an implantable cardioverter 

defibrillator? J Cardiopulm Rehabil 

2004;24(5):324-31. 

184. Takahashi T, Bhandari AK, Watanuki M, et al. 

High incidence of device-related and leadrelated complications in the dual-chamber 

implantable cardioverter defibrillator 

compared with the single-chamber version. 

Circulation J 2002;66(8):746-50. 

185. Tandri H, Griffith LS, Tang T, et al. Clinical 

course and long-term follow-up of patients 

receiving implantable cardioverterdefibrillators. Heart Rhythm 2006;3(7):762-8. 

186. Telfer EA, Mecca A, Martini M, et al. 

Implantable defibrillator use for de novo 

ventricular tachyarrhythmias encountered after 

cardiac surgery. Pacing Clin Electrophysiol 

2002;25(6):951-6. 

187. Theuns DA, Szili-Torok T, Jordaens LJ. 

Defibrillation efficacy testing: long-term 

follow-up and mortality. Europace 

2005b;7(6):509-15. 

188. Trappe HJ. Biventricular pacing therapy in 

patients with congestive heart failure and 

ventricular tachyarrhythmias [abstract]. 

Jahrestagung: Deutschen Gesellschaft fur 

Biomedizinische Technik: 2002 Sept; 

Karlsurhe, Germany. Dtsch Ges Biomed Tech 

2002;243-9. 

189. Wase A, Basit A, Nazir R, et al. Impact of 

chronic kidney disease upon survival among 

implantable cardioverter-defibrillator 

recipients. J Interv Card Electrophysiol 

2004;11(3):199-204. 

190. Wilkoff BL, Ousdigian KT, Sterns LD, et al. 

A comparison of empiric to physician-tailored 

programming of implantable cardioverterdefibrillators: results from the prospective 

randomized multicenter EMPIRIC trial. J Am 

Coll Cardiol 2006;48(2):330-9. 
192

191. Zecchin M, Di Lenarda A, Proclemer A, et al. 

The role of implantable cardioverter 

defibrillator for primary vs. secondary 

prevention of sudden death in patients with 

idiopathic dilated cardiomyopathy. [erratum 

appears in Europace. 2005 Jan;7(1):91]. 

Europace 2004;6(5):400-6. 

192. Carlsson J, Schulte B, Erdogan A, et al. 

Prospective randomized comparison of two 

defibrillation safety margins in unipolar, active 

pectoral defibrillator therapy. Pacing Clin 

Electrophysiol 2003;26(2 Pt 1):613-8. 

193. Dorian P, Borggrefe M, Al-Khalidi HR, et al. 

Placebo-controlled, randomized clinical trial 

of azimilide for prevention of ventricular 

tachyarrhythmias in patients with an 

implantable cardioverter defibrillator. 

Circulation 2004a;110(24):3646-54. 

194. Friedman PA, McClelland RL, Bamlet WR, et 

al. Dual-chamber versus single-chamber 

detection enhancements for implantable 

defibrillator rhythm diagnosis: the detect 

supraventricular tachycardia study. Circulation 

2006;113(25):2871-9. 

195. Grimm W, Plachta E, Maisch B. 

Antitachycardia pacing for spontaneous rapid 

ventricular tachycardia in patients with 

prophylactic cardioverter-defibrillator therapy. 

Pacing Clin Electrophysiol 2006;29(7):759-64. 

196. Hreybe H, Ezzeddine R, Barrington W, et al. 

Relation of advanced heart failure symptoms 

to risk of inappropriate defibrillator shocks. 

Am J Cardiol 2006;97(4):544-6. 

197. Lickfett L, Bitzen A, Arepally A, et al. 

Incidence of venous obstruction following 

insertion of an implantable cardioverter 

defibrillator. A study of systematic contrast 

venography on patients presenting for their 

first elective ICD generator replacement. 

Europace 2004;6(1):25-31. 

198. Niehaus M, de Sousa M, Klein G, et al. 

Chronic experiences with a single lead dual 

chamber implantable cardioverter defibrillator 

system. Pacing Clin Electrophysiol 

2003;26(10):1937-43. 

199. Saeed M, Jin A, Pontone G, et al. Prevalence 

of sensing abnormalities in dual chamber 

implantable cardioverter defibrillators. Ann 

Noninvasive Electrocardiol 2003;8(3):219-26. 

200. Theuns DA, Klootwijk AP, Goedhart DM, et 

al. Prevention of inappropriate therapy in 

implantable cardioverter-defibrillators: results 

of a prospective, randomized study of 

tachyarrhythmia detection algorithms. J Am 

Coll Cardiol 2004;44(12):2362-7. 

201. Theuns DA, Klootwijk AP, Simoons ML, et 

al. Clinical variables predicting inappropriate 

use of implantable cardioverter-defibrillator in 

patients with coronary heart disease or 

nonischemic dilated cardiomyopathy. Am J 

Cardiol 2005a;95(2):271-4. 

202. Tiroke A, Ganeeva ON, Syrkin AL. 

Unmotivated malfunction of implanted 

cardioverter-defibrillator and ways of its 

correction [in Russian]. Klin Med (Mosk) 

2003;81(5):26-30. 

203. Reynolds MR, Cohen DJ, Kugelmass AD, et 

al. The frequency and incremental cost of 

major complications among medicare 

beneficiaries receiving implantable 

cardioverter-defibrillators. J Am Coll Cardiol 

2006;47(12):2493-7. 

204. Al-Khatib SM, Lucas FL, Jollis JG, et al. The 

relation between patients' outcomes and the 

volume of cardioverter-defibrillator 

implantation procedures performed by 

physicians treating Medicare beneficiaries. J 

Am Coll Cardiol 2005;46(8):1536-50. 

205. Bansch D, Steffgen F, Gronefeld G, et al. The 

1 + 1 trial: a prospective trial of a dual- versus 

a single-chamber implantable defibrillator in 

patients with slow ventricular tachycardias. 

Circulation 2004;110:1022-9. 

206. Boriani G, Wollmann C, Biffi M, et al. 

Evaluation of a dual chamber implantable 

cardioverter defibrillator for the treatment of 

atrial and ventricular arrhythmias. Pace 

2003;26(Pt. II):461-5. 

207. Brockes C, Rahn-Schonbeck M, Duru F, et al. 

ICD implantation with and without combined 

myocardial revascularisation - incidence of 

ICD therapy and late survival. Thorac 

Cardiovasc Surg 2002;50:333-6. 
193

208. Gradaus R, Block M, Brachmann J, et al. 

Mortality, morbidity, and complications in 

3,344 patients with implantable cardioverter 

defibrillators: results from the German ICD 

Registry EURID. Pace 2003 ;26:1511-8. 

209. Hlatky MA, Saynina O, McDonald KM, et al. 

Utilization and outcomes of the implantable 

cardioverter defibrillator, 1987 to 1995. Am 

Heart J 2002;144:397-403. 

210. Nademanee K, Veerakul G, Mower M, et al. 

Defibrillator versus B-blockers for 

unexplained death in Thailand (DEBUT): a 

randomized clinical trial. Circulation 

2003;107:2221-6. 

211. Rosenqvist M, Beyer T, Block M, et al. 

Adverse events with transvenous implantable 

cardioverter-defibrillators: a prospective 

multicenter study. Circulation 1998;98:663-70. 

212. Schlapfer J, Rapp F, Kappenberger L, et al. 

Electrophysiologically guided amiodarone 

therapy versus the implantable cardioverterdefibrillator for sustained ventricular 

tachyarrhythmias after myocardial infarction: 

results of long-term follow-up. J Am Coll 

Cardiol 2002;39:1813-9. 

213. Vollmann D, Ahern T, Gerritse B, et al. 

Worldwide evaluation of a defibrillation lead 

with a small geometric electrode surface for 

high-impedance pacing. Am Heart J 

2003;146:1066-70. 

214. Wiegand UKH, LeJeune D, Boguschewski F, 

et al. Pocket hematoma after pacemaker or 

implantable cardioverter defibrillator surgery: 

influence of patient morbidity, operation 

strategy, and perioperative 

antiplatelet/anticoagulation therapy. Chest 

2004;126:1177-86. 

215. Kindermann M, Hennen B, Jung J, et al. 

Biventricular versus conventional right 

ventricular stimulation for patients with 

standard pacing indication and left ventricular 

dysfunction: the Homburg Biventricular 

Pacing Evaluation (HOBIPACE). J Am Coll 

Cardiol 2006;47(10):1927-37. 

216. Woo GW, Petersen-Stejskal S, Johnson JW, et 

al. Ventricular reverse remodeling and 6-

month outcomes in patients receiving cardiac 

resynchronization therapy: analysis of the 

MIRACLE study. J Interv Card Electrophysiol 

2005;12(2):107-13. 

217. Stevenson LW. Implantable cardioverterdefibrillators for primary prevention of sudden 

death in heart failure: are there enough bangs 

for the bucks? Circulation 2006;114(2):101-3. 

218. Cleland JGF, Daubert JC, Erdmann E, et al. 

Longer-term effects of cardiac 

resynchronization therapy on mortality in heart 

failure [the CArdiac REsynchronization-Heart 

Failure (CARE-HF) trial extension phase]. Eur 

Heart J 2006;27(16):1928-32. 

219. Flather MD, Yusuf S, Kober L, et al. Longterm ACE-inhibitor therapy in patients with 

heart failure or left-ventricular dysfunction: a 

systematic overview of data from individual 

patients. ACE-Inhibitor Myocardial Infarction 

Collaborative Group. Lancet 

2000;355(9215):1575-81. 

220. Brophy JM, Joseph L, Rouleau JL. Betablockers in congestive heart failure. A 

Bayesian meta-analysis. Ann Intern Med 

2001;134(7):550-60. 

221. Pitt B, Zannad F, Remme WJ, et al. The effect 

of spironolactone on morbidity and mortality 

in patients with severe heart failure. 

Randomized Aldactone Evaluation Study 

Investigators. N Engl J Med 

1999;341(10):709-17. 

222. Cohn JN, Tognoni G. A randomized trial of 

the angiotensin-receptor blocker valsartan in 

chronic heart failure. N Engl J Med 

2001;345(23):1667-75. 

223. Hjalmarson A, Goldstein S, Fagerberg B, et al. 

Effects of controlled-release metoprolol on 

total mortality, hospitalizations, and wellbeing in patients with heart failure: the 

Metoprolol CR/XL Randomized Intervention 

Trial in congestive heart failure (MERIT-HF). 

MERIT-HF Study Group. JAMA 

2000;283(10):1295-302. 
194

224. Ellenbogen KA, Hellkamp AS, Wilkoff BL, et 

al. Complications arising after implantation of 

DDD pacemakers: the MOST experience. Am 

J Cardiol 2003;92(6):740-1. 

225. Medina-Ravell VA, Lankipalli RS, Yan GX, et 

al. Effect of epicardial or biventricular pacing 

to prolong QT interval and increase transmural 

dispersion of repolarization: does 

resynchronization therapy pose a risk for 

patients predisposed to long QT or torsade de 

pointes? Circulation 2003;107(5):740-6. 

226. Mehra MR, Greenberg BH. Cardiac 

resynchronization therapy: caveat medicus! J 

Am Coll Cardiol 2004;43(7):1145-8. 

227. Birnie DH, Tang AS. The problem of nonresponse to cardiac resynchronization therapy. 

Curr Opin Cardiol 2006;21(1):20-6. 

228. Yu CM, Abraham WT, Bax J, et al. Predictors 

of response to cardiac resynchronization 

therapy (PROSPECT)--study design. Am 

Heart J 2005;149(4):600-5. 

229. Kass DA. Predicting cardiac resynchronization 

response by QRS duration: the long and short 

of it. J Am Coll Cardiol 2003;42(12):2125-7. 

230. Moss AJ. Should everyone with an ejection 

fraction less than or equal to 30% receive an 

implantable cardioverter-defibrillator? 

Everyone with an ejection fraction < or = 30% 

should receive an implantable cardioverterdefibrillator. Circulation 2005;111(19):2537-

49; discussion 2537-2549. 

231. Buxton AE. Should everyone with an ejection 

fraction less than or equal to 30% receive an 

implantable cardioverter-defibrillator? Not 

everyone with an ejection fraction < or = 30% 

should receive an implantable cardioverterdefibrillator. Circulation 2005;111(19):2537-

49; discussion 2537-2549. 

232. Moss AJ, Greenberg H, Case RB, et al. Longterm clinical course of patients after 

termination of ventricular tachyarrhythmia by 

an implanted defibrillator. Circulation 

2004;110(25):3760-5. 

233. Huikuri HV, Castellanos A, Myerberg RJ. 

Sudden death due to cardiac arryhythmias. N 

Engl J Med 2001;345:1473-82. 

234. Hammill S, Phurrough S, Brindis R. The 

National ICD Registry: now and into the 

future. Heart Rhythm 2006;3(4):470-3. 

235. Myerburg RJ, Castellanos A. Clinical research 

designs and implantable defibrillator 

indications: spend in the beginning or pay at 

the end. J Am Coll Cardiol 2006;47(1):108-11. 

236. De Lurgio DB, Foster E, Higginbotham MB, 

et al. A comparison of cardiac 

resynchronization by sequential biventricular 

pacing and left ventricular pacing to 

simultaneous biventricular pacing: rationale 

and design of the DECREASE-HF clinical 

trial. J Card Fail 2005;11:233-9. 

237. Rosamond W, Flegal K, Friday G, et al. Heart 

Disease and Stroke Statistics--2007 Update. A 

Report from the American Heart Association 

Statistics Committee and Stroke Statistics 

Subcommittee. Circulation 2006;[Epub ahead 

of print]. Available at 

http://circ.ahajournals.org/cgi/reprint/CIRCUL

ATIONAHA.106.179918v1. (Accessed 19 

December 2006) 

238. Cowie MR, Mosterd A, Wood DA. The 

epidemiology of heart failure. Eur Heart J 

1997;18(2):208-825. 

239. Redfield MM, Jacobsen SJ, Burnett JC Jr, et 

al. Burden of systolic and diastolic ventricular 

dysfunction in the community: appreciating 

the scope of the heart failure epidemic. JAMA 

2003;289(2):194-202. 

240. Heart and Stroke Foundation Canada. The 

changing face of heart disease and stroke in 

Canada. Ottawa, ON: Heart and Stroke 

Foundation Canada; 2000. 

241. Lloyd-Jones DM, Wang TJ, Leip EP, et al. 

Lifetime risk for development of atrial 

fibrillation: the Framingham Heart Study. 

Circulation 2002;106(24):3068-72. 

242. MacIntyre K, Capewell S, Stewart S, et al. 

Evidence of improving prognosis in heart 

failure: trends in case fatality in 66,547 

patients hospitalized between 1986 and 1995. 

Circulation 2000;102(10):1126-31. 
195

243. Hunt SA, Abraham WT, Chin MH, et al. 

ACC/AHA 2005 guideline update for the 

diagnosis and management of chronic heart 

failure in the adult: a report of the American 

College of Cardiology/American Heart 

Association Task Force on Practice Guidelines 

(Writing Committee to update the 2001 

guidelines for the evaluation and management 

of heart failure): developed in collaboration 

with the American College of Chest 

Physicians and the International Society for 

Heart and Lung Transplantation: endorsed by 

the Heart Rhythm Society. Circulation 

2005;112(12):e154-235. 

244. Arnold JM, Liu P, Demers C, et al. Canadian 

Cardiovascular Society consensus conference 

recommendations on heart failure 2006: 

diagnosis and management. Can J Cardiol 

2006;22(1):23-45. 

245. Jong P, Vowinckel E, Liu PP, et al. Prognosis 

and determinants of survival in patients newly 

hospitalized for heart failure: a populationbased study. Arch Intern Med 

2002;162(15):1689-94. 

246. Poole-Wilson PA, Uretsky BF, Thygesen K, et 

al. Mode of death in heart failure: findings 

from the ATLAS trial. Heart 2003;89(1):42-8. 

247. Massie BM. Fifteen years of heart-failure 

trials: what have we learned? Lancet 1998;352 

(Suppl 1):SI29-33. 

248. McAlister FA, Ezekowitz JA, Wiebe N, et al. 

Cardiac resynchronization therapy in patients 

with symptomatic heart failure: a systematic 

review. Ann Intern Med 2004;141(5):381-90. 

249. Hartling L, McAlister F, Rowe BH, et al. 

Challenges in systematic reviews of 

therapeutic devices and procedures. Ann 

Intern Med 2005;142(12 Pt 2):1100-11. 

250. Ezekowitz J, Armstrong PW, McAlister F. 

Implantable cardioverter defibrillators in 

primary and secondary prevention: a 

systematic review of randomized, controlled 

trials. Ann Intern Med 2003;138(6):445-52. 

251. Mond HG, Irwin M, Morillo C, et al. The 

world survey of cardiac pacing and 

cardioverter defibrillators: calendar year 2001. 

Pacing Clin Electrophysiol 2004;27(7):955-64. 

252. Schulz KF, Chalmers I, Hayes RJ, et al. 

Empirical evidence of bias. Dimensions of 

methodological quality associated with 

estimates of treatment effects in controlled 

trials. JAMA 1995;273(5):408-12. 

253. Jadad AR, Moore RA, Carroll D, et al. 

Assessing the quality of reports of randomized 

clinical trials: is blinding necessary? Control 

Clin Trials 1996;17(1):1-12. 

254. Downs SH, Black N. The feasibility of 

creating a checklist for the assessment of the 

methodological quality both of randomized 

and non-randomized studies of health care 

interventions. J Epidemiol Community Health 

1998;52(6):377-84. 

255. Follmann D, Elliott P, Suh I, et al. Variance 

imputation for overviews of clinical trials with 

continuous response. J Clin Epidemiol 

1992;45(7):769-73. 

256. DerSimonian R, Laird N. Meta-analysis in 

clinical trials. Control Clin Trials 

1986;7(3):177-88. 

257. Curtin F, Altman DG, Elbourne D. Metaanalysis combining parallel and cross-over 

clinical trials. I: continuous outcomes. Stat 

Med 2002;21(15):2131-44. 

258. Begg CB, Mazumdar M. Operating 

characteristics of a rank correlation test for 

publication bias. Biometrics 1994;50(4):1088-

101. 

259. Egger M, Davey Smith G, Schneider M, et al. 

Bias in meta-analysis detected by a simple, 

graphical test. Br Med J 1997 ;315(7109):629-

34. 

260. Duval S, Tweedie R. A nonparametric "trim 

and fill" method of accounting for publication 

bias in meta-analysis. JAMA 

2000;95(449):89-98. 

261. Hedges LV, Olkin I. Statistical methods for 

meta-analysis. San Diego: Academic Press, 

1985. 
196

262. Gregoratos G, Cheitlin MD, Conill A, et al. 

ACC/AHA Guidelines for Implantation of 

Cardiac Pacemakers and Antiarrhythmia 

Devices: Executive Summary: a report of the 

American College of Cardiology/American 

Heart Association Task Force on Practice 

Guidelines (Committee on Pacemaker 

Implantation). Circulation 1998;97(13):1325-

35. 

263. Berenbom LD, Weiford BC, Vacek JL, et al. 

Differences in outcomes between patients 

treated with single- versus dual-chamber 

implantable cardioverter defibrillators: a 

substudy of the Multicenter Automatic 

Defibrillator Implantation Trial II. Ann 

Noninvasive Electrocardiol 2005 ;10(4):429-

35. 

264. Gasparini M, Lunati M, Bocchiardo M, et al. 

Cardiac resynchronization and implantable 

cardioverter defibrillator therapy: preliminary 

results from the InSync Implantable 

Cardioverter Defibrillator Italian Registry. 

Pacing Clin Electrophysiol 2003b;26(1 Pt 

2):148-51. 

265. Olsson LG, Swedberg K, Clark AL, et al. Six 

minute corridor walk test as an outcome 

measure for the assessment of treatment in 

randomized, blinded intervention trials of 

chronic heart failure: a systematic review. Eur 

Heart J 2005;26(8):778-93. 

266. Rector TS, Kubo SH, Cohn JN. Patients’ selfassessment of their congestive heart failure. 

Content, reliability and validity of a new 

measure—the Minnesota living with heart 

failure questionnaire. Heart Failure 

1987;3:198-208. 

267. Rector TS, Cohn JN. Assessment of patient 

outcome with the Minnesota Living with Heart 

Failure questionnaire: reliability and validity 

during a randomized, double-blind, placebocontrolled trial of pimobendan. Pimobendan 

Multicenter Research Group. Am Heart J 

1992;124(4):1017-25. 

268. Rector TS, Johnson G, Dunkman WB, et al. 

Evaluation by patients with heart failure of the 

effects of enalapril compared with hydralazine 

plus isosorbide dinitrate on quality of life. VHeFT II. The V-HeFT VA Cooperative 

Studies Group. Circulation 1993;87(6 

Suppl):VI71-VI77. 

269. Lindenfeld J, Feldman AM, Saxon L, et al. 

Effects of cardiac resynchronization therapy 

with or without a defibrillator on survival and 

hospitalizations in patients with New York 

Heart Association class IV heart failure. 

Circulation 2007;115(2):204-12. 

270. Kuhlkamp V. Initial experience with an 

implantable cardioverter-defibrillator 

incorporating cardiac resynchronization 

therapy. J Am Coll Cardiol 2002;39(5):790-7. 

271. Bleeker GB, Bax JJ, Fung JW, et al. Clinical 

versus echocardiographic parameters to assess 

response to cardiac resynchronization therapy. 

Am J Cardiol 2006;97(2):260-3. 

272. Gold MR, Auricchio A, Hummel JD, et al. 

Comparison of stimulation sites within left 

ventricular veins on the acute hemodynamic 

effects of cardiac resynchronization therapy. 

Heart Rhythm 2005;2(4):376-81. 

273. Gasparini M, Mantica M, Galimberti P, et al. 

Is the outcome of cardiac resynchronization 

therapy related to the underlying etiology? 

Pacing Clin Electrophysiol 2003;26(1 Pt 

2):175-80. 

274. Breithardt OA, Stellbrink C, Kramer AP, et al. 

Echocardiographic quantification of left 

ventricular asynchrony predicts an acute 

hemodynamic benefit of cardiac 

resynchronization therapy. J Am Coll Cardiol 

2002;40(3):536-45. 

275. Bleeker GB, Schalij MJ, Molhoek SG, et al. 

Relationship between QRS duration and left 

ventricular dyssynchrony in patients with endstage heart failure. J Cardiovasc 

Electrophysiol 2004;15(5):544-9. 

276. Ghio S, Constantin C, Klersy C, et al. 

Interventricular and intraventricular 

dyssynchrony are common in heart failure 

patients, regardless of QRS duration. Eur 

Heart J 2004;25(7):571-8. 

277. Yu CM, Yang H, Lau CP, et al. Regional left 

ventricle mechanical asynchrony in patients 

with heart disease and normal QRS duration: 

implication for biventricular pacing therapy. 

Pacing Clin Electrophysiol 2003;26(2 Pt 

1):562-70. 
197

278. Turner MS, Bleasdale RA, Vinereanu D, et al. 

Electrical and mechanical components of 

dyssynchrony in heart failure patients with 

normal QRS duration and left bundle-branch 

block: impact of left and biventricular pacing. 

Circulation 2004;109(21):2544-9. 

279. Krum H, Gilbert RE. Demographics and 

concomitant disorders in heart failure. Lancet 

2003;362(9378):147-58. 

280. McAlister F, Tu JV, Newman A, et al. How 

many patients with heart failure are eligible for 

cardiac resynchronization? Insights from two 

prospective cohorts. Eur Heart J 

2006;27(3):323-9. 

281. Cleland JG, Swedberg K, Follath F, et al. The 

EuroHeart Failure survey programme—a 

survey on the quality of care among patients 

with heart failure in Europe. Part 1: patient 

characteristics and diagnosis. Eur Heart J 

2003;24(5):442-63. 

282. Pires LA, Sethuraman B, Guduguntla VD, et 

al. Clinical outcomes in heart failure: report 

from a community hospital-based registry. Am 

J Med 1999;107(6):549-55. 

283. Curtis AB, Abraham WT, Chen PS, et al. 

Highlights of Heart Rhythm 2004, the Annual 

Scientific Sessions of the Heart Rhythm 

Society; 2004 May 19-22; San Francisco, CA. 

J Am Coll Cardiol 2004;44(8):1550-6. 

284. Fantoni C, Kawabata M, Massaro R, et al. 

Right and left ventricular activation sequence 

in patients with heart failure and right bundle 

branch block: a detailed analysis using threedimensional non-fluoroscopic electroanatomic 

mapping system. J Cardiovasc Electrophysiol 

2005;16(2):112-9; discussion 120-121. 

285. Pablos Mendez A, Barr RG, Shea S. Run-in 

periods in randomized trials: implications for 

the application of results in clinical practice. 

JAMA 1998;279(3):222-5. 

286. Uretsky BF, Thygesen K, Armstrong PW, et 

al. Acute coronary findings at autopsy in heart 

failure patients with sudden death: results from 

the assessment of treatment with lisinopril and 

survival (ATLAS) trial. Circulation 

2000;102(6):611-6. 

287. Nichol G, Kaul P, Huszti E, et al. Costeffectiveness of cardiac resynchronization 

therapy in patients with symptomatic heart 

failure. Ann Intern Med 2004;141(5):343-51. 

288. Feldman AM, de Lissovoy G, Bristow MR, et 

al. Cost effectiveness of cardiac 

resynchronization therapy in the Comparison 

of Medical Therapy, Pacing, and Defibrillation 

in Heart Failure (COMPANION) trial. J Am 

Coll Cardiol 2005;46(12):2311-21. 

289. Calvert MJ, Freemantle N, Yao G, et al. Costeffectiveness of cardiac resynchronization 

therapy: results from the CARE-HF trial. Eur 

Heart J 2005;26(24):2681-8. 

290. Fox M, Mealing S, Anderson R, et al. The 

effectiveness and cost-effectiveness of cardiac 

resynchronization (biventricular pacing) for 

heart failure: a systematic review and 

economic model [Web Page]. 7 September 

2006; Available at 

http://www.nice.org.uk/page.aspx?o=388638. 

(Accessed 28 September 2006). 

291. Hlatky MA. Cost effectiveness of cardiac 

resynchronization therapy. J Am Coll Cardiol 

2005;46(12):2322-4. 

292. Shen AY, Wang X, Doris J, et al. Proportion 

of patients in a congestive heart failure care 

management program meeting criteria for 

cardiac resynchronization therapy. Am J 

Cardiol 2004;94(5):673-6. 

293. Grimm W, Sharkova J, Funck R, et al. How 

many patients with dilated cardiomyopathy 

may potentially benefit from cardiac 

resynchronization therapy? Pacing Clin 

Electrophysiol 2003;26(1 Pt 2):155-7. 

294. Pedone C, Grigioni F, Boriani G, et al. 

Implications of cardiac resynchronization 

therapy and prophylactic defibrillator 

implantation among patients eligible for heart 

transplantation. Am J Cardiol 2004;93(3):371-

3. 

295. Toma M, McAlister F, Ezekowitz J, et al. 

Proportion of patients followed in a 

specialized heart failure clinic needing an 

implantable cardioverter defibrillator as 

determined by applying different trial 

eligibility criteria. Am J Cardiol 

2006;97(6):882-5. 
198

296. Bennett JA, Riegel B, Bittner V, et al. Validity 

and reliability of the NYHA classes for 

measuring research outcomes in patients with 

cardiac disease. Heart Lung 2002;31(4):262-

70. 

297. Goldenberg I, Moss AJ, Hall WJ, et al. Causes 

and consequences of heart failure after 

prophylactic implantation of a defibrillator in 

the multicenter automatic defibrillator 

implantation trial II. Circulation 

2006;113(24):2810-7. 

298. Zipes DP, Camm AJ, Borggrefe M, et al. 

ACC/AHA/ESC 2006 guidelines for 

management of patients with ventricular 

arrhythmias and the prevention of sudden 

cardiac death: a report of the American 

College of Cardiology/American Heart 

Association Task Force and the European 

Society of Cardiology Committee for Practice 

Guidelines (Writing Committee to Develop 

Guidelines for Management of Patients With 

Ventricular Arrhythmias and the Prevention of 

Sudden Cardiac Death). J Am Coll Cardiol 

2006;48(5):e247-346. 

299. Irvine J, Dorian P, Baker B, et al. Quality of 

life in the Canadian Implantable Defibrillator 

Study (CIDS). Am Heart J 2002;144:282-9. 

300. Sears SF Jr, Todaro JF, Lewis TS, et al. 

Examining the psychosocial impact of 

implantable cardioverter defibrillators: a 

literature review. Clin Cardiol 1999;22(7):481-

9. 

301. Carroll DL, Hamilton G. Quality of life in 

implanted cardioverter defibrillator recipients: 

the impact of a device shock. Heart Lung 

2005;34(3):169-78. 

302. Sneed NV, Finch NJ, Leman RB. The impact 

of device recall on patients and family 

members of patients with automatic 

implantable cardioverter defibrillators. Heart 

Lung 1994;23(4):317-22. 

303. Maisel WH, Sweeney MO, Stevenson WG, et 

al. Recalls and safety alerts involving 

pacemakers and implantable cardioverterdefibrillator generators. JAMA 

2001;286(7):793-9. 

