Indications for ACE Inhibitors in the Early Treatment of Acute Myocardial Infarction
Systematic Overview of Individual Data From 100 000 Patients in Randomized Trials
Background—Several large-scale trials have demonstrated improved survival with ACE-inhibitor therapy started during acute myocardial infarction. A systematic overview was conducted to resolve uncertainties regarding time of initiation, time course of effect, and identification of patients in whom the benefits or the risks may be greater.
Methods and Results—This overview aimed to include individual data from all randomized trials involving more than 1000 patients in which ACE-inhibitor treatment was started in the acute phase (0 to 36 hours) of myocardial infarction and continued for a short time (4 to 6 weeks). Data were available for 98 496 patients from 4 eligible trials, and the results were consistent among the trials. Thirty-day mortality was 7.1% among patients allocated to ACE inhibitors and 7.6% among control subjects, corresponding to a 7% (SD, 2%) proportional reduction (95% CI, 2% to 11%; 2P<0.004). This represented avoidance of ≈5 (SD, 2) deaths per 1000 patients, with most of the benefit observed within the first week. The proportional benefit was similar in patients at different underlying risk. The absolute benefit was particularly large in some high-risk groups (ie, Killip class 2 to 3, heart rate ≥100 bpm at entry) and in anterior MI. ACE-inhibitor therapy also reduced the incidence of nonfatal cardiac failure (14.6% versus 15.2%, 2P=0.01) but was associated with an excess of persistent hypotension (17.6% versus 9.3%, 2P<0.01) and renal dysfunction (1.3% versus 0.6%, 2P<0.01).
Conclusions—These results support the use of ACE inhibitors early in the treatment of acute MI, either to a wide range of patients or selectively in patients with anterior MI and in those at increased risk of death.
A total of more than 120 000 patients have been randomized in several large-scale controlled trials to evaluate the effect of ACE inhibitors during and after acute myocardial infarction (MI).1 2 3 4 5 6 7 8 In general, mortality and morbidity were reduced when ACE inhibitors were given during the acute phase of MI (“early”) in a relatively unselected population of patients,1 2 3 4 5 as well as when they were started sometime after MI (“late”) in patients with evidence of left ventricular dysfunction.6 7 8 However, uncertainty still exists regarding a number of clinically relevant questions: for example, whether there are subgroups of patients in whom the benefits or the risks are greater.9
Thus, a collaborative group involving the principal investigators of all the randomized trials was created to collate the individual patient data from the early and late trials in systematic overviews. Prespecified end points were analyzed by use of an approach already successfully applied to evaluate ACE inhibitors in patients with congestive heart failure,10 antiplatelet therapy in occlusive vascular diseases,11 or thrombolytic therapy in acute MI.12
The results of such systematic overviews should help to guide clinical practice appropriately and thus optimize the benefits attainable with therapeutic approaches. In this report, we present data from an overview of the early trials of ACE inhibitors in MI.
Trials to Be Included
The present overview was to be of the randomized trials in which ACE-inhibitor treatment begun in the acute phase of MI (0 to 36 hours from symptom onset) and continued for a short period of time (generally 4 to 6 weeks) was compared with no routine ACE-inhibitor treatment. Such trials are CONSENSUS-II,1 GISSI-3,2 ISIS-4,3 CCS-1,4 SMILE,5 GISSI-3 Pilot,13 ISIS-4 Pilot,14 and several other smaller studies.15 16 17 18 19 20 21 Long-term trials in which ACE-inhibitor treatment was started after the acute phase of MI in selected patients with left ventricular dysfunction and continued for a longer period (at least 6 months)6 7 8 22 23 24 25 26 will be the subject of a separate overview. The GISSI Coordinating Center, Milan, Italy, was responsible for data collection, checking, and analysis of the present overview, and the Canadian Cardiovascular Collaboration Project Office at McMaster University, Hamilton, Ontario, was responsible for the overview of long-term trials.
