Introduction

Heart failure is the fastest growing

cardiovascular diagnosis in North America, and it

carries a poor prognosis.1,2 To improve survival in

heart failure patients, therapies need to reduce

either sudden cardiac death (the most common

cause of death in patients with New York Heart

Association [NYHA] Class I or II symptoms) or

progressive heart failure (the predominant cause

of death in those with NYHA Class III or IV

symptoms).3,4

Electrical conduction disturbances are common

in heart failure and are associated with increased

mortality risk.5-7 Atrial-synchronized biventricular

pacing (cardiac resynchronization therapy [CRT])

addresses many of the pathophysiological changes

seen in patients with wide QRS complexes in

whom delayed activation of the left free wall

results in mechanical dyssynchrony. 

The University of Alberta Evidence-based

Practice Center conducted a systematic review to

examine the success rate and safety of

biventricular pacemaker implantation and the

efficacy of CRT in patients with heart failure.

Further, the researchers used these data in a

decision analysis to evaluate the incremental costeffectiveness of CRT versus medical therapy

alone. 

Methods

This report addresses the following questions:

1. In adult patients with symptomatic heart

failure, is CRT more effective than optimal

medical care alone? 

2. Is the implantation of a CRT system safe for

patients?

3. What is the role of CRT in the treatment of

heart failure?

4. What is the cost-effectiveness of CRT in

patients with congestive heart failure?

Literature Search

Detailed searches were conducted of the

Cochrane Heart Group Trial Registry, Cochrane

Library, EMBASE, International Pharmaceutical

Abstracts, MEDLINE®, Web of Science®, and

multiple trial registries. In addition, the

researchers contacted the primary authors of

included studies, sought U.S. Food and Drug

Administration reports, and reviewed the

reference lists of all included articles. Additional

unpublished data were sought from the

companies that produce CRT devices: Medtronic,

Inc., Guidant Corporation, and ELA Medical

(Montrouge, France). The search was not limited

by language or publication status and is

considered up to date as of June 30, 2003.

Selection and Data Extraction

Two investigators independently screened all

titles and abstracts, and another two investigators

independently assessed the full text of potentially

relevant studies and extracted data.

Disagreements were resolved through third-party

adjudication or consensus. 

Data Analysis

Intention-to-treat analyses were done using the

same standardized endpoint definitions employed

in the primary studies. Stata 7.0 (Stata

Evidence Report/Technology Assessment

Number 106

Cardiac Resynchronization Therapy for Congestive

Heart Failure

Summary

McAlister F, Ezekowitz J, Wiebe N, Rowe B, Spooner C, Crumley E, Hartling L, 

Kaul P, Nichol G, Klassen T

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

Corporation, version 7.0, 2003) was used to pool data and

calculate summary risk ratios for dichotomous results and

weighted mean differences for continuous variables. Because of

expected differences between studies (particularly in control

group therapies), the researchers decided a priori to combine

results primarily using a random effects model. Fixed effects

models were considered in sensitivity analyses. Statistical

heterogeneity was assessed by the chi-square test and was

quantified and appropriated using the I-squared statistic.8

Time-to-death data were summarized by the log hazards ratio;

Cox proportional hazards and/or Kaplan-Meier curves were

generated where appropriate.9,10

Simple pooling and exact 95-percent confidence intervals

(CIs) were used for the safety analyses. However, given the

possibility that reports may not always have reported zero for

adverse events that did not occur, the researchers performed

sensitivity analyses for safety outcomes in which they assumed

that, if a particular event (for example, peri-implantation death)

was not mentioned in a report, then it did not occur and

assigned a zero for that outcome in that study. 

Decision Analysis Methods

A Markov decision model was constructed to compare the

lifetime effects and costs of CRT versus medical therapy for

patients with symptomatic heart failure. The analysis adopted

the U.S. health care perspective (including costs of

hospitalization, procedures, ambulatory visits, medications, and

laboratory tests), and costs are expressed in 2003 American

dollars. Input data were derived from multiple sources:

1. Outcomes with CRT and risks of the procedure were

derived from a systematic review with annualization using

an exponential approximation.11,12 Transition probabilities

incorporated into the Markov model were adjusted for the

cycle length. 

