Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials

INTRODUCTION — A number of therapies are beneficial in the management of patients with acute myocardial infarction (MI), including revascularization with either percutaneous coronary intervention or fibrinolysis, aspirin, beta blockers, statins, and either angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

The evidence supporting the efficacy of ACE inhibitors and ARBs in this setting will be reviewed here. Recommendations for the use of ACE inhibitors and ARBs after MI and the use of ACE inhibitors in patients with heart failure (HF) due to systolic dysfunction are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

ACE INHIBITOR EFFECTS ON CARDIAC FUNCTION AND MORTALITY — Most randomized trials have demonstrated that angiotensin converting enzyme (ACE) inhibitor therapy with captopril, enalapril, ramipril, trandolapril, or zofenopril started within 24 hours to 16 days following an acute MI improves the left ventricular ejection fraction (LVEF) at one month to one year [1-14]. In these studies, the great majority of patients had an ST-elevation MI (STEMI); data are limited in patients with a non-ST-elevation MI (NSTEMI) [10]. In addition, most patients were treated with either fibrinolytic therapy or no reperfusion; data in patients who underwent percutaneous coronary intervention (PCI) for MI are limited.

The administration of an ACE inhibitor is also associated with an important improvement in patient survival. Large (50 lives saved per 1000 patients treated) mortality benefits post-MI have been demonstrated in patients with low LVEF, HF, or anterior MIs. Smaller benefits (five lives saved per 1000 treated) have been found in low-risk patients.

The benefits derived from ACE inhibition in high-risk patients are generally greater than those achieved by other therapeutic interventions. As an example, a meta-analysis of the nine largest randomized prospective trials comparing intravenous fibrinolysis versus placebo demonstrated approximately 30 lives were saved per 1000 patients treated who presented within six hours of symptom onset. However, the effect of these other interventions are additive to those associated with ACE inhibition.

The magnitude of the mortality benefit seen with ACE inhibitors given within 24 hours of chest pain onset is smaller in studies of all patients (with chest pain) than that seen in subsets of patients with MI (0.5 percent versus four to six percent) [12-15].

Effects in all patients — Both the Fourth International Study of Infarct Survival (ISIS-4) and the GISSI-3 trial, which primarily consisted of patients with STEMI treated with fibrinolysis (approximately 70 percent in both studies), showed that the mortality benefit with an ACE inhibitor starts soon after therapy is began and persists for one year of follow-up (figure 1) [14,15].

●In ISIS-4, 58,050 patients without persistent hypotension were randomly assigned to captopril (6.25 mg initial dose increased to 50 mg twice daily) or placebo within 24 hours after MI [14]. The duration of therapy was one month. Captopril therapy was associated with a significant 7 percent proportional reduction in five-week mortality, which persisted at 12 months; the absolute benefit at 12 months was 0.5 percent (12 versus 12.5 percent in the placebo group). The improvement was primarily limited to those with anterior MIs and was greater in patients with previous MI or HF.

●In GISSI-3, over 19,000 patients were randomly assigned to lisinopril (5 mg initial dose followed by 10 mg/day) or placebo within the first 24 hours [15]. The duration of therapy was six weeks. The odds ratio (OR) for the combined outcome measure of mortality and severe ventricular dysfunction at six weeks was 0.90 (10 percent relative reduction) in the lisinopril group.

Similar to the results in ISIS-4, the benefit from early treatment with lisinopril continued for up to six months [16] and as long as four years [17] despite discontinuation of the drug after six weeks. The mortality benefit with ACE inhibition was primarily seen in patients with diabetes, who comprised about 15 percent of the study population (13 versus 16 percent at six months) (figure 2) [18].

Low ejection fraction — The Survival and Ventricular Enlargement (SAVE) trial assigned 2231 patients with an LVEF of 40 percent or less to placebo or captopril (titrated up to 50 mg three times daily) within 3 to 16 days following an MI [5]. None of the patients had overt HF on entry.

