This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Search for Related Content PubMed PubMed Citation

(Circulation. 1998;97:2202-2212.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Indications for ACE Inhibitors in the Early Treatment of Acute Myocardial Infarction

Systematic Overview of Individual Data From 100 000 Patients in Randomized Trials

ACE Inhibitor Myocardial Infarction Collaborative Group¹

From the Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy.

Correspondence to Dr Maria Grazia Franzosi, ACE Inhibitor Collaborative Group, GISSI Coordinating Centre, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milano, Italy. E-mail depcardio{at}irfmn.mnegri.it

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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.

Key Words: ACE inhibitors • myocardial infarction • trials • systematic overview

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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 control^{1 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 trials^{1 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).

Statistical Methods
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 method^{11 12 28} to calculate stratified estimates of the proportional treatment effect, which were described as odds ratios or as percentage reductions in odds. ² tests for heterogeneity of the proportional effects were calculated between different trials or between subgroups. ² 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%). ² 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

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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 trials^{3 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

View this table: [in this window] [in a new window]   Table 1. Characteristics of Trials of ACE Inhibitors vs Control in Acute MI Involving >1000 Patients

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.

View this table: [in this window] [in a new window]   Table 2. Baseline Characteristics in Relevant Trials

View this table: [in this window] [in a new window]   Table 3. Concomitant Therapies in Hospital

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 (² on 3 df=5.8, 2P=0.1) (Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 1. Effect of ACE-inhibitor therapy on cumulative mortality during days 0 to 30 in all trials combined.

View larger version (22K): [in this window] [in a new window]   Figure 2. Proportional effects of ACE-inhibitor therapy on 30-day mortality in each trial. "Observed minus expected" (O-E) number of deaths among ACE inhibitor–assigned patients (and its variance) is quoted for each trial. This is used to calculate odds ratio of death among patients assigned ACE-inhibitor therapy to that among patients assigned control treatment. Odds ratios (solid squares, with areas proportional to amount of information contributed by each trial) are plotted with their 95% CIs (horizontal lines).

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).

View larger version (38K): [in this window] [in a new window]   Figure 3. Absolute effect of ACE-inhibitor therapy on deaths in days 0 to 1, 2 to 7, and 8 to 30.

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 (² 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).

View larger version (49K): [in this window] [in a new window]   Figure 4. Effects of ACE-inhibitor therapy on mortality in days 0 to 30 subdivided by presentation features. Odds of death among patients allocated to ACE-inhibitor therapy to that among those allocated to control treatment is derived from "observed minus expected" numbers of death (and variances) calculated within each subdivision of presentation features stratified by trial. Odds ratios within each presentation feature are plotted with their 99% CIs, whereas overall result and 95% CI are represented by diamond.

Systolic Blood Pressure and Heart Rate
The proportional reductions in mortality were not significantly influenced by systolic blood pressure at entry (² 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 (² 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%]; ² 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).

View this table: [in this window] [in a new window]   Table 4. Clinical Events by Days After AMI by Allocated Treatment

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.

View this table: [in this window] [in a new window]   Table 5. Effect on 30 Days Persistent Hypotension and Renal Dysfunction

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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.

Clinical Implications
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 ß-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.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
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.

	Acknowledgments

 
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.

	Footnotes

 
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.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
1. Swedberg K, Held P, Kjekshus J, Rasmussen K, Rydén L, Wedel H, on behalf of the CONSENSUS II Study Group. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992;327:678–684.[Abstract]

2. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-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.[Medline] [Order article via Infotrieve]

3. ISIS-4 Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669–685.[Medline] [Order article via Infotrieve]

4. Chinese Cardiac Study Collaborative Group. Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet. 1995;345:686–687.[Medline] [Order article via Infotrieve]

5. Ambrosioni E, Borghi C, Magnani B, for the Survival of Myocardial Infarction Long-term Evaluation (SMILE) Study Investigators. 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.[Abstract/Free Full Text]

6. Pfeffer MA, Braunwald E, Moyé 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, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992;327:669–677.[Abstract]

7. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821–828.[Medline] [Order article via Infotrieve]

8. Køber L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbek J, Cole DS, Auclert L, Pauly NC, Aliot E, Persson S, Camm A, for the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1670–1676.[Abstract/Free Full Text]

9. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G, for the meeting participants. ACE inhibitor use in patients with myocardial infarction: summary of evidence from clinical trials. Circulation. 1995;92:3132–3137.[Free Full Text]

10. Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450–1456.

11. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:80–106.

12. Fibrinolytic Therapy Trialists' Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994;343:311–322.[Medline] [Order article via Infotrieve]

13. Latini R, Avanzini F, De Nicolao A, Rocchetti M, and the GISSI-3 Investigators. Effects of lisinopril and nitroglycerin on blood pressure early after myocardial infarction: the GISSI-3 pilot study. Clin Pharmacol Ther. 1994;56:680–692.[Medline] [Order article via Infotrieve]

14. Flather M, Pipilis A, Collins R, Budaj A, Hargreaves A, Kolettis T, Jacob A, Millane T, Fitzgerald L, Cedro K. Randomised controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction: safety and haemodynamic effects. Eur Heart J. 1994;15:608–619.[Abstract/Free Full Text]

15. Kingma JH, van Gilst WH, Peels CH, Dambrink J-HE, Verheught FWA, Wielenga RP, for the CATS Investigators. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction: results from the Captopril And Thrombolysis Study (CATS). Eur Heart J. 1994;15:898–907.[Abstract/Free Full Text]

16. Nabel EG, Topol EJ, Galeana A, Ellis SG, Bates ER, Werns SW, Walton JA, Muller DW, Schwaiger M, Pitt B. A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction. J Am Coll Cardiol. 1991;17:467–473.[Abstract]

17. Foy SG, Crozier IG, Turner JG, Richards AM, Frampton CM, Nicholls MG, Ikram H. Comparison of enalapril versus captopril on left ventricular function and survival three months after acute myocardial infarction (the `PRACTICAL' Study). Am J Cardiol. 1994;73:1180–1186.[Medline] [Order article via Infotrieve]

18. Galcera-Tomas J, Nuno de la Rosa JA, Torres-Martinez G, Rodriguez-Garcia P, Castillo-Soria FJ, Canton-Martinez A, Campos-Peris JV, Pico-Aracil F, Ruiz-Ros JA, Ruiperez-Abizanda JA. Effect of early use of captopril on haemodynamics and short-term ventricular remodelling in acute anterior myocardial infarction. Eur Heart J. 1993;14:259–266.[Abstract/Free Full Text]

19. Hargreaves AD, Kolettis T, Jacob AJ, Flint LL, Turnbull LW, Muir AL, Boon NA. Early vasodilator treatment in myocardial infarction: appropriate for the majority or minority? Br Heart J. 1992;68:369–373.[Abstract/Free Full Text]

20. Hochman JS, Srichai MB, Picard M, Palmeri S, Deutsch E, Edelstein R, Sands M, Sonnenblick E, LeJemtel T, for the CAPTIN Investigators. Very early ACE inhibition reduces progressive left ventricular dilation when tPA fails to establish early reperfusion during acute anterior myocardial infarction. Circulation. 1994;90(suppl I):I-19. Abstract.

21. Ray SG, Pye M, Oldroyd KG, Christie J, Connelly DT, Northridge DB, Ford I, Morton JJ, Dargie HJ, Cobbe SM. Early treatment with captopril after acute myocardial infarction. Br Heart J. 1993;69:215–222.[Abstract/Free Full Text]

22. Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G. Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin converting enzyme inhibition. Lancet. 1991;337:872–876.[Medline] [Order article via Infotrieve]

23. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet. 1988;1:255–259.[Medline] [Order article via Infotrieve]

24. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988;319:80–86.[Abstract]

25. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.[Abstract]

26. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–691.[Abstract]

27. Stewart LA, Clarke MJ. Practical methodology of meta-analyses (overviews) using updated individual patient data. Stat Med. 1995;14:2057–2079.[Medline] [Order article via Infotrieve]

28. 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.[Medline] [Order article via Infotrieve]

29. Efron B, Morris C. Stein's paradox in statistics. Sci Am. 1977;236:119–127.

30. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: analysis and examples. Br J Cancer. 1977;35:1–39.[Medline] [Order article via Infotrieve]

31. Kjekshus J, Swedberg K, for the CONSENSUS II Study Group. Importance of first dose hypotension with enalaprilat in acute myocardial infarction. J Am Coll Cardiol. 1992;19:206. Abstract.

