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LISINOPRIL REDUCES DEATH AFTER HEART ATTACK IN SMALL BUT STATISTICALLY SIGNIFICANT WAY, GISSI-3 STUDY CONCLUDES; ISIS-4 SHOWS SIMILAR BENEFIT FOR CAPTOPRIL

Executive Summary

Lisinopril's ability to reduce mortality rates in patients who have had acute myocardial infarction is small but statistically significant, results of the GISSI-3 trial show. GISSI-3 trial results were reported by Gianni Tognoni, MD, at the American Heart Association's 66th Scientific Sessions in Atlanta on Nov. 8. The six-week mortality rate for all patients in the trial taking the angiotensin-converting enzyme inhibitor lisinopril (marketed in the U.S. as Merck's Prinivil and Zeneca's Zestril) was 6.3% compared with 7.1% for all patients not taking lisinopril. The trial, run by the GISSI Coordinating Center in Milan, began with 43,047 patients admitted to 200 coronary care units in Italy following acute myocardial infarction. Of the total, 18,895 were randomized. Patients were randomized to lisinopril, nitrates, both or neither. Treatment was withdrawn after six weeks. Endpoints were death and a combined endpoint that included extensive left ventricular damage and late clinical congestive heart failure. Evaluations were again made of the endpoints at six months. Compared to the six-week lisinopril mortality rate, nitrates showed a six-week mortality rate of 6.5% versus 6.9% for no nitrates. This difference was not considered statistically significant, Tognoni said. The lowest six-week mortality rate was 6% in the group of patients receiving both lisinopril and nitrates. For the combined endpoints, lisinopril also showed a statistically significant reduction in left ventricular damage and heart failure (17% to 15.6%), while nitrates did not. These conclusions were also borne out by the analysis of subgroups including women and the elderly, Tognoni said. In the second part of the trial, "we are looking for a preventive effect," Tognoni said. "We are now concluding the six month follow-up in order to see whether the effects which are seen at six weeks are in fact maintained or possibly increased...at six months." Results of another MI study, ISIS-4, showed that captopril (Bristol-Myers Squibb's Capoten) reduced mortality in a statistically significant way. Oxford researcher Rory Collins presented ISIS-4 results to AHA on Nov. 8. The fourth International Study of Infarct Survival studied 58,000 patients in 1,084 hospitals in 30 countries. Suspected acute myocardial infarction patients each were randomized within 24 hours of onset to three concurrent trials: 28 days of captopril or placebo; 28 days of isosorbide mononitrate or placebo; and 24 hours of I.V. magnesium sulfate or open control. There was "no evidence of any interaction between the three treatments tested," Collins noted. The main comparisons were five- week and longer-term mortality. After five weeks, the mortality rate for patients taking captopril was 6.9% compared with 7.3% for the placebo group, a small but statistically significant difference. After six months, captopril's advantage was slightly more pronounced: the death rate for the captopril group was 9.9% versus 10.6% for placebo. Collins noted that "the absolute benefits...are greater among higher- risk patients." Less auspicious were the results from the nitrate and magnesium studies. The nitrate result (7% five-week mortality rate against 7.2% for placebo) was not statistically significant, leading Collins to suggest using nitrates "for symptomatic relief, but not with the expectation of a large mortality reduction." The magnesium result was disappointing because an earlier small trial, the second Leicester Intravenous Magnesium Intervention Trial, had indicated a 24% reduction in mortality. In LIMIT-2, there were 90 deaths out of 1,159 patients assigned to I.V. magnesium (a 7.8% mortality rate) compared to 118 deaths out of 1,157 controls (a 10.2% mortality rate). In contrast to LIMIT-2, ISIS-4 showed a slight adverse trend in five-week mortality rate for magnesium.
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