Clinical trial NCT00251251: Resynchronization/Defibrillation for Ambulatory Heart Failure Trial
Official title: Resynchronization/Defibrillation for Ambulatory Heart Failure Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Failure, Congestive
Keywords: Congestive heart failure
Multicentre randomized controlled trial
Defibrillator
Cardiac resynchronization
Sudden death/mortality
Hospitalization
ICD indication
NYHA Class II
LVEF </equal to 30%
QRS >/equal to 120 ms
Lead sponsor: Ottawa Heart Institute Research Corporation
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Medtronic
First posted: 2005-11-09
Enrollment: 1798
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Congestive heart failure (CHF) is a common health problem that leads to frequent hospitalizations and an increased death rate. In spite of advances in drug therapy, it remains a significant public health problem. Recently, a new therapy has been developed for advanced heart failure patients with a ventricular conduction abnormality. This new therapy, called cardiac resynchronization (CRT), is a device which stimulates the atrium, the right ventricle, and the left ventricle providing synchronization of the contraction of the heart chambers. It is the addition of this therapy to an implantable cardioverter defibrillator (ICD) that will be evaluated in this study. This study will compare whether the implantation of this new therapy device, in combination with an implantable cardioverter defibrillator, will reduce total mortality and hospitalizations for CHF.

Detailed description: Cardiovascular mortality is decreasing in most industrial countries, however mortality for congestive heart failure is increasing. The most important predictors of mortality in heart failure patients are depressed left ventricular function, severity of symptoms (NYHA class), and ventricular conduction abnormality manifested as wide QRS. Recent advances in pharmacological therapy including ACE inhibitors, beta-blocker and spironolactone have resulted in improvement of symptoms and reduction in mortality. Population epidemiological studies demonstrated that mortality and hospitalization rate for heart failure remains very high despite recent pharmacological therapeutic progress. Recent short-term clinical trials demonstrated that cardiac resynchronization therapy (CRT) is effective in improving symptoms of heart failure, functional capacity and quality of life in patients with moderate to severe heart failure and conduction abnormality optimally treated with drug therapy. However, the data for morbidity and mortality in mild to moderate heart failure is lacking.

The objective of this trial is to determine if the addition of CRT to optimal pharmacological therapy and ICD is effect in reducing mortality and morbidity in patients with poor LV function, wide QRS and mild to moderate heart failure symptoms.

This is a double-blinded randomized control trial. A total of 1800 patients with mild to moderate heart failure symptoms, LVEF ≤ 30%, and QRS ≥ 120 ms will be included in the study. Patients will be randomized to either "ICD plus Optimal Medical Therapy (control)" or "CRT/ICD plus Optimal Medical Therapy (experimental)" in a 1:1 randomization ratio. Patients in the control group will be implanted with a single or dual chamber ICD. Patients in the experimental group will receive a device with the capabilities of CRT and ICD. Optimal Medical Therapy will include ACE inhibitors and beta-blockers. Patients will be followed on a regular basis and will have clinical evaluation, quality of life assessment, and six minute walk tests performed. The primary outcome is a composite of total mortality and heart failure hospitalization. Secondary outcome measures will include total mortality, cardiovascular mortality, sudden arrhythmic death, health related quality of life and cost economics. Patient accruement is scheduled for 4.5 years and a minimum follow of 18 months.

DFT sub study:

Overview of sub-study Design Patients participating in the RAFT trial, at participating sites, will be randomized to have DFT testing or no testing at the time of device implant. Up to 450 patients will be eligible for enrollment at Canadian and European centres. The study will have two primary outcomes: a short-term safety outcome and a long-term efficacy outcome. The safety outcome will be a composite of all adverse events potentially related to DFT that occur within 30 days following ICD implant. The long-term efficacy outcome will be a composite of failed first appropriate clinical ICD shock and sudden death. This pilot study is intended primarily to confirm the anticipated rates of events and to demonstrate feasibility of enrollment, but will not have statistical power to determine if intra-operative DFT testing is associated with significant short-term risk. If complication rates are as high as predicted and enrollment is feasible, then a larger study would be justified to determine the impact of intra-operative DFT testing on long-term rates of failed appropriated ICD shocks and sudden death. Events rates determined in this pilot study would then be used to estimate the sample size of this larger study.