32. Bonaduce D, Marciano F, Petretta M, Migaux ML, Morgano G, Bianchi V, Salemme L, Valva G, Condorelli M. Effects of converting enzyme inhibition on heart period variability in patients with acute myocardial infarction. Circulation. 1994;90:108–113.[Abstract/Free Full Text]

33. Van Gilst WH, Kingma JH, Peels KH, Dambrink JE, St John Sutton M, on behalf of the CATS Investigators. Which patient benefits from early angiotensin-converting enzyme inhibition after myocardial infarction? Results of one-year serial echocardiographic follow-up from the Captopril and Thrombolysis Study (CATS). J Am Coll Cardiol. 1996;28:114–121.[Abstract]

This article has been cited by other articles:

				D. S. Bach Angiotensin-converting enzyme inhibitor therapy at the time of coronary artery bypass surgery when a friend turns mean-spirited. J. Am. Coll. Cardiol., November 3, 2009; 54(19): 1785 - 1786. [Full Text] [PDF]

				A. Miceli, R. Capoun, C. Fino, P. Narayan, A. J. Bryan, G. D. Angelini, and M. Caputo Effects of Angiotensin-Converting Enzyme Inhibitor Therapy on Clinical Outcome in Patients Undergoing Coronary Artery Bypass Grafting J. Am. Coll. Cardiol., November 3, 2009; 54(19): 1778 - 1784. [Abstract] [Full Text] [PDF]

				F. Zannad, N. Agrinier, and F. Alla Heart failure burden and therapy Europace, November 1, 2009; 11(suppl_5): v1 - v9. [Abstract] [Full Text] [PDF]

				A. Akbari, G. Knoll, D. Ferguson, B. McCormick, A. Davis, and M. Biyani ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS IN PERITONEAL DIALYSIS: SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS Perit. Dial. Int., September 1, 2009; 29(5): 554 - 561. [Abstract] [Full Text] [PDF]

				S. Sud and J. Douketis The devil is in the details...or not? A primer on individual patient data meta-analysis Evid. Based Med., August 1, 2009; 14(4): 100 - 101. [Full Text] [PDF]

				S. A. Hunt, W. T. Abraham, M. H. Chin, A. M. Feldman, G. S. Francis, T. G. Ganiats, M. Jessup, M. A. Konstam, D. M. Mancini, K. Michl, et al. 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation J. Am. Coll. Cardiol., April 14, 2009; 53(15): e1 - e90. [Full Text] [PDF]

				2005 WRITING COMMITTEE MEMBERS, S. A. Hunt, W. T. Abraham, M. H. Chin, A. M. Feldman, G. S. Francis, T. G. Ganiats, M. Jessup, M. A. Konstam, D. M. Mancini, et al. 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in Collaboration With the International Society for Heart and Lung Transplantation Circulation, April 14, 2009; 119(14): e391 - e479. [Full Text] [PDF]

				Authors/Task Force Members, F. Van de Werf, J. Bax, A. Betriu, C. Blomstrom-Lundqvist, F. Crea, V. Falk, G. Filippatos, K. Fox, K. Huber, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology: Eur. Heart J., December 1, 2008; 29(23): 2909 - 2945. [Full Text] [PDF]

				R. Ferrari Treatment with angiotensin-converting enzyme inhibitors: insight into perindopril cardiovascular protection Eur. Heart J. Suppl., September 1, 2008; 10(suppl_G): G13 - G20. [Abstract] [Full Text] [PDF]

				N. Danchin Which patients would benefit the most from the perindopril-amlodipine combination? Eur. Heart J. Suppl., September 1, 2008; 10(suppl_G): G29 - G35. [Abstract] [Full Text] [PDF]

				H. R. Reynolds and J. S. Hochman Cardiogenic Shock: Current Concepts and Improving Outcomes Circulation, February 5, 2008; 117(5): 686 - 697. [Full Text] [PDF]

				S. A. Saha, J. Molnar, and R. R. Arora Tissue ACE Inhibitors for Secondary Prevention of Cardiovascular Disease in Patients With Preserved Left Ventricular Function: A Pooled Meta-analysis of Randomized Placebo-controlled Trials Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2007; 12(3): 192 - 204. [Abstract] [PDF]

				J. S. Borer Angiotensin-converting enzyme inhibition: a landmark advance in treatment for cardiovascular diseases Eur. Heart J. Suppl., September 1, 2007; 9(suppl_E): E2 - E9. [Abstract] [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): 652 - 726. [Full Text] [PDF]

