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  • Review Article
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The disconnect between phase II and phase III trials of drugs for heart failure

Nature Reviews Cardiology volume 10, pages 85–97 (2013)Cite this article

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Abstract

Hospitalization for heart failure (HF) is a clinical entity associated with high postdischarge morbidity and mortality, yet few therapies are available to improve outcomes in patients with this condition. In the past decade, large phase III studies of HF treatments have failed to demonstrate drug efficacy, safety, or both, despite encouraging results from preceding phase II trials. This Review is focused on this disconnect between the results of phase II and phase III trials of drugs for HF and discusses findings from five drug-development programs (for levosimendan, tezosentan, tolvaptan, rolofylline, and nesiritide) to shed light on common themes in clinical trials conducted in patients hospitalized for HF. In particular, the importance of selecting the 'right' patient population, drug, and clinical end points to optimize the trial design is discussed. Areas that require further investigation are highlighted and we suggest possible directions that will help to guide future clinical trials in these patients. Large, expensive phase III trials should not be initiated without adequate phase II evidence or on the basis of overly optimistic interpretation of phase II data. Additionally, drug development programs should be targeted not only to change short-term symptoms, but also to improve the postdischarge event rate.

Key Points

  • Patients hospitalized for heart failure (HF) are at a significantly high risk of postdischarge death or rehospitalization, despite conventional therapies

  • Large phase III clinical trials in patients hospitalized for HF have mainly provided negative results for primary safety or efficacy end points, despite encouraging results from preceding phase II studies

  • Inpatient surrogate end points such as dyspnoea relief might not correlate with postdischarge end points such as mortality and rehospitalization

  • Successful clinical trials require proper selection of the 'right' drug, target patient population, and end points

  • Analysis of five drug development programs (for levosimendan, tezosentan, tolvaptan, rolofylline, and nesiritide) will help to dissect the disconnect between phase II and phase III trials in patients hospitalized for HF

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Figure 1: Schematic representation of the stages in clinical development of pharmacological and nonpharmacological therapies in patients hospitalized for heart failure.

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Authors and Affiliations

  1. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, GRB-740, 55 Fruit Street, Boston, 02114, MA, USA

    Muthiah Vaduganathan

  2. Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 1006, Chicago, 60611, IL, USA

    Stephen J. Greene & Mihai Gheorghiade

  3. Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Suite S101, Stanford, 94305, CA, USA

    Andrew P. Ambrosy

  4. Division of Cardiology, Emory University, 1365 Clifton Road Northeast, Atlanta, 30322, GA, USA

    Javed Butler

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M. Vaduganathan, S. J. Greene, and J. Butler wrote the article. All authors made substantial contributions to researching data for article, discussion of content, and reviewing and editing of manuscript before submission.

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Correspondence to Mihai Gheorghiade.

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Competing interests

M. Gheorghiade declares that he has been a consultant for the following companies: Abbott, Astellas, AstraZeneca, Bayer, Corthera, Cytokinetics, Debiopharm, Errekappa Euroterapici, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Novartis, Otsuka, PDL Biopharma, PeriCor, Sanofi, Sigma-Tau, and Solvay Pharmaceuticals. J. Butler declares that he has been a consultant for Amgen, Bayer, CardioMEMS, Gambro, Ono Pharmaceutical, Takeda, and Trevena, and he has received research grants from GE Healthcare, Medtronic, National Heart Lung and Blood Institute, and National Institutes of Health. M. Vaduganathan, S. J. Greene, and A. P. Ambrosy declare no competing interests.

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Vaduganathan, M., Greene, S., Ambrosy, A. et al. The disconnect between phase II and phase III trials of drugs for heart failure. Nat Rev Cardiol 10, 85–97 (2013). https://doi.org/10.1038/nrcardio.2012.181

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