2. The health-related quality of life of patients with heart

failure was estimated by eliciting utilities. Since the

purpose of the decision analytic model was to consider an

intervention in the context of resource allocation among

different types of interventions, a generic source of

preferences was used.13 A convenience sample (n = 66)

was recruited of members of the general public age 40 and

over and without underlying cardiac disease. Consenting

subjects estimated utilities for standardized health state

descriptions (NYHA Class II, III, and IV) by using the

standard gamble technique.14 Hypothetical scenarios

describing what one would typically feel and experience if

living with each of these health states were developed with

input from an expert panel based on descriptors from the

Health Utilities Index.15

3. The cost of a device capable of CRT was depreciated over

its anticipated lifespan. Physician costs related to CRT

implantation were based on Current Procedural

Terminology codes.16 The costs of a resynchronization

device were based on a survey of manufacturers’ list prices.

The costs of hospitalizations associated with heart failure

were based on estimates derived from a cohort study of

health resource use by patients participating in a previous

randomized trial of medical therapy for heart failure.17 All

costs were adjusted for inflation by using the U.S.

Consumer Price Index.18

Structure of Decision Model

The primary analysis considered patients with NYHA Class

III symptoms. The analysis considered the lifetime horizon and

employed a state-transition Markov model with a cycle length

of 1 month. During each cycle, patients who received medical

therapy could die of unrelated causes, die of cardiovascular

disease, be hospitalized for heart failure, or remain stable.

Patients who underwent insertion of a device capable of CRT

could die during the initial implantation of the device or

experience lead infection, lead failure, battery failure, or any of

the health states associated with medical therapy for heart

failure.

Decision analyses were performed with DATA ProTM

software (TreeAge Software, Inc., Williamstown, Massachusetts)

and Excel 2000 software (Microsoft Corporation, Redmond,

Washington). 

Assumptions in Decision Analysis

A number of assumptions were necessary because of the

paucity of several pieces of data. First, it was assumed that unit

costs of heart failure therapy were identical between medical

therapy and CRT. Second, it was assumed that the incidence

of complications associated with CRT was constant over time.

However, since the duration of followup in each trial was

relatively short and the incidence of adverse effects in these

trials was higher than generally accepted for ICD

implantation,19 the researchers considered lower incidences of

device or device-related adverse effects than observed in the

trials in the sensitivity analyses. Third, it was assumed that any

mechanical malfunction of the device required battery

replacement with consequent costs. Finally, age-specific

mortality due to unrelated causes was based on life tables.20
Uncertainty and Variability Analyses

The analysis distinguished between parameter uncertainty

(i.e., variation in costs and effects because of sampling and

measurement error) and variability (i.e., heterogeneity in costs

and effects between groups of patients with systematic

differences in cost or effects). Uncertainty was assessed by

using 10,000 probabilistic Monte Carlo simulations.21,22

Empirical cost variables were assigned log-normal distributions.

Empirical probability variables were assigned beta

distributions.21 Variables without a known distributional form

(i.e., those with assumed values or those with values based on a

range of published reports) were assigned triangular

distributions.23

Variability was assessed by substituting the value of each

variable in the decision model by its upper and lower limits

while holding all other values constant.24-26 For empirical

variables, these limits were the 95-percent confidence limits for

each variable. For assumed variables (e.g., cost of CRT device

insertion and discount rate), these limits were based on

reasonable possible limits (i.e., +50 percent). Threshold

analyses identified the value of each variable across its range, if

any, at which one should be indifferent between medical

therapy alone or CRT (i.e., the incremental cost per qualityadjusted life year was $100,000).26

Results

Literature Search

Nine trials reported on the efficacy of CRT; three included

implantable cardioverter-defibrillators (ICDs).27-34 Seventeen

studies (eight trials and nine prospective studies without control

arms) reported on the safety of CRT. Most of the trials were

associated with multiple publications that either expanded on

the main results or reported secondary outcomes not included

in the primary report. This summary includes the reference to

only the primary report for each trial. However, a full listing of

all publications is available in the full evidence report.