				C. B. Granger and M. R. Patel The Search for Myocardial Protection: Is There Still Hope? J. Am. Coll. Cardiol., July 31, 2007; 50(5): 406 - 408. [Full Text] [PDF]

				M. A. Leesar, H. Jneid, X.-L. Tang, and R. Bolli Pretreatment with intracoronary enalaprilat protects human myocardium during percutaneous coronary angioplasty. J. Am. Coll. Cardiol., April 17, 2007; 49(15): 1607 - 1610. [Abstract] [Full Text] [PDF]

				A. Raes, F. Malfait, S. Van Aken, A. France, R. Donckerwolcke, and J. Vande Walle Review: Lisinopril in paediatric medicine: a retrospective chart review of long-term treatment in children Journal of Renin-Angiotensin-Aldosterone System, March 1, 2007; 8(1): 3 - 12. [Abstract] [PDF]

				F. Beygui, J.-P. Collet, J.-J. Benoliel, N. Vignolles, R. Dumaine, O. Barthelemy, and G. Montalescot High Plasma Aldosterone Levels on Admission Are Associated With Death in Patients Presenting With Acute ST-Elevation Myocardial Infarction Circulation, December 12, 2006; 114(24): 2604 - 2610. [Abstract] [Full Text] [PDF]

				M. H. Strauss and A. S. Hall Angiotensin Receptor Blockers May Increase Risk of Myocardial Infarction: Unraveling the ARB-MI Paradox Circulation, August 22, 2006; 114(8): 838 - 854. [Full Text] [PDF]

				A. O. Adesanya, J. A. de Lemos, N. B. Greilich, and C. W. Whitten Management of perioperative myocardial infarction in noncardiac surgical patients. Chest, August 1, 2006; 130(2): 584 - 596. [Abstract] [Full Text] [PDF]

				C. B. Granger and J. J.V. McMurray Using Measures of Disease Progression to Determine Therapeutic Effect: A Sirens' Song J. Am. Coll. Cardiol., August 1, 2006; 48(3): 434 - 437. [Abstract] [Full Text] [PDF]

				Part 8: Stabilization of the Patient With Acute Coronary Syndromes Circulation, December 13, 2005; 112(24_suppl): IV-89 - IV-110. [Full Text] [PDF]

				Prepared by: British Cardiac Society, British Hype JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice Heart, December 1, 2005; 91(suppl_5): v1 - v52. [Full Text] [PDF]

				Part 5: Acute Coronary Syndromes Circulation, November 29, 2005; 112(22_suppl): III-55 - III-72. [Full Text] [PDF]

				M. H. Strauss, E. M. Lonn, and S. Verma Is the jury out? Class specific differences on coronary outcomes with ACE-inhibitors and ARBs: insight from meta-analysis and The Blood Pressure Lowering Treatment Trialists' Collaboration Eur. Heart J., November 2, 2005; 26(22): 2351 - 2353. [Full Text] [PDF]

				R. Mañon Diabetes and acute coronary syndromes -- a diabetologist's view Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 103 - 104. [PDF]

				N. K Hollenberg Spotlight on Renin: Therapeutic opportunities for renin inhibitors Journal of Renin-Angiotensin-Aldosterone System, June 1, 2005; 6(2): 107 - 109. [PDF]

				M. H Strauss and S. Verma Angiotensin receptor blockers and myocardial infarction: Authors' reply BMJ, May 28, 2005; 330(7502): 1270 - 1271. [Full Text]

				W. B. Gibler, C. P. Cannon, A. L. Blomkalns, D. M. Char, B. J. Drew, J. E. Hollander, A. S. Jaffe, R. L. Jesse, L. K. Newby, E. M. Ohman, et al. Practical Implementation of the Guidelines for Unstable Angina/Non-ST-Segment Elevation Myocardial Infarction in the Emergency Department: A Scientific Statement From the American Heart Association Council on Clinical Cardiology (Subcommittee on Acute Cardiac Care), Council on Cardiovascular Nursing, and Quality of Care and Outcomes Research Interdisciplinary Working Group, in Collaboration With the Society of Chest Pain Centers Circulation, May 24, 2005; 111(20): 2699 - 2710. [Abstract] [Full Text] [PDF]

				R Weir and J J V McMurray Treatments that improve outcome in the patient with heart failure, left ventricular systolic dysfunction, or both after acute myocardial infarction Heart, May 1, 2005; 91(suppl_2): ii17 - ii20. [Abstract] [Full Text] [PDF]

