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Bispebjerg Hospital - en del af Københavns Universitetshospital

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


  1. Reproducibility of in-hospital worsening heart failure event adjudication in the RELAX-AHF-EU trial

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. The effect of liraglutide on natriuretic peptides and copeptin in heart failure patients

    Publikation: Bidrag til tidsskriftKonferenceabstrakt i tidsskriftForskningpeer review

  • 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 Gayat
  • Christopher Edwards
  • Gad Cotter
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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.

TidsskriftEuropean Journal of Heart Failure
Udgave nummer9
Sider (fra-til)1698-1707
Antal sider10
StatusUdgivet - sep. 2020
Eksternt udgivetJa

Bibliografisk note

© 2020 European Society of Cardiology.

ID: 61884873