Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use

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".)

Most randomized trials of ACE inhibitors or ARBs started within 24 hours to 16 days following an acute MI showed an improvement in left ventricular ejection fraction (LVEF) at one month to one year. In addition, ACE inhibitors improve survival for at least one year and probably longer. The magnitude of the survival benefit at 12 months is approximately 0.5 percent (12 versus 12.5 percent in the placebo group). (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'ACE inhibitor effects on cardiac function and mortality'.)

Recommendations for the use of ACE inhibitors and ARBs after MI will be reviewed here. The clinical data supporting the efficacy of these agents in this setting and the possible mechanisms by which ACE inhibitors might act are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".)

EVIDENCE OF BENEFIT — Evidence from randomized trials of either angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) compared to placebo demonstrates an improvement in mortality. In a meta-analysis of nearly 100,000 patients from four randomized trials in which ACE inhibitor was started within 36 hours of MI, 30-day mortality was significantly lower in treated patients compared to controls (7.1 versus 7.6 percent; relative risk 0.93, 95% CI 0.89-0.98). [1]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'ACE inhibitor effects on cardiac function and mortality'.)

Randomized trials such as SAVE or AIRE have specifically evaluated patients with either heart failure (HF) or reduced left ventricular ejection fraction (LVEF) and found a significant reduction in the risk of death with ACE inhibitor therapy. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'Low ejection fraction' and "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'Heart failure'.)

When all trials of ACE inhibitors or ARBs are considered, the benefit of these therapies is greater for patients with a reduced LVEF or HF than for patients with normal or near normal LVEF [2]. The meta-analysis discussed above found that there was no significant difference in the relative risk reduction in the subgroup of patients with HF (compared with those without); however, the absolute benefit was greater in this group given the higher baseline risk (14.0 versus 15.4 percent) [1].

In the pivotal ISIS-4 and GISSI-3 trials, the two largest studies, the great majority of patients had an ST-elevation MI (STEMI). Data on the efficacy and safety of these therapies are limited in patients with a non-ST-elevation MI (NSTEMI) [3]. 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. We do not believe there is evidence to support separate recommendations for the use of ACE inhibitors or ARBs in patients with NSTEMI.

The following approach for the use of ACE inhibitors and ARBs in patients with acute MI is consistent with recommendations made in American College of Cardiology/American Heart Association (ACC/AHA) guidelines [4-7]:

●The initiation of ACE inhibitors is recommended in all patients with an acute MI who are not at lower risk; lower risk was defined as a normal LVEF, well-controlled cardiovascular risk factors, and performance of revascularization. For lower-risk patients, we believe it is reasonable to treat with ACE inhibitor therapy.

●ARBs are recommended in patients who are intolerant of ACE inhibitors and have clinical or radiologic signs of HF, an LVEF ≤40 percent, or hypertension.

●The combined use of both ACE inhibitors and ARBs in STEMI patients with systolic dysfunction is discussed below. (See 'ACE inhibitor plus ARB' below.)

CONTRAINDICATIONS — Contraindications for the administration of an angiotensin converting enzyme (ACE) inhibitor include allergy to ACE inhibitors, hypotension (systolic blood pressure less than 90 to 100 mmHg or systolic pressure ≥30 mmHg below baseline), shock, history of bilateral renal artery stenosis, and prior worsening of renal function with ACE inhibitors.

The presence of impaired renal function alone is not a contraindication to the use of ACE inhibitors or angiotensin II receptor blockers. In a retrospective cohort study of over 20,000 patients ≥65 years of age with MI and impaired left ventricular function, administration of an ACE inhibitor was associated with a survival benefit, even in patients with serum creatinine concentrations above 3 mg/dL (265 micromol/L) [8]. These findings were reaffirmed in a 2016 registry study that compared outcomes in MI patients (n = 64,442) treated and not treated with ACE inhibitor or angiotensin receptor blocker [9]. The three-year mortality was lower in those treated (19.8 and 25.4 percent, respectively; adjusted hazard ratio 0.80, 95% CI 0.77-0.83). The benefit was seen in all kidney function strata, including dialysis patients.