				B. J Epstein and J. G Gums Angiotensin Receptor Blockers versus ACE Inhibitors: Prevention of Death and Myocardial Infarction in High-Risk Populations Ann. Pharmacother., March 1, 2005; 39(3): 470 - 480. [Abstract] [Full Text] [PDF]

				K. Okrainec, R. Platt, L. Pilote, and M. J. Eisenberg Cardiac medical therapy in patients after undergoing coronary artery bypass graft surgery: A review of randomized controlled trials J. Am. Coll. Cardiol., January 18, 2005; 45(2): 177 - 184. [Abstract] [Full Text] [PDF]

				D. Bansal, V. Gaddam, Y. W. Aude, J. Bissett, I. Fahdi, L. Garza, J. Joseph, B. Molavi, B. V. Pai, A. Sinha, et al. Trends in the Care of Patients With Acute Myocardial Infarction at a University-Affiliated Veterans Afffairs Medical Center Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2005; 10(1): 39 - 44. [Abstract] [PDF]

				T. Ohta, N. Hasebe, S. Tsuji, K. Izawa, Y.-T. Jin, S. Kido, S. Natori, M. Sato, and K. Kikuchi Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2914 - H2921. [Abstract] [Full Text] [PDF]

				E. J. Velazquez, G. S. Francis, P. W. Armstrong, P. E. Aylward, R. Diaz, C. M. O'Connor, H. D. White, M. Henis, L. M. Rittenhouse, R. Kilaru, et al. An international perspective on heart failure and left ventricular systolic dysfunction complicating myocardial infarction: the VALIANT registry Eur. Heart J., November 1, 2004; 25(21): 1911 - 1919. [Abstract] [Full Text] [PDF]

				Writing Committee Members, E. M. Antman, D. T. Anbe, P. W. Armstrong, E. R. Bates, L. A. Green, M. Hand, J. S. Hochman, H. M. Krumholz, F. G. Kushner, et al. ACC/AHA guidelines for the management of patients with ST-Elevation myocardial infarction--executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction) J. Am. Coll. Cardiol., August 4, 2004; 44(3): 671 - 719. [Full Text] [PDF]

				E. M. Antman, D. T. Anbe, P. W. Armstrong, E. R. Bates, L. A. Green, M. Hand, J. S. Hochman, H. M. Krumholz, F. G. Kushner, G. A. Lamas, et al. ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction) Circulation, August 3, 2004; 110(5): 588 - 636. [Full Text] [PDF]

				Task Force Members, J. Lopez-Sendon, K. Swedberg, J. McMurray, J. Tamargo, A. P. Maggioni, H. Dargie, M. Tendera, F. Waagstein, J. Kjekshus, et al. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease: The Task Force on ACE-inhibitors of the European Society of Cardiology Eur. Heart J., August 2, 2004; 25(16): 1454 - 1470. [Full Text] [PDF]

				L. Pilote, M. Abrahamowicz, E. Rodrigues, M. J. Eisenberg, and E. Rahme Mortality Rates in Elderly Patients Who Take Different Angiotensin-Converting Enzyme Inhibitors after Acute Myocardial Infarction: A Class Effect? Ann Intern Med, July 20, 2004; 141(2): 102 - 112. [Abstract] [Full Text] [PDF]

				M. Azizi and J. Menard Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists Circulation, June 1, 2004; 109(21): 2492 - 2499. [Full Text] [PDF]

				B. H Trichon and M. T Roe Acute coronary syndromes and diabetes mellitus Diabetes and Vascular Disease Research, May 1, 2004; 1(1): 23 - 32. [Abstract] [PDF]

				M A Brouwer, N Clappers, and F W A Verheugt Adjunctive treatment in patients treated with thrombolytic therapy Heart, May 1, 2004; 90(5): 581 - 588. [Full Text] [PDF]

				T. Berl Angiotensin-Converting Enzyme Inhibitors versus AT1 Receptor Antagonist in Cardiovascular and Renal Protection: The case for AT1 Receptor Antagonist J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S71 - 76. [Abstract] [Full Text]

				C Coletta, A Sestili, F Seccareccia, R Rambaldi, R Ricci, A Galati, R Bigi, N Aspromonte, M Renzi, and V Ceci Influence of contractile reserve and inducible ischaemia on left ventricular remodelling after acute myocardial infarction Heart, October 1, 2003; 89(10): 1138 - 1143. [Abstract] [Full Text] [PDF]

