Beth A Davison1, Koji Takagi2, Stefanie Senger1, Gary Koch3, Marco Metra4, Antoine Kimmoun5, Alexandre Mebazaa2, Adriaan A Voors6, Olav W Nielsen7, Ovidiu Chioncel8, Peter S Pang9, Barry H Greenberg10, Aldo P Maggioni11, Alain Cohen-Solal12, Georg Ertl13, Naoki Sato14, John R Teerlink15, Gerasimos Filippatos16, Piotr Ponikowski17, Etienne Gayat18, Christopher Edwards1, Gad Cotter1. 1. Momentum Research, Inc., Durham, NC, USA. 2. Inserm 942-MASCOT, Department of Anaesthesiology and Critical Care Medicine, Assistance Publique - Hôpitaux de Paris, Saint Louis Lariboisière University Hospitals, University of Paris, Paris, France. 3. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA. 4. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 5. Department of Intensive Medicine and Resuscitation Brabois, Regional University Hospitals of Nancy, University of Lorraine, Vandoeuvre les Nancy, France. 6. Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands. 7. Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark. 8. Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', University of Medicine Carol Davila, Bucharest, Romania. 9. Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. 10. Division of Cardiology, University of California San Diego, San Diego, CA, USA. 11. Department of Internal Medicine, Associazione Nazionale Medici Cardiologi Ospedalien (ANMCO) Research Centre, Florence, Italy. 12. Cardiology Service, Lariboisière Hospital, Paris, France. 13. Julius-Maximilians University Würzburg, Wurzburg, Germany. 14. Cardiology and Intensive Care Unit, Nippon Medical School, Musashi-Kosugi Hospital, Kawasaki, Japan. 15. Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California San Francisco, San Francisco, CA, USA. 16. Department of Cardiology, Heart Failure Unit, Athens University Hospital Attikon, Athens, Greece. 17. Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland. 18. Faculty of Medicine Xavier Bichat, Paris Diderot University, Paris, France.
Abstract
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.
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 HFpatients. 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.
Authors: Merle M Krebber; Christian G M van Dijk; Robin W M Vernooij; Maarten M Brandt; Craig A Emter; Christoph D Rau; Joost O Fledderus; Dirk J Duncker; Marianne C Verhaar; Caroline Cheng; Jaap A Joles Journal: Int J Mol Sci Date: 2020-09-14 Impact factor: 5.923