304. Maisel WH. Safety issues involving medical 

devices: implications of recent implantable 

cardioverter-defibrillator malfunctions. JAMA 

2005;294(8):955-8. 

305. Goldenberg I, Moss AJ, McNitt S, et al. Time 

dependence of defibrillator benefit after 

coronary revascularization in the Multicenter 

Automatic Defibrillator Implantation Trial 

(MADIT)-II. J Am Coll Cardiol 

2006;47(9):1811-7. 

306. Costantini O. The Alternans Before 

Cardioverter Defibrillator (ABCD) trial: a 

non-invasive strategy for primary prevention 

of sudden cardiac death using T wave 

alternans. American Heart Association 2006 

Sceientific Sessions; Late Breaking Clinical 

Trials III; 2006 Nov 15; Chicago, IL. [Web 

Page]. Available at 

http://www.medscape.com/viewarticle/547941

. (Accessed 27 December 2006). 

307. Chan PS, Stein K, Chow T, et al. Costeffectiveness of a microvolt T-wave alternans 

screening strategy for implantable 

cardioverter-defibrillator placement in the 

MADIT-II-eligible population. J Am Coll 

Cardiol 2006;48(1):112-21. 

308. Wathen MS, DeGroot PJ, Sweeney MO, et al. 

Prospective randomized multicenter trial of 

empirical antitachycardia pacing versus shocks 

for spontaneous rapid ventricular tachycardia 

in patients with implantable cardioverterdefibrillators: Pacing Fast Ventricular 

Tachycardia Reduces Shock Therapies 

(PainFREE Rx II) trial results. Circulation 

2004;110(17):2591-6. 

309. Auricchio A, Sommariva L, Salo RW, et al. 

Improvement of cardiac function in patients 

with severe congestive heart failure and 

coronary artery disease by dual chamber 

pacing with shortened AV delay. Pacing Clin 

Electrophysiol 1993;16(10):2034-43. 

310. Kuhlkamp V, Dornberger V, Mewis C, et al. 

Clinical experience with the new detection 

algorithms for atrial fibrillation of a 

defibrillator with dual chamber sensing and 

pacing. J Cardiovasc Electrophysiol 

1999;10(7):905-15. 
199

311. Deisenhofer I, Kolb C, Ndrepepa G, et al. Do 

current dual chamber cardioverter 

defibrillators have advantages over 

conventional single chamber cardioverter 

defibrillators in reducing inappropriate 

therapies? A randomized, prospective study. J 

Cardiovasc Electrophysiol 2001;12(2):134-42. 

312. Saad EB, Marrouche NF, Martin DO, et al. 

Frequency and associations of symptomatic 

deterioration after dual-chamber defibrillator 

implantation in patients with ischemic or 

idiopathic dilated cardiomyopathy. Am J 

Cardiol 2002;90(1):79-82. 

313. Wilkoff BL, Cook JR, Epstein AE, et al. Dualchamber pacing or ventricular backup pacing 

in patients with an implantable defibrillator: 

the Dual Chamber and VVI Implantable 

Defibrillator (DAVID) Trial. N Engl J Med 

2002;288(24):3115-23. 

314. Hughes S. DATAS restores confidence in 

dual-chamber ICDs. July 21, 2006. 

theheart.org. [HeartWire>News] [database on 

the Internet]. Montreal (QC): WebMD; c1999-

2006 [cited 2006 Sept 26]. Available from: 

http://www.theheart.org/article/725387.do. 

315. Gregoratos G, Abrams J, Epstein AE, et al. 

ACC/AHA/NASPE 2002 guideline update for 

implantation of cardiac pacemakers and 

antiarrhythmia devices: summary article: a 

report of the American College of 

Cardiology/American Heart Association Task 

Force on Practice Guidelines 

(ACC/AHA/NASPE Committee to Update the 

1998 Pacemaker Guidelines). Circulation 

2002;106(16):2145-61. 

316. Hauser RG. The growing mismatch between 

patient longevity and the service life of 

implantable cardioverter-defibrillators. J Am 

Coll Cardiol 2005;45:2022-5. 

317. Sanders GD, Hlatky MA, Owens DK. Costeffectiveness of implantable cardioverterdefibrillators. N Engl J Med 

2005;353(14):1471-80. 

318. Mark DB, Nelson CL, Anstrom KJ, et al. 

Cost-effectiveness of defibrillator therapy or 

amiodarone in chronic stable heart failure: 

results from the Sudden Cardiac Death in 

Heart Failure Trial (SCD-HeFT). Circulation 

2006;114(2):135-42. 

319. Zwanziger J, Hall WJ, Dick AW, et al. The 

cost-effectiveness of implantable cardioverterdefibrillators. Results from the Multicenter 

Automatic Defibrillator Implantation Trial 

(MADIT-II). J Am Coll Cardiol 

2006;47:2310-8. 

320. Al-Khatib SM, Anstrom KJ, Eisenstein EL, et 

al. Clinical and economic implications of the 

Multicenter Automatic Defibrillator 

Implantation Trial-II. Ann Intern Med 

2005;142:593-600. 

321. Linde C, Gold M, Abraham WT, et al. 

Rationale and design of a randomized 

controlled trial to assess the safety and 

efficacy of cardiac resynchronization therapy 

in patients with asymptomatic left ventricular 

dysfunction with previous symptoms or mild 

heart failure—the REsynchronization 

reVErses Remodelling in Systolic left 

vEntricular dysfunction (REVERSE) study. 

Am Heart J 2006;151:288-94. 

322. Moss AJ, Brown MW, Cannom DS, et al. 

Multicenter automatic defibrillator 

implantation trial—cardiac resynchronization 

therapy (MADIT-CRT): design and clinical 

protocol. Ann Noninvasive Electrocardiol 

2005;19(Suppl 4):34-43. 

323. Teuteberg JJ, Lewis EF, Nohria A, et al. 

Characteristics of patients who die with heart 

failure and a low ejection fraction in the new 

millennium. J Cardiac Failure 2006;12:47-53. 

324. Daubert JC, Leclercq C, Mabo P. There is 

plenty of room for cardiac resynchronization 

therapy devices without back-up defibrillators 

in the electrical treatment of heart failure. J 

Am Coll Cardiol 2005;46:2204-7. 
APPENDIXES: 

to 

“Cardiac Resynchronization Therapy and Implantable Cardiac 

Defibrillators in Left Ventricular Systolic Dysfunction” 

Prepared by the University of Alberta 

Evidence-based Practice Center 

(Contract #290-02-0023) 
APPENDIX A: Exact String Searches 

Electronic Databases 

Searched 

Search Strategies and Results 

MEDLINE®

Ovid Version: rel10.3.2 

2005 to November Week 1 

2006

Searched November 14, 2006 

CRT – efficacy/effectiveness 

Results: 272

1. resynchroni?ation therapy.mp. 

2. biv.mp. 

3. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

4. ((cardiac or heart) adj resynchroni?ation$).mp. 

5. medtronic.mp. 

6. insync.mp. 

7. "ela medical".mp. 

8. exp cardiac pacing, artificial/ 

9. or/1-8 

10. exp heart failure, congestive/ 

11. "congestive heart failure$".mp. 

12. "congestive cardiac failure$".mp. 

13. "chronic cardiac failure$".mp. 

14. "chronic heart failure$".mp. 

15. chf.mp. 

16. exp heart diseases/ 

17. or/10-16 

18. RANDOMIZED CONTROLLED TRIAL.pt. 

19. CONTROLLED CLINICAL TRIAL.pt. 

20. RANDOMIZED CONTROLLED TRIALS/

21. RANDOM ALLOCATION/ 

22. DOUBLE BLIND METHOD/ 

23. SINGLE-BLIND METHOD/ 

24. or/18-23 

25. ANIMAL/ not HUMAN/ 

26. 24 not 25 

27. CLINICAL TRIAL.pt. 

28. exp CLINICAL TRIALS/ 

29. (clin$ adj25 trial$).ti,ab. 

30. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or 

mask$)).ti,ab. 

31. PLACEBOS/ 

32. placebo$.ti,ab. 

33. random$.ti,ab. 

34. RESEARCH DESIGN/ 

35. or/27-34 

A-1 
36. 35 not 25 

37. 36 not 26 

38. COMPARATIVE STUDY/ 

39. exp EVALUATION STUDIES/ 

40. FOLLOW UP STUDIES/ 

41. PROSPECTIVE STUDIES/ 

42. (control$ or prospectiv$ or volunteer$).ti,ab. 

43. or/38-42 

44. 43 not 25 

45. 44 not (26 or 37) 

46. 26 or 37 or 45 

47. "Case series".mp. 

48. "time series".mp. 

49. (efficacy or effectiveness).ti,ab. 

50. meta-analysis.pt. 

51. multicenter study.pt.

52. or/47-51 

53. 52 not 25 

54. or/46,53 

55. and/9,17,54 

CRT Safety 

Results: 90

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. resynchroni?ation therapy.mp. 

3. biv.mp. 

4. ((cardiac or heart) adj resynchroni?ation$).mp. 

5. medtronic.mp. 

6. insync.mp. 

7. "ela medical".mp. 

8. exp cardiac pacing, artificial/ 

9. or/1-8 

10. exp heart failure, congestive/ 

11. exp heart diseases/ 

12. "congestive cardiac failure$".mp. 

13. "congestive heart failure$".mp. 

14. "chronic cardiac failure$".mp. 

15. "chronic heart failure$".mp. 

16. chf.mp. 

17. or/10-16 

18. (safe or safety).mp. 

19. risk$.mp. 

20. exp risk/ 

21. (adverse adj1 (effect$ or symptom$)).mp. 

A-2 
22. side effect$.mp. 

23. harm.mp. 

24. etiology.mp. 

25. aetiology.mp. 

26. contraindicat$.mp. 

27. (cause or causation or causing or causal$).mp. 

28. exp causality/ 

29. predict$.mp. 

30. or/18-29 

31. and/9,17,30 

32. limit 31 to yr="2005 - 2006" 

ICD efficacy/effectiveness 

Results: 194

1. exp Defibrillators, Implantable/ 

2. icd.ti,ab. 

3. aicd.ti,ab. 

4. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

5. or/1-4 

6. exp heart failure, congestive/ 

7. "congestive heart failure$".mp. 

8. "congestive cardiac failure$".mp. 

9. "chronic cardiac failure$".mp. 

10. "chronic heart failure$".mp. 

11. chf.mp. 

12. exp heart diseases/ 

13. or/6-12 

14. RANDOMIZED CONTROLLED TRIAL.pt. 

15. CONTROLLED CLINICAL TRIAL.pt. 

16. RANDOMIZED CONTROLLED TRIALS/

17. RANDOM ALLOCATION/ 

18. DOUBLE BLIND METHOD/ 

19. SINGLE-BLIND METHOD/ 

20. or/14-19 

21. ANIMAL/ not HUMAN/ 

22. 20 not 21 

23. CLINICAL TRIAL.pt. 

24. exp CLINICAL TRIALS/ 

25. (clin$ adj25 trial$).ti,ab. 

26. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or 

mask$)).ti,ab. 

27. PLACEBOS/ 

28. placebo$.ti,ab. 

29. random$.ti,ab. 

30. RESEARCH DESIGN/ 

A-3 
31. or/23-30 

32. 31 not 21 

33. 32 not 22 

34. COMPARATIVE STUDY/ 

35. exp EVALUATION STUDIES/ 

36. FOLLOW UP STUDIES/ 

37. PROSPECTIVE STUDIES/ 

38. (control$ or prospectiv$ or volunteer$).ti,ab. 

39. or/34-38 

40. 39 not 21 

41. 40 not (22 or 33) 

42. 22 or 33 or 41 

43. "Case series".mp. 

44. "time series".mp. 

45. (efficacy or effectiveness).ti,ab. 

46. meta-analysis.pt. 

47. multicenter study.pt.

48. or/43-47 

49. 48 not 21 

50. or/42,49 

51. and/5,13,50 

ICD safety 

Results: 127

1. exp Defibrillators, Implantable/ 

2. icd.ti,ab. 

3. aicd.ti,ab. 

4. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

5. or/1-4 

6. exp heart failure, congestive/ 

7. exp heart diseases/ 

8. "congestive cardiac failure$".mp. 

9. "congestive heart failure$".mp. 

10. "chronic cardiac failure$".mp. 

11. "chronic heart failure$".mp. 

12. chf.mp. 

13. or/6-12 

14. (safe or safety).mp. 

15. risk$.mp. 

16. exp risk/ 

17. (adverse adj1 (effect$ or symptom$)).mp. 

18. side effect$.mp. 

19. harm.mp. 

20. etiology.mp. 

21. aetiology.mp. 

A-4 
22. contraindicat$.mp. 

23. (cause or causation or causing or causal$).mp. 

24. exp causality/ 

25. predict$.mp. 

26. complicat$.mp. 

27. shock$.mp. 

28. bleeding.mp. 

29. exp HEMORRHAGE/ 

30. exp INFECTION/ 

31. infect$.mp. 

32. (inappropriate adj2 pacing).mp. 

33. or/14-32 

34. and/5,13,33 

Ovid MEDLINE® InProcess & Other NonIndexed Citations 

Ovid Version: rel10.3.2 

Searched November 14, 2006 

CRT 

Results: 0

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. resynchroni?ation therapy.mp. 

3. biv.mp. 

4. ((cardiac or heart) adj resynchroni?ation$).mp. 

5. medtronic.mp. 

6. insync.mp. 

7. "ela medical".mp. 

8. or/1-7 

9. "congestive heart failure$".mp. 

10. "congestive cardiac failure$".mp. 

11. "chronic cardiac failure$".mp. 

12. "chronic heart failure$".mp. 

13. heart disease$.mp. 

14. chf.mp. 

15. or/9-14 

16. 8 and 15 

ICD 

Results: 1

1. icd.ti,ab. 

2. aicd.ti,ab. 

3. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

4. or/1-3 

5. "congestive heart failure$".mp. 

6. "congestive cardiac failure$".mp. 

7. "chronic cardiac failure$".mp. 

8. "chronic heart failure$".mp. 

A-5 
9. heart disease$.mp. 

10. chf.mp. 

11. or/5-10 

12. 4 and 11 

Cochrane Central 

Register of Controlled 

Trials 

Ovid Version: rel10.3.2 

2005 - 4th Quarter 2006

Searched November 14, 2006 

CRT 

Results: 0

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. resynchroni?ation therapy.mp. 

3. biv.mp. 

4. ((cardiac or heart) adj resynchroni?ation$).mp. 

5. medtronic.mp. 

6. insync.mp. 

7. "ela medical".mp. 

8. or/1-7 

9. "congestive heart failure$".mp. 

10. "congestive cardiac failure$".mp. 

11. "chronic cardiac failure$".mp. 

12. "chronic heart failure$".mp. 

13. heart disease$.mp. 

14. chf.mp. 

15. or/9-14 

16. 8 and 15 

ICD 

Results: 2

1. icd.ti,ab. 

2. aicd.ti,ab. 

3. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

4. or/1-3 

5. "congestive heart failure$".mp. 

6. "congestive cardiac failure$".mp. 

7. "chronic cardiac failure$".mp. 

8. "chronic heart failure$".mp. 

9. heart disease$.mp. 

10. chf.mp. 

11. or/5-10 

12. 4 and 11 

A-6 
Cochrane Database of 

Systematic Reviews 

(CDSR) 

Ovid Version: rel10.3.2 

2005 - 4th Quarter 2006

Searched November 14, 2006 

CRT 

Results: 2

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. resynchroni?ation therapy.mp. 

3. biv.mp. 

4. ((cardiac or heart) adj resynchroni?ation$).mp. 

5. medtronic.mp. 

6. insync.mp. 

7. "ela medical".mp. 

8. or/1-7 

9. "congestive heart failure$".mp. 

10. "congestive cardiac failure$".mp. 

11. "chronic cardiac failure$".mp. 

12. "chronic heart failure$".mp. 

13. heart disease$.mp. 

14. chf.mp. 

15. or/9-14 

16. 8 and 15 

ICD 

Results: 5

1. icd.ti,ab. 

2. aicd.ti,ab. 

3. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

4. or/1-3 

5. "congestive heart failure$".mp. 

6. "congestive cardiac failure$".mp. 

7. "chronic cardiac failure$".mp. 

8. "chronic heart failure$".mp. 

9. heart disease$.mp. 

10. chf.mp. 

11. or/5-10 

12. 4 and 11 

Database of Abstracts 

of Reviews of Effects 

(DARE) 

Ovid Version: rel10.3.2 

2005 - 4th Quarter 2006

Searched November 14, 2006 

CRT 

Results: 0

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. resynchroni?ation therapy.mp. 

3. biv.mp. 

4. ((cardiac or heart) adj resynchroni?ation$).mp. 

5. medtronic.mp. 

A-7 
6. insync.mp. 

7. "ela medical".mp. 

8. or/1-7 

9. "congestive heart failure$".mp. 

10. "congestive cardiac failure$".mp. 

11. "chronic cardiac failure$".mp. 

12. "chronic heart failure$".mp. 

13. heart disease$.mp. 

14. chf.mp. 

15. or/9-14 

16. 8 and 15 

ICD 

Results: 1

1. icd.ti,ab. 

2. aicd.ti,ab. 

3. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

4. or/1-3 

5. "congestive heart failure$".mp. 

6. "congestive cardiac failure$".mp. 

7. "chronic cardiac failure$".mp. 

8. "chronic heart failure$".mp. 

9. heart disease$.mp. 

10. chf.mp. 

11. or/5-10 

12. 4 and 11 

Health Technology 

Assessment Database 

(HTA) via The 

Cochrane Library 

Wiley InterScience®

Searched November 14, 2006 

CRT 

Results: 1

MeSH descriptor Cardiac Pacing, Artificial explode all trees 

ICD 

Results: 2

MeSH descriptor Defibrillators, Implantable explode all 

trees 

EMBASE 

Ovid Version: rel10.3.2 

2005 - 2006 Week 45

Searched November 14, 2006 

CRT efficacy/effectiveness 

Results: 431

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. exp heart pacing/ 

3. resynchroni?ation therapy.mp. 

4. biv.mp. 

A-8 
5. ((cardiac or heart) adj resynchroni?ation$).mp. 

6. medtronic.mp. 

7. insync.mp. 

8. "ela medical".mp. 

9. or/1-8 

10. exp congestive heart failure/ 

11. "congestive heart failure$".mp. 

12. chf.mp. 

13. exp heart disease/ 

14. "congestive cardiac failure$".mp. 

15. "chronic cardiac failure$".mp. 

16. "chronic heart failure$".mp. 

17. or/10-16 

18. Randomized Controlled Trial/ 

19. exp Randomization/ 

20. Double Blind Procedure/ 

21. Single Blind Procedure/ 

22. or/18-21 

23. Clinical Trial/ 

24. (clin$ adj25 trial$).mp. 

25. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or 

mask$)).mp.

26. exp Placebo/ 

27. (placebo$ or random$).mp. 

28. exp Methodology/ 

29. exp Comparative Study/ 

30. exp Evaluation/ 

31. exp Follow Up/ 

32. exp Prospective Study/ 

33. (control$ or prospectiv$ or volunteer$).mp. 

34. or/23-33 

35. 22 or 34 

36. limit 35 to human 

37. Nonhuman/ 

38. 36 not 37 

39. exp Controlled Study/ 

40. "systematic review"/ 

41. Meta Analysis/ 

42. ((multi center or multi centre or multicenter or 

multicentre) adj1 trial$).mp. 

43. exp Case Study/ 

44. "Case series".mp. 

45. "Time series".mp. 

46. (efficacy or effectiveness).ti,ab. 

47. or/39-46 

48. limit 47 to human 

A-9 
49. 48 not 37 

50. 38 or 49 

51. and/9,17,50 

CRT safety 

Results: 91

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. exp heart pacing/ 

3. resynchroni?ation therapy.mp. 

4. biv.mp. 

5. ((cardiac or heart) adj resynchroni?ation$).mp. 

6. medtronic.mp. 

7. insync.mp. 

8. "ela medical".mp. 

9. or/1-8 

10. exp congestive heart failure/ 

11. "congestive heart failure$".mp. 

12. chf.mp. 

13. exp heart disease/ 

14. "congestive cardiac failure$".mp. 

15. "chronic cardiac failure$".mp. 

16. "chronic heart failure$".mp. 

17. or/10-16 

18. (safe or safety).mp. 

19. exp risk/ 

20. risk$.mp. 

21. exp side effect/ 

22. side effect$.mp. 

23. (adverse adj1 (effect$ or symptom$)).mp. 

24. harm.mp. 

25. exp etiology/ 

26. aetiology.mp. 

27. treatment contraindication/ 

28. contraindicat$.mp. 

29. (cause or causation or causing or causal$).mp. 

30. *epidemiology/ 

31. exp prediction/ 

32. or/18-31 

33. and/9,17,32 

34. limit 33 to yr="2005 - 2006" 

ICD efficacy/effectiveness 

Results: 350

A-10 
1. exp defibrillator/ 

2. icd.ti,ab. 

3. aicd.ti,ab. 

4. exp DEFIBRILLATION/ 

5. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

6. or/1-5 

7. exp congestive heart failure/ 

8. "congestive heart failure$".mp. 

9. chf.mp. 

10. exp heart disease/ 

11. "congestive cardiac failure$".mp. 

12. "chronic cardiac failure$".mp. 

13. "chronic heart failure$".mp. 

14. or/7-13 

15. Randomized Controlled Trial/ 

16. exp Randomization/ 

17. Double Blind Procedure/ 

18. Single Blind Procedure/ 

19. or/15-18 

20. Clinical Trial/ 

21. (clin$ adj25 trial$).mp. 

22. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or 

mask$)).mp.

23. exp Placebo/ 

24. (placebo$ or random$).mp. 

25. exp Methodology/ 

26. exp Comparative Study/ 

27. exp Evaluation/ 

28. exp Follow Up/ 

29. exp Prospective Study/ 

30. (control$ or prospectiv$ or volunteer$).mp. 

31. or/20-30 

32. 19 or 31 

33. limit 32 to human 

34. Nonhuman/ 

35. 33 not 34 

36. exp Controlled Study/ 

37. "systematic review"/ 

38. Meta Analysis/ 

39. ((multi center or multi centre or multicenter or 

multicentre) adj1 trial$).mp. 

40. exp Case Study/ 

41. "case series".mp. 

42. "time series".mp. 

43. (efficacy or effectiveness).ti,ab. 

44. or/36-43 

A-11 
45. limit 44 to human 

46. 45 not 34 

47. or/35,46 

48. and/6,14,47 

ICD safety 

Results: 239

1. exp defibrillator/ 

2. icd.ti,ab. 

3. aicd.ti,ab. 

4. exp DEFIBRILLATION/ 

5. (implant$ adj2 (defibrillat$ or defibrilat$)).mp. 

6. or/1-5 

7. exp congestive heart failure/ 

8. "congestive heart failure$".mp. 

9. chf.mp. 

10. exp heart disease/ 

11. "congestive cardiac failure$".mp. 

12. "chronic cardiac failure$".mp. 

13. "chronic heart failure$".mp. 

14. or/7-13 

15. (safe or safety).mp. 

16. exp risk/ 

17. risk$.mp. 

18. exp side effect/ 

19. side effect$.mp. 

20. (adverse adj1 (effect$ or symptom$)).mp. 

21. harm.mp. 

22. exp etiology/ 

23. aetiology.mp. 

24. treatment contraindication/ 

25. contraindicat$.mp. 

26. (cause or causation or causing or causal$).mp. 

27. *epidemiology/ 

28. exp prediction/ 

29. complicat$.mp. 

30. shock$.mp. 

31. exp BLEEDING/ 

32. bleeding.mp. 

33. exp Infection/ 

34. infect$.mp. 

35. (inappropriate adj2 pacing).mp. 

36. or/15-35 

37. and/6,14,36 

38. limit 37 to yr="2005 - 2006" 

A-12 
Science Citation Index 

Expanded (via Web of 

Science®), 

2005 – 2006 

Searched November 14, 2006 

CRT, ICD efficacy/effectiveness 

Results: 20

#10 #9 NOT #7 

#9 #8 AND #6 AND #1 

#8 TS=(implantable same defibrillat*) or

TS=(implantable same defibrilat*) 

#7 #6 AND #2 AND #1 

#6 #5 OR #4 OR #3 

#5 

TS=(randomized controlled trial* or controlled 

clinical trial* or research design or comparative 

stud* or evaluation stud* or controlled trial* or 

follow-up stud* or prospective stud*) 

#4 TS=(single blind* or double blind* or clinical 

trial* or placebo* or random*) 

#3 

TS=(case series or time series or efficacy or 

effectiveness or meta-analysis or multicenter study 

or multicentre study) 

#2 

TS=(biventricular pacing or biventricular pacer* 

or resynchronization therap* or resynchronisation 

therap* or biv or dual-chamber pacing or dualchamber pacer* or dual-chamber stimulat* or

single-chamber pacing or single-chamber pacer* 

or single-chamber stimulat* or cardiac 

resynchronization or cardiac resynchronisation or 

heart resynchronization or heart resynchronisation 

or cardiac pacing or medtronic or insync or ela 

medical) 

#1 

TS=(congestive heart failure* or chf or heart 

disease or congestive cardiac failure* or chronic 

cardiac failure* or chronic heart failure*) 

CRT/ICD safety (Searched from 2005-2006) 

Results: 20

#16 #15 NOT (#7 OR #10 OR #13) 

#15 #14 AND #8 AND #1 

#14 

TS=(safe or safety or risk* or adverse effect* or 

adverse symptom* or side effect* or harm or 

etiology or aetiology or contraindicat* or cause or 

causation or causing or causal* or predict* or 

complicat* or shock* or bleeding or hemorrhag* 

A-13 
or infect*) or TS=(inappropriate same pacing) 

#13 #12 NOT (#7 OR #10) 

#12 #11 AND #2 AND #1 

#11 

TS=(safe or safety or risk* or adverse effect* or 

adverse symptom* or side effect* or harm or 

etiology or aetiology or contraindicat* or cause or 

causation or causing or causal* or predict*) 

#10 #9 NOT #7 

#9 #8 AND #6 AND #1 

#8 TS=(implantable same defibrillat*) or

TS=(implantable same defibrilat*) 

#7 #6 AND #2 AND #1 

#6 #5 OR #4 OR #3 

#5 

TS=(randomized controlled trial* or controlled 

clinical trial* or research design or comparative 

stud* or evaluation stud* or controlled trial* or 

follow-up stud* or prospective stud*) 

#4 TS=(single blind* or double blind* or clinical 

trial* or placebo* or random*) 

#3 

TS=(case series or time series or efficacy or 

effectiveness or meta-analysis or multicenter study 

or multicentre study) 

#2 

TS=(biventricular pacing or biventricular pacer* 

or resynchronization therap* or resynchronisation 

therap* or biv or dual-chamber pacing or dualchamber pacer* or dual-chamber stimulat* or

single-chamber pacing or single-chamber pacer* 

or single-chamber stimulat* or cardiac 

resynchronization or cardiac resynchronisation or 

heart resynchronization or heart resynchronisation 

or cardiac pacing or medtronic or insync or ela 

medical) 

#1 

TS=(congestive heart failure* or chf or heart 

disease or congestive cardiac failure* or chronic 

cardiac failure* or chronic heart failure*) 

International 

Pharmaceutical 

Abstracts 

Ovid Version: rel10.3.2 

2005 to November 2006 

Searched November 14, 2006 

CRT 

Results: 0

1. ((biventricular or dual-chamber or single-chamber) adj1 

(pacing or pacer or stimulat$)).mp. 

2. resynchroni?ation therapy.mp. 

3. biv.mp. 

A-14 
4. ((cardiac or heart) adj resynchroni?ation$).mp. 

5. medtronic.mp. 

6. insync.mp. 

7. "ela medical".mp. 

8. or/1-7 

9. "congestive heart failure$".mp. 

10. "congestive cardiac failure$".mp. 

11. "chronic cardiac failure$".mp. 

12. "chronic heart failure$".mp. 

13. heart disease$.mp. 

14. chf.mp. 