TIMING OF THERAPY — Therapy with angiotensin converting enzyme (ACE) inhibitor has been shown to be beneficial when administered either early or late. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'Timing of therapy'.)

The large GISSI-3 and ISIS-4 trials evaluated the administration of ACE inhibitors within 24 hours of presentation [3,10,11] and found that approximately 30 percent of the total mortality reduction occurred within 24 hours of symptom onset [12].

In a meta-analysis of four smaller trials of late administration of ACE inhibitor (more than 48 hours), therapy was associated with a significant reduction in one-year mortality (14.3 versus 16.5 percent; odds ratio 0.84, 95% CI 0.73-0.97) [13].

We start therapy prior to hospital discharge in stable patients with MI. We consider starting treatment within the first 24 hours in hemodynamically stable patients with large anterior ST-elevation MI.

DOSING — The safe use of angiotensin converting enzyme (ACE) inhibitors soon after acute MI requires oral administration at low doses with careful monitoring of the blood pressure. Recommended initial regimens include captopril (initial dose of 6.25 mg, which is increased at six- to eight-hour intervals to a maximum of 50 mg three times daily as long as the systolic blood pressure is above 90 to 100 mmHg), enalapril (initial dose 2.5 mg/day increased up to 20 mg twice daily), or lisinopril (initial dose 2.5 mg/day increased to a maximum of 10 mg/day). In some patients, attainment of these doses requires the weaning of nitroglycerin (in the absence of ongoing ischemia) and reduction or elimination of diuretics. Neither ISIS-4 nor GISSI-3 demonstrated mortality reduction from the use of nitrates in the absence of ongoing ischemia [3,10]. It may therefore be preferable to decrease the routine utilization of these agents in favor of ACE inhibition when blood pressure considerations are limiting.

Although different ACE inhibitors show differences in their affinity for the cardiac renin-angiotensin system [14], the protective effects post-MI appear to be a class effect and all ACE inhibitors are likely to be equally effective.

The use of an intravenous ACE inhibitor is not recommended because of the risk of hypotension [5].

DURATION OF THERAPY — The duration of treatment in many of the relevant trials of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) after MI was four to six weeks. In one MI trial (VALIANT), approximately 90 percent of patients were taking either study drug or open-label ACE inhibitor at one year.

The benefits of long-term therapy with an ACE inhibitor or ARB have been demonstrated for patients with a specific indication for such therapy, such as HF, diabetes, vascular disease, hypertension, or chronic kidney disease. (See "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Duration of therapy'.)

We treat indefinitely all patients at high risk after an MI with ACE inhibitor or ARB . This approach is consistent with that given by in the American College of Cardiology/American Heart Association guidelines [4,5,7]. In those patients at lower risk (a normal left ventricular ejection fraction, well-controlled cardiovascular risk factors, and performance of revascularization) the benefits of long-term therapy should be weighed against the potential burdens (side effects, complicated medical regimens, or financial concerns) [4]. The decision in these lower-risk patients should take into account patient preferences.

ACE INHIBITOR VERSUS ARB — The available evidence suggests that cardiovascular outcomes are similar in patients receiving treatment with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II receptor blockers (ARBs).

The two randomized trials (OPTIMAAL and VALIANT) enrolled only high-risk (HF or anterior MI) patients and found no significant difference in mortality between the two therapies. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'Comparison to ACE inhibitor'.)

OPTIMAAL found a nonsignificant trend toward lower mortality at 2.7 years with captopril compared to losartan (16.4 versus 18.2 percent, relative risk 0.88, 95% CI 0.78-1.01) [15], while VALIANT found no difference [16]. We have a preference for ACE inhibitors based on the larger experience with ACE inhibitors in randomized trials and the much longer clinical experience with ACE inhibitors.

