Hierarchical win ratio analysis in the Budapest CRT-Upgrade Trial

Background Cardiovascular outcome trials have conventionally applied time-to-event analyses in which all components of a composite endpoint are weighted equally potentially diminishing the influence of clinically critical events such as mortality. The win ratio (WR) method introduces a hierarchical, pairwise comparison framework that ranks endpoint components according to their clinical significance. The Budapest CRT-Upgrade Trial offers a suitable setting to implement WR methodology and to re-evaluate the therapeutic benefit of cardiac resynchronization therapy with defibrillator (CRT-D) upgrade in patients with heart failure with reduced ejection fraction (HFrEF) and right ventricular pacing. Methods In the Budapest CRT-Upgrade Trial, 360 patients with HFrEF, previously implanted with a pacemaker or implantable cardioverter-defibrillator and exposed to a high burden of right ventricular pacing, were randomized to receive either CRT-D upgrade (n=215) or ICD upgrade alone (n=145) and followed for 12 months. The WR analysis was conducted according to the intention-to-treat principle using unmatched pairwise comparisons between treatment groups. A prespecified hierarchical composite endpoint was constructed, prioritizing all-cause mortality first, followed by heart failure hospitalization, a ≥15% relative reduction in left ventricular end-systolic volume (LVESV), and a ≥30% relative decrease in NT-proBNP levels. Multiple models assessed outcomes with sensitivity analyses addressing ties, missing data, and alternative cut-offs. Results Baseline demographic and clinical parameters were comparable between the two study arms, reflecting a highly comorbid population with frequent prior heart failure hospitalizations. The mean left ventricular ejection fraction was 24.8 ± 6.6%. A substantial right ventricular pacing burden was present in both groups (85.4 ± 21.1% in the CRT-D arm and 88.1 ± 18.8% in the ICD arm). Overall, 31,175 pairwise comparisons were performed, yielding 16,419 wins, 4,239 losses, and 10,517 ties in favor of CRT-D upgrade. The calculated win ratio was 3.87 (95% CI 2.73–5.50; p<0.001), indicating a robust treatment effect. Importantly, win ratios consistently exceeded 1.0 across examined subgroups, supporting the stability of the findings. Conclusions Applying the WR approach to the Budapest CRT-Upgrade Trial highlights the added value of hierarchical composite endpoint analysis in cardiovascular device studies. By emphasizing clinically paramount outcomes, this method provides a more nuanced and clinically aligned interpretation of treatment benefit.