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Executive Summary

The angiotensin converting enzyme inhibitor lisinopril was unanimously recommended for approval as a treatment for congestive heart failure by FDA's Cardiovascular and Renal Drugs Advisory Committee on Feb. 18 based on two placebo trials and a comparison study with Bristol-Myers Squibb's Capoten (captopril). Merck conducted three 12-week, multicenter, double-blind, controlled Phase III trials of lisinopril which evaluated patients' exercise tolerance, dyspnea-fatigue index, and signs and symptoms of heart failure. Two of the studies used a placebo control, while the third compared lisinopril to captopril. The company also conducted two open-label hemodynamic studies enrolling 90 patients. The results of the studies were presented to the committee by Merck Executive Director of Cardiovascular Research Geraldine Mentell, MD. Merck markets lisinopril for hypertension under the brandname Prinivil. Lisinopril is also marketed by ICI Pharmaceuticals under the tradename Zestril. If approved for treating CHF, Prinivil and Zestril will join a growing field of ACE inhibitors shown to be effective in the treatment of CHF. Bristol-Myers Squibb's Capoten has been available as adjunctive therapy for CHF since 1982 and was approved as a first-line treatment in mild-to-moderate CHF in 1989. Merck's Vasotec (enalapril) has been marketed for CHF since July 1988. The committee discussed expanded labeling for both products on Feb. 19 (see related stories, pp. 19-20) and recommended approval for Warner-Lambert's ACE inhibitor Accupril (quinapril) for use in treating CHF on Feb. 18 (see related story above). In the two placebo-controlled Phase III trials -- one multinational and one conducted in the U.S. -- 313 out of 468 patients received oral lisinopril in conjunction with digitalis and diuretics. Patients on lisinopril were given a starting dose of 5 mg once a day titrated to a maximum dose of 20 mg once a day. All were New York Heart Association class II-IV, and most were NYHA III. The multinational placebo-controlled trial, which enrolled 275 patients, found a statistically significant improvement in exercise tolerance over placebo while the U.S. placebo-controlled trial did not. The committee was confident, however, of a difference between lisinopril and placebo with respect to exercise tolerance and other CHF symptoms when viewed in the context of data from other lisinopril trials, data for secondary endpoints in the U.S. trial, and the data for other ACE inhibitors. "I'm actually quite impressed with this product," committee member Salim Yusuf, McMaster University, said. "It's one of the best products we've seen for exercise tolerance." Committee reviewer Peter Kowey, MD, Lankenau Hospital, Wynnewood, Penn., added: "I'm not terribly disappointed that we didn't make it to the holy grail [of statistical significance for exercise tolerance in the U.S. trial.]" Lisinopril showed a statistically significant improvement for dyspnea-fatigue and left ventricular ejection fraction in both placebo-controlled trials. In the captopril-controlled Phase III trial, both drugs showed an improvement in exercise tolerance at 12 weeks with no statistically significant difference between them. Based on the numbers in the study, Mentell said, "We are 75% confident that lisinopril is at least as good as captopril in exercise capacity." Lisinopril did show statistically significant superiority to captopril for the dyspnea-fatigue index, with both treatments demonstrating statistical improvement over baseline. The two products also showed similar improvement over baseline for left ventricular ejection fraction. In the Capoten trial, lisinopril dosing was the same as in the placebo trials and the subjects were also NYHA II-IV. Captopril patients received an initial dose of 12.5 mg t.i.d. and were titrated to a maximum of 50 mg t.i.d. Ninety-four patients received lisinopril, and 95 received captopril. The committee voted to recommend approval of lisinopril at a recommended dosage identical to that used in the clinical trials. The committee also asked FDA to encourage Merck to perform further subgroup analysis of adverse experiences focusing on renally impaired patients and older patients. Committee chairman Craig Pratt, MD, Baylor College of Medicine, also requested that Merck examine exercise tolerance specifically for the 11% of patients in the studies who were NYHA class IV. At FDA's request, the committee also addressed the growing ethical problem of conducting placebo-controlled trials of new ACE inhibitors given the existence of five drugs in the class with proven efficacy for treating CHF. In its questions to the committee, FDA acknowledged that it can be difficult to generate meaningful results from positive-control trials given the inconsistency of exercise tolerance and symptom improvement results for ACE inhibitors. FDA noted that of the 11 ACE inhibitor trials for CHF reviewed by the agency, only five have yielded statistically significant results for exercise tolerance or symptoms of congestive heart failure. The agency noted that it considers consistent superiority to placebo to be a "minimum criterion" for the use of a product as a positive control. In addition, FDA pointed out that while using mortality as an endpoint has shown more consistent results in placebo trials, it would require a positive control trial of untenable size to provide reasonable confidence in a demonstration of equivalence. The committee had no simple answer to the problem, but suggested that positive control trial use some combination of endpoints to capture the efficacy results -- possibly looking at hospitalization as well as symptom improvement and mortality. Former committee member and invited expert Milton Packer, MD, explained: "I think the safest thing to do is measure all the things that you think can reflect clinical improvement. If they all go in the right direction...then you feel very comfortable. And the degree to which you miss that will increase your discomfort."

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