In the present overview, only those “early short-term” trials that randomized more than 1000 patients to ACE-inhibitor therapy versus control1 2 3 4 5 were to be included, because patients from these trials represent ≈98% of all randomized patients, and retrieving reliable individual patient data from small trials is generally more difficult.12 As a result, several smaller trials were excluded.13 14 15 16 17 18 19 20 21
Individual Patient Data Collection
Data were collected for individual patients because this allows more detailed consistency checking, analysis, and life-table calculations.11 12 27 A common protocol was developed to provide data to the overview coordinating centers in a standardized format. These included data recorded before randomization (such as ECG classification, supplemented by discharge ECG in the GISSI-3 study; age and sex; systolic blood pressure and heart rate; history of MI, diabetes, or hypertension; Killip class; and hours from onset of symptoms), as well as concomitant medications, clinical events (such as hypotension, renal dysfunction, cardiogenic shock, second- to third-degree atrioventricular block, heart failure, ventricular fibrillation, and stroke), and mortality after randomization. The last date of follow-up was also collected to allow survival analyses. The original definitions adopted in each trial for clinical events were used. Data were checked for completeness and consistency with the published results; apparent discrepancies were reviewed with the principal investigators, and any corrections required were included in the main database.
Available Data From Different Trials
Individual data were available for 98 496 patients in four of the eligible trials1 2 3 4 but not for the 1556 patients in SMILE,5 representing availability of 98% of eligible patients. Mortality data and most other key clinical outcomes were available from each trial, but some other data items were not systematically collected in each trial. For example, history of hypertension or diabetes was not recorded in ISIS-4; dates of some clinical events were not always collected in CONSENSUS-II and CCS-1; heart failure at entry, rather than Killip class, was recorded in ISIS-4 and CONSENSUS-II (and considered equivalent to Killip class >1 in this overview); and the randomization date was not available for 13 patients in CCS-1.
All randomized patients were to be included in the analyses, and follow-up for survival to day 30 was almost complete. Only 2% of patients were lost before day 30 (474 on day 0, 414 on days 1 to 7, and 950 on days 8 to 30), and they were well balanced between the two groups (920 allocated ACE inhibitors versus 918 allocated control treatment). No significant differences between baseline characteristics were found, except for a slight imbalance in history of hypertension (37.7% ACE inhibitors versus 36.7% control, 2P=0.04).
The main analyses were of mortality and clinical events up to day 30 (with special emphasis on days 0 to 7) and of mortality by subgroup based on baseline characteristics. Statistical analyses used the modified Mantel-Haenszel method11 12 28 to calculate stratified estimates of the proportional treatment effect, which were described as odds ratios or as percentage reductions in odds. χ2 tests for heterogeneity of the proportional effects were calculated between different trials or between subgroups. χ2 tests for linear trend were also calculated whenever appropriate. Given the modest size of the overall effect and the number of subgroups studied, such subgroup analyses need to be interpreted cautiously; indeed, in many instances, the overall proportional effect may provide more reliable guidance as to the proportional effect in some particular subgroup than the effect observed just within that subgroup.11 12 29
To investigate whether the treatment benefit varied according to the underlying risk, the effects were evaluated in subgroups according to a prognostic index derived from logistic regression analysis among all study patients (irrespective of allocated treatment). The following variables adjusted by treatment allocation were included in the model: age (as a continuous variable), sex, systolic blood pressure (<100, 100 to 120, 121 to 150, and >150 mm Hg), heart rate (<80, 80 to 99, and ≥100 bpm), previous MI, Killip class (1 and >1), and location of MI (anterior and nonanterior). The patients were divided into four groups that included approximately equal numbers of deaths: low risk (30-day mortality of 2% to 6%), medium risk (6% to 10%), high risk (10% to 16%), and very high risk (16% to 42%). χ2 values for heterogeneity and for linear trend were calculated to test the treatment effects between these groups.
All P values are two-sided; values of 2P<0.05 and 2P<0.01 were considered conventionally significant in the overall and subgroup analyses, respectively. Similarly, 95% CIs were used for overall analyses and 99% CIs for subgroup analyses to make some allowance for the effects on probability values of multiple comparisons. For survival analyses, the Kaplan-Meier method was used, and the P value was determined by the log-rank test.30
Features of Trials and Available Data
The 4 trials of early ACE-inhibitor therapy versus control treatment, which provided individual patient data for the overview, recruited a total of 98 496 patients (Table 1⇓). Captopril was used in 2 of these trials,3 4 enalapril in 1,1 and lisinopril in 1.2 Three trials were placebo controlled,1 3 4 and 1 used an open control2 ; all trials used a 1:1 allocation ratio. Three trials included patients presenting within 24 hours from the onset of symptoms,1 2 3 and 1 up to 36 hours.4 Patients with definite or suspected acute MI were eligible for 2 trials3 4 : 1 included only patients with ST-segment elevation, new pathological Q waves, or raised cardiac enzymes1 ; and 1 required two of the following: typical chest pain, abnormal Q waves with evolutionary ST-T wave changes on serial ECG, or enzymatic evidence.2
There was no specified upper age limit in any of the trials: even so, the percentage of patients >75 years old varied from 9% in CCS-1 to 23% in CONSENSUS-II (Table 2⇓). Patients presenting with cardiogenic shock (ie, Killip class 4) were generally excluded from the trials, with a larger proportion of those patients in CCS-1 in Killip class >1. Antiplatelet and fibrinolytic therapy were explicitly recommended in GISSI-3 and ISIS-4 (Table 3⇓), and they were used more commonly in those trials. Nitrates were used commonly in the CCS-1 trial (87% of patients), and oral or transdermal nitrates were given to approximately half of the patients in the GISSI-3 and ISIS-4 trials, because such nitrates were also allocated at random in factorial study designs.
