Abstract
BACKGROUND: Patient-reported outcomes such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) are increasingly recognized for their prognostic value. While the composite endpoint of cardiovascular death and heart failure (HF) hospitalization is the standard primary outcome in contemporary HF trials, the potential for KCCQ changes to serve as an intermediate endpoint for these clinical events requires further evaluation. METHODS: We conducted a trial-level meta-regression analysis of phase 3 randomized controlled trials (RCTs) evaluating pharmacological therapies for chronic HF that reported both changes in KCCQ and the primary composite endpoint of cardiovascular death and HF hospitalization. Weighted random-effects meta-regression models were used to assess the association between changes in KCCQ scores and treatment effects on clinical outcomes. RESULTS: Twelve phase 3 RCTs were included, comprising eight enrolling patients with HF with reduced ejection fraction and four enrolling those with preserved ejection fraction. Changes in KCCQ scores were significantly associated with treatment effects on the primary composite endpoint (regression coefficient [95% CI] = -0.0611 [-0.0930, -0.0292]; p = 0.001; I(2) = 2.2%), cardiovascular death (-0.0676 [-0.1099, -0.0254]; p = 0.004; I(2) = 0%), and HF hospitalization (-0.0700 [-0.1322, -0.0775]; p = 0.031; I(2) = 54%). CONCLUSION: Treatment-induced changes in KCCQ scores are significantly correlated with clinical outcomes in phase 3 HF trials. These findings support KCCQ as a promising candidate intermediate endpoint that provides supportive evidence for the clinical benefit of HF therapies. However, our results remain hypothesis-generating, and further validation using individual patient data and cross-mechanism studies is warranted before KCCQ can be formally established as a regulatory surrogate endpoint.