15. or/9-14 

16. 8 and 15 

PubMed®

U.S. National Library of 

Medicine 

Searched from June 

2006 to November 2006 

CRT/ICD efficacy/effectiveness and safety 

Results: 50

#16 Search #15 NOT (#6 OR #8 OR #13) 

#15 Search #3 AND #7 AND #14 

#14 Search safe OR safety OR risk* OR risk[MeSH] 

OR (adverse AND (effect* OR symptom*)) OR 

side effect* OR harm OR etiology OR aetiology 

OR contraindicat* OR cause OR causation OR 

causing OR causal* OR causality[MeSH] OR 

predict* OR bleeding OR hemorrhage[MeSH] OR 

complicat* OR shock* OR (inappropriate AND 

pacing) 

#13 Search #12 NOT (#6 OR #8) 

#12 Search #3 AND #4 AND #11 

#11 Search safe OR safety OR risk* OR risk[MeSH] 

OR (adverse AND (effect* OR symptom*)) OR 

side effect* OR harm OR etiology OR aetiology 

OR contraindicat* OR cause OR causation OR 

causing OR causal* OR causality[MeSH] OR 

predict* 

#10 Search #8 NOT #6 

#8 Search #3 AND #5 AND #7 

#7 Search "Defibrillators, Implantable"[MeSH] OR 

icd[tiab] OR aicd[tiab] OR (implant* AND 

(defibrillat* OR defibrilat*))

#6 Search #3 AND #4 AND #5 

#5 Search #1 OR #2 

#4 Search (resynchronization therapy OR

A-15 
resynchronisation therapy OR biv OR 

((biventricular OR dual-chamber OR singlechamber) AND (pacing OR pacer OR stimulat*)) 

OR ((cardiac OR heart) AND (resynchronization* 

OR resynchronisation*)) OR medtronic OR insync 

OR ela medical OR cardiac pacing, 

artificial[MESH]) 

#3 Search "Heart Failure, Congestive"[MeSH] OR 

"Heart Diseases"[MeSH] OR congestive heart 

failure* OR congestive cardiac failure* OR 

chronic cardiac failure* OR chronic heart failure* 

OR chf 

#2 Search case series OR time series OR 

efficacy[tiab] OR effectiveness[tiab] OR metaanalysis[pt] OR multicenter study[pt] 

#1 Search ("Clinical Trial"[Publication Type] OR 

"Clinical Trials"[MeSH] OR "Randomized 

Controlled Trial"[Publication Type] OR 

"Randomized Controlled Trials"[MeSH] OR 

"Random Allocation"[MeSH] OR "double-blind 

method" [MeSH] OR "single-blind method" 

[MeSH] OR placebos [MeSH] OR research design 

[MeSH] OR comparative study [MeSH] OR 

evaluation studies [MeSH] OR follow-up studies 

[MeSH] OR prospective studies [MeSH] OR 

(clinical[Title/Abstract] AND 

trial*[Title/Abstract]) OR control*[Title/Abstract]

OR prospectiv* [Title/Abstract] OR 

volunteer*[Title/Abstract] OR random*

[Title/Abstract] OR ((singl*[Title/Abstract] OR 

doubl* [Title/Abstract] OR trebl* 

[Title/Abstract]OR tripl* [Title/Abstract]) AND 

(blind* [Title/Abstract] OR 

mask*[Title/Abstract])))

OCLC Proceedings 

First and Papers First 

OCLC FirstSearch 

Searched 2005 – 

November 14, 2006 

CRT 

Results: 4

biventricular pacing or biventricular pacer* or

resynchronization therap* or resynchronisation therap* or biv 

or dual-chamber pacing or dual-chamber pacer* or dualchamber stimulat* or single-chamber pacing or singlechamber pacer* or single-chamber stimulat* or cardiac 

resynchronization or cardiac resynchronisation or heart 

resynchronization or heart resynchronisation or cardiac pacing 

or medtronic or insync or ela medical 

A-16 
AND 

congestive heart failure* or chf or heart disease or congestive 

cardiac failure* or chronic cardiac failure* or chronic heart 

failure* 

ICD 

Results: 0

(implantable and defibrillat*) or (implantable and defibrilat*) 

AND 

congestive heart failure* or chf or heart disease or congestive 

cardiac failure* or chronic cardiac failure* or chronic heart 

failure* 

A-17 
APPENDIX B: Sample Data Extraction Form 

Study Characteristics 

First Author: 

Title: 

Journal citation: (yyyy; vol:pp-pp)

Year of 

publication: 

Language: Country(ies) where study conducted: 

Funding: 

 Private industry 

 Foundation 

 Government 

 Internal 

 Other 

 Unclear 

Author’s primary outcome:

Author’s inclusion criteria: Author’s exclusion criteria:

Comments:

B-1 
 

Design Characteristics 

Study design:

 RCT – Parallel 

 RCT – Crossover 

 Cohort 

 Registry 

 Case series

 Other 

If Crossover, was carryover effect mentioned? 

 Yes

 No 

Other 

Intent to treat analysis:  Yes  No  N/A 

Patient or data source 

Intervention 1:

Intervention 2 (if applicable): 

Participants

Number enrolled in study: Number completed study: 

Number excluded after meeting 

inclusion criteria: 

Number lost to follow up: 

Length of study 

Reasons for exclusion : [not the same as exclusion criteria on page 1; ones stated to explain why not 

included in analysis] 

Number Withdrawals/dropouts: 

Intervention 1:

Intervention 2 (if applicable): 

If yes, reasons: 

All participants: 

B-2 
 

Baseline Characteristics Please indicate the statistic, e.g., %, mean, SD, range, etc AND the units

Intervention 1 Intervention 2 All participants 

Males/females: 

Age: 

Race: 

Ischemic/nonischemic: 

Diabetes 

Mellitus: 

Hypertension:

Ejection 

Fraction (%) 

QRS duration

previous MI 

previous PTCA 

CABG 

History of SCD: 

Atrial fibrillation: 

Other 

Baseline data on QOL; 6MWT; NYHA class; etc on same table as outcomes [to save space] 

B-3 
 

Procedural Characteristics Indicate the statistic, e.g., %, mean, SD, range, IQ, etc AND the units

Intervention 1 Intervention 2 All participants 

Drug therapy: 

Angiotensin 

receptor

blockers 

ACE inhibitors 

Antiarrhythmics

Beta blockers 

digoxin

diuretics

furosemide

lipid lowering 

agents 

antiplatelet 

agents 

Nitrates

Spironolactone

Warfarin 

Other 

Not reported

Device: 

Method of 

implantation:

Other cointerventions:

B-4 
 

Outcomes Timepoints indicate time since RANDOMIZATION in DAYS. 

Intervention 1 Intervention 2

Time to death:

 All-cause 

mortality or 

Transplant 

Number at 

risk

Number 

of events 

Number at

risk

Number of 

events 

 Timepoint: 

 Timepoint: 

 Timepoint: 

 Timepoint: 

Intervention 1 Intervention 2

Time to death:

 Sudden 

cardiac 

death 

Number at 

risk

Number 

of events 

Number at

risk

Number of 

events 

 Timepoint: 

 Timepoint: 

 Timepoint: 

 Timepoint: 

Intervention 1 Intervention 2

Time to death:

 CHF 

Number at 

risk

Number 

of events 

Number at

risk

Number of 

events 

 Timepoint: 

 Timepoint: 

 Timepoint: 

 Timepoint: 

Intervention 1 Intervention 2

Time to death:

 Cardiac 

Number at 

risk

Number 

of events 

Number 

censored

Number at 

risk

Number of 

events 

Number censored 

 Timepoint: 

 Timepoint: 

 Timepoint: 

Indicate which period if it’s a crossover study or which subgroup where necessary:

B-5 
 

Outcomes Timepoints indicate time since RANDOMIZATION in DAYS. 

Indicate which period if it’s a crossover study or which subgroup where necessary:

Intervention 1 Intervention 1

Dichotomous 

outcomes: 

n/N

Baseline Timepoint Timepoint Timepoint Baseline Timepoint Timepoint Timepoint 

CHF 

hospitalizations 

ED visits

Transplants 

Other 

Intervention 1 Intervention 2

Continuous 

outcomes: 

n 

mean(sd) 

Baseline Timepoint Timepoint Timepoint Baseline Timepoint Timepoint Timepoint 

6 minute 

walk test

QoL [name 

scale] 

LV ejection 

fraction 

(LVEF) 

Other 

B-6 
 

Outcomes Timepoints indicate time since RANDOMIZATION in DAYS. 

Indicate which period if it’s a crossover study or which subgroup where necessary:

NYHA 

Intervention 1 Intervention 2

n/N or % Baseline Timepoint 

Timepoint Or % 

who 

improved

1 class 

Baseline Timepoint Timepoint Or % who

improved

1 class 

class I

class II

class III 

class IV

Safety: 

n/N or % Baseline Timepoints (specify)

Implantation Risks:

• Death 

• Lead misplacement 

• Device-related malfunction

Post-Implantation Risks 

• Mechanical malfunction 

• Lead dislodgement

• Infection 

ICD 

• Inappropriate delivery of 

therapy 

Successful implant rate 

Battery longevity 

Recall of devices 

B-7 
APPENDIX C: Primary Publications and Associated 

Publications of Included Studies 

Cardiac resynchronization therapy studies 

CARE-HF 

Primary report: Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization therapy 

on morbidity and mortality in heart failure. N Engl J Med 2005; 352(15):1539-49. 

Other publications associated with CARE-HF

Cleland JG, Daubert JC, Erdmann E, et al. Baseline characteristics of patients recruited into the 

CARE-HF study. Eur J Heart Fail 2005; 7(2):205-14t 

Cleland JG, Daubert JC, Erdmann E, et al. Longer-term effects of cardiac resynchronization therapy

on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension 

phase]. Eur Heart J 2006; 27(16):1928-1932. 

COMPANION 

Primary report: Bristow MR, Saxon LA, Boehmer J, et al. Cardiac resynchronization therapy with or 

without an implantable defibrillator in advanced chronic heart failure. 

Other publications associated with COMPANION 

Bristow MR, Feldman AM, Saxon LA. Heart failure management using implantable devices for 

ventricular resynchronization: Comparison of medical therapy, pacing, and defibrillation in chronic heart 

failure (COMPANION) trial. J Card Fail 2000; 6(3):276-85

Bristow MR, et al. Comparison of medical therapy, pacing and defibrillation in heart failure. Presented 

at the 52nd Annual Scientific Conference, American College of Cardiology, Chicago, Illinois, USA, 

March 31st, 2003. 

Carson P, Anand I, O’Connor C, et al. Mode of death in advanced heart failure: the Comparison of 

Medical, Pacing, and Defibrillation Therapies in Heart Failure (COMPANION) trial. J Am Coll Cardiol 

2005; 46(12): 2329-34 

CONTAK CD 

Primary report: Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the 

treatment of heart failure in patients with inraventricular conduction delay and malignant ventricular 

tachyarrhythmia. J Am Coll Cardiol 2003; 42(12):2109-16

Other publications associated with CONTAK CD 

Knight BP, Desai A, Coman J, Faddis M, Yong P. Long-term retention of cardiac resynchronization 

therapy. J Am Coll Cardiol 2004; 44(1):72-7 

GUIDANT Corporation, Cardiac Rhythm Management. Summary of safety and effectiveness: Guidant 

CONTAK CD CRT-D system including the CONTACK CD CRT-D pulse generator model 1823, and 

software application model 2848. PMA: P010012. Food and Drug Administration July 10, 2002. 

Boehmer JP, DeMarco T, Jaski BE, et al. Why ICD patients with heart failure (Class II-IV) are 

hospitalized: Do the reasons differ for patients who are treated with cardiac resynchronization therapy? 

[abst] J Am Coll Cardiol 2002;39(5):159A 

Higgins SL, Yong P, Sheck D, et al. Biventricular pacing diminishes the need for implantable 

cardioverter defibrillator therapy. Ventak CHF Investigators. J Am Coll Cardiol 2000;36(3):824-7 

Lozano I, Bocchiardo M, Achtelik M, et al. Impact of biventricular pacing on mortality in a randomized

crossover study of patients with heart failure and ventricular arrhythmias. Pacing Clin Electrophysiol 

2000;23(11Pt2):1711-12 

Saxon LA, Boehmer JP, Hummel J, et al. Biventricular pacing in patients with congestive heart failure: 

two prospective randomized trials. The VIGOR CHF and VENTAK CHF Investigators. Am J Cardiol 

1999;83(5B):120-23D 

Saxon LA, De Marco T, Schafer J, et al. Effects of long-term biventricular stimulation for 

resynchronization on echocardiographic measures of remodeling. Circulation 2002;105(11):1304-10

C-1 
 

Leclercq studies 

Primary report: Leclercq C, Victor F, Alonso C, et al. Comparative effects of permanent biventricular pacing 

for refractory heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardiol 

2000;85(9):1154-56. 

Other publications associated with Leclercq study

Leclercq C, Cazeau S, Ritter P, et al. A pilot experience with permanent biventricular pacing to treat 

advanced heart failure. Am Heart J 2000;140(6): 862-70 

MIRACLE 

Primary report: Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart 

failure. N Engl J Med 2002;346(24):1845-1853 

Other publications associated with the MIRACLE study 

Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of 

cardiac resynchronization therapy in patients with advanced heart failure: The Multicenter InSync 

Randomized Clinical Evaluation (MIRACLE). J Card Fail 2000;6(4):369-80

Abraham WT, Fisher W, Smith A, et al. Cardiac resynchronization therapy reduces morbidity in

patients with moderate to severe systolic heart failure and intraventricular conduction delays [abst]. J 

Am Coll Cardiol 2002;39(5):171A 

Abraham WT, Fisher W, Smith A, et al. Long-term improvement in functional status, quality of life and 

exercise capacity with cardiac resynchronization therapy: The MIRACLE Trial experience [abst]. J Am 

Coll Cardiol 2002;39(5):171A

Aranda JM, Curtis AB, Conti JB, et al. Rationale and design of a randomized clinical trial to assess the 

safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: The 

Multicenter InSync Randomized Clinical Evaluation (MIRACLE) [abst]. J Am Coll Cardiol 

2002;39(5):96A

Packer M & Abraham WT. Effect of cardiac resynchronization on a composite clinical status endpoint 

in patients with chronic heart failure: Results of the MIRACLE trial [abst]. Circulation 

2001;104(17):1995 

Sutton MGS, Plappert T, Abraham WT, et al. Cardiac resynchronization improves diastolic ventricular 

function in advanced heart failure: The MIRACLE trial [abst]. Circulation 2001;104(17):2920 

Wagoner LE, Zengel PW, Abraham WT, et al. Cardiac resynchronization therapy with the InSync 

stimulation system improves exercise performance in patients with heart failure: MIRACLE trial 

substudy results [abst]. Circulation 2001;104(17):2919 

MIRACLE-ICD 

Primary report: Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and 

implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial. JAMA 

2003; 289 (20):2685-94. 

Other publications associated with MIRACLE ICD 

Medtronic, Inc. Summary of Safety and Effectiveness: InSync ICD Model 7272 dual chamber 

implantable cardioverter defibrillator with biventricular pacing for cardiac resynchronization, Attain 

Models 2187, 2188, 4189 leads. PMA: P010031. Food and Drug Administration, Dec 3, 2001 

Medtronic, Inc. Summary of Safety and Effectiveness: InSync ICD Model 7272 dual chamber 

implantable cardioverter defibrillator with cardiac resynchronization therapy and the model 9969 

Application Software. PMA: P010031. Food and Drug Administration, March 5, 2002 

PATH CHF 

Primary report: Auricchio A, Stellbrink C, Sack S, et al. Long-term clinical effect of hemodynamically

optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J 

Am Coll Cardiol 2002;39(12):2026-33 

 

Other publications associated with PATH-CHF

Auricchio A, Stellbrink C, Sack S, et al. The Pacing Therapies for Congestive Heart Failure (PATHCHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J 

Cardiol 1999;83(5B):130D 

Auricchio A, Klein H, Spinelli J. Pacing for heart failure: selection of patients, techniques and benefits. 

Eur J Heart Fail 1999;1(3);275-79 

Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute 

systolic function of paced patients with congestive heart failure. Circulation 1999;99(23):2993-3001 

C-2 
 

Auricchio A, Ding J, Spinelli JC, et al. Cardiac resynchronization therapy restores optimal

atrioventricular mechanical timing in heart failure patients with ventricular conduction delay. J Am Coll 

Cardil 2002;39(7):1163-69 

Baumann LS, Kadhiresan VA, Yu Y, et al. Optimization of cardiac resynchronization therapy in heart 

failure patients by measuring transient cycle length changes [abst]. Eur Heart J 2001;22:443 

Butter C, Auricchio A, Stellbrink C, et al. Effect of resynchronization therapy stimulation site on the 

systolic function of heart failure patients. Circulation 2001;104(25):3026-29

Cuesta F, Sack S, Auricchio A, et al. Long-term benefit of cardiac resynchronization therapy in heart 

failure patients: results of the PATH-CHF study. Eur Heart J 2001;22:130

Cuesta F, Stellbrink C, Auricchio A, et al. Cardiac resynchronization therapy reduces heart failure 

hospitalization in the PATH-CHF study [abst]. Eur Heart J 2001;22:441

Huth C, Friedl A, Klein H, Auricchio A. Pacing therapies for congestive heart failure considering the 

results of the PATH-CHF study] Zeitschrift fur Kardiologie 2001; 90 (Supp 1):10-15 

Stellbrink C, Auricchio A, Butter C, et al. Pacing therapies in congestive heart failure II study. Am J 

Cardiol 2000;86 (9 Supp 1):138K 

Stellbrink C, Breithardt OA, Franke A, et al. Impact of cardiac resynchronization therapy using 

hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart 

failure and ventricular conduction disturbances. Am J Cardiol 2001;38(7):1957-65

Vogt J, Krahnefeld O, Lamp B, et al. Electrocardiographic remodeling in patients paced for heart 

failure. Am J Cardiol 2000;86(Supp 1):152-56K 

PATH CHF II 

Primary report: Auricchio A., Stellbrink C, Butter C, Sack S, et al. Clinical efficacy of cardiac 

resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of 

ventricular conduction delay.[see comment]. J Am Coll Cardiol.;42(12):2109-16 

Other publications associated with PATH-CHF II 

Butter C, Auricchio A, Stellbrink C, et al. Clinical efficacy of one year cardiac resynchronization 

therapy in heart failure patients stratified by QRS duration: Results of the PATH-CHF II trial. Eur Heart 

J 2003;24:363

INSYNC (observational) 

Primary report: Gras D, Leclercq C, Tang AS, et al. Cardiac resynchronization therapy in advanced heart 

failure the multicenter InSync clinical study. Eur J Heart Fail 2002;4(3):311-20. 

Other publications associated with InSync

Gasparini M, Lunati M, Bocchiardo M, et al. Cardiac resynchronization and implantable cardioverter 

defibrillator therapy: preliminary results from the InSync Implantable Cardioverter Defibrillator Italian 

Registry. Pacing Clin Electrophysiol 2003;26(1 Pt 2): 148-151 

Gras D, Mabo P, Tang T, et al. Multisite pacing as a supplemental treatment of congestive heart 

failure: preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol 1998;21(11 

pt2):2249-55

Gras D, Cazeau S, Ritter P, et al. Long term results of cardiac resynchronization for heart failure

patients: The InSync Clinical Trial [abst] Circulation 1999;100(18):2714 

Gras D, Cazeau S, Mabo P, et al. Long-term benefit of cardiac resynchronization in heart failure

patients: The 12 month results of the InSync trial. [abst] J Am Coll Cardiol 2000;35(2):230A. 

Gras D, Mabo P, Bucknall C, et al. Responders and nonresponders to cardiac resynchronization 

therapy: Results from the InSync trial. J Am Coll Cardiol 2000;35(2):230A-230A 

Tang ASL, Gras D, Mabo P, et al. Mortality and outcome differences between survivors and 

nonsurvivors in the InSync cardiac resynchronization trial [abst] Circulation 1999;100(18):2715 

Zardini M, Tritto M, Bargiggia G, et al. The InSync-Italian Registry: analysis of clinical outcome and 

considerations on the selection of candidates to left ventricular resynchronization. Eur Heart J Supp 

2002;2:J16-22

C-3 
 

Implantable cardioverter defibrillator studies 

AVID 

Primary report: The Antiarrhythmics vs. Implantable Defibrillators (AVID) Investigators. A comparison of 

antiarrhythmic-drug therapy with implantable defibrillators in patients rescuscitated from near-fatal 

ventricular arrhythmias. N Engl J Med 1997; 337(22):1576-83 

Other publications associated with AVID 

Kron J. Clinical significance of device-related complications in clinical trials and implications for future 

trials: insights from the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. Card 

Electrophysiol Rev 2003; 7(4)473-8 

Klein RC, Raitt MH, Wilkoff BL et al. Analysis of implantable cardioverter defibrillator therapy in the 

Antiarrhythmics Versus Implantable Cardioverter Defibrillators (AVID) Trial. J Cardiovasc

Electrophysiol 2003; 14(9):940-8 

AMIOVIRT 

Primary report: Strickberger SA, Hummel JD, Bartlett TG et al. Amiodarone versus implantable 

cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and 

aymoptomatic nonsustained ventricular tachycardia—AMIOVIRT. J Am Coll Cardiol 2003; 41(10): 1707-12. 

Other publications associated with AMIOVIRT

Wijetunga M, Strickberger SA, Amiodarone Versus Implantable Defibrillators Randomized Trial. 

Amiodarone versus Implantable Defibrillator(AMIOVIRT): background, rationale, design, methods, 

results and implications. Card Electrophysiol Rev 2003; 7(4):452-6. 

C-4 
APPENDIX D: List of Excluded Studies 

Excluded Studies: CRT Alone and Combined CRT-ICD 

The four main reasons for exclusion were based on the publication not having the right study 

design, population, intervention or outcomes. 

Population

1. Becker R, Ruf-Richter J, Senges-Becker JC, et al. 

Patient alert in implantable cardioverter

defibrillators: toy or tool? J Am Coll Cardiol 

2004;44(1):95-8. 

2. D'Andrea A, Ducceschi V, Caso P, et al. Usefulness

of Doppler tissue imaging for the assessment of 

right and left ventricular myocardial function in 

patients with dual-chamber pacing. Int J Cardiol 

2001;81(1):75-83. 

3. Daoud EG, Kalbfleisch SJ, Hummel JD, et al. 

Implantation techniques and chronic lead

parameters of biventricular pacing dual-chamber 

defibrillators. J Cardiovasc Electrophysiol 

2002;13(10):964-70. 

4. De Souza FSO, Mortati NL, Braile DM, et al. 

Technical aspects of coronary sinus catheterization 

based on the atrial component of the intracavitary

electrogram and radiological anatomy during the

implantation procedure of a biventricular 

pacemaker. Arq Bras Cardiol 2006;86(4):261-7. 

5. Dorwarth U, Frey B, Dugas M, et al. Transvenous 

defibrillation leads: high incidence of failure during 

long-term follow-up. J Cardiovasc Electrophysiol 

2003;14(1):38-43. 

6. Doshi RN, Daoud EG, Fellows C, et al. Left 

ventricular-based cardiac stimulation post AV nodal 

ablation evaluation (the Pave Study). J Cardiovasc

Electrophysiol 2005;16(11):1160-5. 

7. Ferro A, Duilio C, Santomauro M, Cuocolo A. 

Walk test at increased levels of heart rate in patients 

with dual-chamber pacemaker and with normal or

depressed left ventricular function. Eur Heart J 

2003;24(23):2123-32. 

8. Gould PA, Krahn AD. Complications associated

with implantable cardioverter-defibrillator

replacement in response to device advisories. 

JAMA 2006;295(16):1907-11. 

9. Greenberg JM, Leon AR, Book WM, et al. Benefits 

of cardiac resynchronization therapy in outpatients 

with indicators for heart transplantation. J Heart

Lung Transplant 2003;22(10): 1134-40. 

10. Hansky B, Vogt J, Gueldner H, et al. Left heart

pacing–experience with several types of coronary

vein leads. J Interv Card Electrophysiol 

2002;6(1):71-5. 

11. Hauser RG, Hayes DL, Epstein AE, et al.

Multicenter experience with failed and recalled 

implantable cardioverter-defibrillator pulse 

generators. Heart Rhythm 2006;3(6):640-4. 

12. Hoffmeister P, Chaudhry GM, Orlov MV, Shukla 

G, Haffajee CI. Sheathless implantation of 

permanent coronary sinus-LV pacing leads. Pacing

Clin Electrophysiol 2006;29(2):117-23. 

13. James KB, Militello M, Barbara G, Wilkoff BL. 

Biventricular pacing for heart failure patients on

inotropic support: a review of 38 consecutive cases. 

Tex Heart Inst J 2006;33(1):19-22. 

14. Janousek J, Tomek V, Chaloupecky VA, et al. 

Cardiac resynchronization therapy: a novel adjunct 

to the treatment and prevention of systemic right 

ventricular failure. J Am Coll Cardiol 

2004;44(9):1927-31. 

15. Kolb C, Deisenhofer I, Schmieder S, et al. Longterm follow-up of patients supplied with singlechamber or dual-chamber cardioverter

defibrillators. Pacing Clin Electrophysiol

2006;29(9):946-52. 

16. Kuhlkamp V, Wilkoff BL, Brown AB, et al. 

Experience with a dual chamber implantable

defibrillator. Pacing Clin Electrophysiol

2002;25(7):1041-8. 

17. Porterfield JG, Porterfield LM, Smith BA, Bray L. 

Experience with three different third-generation

cardioverter-defibrillators in patients with coronary

artery disease or cardiomyopathy. Am J Cardiol 

1993;72(3):301-4. 

D-1 
 

18. Proclemer A, Facchin D, Pagnutti C, Fioretti P, De

Michele C. Safety of pacemaker implantation prior 

to radiofrequency ablation of atrioventricular

junction in a single session procedure. Pacing Clin 

Electrophysiol 2000;23(6):998-1002. 

19. Sadoul N, Jung W, Jordaens L, et al. Diagnostic 

performance of a dual-chamber cardioverter 

defibrillator programmed with nominal settings: a 

European prospective study. J Cardiovasc 

Electrophysiol 2002;13(1):25-32. 

20. Seif M, Al-Ajmi T, Khokhar A, Idris M, Al-Khadra 

A. Doppler echocardiographic assessment of left

ventricular diastolic function following 

biventricular pacing in patients with congestive 

heart failure. The XIIth World Congress on Cardiac 

Pacing & Electrophyiology. Tse HF, Lee KLF, Lau 

CPMonduzzi, 2003: 833-6. 

21. Senges-Becker JC, Klostermann M, Becker R, et

al. What is the 'optimal' follow-up schedule for ICD 

patients? Europace 2005;7(4):319-26. 

22. Thackray SD, Witte KK, Nikitin NP, Clark AL,

Kaye GC, Cleland JG. The prevalence of heart

failure and asymptomatic left ventricular systolic

dysfunction in a typical regional pacemaker

population. Eur Heart J 2003;24(12):1143-52. 

Intervention

1. Al-Khadra AS. Use of preshaped sheath to plan and 

facilitate cannulation of the coronary sinus for the 

implantation of cardiac resynchronization therapy

devices: preshaped sheath for implantation of 

biventricular devices. Pacing Clin Electrophysiol 

2005;28(6):489-92. 

2. Blanc JJ, Bertault-Valls V, Fatemi M, Gilard M,

Pennec PY, Etienne Y. Midterm benefits of left 

univentricular pacing in patients with congestive

heart failure. Circulation 2004;109(14):1741-4. 

3. Blanc JJ, Fatemi M, Bertault V, Baraket F, Etienne 

Y. Evaluation of left bundle branch block as a 

reversible cause of non-ischaemic dilated 

cardiomyopathy with severe heart failure. A new 

concept of left ventricular dyssynchrony-induced

cardiomyopathy. Europace 2005;7(6):604-10. 

4. Bongiorni MG, Soldati E, Arena G, et al. 

Multicenter clinical evaluation of a new SSIR 

pacemaker. Pacing Clin Electrophysiol 1992;15(11

Pt 2):1798-803. 

5. Bordachar P, Garrigue S, Reuter S, et al.

Hemodynamic assessment of right, left, and 

biventricular pacing by peak endocardial 

acceleration and echocardiography in patients with

end-stage heart failure. Pacing Clin Electrophysiol 

2000;23(11 Pt 2):1726-30. 

6. Bracke FALE, Meijer A, van Gelder LM. Lead 

extraction for device related infections: a singlecentre experience. Europace 2004;6(3):243-7. 

7. Butter C, Gras D, Ritter P, et al. Comparative

prospective randomized efficacy testing of different 

guiding catheters for coronary sinus cannulation in 

heart failure patients. J Interv Card Electrophysiol 

2003;9(3):343-51. 

8. Butter C, Meisel E, Tebbenjohanns J, et al. 

Transvenous biventricular defibrillation halves

energy requirements in patients. Circulation

2001;104(21):2533-8. 

9. Capucci A, Romano S, Puglisi A, et al. Dual 

chamber pacing with optimal AV delay in 

congestive heart failure: a randomized study.

Europace 1999;1(3):174-8. 

10. da Silva Menezes A. Outcome of right ventricular

bifocal pacing in patients with permanent atrial 

fibrillation and severe dilated cardiomiopathy due to 

Chagas disease: three years of follow-up. J Interv

Card Electrophysiol 2004;11(3):193-8. 

11. Doll N, Opfermann UT, Rastan AJ, et al. Facilitated

minimally invasive left ventricular epicardial lead 

placement. Ann Thorac Surg 2005;79(3):1023-5. 

12. Ector B, Willems R, Heidbuchel H, et al. Epicardial 

pacing: a single-centre study on 321 leads in 138

patients. Acta Cardiol 2006;61(3):343-51. 

13. Etienne Y, Mansourati J, Touiza A, et al. Evaluation 

of left ventricular function and mitral regurgitation 

during left ventricular-based pacing in patients with 

heart failure. Eur J Heart Fail 2001;3(4):441-7. 

D-2 
 

14. Fatemi M, Etienne Y, Gilard M, Mansourati J,

Blanc JJ. Short and long-term single-centre 

experience with an S-shaped unipolar lead for left

ventricular pacing. Europace 2003;5(2):207-11. 

15. Feruglio GA, Petz E, Zanuttini D, Ragonese P.

Un'esperienza regionale di elettrostimolazione 

cardiaca: nel Friuli-Venezia Giulia la maggior 

densita di portatori di pacemaker in Italia, oggi [A

regional experience with permanent cardiac pacing: 

in Friuli-Venezia Giulia the highest density of

pacemaker patients in Italy, to-day (author's transl)]. 

