Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Comparison of Enalapril Versus Captopril on Left Ventricular Function and Survival Three Months After Acute Myocardial Infarction (the "PRACTICAL" Study) Stephan G, Foy, MB, ChB, Ian G. Crozier, MD, John G. Turner, MD, A. Mark Richards, MD, Christopher M. Frampton, PhD, M. Gary Nicholls, MD, and Hamid Ikram, PhD Left ventricular (LV) function and survival can be improved with captopril when initiated later than 24 hours after acute myocardial infarction. Animal studies suggest additional benefits may be obtained with earlier initiation of angiotensinconverting enzyme (ACE) inhibitors. The effects on LV function of captopril and enalapril initiated within 24 hours of myocardial infarction were studied. Two hundred twenty-five patients with acute myocardial infarction were enrolled within 24 hours of the onset of chest pain. They were randomized to receive either captopril 25 mg three times daily, enalapril 5 mg three times daily, or placebo. LV ejection fraction (EF) and volumes were measured by radionuclide ven-triculography at baseline during treatment and at 3 months after a 3-day withdrawal from therapy. The ACE inhibitor group had a significant increase in EF (45 ± 1 to 47 ± 1%; p = 0.005) and significantly attenuated LV dilatation compared with results in the placebo group (175 ± 6 to 189 ± 7 ml in the placebo group vs 168 ± 4 to 172 ± 4 ml in the ACE inhibitor group; p = 0.051 for LV end-diastolic volume; and 99 ± 6 to 108 ± 7 ml in the placebo group vs 94 ± 3 to 94 ± 4 ml; p s 0.026 for LV end-systolic volume). The beneficial effects of ACE inhibitor therapy on LV function were observed irrespective of the degree of initial LV dysfunction and were comparable in both the captopril and enalapril groups. Survival at 90 days and 12 months was significantly improved in the enalapril group (7 placebo, 9 captopril, 1 enalapril [p = 0.038] and 12 placebo, 10 captopril, 2 enalapril [p = 0.022]; deaths at 90 days and 12 months, respectively). Immediate administration of captopril and enalapril improved LV function and prevented LV dilatation after acute myocardial infarction. The benefit was similar with both ACE inhibitors and was in excess of the benefits of optimal conventional therapy. (Am J Cardiol 1994;73:1180-1186) left ventricular (LV) dilatation is an imProgressive portant determinant of prognosis after acute myocardial infarction. 1 Captopril administered later than 24 hours after the onset of acute myocardial infarction has been demonstrated to attenuate LV dilatation in patients with impaired LV function.2-5 That earlier administration of angiotensin-converting enzyme (ACE) inhibitor therapy could result in additional clinical benefit is suggested by experimental work on myocardial infarction.6-8 ACE inhibition soon after sustained coronary occlusion in anesthetized dogs reduced infarct size and improved regional myocardial blood flow.6 In the isolated rat heart both the addition of ACE inhibitor to the perfusate and oral pretreatment with an ACE inhibitor increased coronary blood flow7,8 and improved left ventricular mechanics during ischemia,7 while pro-tecting against reperfusion arrhythmias.7 However, to date, early administration of ACE inhibitor therapy af-ter acute myocardial infarction has had no beneficial ef-feet9-11 or has had beneficial effects on LV function in only some categories of patients.12 Several important practical issues concerning the ad-ministration of ACE inhibitor therapy in acute myocar-dial infarction remain unresolved: (1) whether beneficial effects occur with earlier administration, (2) whether benefits are confined to patients with reduced LV ejection fraction (EF), (3) whether all ACE inhibitors are equally efficacious, and (4) whether alternative dosing regimens can improve drug tolerability yet maintain ef-ficacy. We examined these issues in a placebo-controlled, randomized, ACE inhibitor, comparative trial in cardiac infarction and LV function (PRACTICAL), conducted in a single center. This study presents the results of a comparison of the effects of immediate postinfarction treatment with either captopril or enalapril with placebo on LV function, the primary end point, after 90 days of treatment, and survival after 12 months treatment. METHODS Patient selection: The study was approved by the From the Departments of Cardiology and Nuclear Medicine, The Canterbury Area Health Board Ethics Committee and Princess Margaret Hospital and Christchurch Hospital, Christchurch, New Zealand. Manuscript received June 23, 1993; revised manuscript received all patients gave written informed consent. Patients November 4, 1993, and accepted November 6. were el-igible for enrollment if they presented within Address tor reprints: Humid Ikram, PhD. The Princess Margaret 24 hours of the onset of chest pain considered to be the Hospital, Private Bag, Christchurch, New Zealand. initial-symptom of acute myocardial infarction, and if the pain was associated with at least 1 of the following features: elevation of the ST segment in 2 contiguous electro-cardiographic leads, new pathologic Q waves, or eleva-tion of plasma creatine phosphokinase. 1180 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JUNE 15, 1994 TABLEI Clinical Characteristics of Treatment Groups at Baseline Characteristic Mean age (years) Age >70 years (%) Men/women (%) Thrombolytic therapy (%) Prior clinical history (%) Myocardial infarction CHF CABG PTCA Medications at entry (%) blocker Calcium antagonist Digoxin Diuretic NSAID Infarct location and type (%) Anterior Inferior Q-wave Non-Q-wave Mean ST elevation (mm) Mean time to entry (min) Mean peak creatine kinase(U/L) Mean systolic blood pressure (mm Hg) Mean serum sodium (mmol/L) Mean serum potassium (mmol/L) Placebo (n = 75) Captopril (n = 75) Enalapril (n = 75) 64 20 (27) 58 (77)/7(23) 55 (73) 64 17(23) 48 (75)/ 16(25) 51 (68) 63 21 (28) 59(79)/16(21) 56 (75) 8(11) 4(5) 0 1(1) 13(17) 2 (3) 5(7) 2(3) 10(13) 0 5(7) 1(1) 11(15) 11(15) 3(4) 10(13) 3(4) 19 (25)* 16 (21) 2(3) 7(9) 8(11) 8(11) 11(15) 3(4) 3(4) 9(12) 37 (49) 38 (51) 55 (73) 19 (25) 2 746 1979 34(45) 40 (53) 52 (69) 23 (31) 37 (49) 33 (44) 52 (69) 22 (29) 2 650 1762 2 569 1949 129 133 139 140 140 139 4 4 4 *p = 0.046. CABG = coronary artery bypass grafting; CHF = congestive heart failure; NSAID = nonsteroidal antiinflammatory drug; PTCA = percutaneous transluminal coronary angioplasty. Patients were excluded if they had any of the following: persistent hypotension with systolic blood pressure <90 mm Hg, a history of sensitivity to ACE inhibitors or the use of ACE inhibitors within 1 week of the infarction, hemodynamically significant valvular stenosis, clinically severe renal or hepatic disorders, or a clear indication for treatment with an ACE inhibitor. Those who did not give informed consent or those who were expected to comply poorly with treatment were also excluded. Study design: Patients were randomized, in a double-blind manner, to 1 of 3 parallel treatment groups. One group received oral captopril 6.25 mg at 2-hour intervals for 3 doses, followed by 25 mg 3 times daily begun 6 hours after initial dose; the second group received oral enalapril 1.25 mg at 2 hourly intervals for 3 doses, followed by 5 mg 3 times daily begun 6 hours after initial dose; the third group received placebo at matching times with groups 1 and 2. Blood pressure was recorded before each scheduled dose in the first 48 hours. Doses were withheld if systolic blood pressure was <90 mm Hg at the scheduled dose time. Randomized therapy was continued for a total of 12 months. All patients otherwise received conventional therapy as clinically indicated including thrombolytic agents and blockers. Open ACE inhibitor therapy was used if, after randomization, a clear indication for ACE inhibitor treatment developed. Patients were reviewed at 1 and 3 months, and then at 3-month intervals. Methods of assessment: The primary end points of the study were EF and LV volumes as measured by radionuclide ventriculography. The baseline study was performed during randomized treatment within 10 days of infarction