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Mega‐trials in heart failure: effects of dilution in examination of new therapies
Author(s) -
Davison Beth A.,
Takagi Koji,
Senger Stefanie,
Koch Gary,
Metra Marco,
Kimmoun Antoine,
Mebazaa Alexandre,
Voors Adriaan A.,
Nielsen Olav W.,
Chioncel Ovidiu,
Pang Peter S.,
Greenberg Barry H.,
Maggioni Aldo P.,
CohenSolal Alain,
Ertl Georg,
Sato Naoki,
Teerlink John R.,
Filippatos Gerasimos,
Ponikowski Piotr,
Gayat Etienne,
Edwards Christopher,
Cotter Gad
Publication year - 2020
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1002/ejhf.1780
Subject(s) - medicine , heart failure , placebo , clinical trial , ejection fraction , heart failure with preserved ejection fraction , randomized controlled trial , sample size determination , cardiology , intensive care medicine , alternative medicine , pathology , statistics , mathematics
Aims Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power. Methods and results Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta‐analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of ‘real‐life’ registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients. Conclusions The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials.