Author + information
- Stephen J. Greene, MD and
- Mihai Gheorghiade, MD∗ ()
- ↵∗Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 201 East Huron Street, Galter 3-150, Chicago, Illinois 60611
We thank Dr. Ghali for his interest in our editorial. We fully agree that narrow inclusion and exclusion criteria within clinical trials limit generalizability of study results to a smaller segment of the overall population. However, heart failure (HF) is a clinical syndrome and not a specific disease, representing a final common pathway for various admixtures of cardiac and noncardiac abnormalities. This heterogeneity applies to chronic HF with reduced ejection fraction, but is especially true for HF with preserved ejection fraction (1) and hospitalized HF (HHF) populations where randomized trials have consistently failed to improve long-term patient outcomes (2).
Testing new molecules in HHF without the rigorous early phase testing we suggest does not preclude a subsequent positive trial result. However, on the basis of past HHF trial experiences and increasing understanding of the diversity in precipitants, amplifying factors, and cardiac substrates among HHF patients, this approach fails to maximize the chances of achieving a successful study result. The traditional strategy has also proven expensive, both in terms of direct financial costs and opportunity costs of investing several years for completion of trials with lower probability of showing clinical benefit (3). Moreover, using heterogeneous populations to test suboptimally understood therapies increases the risk for any of 3 potential problematic scenarios: 1) overall primary endpoint is met but a segment of the study population derives no benefit or harm; 2) overall primary endpoint is not met, effectively “killing” further drug development, but a bidirectional drug effect exists whereby specific subgroups derive offsetting benefit (i.e., a potentially useful therapy is abandoned) and harm (4); and 3) overall primary endpoint is met, but size of the effect is small and despite regulatory approval, the therapy is not widely accepted by payers.
We recognize the potential for discordance between efficacy and “real world” clinical effectiveness of therapies within medicine. We also appreciate the differences in patient characteristics between HHF clinical trials and registries (5). However, the “1 size fits all” approach to HHF drug development has thus far failed to be productive (2). Rather, we favor identifying the “disease” within HHF and targeting the specific abnormality or process. A pragmatic approach going forward would involve proving clear clinical benefit with a therapy in select HHF patients. Subsequently, the therapy could be serially trialed in additional patient subgroups for which sound biologic plausibility may exist. Such an approach could theoretically widen the application of the novel therapy while, at minimum, provide a treatment capable of helping an HHF patient subset. With over 1 million primary hospitalizations for HF annually in the United States alone, improving outcomes for even a segment of this population could yield enormous public health benefits.
Please note: Dr. Gheorghiade has served as a consultant or received honoraria from Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd., CorThera, Cytokinetics, CytoPherx, Inc., DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Inc., Johnson & Johnson, Medtronic, Merck & Co., Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics. Dr. Greene has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Shah S.J.
- Maggioni A.P.,
- Greene S.J.,
- Fonarow G.C.,
- et al.
- Ambrosy A.P.,
- Fonarow G.C.,
- Butler J.,
- et al.