As part of the US Food and Drug Administration's (FDA's) drug evaluation process, the agency turns to advisory panels for opinions on specific questions related to issues such as approval of new drug entities or changes in labeling. On February 27 and 28, 1997, the Cardiovascular and Renal Advisory Panel considered four drugs.
1. A fixed combination of hydralazine and isosorbide dinitrate (H-ISDN) as adjunctive therapy to digitalis and diuretics in congestive heart failure. V-HeFT (Veterans Administration Heart Failure Trial), an initial evaluation of vasodilator therapy in congestive heart failure, reported no effect of prasozin but did indicate a beneficial effect of H-ISDN versus placebo in patients with congestive heart failure. However, the mortality benefit was not statistically significant when protocol-defined methods of analysis were used. A follow up trial, V-HeFT II, compared enalapril with H-ISDN (without placebo) and found that the survival rate was significantly improved with enalapril. Given the superiority of enalapril versus H-ISDN in V-HeFT II, the clinical situations in which H-ISDN would be used were discussed. Patients intolerant of ACE inhibitors, with NYHA class IV heart failure, or already receiving ACE inhibitors were all considered; however, no data were available to evaluate the effects of the combination in these situations. Moreover, the usual standard is two positive trials, and V-HeFT II was not thought to provide confirmation of a benefit of H-ISDN. In addition, combination products generally require a demonstration of efficacy for both components; efficacy was lacking for H-ISDN. The application was not recommended for approval.
2. Carvedilol in congestive heart failure. At a meeting in Spring 1996, the Advisory Panel recommended disapproval of an application for the use of the α1/β-blocker carvedilol for the treatment of patients with heart failure. Carvedilol in congestive heart failure was discussed in four articles in the December 1, 1996, issue of Circulation (Circulation. 1996;94:2793-2799, 2800-2806, 2807-2816, 2817-2825.). The use of carvedilol has been controversial because a single trial or combination of trials that demonstrate a mortality benefit but do not prespecify mortality as an end point for analysis may be biased. New data from an Australia/New Zealand study (Lancet. February 8, 1997) support the contention that carvedilol exerts a beneficial effect in the treatment of congestive heart failure. However, a trial to evaluate the effect of the drug on mortality as a primary end point has not been conducted. The Advisory Panel recommended approval on the basis of an assessment that the totality of the data on carvedilol in heart failure support a beneficial effect, which may include reduction in hospitalizations, the use of heart failure medications, and possibly mortality.
3. Mibefradil, a calcium channel blocker, was proposed for use in angina and hypertension. Efficacy was demonstrated in a series of placebo-controlled studies. However, during FDA evaluation of the New Drug Application, studies were identified in which relatively high doses of the drug were found to produce apparent changes in the QT or QTU interval. Data were presented to the Advisory Panel that suggested that these changes are in QT morphology rather than prolongation of the QT interval and that similar changes occur with the use of high doses of verapamil and diltiazem. Preclinical studies indicated that the drug does not prolong cardiac action potential duration or provoke torsades de pointes in animal models. A large mortality study in congestive heart failure is under way. Approval for use of mibefradil to treat angina and hypertension was recommended.
4. Integrilin, a platelet IIB/IIIA receptor antagonist. Preclinical and clinical data support the concept that Integrilin, by binding to the platelet glycoprotein IIB/IIIA receptor, rapidly and reversibly inhibits platelet function. Data from IMPACT II (Integrilin to Manage Platelet Aggression to Combat Thrombosis II), a trial of Integrilin use in patients undergoing angioplasty or other coronary mechanical procedures, were presented. The proposed analysis in IMPACT II was to compare the effect of two infusion regimens of Integrilin and placebo in a composite primary end point, which included mortality, myocardial infarction, and need for urgent revascularization at 30 days after drug administration. These data showed a significant effect of both drug regimens at 24 hours and a statistically borderline effect of the low dose (but not the high dose) regimen at 30 days after drug administration. The overall reduction in events was less than the 30% for which the trial was powered. The Advisory Panel agreed that while IMPACT II suggested a beneficial effect of Integrilin in this setting, further substantiation of that effect was needed. Ongoing trials in unstable angina may provide those data. The Advisory Panel did not recommend approval.
- Copyright © 1997 by American Heart Association