Effects on 30-Day Mortality and on 7-Day Mortality
Overall, the cumulative mortality for patients allocated to ACE inhibitors and to control showed a significant difference in survival at 30 days (log-rank test, P=0.004). There were 3501 deaths (7.11%) during days 0 to 30 among 49 214 patients allocated to ACE inhibitor compared with 3740 deaths (7.59%) among 49 269 control patients (Figure 1⇓). This 7% (SD, 2%) proportional reduction in 30-day mortality (95% CI, 2% to 11% reduction) corresponds to the avoidance of 4.8 (SD, 1.7) deaths per 1000 patients. There was no statistical difference between the effects in the four trials (χ2 on 3 df=5.8, 2P=0.1) (Figure 2⇓).
Among patients allocated ACE inhibitors, there were 239 fewer deaths, and subdivision of these deaths by day from initiation of treatment indicates that 200 (ie, four fifths) were avoided during the first week (Figure 3⇑). The treatment was associated with a significant 8% (SD, 3%) proportional reduction during days 0 to 7 (95% CI, 3% to 14% reduction), with similar benefit in days 0 to 1 and 2 to 7. This corresponded to avoidance of 4.0 deaths (SD, 1.4) per 1000 patients in the first week (Figure 3⇑).
Effects on 30-Day Mortality in Different Subgroups
Age and Sex
The mortality reductions at 30 days were separately significant in the patients 55 to 64 years old (16% [SD, 5%] proportional reduction; 2P=0.001) and 65 to 74 years (10.8% [SD, 3.7%] proportional reduction; 2P=0.004; Figure 4⇓). There was a trend toward greater proportional mortality reduction among younger patients (χ2 on 1 df=6.2; 2P=0.01) (Figure 4⇓). The proportional and absolute reductions in death were similar for both sexes (4.6 [SD, 1.8] lives saved per 1000 in men versus 5.5 [SD, 3.9] in women) (Figure 4⇓).
Systolic Blood Pressure and Heart Rate
The proportional reductions in mortality were not significantly influenced by systolic blood pressure at entry (χ2 for trend=2.2, 2P=0.1). However, few patients with systolic blood pressure <100 mm Hg were studied, because such patients were often excluded (Figure 4⇑). By contrast, there was a significant trend toward greater proportional mortality reductions among patients with higher heart rates at entry (χ2 for trend=9.9, 2P=0.002). Hence, the absolute benefits observed among patients with higher heart rates were larger: 22.7 (SD, 6.7) fewer deaths per 1000 among those with heart rates ≥100 bpm and 8.7 (SD, 3.1) fewer deaths per 1000 among those with heart rates 80 to 99 bpm (Figure 4⇑).
Prior MI, Diabetes, Hypertension
The proportional reductions in mortality in patients with a history of MI, of diabetes, or of hypertension were nonsignificantly different from those observed in patients without these conditions (Figure 4⇑). Because such patients are at higher absolute risk of death after MI, the absolute benefits of ACE-inhibitor treatment were greater among patients with prior MI (8.9 [SD, 4.7] versus 4.1 [SD, 1.8] lives saved per 1000), among diabetics (17.3 [SD, 8.9] versus 3.2 [SD, 2.7] lives saved per 1000), and among hypertensives (9.0 [SD, 4.7] versus 2.1 [SD, 3.1] lives saved per 1000).
Killip Class at Entry
There was no significant difference between the proportional mortality reduction among patients with heart failure or Killip class >1 at entry (11% [SD, 4%]) and that among patients in Killip class 1 (5% [SD, 3%]). Because patients with heart failure are at greater risk of death, the absolute benefit of treatment was greater among these patients (14.1 [SD, 5.4] versus 2.9 [SD, 1.6] lives saved per 1000) (Figure 4⇑).