Sub-study Long-Term Outcomes of the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT)

Coordinating Investigator:

John L. Sapp, Jr., MD, FRCPC

Funder:

John Sapp, QEII Div. of Cardiology, Halifax, NS

Coordinating Center:

QEII Heart Rhythm Research, Halifax, NS

The Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) was a multicenter, double-blind, randomized, controlled trial that aimed to determine whether the addition of CRT to an ICD, along with optimal medical therapy would reduce mortality and the rate of hospitalizations for HF, as compared to an ICD and optimal medical therapy alone. However, despite the established benefits of CRT among patients with mild to moderate HF, long term data is still lacking. We propose to determine the sustained, long-term outcomes of CRT among this high-risk patient population. A total of 8 sites enrolled more than 100 patients. Those 8 sites will ascertain long-term rates of survival, heart transplant and implantation of ventricular assist devices in a total of 1050 patients. The primary outcome will be all cause mortality. A secondary outcome will be the composite of mortality, implantation of ventricular assist device, and transplant. The 8 sites include UOHI, LHSC, QEII, Libin CV Calgary, HHSC, MHI, VCAT and Mazankowski Alberta Heart Institute.

The primary outcome is mortality (all cause). The primary analysis will compare the CRT-D and ICD groups for time to mortality. The survival experience (time-to-event) in each of the two groups will be analyzed using Kaplan-Meier product limit estimates and the nonparametric log-rank test. The hazard ratio (HR) and associated 95% CI will be calculated. In addition, the Cox proportional hazards model will be used to assess the consistency of the therapy group effect on this outcome taking the randomization stratification factors (clinical center, atrial rhythm (atrial fibrillation or flutter or sinus-atrial pacing), and a planned implantation of a single- or dual-chamber ICD)); as well, the Cox proportional hazards model analysis will be conducted as a sensitivity analysis to assess the therapy group effect on mortality while accounting for important baseline characteristics (any variable with a p value of less than 0.10 at baseline). Underlying assumptions for these statistical procedures will be assessed; in particular, the proportional hazard's assumption will be assessed using graphical (i.e., visual inspection of the log-negative-log plot) and numerical tests (i.e., test of the interaction term group x time). Should this assumption fail, a stratified Cox model will be fitted in order to correct for non-proportional hazards or, if ineffective, time-dependent variables will be introduced. In addition, chi-square tests will be used to compare the Kaplan-Meier (actuarial) rate of event-free survival at 10 years. The ITT population will be used.

The secondary outcome is the composite outcome of ventricular assist device implant (LVAD) or heart transplant or mortality (all cause). The primary analysis will compare the CRT-d and ICD groups for this composite outcome. For this analysis, the time-to-event analysis for Study Questions 1 will be followed. In addition, chi-square tests will be used to compare the Kaplan-Meier (actuarial) rate of event-free survival at 10 years. Also, the event rates for the composite outcome will be calculated for each therapy group and the relative risk (RR) and 95% CI calculated.

Secondary analysis - As a sensitivity analysis, the analysis for the primary and secondary questions 1 and will be repeated for the PP population.

Subgroup analysis - Subgroup analyses based on patient characteristics will be undertaken, primarily for sensitivity analyses to assess the robustness of the results, as well as for exploratory purposes for hypothesis generation. In particular, planned subgroups include: age (\<65, ≥65), sex (male, female), NYHA Class (I, II), ischemic heart disease (\<150, ≥150) paced QRS, LV ejection fraction, atrial rhythm (permanent Afib/flutter, sinus or atrial paced). The interaction of the therapy and subgroup will be included in the models.

Eligibility criteria: Inclusion Criteria:

* New York Heart Association (NYHA) Class II
* Left ventricular ejection fraction (LVEF) less than or equal to 30% by multigated acquisition scan (MUGA)/catheterization OR LVEF less than or equal to 30% and LV end diastolic dimension ≥ 60 mm (by echocardiogram) within 6 months prior to randomization
* Intrinsic QRS complex width ≥ 120 ms OR paced QRS measurement ≥ 200 ms
* ICD indication for primary or secondary prevention
* Optimal heart failure pharmacological therapy
* Normal sinus rhythm; OR chronic persistent atrial tachyarrhythmia with resting ventricular heart rate ≤ 60 beats per minute (bpm) and 6 minute hall walk ventricular heart rate of ≤ 90 bpm; OR chronic persistent atrial tachyarrhythmia with resting ventricular heart rate \> 60 bpm and 6 minute hall walk ventricular heart rate of \> 90 bpm and booked for atrioventricular junction ablation.

Exclusion Criteria:

* Intravenous inotropic agent in the last 4 days
* Patients with a life expectancy of less than one year from non-cardiac cause
* Expected to undergo cardiac transplantation within one year (status I)
* In hospital patients who have acute cardiac or non-cardiac illness that requires intensive care
* Uncorrected or uncorrectable primary valvular disease
* Restrictive, hypertrophic, or reversible form of cardiomyopathy
* Severe primary pulmonary disease such as cor pulmonale
* Tricuspid prosthetic valve
* Patients with an existing ICD (patients with an existing pacemaker may be included if the patients satisfy all other inclusion/exclusion criteria)
* Coronary revascularization (coronary artery bypass graft surgery \[CABG\] or percutaneous coronary intervention \[PCI\]) \< 1 month if previously determined LVEF \> 30%. Patients with a more recent revascularization can be included if a previously determined LVEF was ≤ 30%.
* Patients with an acute coronary syndrome including myocardial infarction (MI) can be included if the patients have had a previous MI with LV dysfunction (LVEF ≤ 30%).
* Patients included in another clinical trial that will affect the objectives of this study
* History of noncompliance to medical therapy
* Unable or unwilling to provide informed consent

Primary outcomes:
measure: Primary outcome is a composite of all cause total mortality and hospitalization for CHF
timeFrame: Study end
Secondary outcomes:
measure: Total mortality
timeFrame: Study end
measure: Cardiovascular mortality
timeFrame: Study end
measure: Sudden arrhythmic death
timeFrame: Study end
measure: Progressive HF death
timeFrame: Study end
measure: All cause hospitalization rate
timeFrame: Study end
measure: CHF hospitalization rate
timeFrame: Study end
measure: Health related quality of life
timeFrame: Study end
measure: Cost economics
timeFrame: Study end
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
city: Leuven
country: Belgium
facility: University Ziekenhuis
city: Calgary
country: Canada
facility: University of Calgary/Foothill Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Alberta Heart Institute
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Victoria Cardiac Arrhythmia Trials
state: British Columbia
city: St. John
country: Canada
facility: NB Heart Centre Research Initiative
state: New Brunswick
city: St. Johns
country: Canada
facility: Memorial Hospital
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: Queen Elizabeth II
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Centre
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Kitchener
country: Canada
facility: St. Mary's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Newmarket
country: Canada
facility: Southlake Regional Health Care
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: UHN Toronto General
state: Ontario
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Montreal
country: Canada
facility: CHUM Hopital Notre Dame
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: Hopital du Sacre Coeur de Montreal
state: Quebec
city: Quebec City
country: Canada
facility: Laval Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: CHUS Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Aarhus
country: Denmark
facility: Skejby University Hospital
city: Bad Berka
country: Germany
facility: Zentralklinik
city: Frankfurt
country: Germany
facility: J.W. Goethe University
city: Giessen
country: Germany
facility: University of Giessen
city: Ludwigshafen
country: Germany
facility: Ludwigshafen
city: Mainz
country: Germany
facility: University of Mainz
city: Zwolle
country: Netherlands
facility: Isala Klinieken
city: Izmir
country: Turkey
facility: Ege University
Study officials:
affiliation: Ottawa Heart Institute Research Corporation