(Ita). G Ital Cardiol 1978;8 Suppl 1:159-65. 

16. Fonarow GC, Feliciano Z, Boyle NG et al. 

Improved survival in patients with nonischemic 

advanced heart failure and syncope treated with an

implantable cardioveter-defibrillator. Am J Cardiol 

2000;85(8):981-5. 

17. Galizio NO, Pesce R, Valero E, et al. Which

patients with congestive heart failure may benefit 

from biventricular pacing? Pacing Clin

Electrophysiol 2003;26(1 Pt 2):158-61. 

18. Gasparini M, Bocchiardo M, Lunati M, et al. 

Comparison of 1-year effects of left ventricular and 

biventricular pacing in patients with heart failure

who have ventricular arrhythmias and left bundlebranch block: the Bi vs Left Ventricular Pacing: an 

International Pilot Evaluation on Heart Failure

Patients with Ventricular Arrhythmias (BELIEVE) 

multicenter prospective randomized pilot study . 

Am Heart J 2006;152(1):155.e1-7. 

19. Giudici MC, Lee M, Higgins S, West GR, Moeller 

AK, Decker JB. Experience with a higher 

impedance, fixed helix, steroid-eluting pacing lead. 

Pacing Clin Electrophysiol 2000;23(7):1103-8. 

20. Gold MR, Brockman R, Peters RW, et al. Acute

hemodynamic effects of right ventricular pacing site

and pacing mode in patients with congestive heart 

failure secondary to either ischemic or idiopathic 

dilated cardiomyopathy. Am J Cardiol 

2000;85(9):1106-9. 

21. Hayes DL, Graham KJ, Irwin M, et al. Multicenter 

experience with a bipolar tined polyurethane 

ventricular lead. Pacing Clin Electrophysiol 

1995;18(5 Pt 1):999-1004. 

22. Higgins SL, Pak JP, Barone J, et al. The first-year

experience with the dual chamber ICD. Pacing Clin 

Electrophysiol 2000;23(1):18-25. 

23. Joglar JA, Welch PJ, Wilkinson WE, Hamdan MH, 

Page RL. Initial experience with a high-impedance 

tined endocardial pacemaker lead: evidence for

increased lead failure. Am Heart J 1997;134(2 

I):161-4. 

24. Kasravi B, Tobias S, Barnes MJ, Messenger JC. 

Coronary sinus lead extraction in the era of cardiac 

resynchronization therapy: single center experience.

Pacing Clin Electrophysiol 2005;28(1):51-3. 

25. Kay GN, Brinker JA, Kawanishi DT, et al. Risks of 

spontaneous injury and extraction of an active 

fixation pacemaker lead: report of the accufix

multicenter clinical study and worldwide registry.

Circulation 1999;100(23):2344-52. 

26. Kettering K, Mewis C, Dornberger V, et al. Longterm experience with subcutaneous ICD leads: a

comparison among three different types of 

subcutaneous leads. Pacing Clin Electrophysiol 

2004;27(10):1355-61. 

27. Krupa W, Kozlowski D, Derejko P, Swiatecka G. 

Permanent cardiac pacing and its influence on 

tricuspid valve function. Folia Morphol (Warsz) 

2001;60(4):249-57. 

28. Lupi G, Brignole M, Oddone D, Bollini R, Menozzi

C, Bottoni N. Effects of left ventricular pacing on

cardiac performance and on quality of life in

patients with drug refractory heart failure. Am J 

Cardiol 2000;86(11):1267-70. 

29. Meisel E, Rauwolf T, Burghardt M, Kappenberger 

L. [Pacemaker therapy of hypertrophic obstructive 

cardiomyopathy. PIC (Pacing in Cardiomyopathy) 

Study Group]. Herz 2000;25(4):1267-70. (Ger).

30. Morichika N, Okamoto M, Honda T, et al. Left

ventricular wall motion analysis during ventricular 

pacing. J Cardiol 1993;23(Suppl 37):85-8. 

31. Munoz P, Blanco JR, Rodriguez-Creixems M, 

Garcia E, Delcan JL, Bouza E. Bloodstream 

infections after invasive nonsurgical cardiologic 

procedures. Arch Intern Med 2001;161(17):2110-5. 

Erratum in: Arch Intern Med 2002;162(1):110. 

32. Nagele H, Schomburg R, Petersen B, Rodiger W.

Dual chamber pacing in patients with severe heart 

failure on beta blocker and amiodarone treatment: 

preliminary results of a randomised study. Heart 

2002;87(6):566-7. 

33. Oldershaw PJ , Sutton MG, Ward D, Jones S, Miller 

GA. Ten-year experience of 359 epicardial

pacemaker systems: complications and results. Clin 

Cardiol 1982;5(10):515-9. 

34. Perrins EJ, Morely CA, Chan SL, Sutton R.

Randomised controlled trial of physiological and 

ventricular pacing. Br Heart J 1983;50(2):112-7. 

D-3 
 

35. Pires LA, Hassan SA, Johnson KM. Coronary sinus 

lead placement via the internal jugular vein in 

patients with advanced heart failure: a simplified 

percutaneous approach. J Int Cardiac Electrophysiol 

2005;12(2):157-62. 

36. Schwaab B, Frohlig G, Berg M, Schwerdt H, 

Schieffer H. Five-year follow-up of a bipolar

steroid-eluting ventricular pacing lead. Pacing Clin 

Electrophysiol 1999;22(8):1226-8. 

37. Schwaab B, Kindermann M, Frohlig G, Berg M, 

Kusch O, Schieffer H. Septal lead implantation for 

the reduction of paced QRS duration using passivefixation leads. Pacing Clin Electrophysiol

2001;24(1):28-33. 

38. Sharma AD, Rizo-Patron C, Hallstrom AP, et al. 

Percent right ventricular pacing predicts outcomes 

in the DAVID trial. Heart Rhythm 2005;2(8):830-4. 

39. Shinke T, Takeuchi M, Takaoka H, Yokoyama M.

Beneficial effects of heart rate reduction on cardiac 

mechanics and energetics in patients with left 

ventricular dysfunction. Jpn Circ J 

1999;63(12):957-64. 

40. Tatarchenko IP, Iskenderov BG, Koledinov VI. 

Results of 5-year follow-up of patients suffering

from chronic circulatory insufficiency and having

an implantable pacemaker. [abst]. Kardiologiia

1992;32(2):45-8. 

41. Tse HF, Yu C, Lee KL, et al. Initial clinical

experience with a new self-retaining left ventricular 

lead for permanent left ventricular pacing. Pacing 

Clin Electrophysiol 2000;23(11 Pt 2):1738-40. 

42. Tse HF, Yu C, Paul VE, et al. Effect of left

ventricular function on long-term left ventricular

pacing and sensing threshold. J Interv Card 

Electrophysiol 2003;9(1):21-4. 

43. Valls-Bertault V, Mansourati J, Gilard M, Etienne 

Y, Munier S, Blanc JJ. Adverse events with 

transvenous left ventricular pacing in patients with 

severe heart failure: early experience from a single 

centre. Europace 2001;3(1):60-3.

44. Vogt P, Goy JJ, Kuhn M, et al. Single versus double 

chamber rate responsive cardiac pacing: comparison 

by cardiopulmonary noninvasvice exercise testing. 

Pacing Clin Electrophysiol 1988;11(11 Pt 2):1896-

901. 

45. Wilkoff BL, Cook JR, Epstein AE, et al. Dualchamber pacing or ventricular backup pacing in 

patients with an implantable defibrillator: the Dual 

Chamber and VVI Implantable Defibrillator

(DAVID) Trial. JAMA 2002;288(24):3115-23. 

46. Yu CM, Lin H, Zhang Q, Sanderson JE. High

prevalence of left ventricular systolic and diastolic 

asynchrony in patients with congestive heart failure 

and normal QRS duration. Heart 2003;89(1):54-60. 

47. Yu CM, Yang H, Lau CP, et al. Regional left 

ventricle mechanical asynchrony in patients with 

heart disease and normal QRS duration: implication 

for biventricular pacing therapy. Pacing Clin 

Electrophysiol 2003;26(2 Pt 1):562-70. 

48. Zagrodzky JD , Ramaswamy K, Page RL, et al. 

Biventricular pacing decreases the inducibility of

ventricular tachycardia in patients with ischemic 

cardiomyopathy. Am J Cardiol 2001;87(10):1208-

10; A7. 

Outcomes 

1. Adamson PB, Kleckner KJ, VanHout WL, 

Srinivasan S, Abraham WT. Cardiac

resynchronization therapy improves heart rate 

variability in patients with symptomatic heart 

failure. Circulation 2003;108(3):266-9. 

2. Alonso C, Leclercq C, d'Allonnes FR, et al. Six year 

experience of transvenous left ventricular lead 

implantation for permanent biventricular pacing in 

patients with advanced heart failure: technical 

aspects. Heart 2001;86(4):405-10. 

3. Alonso C, Ritter P, Leclercq C, et al. Effects of

cardiac resynchronization therapy on heart rate 

variability in patients with chronic systolic heart

failure and intraventricular conduction delay. Am J 

Cardiol 2003;91(9):1144-7. 

4. Aranda JM Jr, Conti JB, Johnson JW, PetersenStejskal S, Curtis AB. Cardiac resynchronization 

therapy in patients with heart failure and conduction 

abnormalities other than left bundle-branch block:

analysis of the Multicenter InSync Randomized 

Clinical Evaluation (MIRACLE). Clin Cardiol 

2004;27(12):678-82. 

D-4 
 

5. Arya A, Haghjoo M, Dehghani MR, et al. Effect of 

cardiac resynchronization therapy on the incidence 

of ventricular arrhythmias in patients with an

implantable cardioverter-defibrillator. Heart 

Rhythm 2005;2(10):1094-8. 

6. Auricchio A, Ding J, Spinelli JC, et al. Cardiac

resynchronization therapy restores optimal 

atrioventricular mechanical timing in heart failure

patients with ventricular conduction delay. J Am 

Coll Cardiol 2002;39(7):1163-9. 

7. Auricchio A, Spinelli JC, Trautmann SI, Kloss M. 

Effect of cardiac resynchronization therapy on

ventricular modeling. J Card Fail 2002;8(2):S549-

55. 

8. Auricchio A, Stellbrink C, Block M, et al. Effect of

pacing chamber and atrioventricular delay on acute 

systolic function of paced patients with congestive 

heart failure. The Pacing Therapies for Congestive 

Heart Failure Study Group. The Guidant Congestive 

Heart Failure Research Group. Circulation 

1999;99(23):2993-3001. 

9. Auricchio A, Stellbrink C, Sack S, et al. The Pacing 

Therapies for Congestive Heart Failure (PATHCHF) study: rationale, design, and endpoints of a 

prospective randomized multicenter study. Am J 

Cardiol 1999;83(5B):130D-5D. 

10. Baumann LS, Kadhiresan VA, YU Y, et al. 

Optimization of cardiac resynchronization therapy

in heart failure patients by measuring transient cycle

length changes. [abst]. Eur Heart J 2001;22:443. 

11. Berenbom LD, Weiford BC, Vacek JL, et al. 

Differences in outcomes between patients treated 

with single-versus dual-chamber implantable

cardioverter defibrillators: a substudy of the

Multicenter Automatic Defibrillator Implantation 

Trial II. Ann Noninvasive Electrocardiol

2005;10(4):429-35. 

12. Berger T, Hanser F, Hintringer F, et al. Effects of

cardiac resynchronization therapy on ventricular

repolarization in patients with congestive heart 

failure. J Cardiovasc Electrophysiol 

2005;16(6):611-7. 

13. Birnie D, Soucie LP, Smith S, Tang ASL. Effects of 

cardiac resynchronisation on maximal and

submaximal exercise performance in advanced

heart failure patients with conduction abnormality. 

Heart 2001;86:703-4. 

14. Bleeker GB, Bax JJ, Fung JW, et al. Clinical versus 

echocardiographic parameters to assess response to 

cardiac resynchronization therapy. Am J Cardiol 

2006 ;97(2):260-3. 

15. Bleeker GB, Kaandorp TA, Lamb HJ, et al. Effect 

of posterolateral scar tissue on clinical and

echocardiographic improvement after cardiac 

resynchronization therapy. Circulation

2006;113(7):969-76. 

16. Bleeker GB, Schalij MJ, Boersma E, Steendijk P,

Van Der Wall EE, Bax JJ. Does a gender difference 

in response to cardiac resynchronization therapy

exist? Pacing Clin Electrophysiol

2005;28(12):1271-5. 

17. Bocchiardo M , Achtelik M, Gaita F, et al. Efficacy

of biventricular sensing and treatment of ventricular 

arrhythmias. Pacing Clin Electrophysiol 2000;23(11 

Pt 2):1989-91. 

18. Bordachar P, Lafitte S, Reuter S, et al. Biventricular 

pacing and left ventricular pacing in heart failure:

similar hemodynamic improvement despite marked 

electromechanical differences. J Cardiovasc

Electrophysiol 2004;15(12):1342-7. 

19. Braunschweig F, Sorensen J, Von Bibra H, et al. 

Effects of biventricular pacing on myocardial blood 

flow and oxygen consumption using carbon-11 

acetate positron emission tomography in patients 

with heart failure. Am J Cardiol 2003;92(1):95-9. 

20. Breithardt OA, Stellbrink C, Herbots L, et al. 

Cardiac resynchronization therapy can reverse 

abnormal myocardial strain distribution in patients 

with heart failure and left bundle branch block. J 

Am Coll Cardiol 2003;42(3):486-94. 

21. Brignole M, Gammage M, Puggioni E, et al. 

Comparative assessment of right, left, and

biventricular pacing in patients with permanent 

atrial fibrillation. Eur Heart J 2005;26(7):712-22. 

22. Bulava A, Ansalone G, Ricci R, et al. Triple-site

pacing in patients with biventricular deviceincidence of the phenomenon and cardiac 

resynchronization benefit. J Interv Card 

Electrophysiol 2004;10(1):37-45. 

23. Butter C, Auricchio A, Stellbrink C, et al. Effect of

resynchronization therapy stimulation site on the

systolic function of heart failure patients. 

Circulation 2001;104(25):3026-9. 

24. Calvert MJ, Freemantle N, Cleland JG. The impact

of chronic heart failure on health-related quality of 

life data acquired in the baseline phase of the 

CARE-HF study. Eur J Heart Fail 2005;7(2):243-

51. 

25. Cappola TP, Harsch MR, Jessup M, et al. Predictors 

of remodeling in the CRT era: influence of mitral

regurgitation, BNP, and gender. J Cardiac Fail 

2006;12(3):182-8. 

D-5 
 

26. Cazeau S, Bordachar P, Jauvert G, et al. 

Echocardiographic modeling of cardiac 

dyssynchrony before and during multisite

stimulation: a prospective study. Pacing Clin 

Electrophysiol 2003;26(1 Pt 2):137-43. 

27. Cholewinski W, Tarkowska A, Kutarski A, 

Stefaniak B, Poniatowicz-Frasunek E, Oleszczak K. 

Effect of biventricular pacing on heart function 

evaluated by gated blood pool study in patients with 

end-stage heart failure. Nucl Med Rev 

2002;5(2):155-7. 

28. Cleland JG, Daubert JC, Erdmann E, et al. Baseline 

characteristics of patients recruited into the CAREHF study. Eur J Heart Fail 2005;7(2):205-14. 

29. Curnis A, Caprari F, Mascioli G, et al. Valutazione 

economica della resincronizzazione cardiaca nei 

pazienti affetti da scompenso cardiaco moderatoavanzato. [Biventricular resynchronization in heart 

failure: analysis of hospital costs and clinical

effectiveness]. (Ita). Pharmacoeconomics Italian

Research Articles 2003;5(1):11-22. 

30. De Cock CC, Jessurun ER, Allaart CA, Visser CA.

Repetitive intraoperative dislocation during

transvenous left ventricular lead implantation:

usefulness of the retained guidewire technique. 

Pacing Clin Electrophysiol 2004;27(12):1589-93. 

31. De Lurgio DB , Foster E, Higginbotham MB, 

Larntz K, Saxon LA. A comparison of cardiac 

resynchronization by sequential biventricular pacing 

and left ventricular pacing to simultaneous 

biventricular pacing: rationale and design of the 

DECREASE-HF clinical trial. J Cardiac Fail

2005;11(3):233-9. 

32. De Marco T, Foster E, Schafer J, et al. Effect of 

chronic cardiac resynchronization on left ventricular 

remodeling and neurohormonal activation [abst]. J 

Am Coll Cardiol 2001;37(2):118A-9A. 

33. Diaz-Infante E, Berruezo A, Mont L, et al. 

Predictores de ausencia de mejoria clinica a medio 

plazo con la terapia de resincronizacion cardiaca 

[Predictors of lack of clinical improvement at midterm follow-up with cardiac resynchronization

therapy]. (Spa). Rev Esp Cardiol 2004;57(4):306-

12. 

34. DiCarlo LA Jr, Morady F, Krol RB, et al. The

hemodynamic effects of ventricular pacing with and 

without atrioventricular synchrony in patients with 

normal and diminished left ventricular function. Am

Heart J 1987;114(4 Pt 1):746-52. 

35. Dohi K, Suffoletto MS, Schwartzman D, Ganz L, 

Pinsky MR, Gorcsan J 3rd. Utility of 

echocardiographic radial strain imaging to quantify

left ventricular dyssynchrony and predict acute

response to cardiac resynchronization therapy. Am 

J Cardiol 2005;96(1):112-6. 

36. Duncan A, Wait D, Gibson D, Daubert JC, 

MUSTIC (Multisite Stimulationin 

Cardiomyopathies) Trial. Left ventricular 

remodelling and haemodynamic effects of multisite

biventricular pacing in patients with left ventricular 

systolic dysfunction and activation disturbances in

sinus rhythm: sub-study of the MUSTIC (Multisite 

Stimulationin Cardiomyopathies) trial. Eur Heart J 

2003;24(5):430-41. 

37. Ferreira Santos J, Caetano F, Parreira L, et al. 

Ecocardiografia com doppler tecidcular para

avaliaca~o de doentes com terapeutica de

ressincronizaca~o ventricular [Tissue doppler

echocardiography for evaluation of patients with 

ventricular resynchronization therapy]. (Por). Rev 

Port Cardiol 2003;22(11):1363-71. 

38. Ferreira Santos J, Caetano F, Parreira L, et al. 

Efeitos da terapeutica de ressincronizaca~o 

ventricular na funca~o ventricular direitaavaliaca~o por ecocardiografia com doppler 

tecidular [Effects of cardiac resynchronization

therapy on right ventricular function: evaluation

with tissue doppler echocardiography]. (Por). Rev 

Port Cardiol 2003;22(11):1347-55. 

39. Ferro A, Duilio C, Santomauro M, Salvatore M, 

Cuocolo A. Haemodynamic effects of dual-chamber 

pacing versus ventricular pacing during a walk test 

in patients with depressed or normal left ventricular 

function. Eur J Nucl Med Mol Imaging 

2005;32(9):1075-80. 

40. Filzmaier K, Sinha AM, Breithardt OA, et al. Shortterm effects of cardiac resynchronization on brain

natriuretic peptide release in patients with systolic

heart failure and ventricular conduction disturbance 

[abst]. J Am Coll Cardiol 2002;39(5): 111A. 

41. Gasparini M, Auricchio A, Regoli F, et al. Fouryear efficacy of cardiac resynchronization therapy 

on exercise tolerance and disease progression: the 

importance of performing atrioventricular junction 

ablation in patients with atrial fibrillation.

2006;48(4):734-43. 

42. Gasparini M, Lunati M, Bocchiardo M, et al. 

Cardiac resynchronization and implantable 

cardioverter defibrillator therapy: preliminary 

results from the InSync Implantable Cardioverter

Defibrillator Italian Registry. Pacing Clin

Electrophysiol 2003;26(1 Pt 2):148-51. 

D-6 
 

43. Gasparini M, Mantica M, Galimberti P, et al. Is the 

left ventricular lateral wall the best lead

implantation site for cardiac resynchronization

therapy? Pacing Clin Electrophysiol 2003;26(1 Pt 

2):162-8. 

44. Gasparini M, Mantica M, Galimberti P, et al. Is the 

outcome of cardiac resynchronization therapy 

related to the underlying etiology? Pacing & Clin

Electrophysiol 2003;26(1 Pt 2):175-80. 

45. Gold MR, Auricchio A, Hummel JD, et al. 

Comparison of stimulation sites within left

ventricular veins on the acute hemodynamic effects 

of cardiac resynchronization therapy. Heart Rhythm

2005;2(4):376-81. 

46. Gorcsan J 3rd, Kanzaki H, Bazaz R, Dohi K,

Schwartzman D. Usefulness of echocardiographic 

tissue synchronization imaging to predict acute

response to cardiac resynchronization therapy. Am J 

Cardiol 2004;93(9):1178-81. 

47. Gras D, Mabo P, Tang T, et al. Multisite pacing as a 

supplemental treatment of congestive heart failure: 

preliminary results of the Medtronic Inc. InSync

Study. Pacing Clin Electrophysiol 1998;21(11 Pt 

2):2249-55. 

48. Greenberg JM , Baker CN, Mera FV et al. Cardiac 

resynchronization improves ventricular function and 

symptoms of congestive heart failure in the absence 

of any mechanical atrial contribution. [abst]. J Am

Coll Cardiol 2002;39(5):77A. 

49. Gurevitz O, Nof E, Carasso S, et al. Programmable 

multiple pacing configurations help to overcome

high left ventricular pacing thresholds and avoid

phrenic nerve stimulation. Pacing Clin

Electrophysiol 2005;28(12):1255-9. 

50. Hamdan MH, Barbera S, Kowal RC, et al. Effects 

of resynchronization therapy on sympathetic 

activity in patients with depressed ejection fraction 

and intraventricular conduction delay due to 

ischemic or idiopathic dilated cardiomyopathy. Am

J Cardiol 2002;89(9):1047-51. 

51. Hamdan MH, Zagrodzky JD, Joglar JA, et al. 

Biventricular pacing decreases sympathetic activity 

compared with right ventricular pacing in patients

with depressed ejection fraction. Circulation

2000;102(9):1027-32. 

52. Hansen C, Sperzel J, Neumann T, Pitschner HF, 

Neuzner J. Akute hamodynamische Effekte einer

biventrikularen und linksventrikularen Stimulation 

bei Patienten mit fortgeschrittener Herzinsuffizienz

unter einer chronischen Herzschrittmachertherapie 

[Acute hemodynamic effects of biventricular and 

left ventricular pacing in chronic pacemakerdependent patients with advanced heart failure].

(Ger). Z Kardiol 2003;92(10):862-8. 

53. Hay I, Melenovsky V, Fetics BJ, et al. Short-term 

effects of right-left heart sequential cardiac

resynchronization in patients with heart failure,

chronic atrial fibrillation, and atrioventricular nodal 

block. Circulation 2004;110(22):3404-10. 

54. Heist EK, Fan D, Mela T, et al. Radiographic left

ventricular-right ventricular interlead distance

predicts the acute hemodynamic response to cardiac 

resynchronization therapy. Am J Cardiol 

2005;96(5):685-90. 

55. Heist EK, Taub C, Fan D, et al. Usefulness of a

novel "response score" to predict hemodynamic and 

clinical outcome from cardiac resynchronization

therapy. Am J Cardiol 2006;97( 12):1732-6. 

56. Higgins SL, Yong P, Sheck D, et al. Biventricular

pacing diminishes the need for implantable 

cardioverter defibrillator therapy. Ventak CHF 

Investigators. J Am Coll Cardiol 2000;36(3):824-7. 

57. Kanzaki H, Bazaz R, Schwartzman D, Dohi K, Sade 

LE, Gorcsan J 3rd. A mechanism for immediate 

reduction in mitral regurgitation after cardiac 

resynchronization therapy: insights from 

mechanical activation strain mapping. J Am Coll

Cardiol 2004;44(8):1619-25. 

58. Kanzaki H, Jacques D, Sade LE, Severyn DA,

Schwartzman D, Gorcsan J 3rd. Regional 

correlation by color-coded tissue Doppler to

quantify improvements in mechanical left 

ventricular synchrony after biventricular pacing 

therapy. Am J Cardiol 2003;92(6):752-5. 

59. Kerwin WF, Botvinick EH, O'Connell JW, et al.

Ventricular contraction abnormalities in dilated

cardiomyopathy: effect of biventricular pacing to

correct interventicular dyssynchrony. J Am Coll

Cardiol 2000;35(5):1221-7. 

60. Kitamura S, Satomi K, Kurita T, et al. Long-term 

follow-up of transvenous defibrillation leads–high

incidence of fracture in coaxial polyurethane lead. 

Circ J 2006;70(3):273-7. 

61. Knaapen P, van Campen LM, de Cock CC, et al.

Effects of cardiac resynchronization therapy on 

myocardial perfusion reserve. Circulation 

2004;110(6):646-51. 

D-7 
 

62. Knuuti J, Sundell J, Naum A, et al. Assessment of

right ventricular oxidative metabolism by PET in 

patients with idiopathic dilated cardiomyopathy

undergoing cardiac resynchronization therapy. Eur J 

Nucl Med Mol Imaging 2004;31(12):1592-8. 

63. Kowal RC, Wasmund SL, Smith ML, et al. 

Biventricular pacing reduces the induction of 

monomorphic ventricular tachycardia: a potential 

mechanism for arrhythmia suppression. Heart 

Rhythm 2004;1(3):295-300. 

64. Kurzidim K, Reinke H, Sperzel J, et al. Invasive 

optimization of cardiac resynchronization therapy:

role of sequential biventricular and left ventricular 

pacing. Pacing Clin Electrophysiol 2005;28(8):754-

61. 

65. Lancellotti P, Melon P, Sakalihasan N, et al. Effect 

of cardiac resynchronization therapy on functional 

mitral regurgitation in heart failure. Am J Cardiol

2004;94(11):1462-5. 

66. Leclercq C, Cazeau S, Ritter P, et al. A pilot

experience with permanent biventricular pacing to 

treat advanced heart failure. Am Heart J

2000;140(6):862-70. 

67. Leclercq C, Gras D, Tang A, et al. Comparative

effects of ventricular resynchronization therapy in

heart failure patients with or without coronary

artery disease. Ann Cardiol Angeiol 

2004;53(4):171-6. 

68. Lehmann A, Lang J, Thaler E, Zeitler C, Weisse U, 

Boldt J. Considerations in patients undergoing 

implantation of a biventricular pacemaker. J

Cardiothorac Vasc Anesth 2002;16(2):175-9. 

69. Linde C, Braunschweig F, Gadler F, Bailleul C, 

Daubert JC. Long-term improvements in quality of 

life by biventricular pacing in patients with chronic 

heart failure: results from the MUltisite STimulation 

In Cardiomyopathy study (MUSTIC). Am J Cardiol 

2003;91(9):1090-5. 

70. Linde C, Leclercq C, Rex S, et al. Long-term 

benefits of biventricular pacing in congestive heart 

failure: results from the MUltisite STimulation In

Cardiomyopathy (MUSTIC) study. J Am Coll 

Cardiol 2002;40(1):111-8. 

71. Lozano I, Bocchiardo M, Achtelik M, et al. Impact 

of biventricular pacing on mortality in a randomized 

crossover study of patients with heart failure and

ventricular arrhythmias. Pacing Clin Electrophysiol 

2000;23(11 Pt 2):1711-2. 

72. Lunati M, Paolucci M, Oliva F, et al. Patient

selection for biventricular pacing. J Cardiovasc 

Electrophysiol 2002;13(1 Suppl):S63-7. 

73. Macias A, Gavira JJ, Alegria E, Azcarate PM, 

Barba J, Garcia-Bolao I. Efecto de la localizaci_on 

del electrodo ventricular izquierdo sobre los

parametros ecocardiograficos de asincronia en 

pacientes sometidos a terapia de resincronizaci_on 

cardiaca [Effect of the left ventricular pacing site on 

echocardiographic parameters of ventricular

dyssynchrony in patients receiving cardiac

resynchronization therapy]. (Spa). Rev Esp Cardiol 

2004;57(2):138-45. 

74. Mair H, Jansens JL, Lattouf OM, Reichart B,

Dabritz S. Epicardial lead implantation techniques 

for biventricular pacing via left lateral minithoracotomy, video-assisted thoracoscopy, and

robotic approach. Heart Surg Forum 2003;6(5):412-

7. 

75. Mansourati J , Etienne Y, Gilard M, et al. Left 

ventricular-based pacing in patients with chronic 

heart failure: comparison of acute hemodynamic 

benefits according to underlying heart disease. Eur J

Heart Fail 2000;2(2):195-9. 

76. Marcus GM, Rose E, Viloria EM, et al. Septal to 

posterior wall motion delay fails to predict reverse 

remodeling or clinical improvement in patients 

undergoing cardiac resynchronization therapy. J Am 

Coll Cardiol 2005;46(12):2208-14. 

77. Meluzin J, Novak M, Mullerova J, et al. A fast and 

simple echocardiographic method of determination 

of the optimal atrioventricular delay in patients after 

biventricular stimulation. Pacing Clin

Electrophysiol 2004;27(1):58-64. 

