Resynchronization/Defibrillation for Ambulatory Heart Failure Trial

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.