Cardiology · Medical Literature
Comprehensive clinical benefit of CCM in HFrEF patients: a win-ratio analysis of FIX-HF-5C randomized trial.
Abstract
FIX-HF-5C multicentre, randomized study demonstrated cardiac contractility modulation (CCMTM) improved patient-centred 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-centred outcomes. The hierarchical win-ratio prioritized cardiovascular mortality, HFH, and patient-centred 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. In the primary analysis of 160 randomized patients (6364 patient pairs), the overall win ratio was 2.48 (95% CI 1.76 to 3.64; P < .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 favouring CCM (range: 1.52 to 2.42). Treatment effects were consistent across NYHA class III and IV subgroups. 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-centred functional outcomes. The findings, while clinically highly encouraging, are hypothesis-generating and warrant validation in future confirmatory studies.
Clinical relevance
Does a hierarchical win-ratio analysis of the FIX-HF-5C randomized trial — integrating cardiovascular mortality, heart failure hospitalization, and patient-centred functional outcomes — demonstrate a comprehensive clinical benefit of cardiac contractility modulation (CCM) plus optimal medical therapy (OMT) compared with OMT alone in patients with HFrEF? __SNAPSHOT__ {"studyDesign":"Pre-planned secondary (win-ratio) analysis of a prospective, multicentre, randomized controlled trial (FIX-HF-5C). The original trial was unblinded with 1:1 randomization to CCM plus OMT versus OMT alone.","setting":"Multicentre; US and international sites (country mix not further specified in the abstract). The original FIX-HF-5C trial recruited from up to 40 sites across the United States and Europe.","sampleSize":"n=160 randomized patients (CCM: n=74; control/OMT: n=86), generating 6,364 pairwise comparisons for the win-ratio analysis.","population":"Adults with NYHA functional class III or ambulatory class IV heart failure despite OMT, LVEF 25–45% by echocardiographic core laboratory, QRS duration <130 ms (not a candidate for cardiac resynchronization therapy), and normal sinus rhythm. Patients with LVEF ≤35% were required to have an ICD unless contraindicated.","intervention":"Cardiac contractility modulation (CCM) therapy via the OPTIMIZER Smart System (Impulse Dynamics) delivering non-excitatory electrical signals during the ventricular absolute refractory period, in addition to continued OMT.","comparator":"Optimal medical therapy (OMT) alone (control group).","primaryOutcome":"Hierarchical win-ratio composite: (1) cardiovascular mortality [highest priority], (2) heart failure hospitalization, and (3) an equally weighted patient-centred composite of peak oxygen consumption (peak VO₂), Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score, 6-minute walk distance (6MWD), and NYHA functional class, assessed at 24 weeks.","followUp":"24 weeks (mean follow-up as reported in the original FIX-HF-5C trial); duration of follow-up for the win-ratio analysis endpoints is not separately reported beyond the abstract.","fundingSource":"Not explicitly reported in the abstract. The original FIX-HF-5C trial and device development were supported by Impulse Dynamics (industry sponsorship)."}
Key findings
In the primary analysis of all 160 randomized patients (6,364 pairwise comparisons), the overall hierarchical win ratio was 2.48 (95% CI 1.76–3.64; p<0.001), corresponding to a 71% pairwise comparative probability that a randomly selected CCM-treated patient fared better than a randomly selected OMT-only patient. The abstract describes reductions in cardiovascular death and heart failure hospitalization in the original FIX-HF-5C trial (composite reduced from 10.8% in controls to 2.9% in the CCM arm, p=0.048, from the parent trial — not reported as part of the win-ratio primary analysis itself and were not prespecified efficacy endpoints in the parent trial). The win-ratio method reintegrated these event-driven outcomes with the patient-centred outcomes. Subgroup analyses by NYHA Class III versus IV were performed; specific win-ratio values and confidence intervals for these subgroups are not reported in the available abstract. No new device-related adverse event data beyond those of the original trial are reported in the abstract. NNT is not calculable from the available abstract data. All values above are taken directly from the abstract; no values were independently calculated.
Practice implications
This win-ratio reanalysis of FIX-HF-5C provides a methodologically complementary perspective on the original trial by integrating event-driven clinical endpoints (cardiovascular death, HF hospitalization) with validated patient-centred outcomes (peak VO₂, MLWHFQ, 6MWD, NYHA class) into a single hierarchical composite. The win ratio of 2.48 (p 45%. The 2022 ACC/AHA/HFSA guidelines acknowledge CCM effects on exercise capacity and quality of life but do not recommend it for mortality or hospitalization reduction due to lack of adequately powered hard-outcome data. This win-ratio analysis, while strengthening the signal, does not resolve that gap. NYHA Class III vs. IV subgroup findings are referenced but not fully reported in the abstract. Only the abstract is available for this summary; full methodology, subgroup win ratios, sensitivity analyses, and adverse event reporting cannot be assessed. Practice should not change on the basis of this reanalysis alone; confirmation from adequately powered, blinded, hard-outcome trials (e.g., AIM HIGHer) is needed. __LIMITATIONS__ Post-hoc win-ratio reanalysis of a trial not powered or designed for event-driven endpoints; cardiovascular death and HFH were explicitly non-prespecified efficacy endpoints in FIX-HF-5C.,Small sample size (n=160); the original trial was powered for peak VO₂ as primary endpoint, not for mortality or hospitalization.,Unblinded original trial design (CCM vs. OMT alone) introduces performance bias and placebo/nocebo effects in patient-reported and clinician-assessed outcomes (MLWHFQ, NYHA class) that propagate into the win-ratio composite.,Short follow-up (24 weeks); long-term durability of benefit, survival impact, and cumulative hospitalization burden cannot be assessed.,Hierarchical win-ratio methodology weights cardiovascular death first, but the small number of events in this trial means the win ratio may be predominantly driven by patient-centred outcomes rather than hard clinical endpoints.,Restricted and highly selected population (NYHA III–IV, LVEF 25–45%, narrow QRS, sinus rhythm, CRT-ineligible) limits generalisability to the broader HFrEF population.,Industry sponsorship of the original FIX-HF-5C trial (Impulse Dynamics) is a potential source of bias.,NYHA Class III vs. IV subgroup win ratios are referenced but specific results not reported in the available abstract; this limits assessment of treatment effect heterogeneity.,Only abstract available; full methods, sensitivity analyses, win-ratio component decomposition, and adverse event data cannot be reviewed.,The win-ratio approach is sensitive to the chosen hierarchy and weighting assumptions; alternative hierarchies could yield different conclusions. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This win-ratio reanalysis of FIX-HF-5C demonstrates a statistically significant and numerically large comprehensive clinical benefit of CCM plus OMT over OMT alone (win ratio 2.48, 95% CI 1.76–3.64; p<0.001) in a carefully selected HFrEF population with LVEF 25–45%, narrow QRS, and NYHA Class III–IV symptoms. However, this is a post-hoc secondary analysis of an unblinded, small, short-duration trial not powered for hard clinical events, and the win-ratio composite includes non-prespecified endpoints. Clinicians should regard these findings as hypothesis-generating and hypothesis-reinforcing rather than practice-changing; definitive evidence from adequately powered, blinded, hard-outcome trials is still required before CCM can be broadly recommended for mortality or hospitalization reduction.