Description of Included Studies

All nine of the trials enrolled only patients with prolonged

QRS duration: >120 millisecond (msec) in three trials,27-29 >130

msec in two trials,30,31 >140 msec in one trial,32 >150 msec in

one trial,33 >180 msec in one trial, and >200 msec in the

remaining trial.34 Left bundle branch block was present in 64

percent of patients, and 95 percent of patients were in sinus

rhythm. All trials also restricted enrollment to patients with

reduced ejection fractions (<35 percent in six trials, <25 percent

in one trial, and <40 percent in the other), and the mean

ejection fractions were similar in all trials (from 21 percent to

26 percent). 

In total, 3,574 patients were enrolled and 3,216 were

randomized to receive CRT (n = 2,063) or control (most

commonly pacemaker turned off, n = 1,153) in the nine trials.

The mean age was 64 years, 74 percent were male, 75 percent

had NYHA Class III symptoms, and 10 percent had NYHA

Class IV symptoms. Two trials included some patients with

NYHA Class II symptoms.27,31 Most of the patients in these

trials had ischemic etiologies for their heart failure (mean 58

percent, range 29 percent to 69 percent). 

Including the nine additional single-arm prospective cohort

studies, a total of 3,512 patients who had undergone CRT

implantation were included in the safety analyses. 

Quantitative Results

All-cause mortality. Based on data pooled from the nine

randomized controlled trials, CRT significantly reduced allcause mortality (relative risk [RR] 0.75, 95-percent CI 0.60 to

0.93). The results were identical when analyses were limited to

patients with NYHA Class III or IV symptoms (RR 0.76, 95-

percent CI 0.60 to 0.95). There was no significant statistical

heterogeneity between trials (p = 0.88, I-squared = 0 percent).

The all-cause mortality rate in the control patients was 14.9

percent, and the number needed to treat (NNT) to prevent one

death in patients with symptomatic heart failure was 27. A

Cox proportional hazards model revealed that the mortality

hazard ratio with CRT was 0.59 (95-percent CI 0.43 to 0.81)

after the first 3 months.

Cardiac mortality. Seven trials reported progressive heart

failure mortality (n = 60 deaths in 1,647 patients); the relative

risk favored CRT (random effects RR 0.60, 95-percent CI 0.36

to 1.01; fixed effects RR 0.59, 95-percent CI 0.35 to 0.98).

Results were similar when analysis was restricted to patients

with NYHA Class III or IV symptoms (random effects RR

0.58, 95-percent CI 0.32 to 1.06). In contrast, CRT did not

significantly reduce overall cardiac deaths (n = 91 in 1,628

patients, RR 0.84, 95-percent CI 0.56 to 1.25) because of a

nonsignificant excess in sudden cardiac deaths (n = 28 in 1,691

patients, RR 1.99, 95-percent CI 0.95 to 4.16). Data on

causes of death for patients in the COMPANION trial28 were

not yet available.

Noncardiac mortality. Using data pooled from the six trials

that reported noncardiac death (RR 0.90, 95-percent CI 0.35

to 2.35), results for CRT and control therapy did not

significantly differ. 

Heart failure hospitalizations. The pooled data revealed

benefits with CRT (random effects RR 0.68, 95-percent CI

0.41 to 1.12; fixed effects RR 0.80, 95-percent CI 0.64 to

3
4

1.003). This result was heterogeneous (p = 0.01, I-squared =

65 percent). Restricting this analysis to patients with NYHA

Class III or IV symptoms revealed homogeneous (p = 0.31, Isquared = 16 percent) and statistically significant reductions in

heart failure hospitalizations (RR 0.65, 95-percent CI 0.48 to

0.88; NNT = 12).

Six-minute walk test. CRT was associated with an

improved 6-minute walk test, with a weighted mean difference

(WMD) of 23 meters (95-percent CI 9 m to 38 m). This

improvement was similar in patients with NYHA Class III or

IV symptoms (WMD 26 m, 95-percent CI 11 m to 41 m).

Although the data from the RD-CHF Trial were not available

for pooling, the RD-CHF investigators reported statistically

significant improvements in 6-minute walk test distances.35

New York Heart Association Functional Class.

Combining the data on change in NYHA class from the three

studies that reported this endpoint revealed that 57 percent of

CRT-treated patients, compared to 34 percent of controls,

improved by at least one NYHA class. Thus, CRT was

associated with an RR for improving at least one NYHA class

of 1.6 (95-percent CI 1.1 to 2.5). Although the data from

MIRACLE-ICD31 and RD-CHF were not reported in a way

that they could be pooled with the other trials, both reported

statistically significant improvements in NYHA class with CRT.