or as soon thereafter as practicable. Followup study was scheduled at 3 months after infarction following a 3-day withdrawal of randomized treatment. Each study was performed using a General Electric 400T gamma camera interfaced to a General Electric STAR II computer system after in-vivo technetium-99m red blood cell labeling. General Electric PAGE software was used for analysis of EF based on a count-generated method, and an area-length method was used to measure LV end-diastolic volume. The method developed at our institution uses the PAGE edge-detection algorithm and radial vectors defining the ventricular edge at enddiastole. The volume was generated from data acquired from the left anterior oblique view. LV end-systolic volume was calculated from EF and end-diastolic volume. The effect of the 2 ACE inhibitor regimens on blockade of the circulating renin-angiotensin axis was tested in a subgroup of 36 patients. Plasma angiotensin II was measured before the first dose of randomized treatment and 2 and 12 hours after the first dose. Patients entered the trial within 6 hours of acute myocardial infarction, but were otherwise unselected. Plasma angiotensin II was measured by radioimmunoassay. 13,14 Statistical analysis: Power analysis based on data from a previous study2 indicated that 50 patients were ACE INHIBITION AFTER MYOCARDIAL INFARCTION 1181 required in each treatment group in order to detect a 3% difference in the EF from baseline between the combined ACE inhibitor group and placebo, with = 0.05 and = 0.20. This would also allow detection of a difference in the change in EF of 4% between the active and placebo groups ( = 0.05 and = 0.20). The enrollment target was therefore set at 75 per treatment group to allow for attrition. All end points were evaluated by the intention-to-treat principle. Characteristics were compared by the-chi-square test for categorical variables, and continuous variables were tested by analysis of variance, and analysis of variance with repeated measures as appropriate. Survival analysis with the Kaplan-Meier estimate was used to estimate survival curves. Comparison of survival curves was obtained by the Mantel-Cox statistic. Statistical significance (2-tailed tests) was set at 5%. Data are presented as mean ± SEM. RESULTS Patient population: The study group was taken from 523 consecutive patients with acute myocardial infarction admitted to The Princess Margaret Hospital Coronary Care Unit. Two hundred twenty-five patients (43%) were randomized, 75 patients to each treatment group. Patients were excluded for the following reasons: consent declined (n = 101), administrative reasons (n = 80), current ACE inhibitor therapy (n = 46), pain onset >24 hours after admission (n = 41), persistent hypotension (n = 27), malignancy (n = 2), and known adverse effects with an ACE inhibitor (n = 1). Baseline characteristics (Table I) were similar except there were significantly more patients using blockers in the captopril group (p = 0.046). Patient withdrawals and drug tolerabitity: Fortytwo patients were withdrawn from randomized treatment; 12 (16%) taking placebo, 18 (24%) taking captopril, and 12 (16%) taking enalapril. The most frequent reasons for withdrawal were hypotension (2 placebo, 5 captopril, 5 enalapril), rash (1 placebo, 3 captopril, 4 enalapril) and withdrawal of consent (3 placebo, 1 captopril, 4 enalapril). A further 12 patients underwent dose reduction because of intolerable adverse effects at the target dose (8 captopril and 4 enalapril). The target dose level was achieved in 75% of patients (80% placebo, 65% captopril, 79% enalapril) and was not significantly different between groups (chi-square = 5.2, degrees of freedom [df] = 2, p = 0.074). Other adverse effects not requiring withdrawal of randomized treatment or dose reduction included: dizziness (6 placebo, 15 captopril, 14 enalapril); rash (6 captopril, 4 enalapril); cough (2 placebo, 6 captopril, 4 enalapril); loss of taste (5 captopril, 1 enalapril); gastrointestinal upset (1 placebo, 2 captopril); and headache (1 