				S Ye, S Dhillon, R Seear, L Dunleavey, L B Day, W Bannister, I N M Day, and I Simpson Epistatic interaction between variations in the angiotensin I converting enzyme and angiotensin II type 1 receptor genes in relation to extent of coronary atherosclerosis Heart, October 1, 2003; 89(10): 1195 - 1199. [Abstract] [Full Text] [PDF]

				A. K. Berger, S. Duval, and H. M. Krumholz Aspirin, beta-blocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction J. Am. Coll. Cardiol., July 16, 2003; 42(2): 201 - 208. [Abstract] [Full Text] [PDF]

				T. Sugie, Y. Kagaya, M. Takeda, H. Yahagi, C. Takahashi, J. Takahashi, M. Ninomiya, J. Watanabe, R. Ichinohasama, F. Tezuka, et al. Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction? Cardiovasc Res, June 1, 2003; 58(3): 611 - 620. [Abstract] [Full Text] [PDF]

				M.A. Pfeffer The intersection between acute coronary syndrome and heart failure Eur. Heart J. Suppl., April 1, 2003; 5(suppl_C): C19 - C23. [Abstract] [PDF]

				K. Tu, M. M. Mamdani, R. M. Jacka, N. J. Forde, D. M. Rothwell, and J. V. Tu The striking effect of the Heart Outcomes Prevention Evaluation (HOPE) on ramipril prescribing in Ontario Can. Med. Assoc. J., March 4, 2003; 168(5): 553 - 557. [Abstract] [Full Text] [PDF]

				L. Pilote Ramipril use in Canada: HOPE or HYPE? Can. Med. Assoc. J., March 4, 2003; 168(5): 568 - 569. [Full Text] [PDF]

				H.L. Hillege, W.H. van Gilst, D.J. van Veldhuisen, G. Navis, D.E. Grobbee, P.A. de Graeff, and D. de Zeeuw Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial Eur. Heart J., March 1, 2003; 24(5): 412 - 420. [Abstract] [Full Text] [PDF]

				PROGRESS Collaborative Group Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease Eur. Heart J., March 1, 2003; 24(5): 475 - 484. [Abstract] [Full Text] [PDF]

				W. M. Yarbrough, R. Mukherjee, T. A. Brinsa, K. B. Dowdy, A. A. Scott, G. P. Escobar, C. Joffs, D. G. Lucas, F. A. Crawford Jr, and F. G. Spinale Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs J. Thorac. Cardiovasc. Surg., March 1, 2003; 125(3): 602 - 610. [Abstract] [Full Text] [PDF]

				The Task Force on the Management of Acute Myocardi, F. Van de Werf, D. Ardissino, A. Betriu, D. V. Cokkinos, E. Falk, K. A.A. Fox, D. Julian, M. Lengyel, F.-J. Neumann, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation Eur. Heart J., January 1, 2003; 24(1): 28 - 66. [Full Text] [PDF]

				J. Soler-Soler and D. Garcia-Dorado How to best to counteract the enemies? By blocking neurohormonal activation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G45 - G50. [Abstract] [PDF]

				B. H. Greenberg Angiotensin receptor blockers in heart failure: A work in progress J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1422 - 1424. [Full Text] [PDF]

				P Underwood and P Beck Secondary prevention following myocardial infarction: evidence from an audit in South Wales that the National Service Framework for coronary heart disease does not address all the issues Qual. Saf. Health Care, September 1, 2002; 11(3): 230 - 232. [Abstract] [Full Text] [PDF]

				R. M. Califf and D. L. DeMets Principles From Clinical Trials Relevant to Clinical Practice: Part I Circulation, August 20, 2002; 106(8): 1015 - 1021. [Full Text] [PDF]

				H. L. Kennedy and R. S. Rosenson Physicians' interpretation of "class effects": A need for thoughtful re-evaluation J. Am. Coll. Cardiol., July 3, 2002; 40(1): 19 - 26. [Abstract] [Full Text] [PDF]

				M. A. Pfeffer and J. J.V. McMurray Myocardial Infarct: No One Size Fits All Circulation, June 4, 2002; 105(22): 2577 - 2579. [Full Text] [PDF]

				B. I. Jugdutt and V. Menon Beneficial Effects of Therapy on the Progression of Structural Remodeling During Healing After Reperfused and Nonreperfused Myocardial Infarction: Different Effects on Different Parameters Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2002; 7(2): 95 - 107. [Abstract] [PDF]

				B. I. Jugdutt Monocytosis and adverse left ventricular remodeling after reperfused myocardial infarction J. Am. Coll. Cardiol., January 16, 2002; 39(2): 247 - 250. [Full Text] [PDF]

				S. G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, J. A. Camm, R. Cappato, S. M. Cobbe, C. Di Mario, et al. TASK FORCE ON SUDDEN CARDIAC DEATH, EUROPEAN SOCIETY OF CARDIOLOGY: Summary of Recommendations Europace, January 1, 2002; 4(1): 3 - 18. [Abstract] [PDF]

				F Pizzetti, F M Turazza, M G Franzosi, S Barlera, A Ledda, A P Maggioni, L Santoro, and G Tognoni Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data Heart, November 1, 2001; 86(5): 527 - 532. [Abstract] [Full Text] [PDF]

				B. Pouzet, S. Ghostine, J.-T. Vilquin, I. Garcin, M. Scorsin, A. A. Hagege, D. Duboc, K. Schwartz, and P. Menasche Is Skeletal Myoblast Transplantation Clinically Relevant in the Era of Angiotensin-Converting Enzyme Inhibitors? Circulation, September 18, 2001; 104 (2009): I-223 - I-228. [Abstract] [Full Text] [PDF]

				S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, A.J. Camm, R. Cappato, S.M. Cobbe, C. Di Mario, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology Eur. Heart J., August 2, 2001; 22(16): 1374 - 1450. [PDF]

				G. G. Neri Serneri, M. Boddi, L. Poggesi, I. Simonetti, M. Coppo, M. L. Papa, G. F. Lisi, M. Maccherini, R. Becherini, A. Boncompagni, et al. Activation of cardiac renin-angiotensin system in unstable angina J. Am. Coll. Cardiol., July 1, 2001; 38(1): 49 - 55. [Abstract] [Full Text] [PDF]

				M. E. Khalil, A. W. Basher, E. J. Brown Jr, and I. A. Alhaddad A remarkable medical story: benefits of angiotensin-converting enzyme inhibitors in cardiac patients J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1757 - 1764. [Abstract] [Full Text] [PDF]

				E. Braunwald Congestive heart failure: a half century perspective Eur. Heart J., May 2, 2001; 22(10): 825 - 836. [PDF]

				C. Baigent, R. Collins, and R. Peto Benefit of aspirin plus angiotensin-converting enzyme inhibitor J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1474 - 1475. [Full Text] [PDF]

				J. H. O'Keefe, M. Wetzel, R. R. Moe, K. Brosnahan, and C. J. Lavie Should an angiotensin-converting enzyme inhibitor be standard therapy for patients with atherosclerotic disease? J. Am. Coll. Cardiol., January 1, 2001; 37(1): 1 - 8. [Abstract] [Full Text] [PDF]

				Q.-G. Xia, O. Chung, H. Spitznagel, S. Illner, G. Janichen, B. Rossius, P. Gohlke, and T. Unger Significance of timing of angiotensin AT1 receptor blockade in rats with myocardial infarction-induced heart failure Cardiovasc Res, January 1, 2001; 49(1): 110 - 117. [Abstract] [Full Text] [PDF]

				H. Oxenham and N. Sharpe Angiotensin-converting enzyme inhibitor treatment after myocardial infarction: A selective approach for maximum benefit J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2054 - 2055. [Full Text] [PDF]

				W. J. Rogers, J. G. Canto, C. T. Lambrew, A. J. Tiefenbrunn, B. Kinkaid, D. A. Shoultz, P. D. Frederick, N. Every, and for the Investigators in the National Registry of Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the U.S. from 1990 through 1999: The National Registry of Myocardial Infarction 1, 2 and 3 J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2056 - 2063. [Abstract] [Full Text] [PDF]

				S. E WIEGERS and M. S. J. SUTTON When should ACE inhibitors or warfarin be discontinued after myocardial infarction? Heart, October 1, 2000; 84(4): 361 - 362. [Full Text]

				W. S. Waring Early initiation of ACE inhibitor treatment after acute myocardial infarction - a missed therapeutic opportunity? Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 245 - 251. [PDF]

				A. P Maggioni Secondary prevention: improving outcomes following myocardial infarction Heart, September 1, 2000; 84(90001): 5i - 7. [Full Text]