Quality of life. The minimal clinically important difference

for the Minnesota Living With Heart Failure® Questionnaire

has been established in placebo-controlled trials as being 5

points.36-38 Pooled results from the six trials that used the

Minnesota Living With Heart Failure Questionnaire showed a

statistically and clinically significant improvement with CRT

(WMD -5.5 points, 95-percent CI -9 to -2 points). This result

was statistically heterogeneous (p = 0.008, I-squared = 68

percent); however, results were consistent in direction in all six

trials. Restricting the analysis to only patients with NYHA

Class III or IV symptoms increased the difference between the

CRT and control groups (WMD -6.4 points, 95-percent CI 

-9.4 to -3.4 points), and the results were less heterogeneous (p

= 0.07, I-squared = 50 percent). Further, although the use of a

different scale prevented pooling with the other trials, the RDCHF investigators reported statistically significant

improvements in quality of life with CRT.35

Other outcomes. CRT was associated with improvements

in peak oxygen consumption (WMD versus control of 0.7

ml/kg/min, 95-percent CI 0.3 to 1.0 ml/kg/min), ejection

fraction (WMD 3.5 percent, 95-percent CI 1.5 to 5.5 percent),

and QRS interval (WMD 28 msec, 95-percent CI -47 to -9). 

Peri-implantation risks. Ten studies reported data on

deaths while undergoing implantation of a biventricular

pacemaker. There were 13 deaths in 3,113 patients (pooled

risk 0.4 percent, 95-percent CI 0.2 percent to 0.7 percent); a

sensitivity analysis, in which it was assumed any studies that did

not report mortality had zero occurrences, yielded the same

result. Device implantation was successful in 90 percent of

attempts (95-percent CI 89 percent to 91 percent) in 3,475

patients (16 studies). 

Post-implantation risks. Over a median 6 months of

followup, mechanical malfunction of the cardiac

resynchronization device was noted with 7 percent of successful

implants (95-percent CI 5 percent to 8 percent); on sensitivity

analysis, in which it was assumed any studies that did not

report this outcome had zero occurrences, this rate was 4

percent (95-percent CI 4 percent to 5 percent). Lead

dislodgment occurred in 9 percent of patients (95-percent CI 7

percent to 10 percent). There were no differences in lead

dislodgment in studies using specially designed left ventricular

leads; the estimate was reduced to 8 percent (7 percent to 10

percent) on sensitivity analysis. Post-implantation infection

(most commonly in the device pocket) occurred in 1.4 percent

of patients (95-percent CI 0.8 percent to 2.3 percent); the

estimate was reduced to 0.9 percent (95-percent CI 0.5 percent

to 1.4 percent) with sensitivity analysis. Two percent (95-

percent CI 1 percent to 3 percent) of patients had arrhythmias

in followup. 

Sensitivity Analyses for Systematic Review 

Using meta-regression (a between-study nonrandomized

comparison), the researchers explored the impact of CRT when

combined with ICDs. The benefits of CRT on all-cause

mortality and heart failure hospitalizations were not appreciably

different in patients with an ICD and patients without an

ICD. The data from COMPANION were not eligible for this

analysis since only one arm in COMPANION received both

CRT and an ICD.39 Indeed, the COMPANION trial data

permit the only direct comparison between CRT with/without

an ICD. While the chi-square test for all-cause mortality

approached significance (p = 0.07) in favor of cardiac

defibrillators with CRT, the reductions in heart failure

hospitalizations were similar in CRT-treated patients

with/without ICDs.28 However, until detailed data from the

COMPANION subanalyses are made available, the most

conservative conclusion to make is that the benefits of CRT are

similar with/without an ICD. 

Cost-Effectiveness of CRT

In patients with NYHA Class III heart failure, medical

therapy was associated with a median gain of 2.68 discounted

quality-adjusted life years (interquartile range [IQR] = 2.49 to

2.85) and median $34,700 lifetime costs (IQR = $31,100 to

$38,100). CRT was associated with a median gain of 3.03
discounted quality-adjusted life years (IQR = 2.82 to 3.27) and

median $67,600 lifetime costs (IQR = $62,000 to $73,800).