After an average of 42-month follow-up, captopril therapy was associated with a 19 percent (95% CI 3-32 percent) decrease in mortality (20 versus 25 percent for placebo), (figure 3), a 37 percent reduction (95% CI 20-50 percent) in the incidence of severe HF, a 22 percent reduction (95% CI 4-37) in hospitalization for HF, and a 25 percent (95% CI 5-40 percent) reduction in the incidence of recurrent MI [5,19].

Similar findings on mortality and sudden death were noted in the Trandolapril Cardiac Evaluation (TRACE) trial in which trandolapril (titrated to a dose of 4 mg/day) or placebo was given to 1749 patients three to seven days after an acute MI that was associated with an LVEF ≤35 percent [7]. At two- to four-year follow-up, there were 25 to 30 percent reductions in mortality (34.7 versus 42.3 percent with placebo), sudden death, and progression to severe HF in the patients treated with trandolapril. At a minimum follow-up of six years, patients receiving trandolapril had a life expectancy of 6.2 years versus 4.6 years for placebo (figure 4) [20]. The benefits persisted at 10 to 12 years [21]. In contrast to the SAVE trial, no reduction in subsequent MI was seen.

Heart failure — The efficacy of ACE inhibition in patients who develop HF post-MI was evaluated in the Acute Infarction Ramipril Efficacy trial (AIRE) [8]. This study randomly assigned 2006 patients with clinical evidence of HF to ramipril or placebo between day 3 and 10 post-MI. After an average of 15-month follow-up, ramipril was associated with a six percent absolute decrease in mortality (17 percent versus 23 percent with placebo). Ramipril had no effect upon the rate of reinfarction or stroke but significantly reduced the risk of sudden death by 30 percent, largely due to a reduction in progressive HF, which occurred in 45 percent of those who died suddenly [22].

The survival benefit associated with ramipril was maintained long-term. Among 603 patients who were followed for a mean of 59 months, the mortality was significantly lower in those who received ramipril (28 versus 39 percent), representing a relative risk reduction of 36 percent [9].

Early in anterior wall MI

After no reperfusion — The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Trial randomly assigned 1556 patients with an anterior wall MI (two-thirds STEMI) who did not receive reperfusion therapy to zofenopril within 24 hours of chest pain onset (7.5 mg initial dose and progressively doubled every 12 hours until the target dose of 30 mg twice daily was reached) or placebo for six weeks. Zofenopril significantly lowered the primary endpoint of mortality plus severe HF at six weeks (7.1 versus 10.6 percent) and at one year (10 versus 14 percent).

After fibrinolytic therapy — The efficacy of early ACE inhibition in patients with an anterior wall MI who are treated with a fibrinolytic agent has been assessed in several trials. Some studies showed improved outcomes with ACE inhibition [23] while others did not [11,24]. The inconsistent effects of early treatment with an ACE inhibitor in patients receiving fibrinolytic may have been due in part to the small number of patients in these studies. In a meta-analysis of three trials that included 845 patients who underwent fibrinolytic therapy, there was no evidence of benefit (attenuation of ventricular volumes) [25].

Timing of therapy — Several meta-analyses of ACE inhibitor trials have confirmed beneficial effects on mortality after an acute MI [26-29]. The most complete analysis examined early and late administration of an ACE inhibitor separately, and confirmed that both are associated with a mortality benefit [26]:

●In 11 trials of early administration (within 48 hours of infarction), ACE inhibitor therapy was associated with a significant reduction in mortality at one month (9.5 versus 10.1 percent).

●In four small trials of late administration (more than 48 hours after infarction), ACE inhibitor therapy was associated with a significant reduction in mortality at one year (14.3 versus 16.5 percent).

Another meta-analysis of three trials (SAVE, AIRE, and TRACE), all of which were included in the late administration group described above, documented both a long-term mortality benefit and additional improvements in outcome with ACE inhibition [27]:

●A significant reduction in mortality at three years (23.4 versus 29 percent for control, OR 0.74) (figure 5). The absolute event-rate difference was 5.7 percent; to avoid one death, 15 patients would have to be treated for 30 months. The benefits of treatment were apparent soon after the initiation of therapy, as a reduction in mortality was noted by six weeks after randomization (6 versus 7.9 percent).

