Mega-trials in heart failure: effects of dilution in examination of new therapies

Beth A. Davison, Koji Takagi, Stefanie Senger, Gary Koch, Marco Metra, Antoine Kimmoun, Alexandre Mebazaa, Adriaan A. Voors, Olav W. Nielsen, Ovidiu Chioncel, Peter S. Pang, Barry H. Greenberg, Aldo P. Maggioni, Alain Cohen-Solal, Georg Ertl, Naoki Sato, John R. Teerlink, Gerasimos Filippatos, Piotr Ponikowski, Etienne GayatChristopher Edwards, Gad Cotter

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalEuropean Journal of Heart Failure
StateAccepted/In press - 2020


  • Acute heart failure
  • Chronic heart failure
  • Meta-analysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Davison, B. A., Takagi, K., Senger, S., Koch, G., Metra, M., Kimmoun, A., Mebazaa, A., Voors, A. A., Nielsen, O. W., Chioncel, O., Pang, P. S., Greenberg, B. H., Maggioni, A. P., Cohen-Solal, A., Ertl, G., Sato, N., Teerlink, J. R., Filippatos, G., Ponikowski, P., ... Cotter, G. (Accepted/In press). Mega-trials in heart failure: effects of dilution in examination of new therapies. European Journal of Heart Failure.