Thus, CRT was associated with an incremental cost of a

median $90,700 (IQR = $69,500 to $124,900) per additional

quality-adjusted life year. The cost-effectiveness acceptability

curve illustrates that the probability that resynchronization is

cost effective is less than 59 percent, given a maximum

willingness to pay for a quality-adjusted life year of $100,000. 

Variability Analyses

The incremental cost-effectiveness of CRT was sensitive to

reasonable changes in the values of several variables, particularly

the incidence of device-related complications.

Discussion

In summary, when added to medical therapy in patients with

symptomatic heart failure who have prolonged QRS duration

and reduced left ventricular ejection fraction, CRT reduces allcause mortality by 25 percent and heart failure hospitalizations

by 32 percent. These benefits were particularly marked in heart

failure patients at higher risk (i.e., those with NYHA Class III

or IV symptoms). These benefits are similar to those reported

for ACE inhibitors, beta-blockers, and aldosterone antagonists

in recent trials.40-43 CRT also conferred statistically and

clinically significant benefits in a variety of surrogate outcomes.

Indeed, a pooled six-point improvement on the Minnesota

Living With Heart Failure® Questionnaire is greater than that

seen in recent heart failure trials testing pharmacologic

therapies.44,45 However, CRT for patients with heart failure is

associated with large uncertainty in the incremental costs per

quality-adjusted life year; in particular, the results are sensitive

to the incidence of device-related adverse effects.

The survival benefits with CRT appear to be attributable

largely to reductions in progressive heart failure deaths and

become apparent by 3 months after implantation. This is not

surprising, as the benefits of CRT are thought to be mediated

through morphometric remodeling of the left ventricle (leading

to increased left ventricular filling time, reduced mitral

regurgitation, and reduced septal dyskinesis) rather than acute

changes in the neurohormonal system.46

While the researchers found a nonsignificant trend toward

increased sudden cardiac death that was consistent across these

trials, it was based on a very small number of events (28 in

total). In particular, the lack of difference in the number of

ventricular arrhythmia episodes between patients with

compared to without CRT in the MIRACLE-ICD Trial (22

percent vs. 26 percent, p = 0.47) suggests that the trend toward

excess sudden cardiac deaths may well be due to small

numbers.31 Regardless, the benefits of CRT are similar in

patients with or without implantable cardioverter-defibrillators,

providing some reassurance that, in those patients who have

indications for both a defibrillator and CRT, the two may be

administered together. The indications for an ICD in heart

failure patients without an ischemic etiology remain uncertain

pending completion of the SCD-HeFT Trial.47

An important finding of this systematic review is the safety

of CRT and its tolerability in patients with advanced heart

failure. Peri-implantation mortality rates were less than 1

percent and post-implantation infection rates were also low.

Although there were few serious complications, implantation of

a biventricular pacemaker (in particular the left ventricular lead)

is technically challenging: the systematic review identified a 10-

percent failure rate. Furthermore, even if implantation is

successful, patients with these devices require close followup, as

7 percent of devices malfunctioned over a median followup of

6 months and 9 percent of left ventricular leads dislodged.

Because these complications necessitate another procedure, the

failure rates have to be incorporated into any policy decisions.

Although the systematic review results are promising, the

results of the decision analysis suggest caution given the

magnitude of the uncertainty in the long-term results. Indeed,

the researchers believe that there are insufficient long-term

effectiveness and cost data to warrant broad implementation of

CRT at this time.

Limitations of Research

A substantial limitation of the trials included in this analysis

is that randomization occurred after implantation of the device

in all but one trial. This design, similar to the run-in period

used in some pharmaceutical trials, does not affect the internal

validity of the trials but does impact the generalizability of the

results, as patients who could not tolerate the procedure or in

whom implantation was unsuccessful were not included. As a

result, these trials likely overestimate the potential benefits from

CRT.48 Because very few patients in these trials had

bradyarrhythmias or atrial fibrillation, the role of CRT in such

patients is unknown and is an important area for further study,

particularly since almost one-third of CHF patients have atrial

fibrillation or indications for conventional pacemakers.49

Finally, it should be emphasized that only selected cases and

experienced providers participated in these trials, so it is

plausible that the observed complication rates may not be

applicable to other settings and, in particular, clinicians less

experienced with device implantation. If so, this decision

analysis overestimates survival and underestimates the

incremental cost of CRT. Conversely, if adverse effects are less

frequent as providers gain experience, the analysis may

underestimate survival and overestimate the incremental cost of

5
6

CRT. This is particularly important, since the results of the

analysis were sensitive to the rate of complications associated

with CRT. 

