title: The disconnect between phase II and phase III trials of drugs for heart failure.
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.
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, GRB-740, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Vaduganathan
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Greene
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Ambrosy
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000627:therapeutic use; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D019317:Evidence-Based Medicine; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D006835:Hydrazones / Q000627:therapeutic use; D020097:Natriuretic Peptide, Brain / Q000627:therapeutic use; D010359:Patient Readmission; D018579:Patient Selection; D011724:Pyridazines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D018570:Risk Assessment; D012307:Risk Factors; D000077464:Simendan; D013777:Tetrazoles / Q000627:therapeutic use; D013997:Time Factors; D000077602:Tolvaptan; D016896:Treatment Outcome; D014970:Xanthines / Q000627:therapeutic use
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; D006835:Hydrazones; D011724:Pyridazines; D011725:Pyridines; D013777:Tetrazoles; D014970:Xanthines; D020097:Natriuretic Peptide, Brain; D000077602:Tolvaptan; D000077464:Simendan; C120582:tezosentan; C073525:rolofylline