placebo, 1 enalapril). Reproducibility of radioniiclide ejection fraction and end-diastolic volume: The precision of the radionuclide method was determined by repeating studies on the same day in 29 patients. The coefficient of vari ation (10% at end-diastolic volume [125 ml] to 4% at end-diastolic volume [250 ml]) followed an essentially linear pattern. The coefficient of variation for EF was 4% over the EF range 35% to 75%. Effects of angiotensin-converting enzyme inhibi-tion on left ventricular function: Paired baseline and 3-month assessments of LV function were not available in 43 patients; 17 because of death, 21 for administrative reasons, and 5 patients withdrew consent Mean times from infarction to baseline and 3month assessment were 7 ± 0.3 days and 13 ± 0.1 weeks, respectively. EF was not significantly changed in the placebo group (n = 62; 45 ± 2 to 45 ± 2%; p = 0.68), but increased 2% in patients receiving an ACE inhibitor (n = 120; 45 ± 1 to 47 ± 1%; p = 0.005); however, the difference in the changes was not significant when compared with the placebo group; p = 0.15 (Figure 1). The placebo group had a significant increase in enddiastolic volume (175 ± 6 to 189 ± 7 ml; p = 0.004), whereas in the ACE inhibitor group the increase in enddiastolic volume was attenuated (168 ± 4 to 172 ± 4 ml; p = 0.30). The difference in the change between placebo and ACE inhibitor groups did not quite achieve statistical significance; p = 0.051 (Figure I). After 3 months of treatment, the placebo group had a significant increase in end-systolic volume (99 ± 6 to 108 ± 7 ml; p = 0.007), but this did not change in pa- FIGURE 1. Changes in left ventricular (LV) function and volume from baseline (B) to 3 months (Mo) in patients re ceiving an angiotensin-converting enzyme inhibitor or placebo after acute myocardial infarction. Closed circles represent the angiotensin-converting enzyme inhibitor group; open circles represent the placebo group. 1182 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JUNE 15, 1994 tients receiving an ACE inhibitor (94 ± 3 to 94 ± 4 ml; p = 0.94). The difference in the changes in end-systolic volume was statistically significant; p=0.026 (Figure 1). Effect of individual angfotensin-converting enzyme inhibitors on left ventricular function: Captopril (n = 55) significantly increased EF by 2% (45 ± 6 to 47 ± 6%; p = 0.023), whereas in the enalapril group (n = 65) EF increased by 2% (46 ± 6 to 48 ± 6%) and the change almost achieved statistical significance (p = 0.08). There was no significant difference in these changes between groups (p = 0.66) (Figure 2). End-diastolic volume did not change significantly in either the captopril (171 ± 23 to 176 ± 24 ml; p = 0.23) or the enalapril (167 ± 21 to 168 ± 21 ml; p = 0.65) groups, nor was there a statistically significant difference between groups (p = 0.51). End-systolic volume showed little change in either the captopril (97 ± 5 to 98 ± 7 ml; p = 0.78) or the enalapril (92 ± 5 to 91 ± 5 ml; p = 0.88) groups, nor was there a significant difference between groups (p = 0.75). Benefits in patients with ejection fraction >40%: Sixty-five percent of patients had a baseline EF >40%. In these patients, EF did not change in the placebo group (n = 44; 51 ± 1 to 51 ± 1%), but tended to increase with ACE inhibition (n = 84; 52 ± 1 to 53 ± 1%; p = 0.28). The placebo group had a 7% increase in end-diastolic volume (160 ± 5 to 171 ± 6 ml; p = 0.066), whereas in the ACE inhibitor group there was a 1% decrease in end-diastolic volume (158 ± 4 to 156 ± 4 ml; p = 0.61). The difference in these changes between placebo and ACE inhibitor almost achieved statistical significance (p = 0.056) (Figure 3). End-systolic volume increased by 8% in the placebo group (78 ± 3 to 84 ± 4 ml; p = 0.096), whereas there was a 4% decline in the ACE inhibitor group (77 ± 3 to 74 ± 3 ml: p = 0.19). There was a significant difference in these changes between placebo and ACE inhibitor groups (p = 0.026) (Figure 3). Comparability of angiotensin-converting enzyme inhibitor regimens on circulating