Assessing Benefit in Patients With Heart Failure and Reduced Ejection Fraction: Analysis of the VICTORIA Trial Using...

Area of Science:

• Cardiovascular Medicine
• Clinical Trials Methodology
• Pharmacological Research

Background:

• Randomized trials are standard for therapy evaluation but can be limited by primary endpoint risk heterogeneity.
• The 5-step stratified testing and amalgamation routine (5-STAR) methodology addresses these limitations.
• This study applied 5-STAR to the VICTORIA trial database, incorporating ancillary data.

Purpose of the Study:

• To re-evaluate vericiguat efficacy using the 5-STAR methodology on the VICTORIA trial data.
• To assess the impact of risk stratification on treatment effect estimation for heart failure therapies.

Main Methods:

• Elastic net Cox regression and conditional inference trees were used for risk stratification, blinded to treatment.
• Core laboratory biomarkers and electrocardiographic variables were integrated into the dataset.
• Treatments were compared within risk strata for the composite endpoint of cardiovascular death or heart failure hospitalization (HFH), with results averaged for overall inference.

Main Results:

• The 5-STAR analysis demonstrated greater vericiguat efficacy (HR: 0.85, 95% CI: 0.77-0.94) compared to the original VICTORIA analysis (HR: 0.90, 95% CI: 0.82-0.98).
• Enhanced efficacy was observed for both cardiovascular death (5-STAR HR: 0.79) and HFH (5-STAR HR: 0.89) components.
• Five biomarkers, including GDF-15 and NT-proBNP, defined the risk strata across the endpoints.

Conclusions:

• The 5-STAR methodology effectively mitigates the dilution of treatment effects caused by prognostic risk heterogeneity.
• This retrospective VICTORIA analysis confirms greater efficacy of vericiguat on the primary composite endpoint and its components.
• Growth differentiation factor 15 (GDF-15) emerged as the strongest prognostic risk factor across the composite endpoint and its components.