Effects of administration of captopril, metoprolol, and the captopril-metoprolol combination as adjuvant therapy during thrombolysis in acute myocardial infarction

Dear Sir, Beta-receptor blocking agents (BB) have been proven safe therapy both in the acute phase of myocardial infarction (AMI) and after myocardial infarction. Mortality may be reduced by 10-40% 1 year following the acute event [1-3]. ACE inhibitors may possibly contribute to decreased mortality in long-term therapy after AMI [4-7]. The question should be raised whether both drugs are more significantly potent to reduce the late mortality of AMI than either of the monotherapy interventions. Is there a more profound benefit from ACE inhibitors than from a beta-receptor blocking agent or from their combination during AMI after thrombolysis? Little data are available regarding the effects of combined BB and ACE inhibitors as adjuncts to thrombolysis. In order to evaluate the feasibility and effects over the shortand long-term administration of BB, captopril, and their combination versus placebo in anterior AMI subject to thrombolysis, we have assessed (1) ventricular arrhythmias during the first 2 hours after thrombolysis; (2) maximum creatine kinase value; (3) creatine kinase peak normalization time (NTE); (4) incidence of late ventricular arrhythmias in Lown's class >2, at a Holter predischarge test; (5) ejection fraction, end-systolic volume, in patients subject to a hemodynamic test 3 weeks after AMI; and (6) mortality for reinfarction and progressive left ventricular dysfunction during follow-up. From November 30, 1988 to December 31, 1992, 479 patients (106 F, 373 M) were consecutively admitted to G.F. Ingrassia Hospital for suspected AMI (first episode) within 4 hours of the onset of symptoms. No age limit was applied (mean age 59 _+ 3 years). Patients not eligible for thrombolysis, or those with left bundle branch block or a history of myocardiopathy or heart failure, and patients who did not show signs of reperfusion, were excluded from the study. Also excluded were patients with inferior AMIs or in Killip class 3-4. The basal creatine kinase (CK) before thrombolysis always had to be within the normal range. All patients had to show at least two reperfusion criteria: characteristic behavior of the S-T segment, rapid regression of precordial pain, enzymatic peak (CK) within 12 hours of thrombolysis, and early ventricular arrhythmias (first 2 hours). The creatine kinase peak within 12 hours of thrombolysis was considered mandatory. Patients eligible for thrombolysis and, where possible, for administration of metoprolol were admitted to the study and randomized (single blind) to receive 6.25 mg of captopril orally (as the first dose) 15 minutes before thrombolysis or placebo. Where possible, metoprolol was given intravenously (5 + 5 + 5 mg) within 1 hour of thrombolysis. Captopril and BB were given every 8 hours after the first dose. Patients receiving placebo, where possible, received metoprolol, and they also received captopril 6.25 mg 3 days after thrombolysis. Therefore, all patients received captopril. Successively, doses were increased according to blood pressure (maximum 25 mg three times a day). The enrolled patients continued to be treated with captopril, BB, or their combination. We thus obtained four groups: Group A (42 patients) received captopril 15 minutes before thrombolysis and BB within 1 hour of thrombolysis. Group B (42 patients) received captopril before thrombolysis. Group C (37 patients) received placebo before thrombolysis and BB within 1 hour of thrombolysis. Group D (45 patients) received only placebo before thrombolysis. Blood pressure (first 6 hours) and ventricular arrhythmias (first 2 hours) were monitored continu-