●A significant reduction in the incidence of readmission for HF (12 versus 15.5 percent, OR 0.73).

●A significant reduction in the incidence of reinfarction (10.8 versus 13.2 percent, OR 0.80).

●No difference in the risk of stroke (4 versus 3.7 percent).

Class differences — It is not known whether all ACE inhibitors have an equivalent effect on survival after MI. This issue was addressed in a retrospective cohort study of 7512 patients who had an acute MI, filled a prescription for an ACE inhibitor within 30 days of discharge, and continued to receive the same drug [30]. At one year, mortality was lower for ramipril and perindopril than for enalapril, lisinopril, fosinopril, captopril, or quinapril. However, this conclusion is limited by baseline differences in the groups [31].

Mechanism of action — The best documented mechanism by which these agents act is to reduce ventricular remodeling over days to weeks after myocardial damage. However, the very early mortality benefit may also be mediated by other, possibly neurohumoral mechanisms.

ACE INHIBITOR EFFECTS ON ARRHYTHMIA — While there is no evidence that angiotensin converting enzyme (ACE) inhibitors have direct antiarrhythmic effects, blockade of the renin-angiotensin system, reduction in ventricular and atrial wall stress, interference with ion currents, and the decrease in sympathetic tone resulting from improved left ventricular (LV) function may reduce the development of atrial and ventricular arrhythmia.

Ventricular arrhythmia — In a substudy of ISIS-4 involving 304 patients, ventricular ectopic beats per hour were significantly less frequent in patients treated with captopril compared to those on placebo at days 3 and 14 [32]. However, captopril therapy did not affect the frequency of complex ventricular arrhythmia or episodes of ventricular tachycardia.

In the VHeFT II that randomly assigned 806 men with HF to hydralazine/isosorbide dinitrate or enalapril, the mortality rate was significantly lower in the enalapril group (16 versus 25 percent) after two years [33]. This benefit was attributable to a reduction in the incidence of sudden death and was more prominent in patients with less severe symptoms (New York Heart Association [NYHA] class I or II).

In a study of 58 patients with LV dysfunction after MI randomly assigned to either captopril or placebo, patients who received captopril had a significant decrease in ventricular arrhythmia during a six-month follow-up [34]. The LV end-systolic and end-diastolic volumes at baseline and at six months were significantly increased in those with ventricular arrhythmia; an increase in LV end-diastolic volume, seen only in the placebo group, was an independent predictor of ventricular arrhythmia. (See "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action", section on 'ACE inhibitors'.)

Effect on sudden death — A decreased risk of sudden death has been seen in some [7,22,35] but not all trials [12].

A meta-analysis of 15,104 patients who were within 14 days of an acute MI found that ACE inhibitor therapy significantly reduced the risk of overall and cardiovascular mortality (odds ratio [OR] 0.82) and sudden death (OR 0.80, absolute benefit about 1.4 percent) [35].

There are several mechanisms that might contribute to the reduction in sudden death, including a reduction in sympathetic activity, improvement in substrate resulting from a reduction in ventricular remodeling and dilatation, and a decrease in recurrent MI.

Atrial fibrillation — A number of observations suggest that ACE inhibitors and angiotensin II receptor blockers may prevent the development of new or recurrent atrial fibrillation in a variety of clinical settings. Evidence that these agents reduce the incidence of AF in patients who have had an MI comes from the TRACE and SOLVD trials. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation".)

ANGIOTENSIN II RECEPTOR BLOCKERS — Angiotensin II receptor blockers (ARBs) act by a different mechanism than the angiotensin converting enzyme (ACE) inhibitors, although both reduce the stimulation of angiotensin II receptors (figure 6). (See "Differences between angiotensin-converting enzyme inhibitors and receptor blockers".)