78. Najem B, Preumont N, Unger P, et al. Sympathetic 

nerve activity after thoracoscopic cardiac

resynchronization therapy in congestive heart 

failure. J Cardiac Fail 2005;11(7):529-33. 

79. Nelson GS, Berger RD, Fetics BJ, et al. Left

ventricular or biventricular pacing improves cardiac 

function at diminished energy cost in patients with

dilated cardiomyopathy and left bundle-branch 

block. Circulation 2000;102(25):3053-9. Erratum

in: Circulation 2001;103(3):476 

80. Neri G, Zanco P, Bertaglia E, Zerbo F, Zanon F, 

Buchberger R. Myocardial perfusion and metabolic 

changes induced by conventional right and

biventricular pacing in dilated cardiomyopathy

evaluated by positron emission tomography. Ital 

Heart J 2002;3(11):637-42. 

81. Neri G, Zanco P, Zanon F, Buchberger R. Effect of

biventricular pacing on metabolism and perfusion in 

patients affected by dilated cardiomyopathy and left 

bundle branch block: evaluation by positron 

emission tomography. Europace 2003;5(1):111-5. 

D-8 
 

82. Nowak B, Sinha AM, Schaefer WM, et al. Cardiac 

resynchronization therapy homogenizes myocardial 

glucose metabolism and perfusion in dilated

cardiomyopathy and left bundle branch block. J Am

Coll Cardiol 2003;41(9):1523-8. 

83. Nowak B, Stellbrink C, Sinha AM, et al. Effects of 

cardiac resynchronization therapy on myocardial

blood flow measured by oxygen-15 water positron

emission tomography in idiopathic-dilated

cardiomyopathy and left bundle branch block. Am J 

Cardiol 2004;93(4):496-9. 

84. Olshansky B, Day J, McGuire M, Hahn S, Brown S, 

Lerew DR. Reduction of right ventricular pacing in 

patients with dual-chamber ICDs. Pacing Clin 

Electrophysiol 2006;29(3):237-43. 

85. Padeletti L, Musilli N, Porciani MC, et al. Atrial

fibrillation and cardiac resynchronization therapy:

the MASCOT study. Europace 2004;5 Suppl 1:S49-

54. 

86. Padelitti L, Porciani MC, Colella A, et a1. Cardiac

resynchronization reverses left ventricular 

remodeling and reduces cytokine activation in 

patients with dilated cardiomyopathy and left

bundle branch block [abst]. J Am Coll Cardiol 

2002;39(5): 78A. 

87. Pappone C, Rosanio S, Oreto G, et al. Cardiac 

pacing in heart failure patients with left bundle 

branch block: impact of pacing site for optimizing

left ventricular resynchronization. Ital Heart J 

2000;1(7):464-9. 

88. Pitzalis MV, Iacoviello M, Romito R, et al. Cardiac 

resynchronization therapy tailored by

echocardiographic evaluation of ventricular

asynchrony. J Am Coll Cardiol 2002;40(9):1615-

22. 

89. Popovic ZB, Grimm RA, Perlic G, et al. 

Noninvasive assessment of cardiac 

resynchronization therapy for congestive heart 

failure using myocardial strain and left ventricular 

peak power as parameters of myocardial synchrony

and function. J Cardiovasc Electrophysiol 

2002;13(12):1203-8. 

90. Porciani MC, Puglisi A, Colella A, et al.

Echocardiographic evaluation of the effect of

biventricular pacing: The InSync Italian Registry. 

Eur Heart J Suppl 2000;2(J):J23-J30. 

91. Porciani MC, Sabini A, Colella A, et al. Interatrial 

septum pacing avoids the adverse effect of

interatrial delay in biventricular pacing: an echoDoppler evaluation. Europace 2002;4(3):317-24. 

92. Proclemer A, Ghidina M, Cicuttini G, Gregori D, 

Fioretti PM. The Italian Implantable CardioverterDefibrillator Registry. A survey of the national 

activity during the years 2001-2003. Ital Heart J 

2005;6(3):272-80. 

93. Reynolds MR, Joventino LP, Josephson ME, 

Miracle ICD Investigators. Relationship of baseline 

electrocardiographic characteristics with the

response to cardiac resynchronization therapy for

heart failure. Pacing Clin Electrophysiol

2004;27(11):1513-8. 

94. Ricci R, Ansalone G, Toscano S, et al. Cardiac 

resynchronization: materials, technique and results. 

The InSync Italian Registry. Eur Heart J Suppl 

2000;2(J):J6-J15. 

95. Riedlbauchova L, Fridl P, Kautzner J, Peichl P. 

Performance of left ventricular versus biventricular 

pacing in chronic heart failure assessed by stress 

echocardiography. Pacing Clin Electrophysiol 

2004;27(5):626-31. 

96. Riedlbauchova L, Kautzner J, Fridl P. Influence of 

different atrioventricular and interventricular delays

on cardiac output during cardiac resynchronization 

therapy. Pacing Clin Electrophysiol 2005;28 Suppl 

1:S19-23. 

97. Saxon LA, De Marco T, Schafer J, et al. Effects of 

long-term biventricular stimulation for 

resynchronization on echocardiographic measures 

of remodeling. Circulation 2002;105( 11):1304-10. 

98. Scharf C, Li P, Muntwyler J, et al. Rate-dependent 

AV delay optimization in cardiac resynchronization 

therapy. Pacing Clin Electrophysiol 

2005;28(4):279-84. 

99. Senatore G, Carreras G, Taglieri C, et al. Role of

biventricular pacing in congestive heart failure: 

randomized study: EUROPACE 

2001;2SupplA:A56. Thomsen PEBW.B.Saunders, 

2001: 551-4. 

100. Skobel EC, Sinha AM, Norra C, et al. Effect of

cardiac resynchronization therapy on sleep quality, 

quality of life, and symptomatic depression in

patients with chronic heart failure and CheyneStokes respiration. Sleep Breath 2005;9(4):159-66. 

 101. Sogaard P, Egeblad H, Pedersen AK, et al. 

Sequential versus simultaneous biventricular 

resynchronization for severe heart failure: 

evaluation by tissue Doppler imaging. Circulation

2002;106(16):2078-84. 

D-9 
 

102. Sogaard P, Kim WY, Jensen HK, et al. Impact of 

acute biventricular pacing on left ventricular

performance and volumes in patients with severe

heart failure. A tissue Doppler and threedimensional echocardiographic study. Cardiology

2001;95(4):173-82. 

 103. Sperzel J, Schwarz T, Neumann T, et al. 

Biventrikulare stimulation: zentrumserf ahrung 

ahrung mit transvenosen und epimyokardialen

linksventrikularen elektrodensystemen 

[Biventricular stimulation: a center experience with 

transvenous and epimyocordial left ventricular

electrode systems]. (Ger). Herzschrittmacherther

Elektrophysiol 2002;13(suppl 1):73-4. 

 104. St John Sutton MG, Plappert T, Abraham WT, et al. 

Effect of cardiac resynchronization therapy on left

ventricular size and function in chronic heart 

failure. Circulation 2003;107(15):1985-90. 

 105. Stellbrink C, Auricchio A, Butter C, et al. Pacing

therapies in congestive heart failure II study. Am J 

Cardiol 2000;86(9A):138K-43K. 

 106. Stellbrink C, Auricchio A, Diem B, et al. Potential 

benefit of biventricular pacing in patients with

congestive heart failure and ventricular 

tachyarrhythmia. Am J Cardiol 1999;83(5 B):143D50D. 

107. Strohmer B, Mermi J, Castellanos E, et al. Impact 

of dual chamber pacing on the incidence of atrial 

and ventricular tachyarrhythmias in recipients of 

implantable cardioverter defibrillators. Pacing Clin 

Electrophysiol 2005;28 Suppl 1:S249-54. 

108. Sukhija R, Aronow WS, Sorbera C, et al. Left

ventricular ejection fraction and prevalence of new 

left ventricular wall motion abnormality at longterm follow-up in patients with automatic

implantable cardioverter-defibrillators treated with

dual-chamber rate-responsive pacing at a rate of 

70/minute versus backup ventricular pacing at a rate 

of 40/minute. Am J Cardiol 2005;96(3):412-3. 

109. Sun JP, Chinchoy E, Donal E, et al. Evaluation of

ventricular synchrony using novel Doppler 

echocardiographic indices in patients with heart 

failure receiving cardiac resynchronization therapy.

J Am Soc Echocardiogr 2004;17(8):845-50 . 

110. Sundell J, Engblom E, Koistinen J, et al. The effects 

of cardiac resynchronization therapy on left

ventricular function, myocardial energetics, and

metabolic reserve in patients with dilated

cardiomyopathy and heart failure. J Am Coll 

Cardiol 2004;43(6):1027-33. 

111. Sutton MG, Plappert T, Hilpisch KE, Abraham WT, 

Hayes DL, Chinchoy E. Sustained reverse left 

ventricular structural remodeling with cardiac 

resynchronization at one year is a function of

etiology: quantitative Doppler echocardiographic 

evidence from the Multicenter InSync Randomized 

Clinical Evaluation (MIRACLE). Circulation 

2006;113(2):266-72. 

112. Taieb J, Barnay C, Benchaa T, et al. 

Resynchronisation cardiaque dans l'insuffisance 

cardiaque: interet de l'echodoppler pour la selection 

des patients et l'evaluation de la stimulation

[Cardiac resynchronisation in congestive heart 

failure: role of Doppler echocardiography in patient 

selection]. (Fre). Ann Cardiol Angeiol

2003;52(6):353-7. 

113. Thibault B, Roy D, Guerra PG, et al. Anodal right 

ventricular capture during left ventricular 

stimulation in CRT-implantable cardioverter 

defibrillators. Pacing & Clin Electrophysiol 

2005;28(7):613-9. 

 114. Toussaint JF, Lavergne T, Ollitraut J, et al. 

Biventricular pacing in severe heart failure patients 

reverses electromechanical dyssynchronization

from apex to base. Pacing Clin Electrophysiol 

2000;23(11 Pt 2):1731-4. 

 115. Tse HF, Lee KL, Wan SH, et al. Area of left

ventricular regional conduction delay and preserved 

myocardium predict responses to cardiac 

resynchronization therapy. J Cardiovasc 

Electrophysiol 2005;16(7):690-5. 

116. Tsurugaya H, Tada H, Toyama T, et al. Usefulness

of quantitative gated single-photon emission 

computed tomography to evaluate ventricular

synchrony in patients receiving biventricular 

pacing. Am J Cardiol 2004;94(1):127-30. 

 117. Ukkonen H, Beanlands RS, Burwash IG, et al. 

Effect of cardiac resynchronization on myocardial 

efficiency and regional oxidative metabolism.

Circulation 2003;107(1):28-31. 

118. Van Gelder BM, Bracke FA, Meijer A, Lakerveld

LJM, Pijls NHJ. Effect of optimizing the VV 

interval on left ventricular contractility in cardiac

resynchronization therapy. Am J Cardiol 

2004;93(12):1500-3. 

 119. Varma C, O'Callaghan P, Mahon NG, et al. Effect 

of multisite pacing on ventricular coordination.

Heart 2002;87(4):322-8. 

D-10 
 

 120. Varma C, O'Callaghan P, Rowland E, et al. 

Comparison between biventricular pacing and

single site pacing in patients with poor ventricular 

function: a hemodynamic study. Pacing Clin 

Electrophysiol 2003;26(2 Pt 1):551-8. 

121. Varma C, Sharma S, Firoozi S, McKenna WJ, 

Daubert JC, MUltisite STimulation In 

Cardiomyopathy (MUSTIC) Study Group. 

Atriobiventricular pacing improves exercise 

capacity in patients with heart failure and 

intraventricular conduction delay. J Am Coll 

Cardiol 2003;41(4):582-8. 

122. Vinereanu D, Bleasdale R, Turner M, Frenneaux

MP, Fraser AG. Comparison of left ventricularbiventricular pacing on ventricular synchrony,

mitral regurgitation, and global left ventricular

function in patients with severe chronic heart 

failure. Am J Cardiol 2004;94(4):519-21. 

 123. Vollmann D, Erdogan A, Himmrich E, et al. Patient 

AlertTM to detect ICD lead failure: efficacy,

limitations, and implications for future algorithms. 

Europace 2006;8(5):371-6. 

124. Vural A, Agacdiken A, Ural D, et al. Effect of 

cardiac resynchronization therapy on left atrial

appendage function and pulmonary venous flow 

pattern. Int J Cardiol 2005;102(1):103-9. 

 125. Waggoner AD , Faddis MN, Gleva MJ, et al. 

Cardiac resynchronization therapy acutely improves

diastolic function. J Am Soc Echocardiog

2005;18(3):216-20. 

126. Walker S, Levy TM, Rex S, et al. Usefulness of 

suppression of ventricular arrhythmia by

biventricular pacing in severe congestive cardiac 

failure. Am J Cardiol 2000;86(2):231-3. 

 127. Woo GW, Petersen-Stejskal S, Johnson JW, Conti 

JB, Aranda JA Jr, Curtis AB. Ventricular reverse

remodeling and 6-month outcomes in patients 

receiving cardiac resynchronization therapy:

analysis of the MIRACLE study. J Interv Card 

Electrophysiol 2005;12(2):107-13. 

128. Yu CM, Fung JW, Zhang Q, et al. Improvement of 

serum NT-ProBNP predicts improvement in cardiac

function and favorable prognosis after cardiac 

resynchronization therapy for heart failure. 

2005;11(5 Suppl):42-6. 

129. Yu CM, Fung JW, Zhang Q, et al. Tissue Doppler 

imaging is superior to strain rate imaging and

postsystolic shortening on the prediction of reverse 

remodeling in both ischemic and nonischemic heart 

failure after cardiac resynchronization therapy.

Circulation 2004;110(1):66-73 . 

130. Yu CM, Lin H, Fung WH, Zhang Q, Kong SL, 

Sanderson JE. Comparison of acute changes in left 

ventricular volume, systolic and diastolic functions, 

and intraventricular synchronicity after biventricular 

and right ventricular pacing for heart failure. Am 

Heart J 2003;145(5):E18. 

131. Yu CM, Zhang Q, Fung JW, et al. A novel tool to

assess systolic asynchrony and identify responders 

of cardiac resynchronization therapy by tissue 

synchronization imaging. J Am Coll Cardiol

2005;45(5):677-84. 

 132. Zanon F, Aggio S, Baracca E, et al. Reduced mitral 

regurgitation in heart failure patients submitted to

cardiac resynchronization therapy: a short-term

prospective study. Ital Heart J 2004;5(11):826-30. 

133. Zardini M, Tritto M, Bargiggia G, et al. The InSync 

Italian registry: analysis of clinical outcome and 

considerations on the selection of candidates to left 

ventricular resynchronization. Eur Heart J Suppl 

2000;2(J):J16-J22. 

134. Zhang Q, Yu CM, Fung JW, et al. Assessment of 

the effect of cardiac resynchronization therapy on

intraventricular mechanical synchronicity by

regional volumetric changes. Am J Cardiol 2005;95

(1):126-9. 

Study Design

1. Anonymous. Long term benefits of pacemaker-like 

device for heart failure patients. Can J Cardiol

2000;16(4):539-9. 

2. Ansalone G, Giannantoni P, Ricci R, et al. Doppler 

myocardial imaging in patients with heart failure

receiving biventricular pacing treatment. Am Heart 

J 2001;142(5):881-96. 

3. Auricchio A, Klein HU. Beyond expectations: a 

decade of positive results with cardiac 

resynchronization therapy on ventricular 

remodeling. Eur Heart J Supp 2002;8(2):D95-D101. 

4. Auricchio A, Stellbrink C, Block M, Mortensen P. 

Clinical and objective improvements in severe

congestive heart failure patients using 

univentricular or biventricular pacing: preliminary 

results of a randomized prospective study. J Am 

Coll Cardiol 1998;31(2):31A. 

D-11 
 

5. Barbieri A, Bursi F, Bonatti S, et al. Evidence of

reverse remodeling after long-term biventricular 

stimulation for resynchronization in patients with

wide QRS selected on the basis of

echocardiographic electromechanical delays. Ital 

Heart J 2004;5(11):818-25. 

6. Barold SS, Ovsyshcher IE. Pacemaker-induced

mitral regurgitation. Pacing Clin Electrophysiol

2005;28(5):357-60. 

7. Belardinelli R, Capestro F, Misiani A, Scipione P,

Georgiou D. Moderate exercise training improves 

functional capacity, quality of life, and 

endothelium-dependent vasodilation in chronic 

heart failure patients with implantable cardioverter

defibrillators and cardiac resynchronization therapy.

Eur J Cardiovasc Prev Rehabil 2006;13(5):818-25. 

8. Blanc JJ, Fatemi M. A new cause of pacemakermediated tachycardia in patients implanted with a

biventricular device. Pacing Clin Electrophysiol 

2001;24(12):1711-2. 

9. Bradley DJ, Bradley EA, Baughman KL, et al. 

Cardiac resynchronization and death from 

progressive heart failure: a meta-analysis of

randomized controlled trials. JAMA 

2003;289(6):730-40. 

10. Braunschweig F, Gadler F, Linde C, Kjellstrom B, 

Ryden L. Biventrikular pacing ny

behandlingsmetod vid hjartsvikt. Alternativ for

patienter med intraventrikulara 

retledningsrubbningar [Biventricular pacing as a 

new therapeutic method in heart failure. An 

alternative for patients with intraventricular

conduction disorders]. (Swe). Lakartidningen 

4455;97(40):4450-2. 

11. Braunschweig F, Linde C, Gadler F, Ryden L. 

Reduction of hospital days by biventricular pacing. 

Eur J Heart Fail 2000;2(4):399-406. 

12. Breithardt G , Kuhn H, Hammel D, et al. Cardiac 

resynchronization therapy into the next decade:

from the past to morbidity/mortality trials. Eur

Heart J Supp 2002;4(D):D102-D110. 

13. Brophy J, Costa V. The use of biventricular

pacemakers at the McGill University Health Centre: 

a technology assessment: A Report by the 

Technology Assessment Unit (TAU) of the McGill 

University Health Centre (MUHC) [database on 

internet]. [cited 2006 Dec7]. Available from: 

http://www.mcgill.ca/files/tau/biventricular_pacema

ker_final_report1.pdf. 

14. Bulava A, Lukl J. Postmortem anatomy of the 

coronary sinus pacing lead. Pacing Clin

Electrophysiol 2005;28(7):736-9. 

 15. Castellanos A, Aranda JM. Simultaneous 

biventricular stimulation for ventricular 

arrhythmias. Am J Cardiol 2001;88(10):1217-8. 

16. Cazeau S, Gras D, Lazarus A, et al. Multisite 

stimulation for correction of cardiac asynchrony. 

Heart 2000;84(6):579-81. 

17. Cazeau S, Ritter P, Lazarus A, et al. Multisite

pacing for end-stage heart failure: early experience. 

Pacing Clin Electrophysiol 1996;19(11 Pt 2):1748-

57. 

18. Cazeau S, Ritter P, Lazarus A, et al. Premiere

experience de traitement de l'insuffisance cardiaque 

terminale par la stimulation multisite [First 

experience in treatment of terminal cardiac

insufficiency using multisite stimulation]. (Fre).

Bull Acad Natl Med 1996;180(9):2065-75; 

discussion 2075-8. 

19. Cleland JG, Daubert JC, Erdmann E, et al. The 

CARE-HF study (CArdiac REsynchronisation in

Heart Failure study): rationale, design and endpoints. Eur J Heart Fail 2001;3(4):481-9. 

20. Conaway DG, Sullivan R, McCullough PA. 

Improved symptoms, physical limitation, and selfefficacy after resynchronization in a patient with

heart failure and a prolonged QRS duration. Rev 

Cardiovasc Med 2004;5(1):53-7.

21. Cowburn PJ, Patel H, Jolliffe RE, Wald RW, Parker 

JD. Cardiac resynchronization therapy: an option

for inotrope-supported patients with end-stage heart 

failure? Eur J Heart Fail 2005;7(2):215-7. 

22. Cuzin B, Kirkorian G, MaisonneuveH. Cardiac 

pacemakers: when clinical evluation lags behind 

technological process. Int J Technol Assess Health 

Care 2000;16(3):910-23. 

23. De Cock CC, Van Campen LM, Jessurun ER, 

Allaart CA, Vos DS, Visser CA. Long-term followup of patients with refractory heart failure and

myocardial ischemia treated with cardiac

resynchronization therapy. Pacing Clin

Electrophysiol 2005;28 Suppl 1:S8-S10. 

24. De Maria E, Gallo P, Damiano M, et al. Predictive 

parameters of left ventricular reverse remodeling in 

response to cardiac resynchronization therapy in

patients with severe congestive heart failure. Ital 

Heart J 2005;6(9):734-9. 

25. De Sutter J, De Bondt P, Van de Wiele C, et al. 

Prevalence of potential candidates for biventricular 

pacing among patients with known coronary artery

disease: a prospective registry from a single center. 

Pacing Clin Electrophysiol 2000;23(11 Pt 2):1718-

21. 

D-12 
 

26. DeLacey WA, Dow MT. Upgrade of a chronic 

unipolar pacemaker to a biventricular pacemaker 

system. Pacing Clin Electrophysiol 

2003;26(12):2324-5. 

27. Di Cori A, Bongiorni MG, Arena G, et al. Newonset ventricular tachycardia after cardiac

resynchronization therapy. J Interv Card 

Electrophysiol 2005;12(3):231-5. 

28. Dohi K, Suffoletto M, Ganz L, Zenati M, Gorcsan J 

3rd. Utility of echocardiographic tissue 

synchronization imaging to redirect left ventricular 

lead placement for improved cardiac

resynchronization therapy. Pacing Clin

Electrophysiol 2005;28(5):461-5. 

29. Egoavil CA, Ho RT, Greenspon AJ, Pavri BB. 

Cardiac resynchronization therapy in patients with

right bundle branch block: analysis of pooled data 

from the MIRACLE and Contak CD trials. Heart

Rhythm 2005;2(6):611-5. 

30. Ellery SM, Paul VE. Complications of biventricular 

pacing. Eur Heart J Suppl 2004;6(D):D117-D121. 

31. Erol MK, Sevimli S, Ates A. Pericardial tamponade 

caused by transvenous temporary endocardial 

pacing. Heart 2005;91(4):459. 

32. Faerestrand S, Schuster P, Ohm OJ. Biventrikulaer 

pacemakerbehandling av pasienter med alvorlig

hjertesvikt [Biventricular pacemaker treatment of

patients with severe heart failure]. (Nor). Tidss Nor 

Laegeforen 2001;121(8):925-30. 

33. Filho MM, Pedrosa AA, Costa R, et al. 

Biventricular pacing improves clinical behavior and 

reduces prevalence of ventricular arrhythmia in 

patients with heart failure. Arq Bras Cardiol 

2002;78(1):110-3. 

34. Franzen D. Langzeitverlauf nach biventrikulärer 

Herzschrittmachertherapie bei Herzinsuffizienz 

[Long-term follow up of biventricular pacing in 

heart failure–a case report]. (Ger). Med Welt 

2004;55(3):45-8. 

35. Gabor JY, Newman DA, Barnard-Roberts V, et al. 

Improvement in Cheyne-Stokes respiration 

following cardiac resynchronisation therapy. Eur

Respir J 2005;26(1):95-100. 

36. Garcia-Bolao I, Macias A, Alegria E, et al.

Tratamiento de la insuficiencia cardiaca avanzada 

mediante estimulacion biventricular. Experiencia 

inical en una serie de 22 casos consecutivos

[Biventricular pacing as a treatment for advanced

heart failure. Preliminary experience in a series of

22 consecutive patients]. (Spa). Rev Esp Cardiol 

2003;56(3):245-52. 

37. Garrigue S, Bordachar P, Reuter S, Jais P, 

Haissaguerre M, Clementy J. Comparison of 

permanent left ventricular and biventricular pacing

in patients with heart failure and chronic atrial

fibrillation: a prospective hemodynamic study.

[Review] [46 refs]. Cardiac Electrophysiol Rev

2003;7(4):315-24. 

38. Garrigue S, Bordachar P, Reuter S, et al. 

Comparison of permanent left ventricular and 

biventricular pacing in patients with heart failure

and chronic atrial fibrillation: prospective 

haemodynamic study. Heart 2002;87(6):529-34. 

39. Garrigue S, Jais P, Espil G, et al. Comparison of 

chronic biventricular pacing between epicardial and 

endocardial left ventricular stimulation using 

Doppler tissue imaging in patients with heart 

failure. Am J Cardiol 2001;88(8):858-62. 

40. Garrigue S, Reuter S, Labeque JN, et al. Usefulness 

of biventricular pacing in patients with congestive 

heart failure and right bundle branch block. Am J 

Cardiol 2001;88(12):1436-41. 

41. Gasparini M, Galimberti P, Simonini S, et al. 

Cardiac resynchronization therapy in patients with

narrow QRS [5] (multiple letters). J Am Coll

Cardiol 2004;44(10):2096-7. 

42. Gasparini M, Mantica M, Galimberti P, et al. Relief 

of drug refractory angina by biventricular pacing in 

heart failure. Pacing Clin Electrophysiol 2003;26(1 

Pt 2):181-4. 

43. Gerber TC, Nishimura RA, Holmes DR Jr, et al. 

Left ventricular and biventricular pacing in 

congestive heart failure. Mayo Clin Proc 

2001;76(8):803-12. 

44. Ghosh J, Freemantle N, Cleland J, Salukhe TV, 

Francis DP. Meta-analysis does not show that 

cardiac resynchronisation reduces all-cause 

mortality [3] (multiple letters). Int J Cardiol

2005;103(2):230-3. 

45. Gras D, Ruffy R, Cebron JP, Brunel P, Leurent B, 

Banus Y. Treatment of refractory congestive heart 

failure by cardiac resynchronization. Minerva 

Cardioangiol 2003;51(2):185-95. 

46. Grassi G, Vincenti A, Brambilla R, et al. Sustained 

sympathoinhibitory effects of cardiac 

resynchronization therapy in severe heart failure. 

Hypertension 2004;44(5):727-31. 

47. Greenberg JM , Mera F, Smith AL, DeLurgio DB, 

Langberg JJ, Leon AR. Biventricular pacing in CHF 

and chronic atrial fibrillation. Cardiol Rev 

2003;20(7):30-4. 

D-13 
 

48. Guerra JM, Wu J, Miller JM, Groh WJ. Increase in 

ventricular tachycardia frequency after biventricular 

implantable cardioverter defibrillator upgrade. J 

Cardiovasc Electrophysiol 2003;14(11):1245-7. 

49. Gururaj AV. Cardiac resynchronization therapy:

effects on exercise capacity in the patient with 

chronic heart failure. J Cardiopulm Rehabil 

2004;24(1):1-7. 

50. Heinzel F, Sack S, Wolfhardt U, Dagres N, Herold 

U, Erbel R. Erfahrungen mit einer neuen

transvenosen Sonde zur linksventrikularen 

Stimulation[Experiences with a new transvenous

electrode for left ventricular stimulation]. (Ger). 

Herz 2001;26(1):79-83. 

51. Hoijer CJ, Meurling C, Brandt J. Upgrade to

biventricular pacing in patients with conventional 

pacemakers and heart failure: a double-blind,

randomized crossover study. Europace 

2006;8(1):51-5 . 

52. Hoppe UC, Erdmann E. Cardiac resynchronization 

in heart failure. Dtsch Med Wochenschr 

2002;127(13):667-81. 

53. Horwich T, Foster E, De Marco T, Tseng Z, Saxon 

L. Effects of resynchronization therapy on cardiac 

function in pacemaker patients "upgraded" to 

biventricular devices. J Cardiovasc Electrophysiol 

2004;15(11):1284-9. 

54. Hummel JP, Lindner JR, Belcik JT, et al. Extent of 

myocardial viability predicts response to 

biventricular pacing in ischemic cardiomyopathy.

Heart Rhythm 2005;2(11):1211-7. 

55. Inoue N, Ishikawa T, Sumita S, et al. Long-term 

follow-up of atrioventricular delay optimization in

patients with biventricular pacing. Circ J

2005;69(2):201-4. 

56. Issa ZF, Jaradat Z, Bhakta D, Miller JM.

Appropriate or inappropriate ICD therapy? Heart 

Rhythm 2005;2(10):1150-2. 

57. Jais P, Douard H, Shah DC, Barold S, Barat JL, 

Clementy J. Endocardial biventricular pacing.

Pacing Clin Electrophysiol 1998;21(11 Pt 1):2128-

31. 

58. Jansens JL, Jottrand M, Preumont N, Stoupel E, de

Canniere D. Robotic-enhanced biventricular

resynchronization: an alternative to endovenous 

cardiac resynchronization therapy in chronic heart 

failure. Ann Thorac Surg 2003;76(2):413-7; 

discussion 417. 

59. Jarcho JA. Resynchronizing ventricular contraction 

in heart failure. N Engl J Med 2005;352(15):1594-

7. 

60. Kanhai SM, Viergever EP, Bax JJ. Cardiogenic 

shock shortly after initial success of cardiac

resynchronization therapy. Eur J Heart Fail

2004;6(4):477-81. 

61. Kies P, Bax JJ, Molhoek SG, et al. Effect of left

ventricular remodeling after cardiac

resynchronization therapy on frequency of

ventricular arrhythmias. Am J Cardiol 

2004;94(1):130-2. 

