Increasing sample size in heart failure trials leads to reduced event rates and smaller treatment effects, explaining why appropriately powered Phase 3 trials should have yielded ~35% positive results.
Meta-Analysis
Does increasing trial size reduce placebo event rates and treatment effects in heart failure trials?
Increasing sample size in heart failure trials is associated with reduced placebo event rates and smaller treatment effects, which may explain the high rate of neutral Phase 3 trials in HFpEF and acute HF.
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.
Davison et al. (Mon,) conducted a meta-analysis in Heart failure. Increasing trial size vs. Smaller trial size (Phase 2) was evaluated on Placebo event rates and treatment effects for HF events and death. Increasing sample size in heart failure trials leads to reduced event rates and smaller treatment effects, explaining why appropriately powered Phase 3 trials should have yielded ~35% positive results.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: