Comprehensive Clinical Benefit of CCM in HFrEF Patients – a win-ratio analysis of FIX-HF-5C randomized trial

Q: What are the key findings of this study?

Cardiac contractility modulation plus OMT yielded a win ratio of 2.48 (95% CI 1.76-3.64; p<0.001) versus OMT alone across mortality, hospitalizations, and functional status at 24 weeks.

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Symptomatic heart failure with reduced ejection fraction (HFrEF, LVEF 25% to 45%) (n=160). Intervention: Cardiac contractility modulation (CCM) via Optimizer Smart device plus optimal medical therapy (OMT) vs. Optimal medical therapy (OMT) alone. Primary outcome: 3-level hierarchical composite evaluated at 24 weeks: (1) cardiovascular mortality, (2) number of heart failure hospitalizations, and (3) equally weighted composite of changes from baseline in pVO2, 6MWD (>=25 m), MLWHFQ score (<=-5 points), and NYHA class (Win ratio 2.48, 95% CI 1.76 to 3.64, p=<0.001).

Q: What does this research mean for the field?

Cardiac contractility modulation combined with optimal medical therapy provides a significant comprehensive clinical benefit over medical therapy alone across hierarchical mortality, hospitalization, and functional outcomes in HFrEF patients (win ratio 2.48). Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To comprehensively evaluate the overall clinical benefit of cardiac contractility modulation by integrating hard clinical endpoints with patient-centered functional outcomes using a hierarchical win-ratio approach.

Rami Kahwash; Poying Lai; William T. Abraham; Daniel Burkhoff; Rodrigo Chan; Andrew J. Kaplan; G Tomassoni; Lee Ming Boo

doi:10.1093/eschf/xvag179

June 23, 2026ESC Heart FailureOpen Access

Comprehensive Clinical Benefit of CCM in HFrEF Patients – a win-ratio analysis of FIX-HF-5C randomized trial

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Key result

Cardiac contractility modulation yields a ~2.5-fold higher win ratio over medical therapy alone at 24 weeks.

Win ratio 2.48
95% CI 1.76 to 3.64
P<0.001
n=160

Figures

Graphical abstract published by ESC Heart Failure — Graphical abstract · Published by ESC Heart Failure · CC BY

Why the study?

Does cardiac contractility modulation (CCM) therapy added to optimal medical therapy improve a hierarchical composite of cardiovascular mortality, heart failure hospitalizations, and patient-centered functional and quality-of-life outcomes compared to optimal medical therapy alone in patients with NYHA class III-IVa HFrEF (LVEF 25%-45%) and narrow QRS?

Key Points

To comprehensively evaluate the overall clinical benefit of cardiac contractility modulation by integrating hard clinical endpoints with patient-centered functional outcomes using a hierarchical win-ratio approach.
Conducted a hierarchical win-ratio re-analysis of the FIX-HF-5C multicenter randomized trial comprising 160 patients (74 assigned to cardiac contractility modulation and 86 to optimal medical therapy control).
Formed 6,364 patient pairs evaluated across a hierarchy prioritizing cardiovascular mortality, heart failure hospitalization, and patient-centered functional outcomes (peak oxygen consumption, Minnesota Living with Heart Failure Questionnaire score, 6-minute walk distance, and NYHA functional class).
Conducted sensitivity analyses across alternative hierarchical endpoint configurations and stratified analyses by baseline NYHA functional class (Class III versus IV).
The primary overall win ratio was 2.48 (95% CI 1.76 to 3.64; p < 0.001), indicating a 71% pairwise comparative probability of clinical benefit favoring cardiac contractility modulation over optimal medical therapy.
Event-driven clinical endpoints contributed 22% of total wins (cardiovascular mortality win ratio 2.48; heart failure hospitalization win ratio 1.48), while patient-centered functional endpoints contributed 56.2% of total wins (win ratio 2.98).
Sensitivity analyses consistently demonstrated significant clinical benefit favoring cardiac contractility modulation (win ratios ranging from 1.52 to 2.42), with consistent primary win ratios observed across NYHA class III (2.46) and class IV (3.22; p = 0.699 for difference).

Study Design

Type

RCT (n=160)

Blinding

Unblinded (core laboratory read pVO2 tests blinded)

Randomization

Randomized controlled trial (post-hoc win-ratio reanalysis)

Multicenter

Yes

Structured PICO

Does cardiac contractility modulation (CCM) therapy added to optimal medical therapy improve a hierarchical composite of cardiovascular mortality, heart failure hospitalizations, and patient-centered functional and quality-of-life outcomes compared to optimal medical therapy alone in patients with NYHA class III-IVa HFrEF (LVEF 25%-45%) and narrow QRS?

P

Population

160 patients with NYHA class III or IVa heart failure, LVEF 25% to 45%, and QRS duration <130 ms followed for 24 weeks.

I

Intervention

Cardiac contractility modulation (CCM) therapy delivered via the implanted Optimizer Smart device (high-voltage, non-excitatory electrical signals during the absolute refractory period) added to optimal medical therapy (OMT) over 24 weeks (n=74 randomized, 68 implanted).

C

Comparator

Optimal medical therapy (OMT) alone without sham control (n=86 randomized).

O

Outcome

Hierarchical composite win-ratio endpoint at 24 weeks prioritizing: (1) cardiovascular mortality (adjudicated by an independent clinical events committee), (2) number of heart failure hospitalizations (adjudicated), and (3) a composite of equally weighted changes from baseline to 24 weeks in patient-centered outcomes: peak oxygen consumption (pVO2, read blinded by core laboratory), Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score (≥5-point reduction threshold), 6-minute walk distance (6MWD, ≥25-meter increase threshold), and NYHA functional class.composite

Main Result

Effect estimate: Win ratio 2.48 (95% CI 1.76 to 3.64)

Absolute Event Rate: 55.8% vs 22.5%

p-value: p=<0.001

This post-hoc win-ratio reanalysis of the FIX-HF-5C trial demonstrates that cardiac contractility modulation provides a significant multidimensional clinical benefit over optimal medical therapy alone (win ratio 2.48, p < 0.001) when integrating cardiovascular death, heart failure hospitalizations, and functional/quality-of-life outcomes.

Limitations

Post-hoc evaluation of the FIX-HF-5C trial and should be regarded as hypothesis-generating
Residual ties inherent to the win-ratio method (21.7% of pairwise comparisons remained tied in the primary analysis)
Lack of temporal information on when clinical events occurred
Lack of a sham-control arm and unblinded design, creating potential placebo effect for MLWHFQ, 6MWD, and NYHA
Small sample size in the NYHA class IV subgroup limiting definitive conclusions in that stratum
Post-hoc nature of the analysis, making the findings hypothesis-generating.
Residual ties inherent to the win-ratio method (approximately 21% of pairwise comparisons remained tied in the primary analysis).
Lack of temporal information regarding when clinical events occurred.
Lack of sham-control arm and unblinded design, introducing potential placebo effect or variability in responses/measurements for MLWHFQ, 6MWD, and NYHA.
Small sample size in the NYHA class IV subgroup, preventing definitive conclusions in this population.

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Supports CCM addition to OMT in NYHA III-IVa HFrEF; extends FIX-HF-5C with win-ratio integration of hard and functional endpoints.

Abstract

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.

Discussion

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Cite This Study

Kahwash et al. (2026) conducted an RCT in Symptomatic heart failure with reduced ejection fraction (HFrEF, LVEF 25% to 45%) (n=160). Cardiac contractility modulation (CCM) via Optimizer Smart device plus optimal medical therapy (OMT) vs. Optimal medical therapy (OMT) alone was evaluated on 3-level hierarchical composite evaluated at 24 weeks: (1) cardiovascular mortality, (2) number of heart failure hospitalizations, and (3) equally weighted composite of changes from baseline in pVO2, 6MWD (>=25 m), MLWHFQ score (<=-5 points), and NYHA class (Win ratio 2.48, 95% CI 1.76 to 3.64, p=<0.001). Cardiac contractility modulation plus OMT yielded a win ratio of 2.48 (95% CI 1.76-3.64; p<0.001) versus OMT alone across mortality, hospitalizations, and functional status at 24 weeks.

synapsesocial.com/papers/6a3c230ed15afadd906f9c8c https://doi.org/10.1093/eschf/xvag179

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Comprehensive Clinical Benefit of CCM in HFrEF Patients – a win-ratio analysis of FIX-HF-5C randomized trial

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Comprehensive Clinical Benefit of CCM in HFrEF Patients – a win-ratio analysis of FIX-HF-5C randomized trial

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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