Delay From Symptom Onset and Concomitant Fibrinolytic Therapy
The benefits of ACE inhibitors were not significantly influenced by the delay from onset of symptoms to randomization (within 24 to 36 hours) (Figure 4⇑) or by whether fibrinolytic therapy was used (7.1% [SD, 3.2%] proportional reduction with ACE inhibitors in the presence of fibrinolytic therapy and 6.6% [SD, 3.5%] reduction in its absence; data not shown).
Site of MI
Among patients with evidence of anterior MI (ie, anterior ST-segment elevation with or without other changes), the proportional reduction of 14% (SD, 3.6%) was greater than that among patients with other MI locations (2% [SD, 3%]; χ2 for heterogeneity on 1 df=6.3, 2P=0.01). This corresponds to 10.6 (SD, 2.9) deaths avoided per 1000 patients with anterior MI (Figure 4⇑).
Subgroups at Different Risk
When the effects of ACE-inhibitor treatment were evaluated in subgroups of patients according to a multivariate prognostic index (see “Methods”), there was no evidence of a difference in the proportional benefits in patients at different underlying risk (Figure 4⇑, bottom). Hence, the absolute benefits were greater in patients at greater risk of death (3.8 [SD, 1.5] lives saved per 1000 low-risk patients compared with 13.6 [SD, 9.1] in very-high-risk patients). Mortality after MI increased steeply with increasing age, whereas the univariate analyses (above) indicated that the proportional reductions in mortality with ACE inhibitors were greater at younger ages. Prognostic scores were therefore also constructed with age excluded, both for all patients and, separately, for those <75 years old and those ≥75 years old. In each case, the proportional benefits among patients at different absolute risk were not significantly different from each other (data not shown).
Effects on Nonfatal Heart Failure
ACE-inhibitor therapy significantly reduced the incidence of nonfatal cardiac failure: there were 6687 cases of nonfatal heart failure (14.6%) during days 0 to 30 among patients allocated to ACE inhibitors compared with 6937 cases (15.2%) among control subjects. This corresponds to the avoidance of 6.1 (SD, 2.4) cases of nonfatal heart failure per 1000 patients (2P=0.01), which was distributed throughout the period of hospitalization (Table 4A⇓).
Effect on Other Clinical Events
The incidence rates of reinfarction and stroke were similar in the two treatment groups (Table 4B⇑). ACE-inhibitor therapy was associated with a significant excess of 84 (SD, 2) cases of persistent hypotension per 1000 patients treated (17.6% versus 9.3%). There were also small but significant increases in cardiogenic shock (4.6 [SD, 1.2] per 1000) and in second- to third-degree atrioventricular block (5.4 [SD, 1.2] per 1000). Most of these excesses occurred during days 0 to 7, when most of the mortality benefit was also observed. There was also a significant excess of 6.2 (SD, 0.6) cases of renal dysfunction per 1000 (1.3% ACE inhibitor versus 0.6% control), which was distributed throughout the period of hospitalization (Table 4B⇑).
There was a slight but significant increase with increasing age in the proportional effect on persistent hypotension after ACE-inhibitor treatment (test for trend, 2P=0.003) (Table 5⇓). Otherwise, the proportional effects on hypotension and on renal dysfunction in the subgroups examined were not clearly different from those observed overall. In some subgroups, however, the control risks were much higher, and thus the absolute excesses of complications were greater. For example, among patients presenting with systolic blood pressure <100 mm Hg, the absolute excess of persistent hypotension was 132 per 1000 compared with an overall excess of 84 per 1000. Similarly, the absolute risks of renal dysfunction were greater in the elderly, with an absolute excess of 17 per 1000 among those ≥75 years old compared with 6 per 1000 overall.
This systematic overview of trials of early ACE-inhibitor therapy in acute MI yields four main messages. First, the benefit on 30-day mortality is consistent among the trials and, on average, corresponds to ≈5 lives saved per 1000 patients treated for ≈1 month. Second, most of the benefit occurs during the first few days, when mortality is highest. Third, the proportional benefit is generally consistent among patients with differing baseline characteristics, so patients at higher risk generally benefit to a greater absolute extent. Fourth, there is no subgroup in which the treatment was shown to be definitely harmful, although hypotension and renal dysfunction with therapy were more common in patients ≥75 years old, and there was no direct evidence of any survival advantage in such patients. It should be remembered that patients presenting in cardiogenic shock or with persistently low systolic blood pressure (ie, <100 mm Hg) were generally excluded from these studies.
