Correspondence
Zofenopril after Anterior Myocardial Infarction
N Engl J Med 1995; 332:1715-1716June 22, 1995
- Article
To the Editor:
In the study of zofenopril reported by Ambrosioni et al. (Jan. 12 issue),1 the subgroup analysis (their Table 5) showed beneficial effects in patients concomitantly treated with calcium-channel blockers during the six-week treatment period. During the observation period, significantly more patients in the zofenopril group (21.1 percent) than in the placebo group (15.9 percent) received calcium-channel blockers (P = 0.02, as shown in their Table 4). This difference raises the possibility that the favorable outcome in the zofenopril group may have been due in part to the calcium-channel blockers. Indeed, the administration of calcium-channel blockers after acute myocardial infarction has been shown to be beneficial. In the Second Danish Verapamil Infarction Trial, mortality rates at 18 months among patients without heart failure were 7.7 percent in the verapamil group and 11.8 percent in the placebo group (P = 0.02).2 Although diltiazem did not have an overall effect on cumulative mortality or cardiac events, among patients without pulmonary congestion after myocardial infarction, the drug was associated with a reduced frequency of cardiac events (8 percent in the diltiazem group, as compared with 11 percent in the placebo group).3
3 ReferencesKlaus Mörike, M.D.
Gerd Mikus, M.D.
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany1
Ambrosioni E ,Borghi C ,Magnani B . The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-85
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The Danish Study Group on Verapamil in Myocardial Infarction
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The Multicenter Diltiazem Postinfarction Trial Research Group
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To the Editor:
We commend the authors of the report on the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) trial for advancing our understanding of the use of angiotensin-converting–enzyme (ACE) inhibitors after myocardial infarction. This trial demonstrated that ACE inhibitors can safely be started within 24 hours after the onset of infarction and that their benefit persists after six weeks of therapy. However, we wish to caution readers and the authors that very early use of ACE inhibitors during or before thrombolytic therapy has not yet been proved to be beneficial and, in fact, may be detrimental. The SMILE trial restricted enrollment to patients not treated with thrombolytic therapy.
Paul A. Gurbel, M.D.
University of Maryland School of Medicine, Baltimore, MD 21201Christopher M. O'Connor, M.D.
Duke University Medical Center, Durham, NC 27710To the Editor:
In the past decade, various trials have shown that ACE inhibitors help manage the manifestations of congestive heart failure and improve the functional status of patients, in addition to the beneficial effects of these agents on mortality.1 Ambrosioni et al. imply that the use of ACE inhibitors reduces the incidence of congestive heart failure after anterior myocardial infarction. For the purpose of the study, patients were considered to have congestive heart failure if they met at least three of the following criteria: a third heart sound, bilateral pulmonary rales, radiologic evidence of pulmonary congestion, and peripheral edema. It is inappropriate to say that there is a reduction in the incidence of clinical congestive heart failure with the administration of an agent that has already been established to be useful in managing (or masking) the clinical manifestations.
In addition, it was surprising that in the 1990s approximately 80 percent of the patients were not given beta-blockers, and almost half were not given aspirin. Even during the first year of observation, only 13.1 percent of the patients in the placebo group and 10.4 percent of those in the zofenopril group were given beta-blockers, despite the overwhelming evidence that these agents are beneficial after myocardial infarction.2,3
3 ReferencesG. Muqtada Chaudhry, M.D.
St. Elizabeth's Medical Center, Boston, MA 02135Neenoofar Haneef, M.D.
55 Farwell St., Newton, MA 021601
Baker DW ,Konstam MA ,Bottorff M ,Pitt B . Management of heart failure. I. Pharmacologic treatment. JAMA 1994;272:1361-1366
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Yusuf S ,Peto R ,Lewis J ,Collins R ,Sleight P . Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-371
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Antiplatelet Trialists' Collaboration
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Author/Editor Response
The authors reply:
To the Editor: The definition of congestive heart failure was an important issue in the SMILE study. To avoid any nonspecific effect of drugs on individual symptoms, for the analysis of the primary end point we included only the patients who had objective signs of congestive heart failure (a third heart sound, pulmonary rales, and radiologic evidence of pulmonary congestion), despite concomitant treatment with digoxin, diuretics, and vasodilators.
In the SMILE study a small proportion of patients were given aspirin during the first 24 hours after admission, but the cumulative proportion of patients given aspirin was over 70 percent. The proportion of patients given beta-blockers during the early phase of the study (about 20 percent) was greater than that recently reported in the Fourth International Study of Infarct Survival1 (9 percent for intravenous beta-blockers) and slightly lower than that reported in the third study by the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico2 (30.1 percent), suggesting a wide range of opinions about the combined use of ACE inhibitors and beta-blockers.
Drs. Mörike and Mikus emphasize the therapeutic advantage of the concomitant administration of ACE inhibitors and calcium-channel blockers. Although the results of the SMILE study seem to support a positive interaction between these classes of drugs, the data should be interpreted cautiously because of the small size of the subgroups. It is interesting to note, however, that the concomitant administration of zofenopril and calcium-channel blockers reduced the trend toward a higher event rate observed during the six weeks of double-blind treatment in the group of patients treated with calcium-channel blockers alone. During the acute phase of myocardial infarction, the use of ACE inhibitors may offset some of the reported negative effects of calcium-channel blockers.3 This benefit was not confirmed during the long-term phase of the trial.
3 ReferencesClaudio Borghi, M.D.
Ettore Ambrosioni, M.D.
Bruno Magnani, M.D.
Policlinico S. Orsola, 40138 Bologna, Italyfor the SMILE Study Investigators
1
ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group
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Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto MiocardicoGISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115-1122
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Yusuf S ,Furberg CD . Effects of calcium channel blockers on survival after myocardial infarction. Cardiovasc Drugs Ther 1987;1:343-344
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