Comprehensive Clinical Benefit of CCM in HFrEF Patients – a win-ratio analysis of FIX-HF-5C randomized trial
Rami Kahwash, Poying Lai, William T Abraham, Daniel Burkhoff, Rodrigo Chan, Andrew J Kaplan, Gery Tomassoni, Lee Ming BooAbstract
Background
FIX-HF-5C multicenter, randomized study demonstrated cardiac contractility modulation (CCMTM) improved patient-centered outcomes, including functional capacity, symptom burden, and health-related quality of life. Reductions in cardiovascular death and heart failure hospitalization (HFH) were observed. These event-driven outcomes were not prespecified efficacy endpoints and were not incorporated into overall assessment of treatment benefit. Comprehensive clinical benefit of CCM therapy was re-analyzed by a win-ratio method that integrated event-driven clinical endpoints with patient-centered outcomes.
Methods
The hierarchical win-ratio prioritized cardiovascular mortality, HFH, and patient-centered outcomes comprising equally weighted components of peak oxygen consumption, Minnesota Living with Heart Failure Questionnaire score, 6-minute walk distance, and NYHA functional class. Sub-group analyses were performed in patients with NYHA Class III versus IV.
Results
In the primary analysis of 160 randomized patients (6,364 patient pairs), the overall win ratio was 2.48 (95% CI 1.76 to 3.64; p < 0.001), corresponding to a 71% pairwise comparative probability of clinical benefit with CCM versus OMT. Event-driven clinical endpoints accounted for 22% of total wins while 56.2% came from patient-centric endpoints. CCM consistently outperformed OMT across all hierarchies. Sensitivity analyses yielded similar findings with win ratios favoring CCM (range: 1.52 to 2.42). Treatment effects were consistent across NYHA class III and IV subgroups.
Conclusions
The win-ratio re-analysis supports and extends the original study results demonstrating a consistent clinical benefit of CCM therapy over OMT across a hierarchical framework integrating event-driven clinical endpoints with patient-centered functional outcomes. The findings, while clinically highly encouraging, are hypothesis-generating and warrant validation in future confirmatory study.