Before these points are discussed in detail, some limitations of this overview should be underlined: for example, if only the larger trials (>1000 randomized patients) were considered, information from smaller trials was lost; also, individual patient data were not available from the SMILE study.5 However, these trials would have added only ≈5% to the total number of patients, and their overall results are consistent with the present ones. In particular, adding the published results for the 1556 patients randomized within 24 hours of the onset of anterior MI in the SMILE study (38 deaths at 42 days among 772 patients allocated to ACE-inhibitor therapy versus 51 among 784 control subjects) to those for the nearly 100 000 patients included in this overview would not alter the findings even minimally (data not shown).
A second potential limitation concerns heterogeneity between different studies. Differences in the drug regimens studied include the study agents (eg, drugs with a short half-life, such as captopril, and a long half-life, such as lisinopril), dosages (eg, captopril dose in CCS-1 versus ISIS-4), and routes of administration (in particular, an initial intravenous infusion was used in CONSENSUS-II, which was the only trial to report an adverse trend, albeit nonsignificant, on mortality), and concomitant nonstudy treatments (Table 3⇑). Moreover, there were some differences in the types of patients studied in the different trials (Table 2⇑) and in some of the definitions of variables used (such as “site of MI” or “persistent hypotension”). In assessments of the differences between subgroups, variations in definitions or baseline characteristics would tend to decrease the sensitivity of such analyses to show interactions. However, such differences are inherent to all overviews and do not introduce any biases into ascertainment of the average effects observed among the patients included.
Benefit of Early ACE-Inhibitor Therapy
An average 7% proportional reduction in mortality with ACE inhibitors was observed within 30 days of acute MI, corresponding to an average absolute benefit of ≈5 lives saved per 1000 patients treated. In other words, on average, ACE-inhibitor therapy begun early in acute MI and continued for only 1 month in ≈200 patients leads to the saving of 1 life. At first glance, this beneficial effect may appear modest compared with that observed in the trials of long-term ACE-inhibitor therapy among high-risk post-MI patients. But those trials involved a much longer treatment period (1 to 3 years), so the number of lives saved per month of treatment per 1000 individuals varied from 1.0 in SAVE to 3 to 4 in AIRE.9 Thus, the early use of ACE inhibitors in relatively unselected MI patients leads to at least comparable absolute survival benefits during the first month of treatment.
In addition, nonfatal heart failure, which was not a primary end point in any of the studies, was also significantly reduced by early ACE-inhibitor treatment. This corresponds to 6 additional events avoided per 1000 patients on top of the survival benefit.
Time Course of the Beneficial Effect of ACE-Inhibitor Therapy on Survival
ACE-inhibitor therapy saved lives early after its initiation, with 40% of the 30-day survival advantage observed in days 0 to 1, ≈45% in days 2 to 7, and ≈15% subsequently (Figure 3⇑). Data from the different studies were consistent in this respect, strongly supporting the strategy of starting ACE inhibitors early to maximize their potential benefits. But because the reduction in mortality was observed irrespective of the interval between symptom onset and randomization, ACE inhibitors should not be withheld from patients who present late.
Effects of ACE-Inhibitor Therapy on Survival in Different Patient Subgroups
In general, most of the patient subgroups studied benefited from ACE inhibition, and there was no subgroup in which the treatment was clearly shown to be harmful. The CIs for the proportional effects on 30-day mortality in different subgroups overlap each other substantially and, in general, did not differ significantly from the overall proportional reduction of 7% (Figure 4⇑). Similarly, when the results were analyzed in groups subdivided with respect to a risk score based on multivariate logistic regression (even with age excluded), the proportional reductions in mortality were similar at different levels of risk (Figure 4⇑). However, certain characteristics, such as anterior site of MI and high heart rate, were clearly associated with a higher benefit. But such patients represent only a minority of those who present with suspected acute MI, and the beneficial effects of early ACE-inhibitor therapy in a lower-risk population may still have some influence on the impact of the treatment.
Safety of ACE-Inhibitor Therapy During Acute MI
Hypotension was anticipated, and this was the reason for titration of the initial doses of the ACE inhibitors. It was significantly more common than among control subjects (17.6% versus 9.3%), and although there was an increase in mortality (2.3% versus 1.6%) among patients who became hypotensive, this may well indicate differences in their baseline risk.31 Moreover, the excess of hypotension was seen primarily during the first week, when most of the survival advantage was also seen. A significant increase in the incidence of renal dysfunction and cardiogenic shock was also observed in the ACE inhibitor–treated patients, perhaps reflecting the hypotensive effect of treatment during this acute phase. The higher incidence of second- to third-degree AV block might have been a consequence of increased parasympathetic activity and decreased sympathetic tone induced by the ACE inhibitor32 or, perhaps, of hypotension-induced ischemia in some patients.