62. Kies P, Bax JJ, Molhoek SG, et al. Effect of cardiac

resynchronization therapy on inducibility of 

ventricular tachyarrhythmias in cardiac arrest

survivors with either ischemic or idiopathic dilated 

cardiomyopathy. Am J Cardiol 2005 ;95(9):1111-4. 

63. Kikuchi F, Miura T, Yamamoto T, Misawa A. 

[Usefulness and short-term results of biventricular 

pacing using modified monorail lead system 

improved on usual endocardilal pacing lead in 

patients with chronic heart failure]. (Jap). Ther Res

2003;24(8):1528-31. 

64. Kloss M, Auricchio A, Trautmann S, Klein H.

Cardiac resynchronization therapy improves 

chronotropic response in patients with heart failure

[abst]. Eur Heart J 2001;22:443. 

65. Kusaba T, Tanda S, Kameyama H, et al. Efficacy of 

biventricular pacing for dialysis-related hypotension 

due to idiopathic dilated cardiomyopathy. Clin Exp 

Nephrol 2005;9(3):255-9. 

66. Lafitte S, Garrigue S, Perron JM, et al. 

Improvement of left ventricular wall 

synchronization with multisite ventricular pacing in 

heart failure: a prospective study using Doppler 

tissue imaging. Eur J Heart Fail 2004;6(2):203-12. 

67. Lau CP, Yu CM, Chau E, et al. Reversal of left 

ventricular remodeling by synchronous 

biventricular pacing in heart failure. Pacing Clin

Electrophysiol 2000;23(11 Pt 2):1722-5. 

68. Lawo T, Pfeiffer U, Deneke T, Calcum B, Lemke 

B. Einfluss der linkscentrikularen stimulation auf 

die QRS-breite bei linksschenkeiblock im rahmen

der resynchronisationsherapie [Influence of left 

ventricular stimulation on the QRS width in left 

bundle branch block in the framework of 

resynchronization therapy]. (Ger).

Herzschrittmacherther Elektrophysiol

2002;13(suppl 1):69-70. 

D-14 
 

69. Le Rest C, Couturier O, Turzo A, et al. Use of left

ventricular pacing in heart failure: evaluation by

gated blood pool imaging. J Nucl Cardiol 

1999;6(6):651-6. 

70. Leclercq C, Cazeau S, Ritter P, Daubert C.

Stimulation cardiaque et insuffisance cardiaque 

[Pacing and cardiac failure]. (Fre). Arch Mal Coeur 

Vaiss 1998;91(11):1389-97. 

71. Lehmann MH, Aaronson KD. CRT-D therapy in

heart failure: How much do NYHA class IV 

patients benefit? J Cardiovasc Electrophysiol 

2006;17(5):491-4. 

72. Leon AR, Abraham WT, Curtis AB, et al. Safety of 

transvenous cardiac resynchronization system 

implantation in patients with chronic heart failure: 

combined results of over 2,000 patients from a 

multicenter study program. J Am Coll Cardiol 

2005;46(12):2348-56. 

73. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac 

resynchronization in patients with congestive heart 

failure and chronic atrial fibrillation: effect of

upgrading to biventricular pacing after chronic right 

ventricular pacing. J Am Coll Cardiol 

2002;39(8):1258-63. 

74. Lewicka-Nowak E, Dabrowska-Kugacka A, Faran 

A, et al. Stymulcaja dwukomorowa u pacjentow z 

zaawansonwana niewydolnoscia sercadoswiadczenie wiasne [Biventricular pacing in 

patients with advanced heart failure–single center 

experience]. (Pol). Folia Cardiol 2003;10(1):91-

103. 

75. Linde C, Gold M, Abraham WT, Daubert JC, 

REVERSE Study. Rationale and design of a 

randomized controlled trial to assess the safety and 

efficacy of cardiac resynchronization therapy in

patients with asymptomatic left ventricular

dysfunction with previous symptoms or mild heart 

failure--the REsynchronization reVErses 

Remodeling in Systolic left vEntricular dysfunction 

(REVERSE) study. 2006;151(2):288-94. 

76. Livanis EG, Flevari P, Theodorakis GN, Kolokathis 

F, Leftheriotis D, Kremastinos DT. Effect of 

biventricular pacing on heart rate variability in

patients with chronic heart failure. Eur J Heart Fail 

2003;5(2):175-8. 

77. Lux RL, Hamdan MH. Cardiac resynchronization 

therapy and the arrhythmogenic substrate. J

Cardiovasc Electrophysiol 2005;16(6):618-9. 

78. Mahaux V, Demoulin JC, Pierard L, Soyeur D. 

Biventricular stimulation in congestive heart 

failure: initial clinical experience: cardiac pacing: 

Europace '95: 7th European Symposium on Cardiac 

Pacing. 1995: 533-6. 

79. Mahaux V, Legrand V, Waleffe A, Soyeur D. 

Acute hemodynamics of biventricular stimulation in 

congestive heart failure: cardiac pacing: Europace 

'95: 7th European Symposium on Cardiac Pacing. 

1995: 359-62. 

80. Makaryus AN, Arduini AD, Mallin J, et al. 

Echocardiographic features of patients with heart 

failure who may benefit from biventricular pacing. 

Echocardiography 2003;20(3):217-23. 

81. Martinelli Filho M, Pedrosa AA, Costa R, et al. 

Biventricular pacing improves clinical behavior and 

reduces prevalence of ventricular arrhythmia in 

patients with heart failure. Arq Bras Cardiol 

2002;78(1):110-3. 

82. McAlister FA , Ezekowitz JA, Wiebe N, et al.

Systematic review: cardiac resynchronization in

patients with symptomatic heart failure. [Review]

[52 refs]. Ann Intern Med 2004;141(5): 381-90. 

Erratum in: Ann Intern Med. 2005;142(4):311. 

83. Memon RA, Buckley J, O'Donnell A. Percutaneous 

extraction of entrapped infective transvenous pacing 

lead. Asian Cardiovasc Thorac Ann 2002;10(1):69-

71. 

84. Merkely B, Vago H, Bartha E, Zima E, Moravcsik 

E, Geller L. Sulyos szivelegtelenseg kezelese

biventricularis ingerlessel [Biventicular pacing in

patients with severe heart failure]. (Hun). Orv Hetil 

2001;142(51):2835-40. 

85. Moshenyat R, Kupfer YY, Tessler S. Efficacy of

biventricular pacing in congestive heart failure. J 

Am Coll Cardiol 2003;41(4):709; author reply 709-

10. 

86. Neri G, Zanco P, Buchberger R. Myocardial 

perfusion and metabolic changes induced by

biventricular pacing in dilated cardiomyopathy and 

left bundle branch block: description of a case 

evaluated by positron emission tomography. Ital 

Heart J 2001;2(6):472-4. 

87. Nielsen JC, Bottcher M, Jensen HK, Nielsen TT, 

Pedersen AK, Mortensen PT. Regional myocardial 

perfusion during chronic biventricular pacing and

after acute change of the pacing mode in patients

with congestive heart failure and bundle branch

block treated with an atrioventricular sequential 

biventricular pacemaker. Eur J Heart Fail

2003;5(2):179-86. 

D-15 
 

88. Nishimura M, Ogiwara M, Ishikawa M, et al. 

Successful bridge to resynchronization therapy with 

a left ventricular assist system in a patient with 

idiopathic dilated cardiomyopathy. J Artif Organs

2005;8(3):210-3. 

89. Oginosawa Y, Abe H, Nakashima Y. Right 

pneumothorax resulting from an endocardial screwin atrial lead in an implantable cardioverter

defibrillator system. Pacing Clin Electrophysiol

2002;25(8):1278-9. 

90. Oguz E, Dagdeviren B, Bilsel T, et al. 

Echocardiographic prediction of long-term response 

to biventricular pacemaker in severe heart failure. 

Eur J Heart Fail 2002;4(1):83-90. 

91. Okusu Y, Ishikawa T, Takahashi N, et al. [Efficacy

of biventricular pacing on myocardial glucose 

metabolism in a patient with heart failure using 2-

deoxy-2[18F]fluoro-d-glucose positron emission 

tomography: a case report]. (Jap). J Cardiol 

2002;39(3):165-70. 

92. Pacemaker resynchronization of ventricular rhythm

in chronic heart failure–early assessment briefs 

(Alert). [database on internet]. Stockholm: Swedish 

Council on Technology Assessment in Health Care. 

[cited 2006 Dec 7]. Available from: http:, 

www.sbu.se/www/index.asp. 

93. Pastore CA, Tobias NM, Kaiser E, et al. 

Electrocardiographic, vectorcardiographic and body

surface potential mapping analyses of patients with

congestive heart failure and left bundle branch

block, treated with biventricular pacing: 

electrocardiology; electrocardiology and 

neurophysiology. Int Soc Bioelectromagnetism 

2002;4(2):317-18. 

94. Pelicano N, Oliveira M, Da Silva N, et al. Longterm clinical outcome in patients with severe left

ventricular dysfunction and an implantable

cardioverter-defibrillator after ventricular 

tachyarrhythmias. Rev Port Cardiol 

2005;24(4):487-98. 

95. Peters RW, Gold MR. Pacing for patients with

congestive heart failure and dilated cardiomyopathy

. Cardiol Clin 2000;18(1):55-66. 

96. Petutschnigg B, Fruhwald F, Prenner G, Marte W, 

Tscheliessnigg KH. Multisite-stimulation als 

bridging fur transplantationspatienten [Multisite 

cardiac stimulation as bridging for transplantation

patients]. (Ger). Z Kardiol 1999;6(4):199-202. 

97. Philippon F. Cardiac resynchronization therapy:

device-based medicine for heart failure. [Review]

[56 refs]. J Cardiac Surg 2004;19(3):270-4. 

98. Poullis M, Shackcloth M, D'Ancona G. Coronary

grafts flow and cardiac pacing modalities: the

importance of the cardiac resynchronisation trials

[4] (multiple letters). Eur J CardioThorac Surg 

2005;27(1):177-8. 

99. Richardson K, Cook K, Wang PJ, Al-Ahmad A. 

Loss of biventricular pacing: what is the cause?

Heart Rhythm 2005;2(1):110-1. 

100. Ritter P, Lazarus A, Jauvert G, Alonso C, Cazeau 

S. Endovenous implantation of the left ventricular 

lead for cardiac resynchronization therapy in 

congestive heart failure: new developments in

cardiac pacing and electrophysiology. Ovsyschcher 

IE Futura Publishing Co, 2002: 229-38. 

101. Rust H, Achtelik M, Horstmann E, Trappe HJ. 

Globale und regionale kontraktilitat bei patienten

mit schwerer chronischer linksherzinsuffizienz 

unter biventrikularer schrittmachertherapie: eine

echokardiographische studie. [Global and regional 

contractility in patients with severe chronic left 

heart failure during biventricular pacing: an

echocardiographic study]. (Ger). 

Herzschrittmacherther Elektrophysiol

2001;12(suppl):77-8. 

102. Rust H, Meine M, Achtelik M, Trappe HJ. 

Echokardiographische av-zeit-optimierung bei 

patienten mit biventrikularer schmittmachertherapie 

[Echocardiographic atrioventricular time 

optimization in patients with biventricular pacing].

(Ger). Herzschrittmacherther Elektrophysiol 

2001;12(suppl):73-4. 

 103. Sack S, Heinzel F, Dagres N, et al. Stimulation of 

the left ventricle through the coronary sinus with a 

newly developed 'over the wire' lead system–early

experiences with lead handling and positioning. 

Europace 2001;3(4):317-23. 

 104. Salukhe TV, Dimopoulos K, Francis D. Cardiac 

resynchronisation may reduce all-cause mortality: 

meta-analysis of preliminary COMPANION data 

with CONTAK-CD, InSync ICD, MIRACLE and 

MUSTIC. Int J Cardiol 2004;93(2-3):101-3. 

105. Sassara M, Achilli A, Bianchi S, et al. Long-term

effectiveness of dual site left ventricular cardiac

resynchronization therapy in a patient with

congestive heart failure. Pacing Clin Electrophysiol 

2004;27(6 Pt 1):805-7. 

106. Satish OS, Yeh KH, Wen MS, Wang CC. Cardiac 

resynchronisation therapy versus dual site right 

ventricular pacing in a patient with permanent

pacemaker and congestive heart failure. Europace

2005;7(4):380-4. 

D-16 
 

107. Saxon LA, Boehmer JP, Hummel J, et al. 

Biventricular pacing in patients with congestive

heart failure: two prospective randomized trials. 

The VIGOR CHF and VENTAK CHF 

Investigators. [Review] [20 refs]. Am J Cardiol 

1999;83(5B):120D-3D. 

108. Sbragia P, Nait-Saidi L, Alexandre Trigano J, 

Saadjian A, Barnay P, Levy S. Intra-atrial

thrombosis and pulmonary embolism complicating 

pacemaker leads for cardiac resynchronization

therapy. J Interv Card Electrophysiol 2003;9(1):25-

7. 

109. Scharf C, Attenhofer Jost CH. Concepts and 

questions in programming cardiac 

resynchronization devices. Heart Rhythm 

2005;2(10):1073-5. 

110. Schuster P, Faerestrand S, Ohm OJ. Reverse 

remodelling of systolic left ventricular contraction 

pattern by long term cardiac resynchronisation 

therapy: Colour Doppler shows resynchronisation. 

Heart 2004;90(12):1411-6. 

 111. Sciagra R, Giaccardi M, Porciani MC, et al. 

Myocardial perfusion imaging using gated SPECT

in heart failure patients undergoing cardiac 

resynchronization therapy. J Nucl Med 

2004;45(2):164-8. 

112. Seidl K, Rameken M, Vater M, Senges J. Cardiac 

resynchronization therapy in patients with chronic 

heart failure: pathophysiology and current

experience. [Review] [53 refs]. Am J Cardiovasc 

Drugs 2002;2(4):219-26. 

 113. Sharma A, Epstein AE, Herre JM, et al. A 

comparison of the AVID and DAVID trials of 

implantable defibrillators. Am J Cardiol

2005;95(12):1431-5. 

114. Shi HY, Pan CZ, Shu XH, et al. [Immediate effect 

of cardiac resynchronization therapy by tissue 

synchronization imaging and tissue tracking in

patients with congestive heart failure]. [Chinese].

Chung-Hua Hsin Hsueh Kuan Ping Tsa Chih [Chin 

J Cardiol] 2005;33(1):26-9. 

115. Shukla G, Chaudhry GM, Orlov M, Hoffmeister P, 

Haffajee C. Potential proarrhythmic effect of 

biventricular pacing: fact or myth? Heart Rhythm 

2005;2(9):951-6. 

116. Singh JP, Ruskin JN. Cardiac resynchronization 

therapy: the MGH experience. Ann Noninvasive 

Electrocardiol 2005;10(4 Suppl):44-54. 

 117. Sinha AM, Filzmaier K, Breithardt OA, et al. 

Usefulness of brain natriuretic peptide release as a 

surrogate marker of the efficacy of long-term 

cardiac resynchronization therapy in patients with

heart failure. Am J Cardiol 2003;91(6):755-8. 

 118. Sinha AM, Skobel EC, Breithardt OA, et al. Cardiac 

resynchronization therapy improves central sleep

apnea and Cheyne-Stokes respiration in patients 

with chronic heart failure. J Am Coll Cardiol

2004;44(1):68-71. 

 119. Stellbrink C, Breithardt OA, Hanrath P. Technical 

considerations in implanting left ventricular pacing

leads for cardiac resynchronisation therapy. Eur

Heart J Suppl 2004;6(D):D43-D46. 

120. Stellbrink C, Sinha AM, Diem B, et al. Implantable 

cardioveter-defibrillators with or without cardiac 

resynchronization therapy–multiple therapy in a

single device: a review with special reference to the 

PACMAN study. Eur Heart J Suppl 

2002;4(D):D88-D94. 

 121. Sterlinski M, Lewicka-Nowak E, Przybylski A, et 

al. Zastosowanie kardiowerterow-defibrylatorow z 

funkcja resynchronizujacej stymulacji 

dwukomoroej u chorych z ciezka niewydolnoscia 

serca i ziosliwymi komorowymi zamurzeniami 

rytmu [Implantable cardioverter-defibrillator with

biventricular resynchronization therapy in patients 

with severe congestive heart failure and malignant

ventricular arrhythmias]. (Pol). Folia Cardiol 

2003;10(5):603-10. 

 122. Tada H, Toide H, Naito S, et al. Tissue Doppler

imaging and strain Doppler imaging as modalities

for predicting clinical improvement in patients

receiving biventricular pacing. Circ J 

2005;69(2):194-200. 

 123. Takemoto M, Sakamoto M, Kawagoe J, et al. Effect 

of biventricular pacing therapy in patients with 

dilated cardiomyopathy with severe congestive 

heart failure. Jpn J Thorac Cardiovasc Surg 

2004;52(4):175-80. 

124. Tanabe M, Onishi K, Kitamura T, et al. Effective 

cardiac resynchronization after Dor procedure and

mitral annuloplasty. Can J Cardiol 2004;20(4):449-

51. 

125. Tanaka H, Okishige K, Mizuno T, et al. Temporary

and permanent biventricular pacing via left 

ventricular epicardial leads implanted during 

primary cardiac surgery. Jpn J Thorac Cardiovasc

Surg 2002 ;50(7):284-9. 

 126. Tavazzi L. Electrical stimulation of the failing

heart: a new therapeutical strategy? Eur Heart J

Suppl 2000;2(J):J2-J5. 

D-17 
 

 127. Tavazzi L. Ventricular pacing: a promising new 

therapeutic strategy in heart failure. For whom? Eur 

Heart J 2000;21(15):1211-4. 

128. Thaman R, Murphy RT, Firoozi S, et al. Restrictive 

transmitral filling patterns predict improvements in 

left ventricular function after biventricular pacing. 

Heart 2005;91(7):920-5. 

129. Toff WD, Skehan JD, De Bono DP, Camm AJ. The 

United Kingdom Pacing And Cardiovascular Events 

(UKPACE) trial. Heart 1997;78(3):221-3. 

 130. Touiza A, Etienne Y, Gilard M, Fatemi M, 

Mansourati J, Blanc JJ. Long-term left ventricular 

pacing: assessment and comparison with 

biventricular pacing in patients with severe 

congestive heart failure. J Am Coll Cardiol 

2001;38(7):1966-70. 

 131. Valls-Bertault V, Fatemi M, Gilard M, Pennec PY, 

Etienne Y, Blanc JJ. Assessment of upgrading to 

biventricular pacing in patients with right 

ventricular pacing and congestive heart failure after 

atrioventricular junctional ablation for chronic atrial 

fibrillation. Europace 2004;6(5):438-43. 

132. Van Gelder BM, Bracke FA, Pilmeyer A, Meijer A. 

Triple-site ventricular pacing in a biventricular

pacing system. Pacing Clin Electrophysiol

2001;24(7):1165-7. 

 133. Vanderheyden M, De Backer T, Rivero-Ayerza M, 

et al. Tailored echocardiographic interventricular

delay programming further optimizes left

ventricular performance after cardiac

resynchronization therapy. Heart Rhythm 

2005;2(10):1066-72. 

 134. Vanderheyden M, Wellens F, Bartunek J, et al. 

Cardiac resynchronization therapy delays heart 

transplantation in patients with end-stage heart 

failure and mechanical dyssynchrony. J Heart Lung

Transplant 2006;25(4):447-53. 

 135. Walker S, Levy TM, Coats AJS, et al. Biventricular pacing in congestive cardiac dailure: 

current experience and future directions. Eur Heart J

2000;21(11):884-9. 

136. Wang L. Cardiac resynchronization therapy in 

congestive heart failure: the state of the art and 

future perspectives. Exp Clin Cardiol 

2003;7(4):212-5. 

137. Wilkoff BL, Dual Chamber and VVI Implantable 

Defibrillator trial investigators. The Dual Chamber 

and VVI Implantable Defibrillator (DAVID) Trial: 

rationale, design, results, clinical implications and

lessons for future trials. Cardiac Electrophysiol Rev 

2003;7(4):468-72. 

138. Yu CM, Abraham WT, Bax J, et al. Predictors of

response to cardiac resynchronization therapy

(PROSPECT)–study design. Am Heart J

2005;149(4):600-5. 

139. Yu CM, Lau CP, Tang AS. Case report: resolution

of pulsus alternans by synchronous atriobiventricular pacing. J Interv Card Electrophysiol 

2000;4(4):595-7. 

Not Obtained 

1. Abdul-Khaliq H, Rentzsch A, Schuck R, et al. 

Midterm effects of resynchronization therapy on left 

ventricular performance: a prospective study in 28

patients with congenital heart disease and dilatative 

cardiomyopathy. Cambridge University Press, 

2006: O6. 

2. Eksik A, Akyol A, Norgaz T, et al. Takilabilir 

kardiyoverter defibrilator ile tedavi edilen malign

ventrikul tasiaritmili hastalarm uzun donem

sonculari [Long-term results of cardioverter

defibrillator implantation in patients with malignant 

ventricular tachyarrhythmias]. (Tur). Turk 

Kardiyoloji Dernegi Arsivi 2005;33(7):398-403. 

3. Hansky B, Vogt J, Guldner H, et al. 

Komplikationen linksventrikularer kornonarvene 

(CV)–elektroden [Complications of left ventricular 

coronary arteries–electrodes]. (Ger).

Herzschrittmacherther Elektrophysiol

2001;12(suppl):69-70. 

4. Huth C, Friedl A, Klein H, Auricchio A. 

Schrittmachertherapie der Herzinsuffizienz unter

Berucksichtigung der Ergebnisse der PATH-CHFStudie [Pacing therapies for congestive heart failure 

considering the results of the PATH-CHF study]. 

(Ger). Z Kardiol 2001;90 Suppl 1:10-5. 

5. Kazmierczak J , Zielonka J, Rzeuski R, et al. 

Hospital readmission in patients with implantable

cardioverter- defibrillators. Kardiol Pol 

2006;64(7):684-91. 

D-18 
 

6. Malinowski K, Bondke HJ, Witte J, et al. 

Biventrikulare stimulation mit einer helikal

geformten koronarsinus-elektrode: erste ergebnisse 

einer anwendungsbeobachtung [Biventricular 

stimulation with a coronary sinus electrode: first 

results of an observational study] (Ger). 

Herzschrittmacherther Elektrophysiol

2003;14(suppl 1):53-4. 

7. Poschmann U, Steiner S, Knake W, Oster H, 

Vallbracht C. Vergleich der transvenosen und

epikardialen implantation von LV-elektroden zur

kardialen resynchronisationstherapie [Comparison 

of transvenous and epicardial implantation of LV 

electrodes for cardiac resynchronization therapy]. 

(Ger). Herzschrittmacherther Elektrophysiol 

2002;12(suppl 1):71-2. 

8. Salerno-Uriarte JA, Tritto M. Effetti della

stimolazione biventricolare nei pazienti con

insufficienza cardiaca e ritardo di conduzione 

intraventricolare [Effects of multisite biventricular 

pacing in patients with heart failure and

intraventricular conduction delay]. (Ita). Ital Heart J 

Supp 2001;2(8):912-4. 

9. Spitzer SG, Wacker P, Malinowski K, Schibgilla V, 

Gazarek S. Multisite pacing im rechten vorhof - 

unterscheiden sich intraoperative messwerte, opzeiten und peri-/post-operative komplikationen im 

vergleich zur standardtherapie? [Does multisite

pacing into the right atrium differ in 

intraoperatively measured values, surgery times and 

peri- and postoperative complications compared to 

standard therapy?]. (Ger). Herzschrittmacherther

Elektrophysiol 2003;13(suppl 1):55-6. 

10. Wang DM, Han YL, Zang HY, et al. [Long-term 

effects and mortality of biventricular pacing therapy

in patients with congestive heart failure]. (Chi).

Chung-Hua Hsin Hsueh Kuan Ping Tsa Chih [Chin 

J Cardiol] 2005;33(8):717-9. 

D-19 
 

Excluded Studies: ICD Alone

The four main reasons for exclusion were based on the publication not having the right study design, population, 

intervention or outcomes. 

Population 

1. Aronow WS, Sorbera C, Chagarlamudi A, 

Tabandeh H, Gupta S, Cohen M. Indications for and 

long-term survival in patients with automatic 

implantable cardioverter-defibrillators. Cardiol Rev 

2005;13(1):50-1. 

2. Ashwath ML, Sogade FO. Ejection fraction and

QRS width as predictors of event rates in patients 

with implantable cardioverter defibrillators. South

Med J 2005;98(5):513-7. 

3. Cabell CH, Heidenreich PA, Chu VH, et al. 

Increasing rates of cardiac device infections among 

Medicare beneficiaries: 1990-1999. Am Heart J 

2004;147(4):582-6. 

4. Cappato R, Boczor S, Kuck KH, CASH 

Investigators. Response to programmed ventricular 

stimulation and clinical outcome in cardiac arrest

survivors receiving randomised assignment to 

implantable cardioverter defibrillator or

antiarrhythmic drug therapy. Eur Heart J

2004;25(8):642-9. 

5. Carroll DL, Hamilton GA. Quality of life in 

implanted cardioverter defibrillator recipients: the

impact of a device shock. Heart Lung 

2005;34(3):169-78. 

6. Chow BJW, Hassan AH, Chan KL, Tang ASL. 

Prevalence and significance of lead-related thrombi 

in patients with implantable cardioverter

defibrillators. Am J Cardiol 2003;91(1):88-90. 

7. Crevenna R, Stix G, Pleiner J, et al. 

Electromagnetic interference by transcutaneous

neuromuscular electrical stimulation in patients 

with bipolar sensing implantable cardioverter

defibrillators: a pilot safety study. Pacing Clin 

Electrophysiol 2003;26(2 I): 626-9. 

8. del Rio A, Anguera I, Miro JM, et al. Surgical 

treatment of pacemaker and defibrillator lead 

endocarditis: the impact of electrode lead extraction 

on outcome. Chest 2003;124(4):1451-9. 

9. Deneke T, Lawo T, Gerritse B, Lemke B, The

European GEM DR Trade Mark Investigators. 

Mortality of patients with implanted 

cardioverter/defibrillators in relation to episodes of

atrial fibrillation. Europace 2004;6(2):151-8. 

10. Dogra V, Oliver R, Lapidus J, et al. Apparent

protective effect of increased left ventricular wall

thickness in an ICD population. J Card Fail 

2003;9(5):412-5. 

11. Fitchet A, Doherty PJ, Bundy C, Bell W, Fitzpatrick 

AP, Garratt CJ. Comprehensive cardiac

rehabilitation programme for implantable 

cardioverter-defibrillator patients: a randomised 

controlled trial. Heart 2003;89(2):155-60. 

12. Garcia-Moran E, Mont L, Cuesta A, Matas M, 

Brugada J. Low recurrence of syncope in patients

with inducible sustained ventricular 

tachyarrhythmias treated with an implantable

cardioverter-defibrillator. Eur Heart J 

2002;23(11):901-7. 

13. Godemann F, Butter C, Lampe F, et al. Panic 

disorders and agoraphobia: side effects of treatment 

with an implantable cardioverter/defibrillator. Clin 

Cardiol 2004;27(6):321-6. 

14. Godemann F, Butter C, Lampe F, Linden M,

Werner S, Behrens S. Determinants of the quality of 

life (QoL) in patients with an implantable

cardioverter/defibrillator (ICD). Qual Life Res 

2004;13(2):411-6. 

15. Gold MR, Sulke N, Schwartzman DS, Mehra R, 

Euler DE, Worldwide Jewel AFOnly I. Clinical

experience with a dual-chamber implantable

cardioverter defibrillator to treat atrial 

tachyarrhythmias. J Cardiovasc Electrophysiol 

2001;12(11):1247-53. 

16. Gradaus R, Gonska BD, Stellbrink C, et al. 

European clinical experience with a dual chamber 

single pass sensing and pacing defibrillation lead. 

Pacing Clin Electrophysiol 2002;25(7):1079-86. 

17. Gronefeld GC, Israel CW, Padmanabhan V, et al.

Ventricular rate stabilization for the prevention of

pause dependent ventricular tachyarrhythmias: 

results from a prospective study in 309 ICD 

recipients. Pacing Clin Electrophysiol

2002;25(12):1708-14. 

18. Gunderson BD, Patel AS, Bounds CA, Shepard RK, 

Wood MA, Ellenbogen KA. An algorithm to predict 

implantable cardioverter-defibrillator lead failure. J

Am Coll Cardiol 2004;44(9):1898-902. 

D-20 
 

19. Hauser RG, Kallinen L. Deaths associated with

implantable cardioverter defibrillator failure and 

deactivation reported in the United States Food and 

Drug Administration Manufacturer and User 

Facility Device Experience Database. Heart Rhythm

2004;1(4):399-405. 

20. Hennersdorf MG, Niebch V, Vester EG, Winter J, 

Perings C, Strauer BE. Long-term follow-up of 

sudden cardiac arrest survivors and 

electrophysiologically guided antiarrhythmic

therapy. Cardiology 2003;99(4):190-7. 

21. Herzog CA, Li S, Weinhandl ED, Strief JW, Collins 

AJ, Gilbertson DT. Survival of dialysis patients 

after cardiac arrest and the impact of implantable 

cardioverter defibrillators. Kidney Int 

2005;68(2):818-25. 