In a 2019 observational study, however, that included nearly 60,000 patients with MI, the primary composite cardiovascular outcome (cardiovascular death, hospitalization for MI, or unstable angina at three years) occurred at a slightly higher rate with ACE inhibitors compared with ARBs (16.0 versus 15.1 percent; hazard ratio 1.17 95% CI 1.10-1.26) [17].

For patients who are intolerant of ACE inhibitors, ARBs are recommended.

ACE INHIBITOR PLUS ARB — Based upon the VALIANT trial, an angiotensin receptor blocker (ARB) therapy should not be given in addition to an angiotensin converting enzyme (ACE) inhibitor in the immediate post-MI setting [16]. At a median follow-up of 25 months, there was no difference among the three groups (valsartan, captopril, or both) in the primary end point of all-cause mortality (19.9, 19.5, and 19.3 percent, respectively). However, 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). (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials", section on 'Combination with ACE inhibitor'.)

The role of combination therapy in symptomatic patients with chronic HF is discussed separately.

ASPIRIN AND ANGIOTENSIN INHIBITION — Aspirin should be administered to all patients without a contraindication after an acute MI. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)

There have been concerns that aspirin may reduce the overall benefit of angiotensin converting enzyme (ACE) inhibitors. Such an interaction was suggested in a post-hoc analysis from CONSENSUS-II, in which intravenous enalapril was given very early after infarction, and in GUSTO-I and EPILOG, which were not trials evaluating ACE inhibitors [18,19]. In contrast, no significant effect of aspirin on the benefit from ACE inhibition after acute MI was found in other trials or systematic reviews [3,20-22].

Although not randomized, the best available data in acute MI come from a review of almost 100,000 patients in large trials comparing ACE inhibitors to placebo during the acute phase of an MI [21]. Patients treated with an ACE inhibitor and aspirin (89 percent) had the same proportionate mortality benefit as those not taking aspirin.

A direct comparison of ACE inhibitors with or without aspirin is unlikely to be performed given the proven benefit of aspirin in patients who have had an MI. It may be prudent to use a maintenance aspirin dose of 75 to 150 mg/day in patients with an acute MI who are concurrently treated with an ACE inhibitor; low dose aspirin appears to provide the same cardiovascular benefit as higher doses with less toxicity. This approach, while reasonable, has not been tested in prospective trials. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

BETA BLOCKERS AND ANGIOTENSIN INHIBITION — The concomitant use of beta blockers and angiotensin inhibitors is discussed separately. (See "Acute myocardial infarction: Role of beta blocker therapy", section on 'Contraindications'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST-elevation myocardial infarction (STEMI)".)

SUMMARY AND RECOMMENDATIONS — The addition of angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to standard medical therapy (including antiplatelet therapy, beta blocker, and statin) in patients with recent myocardial infarction (MI) improves cardiovascular outcomes. (See "Overview of the nonacute management of ST-elevation myocardial infarction" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction".)

The benefit is present in patients with either ST-elevation or non-ST-elevation MI. Evidence of benefit is somewhat stronger for patients with HF or less than normal left ventricular ejection fraction (LVEF). (See 'Evidence of benefit' above.)

We recommend the addition of an ACE inhibitor or an ARB to standard medical therapy in patients with acute MI who are at high risk (HF, LVEF ≤40 percent, diabetes, or chronic kidney disease) of a subsequent cardiovascular event (Grade 1A). We suggest an ACE inhibitor rather than an ARB, unless specific contraindications exist for the use of an ACE inhibitor (Grade 2C).

We suggest the addition of an ACE inhibitor or an ARB to standard medical therapy in patients with acute MI who are not at high risk (Grade 2B). We suggest an ACE inhibitor rather than an ARB (Grade 2C).

The following points should be considered in the use of these therapies:

●Benefits have been shown with both early and late administration, with evidence for the former being stronger. We prefer starting therapy as early as possible. (See 'Timing of therapy' above.)

●Irrespective of which agent and dose is chosen, the blood pressure must be monitored carefully to avoid hypotension. (See 'Dosing' above.)

●We suggest continuing therapy indefinitely (Grade 2B).