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BOOTS MANOPLAX ADDITION TO TRIPLE CHF THERAPY IMPROVES EXERCISE TOLERANCE

Executive Summary

BOOTS MANOPLAX ADDITION TO TRIPLE CHF THERAPY IMPROVES EXERCISE TOLERANCE and quality of life in patients with congestive heart failure, according to results of the Flosequinan-ACE Inhibitor Trial (FACET) presented at a Nov. 15 symposium held in conjunction with the American Heart Association's 65th Scientific Sessions in New Orleans. The study also was presented on Nov. 18 during AHA's meeting. FACET is the first trial to evaluate the use of adding a direct-acting vasodilator, flosequinan, to a standard CHF combination treatment regimen of a diuretic, digoxin and an ACE inhibitor. Study investigator Barry Massie, MD, San Francisco V-A Medical Center, presented results from the study. An NDA for flosequinan is pending at FDA. Manoplax was recommended for approval in treating heart failure patients who are intolerant to ACE inhibitors by FDA's Cardiovascular & Renal Drugs Advisory Committee on Oct. 24, 1991 ("The Pink Sheet" Oct. 28, 1991 p. 17). A general CHF indication was rejected by the committee because a meta-analysis showed that patients on flosequinan may have had an increased mortality compared to placebo. Explaining the rationale for FACET, Massie said that many CHF patients treated with two or three agents can remain symptom- limited and that adding a direct-acting vasodilator to an ACE inhibitor can produce additional hemodynamic and clinical benefits. The randomized, double-blind, placebo-controlled, multicenter trial involved 322 patients with NYHA Class II and Class III congestive heart failure. A few patients had Class IV heart failure. In the 16-week trial, patients were randomized to receive either placebo, flosequinan 100 mg once-daily, or flosequinan 75 mg twice-daily, Massie said. The efficacy assessments were maximal treadmill time and the Minnesota Living With Heart Failure questionnaire. Most patients were on baseline therapy with furosemide, digoxin, and captopril or enalapril. In the assessment of exercise tolerance, "the flosequinan 100 mg dosage, which is the one that has been most widely used in trials, showed an improvement which achieved statistical significance," Massie stated. "Interestingly, the higher dose showed an intermediate response." For the Class III/IV group "both the low dose...and the higher dose group tended to improve their exercise tolerance." However, for "the patients with milder heart failure, the improvement in exercise tolerance was only seen with the low dose and not at all with the high dose." The quality-of-life questionnaire "showed a significant improvement [overall] with the 100 mg dosages," Massie said. "The higher dose was not much different from placebo," which did not show any change. "If we just look at the components of that score that reflect physical indices...however, both dosages were very similar and statistically significant compared to the placebo group." About 30% of patients on active therapy needed a reduction in dose because of tachycardia or side effects, Massie said. But the percentage of patients that withdrew because of side effects were similar in the three groups. "Deaths were essentially equally distributed among the three groups." Massie concluded that "there is room for further improvement when you add a direct vasodilator to triple therapy with a diuretic, an ACE inhibitor and digoxin." He noted that "this therapy appears to be fully additive in the sense that it adds as much to those patients as it does to patients without an ACE inhibitor." He added that the remaining question is how flosequinan affects survival, which is the focus of the PROFILE Study of flosequinan or placebo added to a diuretic, digoxin and an ACE inhibitor in 3,500 patients with Class III and Class IV heart failure. The patients will be followed for an average of two to three years. So far half of the number of target patients have been randomized.
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