The decision analysis also has some limitations. First,

although cardiac resynchronization is more costly and more

effective than medical therapy, the incremental costeffectiveness ratio had a large range and there are insufficient

data to determine whether to adopt resynchronization therapy

for broad use. Second, it is likely that the incidence of

complications associated with CRT decreases over time,

although for the purposes of our analysis it had to be assumed

that they were constant. Thus, the model may underestimate

survival and overestimate the incremental cost-effectiveness of

CRT. Long-term followup of patients enrolled in the

previously completed trials will determine whether the

incidence of complications does indeed decline over time.

Third, it is unlikely that the relative benefits of CRT will be

constant, as the severity of heart failure varies. Therefore, as

results from other trials and registries become available, the

analysis should be revised to reflect better estimates of the true

effectiveness and costs of the program in patients with other

classes of CHF. Fourth, it was assumed that heart failure costs

were constant even though CRT will decrease heart failure costs

if ventricular remodeling decreases the frequency of use of

outpatient pharmaceuticals or duration of hospitalization.

Finally, the input data were derived from several sources and

may be confounded by information that was not incorporated

into the model. For example, the effectiveness of CRT was not

adjusted for the patient’s comorbid illnesses. 

Conclusions

CRT exerts a 24-percent relative reduction in all-cause

mortality (largely driven by a 42-percent reduction in

progressive heart failure deaths) and a 35-percent reduction in

heart failure hospitalizations in patients with reduced ejection

fractions, NYHA Class III or IV symptoms despite medical

management, and a prolonged QRS duration on

electrocardiogram. While preliminary data suggest similar

relative benefits in patients with NYHA Class II symptoms, this

is based on very few events. Further data are required before

extending the device indications beyond those currently

authorized by the U.S. Food and Drug Administration (i.e.,

patients with NYHA Class III or IV symptoms). Moreover, as

very few such patients were enrolled in the trials, the role of

CRT in patients with indications for conventional pacemakers

or with atrial fibrillation remains uncertain and requires further

study. Approximately 10 percent of heart failure patients have

NYHA Class III or IV symptoms, reduced ejection fraction,

and a prolonged QRS duration, and up to one-half of these

patients may also have indications for an implantable

cardioverter-defibrillator.50

While CRT should join the list of proven efficacious

therapies for selected patients with heart failure, it is an

expensive therapy and cost-effectiveness analysis reveals

uncertainty in the incremental costs per quality-adjusted life

year. In particular, there are insufficient long-term effectiveness

and cost data to determine whether CRT is sufficient value for

money to warrant its broad implementation at this time. This

is in contradistinction to ACE inhibitors, beta-blockers, and

spironolactone for patients with advanced symptomatic heart

failure. 

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the University of Alberta Evidence-based

Practice Center under Contract No. 290-02-0023. It is

expected to be available in November 2004. At that time,

printed copies may be obtained free of charge from the AHRQ

Publications Clearinghouse by calling 800-358-9295.

Requesters should ask for Evidence Report/Technology

Assessment No. 106, Cardiac Resynchronization Therapy for

Congestive Heart Failure. In addition, Internet users will be able

to access the report and this summary online through AHRQ’s

Web site at www.ahrq.gov.

Suggested Citation

McAlister F, Ezekowitz J, Wiebe N, Rowe B, Spooner C,

Crumley E, Hartling L, Kaul P, Nichol G, Klassen T. Cardiac

Resynchronization Therapy for Congestive Heart Failure.

Summary, Evidence Report/Technology Assessment No. 106.

(Prepared by the University of Alberta Evidence-based Practice

Center under Contract No. 290-02-0023.) AHRQ Publication

No. 05-E001-1. Rockville, MD: Agency for Healthcare

Research and Quality. November 2004.

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