Comparison of clinical trials evaluating cardiac resynchronization therapy in mild to moderate heart failure

Recently, three large randomized clinical trials: REVERSE, MADIT-CRT, and RAFT were completed aiming to determine the effects of cardiac resynchronization therapy (CRT) or CRT with defibrillator (CRT-D) in less advanced, predominantly NYHA class II heart failure (HF) patients. The REVERSE trial, significantly smaller than the other two trials, could be considered as a phase II study indicating that mild-to-moderate HF patients show symptomatic and hemodynamic improvement in response to CRT. The MADIT-CRT and RAFT are considered as definitive trials with large patient populations of about 1,800 patients each, and HF event/hospitalization or death as the primary endpoint. Both trials showed a significant reduction in the risk of primary endpoints: a 34% reduction in MADIT-CRT and 25% reduction in RAFT. However, RAFT also showed a significant reduction in mortality which was not observed in MADIT-CRT. The clinical characteristics of patients studied in both trials were different despite somewhat similar entry criteria. RAFT enrolled more advanced HF patients (including 20% NYHA class III patients) than MADIT-CRT. In the CRT-D arm, RAFT patients had about 20% two-year mortality in comparison to approximately 6% two-year mortality in MADIT-CRT. Mortality in RAFT was in similar to those observed in CRT-D patients in the COMPANION trial (estimated 25% two-year mortality), and in the CRT arm of the CARE-HF trial (estimated 18% two-year mortality), both older studies which enrolled NYHA class III and IV HF patients. Based on the above comparison, one could conclude that RAFT enrolled moderate-to-advanced HF patients whereas MADIT-CRT enrolled truly mild-to-moderate patients.