Comparison to ACE inhibitor — Two major trials have compared an ARB to an ACE inhibitor in patients with an acute MI: OPTIMAAL and VALIANT. The OPTIMAAL trial compared the efficacy of captopril (50 mg three times daily) to losartan (50 mg once daily) in 5770 high-risk patients after an acute ST-elevation anterior infarction or reinfarction or after any MI associated with HF during the acute phase [36]. The following findings were noted at a mean follow-up of 2.7 years:

●Captopril was associated with an almost significant trend toward lower mortality at 2.7 years than losartan (16.4 versus 18.2 percent, relative risk 0.88, 95% CI 0.78-1.01).

●There was a similar trend with sudden cardiac death or resuscitated cardiac arrest (7.4 versus 8.7 percent), but no apparent difference in fatal or nonfatal reinfarction or all-cause hospitalization.

●Significantly fewer patients discontinued losartan (17 versus 23 percent) due primarily to less cough, angioedema, rash, and taste disturbance. The last two side effects are unusual with ACE inhibitors other than captopril.

The VALIANT trial found no difference in efficacy between valsartan and captopril in patients with HF occurring within 10 days after an acute MI [37]. This study included 14,808 patients with an acute MI (two-thirds with an ST-elevation MI [STEMI]) within the prior 10 days complicated by clinical or radiologic signs of HF, evidence of LV systolic dysfunction, or both. Patients were randomly assigned to valsartan (target dose 160 mg twice daily), captopril (target dose 50 mg three times daily), or both agents (target regimen 80 mg valsartan twice daily and 50 mg captopril three times daily).

At a median follow-up of 25 months, there was no difference among the three groups (valsartan, captopril, or both) in the primary endpoint of all-cause mortality (19.9, 19.5, and 19.3 percent, respectively) or in the incidence of cardiovascular death, recurrent MI, or hospitalization for HF (31.1, 31.1, and 31.9 percent, respectively). A noninferiority test confirmed that valsartan and captopril had equivalent efficacy.

ARBs likely reduce the incidence of MI to the same degree as ACE inhibitors; in VALIANT, the rate of reinfarction was similar in the valsartan and captopril groups [38]. The magnitude of this benefit can be estimated using a meta-analysis that found that ACE inhibitors significantly reduced the incidence of reinfarction compared to placebo (10.8 versus 13.2 percent, odds ratio 0.80) [26].

Thus, neither OPTIMAAL nor VALIANT found ARBs to be superior to ACE inhibitors in patients with an acute MI. Based upon VALIANT, valsartan at a dose of 160 mg twice daily appears to be as effective as an ACE inhibitor for reduction in mortality after an MI. It is possible that losartan at a higher dose than that used in OPTIMAAL (eg, 100 mg once daily) would be similarly effective, although this has not been proven directly [39].

Combination with ACE inhibitor — As mentioned in the preceding section, the VALIANT trial did not find a benefit of combined therapy with valsartan and captopril compared to monotherapy with either drug alone in patients with HF occurring within 10 days after an acute MI [37].

Adverse events leading to a reduction in drug dose occurred more frequently with combination therapy than with either valsartan or captopril alone (34.8 versus 29.4 and 28.4 percent). Hypotension and renal dysfunction occurred more often in the valsartan arm, while cough, rash, and taste disturbance occurred more often in the captopril arm.

SUMMARY — A number of individual therapies are beneficial in the management of patients with acute myocardial infarction (MI), including revascularization with percutaneous coronary intervention or fibrinolysis, aspirin, beta blockers, and statins. Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have beneficial effects on mortality after an acute MI. Neither class of drugs has been shown to be superior to the other. (See 'ACE inhibitor effects on cardiac function and mortality' above.)

The evidence supporting the efficacy of ACE inhibitors and ARBs in this setting is reviewed in this topic. Recommendations for the use of ACE inhibitors and ARBs after MI, the use of ACE inhibitors in patients with heart failure (HF) due to systolic dysfunction, and the mechanisms by which ACE inhibitors might act are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Evidence'.)

There is no evidence of benefit of combined therapy with both classes of drugs compared to monotherapy with either drug alone in patients with HF occurring within 10 days after an acute MI. (See 'Combination with ACE inhibitor' above.)