				A. Cargnoni, C. Ceconi, P. Bernocchi, A. Boraso, G. Parrinello, S. Curello, and R. Ferrari Reduction of oxidative stress by carvedilol: role in maintenance of ischaemic myocardium viability Cardiovasc Res, August 18, 2000; 47(3): 556 - 566. [Abstract] [Full Text] [PDF]

				F. A. McAlister, S. E. Straus, G. H. Guyatt, R. B. Haynes, and for the Evidence-Based Medicine Working Group Users' Guides to the Medical Literature: XX. Integrating Research Evidence With the Care of the Individual Patient JAMA, June 7, 2000; 283(21): 2829 - 2836. [Abstract] [Full Text] [PDF]

				R. Latini, G. Tognoni, A. P. Maggioni, C. Baigent, E. Braunwald, Z.-M. Chen, R. Collins, M. Flather, M. Franzosi, J. Kjekshus, et al. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: Systematic overview of individual data from 96,712 randomized patients J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1801 - 1807. [Abstract] [Full Text] [PDF]

				C. Torp-Pedersen and L. Kober Prolongation of life with angiotensin converting enzyme inhibitor therapy. Eur. Heart J., April 2, 2000; 21(8): 597 - 598. [PDF]

				J. Muntwyler and T.F. Luscher Assessment of cardiovascular risk: time to apply genetic risk factors? Eur. Heart J., April 2, 2000; 21(8): 611 - 613. [PDF]

				Tackling myocardial infarction DTB, March 1, 2000; 38(3): 17 - 22. [Abstract] [Full Text] [PDF]

				W. J. Rogers, J. G. Canto, H. V. Barron, J. A. Boscarino, D. A. Shoultz, N. R. Every, and for the Investigators in the National Registry of Treatment and outcome of myocardial infarction in hospitals with and without invasive capability J. Am. Coll. Cardiol., February 1, 2000; 35(2): 371 - 379. [Abstract] [Full Text] [PDF]

				D. W. O'Brien, Y. Xu, V. Menon, and B. I. Jugdutt Efficacy of Pretreatment With the Angiotensin II Type 1 Receptor Blocker UP269-6 and Losartan in the Dog: Effect on Hemodynamics and Ischemia-Reperfusion Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(2): 129 - 137. [Abstract] [PDF]

				R. D. Feldman, N. Campbell, P. Larochelle, P. Bolli, E. D. Burgess, S. G. Carruthers, J. S. Floras, R. B. Haynes, G. Honos, F. H.H. Leenen, et al. 1999 Canadian recommendations for the management of hypertension Can. Med. Assoc. J., December 14, 1999; 161(90120): S1 - 17. [Abstract] [Full Text] [PDF]

				V. Gaussin and M. D. Schneider Surviving Infarction One Gene at a Time : Decreased Remodeling and Mortality in Engineered Mice Lacking the Angiotensin II Type 1A Receptor Circulation, November 16, 1999; 100(20): 2043 - 2044. [Full Text] [PDF]

				M. A. Leesar, M. F. Stoddard, S. Manchikalapudi, and R. Bolli Bradykinin-induced preconditioning in patients undergoing coronary angioplasty J. Am. Coll. Cardiol., September 1, 1999; 34(3): 639 - 650. [Abstract] [Full Text] [PDF]

				J. K. French, D. J. Amos, B. F. Williams, D. B. Cross, J. M. Elliott, H. H. Hart, M. G. Williams, R. M. Norris, N. G. Ashton, R. M. L. Whitlock, et al. Effects of early captopril administration after thrombolysis on regional wall motion in relation to infarct artery blood flow J. Am. Coll. Cardiol., January 1, 1999; 33(1): 139 - 145. [Abstract] [Full Text] [PDF]

				S. KAUL Myocardial contrast echocardiography in acute myocardial infarction: time to test for routine clinical use? Heart, January 1, 1999; 81(1): 2 - 5. [Full Text]

				C. J. Pepine, E. Handberg-Thurmond, R. G. Marks, M. Conlon, R. Cooper-Dehoff, P. Volkers, P. Zellig, and for The INVEST Investigators Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1228 - 1237. [Abstract] [Full Text] [PDF]

				ACE Inhibitors in Early AMI: Who Benefits Most? Journal Watch Emergency Medicine, September 1, 1998; 1998(901): 1 - 1. [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Search for Related Content PubMed PubMed Citation