22. Kamke W, Dovifat C, Schranz M, Behrens S, 

Moesenthin J, Voller H. Cardiac rehabilitation in

patients with implantable defibrillators. Feasibility

and complications. Z Kardiol 2003;92(10):869-75. 

23. Kamphuis HC, De Leeuw JR, Derksen R, Hauer R, 

Winnubst JA. A 12-month quality of life assessment 

of cardiac arrest survivors treated with or without an 

implantable cardioverter defibrillator. Europace 

2002;4(4):417-25. 

24. Kamphuis HC, de Leeuw JR, Derksen R, Hauer

RN, Winnubst JA. Implantable cardioverter

defibrillator recipients: quality of life in recipients

with and without ICD shock delivery: a prospective 

study. Europace 2003;5(4):381-9. 

25. Kettering K, Mewis C, Dornberger V, Vonthein R, 

Bosch RF, Kuhlkamp V. Efficacy of metoprolol and 

sotalol in the prevention of recurrences of sustained 

ventricular tachyarrhythmias in patients with an

implantable cardioverter defibrillator. Pacing Clin

Electrophysiol 2002;25(11):1571-6. 

26. Klein G, Lissel C, Fuchs AC, et al. Predictors of

VT/VF-occurrence in ICD patients: Results from

the PROFIT-Study. Europace 2006;8(8):618-24. 

27. Kouakam C, Kacet S, Hazard JR, et al. Performance 

of a dual-chamber implantable defibrillator 

algorithm for discrimination of ventricular from 

supraventricular tachycardia. Europace

2004;6(1):32-42. 

28. Kozak M, Sepsi M, Vlasinova J. Dlouhodobe 

prezivani pacientu s implantabilnimi kardioverterydefibrilatory implantovanymi ze sekundarne 

preventivnich indikaci [Long-lasting survival of

patients with implantable cardioverter-defibrillators 

implanted for secondary preventive reasons]. (Cze). 

Cas Lek Cesk 2005;144(5):309-12; discussion 313-

4. 

29. Krivan L, Kozak M, Sepsi M, Svobodnik A, Spinar 

J. Specificke komplikace terapie implantabilnimi 

kardiovertery defibrilatory [Specific complications

in the treatment with implantable cardioverterdefibrillators]. (Cze). Cas Lek Cesk 

2004;143(8):521-5; discussion 526-7. 

30. Krivan L, Kozak M, Sepsi M, Svobodnik A, Spinar 

J. Treatment of arrhythmic storm in implantable 

defibrillator patients. Med Sci Monit 

2005;11(9):CR426-CR429. 

31. Ladwig KH, Marten-Mittag B, Deisenhofer I, et al. 

Exaggerated electrodermal startle responses after

intracardiac shock discharges in patients with

implanted cardioverter defibrillators. Psychosom 

Med 2003;65(2):222-8. 

32. Lampert R, Joska T, Burg MM, Batsford WP,

McPherson CA, Jain D. Emotional and physical 

precipitants of ventricular arrhythmia. Circulation 

2002;106(14):1800-5. 

33. Lau EW, Griffith MJ, Pathmanathan RK, et al. The 

Midlands Trial of Empirical Amiodarone versus 

Electrophysiology-guided Interventions and 

Implantable Cardioverter-defibrillators

(MAVERIC): a multi-centre prospective 

randomised clinical trial on the secondary

prevention of sudden cardiac death. Europace 

2004;6(4):257-66. 

34. Lin G, Nishimura RA, Connolly HM, Dearani JA, 

Sundt TM 3rd, Hayes DL. Severe symptomatic 

tricuspid valve regurgitation due to permanent 

pacemaker or implantable cardioverter-defibrillator 

leads. J Am Coll Cardiol 2005; 45(10):1672-5. 

35. Liu QM, Zhang Y, Zhou SH. [Implantable 

cardioventer defibrillator in the treatment of 

malignant ventricular arrhythmias and its short-term 

follow-up]. (Chi). Hunan Yi Ke Da Xue Xue Bao 

2002;27(2):179-80. 

36. Matsushita T, Chun S, Liem LB, Friday KJ, Sung 

RJ. Significance of inducible ventricular 

flutter/fibrillation in risk stratification in patients 

with coronary artery disease. Int J Cardiol 2004;94

(1):67-71. 

37. Mletzko R, Aliot E, Seidl K, et al. Safety and 

efficacy of a dual chamber implantable cardioverter 

defibrillator capable of slow ventricular tachycardia 

discrimination: a randomized study. Pacing Clin 

Electrophysiol 2003;26(12):2275-82. 

38. Nanthakumar K, Dorian P, Paquette M, et al. Is

inappropriate implantable defibrillator shock

therapy predictable? J Interv Card Electrophysiol

2003;8(3):215-20. 

D-21 
 

39. Nanthakumar K, Newman D, Paquette M, Dorian P.

Systematic evaluation of the determinants of 

defibrillation efficacy. Heart Rhythm 2005;2(1):36-

41. 

40. Newman DM, Dorian P, Paquette M, et al. Effect of 

an implantable cardioverter defibrillator with atrial

detection and shock therapies on patient-perceived, 

health-related quality of life. Am Heart J

2003;145(5):841-6. 

41. Ommen SR, Hammill SC, Gibbons RJ. The relative 

lymphocyte count predicts death in patients 

receiving implantable cardioverter defibrillators. 

Pacing Clin Electrophysiol 2002;25(10):1424-8. 

42. Pelletier D, Gallagher R, Mitten-Lewis S, McKinley

S, Squire J. Australian implantable cardiac

defibrillator recipients: quality-of-life issues. Int J 

Nurs Pract 2002;8(2):68-74. 

43. Przybylski A , Baranowski R, Zebrowski JJ, Szwed 

H. Verification of implantable cardioverter 

defibrillator (ICD) interventions by nonlinear

analysis of heart rate variability–preliminary results. 

Europace 2004;6(6):617-24. 

44. Ricci R, Pignalberi C, Disertori M, et al. Efficacy of 

a dual chamber defibrillator with atrial

antitachycardia functions in treating spontaneous 

atrial tachyarrhythmias in patients with lifethreatening ventricular tachyarrhythmias. Eur Heart 

J 2002;23(18):1471-9. 

45. Rinaldi CA, Simon RD, Baszko A, et al. Can we

predict which patients with implantable cardioverter 

defibrillators receive appropriate shock therapy? A 

study of 155 patients. Int J Cardiol 2003;88(1):69-

75. 

46. Rinaldi CA, Simon RD, Geelen P, et al. A 

randomized prospective study of single coil versus

dual coil defibrillation in patients with ventricular

arrhythmias undergoing implantable cardioverter 

defibrillator therapy. Pacing Clin Electrophysiol 

2003;26(8):1684-90. 

47. Ruskin JN, Camm AJ, Zipes DP, Hallstrom AP,

McGrory-Usset ME. Implantable cardioverter

defibrillator utilization based on discharge 

diagnoses from Medicare and managed care 

patients. J Cardiovas Electrophysiol 2002;13(1):38-

43. 

48. Schimpf R, Wolpert C, Bianchi F, et al. Congenital 

short QT syndrome and implantable cardioverter 

defibrillator treatment: inherent risk for 

inappropriate shock delivery. J Cardiovas 

Electrophysiol 2003;14(12):1273-7. 

49. Schuchert A, Boriani G, Wollmann C, et al. 

Implantable dual-chamber defibrillator for the

selective treatment of spontaneous atrial and 

ventricular arrhythmias: arrhythmia incidence and 

device performance. J Interv Card Electrophysiol 

2005;12(2):149-56. 

50. Schuchert A, Schmitz D, Bondke HJ, et al. Erste 

erfahrungen zur detektion von tachyarrhythmien mit 

einem single-pass ICD in verbrindung mit einer

defibrillationssonde mit freiflottierendem atrialem 

bipol [First experience for detection of 

tachyarrhtthmias with a single-pass ICD in 

connection with a defibrillation lead with freefloating atrial bipole]. (Ger). Herzschrittmacherther 

Elektrophysiol 2003;14(suppl 1):33-4. 

51. Sharma AD, Fain E, O'Neill PG, et al. Shock on T 

versus direct current voltage for induction of 

ventricular fibrillation: a randomized prospective 

comparison. Pacing Clin Electrophysiol 

2004;27(1):89-94. 

52. Sterk B, van Alem AP, Tukkie R, Simmers TA, 

Koster RW. ICD-implantation guidelines versus 

clinical practice: a prospective study of out-ofhospital cardiac arrest survivors. Europace 

2004;6(3):179-83. 

53. Sukhija R, Aronow WS, Sorbera C, Yalamanchili 

K, Cohen M. Patients, mean age 70 years, with

automatic implantable cardioverter-defibrillators 

treated with dual-chamber rate responsive pacing 

(DDDR-70) have a higher mortality than patients 

with backup ventricular pacing (VVI-40) at 3.7-year 

follow-up. J Gerontol A Biol Sci Med Sci 

2005;60(5):603-4. 

54. Tsai CT, Huang SK, Lin JL, Lai LP, Taiwan ICD 

Registry Investigators. Distinct clinical features in

the recipients of the implantable cardioverter 

defibrillator in Taiwan: a multicenter registry study.

Pacing Clin Electrophysiol 2003;26(11):2083-90. 

55. Voigt A, Ezzeddine R, Barrington W, et al. 

Utilization of implantable cardioverter-defibrillators 

in survivors of cardiac arrest in the United States

from 1996 to 2001. J Am Coll Cardiol 2004;44 

(4):855-8. 

56. Wallace RL, Sears Jr SF, Saia Lewis T, Griffis JT,

Curtis A, Conti JB. Predictors of quality of life in

long-term recipients of implantable cardioverter 

defibrillators. J Cardiopulm Rehabil 

2002;22(4):278-81. 

D-22 
 

57. Weiss JP, Saynina O, McDonald KM, McClellan 

MB, Hlatky MA. Effectiveness and costeffectiveness of implantable cardioverter 

defibrillators in the treatment of ventricular

arrhythmias among medicare beneficiaries. Am J

Med 2002;112(7):519-27. 

58. Weretka S, Michaelsen J, Becker R, et al.

Ventricular oversensing: a study of 101 patients 

implanted with dual chamber defibrillators and two 

different lead systems. Pacing Clin Electrophysiol 

2003;26(1 Pt 1):65-70. 

59. Wu LA, Kottke TE, Friedman PA, Luria DM, Grill 

DE, Maurer MJ. Implantable cardioverter 

defibrillator implantation rates in the Olmsted 

County, Minnesota, population: 1989-1999. J Clin 

Epidemiol 2002;55(5):458-61. 

60. Zareba W, Moss AJ, Daubert JP, Hall WJ, 

Robinson JL, Andrews M. Implantable cardioverter 

defibrillator in high-risk long QT syndrome 

patients. J Cardiovas Electrophysiol 2003;14(4): 

337-41. 

61. Zhou X, Gunderson BD, Olson WH, Gem DR ICD 

Clinical Worldwide Investigators. Incidence of 

nonsustained and sustained ventricular 

tachyarrhythmias in patients with an implantable

cardioverter defibrillator. J Cardiovas 

Electrophysiol 2004;15(1):14-20. 

Intervention

1. Baessler C, Murphy S, Gebhardt L, et al. Time to 

resumption of driving after implantation of an 

automatic defibrillator (from the Dual chamber and 

VVI Implantable Defibrillator [DAVID] trial). Am J 

Cardiol 2005;95(5):665-6. 

 2. Baravelli M, Salerno-Uriarte D, Guzzetti D, et al.

Predictive significance for sudden death of microvoltlevel T wave alternans in New York Heart Association

class II congestive heart failure patients: a prospective 

study. Int J Cardiol 2005;105(1):53-7. 

3. Bloom H, Heeke B, Leon A, et al. Renal insufficiency

and the risk of infection from pacemaker or

defibrillator surgery. Pacing Clin Electrophysiol

2006;29(2):142-5. 

4. Byrd CL, Wilkoff BL, Love CJ, Sellers TD, Reiser C. 

Clinical study of the laser sheath for lead extraction: 

the total experience in the United States. Pacing Clin 

Electrophysiol 2002;25(5):804-8. 

5. Khaleal F, Paterson HS, Cousins KL, Cooper MJ. 

Incidence of defribillator patch infection due to

pulmonary erosion. Heart Lung Circ 2004;13(2):157-

60. 

6. Marti Almor J , Delclos Baulies M, Delclos Urgell J,

Comin Colet J, Cladellas Capdevila M, Bruguera 

Cortada J. Revalencia y evolucion en espan~a de los 

pacientes con infarto agudo de miocardio y fraccion de 

eyeccion severalmente deprimida, con criterios de

implantacion de desfibrilador automaatico [Prevalence 

and clinical course of patients in Spain with acute

myocardial infarction and severely depressed ejection 

fraction who meet the criteria for automatic

defibrillator implantation]. (Spa). Rev Esp Cardiol 

2004;57(7):705-8. 

7. Mathur G, Stables RH, Heaven D, et al. Cardiac

pacemaker lead extraction using conventional

techniques: a single centre experience. Int J Cardiol 

2003;91(2-3):215-9. 

8. Meier-Ewert HK, Gray ME, John RM. Endocardial 

pacemaker or defibrillator leads with infected 

vegetations: a single-center experience and 

consequences of transvenous extraction. Am Heart J 

2003;146(2):339-44. 

 9. Rinaldi CA, Bostock J, Patel N, Bucknall CA.

Determinants of procedural outcome of chronically 

implanted pacemaker and defibrillator leads using the

Excimer laser sheath. Heart 2002;87(2):160-1. 

D-23 
 

Outcomes 

1. Al-Khatib SM, Anstrom KJ, Eisenstein EL, et al.

Clinical and economic implications of the

Multicenter Automatic Defibrillator Implantation 

Trial-II. Ann Intern Med 2005;142(8):593-600. 

2. Arya A, Haghjoo M, Nikoo MH, Dehghani MR, 

Fazelifar AF, Sadr-Ameli MA. Effect of first 

ventricular tachycardia cycle length on rate of

ventricular arrhythmia recurrence in patients with 

implantable cardioverter-defibrillator. J

Electrocardiol 2006;39(4):404-8. 

3. Berkowitsch A , Zareba W, Neumann T, et al. Risk 

stratification using heart rate turbulence and 

ventricular arrhythmia in MADIT II: usefulness and 

limitations of a 10-minute holter recording. Ann 

Noninvasive Electrocardiol 2004;9(3):270-9. 

4. Bracke F, Meijer A, Van Gelder B. Venous 

occlusion of the access vein in patients referred for 

lead extraction: influence of patient and lead 

characteristics. Pacing Clin Electrophysiol

2003;26(8):1649-52. 

5. Brodine WN, Tung RT, Lee JK, et al. Effects of 

beta-blockers on implantable cardioverter 

defibrillator therapy and survival in the patients

with ischemic cardiomyopathy (from the 

multicenter automatic defibrillator implantation

trial-II). Am J Cardiol 2005;96(5):691-5. 

6. Butter C, Meisel E, Engelmann L, et al. Human 

experience with transvenous biventricular 

defibrillation using an electrode in a left ventricular 

vein. Pacing Clin Electrophysiol 2002;25(3):324-

31. 

7. Chan P, Hayward R. Predicting 1-year mortality in

patients receiving implantable cardioverterdefibrillators for congestive heart failure, ischemic 

heart disease, and ventricular arrhythmias.

Circulation 2004;110(17):504 . 

8. Chen RH, Chen KP, Wang FZ, Hua W, Chen X, 

Zhang S. Incidence and causes of inappropriate 

detection and therapy by implantable defibrillators

of cardioversion in patients with ventricular

tachyarrhythmia. Chin Med J 2006;119(7):557-63. 

9. Church TR, Hodges M, Bailey JJ, Mongin SJ. Risk

stratification applied to CAST registry data:

combining 9 predictors. Cardiac Arrhythmia

Suppression Trial. J Electrocardiol 2002;35

Suppl:117-22. 

10. Crevenna R, Wolzt M, Fialka-Moser V, et al. Longterm transcutaneous neuromuscular electrical 

stimulation in patients with bipolar sensing 

implantable cardioverter defibrillators: a pilot safety

study. Artif Organs 2004;28(1):99-102. 

11. Davids JS, McPherson CA, Earley C, Batsford WP, 

Lampert R. Benefits of cardiac rehabilitation in

patients with implantable cardioverterdefibrillators: a patient survey. Arch Phys Med

Rehabil 2005;86(10):1924-8. 

12. Domanski MJ, Epstein A, Hallstrom A, Saksena S,

Zipes DP. Survival of antiarrhythmic or implantable 

cardioverter defibrillator treated patients with

varying degrees of left ventricular dysfunction who 

survived malignant ventricular arrhythmias. J 

Cardiovas Electrophysiol 2002;13(6):580-3. 

13. Ellenbogen KA, Levine JH, Berger RD, et al. Are 

implantable cardioverter defibrillator shocks a 

surrogate for sudden cardiac death in patients with 

nonischemic cardiomyopathy? Circulation

2006;113(6):776-82. 

14. Fiek M, Zieg B, Matis T, Hahnefeld A, Reithmann

C, Steinbeck G. Analyse der Todesursachen von 

ICD-Patienten in der Langzeitbeobachtung

[Analysis of the cause of death of ICD patients 

during long-term follow-up]. (Ger). 

Herzschrittmacherther Elektrophysiol 2006;17(1):6-

12. 

15. Fries R, Steuer M, Schafers HJ, Bohm M. The Ron-T phenomenon in patients with implantable 

cardioverter-defibrillators. Am J Cardiol

2003;91(6):752-5. 

16. Gold MR, Shorofsky SR, Thompson JA, et al. 

Advanced rhythm discrimination for implantable 

cardioverter defibrillators using electrogram vector

timing and correlation. J Cardiovas Electrophysiol 

2002;13(11):1092-7. 

17. Goldberger JJ, Subacius H, Schaechter A, et al.

Effects of statin therapy on arrhythmic events and

survival in patients with nonischemic dilated 

cardiomyopathy. J Am Coll Cardiol 

2006;48(6):1228-33. 

18. Goldenberg I , Moss AJ, Hall WJ, et al. Causes and 

consequences of heart failure after prophylactic

implantation of a defibrillator in the multicenter

automatic defibrillator implantation trial II.

Circulation 2006;113(24):2810-7. 

D-24 
 

19. Greenberg H, Case RB, Moss AJ, et al. Analysis of 

mortality events in the Multicenter Automatic 

Defibrillator Implantation Trial (MADIT-II). J Am 

Coll Cardiol 2004;43(8):1459-65. 

20. Guevara E, Torino AF, Casabe JH, et al.

Endocarditis infecciosa ascoiada a marcapasos: 

ecocardiografia, manejo y evolucion [Infective 

endocarditis associated to pacemakers: sonography, 

management and evolution]. (Spa). Prensa Med 

Argent 2003;90(5):390-3. 

21. Herrmann-Lingen C, Fritzsche K, Kanwischer H, et 

al. Kardiologische und psychosoziale Befunde bei 

Patienten mit malignen ventrikularen 

Herzrhythmusstorungen vor Implantation eines 

internen Defibrillators--Erste Ergebnisse aus der 

deutsch-osterreichischen Multizenterstudie zu 

Krankheitserleben und -verlauf bei Patienten mit 

implantiertem Defibrillator [Cardiological and

psychosocial status of patients with malignant

ventricular arrhythmias before implantation of a 

cardioverter defibrillator. First results from the

German Austrian ICD Multicenter Study

(GAIMS)]. (Ger). Psychother Psychosom Med 

Psychol 2004;54(8):308-19. 

22. Hreybe H, Ezzeddine R, Bedi M, et al. Renal 

insufficiency predicts the time to first appropriate 

defibrillator shock. Am Heart J 2006;151(4):852-6. 

23. Irvine J, Dorian P, Baker B, et al. Quality of life in

the Canadian Implantable Defibrillator Study

(CIDS). Am Heart J 2002;144(2):282-9. 

24. Kadish A, Schaechter A, Subacius H, et al. Patients

with recently diagnosed nonischemic 

cardiomyopathy benefit from implantable 

cardioverter-defibrillators. J Am Coll Cardiol

2006;47(12):2477-82. 

25. Kempa M, Lubinski A, Zienciuk A, et al. 

Mechanizmy wyzwalajace grozne arytmie

komorowe-analiza elektrogramow rejestrowanych

w pamieci holterowskieji implantowanych 

kardiowerterow-defibrylatorow serca [Mechanisms 

inducing malignant ventricular arrhythmias–

analysis of the electrograms stored in holter

memory of implantable cardioverter-defibrillators]. 

(Pol). Folia Cardiol 2002;9(4):349-59. 

26. Klein RC, Raitt MH, Wilkoff BL, et al. Analysis of 

implantable cardioverter defibrillator therapy in the 

Antiarrhythmics Versus Implantable Defibrillators

(AVID) Trial. J Cardiovas Electrophysiol

2003;14(9):940-8. 

27. Klein RC, Schron EB, Renfroe EG, et al. Factors

determining ICD implantation in drug therapy 

patients after termination of antiarrythmics versus 

implantable defibrillators trial. Pacing Clin

Electrophysiol 2003;26(12):2235-40. 

28. Kozak M, Krivan L, Semrad B. Circadian variations

in the occurrence of ventricular tachyarrhythmias in 

patients with implantable cardioverter defibrillators. 

Pacing Clin Electrophysiol 2003;26(3):731-5. 

29. Kron J. Clinical significance of device-related 

complications in clinical trials and implications for 

future trials: insights from the Antiarrhytmics 

Versus Implantable Defibrillators (AVID) trial.

Cardiac Electrophysiol Rev 2003;7(4):473-8. 

30. Lampert R, Shusterman V, Burg MM, et al. Effects

of psychologic stress on repolarization and

relationship to autonomic and hemodynamic 

factors. J Cardiovas Electrophysiol 

2005;16(4):372-7. 

31. Larsen G, Hallstrom A, McAnulty J, et al. Costeffectiveness of the implantable cardioverterdefibrillator versus antiarrhythmic drugs in

survivors of serious ventricular tachyarrhythmias: 

results of the Antiarrhythmics Versus Implantable

Defibrillators (AVID) economic analysis substudy. 

Circulation 2002;105(17):2049-57. 

32. Lee KL, Hafley G, Fisher JD, et al. Effect of 

implantable defibrillators on arrhythmic events and 

mortality in the multicenter unsustained tachycardia 

trial. Circulation 2002;106(2):233-8. 

33. Mark DB, Nelson CL, Anstrom KJ, et al. Costeffectiveness of defibrillator therapy or amiodarone 

in chronic stable heart failure: results from the

Sudden Cardiac Death in Heart Failure Trial (SCDHeFT). Circulation 2006;114(2):135-42. 

34. Melzer C, Bohm M, Bondke HJ, Combs W, 

Baumann G, Theres H. Chronotropic incompetence 

in patients with an implantable cardioverter

defibrillator: prevalence and predicting factors.

Pacing Clin Electrophysiol 2005;28(10):1025-31. 

35. Meyborg M, Mura R, Tiefenbacher C, Becker R,

Michaelsen J, Niroomand F. Comparative follow up 

of patients with implanted cardioverterdefibrillators after induction of sustained

monomorphic ventricular tachycardias or 

ventricular fibrillation by programmed stimulation. 

Heart 2003;89(6):629-32. 

D-25 
 

36. Mitchell LB, Powell JL, Gillis AM, Kehl V, 

Hallstrom AP, AVID Investigators. Are lipidlowering drugs also antiarrhythmic drugs? An 

analysis of the Antiarrhythmics Versus Implantable 

Defibrillators (AVID) trial. J Am Coll Cardiol 

2003;42(1):81-7. 

37. Moss AJ, Vyas A, Greenberg H, et al. Temporal 

aspects of improved survival with the implanted 

defibrillator (MADIT-II). Am J Cardiol 

2004;94(3):312-5. 

38. Parkash R, Tang A, Wells G, et al. Use of 

implantable cardioverter defibrillators after out-ofhospital cardiac arrest: a prospective follow-up

study. Can Med Assoc J 2004;171(9): 1053-6.

39. Perucca A, Parravicini U, Iraghi G, et al. Il decubito 

tardivo della tasca pacemaker o defibrillatore

implantabile: indagine epidemiologica di tre anni in 

Piemonte-Valle d'Aosta [The late pacemaker pocket 

erosion or implantable defibrillator: epidemiological

survey for three years in Piedmont-Valle d'Aosta]. 

(Ita). 2005;(3):157-64. 

40. Pratt CM, Dorian P, Al-Khalidi HR, et al. Design of 

the SHock Inhibition Evaluation with Azimilide 

(SHIELD) study: a novel method to assess 

antiarrhythmic drug effect in patients with an

implantable cardioverter-defibrillator. Am J Cardiol 

2005;95(2):274-6. 

41. Raitt MH, Klein RC, Wyse DG, et al. Comparison 

of arrhythmia recurrence in patients presenting with 

ventricular fibrillation versus ventricular 

tachycardia in the Antiarrhythmics Versus

Implantable Defibrillators (AVID) trial. Am J 

Cardiol 2003;91(7):812-6. 

42. Rankovic V, Karha J, Passman R, Kadish AH, 

Goldberger JJ. Predictors of appropriate implantable 

cardioverter-defibrillator therapy in patients with

idiopathic dilated cardiomyopathy. Am J Cardiol 

2002;89(9):1072-6. 

43. Russo AM, Hafley GE, Lee KL, et al. Racial 

differences in outcome in the Multicenter 

UnSustained Tachycardia Trial (MUSTT): a 

comparison of whites versus blacks. Circulation 

2003;108(1):67-72. 

44. Russo AM, Stamato NJ, Lehmann MH, et al. 

Influence of gender on arrhythmia characteristics 

and outcome in the Multicenter UnSustained 

Tachycardia Trial. J Cardiovas Electrophysiol 

2004;15(9):993-8. 

45. Schaechter A , Kadish AH, DEFibrillators In NonIschemic Cardiomyopathy Treatment Evaluation. 

DEFibrillators In Non-Ischemic Cardiomyopathy

Treatment Evaluation (DEFINITE). Cardiac

Electrophysiol Rev 2003;7(4):457-62. 

46. Schron EB, Exner DV, Yao Q, et al. Quality of life

in the antiarrhythmics versus implantable

defibrillators trial: impact of therapy and influence 

of adverse symptoms and defibrillator shocks. 

Circulation 2002;105(5):589-94. 

47. Shinde AA, Juneman EB, Mitchell B, et al. Shocks

from pacemaker cardioverter defibrillators increase 

with amiodarone in patients at high risk for sudden 

cardiac death. Cardiology 2003;100(3):143-8. 

48. Singh JP, Hall WJ, McNitt S, et al. Factors 

influencing appropriate firing of the implanted

defibrillator for ventricular tachycardia/fibrillation: 

findings from the Multicenter Automatic

Defibrillator Implantation Trial II (MADIT-II). J 

Am Coll Cardiol 2005;46(9):1712-20. 

49. Sinha AM, Stellbrink C, Schuchert A, et al. Clinical

experience with a new detection algorithm for

differentiation of supraventricular from ventricular

tachycardia in a dual-chamber defibrillator. J

Cardiovas Electrophysiol 2004;15(6):646-52. 

50. Steinbeck G, Andresen D, Senges J, et al. 

Immediate Risk-Stratification Improves Survival 

(IRIS): study protocol. Europace 2004;6(5):392-9.

51. Steinberg JS, Arshad A, Kowalski M, et al. 

Increased incidence of life-threatening ventricular

arrhythmias in implantable defibrillator patients 

after the World Trade Center attack. J Am Coll

Cardiol 2004;44(6):1261-4. 

52. Steinberg JS, Fischer A, Wang P, et al. The clinical

implications of cumulative right ventricular pacing

in the multicenter automatic defibrillator trial II. J 

Cardiovas Electrophysiol 2005;16(4):359-65. 

53. Tanno K, Miyoshi F, Watanabe N, et al. Are the 

MADIT II criteria for ICD implantation appropriate

for Japanese patients? Circ J 2005;69(1):19-22. 

54. Tiroke A, Syrkin AL, Ganeeva ON. Prediktory

vozniknoveniia zhizneugrozhaiushchikh narushenii 

ritma kardioverterami-defibrilliatorami [Predictors 

of life-threatening arrhythmias in patients with

implanted cardioverters-defibrillators]. (Rus). Klin

Med 2003;81(3):16-8. 

55. Van Ittersum M, De Greef M, Van Gelder I, Coster 

J, Brugemann J, Van Der Schans C. Fear of exercise

and health-related quality of life in patients with an 

implantable cardioverter defibrillator. Int J Rehabil 

Res 2003;26(2):117-22. 

D-26 
 

56. Voigt A, Shalaby A, Saba S. Rising rates of cardiac 

rhythm management device infections in the United 

States: 1996 through 2003. 2006-;48( 3):590-1.

57. Vollmann D, Luethje L, Zenker D, Domhof S, 

Unterberg C. Subthreshold test pulses versus low 

energy shock delivery to estimate high energy lead 

impedance in implanted cardioverter defibrillator

patients. Pacing Clin Electrophysiol 2003;26(1 

II):457-60. 