name: Anthony Tang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ottawa Heart Institute Research Corporation
name: George Wells, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Manlucu J, Sharma V, Koehler J, Warman EN, Wells GA, Gula LJ, Yee R, Tang AS. Incremental Value of Implantable Cardiac Device Diagnostic Variables Over Clinical Parameters to Predict Mortality in Patients With Mild to Moderate Heart Failure. J Am Heart Assoc. 2019 Jul 16;8(14):e010998. doi: 10.1161/JAHA.118.010998. Epub 2019 Jul 11.
citation: Bennett MT, Leader N, Sapp J, Parkash R, Gardner M, Healey JS, Thibault B, Sterns L, Essebag V, Birnie D, Sivakumaran S, Nery P, Andrade JG, Krahn AD, Tang A. Differentiating Ventricular From Supraventricular Arrhythmias Using the Postpacing Interval After Failed Antitachycardia Pacing. Circ Arrhythm Electrophysiol. 2018 Apr;11(4):e005921. doi: 10.1161/CIRCEP.117.005921.
citation: Linde C, Cleland JGF, Gold MR, Claude Daubert J, Tang ASL, Young JB, Sherfesee L, Abraham WT. The interaction of sex, height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individual-patient data meta-analysis. Eur J Heart Fail. 2018 Apr;20(4):780-791. doi: 10.1002/ejhf.1133. Epub 2018 Jan 4.
citation: Sapp JL, Parkash R, Wells GA, Yetisir E, Gardner MJ, Healey JS, Thibault B, Sterns LD, Birnie D, Nery PB, Sivakumaran S, Essebag V, Dorian P, Tang AS. Cardiac Resynchronization Therapy Reduces Ventricular Arrhythmias in Primary but Not Secondary Prophylactic Implantable Cardioverter Defibrillator Patients: Insight From the Resynchronization in Ambulatory Heart Failure Trial. Circ Arrhythm Electrophysiol. 2017 Mar;10(3):e004875. doi: 10.1161/CIRCEP.116.004875.
citation: Wilton SB, Exner DV, Wyse DG, Yetisir E, Wells G, Tang AS, Healey JS. Frequency and Outcomes of Postrandomization Atrial Tachyarrhythmias in the Resynchronization/Defibrillation in Ambulatory Heart Failure Trial. Circ Arrhythm Electrophysiol. 2016 May;9(5):e003807. doi: 10.1161/CIRCEP.115.003807.
citation: Gillis AM, Kerr CR, Philippon F, Newton G, Talajic M, Froeschl M, Froeschl S, Swiggum E, Yetisir E, Wells GA, Tang AS. Impact of cardiac resynchronization therapy on hospitalizations in the Resynchronization-Defibrillation for Ambulatory Heart Failure trial. Circulation. 2014 May 20;129(20):2021-30. doi: 10.1161/CIRCULATIONAHA.112.000417. Epub 2014 Mar 7.
citation: Birnie DH, Ha A, Higginson L, Sidhu K, Green M, Philippon F, Thibault B, Wells G, Tang A. Impact of QRS morphology and duration on outcomes after cardiac resynchronization therapy: Results from the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail. 2013 Nov;6(6):1190-8. doi: 10.1161/CIRCHEARTFAILURE.113.000380. Epub 2013 Aug 30.
citation: Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J, Sherfesee L, Wells GA, Tang AS. An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J. 2013 Dec;34(46):3547-56. doi: 10.1093/eurheartj/eht290. Epub 2013 Jul 29.
citation: Healey JS, Hohnloser SH, Exner DV, Birnie DH, Parkash R, Connolly SJ, Krahn AD, Simpson CS, Thibault B, Basta M, Philippon F, Dorian P, Nair GM, Sivakumaran S, Yetisir E, Wells GA, Tang AS; RAFT Investigators. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail. 2012 Sep 1;5(5):566-70. doi: 10.1161/CIRCHEARTFAILURE.112.968867. Epub 2012 Aug 14.
citation: Healey JS, Gula LJ, Birnie DH, Sterns L, Connolly SJ, Sapp J, Crystal E, Simpson C, Exner DV, Kus T, Philippon F, Wells G, Tang AS. A randomized-controlled pilot study comparing ICD implantation with and without intraoperative defibrillation testing in patients with heart failure and severe left ventricular dysfunction: a substudy of the RAFT trial. J Cardiovasc Electrophysiol. 2012 Dec;23(12):1313-6. doi: 10.1111/j.1540-8167.2012.02393.x. Epub 2012 Jul 12.
citation: Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010 Dec 16;363(25):2385-95. doi: 10.1056/NEJMoa1009540. Epub 2010 Nov 14.