Heart failure trial control-arm mortality rates remain stable despite intensified background therapy over 20 years
Background
Despite significant advancements in pharmacotherapy for heart failure (HF), particularly heart failure with reduced ejection fraction (HFrEF), the trajectory of clinical event rates in control arms of major trials remains a critical question. Understanding these trends is vital for designing future trials, estimating sample sizes, and interpreting the true impact of novel therapies. Current standard-of-care, including beta-blockers, ACEIs/ARBs/ARNIs, and MRAs, has intensified, yet whether this translates to lower baseline risk in trial populations, reflected by control-arm event rates, is not well-established.
Study Design
Researchers identified 38 Phase 3 HF randomized clinical trials (RCTs) published in the New England Journal of Medicine (NEJM) between 2004 and 2024. Annualized event rates were calculated as events divided by patients multiplied by follow-up to the primary endpoint. Temporal trends were analyzed using weighted least squares, with weights equal to the number of control-arm patients, and adjusted for follow-up duration. The analysis primarily focused on control-arm data from the 31 trials enrolling patients with HFrEF.
Results
In HFrEF control arms, median age was 67 years, 24% were women, and mean LVEF was 28%. Background therapy use significantly increased over the study period: beta-blockers rose by +1.04 percentage points per year (p<0.001) and mineralocorticoid receptor antagonists (MRAs) by +2.05 percentage points per year (p<0.001). Concurrently, LVEF increased (+0.22% per year, p=0.012) and NT-proBNP levels increased (approximately +11.4% per year on the log scale, p=0.004). Despite these changes, all-cause mortality in HFrEF control arms showed no temporal decline.
Unadjusted all-cause mortality had a slope of +0.0019 per year (95% CI -0.0013 to +0.0051,
p=0.252); after adjusting for follow-up duration, the slope was +0.0006 per year (p=0.711). Cardiovascular mortality also remained stable (unadjusted +0.0003 per year). Longer follow-up was associated with lower annualized mortality (coefficient -0.0195 per year,p=0.032).
Key Findings
- Control-arm all-cause mortality in HFrEF trials remained stable over 20 years (unadjusted slope +0.0019 per year,
p=0.252). - Cardiovascular mortality in control arms also showed no temporal decline (unadjusted +0.0003 per year).
- Background therapy use significantly increased: beta-blockers by +1.04 percentage points/year (
p<0.001) and MRAs by +2.05 percentage points/year (p<0.001). - LVEF increased (+0.22% per year,
p=0.012) andNT-proBNProse (+11.4% per year) in control arms. - Longer follow-up was associated with lower annualized mortality (coefficient -0.0195 per year,
p=0.032).
Why It Matters
This analysis highlights a critical insight for heart failure research and clinical practice: despite significant improvements in background medical therapy over two decades, the baseline risk of all-cause and cardiovascular mortality in control arms of major HFrEF trials has not decreased. This implies that new therapeutic agents must demonstrate substantial efficacy to achieve statistically significant reductions in hard clinical endpoints. For researchers, this finding is crucial for power calculations and trial design, suggesting that the 'bar' for demonstrating benefit remains high. For clinicians, it underscores the persistent severity of HF, even with optimal guideline-directed medical therapy, emphasizing the ongoing need for novel interventions.
heart-failure
hfrf
clinical-trials
mortality
cardiovascular
rct-analysis