58. Watanabe H, Chinushi M, Izumi D, et al. Decrease 

in amplitude of intracardiac ventricular electrogram 

and inappropriate therapy in patients with an

implantable cardioverter defibrillator. Int Heart J

2006;47(3):363-70. 

59. Werling C, Weisse U, Siemon G, et al. 

Biventricular pacing in patients with ICD: how

many patients are possible candidates? Thorac 

Cardiovasc Surg 2002;50(2):67-70. 

60. Whang W, Mittleman MA, Rich DQ, et al. Heart

failure and the risk of shocks in patients with

implantable cardioverter defibrillators: results from

the Triggers Of Ventricular Arrhythmias (TOVA) 

study. Circulation 2004;109(11):1386-91. 

61. Wittenberg SM, Cook JR, Hall WJ, et al. 

Comparison of efficacy of implanted cardioverterdefibrillator in patients with versus without diabetes 

mellitus. Am J Cardiol 2005;96( 3):417-9. 

62. Zareba W, Moss AJ, Jackson Hall W, et al. Clinical 

course and implantable cardioverter defibrillator

therapy in postinfarction women with severe left

ventricular dysfunction. J Cardiovas Electrophysiol 

2005;16(12):1265-70. 

63. Zareba W, Piotrowicz K, McNitt S, Moss AJ,

MADIT II Investigators. Implantable cardioverterdefibrillator efficacy in patients with heart failure 

and left ventricular dysfunction (from the MADIT 

II population). Am J Cardiol 2005;95(12):1487-91. 

64. Zareba W, Steinberg JS, McNitt S, Daubert JP,

Piotrowicz K, Moss AJ. Implantable cardioverterdefibrillator therapy and risk of congestive heart 

failure or death in MADIT II patients with atrial

fibrillation. Heart Rhythm 2006;3(6):631-7. 

Study Design 

1. Al-Ahmad A, Link M, Estes NA 3rd, Wang PJ. 

Inappropriate shock and pacing? J Cardiovas 

Electrophysiol 2003;14(2):220-2. 

2. Al-Ahmad A, Wang PJ, Homoud MK, Estes NA 

3rd, Link MS. Frequent ICD shocks due to double 

sensing in patients with bi-ventricular implantable 

cardioverter defibrillators. J Interv Card 

Electrophysiol 2003;9(3):377-81. 

3. Al-Khadra AS. Implantation of pacemakers and

implantable cardioverter defibrillators in orally

anticoagulated patients. Pacing Clin Electrophysiol 

2003;26(1 Pt 2):511-4. 

4. Barbone A, Pini D, Grossi P, et al. Aspergillus left

ventricular assist device endocarditis. Ital Heart J 

2004;5(11):876-80. 

5. Basarakodu K, Lakkireddy D, Li H, Tchou P. 

"Porcelain pocket": dystrophic calcification of an

implantable cardiac defibrillator pocket presenting 

as impending erosion. Heart Rhythm 

2005;2(7):787-8. 

6. Bokhari F, Newman D, Mangat I, et al. Which is

better over the long term: Amiodarone or the 

implantable cardioverter defibrillator? Cardiol Rev 

2005;22(11):21-3. 

7. Bourke JP, Turkington D, Thomas G, McComb JM, 

Tynan M. Florid psychopathology in patients 

receiving shocks from implanted cardioverterdefibrillators. Heart 1997;78(6):581-3. 

8. Bracke F, van Gelder B, Dijkman B, Meijer A.

Lead system causing twiddler's syndrome in 

patients with an implantable cardioverterdefibrillator. J Thorac Cardiovasc Surg 

2005;129(1):231-2. 

9. Brilakis ES, Friedman PA, Maounis TN, et al. 

Programmed ventricular stimulation in patients with 

idiopathic dilated cardiomyopathy and syncope 

receiving implantable cardioverter-defibrillators: a

case series and a systematic review of the literature. 

[Review] [23 refs]. Int J Cardiol 2005;98(3):395-

401. 

10. Bryant J, Brodin H, Loveman E, Payne E, Clegg A. 

The clinical and cost-effectiveness of implantable 

cardioverter defibrillators: A systematic review.

Health Technol Assess (Winchester, England). 

11. Burkhardt JD , Wilkoff BL. Malfunctions in 

implantable cardiac devices: putting the risk in 

perspective. [Review] [11 refs]. Cleve Clin J Med 

2005;72(9):736, 738, 742. 

D-27 
 

12. Cawley PJ, Al-Khatib SM. Amiodarone versus 

implantable cardioverter defibrillator for

asymptomatic nonsustained ventricular tachycardia 

in nonischemic dilated cardiomyopathy. Am Heart J 

2004;147(5):790-1. 

13. Centre for Reviews and Dissemination.

Effectiveness of implantable defibrillators for

preventing arrhythmic events and death: a metaanalysis (Structured abstract). Database of Abstracts 

of Reviews of Effectiveness 2005;(4). 

14. Centre for Reviews and Dissemination. Outcomes 

from the use of the implantable cardiac defibrillator: 

a critical appraisal of the literature (Structured

abstract). Database of Abstracts of Reviews of 

Effectiveness 2005;(4). 

15. Chan NY, Wai-Ling Ho L. Inappropriate 

implantable cardioverter-defibrillator shock due to 

external alternating current leak: report of two 

cases. Europace 2005;7(2):193-6. 

16. Coleman DB, DeBarr DM, Morales DL, Spotnitz 

HM. Pacemaker lead thrombosis treated with atrial

thrombectomy and biventricular pacemaker and

defibrillator insertion. [Review] [26 refs]. Ann 

Thorac Surg 2004;78(5):e83-4.

17. Cook RJ, Orszulak TA, Nkomo VT, Shuford JA, 

Edwards WD, Ryu JH. Aspergillus infection of 

implantable cardioverter-defibrillator. [Review] [21 

refs]. Mayo Clin Proc 2004;79(4):549-52. 

18. Cron TA, Schaer B, Osswald S. Implantable 

cardioverter defibrillator proarrhythmia due to an

interaction with 'noncompetitive atrial pacing': an

algorithm to prevent atrial arrhythmias. Pacing Clin 

Electrophysiol 2002;25(11):1656-9. 

19. De Sousa J. Efficacy of implantable cardioverterdefibrillators: from trials to the real world. Rev Port 

Cardiol 2005;24(4):501-4. 

20. Dilling-Boer D, Ector H, Willems R, Heidbuchel H. 

Pericardial effusion and right-sided pneumothorax 

resulting from an atrial active-fixation lead.

Europace 2003;5(4):419-23. 

21. Disertori M, El-Sherif N. Primary prevention of 

sudden cardiac death. Do we need to implant a 

defibrillator in all the patients with low ejection

fraction? Ital Heart J 2004;5(9):643-7. 

22. Eldadah ZA, Donahue JK. Successful implantable

cardioverter defibrillator placement in an

ambulatory patient without thoracic venous access. 

J Cardiovas Electrophysiol 2004;15( 6):716-8.

23. Emori T, Ohta K, Kusano K, et al. Clusters of 

ventricular fibrillation in a patient with an

implantable cardioverter difibrillator treated with

amiodarone. Circ J 2003;67(2):163-5. 

24. Estes NAM, Weinstock J, Wang PJ, Homoud MK, 

Link MS. Use of Antiarrhythmics and Implantable 

Cardioverter Defibrillators in Congestive Heart 

Failure: Resynchronizing the rhythm in congestive 

heart failure. Naccarelli GVExcerpta Medica, 2003: 

45D-52D. 

25. Ezekowitz JA , Armstrong PW, McAlister FA. 

Implantable cardioverter defibrillators in primary 

and secondary prevention: a systematic review of

randomized, controlled trials. [Review] [39 refs].

Ann Intern Med 2003;138(6):445-52. 

26. Fontaine G, Prost-Squarcioni C. Implantable 

cardioverter defibrillator in arrhythmogenic right

ventricular cardiomyopathies. Circulation 

2004;109(12):1445-7. 

27. Goeb JL, Galloyer-Fortier A, Dupuis JM, Victor J,

Gohier B, Garre JB. Consequence psychiatrique 

apres l'implantation dun defibrillateur automatique: 

a propos d'un cas [Psychiatric complication of an 

implanted automatic defibrillator]. (Fre). Arch Mal 

Coeur Vaiss 2003;96(12):1235-8. 

28. Grimm W. Is prophylactic ICD therapy effective in 

dilated cardiomyopathy? Cardiol Rev 

2002;19(13):20-4. 

29. Gronefeld G, Connolly SJ, Hohnloser SH, 

Defibrillator in Acute Myocardial Infarction Trial 

investigators. The Defibrillator in Acute Myocardial 

Infarction Trial (DINAMIT): rationale, design and 

specific aims. [Review] [39 refs]. Cardiac 

Electrophysiol Rev 2003;7(4):447-51. 

30. Gronefeld G, Kleine P, Israel CW, Hohnloser SH. 

'Twiddler syndrome' in a subpectorally implanted

cardioverter defibrillator. J Cardiovas 

Electrophysiol 2002;13(1):94. 

31. Gurevitz O, Lipchenca I, Yaacoby E, et al. STsegment deviation following implantable 

cardioverter defibrillator shocks: incidence, timing, 

and clinical significance. Pacing Clin Electrophysiol 

2002 ;25(10):1429-32. 

32. Healy E, Goyal S, Browning C, et al. Inappropriate 

ICD therapy due to proarrhythmic ICD shocks and 

hyperpolarization. Pacing Clin Electrophysiol 

2004;27(3):415-6. 

D-28 
 

33. Helmberger TK, Roth U, Empen K. Massive air 

embolism during interventional laser therapy of the 

liver: Successful resuscitation without chest 

compression. Cardiovasc Intervent Radiol 

2002;25(4):335-6. 

34. Herweg B, Barold SS. Ventricular asystole during

atrial antitachycardia pacing by implanted 

cardioverter-defibrillator. Pacing Clin 

Electrophysiol 2005;28(5):432-3. 

35. Ho ICK, Milan DJ, Mansour MC, et al. Fungal 

infection of implantable cardioverter-defibrillators:

case series of five patients managed over 22 years.

Heart Rhythm 2006;3(8):919-23. 

36. Hohnloser SH , Ikeda T, Bloomfield DM, Dabbous 

OH, Cohen RJ. T-wave alternans negative coronary

patients with low ejection and benefit from

defibrillator implantation. Lancet

2003;362(9378):125-6. 

37. Kanagaratnam L, Pavia S, Schweikert R, et al. 

Matching approved "nondedicated" hardware to 

obtain biventricular pacing and defibrillation: 

feasibility and troubleshooting. Pacing Clin

Electrophysiol 2002;25(7):1066-71. 

38. Karchmer AW, Longworth DL. Infections of 

intracardiac devices. [Review] [114 refs]. Cardiol 

Clin 2003;21(2):253-71. 

39. Khan MN, Joseph G, Khaykin Y, Ziada KM,

Wilkoff BL. Delayed lead perforation: A disturbing 

trend. Pacing Clin Electrophysiol 2005;28(3):251-3. 

40. Khoo MSC, Scholl F, Dignan R, Rottman JN. 

Migration and infection of a pace-sense lead from

an abdominal defibrillator system. Pacing Clin

Electrophysiol 2002;25(11):1652-5. 

41. Kolb C, Schmieder S, Schmitt C. Inappropriate

shock delivery due to interference between a 

washing machine and an implantable cardioverter

defibrillator. J Interv Card Electrophysiol

2002;7(3):255-6. 

42. Kostopoulou A, Sbarouni E, Livanis EG, 

Theodorakis GN, Kremastinos D. Superior vena 

cava syndrome and syncope in an implantable 

cardioverter defibrillator recipient. Europace

2004;6(3):205-8. 

43. Kouakam C. Le suivi du patient portuer d'un

defibrillateur implantable [Follow-up of patients 

with implantable defibrillators]. (Fre). Arch Mal

Coeur Vaiss 2004;(127):18-9. 

44. Kubota T, Tomita M, Sakurai T, et al. An ICD 

implanted DCM patient due to sustained VT. (Jap). 

Ther Res 2002;23(10):2012-5. 

45. Kurita T, Mitamura H, Aizawa Y, et al. Japanese

randomized trial for investigation of a combined 

therapy of amiodarone and implantable cardioverter 

defibrillator in patients with ventricular tachycardia 

and fibrillation: the Nippon ICD Plus 

Pharmachologic Option Necessity study design.

Circ J 2006;70(3):316-20. 

46. Kutalek SP. Pacemaker and defibrillator lead 

extraction. [Review] [29 refs]. Curr Opin Cardiol 

2004;19(1):19-22. 

47. Lau EW, Birnie DH, Lemery R, Tang AS, Green

MS. Acupuncture triggering inappropriate ICD 

shocks. Europace 2005;7(1):85-6 . 

48. Lau EW, Green MS, Birnie DH, Lemery R, Tang

ASL. Ventricular tachycardia terminated by an

ICD: Is there more than what meets the eye? Pacing 

Clin Electrophysiol 2004;27(12):1656-8. 

49. Lee DS, Green LD, Liu PP, et al. Effectiveness of

implantable defibrillators for preventing arrhythmic 

events and death: a meta-analysis. J Am Coll

Cardiol 2003;41(9):1573-82. 

50. Lee DSY, Green LD, Liu PP, Grant FC, Alter DA.

Implantable defibrillators vs antiarrhythmic drugs 

for left ventricular dysfunction. Cochrane Database 

Syst Rev 2005;4.

51. Levine PA, Stanton MS, Sims JJ. High quality

performance of pacemakers and implantable 

defibrillators. Pacing Clin Electrophysiol

2002;25(12):1667-9. 

52. Lin D, Dixit S, Russo AM, Hsia HH. Total failure 

to sense ventricular fibrillation with inappropriate 

defibrillator sensitivity adjustment. Pacing Clin

Electrophysiol 2004;27(9):1321-3. 

53. Liu BC, Villareal RP, Hariharan R, Rasekh A, 

Massumi A. Inappropriate shock delivery and 

biventricular pacing cardiac defibrillators. Tex

Heart Inst J 2003;30(1):45-9. 

54. Manolis AG, Chatzis DG. Electrical storm in ICD

recipients: Incidence, causes, and prognosis. 

Mediterranean J Pacing Electrophysiol 

2003;5(3):135-8. 

55. Manolis AG, Katsivas AG, Vassilopoulos C, 

Tsatiris CG. Electrical storms in an ICD-recipient

with 429 delivered appropriate shocks: therapeutic 

management with antiarrhythmic drug combination. 

J Interv Card Electrophysiol 2002;6(1):91-4. 

D-29 
 

56. McBride BF, Guertin D, White CM, Kluger J. 

Inappropriate implantable cardioverter defibrillator 

discharge following consumption of a dietary

weight loss supplement. Pacing Clin Electrophysiol 

2004;27(9):1317-20. 

57. McClellan MB , Tunis SR. Medicare coverage of 

ICDs. New Engl J Med 2005;352(3):222-4. 

58. Meisel SR, Mazur A, Chetboun I, et al. Usefulness 

of implantable cardioverter-defibrillators in

refractory variant angina pectoris complicated by

ventricular fibrillation in patients with 

angiographically normal coronary arteries. Am J

Cardiol 2002;89(9):1114-6. 

59. Melon P. Prevention primaire de la mort subite en

2003: role due defibrillateur automatique 

implantable [Implantable cardioverter-defibrillator 

in primary prevention of sudden cardiac death]. 

(Fre). Rev Med Liege 2003;58(6):396-9. 

60. Messali A, Thomas O, Chauvin M, Coumel P, 

Leenhardt A. Death due to an implantable

cardioverter defibrillator. J Cardiovas 

Electrophysiol 2004;15(8):953-6. 

61. Moore DR, Kok LC, Vijayaraman P. Apparent 

inappropriate shocks from an implantable 

cardioverter defibrillator. J Cardiovas 

Electrophysiol 2004;15(1):116-7. 

62. Morishima I, Sone T, Tsuboi H, Kondo J, Mukawa 

H. Follow-up X rays play a key role in detecting

implantable cardioverter defibrillator lead fracture: 

a case of incessant inappropriate shocks due to lead 

fracture. Pacing Clin Electrophysiol 2003;26(4 Pt 

1):911-3. 

63. Moss A, Zareba W, Hall J, et al. Prophylactic

implantation of a defibrillator improves survival in 

people with prior myocardial infarction and

advanced left ventricular dysfunction. Evid Based

Cardiovasc Med 2002;6(4):141-2.

64. Mykytsey A, Maheshwari P, Dhar G, et al. 

Ventricular tachycardia induced by biventricular

pacing in patient with severe ischemic 

cardiomyopathy. J Cardiovas Electrophysiol 

2005;16(6):655-8. 

65. Nandakumar R , Broadhurst P. An unusual obstacle 

in lead extraction. Pacing Clin Electrophysiol 

2004;27(11):1576-7. 

66. Nanthakumar K, Epstein AE, Kay GN, Plumb VJ,

Lee DS. Prophylactic implantable cardioverterdefibrillator therapy in patients with left ventricular 

systolic dysfunction: a pooled analysis of 10

primary prevention trials. J Am Coll Cardiol

2004;44(11):2166-72. 

67. Neu P, Godemann F. Ersterkrankung einer 

Panikstorung mit Agoraphobie induziert durch eine

Schockserie eines defekten Defibrillators [First 

onset of panic disorder and agoraphobia induced by

a series of inappropriate shocks of an implanted 

cardioverter/defibrillator]. (Ger). Nervenarzt

2003;74(3):266-8. 

68. O'Rourke S, Kapoor S, Carter-Adkins D, Pachulski 

RT. ICD nocardiosis. J Intervent Cardiol 

2003;16(5):375-6. 

69. Oliveira M, da Silva N, Antunes E, et al. Detection 

of minor myocardial damage during implantation of 

transvenous cardioverter-defibrillators. 

Mediterranean J Pacing Electrophysiol 2004;6(1):1-

6. 

70. Omoto T, Hansky B, Minami K, Vogt J, Lamp B, 

Korfer R. Successful bridging by biventricular

pacing for heart transplantation. Ann Thorac Surg 

2002;74(5):1684-5. 

71. Pai RK, Cadman CS. Subcutaneous implantable 

cardioverter-defibrillator lead erosion after weight

loss. Cardiol Rev 2005;13(1):27.

72. Pai RK, Pergam SA, Kedia A, Cadman CS, Osborn 

LA. Pacemaker lead infection secondary to

Haemophilus parainfluenzae. Pacing Clin 

Electrophysiol 2004;27(7):1008-10. 

73. Paraskevaidis S, Polymeropoulos KP, Louridas G. 

Inappropriate ICD therapy due to electrical 

interference: external alternating current leakage. J

Invasive Cardiol 2004;16(6):339. 

74. Pezawas T, Stix G, Kastner J, et al. Unexplained

syncope in patients with structural heart disease and 

no documented ventricular arrhythmias: value of 

electrophysiologically guided implantable

cardioverter defibrillator therapy. Europace

2003;5(3):305-12. 

75. Pickett RA 3rd, Saavedra P, Ali MF, Darbar D,

Rottman JN. Implantable cardioverter-defibrillator 

malfunction due to mechanical failure of the header 

connection. J Cardiovas Electrophysiol 

2004;15(9):1095-9. 

76. Prudente LA. Phantom shock in a patient with an

implantable cardioverter defibrillator: case report.

Am J Crit Care 2003;12(2):144-6. 

77. Pyatt JR, Trenbath D, Chester M, Connelly DT. The 

simultaneous use of a biventricular Implantable 

Cardioverter Defibrillator (ICD) and 

Transcutaneous Electrical Nerve Stimulation 

(TENS) unit: implications for device interaction.

Europace 2003;5(1):91-3. 

D-30 
 

78. Raitt MH. Have increasing rates of defibrillator

implantation reduced the incidence of out-ofhospital cardiac arrest? Heart Rhythm

2004;1(3):260-1. 

79. Rinaldi CA, Simon RD, Baszko A, et al. A 17 year 

experience of inappropriate shock therapy in 

patients with implantable cardioverter-defibrillators: 

are we getting any better? Heart 2004;90(3):330-1. 

80. Sato Y, Horiguchi T, Nishikawa T. Anesthetic 

management of cardiac tamponade after dualchamber implantable cardioverter defibrillator

implantation in a patient with dilated 

cardiomyopathy. J Clin Anesth 2004;16(7):554-6. 

81. Schliamser JE, Avramovitch NA, Karkabi B,

Flugelman MY, Militianu A, Lewis BS. 

Rhabdomyolysis induced by repeated internal 

cardioverter defibrillator discharges. Pacing Clin 

Electrophysiol 2002 ;25(4 Pt 1):516-7. 

82. Shah KB, Gottlieb SS. Implantable cardioverterdefibrillator therapy after myocardial infarction. N 

Engl J Med 2005;352(10):1039-41; author reply

1039-41. 

83. Shapiro M, Hanon S, Schweitzer P. A rare, late 

complication after automated implantable

cardioverter-defibrillator placement. Indian Pacing

Electrophysiol J 2004;4(4):213-6. 

84. Sharifi M, Inbar S, Neckels B, Shook H. Twiddling 

to the extreme: development of twiddler syndrome 

in an implanted cardioverter-defibrilllator. J 

Invasive Cardiol 2005;17(3):195-6. 

85. Shevchenko IuL, Stonogin AV, Popov LV, et al. [A 

case of electrodeinduced endocarditis]. (Rus). Klin

Med 2005;83(5):66-8. 

86. Sinclair CT, Marymount III JH, Rozner MA, 

DiMarco JP. Implantable cardioverter-defibrillators 

and complications [5] (multiple letters). N Engl J 

Med 2004;350(7):734-5. 

87. Siu CW, Tse HF, Lau CP. Inappropriate 

implantable cardioverter defibrillator shock from a 

transcutaneous muscle stimulation device therapy. J 

Interv Card Electrophysiol 2005;13(1):73-5. 

88. Sochman J, Bytesnik J, Skalsky I, Peregrin JH.

Percutaneous extraction of a severed and frayed 

permanent pacing lead. Pacing Clin Electrophysiol 

2004;27(3):412-4. 

89. Sola CL, Bostwick JM. Implantable cardioverterdefibrillators, induced anxiety, and quality of life. 

[Review] [43 refs]. Mayo Clin Proc 

2005;80(2):232-7. 

90. Srivathsan K, Bazzell JL, Lee RW. Biventricular

implantable cardioverter defibrillator and 

inappropriate shocks. J Cardiovas Electrophysiol 

2003;14(1):88-9. 

91. Steinbeck G, Andresen D, Senges J. Implantable 

cardioverter-defibrillator therapy after myocardial

infarction. New Engl J Med 2005;352(10):1039-41; 

author reply 1039-41. 

92. Steinbrook R. The controversy over Guidant's 

implantable defibrillators. New Engl J Med

2005;353(3):221-4. 

 93. Straburzynska-Migaj E, Baszko A, Ochotny R,

Cieslinski A. Bezpieczenstwo i przydatnosc

kliniczna testo w wysikowych u chorych z 

niewydolnoscia serca oraz wszczepionym

kariowerterem-defibrylatorem [Safety and clinical

usefulness of exercise stress tests in patients with 

heart failure and implantable cardioverterdefibrillator]. (Pol). Folia Cardiol 2004;11(12):953-

60. 

94. Swanton BJ, Keane D, Vlahakes GJ, Streckenbach

SC. Intraoperative transesophageal 

echocardiography in the early detection of acute

tamponade after laser extraction of a defibrillator

lead. Anesth Analg 2003;97(3):654-6. 

95. Swerdlow CD. Reappraisal of implant testing of

implantable cardioverter defibrillators. J Am Coll 

Cardiol 2004;44(1):92-4. 

96. Tanabe Y, Chinushi M, Washizuka T, et al. 

Suppression of electrical storm by biventricular

pacing in a patient with idiopathic dilated 

cardiomyopathy and ventricular tachycardia. Pacing 

Clin Electrophysiol 2003;26(1 Pt 1):101-2. 

97. Vollmann D, Luthje L, Vonhof S, Unterberg C.

Inappropriate therapy and fatal proarrhythmia by an 

implantable cardioverter-defibrillator. Heart 

Rhythm 2005;2(3):307-9. 

98. Waheed A, Romano J, Raman AA, Raman A.

Candida glabrata: an unexpected culprit in

endocarditis from an ICD lead. J Crit Illn

2003;18(4):171-3. 

99. Wase A. Random internal component failure of an 

implantable cardioverter defibrillator. J Interv Card 

Electrophysiol 2004;10(2):175-6. 

100. Wasson S, Aggarwal K, Flaker G, Reddy HK. Role 

of transesophageal echocardiography in detecting 

implantable cardioverter defibrillator lead infection. 

Echocardiography 2003;20(3):289-90. 

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 101. Wayar L, Mont L, Silva RMFL, et al. Electrical 

interference from an abdominal muscle stimulator

unit on an implantable cardioverter defibrillator: 

report of two consecutive cases. Pacing Clin 

Electrophysiol 2003;26(5):1292-3. 

102. Wever EF, Hauer RN, van Capelle FL, et al 

Randomized study of implantable defibrillator as

first-choice therapy versus conventional strategy in 

postinfarct sudden death survivors. Circulation 

1995;91 :2195-203. 

103. Wonisch M, Lercher P, Scherr D, et al. Influence of 

permanent right ventricular pacing on 

cardiorespiratory exercise parameters in chronic

heart failure patients with implanted cardioverter 

defibrillators. Chest 2005;127(3):787-93. 

 104. Yagi S, Tsuda E, Shimizu W, et al. Two adults 

requiring implantable defibrillators because of

ventricular tachycardia and left ventricular

dysfunction caused by presumed Kawasaki disease. 

Circ J 2005;69(7):870-4. 

105. Yasuda M, Nakazato Y, Sasaki A, et al. Ventricular 

fibrillation refractory to ICD therapy. Intern Med

2005;44(8):829-31. 

Not Obtained 

1. Bondke H, Witte J, Schonfeld G, Baumann G. Verlauf 

bei 221 ICD-patienten ohne Pra-Hospital-Discharge 

(PHD)-tests. [Course in 221 ICD patients without 

prehospital discharge tests]. (Ger).

Herzschrittmacherther Elektrophysiol 2003;14(suppl 

1):74-5. 

2. McGregor M CJ. Use of the implantable cardiac

defibrillator (ICD) at the McGill University Health 

Centre (MUHC). 2003. 

3. Mendoza Gonzalez C, Iturralde Torres P, Guevara 

Valdivia ME, et al. Seguimiento de un grupo de 

 pacientes con desfibrilador automatico implantable 

[Follow-up of a group of patients with automatic 

implantable defibrillator]. (Spa). Arch Cardiol Mex 

2002;72(3):220-6. 

4. Schuchert A, Winter J, Binner L, Meinertz T. Kurzere

lmplantationszeiten und weniger 

sondenkomplikationen mit neueren implantierbaren 

defibrillatoren [Shorter implantation times and fewer 

lead complications with new implantable cardioverter

defibrillators]. (Ger). Herzschrittmacherther

Elektrophysiol 2003;14(suppl 1):24-5. 

5. Suga C, Matsumoto K, Kato R, et al. [Clinical

characteristics of inappropriate therapy delivery of

implantable cardioverter defibrillator]. (Jap). Ther Res

2004;25(10):2029-3.

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APPENDIX E: Technical Expert Panel 

and Peer Reviewers 

Technical Expert Panel 

William T. Abraham, M.D., F.A.C.P., F.A.C.C., F.A.H.A. 

Professor of Medicine, Chief Division of Cardiovascular Medicine 

The Ohio State University, Columbus, OH 

Mark A. Hlatky, M.D. 

Department of Health Research and Policy 

Stanford University, Stanford, CA 

Richard L. Page, M.D., FA.C.C., F.A.H.A. 

Professor and Head, Division of Cardiology, Department of Medicine 

University of Washington School of Medicine 

Seattle, WA

Gillian D. Sanders, Ph.D. 

Associate Professor or Medicine

Duke University Medical Center 

Durham, NC 

Peer Reviewers 

David Atkins, M.D., M.P.H. 

Chief Medical Officer, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Rockville, MD 

Eric Fain, M.D. 

Executive Vice President, Development and Clinical/Regulatory Affairs 

St. Jude Medical 

Sunnyvale, CA 

Martin Fromer, M.D., F.E.S.C. 

Service de Cardiologie 

Centre Hospitalier Universtaire Vaudois (CHUV) 

Lausanne, Switzerland 

E-1 
 

Gordon Moe, M.S., M.D., F.R.C.P.(C), F.A.C.C. 

Director, Heart Failure Program and Biomarker Laboratory, St. Michael's Hospital 

Associate Professor of Medicine, University of Toronto 

Toronto, ON 

 

Robert F. Rea, M.D. 

Division of Cardiovascular Diseases 

Mayo Clinic 

Rochester, MN 

John Spertus, M.D., M.P.H., F.A.C.C. 

Professor, School of Medicine; Director, Cardiovascular Education and Outcomes Research 

University of Missouri - Kansas City

Kansas City, MO 

Bob Thompson, M.S., M.A. 

Senior Director, Reimbursement, Economics and Health Policy

Medtronic 

Minneapolis, MN 

Clyde W.Yancy, M.D., F.A.C.C., F.A.H.A., F.A.C.P. 

Medical Director, Baylor Heart and Vascular Institute 

Baylor University Medical Center 

Dallas, TX 

E-2