Comparing Analytical Methods for Composite End Points in Clinical Trials: Insights from the Vericiguat Global Study
Cynthia M Westerhout1, Sarah Rathwell1, Kevin J Anstrom2
1Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada.
Insights
Vericiguat improved outcomes in heart failure patients by reducing hospitalizations and cardiovascular death. New analysis methods, weighted composite endpoint and win ratio, confirmed vericiguat
Area of Science:
- Cardiology
- Clinical Trials
- Pharmacology
Background:
- The VICTORIA trial demonstrated vericiguat's efficacy in reducing the composite outcome of heart failure hospitalization (HFH) or cardiovascular death (CVD) in patients with reduced ejection fraction.
- A secondary analysis was conducted to apply weighted composite endpoint (WCE) and win ratio (WR) methods for a complementary assessment of vericiguat's treatment effect.
Purpose of the Study:
- To provide complementary assessments of vericiguat's treatment effect using the weighted composite endpoint (WCE) and win ratio (WR) methods.
- To evaluate the consistency of WCE and WR findings with the primary VICTORIA trial analysis.
Main Methods:
- The WCE method incorporated all 3412 primary clinical events, assigning weights based on event severity: mild HFH (0.39), moderate HFH (0.5), severe HFH (0.67), and CVD (1.0).
- The WR method assessed outcomes based on a hierarchy of CVD followed by recurrent HFH.
- Both methods analyzed data from the VICTORIA trial, comparing vericiguat to placebo.
Main Results:
- The WCE method showed improved HFH-adjusted survival with vericiguat (mean 78.2% vs 75.6%, P < .0001).
- The WR method indicated improved clinical outcomes with vericiguat, with a WR of 1.13 (P = .01), based on over 6.3 million paired comparisons.
- Both WCE and WR results were consistent with the primary VICTORIA trial analysis.
Conclusions:
- The WCE and WR methods provide consistent results with the primary VICTORIA trial analysis, confirming vericiguat's benefit.
- The WCE method offers advantages by including all recurrent events, accounting for HFH severity, and providing an absolute measure of patient experience.
- These complementary assessment methods can better inform consumers about new therapeutics and guide future clinical trial designs.
Background:
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.
Methods And Results:
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). Based on a comparison of 6,375,624 pairs, the WR of 1.13 (95% CI 1.03-1.24, P = .01) also indicated improved clinical outcomes with vericiguat.
Conclusions:
The results of the WCE and WR methods were consistent with the primary analysis of the time to first HFH or CVD. Although both WCE and WR assessed recurrent events, the WCE allowed inclusion of all recurrent events, insights on the severity of HFH events, and an absolute measure of the participant-treatment experience. This approach complements conventional assessment, better informing consumers of new therapeutics and future trial designs.
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