angiotensin II: There was no significant change in plasma angiotensin II level from baseline to 12 hours in patients receiving placebo (n = 11; 37 ± 6 to 36 ± 13 pmol/liter, p = 0.96), but was significantly reduced both in the captopril (n = 13; 43 ± 9 to 18 ± 5 pmol/liter, p = 0.001) and in the enalapril (n = 12; 69 ± 18 to 16 ± 8 pmol/liter, p = 0.01) groups. The difference in the change in angiotensin II levels from baseline to 12 hours was not significantly different between the captopril and enalapril groups (p = 0.13). Blood pressure: In the placebo group (n = 58) there was a significant decrease in systolic blood pressure from FIGURE 2. Change in left ventricular (LV) ejection fraction from baseline (B) to 3 months (Mo) in patients receiving captopril or enalapril after acute myocardial infarction. Diamonds represent the enalapril group; squares represent the captopril group. FIGURE 3. Changes in left ventricular (LV) end-diastolic and end-systolic volume from baseline (B) to 3 months (Mo) in patients with an initial ejection fraction >40% receiving an angiotensin-converting enzyme inhibitor or placebo after acute myocardial infarction. Closed circles represent the angiotensin-converting enzyme inhibitor group; open circles represent the placebo group. ACE INHIBITION AFTER MYOCARDIAL INFARCTION 1183 baseline to 48 hours (129 ± 3 to 113 ± 3 mm Hg; p <0.001). A similar decline in systolic blood pressure was observed in both the captopril (n = 55;130 ± 3 to 116 ± 3 mm Hg; p <0.001) and the enalapril (n = 54; 132 ± 3 to 109 ± 2 mm Hg; p <0.001) groups. The difference in the change from baseline to 48 hours in systolic blood pressure between the captopril and enalapril groups was almost statistically significant (p = 0.052), but there was a significantly greater decrease in blood pressure with captopril at 2 hours (p = 0.004) (Figure 4). Mortality: Seventeen deaths (8%) from all causes occurred during the first 90-day study period (7 placebo, 9 captopril, and 1 enalapril). There were 16 deaths (7%) from cardiac causes, the majority being mechanical (i.e., LV failure and cardiac rupture; 6 placebo, 4 captopril). Six deaths were presumably due to ventricular arrhythmias; 5 were sudden undocumented deaths with no premonitory symptoms (1 placebo, 3 captopril, 1 enalapril) and 1 was from documented ventricular fibrillation. Twenty-four deaths (11%) from all causes occurred in the 12-month follow-up period (12 placebo, 10 captopril, 2 enalapril). There were 21 deaths from cardiac causes (12 placebo, 8 captopril, 1 enalapril) of which 12 (8 placebo, 4 captopril) were due to either LV failure or cardiac rupture and 9 were sudden, due to either documented or presumed ventricular arrhythmias (4 placebo, 4 captopril, 1 enalapril). There were 3 non-cardiac-re lated deaths, 1 due to cerebrovascular accident (capto pril), 1 resulting from acute gastrointestinal bleeding (captopril), and 1 from metastatic carcinoma of the bronchus (enalapril). Kaplan-Meier estimates of survival curves showed a significantly improved survival at 90 days (Mantel-Cox chi-square = 6.52, df = 2; p = 0.038) and at 12 months (Mantel-Cox chi-square = 7.67, df = 2; p = 0.022) in patients treated with enalapril (Figure 5). DISCUSSION Progressive LV dilatation occurs after acute myocardial infarction, leads to heart failure, and is an important predictor of mortality.1,15 Previous studies have shown that captopril initiated late after myocardial infarction attenuated progressive LV dilatation, reduced heart failure, and improved survival.2-5 Data from animal studies suggest that very early ACE inhibition may have addi tional benefits by decreasing infarct size and reducing arrhythmias.6-8 The role of early initiation of ACE in hibitors in humans after myocardial infarction remains unclear. The primary objective of the present study was to evaluate the effects of ACE inhibition on LV function when initiated immediately within 24 hours of the on set of acute myocardial infarction in a relatively unselected group of patients entering a single coronary care