Event rates in major Phase 3 heart failure trials over the last 20 years

Abstract Aims To determine whether control-arm event rates in heart failure (HF) randomized clinical trials (RCTs) published in NEJM from 2004–2024 declined over time, despite intensification of background therapy. Methods We identified Phase 3 HF RCTs published in NEJM (2004–2024). Annualized event rates were calculated as events divided by patients multiplied by follow-up to the primary endpoint. Temporal trends were analyzed with weighted least squares (weights equal to the number of control-arm patients), with adjustment for follow-up duration. Results Thirty-eight trials met criteria; 31 enrolled HF with reduced ejection fraction (HFrEF; 82%). In HFrEF control arms, median age was 67 years (interquartile range IQR 64–69), women were 24% (IQR 21–30), left ventricular ejection fraction (LVEF) was 28% (25–31), N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1,700 ng/L (1,273–2,879), and New York Heart Association (NYHA) class III–IV was 46% (29–71). Background therapy included beta-blockers 91% (82–93), angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs)/angiotensin receptor–neprilysin inhibitors (ARNIs) 93% (90–97), and mineralocorticoid receptor antagonists (MRAs) 52% (42–59). Median control-arm size was 602 patients (308–1,533). Across years, therapy use rose (beta-blockers +1.04 percentage points per year, p0.001; MRAs +2.05 percentage points per year, p0.001), LVEF increased (+0.22% per year, p=0.012), NT-proBNP increased (∼+11.4% per year on the log scale, p=0.004), and follow-up tended to shorten (p=0.052). In control arms, all-cause mortality showed no temporal decline (unadjusted slope +0.0019 per year; 95% confidence interval CI −0.0013 to +0.0051; p=0.252); after adjusting for follow-up, the slope was +0.0006 per year (p=0.711). Longer follow-up was associated with lower annualized mortality (coefficient −0.0195 per year; p=0.032). Cardiovascular mortality was stable (unadjusted +0.0003 per year; 95% CI −0.0036 to +0.0042; p=0.898; follow-up–adjusted −0.0012 per year; p=0.557). The composite of all-cause death or HF hospitalization increased unadjusted (+0.0180 per year; 95% CI +0.0063 to +0.0298; p=0.011) but was not significant after follow-up adjustment (+0.0113 per year; p=0.111). Enrichment intensity did not rise linearly (coefficient +0.032 criteria per year; p=0.111), whereas natriuretic-peptide cutoffs were adopted more often (odds ratio OR per decade 14.09; 95% CI 1.93–102.75; p=0.009). Higher age related to higher mortality (coefficient +0.0039 per year; p=0.043). An interaction between year and log-transformed NT-proBNP indicated risk-dependent temporal patterns (p=0.003). Conclusions In major HFrEF trials, control-arm mortality did not decline from 2004–2024 despite greater uptake of evidence-based therapy. Risk-enriched enrollment and shorter follow-up likely counterbalanced therapeutic gains.