Heart failure & cardiomyopathiesResearch article
Event rates in major Phase 3 heart failure trials over the last 20 years
- Phase 3 Heart Failure (HF) Randomized Clinical Trials (RCTs) published in New England Journal of Medicine (2004-24)
- weighted least squares (weights equal to the number of control-arm patients), with adjustment for follow-up duration
Authors' conclusion
In major HFrEF trials, control-arm mortality did not decline from 2004 to 2024 despite greater uptake of evidence-based therapy. Risk-enriched enrolment and shorter follow-up likely counterbalanced therapeutic gains.
Study context
- Population
- Control arms of Phase 3 heart failure randomized clinical trials published in New England Journal of Medicine, 2004–2024trials, 31 enrolled HF with reduced ejection fraction (HFrEF) (82%)
- Participants
- Thirty-eight participants
- Comparison
- Temporal trends in control-arm event rates across publication years
Main finding
As reported in the abstract
All-cause mortality (control arms)
- unadjusted slope per year
- +.0019
- 95% CI
- −.0013 to +.0051
- P
- P = .252
- follow-up-adjusted slope per year
- +.0006
- follow-up-adjusted P
- P = .711
Further findings
Follow-up duration and annualized mortality
- coefficient per year
- −.0195
- P
- P = 0.032
- Longer follow-up associated with lower annualized mortality
Cardiovascular mortality
- unadjusted per year
- +.0003
- 95% CI
- −.0036 to +.0042
- P
- P = 0.898
- follow-up-adjusted per year
- −.0012
- follow-up-adjusted P
- P = 0.557
- stable
All-cause death or HF hospitalization
- unadjusted per year
- +.0180
- 95% CI
- +.0063 to +.0298
- P
- P = 0.011
- follow-up-adjusted per year
- +.0113
- follow-up-adjusted P
- P = 0.111
- not significant after follow-up adjustment
HFrEF control-arm characteristics
- median age, years
- 67 [IQR 64-69]
- women
- 24% (IQR 21-30)
- Left ventricular ejection fraction (LVEF)
- 28% (25-31)
- NT-proBNP
- 1700 ng/L (1273-2879)
- New York Heart Association (NYHA) class III-IV
- 46% (29-71)
- β-blockers
- 91% (82-93)
- angiotensin-converting enzyme inhibitors/ARBs/angiotensin receptor-neprilysin inhibitors
- 93% (90-97)
- Mineralocorticoid receptor antagonists (MRAs)
- 52% (42-59)
- median control-arm size, patients
- 602 (308-1533)
Temporal trends in therapy and patient characteristics
- β-blockers, percentage points per year
- +1.04 (P < .001)
- MRAs, percentage points per year
- +2.05 (P < .001)
- LVEF per year
- +.22% (P = .012)
- NT-proBNP per year on the log scale
- ∼+11.4% (P = .004)
- follow-up tended to shorten
- P = 0.052
Enrichment intensity and natriuretic-peptide cut-offs
- enrichment intensity, criteria per year
- +.032 (P = .111)
- natriuretic-peptide cut-offs, OR per decade
- 14.09; 95% CI 1.93-102.75; P = .009
Age and mortality
- coefficient per year
- +.0039
- P
- P = 0.043
- Higher age related to higher mortality
Interaction between year and log-transformed NT-proBNP
- risk-dependent temporal patterns
- P = 0.003
Original publication
Event rates in major Phase 3 heart failure trials over the last 20 years. ESC Heart Fail. Published 11 June 2026. doi:10.1093/eschf/xvag169
Summarised from the published abstract; every number is checked against it