unit. We demonstrated that LV enlargement is reduced by both captopril and enalapril, and that these benefits are comparable with results of studies using captopril given later in the course of cardiac infarction.2-4 Enalapril has not previously been documented to improve LV function after myocardial infarction. Our data show that enalapril and captopril had a comparable effect on LV function, and therefore it is likely this was a class effect of ACE inhibition. Because this was a study of immediate administration of ACE inhibitor therapy after the onset of acute myocardial infarction, we elected not to assess LV function before initiation of randomized therapy. LV func- FIGURE 4. Change in systolic blood pressure from baseline to 48 hours in patients receiving captopril or enalapril after acute myocardial infarction. Diamonds represent the enalapril group; squares represent the captopril group; *p = 0.004. 1184 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JUNE 15, 1994 tion in the first few hours after the onset of acute infarction is highly unstable because it is affected by the evolution of the infarction as well as acute treatment, especially thrombolytic therapy. Because >80% of patients had not experienced a previous myocardial infarction, it is likely that LV function was normal and similar in all treatment groups before initiation of randomized therapy. The absence of any discernable drug effect on infarct size and early remodeling is indicated by the absence of significanr differences between groups in LV function and volume at the initial measurement 7 days after infarction. Our trial design almost certainly minimized the magnitude of benefit by excluding the acute effects of afterload reduction because the initial measurement of LV function was performed during randomized treatment, and the subsequent assessment was performed after 3 days without treatment. This is in contrast to previous studies in which assessment was performed during treatment, and thus the changes observed would have been magnified by the effect of afterload reduction in addition to any effects on remodeling. In this study we observed that LV dilatation occurred even in patients with EF >40%. ACE inhibitor therapy attenuated this dilatation and this benefit was comparable to those with EF <40%. These observations extend the conclusions of previous studies in which only patients with EF <40% were considered, by demonstrating beneficial effects on LV function irrespective of initial EF. Concern has been expressed as to the risk of excessive hypotension from the addition of an ACE inhibitor to conventional optimal therapy because the multiple hypotensive drugs may cause deleterious hypotension.11 However, in the present study, despite the inclusion of all patients in an unstable phase of acute infarction, the target dose was reached in 72% treated with active ther- apy without development of a significant excess of patient withdrawals because of early hypotension or other drug side effects. These tolerability data suggest that frequent smaller oral doses of captopril and enalapril may be better tolerated in patients with acute myocardial infarction than larger, less frequent and intravenous regimens.11 This study demonstrated that these lower doses have comparable therapeutic benefit to previous studies of higher doses of captopril after myocardial infarction.2-5 This study was not designed to assess the effects of acute ACE inhibitor therapy on mortality. However, mortality was carefully monitored because of concerns regarding the potential adverse mortality effect of early ACE inhibitor treatment. There was no excess mortality in either ACE inhibitor group and, indeed, in the enalapril group mortality was significantly reduced. This study contrasts with the Cooperative New Scandanavian Enalapril Survival Study II (CONSENSUS II) which failed to demonstrate any mortality benefit over a period of 180 days.11 The reason for the lack of benefit in CONSENSUS II is uncertain, but a major concern that led to premature termination of