Comparing Analytical Methods for Composite End Points in Clinical Trials: Insights from the Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction Trial

• Published in: Journal of cardiac failure 2024-09
• Main Authors: WESTERHOUT, CYNTHIA M., RATHWELL, SARAH, ANSTROM, KEVIN J., HERNANDEZ, ADRIAN F., PONIKOWSKI, PIOTR, EZEKOWITZ, JUSTIN A., VOORS, ADRIAAN A., FELKER, G. MICHAEL, BAKAL, JEFFREY A., BLAUSTEIN, ROBERT O., NKULIKIYINKA, RICHARD, O'CONNOR, CHRISTOPHER M., ARMSTRONG, PAUL W.
• Format: Article
• Language: English
• Subjects: clinical trial; vericiguat; Weighted composite end point; win ratio
• ISSN: 1071-9164; 1532-8414; 1532-8414
• DOI: 10.1016/j.cardfail.2024.08.038

•Alternatives to the traditional time to first event analysis have emerged to advance the interpretation of treatment effect in clinical trials.•As part of a prespecified secondary analysis of VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), we compared the relative incremental and complementary features of the win ratio (WR) and the weighted composite end point (WCE) as compared with the traditional to the time event approach - which revealed a benefit of vericiguat over placebo in the time to first heart failure-related hospitalization (HFH) or cardiovascular death.•The WR approach features a hierarchy of events and a summary of pairwise comparisons as wins vs losses for the study treatment.•The WCE approach includes of all recurrent events and provided estimates of the variability in the severity of HFH events. The WCE approach also allows for weights across and within diverse event types, and provides an absolute measure of the treatment effect.•Both approaches confirmed vericiguat's treatment effect with an observed HFH-adjusted survival advantage of 2.4% and a WR of 1.13.•The WCE approach complements conventional assessment, better informing consumers of new therapeutics and useful in future trial designs. In VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), participants with heart failure (HF) and reduced ejection fraction, vericiguat decreased the primary composite outcome (time to first HF hospitalization [HFH] or cardiovascular death [CVD]) (897 events) compared with placebo (972 events) (hazard ratio, 0.90; 95% confidence interval [CI], 0.82–0.98; P = .02). In this prespecified secondary analysis, we applied the weighted composite end point (WCE) and the win ratio (WR) methods to provide complementary assessments of treatment effect. The WCE method estimated the mean HFH-adjusted survival based on prespecified weights from a Delphi panel of the VICTORIA executive committee and national leaders: mild (weight per event, 0.39), moderate (0.5), or severe (0.67) HFH, and CVD (1.0). The unmatched WR was estimated for the descending hierarchy of CVD, then recurrent HFH. The WCE used all 3412 primary clinical events: 875 severe HFH (vericiguat, 416/ placebo, 459), 1614 moderate HFH (767/847), 68 mild HFH (38/30), and 855 CVD (414/441). Improved HFH-adjusted survival occurred with vericiguat (mean 78.2% vs 75.6%, difference 2.4%, 95% CI, 1.7%–3.2%, P < .0001)