ACE-inhibitor therapy was not generally associated with proportionally higher risks of hypotension or of renal dysfunction in specific patient subgroups, except for hypotension with increasing age. The absolute excesses, however, were greater in certain subgroups at higher risk (eg, hypotension among those presenting with systolic blood pressure <100 mm Hg or renal dysfunction among those ≥75 years old), and this should be considered when we decide whether the likely survival benefit is likely to justify the treatment of a particular patient.
This overview supports and expands the conclusions of a previous consensus meeting9 and leads to the following general considerations. First, ACE-inhibitor treatment may be started immediately during the acute phase of MI, along with other routinely recommended treatments (such as thrombolytics, aspirin, and β-blockers), in the absence of clear contraindications. The presence of cardiogenic shock or systolic blood pressure persistently <100 mm Hg should generally be considered a contraindication to early treatment with an ACE inhibitor. Second, the benefit occurs during the first few days after MI, suggesting that mechanisms other than benefits on the remodeling process may play a role. These mechanisms may include an early effect on infarct expansion, a reduction of neurohormonal activation, or an increase in collateral coronary flow. Irrespective of the mechanisms, however, these findings strongly support early initiation of treatment.33 Third, the proportional benefit is generally larger in higher-risk subgroups, such as those with anterior site of MI or high heart rate. However, elderly patients, particularly those ≥75 years old, are at increased risk of hypotension with ACE inhibitors, and there is no evidence of a survival advantage among them. Finally, the data suggest that the early benefits of ≈1 month of ACE-inhibitor therapy started early in acute MI patients is observed largely during the first week, and it seems likely that this would be complementary to that observed later in trials of prolonged ACE-inhibitor therapy initiated several days or weeks after MI in patients with evidence of heart failure or left ventricular dysfunction (and the absolute benefits per month of treatment are of similar size).
In translating these results into clinical practice, two strategies could be adopted. One strategy involves starting ACE-inhibitor therapy in acute MI in all patients who do not have clear contraindications. Such treatment should be reevaluated at discharge or after a few weeks and should be continued long-term only in patients considered to be at high risk (such as those with extensive left ventricular damage or obvious heart failure). An alternative strategy involves initiating therapy early only in patients presenting with anterior infarct and in certain higher-risk individuals, such as those with tachycardia, heart failure, and perhaps diabetes. By using a number of these risk markers, we may avoid a high proportion (but not all) of the deaths potentially prevented by this treatment. Physicians may justifiably choose either strategy, but irrespective of which they choose, the present results support the benefits of the use of ACE inhibitors early in the treatment of acute MI.
The ACE Inhibitor Myocardial Infarction Collaborative Group
Writing Committee: M.G. Franzosi, E. Santoro, G. Zuanetti, C. Baigent, R. Collins, M. Flather, J. Kjekshus, R. Latini, L.S. Liu, A.P. Maggioni, P. Sleight, K. Swedberg, G. Tognoni, S. Yusuf.
Steering Committee (early and late trials): GISSI-3: L. Tavazzi, G. Tognoni. ISIS-4: R. Collins, C. Baigent, M. Flather, P. Sleight. CCS-1: L.S. Liu. CONSENSUS II: J. Kjekshus, K. Swedberg. AIRE: S. Ball. TRACE: L. Køber, C. Torp-Pedersen. SAVE: E. Braunwald, L. Moyé, M. Pfeffer. SOLVD: S. Yusuf.
Coordinating Centers: Early trials: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI): M.G. Franzosi, R. Latini, A.P. Maggioni, E. Santoro, L. Santoro, G. Zuanetti. Late trials: Canadian Cardiovascular Collaboration (CCC), McMaster Clinic: M. Flather, J. Pogue, Y. Wang, S. Yusuf.
This study was supported in part by a Canadian Medical Research Council joint industry award with Astra, Bristol-Myers Squibb, Hoechst Marion Roussel, Merck, and Zeneca. The collection, analysis, and interpretation of the data were performed independently of the industrial sponsors.
↵1 A list of the ACE Inhibitor Myocardial Infarction Collaborative Group Members appears in the Appendix.
- Received September 25, 1997.
- Revision received January 15, 1998.
- Accepted January 30, 1998.
- Copyright © 1998 by American Heart Association
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