the study was the high incidence of early hypotension, which may have had an adverse effect. This may have been due to the intravenous regimen that, by inducing hypotension and compromising myocardium with marginal viability, may have adversely affected prognosis. In our study, oral enalapril resulted in a gradual, well-tolerated decrease in blood pressure. The conclusions from the PRACTICAL study are that immediate administration of captopril and enalapril improved LV function and prevented progression of ventricular dilatation after myocardial infarction. This benefit was similar with both ACE inhibitors and occurred in patients with impaired LV function and in those with relatively preserved LV function. These benefits were in FIGURE 5. Kaplan-Meler survival curves for 12-month total mortality in patients receiving placebo, captopril, or enalapril after acute myocardial infarction. ACE INHIBITION AFTER MYOCARDIAL INFARCTION 1185 addition to those of optimal conventional therapy. The doses resulted in comparable reduction of circulating angiotensin II and were well tolerated. There was a significant reduction in mortality with enalapril. Acknowledgment: We thank Margaret J. Milne for her administrative assistance, and the nursing, medical, and technical staff of the Coronary Care Unit and the Departments of Cardiology and Nuclear Medicine for their assistance. We are grateful to Merck Sharp & Dohme (NZ) Ltd and Bristol-Myers Squibb (NZ) Ltd for the supply of active drug and placebo. 1. White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44-51. 2. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988;1: 255-259. 3. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N EnglJ Med 1988:319:80-86. 4. Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G. Early prevention of left ventricular dysfunction following myocardial infarction with angiotensinconverting-enzyme inhibition. Lancet 1991;337:872-876. 5. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM. Effect of captopril on 1186 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 mortality and morbidity in patients with left ventricular dysfunction after myocar dial infarction: results of the Survivial and Ventricular Enlargement Trial N Engl J Med 1992;327:669-677. 6. Erfl G, Kloner RA, Alexander RW, Braunwald E. Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor. Circulation 1982;65 40-48. 7. Linz W, Scholkens BA, Han Y-F. Beneficial effects of the converting enzyme inhibitor, ramipril, in ischemic rat hearts. J Cardiovasc. Pharmacol 1986;8(suppl. 10):S91-S99. 8. van Gilst WH, Scholtens E, de Graaf PA, de Langen CD, Wesseling H. Differ ential influences of angiotensin converting-enzyme inhibitors on the coronary circulation Circulation 1988;77(suppl I):I-24-I-29. 9. Nabel EG, Topol EJ, Galaena A, Ellis SG, Bates ER, Werns SW, Walton JA Muller DW, Schwaiger M, Pitt B. A placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator in acute myocardial infarction. J Am Coll Cardial 1991; 17:467-473. 10. Hargreaves AD, Kolettis T, Jacob AJ, Flint LL, Turnbull LW, Muir AL, BoonNA. Early vasodilator treatment in myocardial infarction: appropriate for the majority or minority? Br Heart J 1992;68:369-373. 11. Swedberg K, Held P, Kjekhus J, Rasmussen K, Ryden L, Wedel H. Effects of early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study I (CONSENSUS II). N Engl J Med 1992:327:678-684. 12. Oldroyd KG, Pye MP, Ray SG, Christie J, Ford I, Cobbe SM, Dargie HJ. Ef fects of early captopril administration on infarct expansion, left ventricular remod elling and exercise capacity after acute myocardial infarction. Am J Cardiol 1991;68 713-718. 13. Nicholls MG, Espiner EA. A sensitive rapid radio-immunoasssay for angiotensin II .N Z Med J 1976:83:399-403. 14. Richards AM, Wittert GA, Espiner EA, Yandle TG, Ikram H, Frampton C. Ef fect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers. Circ Res 1992:71:1501-1507. 15. Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial in farction: the Framingham Study. Am J Cardiol 1979;44:53-59. JUNE 15, 1994