In response to our previous conference on acute myocardial infarction we had a question regarding the use of ACE inhibitors in patients with infarcts and hypertension. We felt this was sufficiently important to review in more detail. Dr. Roger Grover has synthesized a brief summary of this relevant topic. We hope you enjoy it.

Introduction

The renin-angiotensin-aldosterone system has important effects on development of cardiac hypertrophy and regulation of left ventricular function.(1) Numerous studies have shown angiotensin-converting enzyme -- or ACE -- inhibitors to be more proficient at reversing cardiac structural changes than are other types of antihypertensive agents. Two meta-analyses(2),(3) have suggested that they may be more effective in decreasing left ventricular mass than beta-blockers, calcium antagonists and diuretics. Furthermore, experimental studies have shown that ACE inhibition can induce reversal of left ventricular hypertrophy, even without a decrease in blood pressure.

The recently published ACC/AHA Guidelines for the Management of Patients with Acute Myocardial Infarction(MI) make the following recommendations for the use of ACE inhibitors on patients(4):

• Within the first 24 hours of a suspected acute MI with ST segment elevation in two or more anterior precordial leads.
• With clinical heart failure in the absence of significant hypotension or known contraindications to the use of ACE inhibitors.
• With MI and LV ejection fraction less than 40%.
• With clinical heart failure on the basis of systolic pump dysfunction during and after convalescence from acute MI.

Rationale or background

A number of large randomized clinical trials have assessed the role of ACE inhibitors early in the course of acute MI. All trials in which only oral ACE inhibitors were used demonstrated benefit in mortality (see Table 1).

Table 1. Ace Inhibitors in Myocardial Infarction.

Early Treatment	Late Treatment
(Avg. six days post MI)	(Avg. 40 days post MI)
Overall Mortality %
Control	23.8 %	36.9 %
Treated	18.7 %	30.5 %

In the ISIS-4 trial, 58,000 patients with suspected acute MI were randomly assigned within the first 24 hours to receive either oral captopril or placebo; a significant 7% proportional reduction was observed in five-week mortality among those randomly assigned to captopril (Capoten).(5) Likewise, the GISSI-3 trial used oral lisinopril in patients with acute coronary syndromes and showed a significant reduction in six-week mortality(6) (see Figure 1).

Figure 1. Incidence of Death or Severe Congestive Heart Failure During Six Weeks of Treatment with ACE Inhibitor or Placebo in Patients with Acute Myocardial Infarction

It appears that the benefits of ACE inhibitors are greater among those with an anterior infarct or who have evidence of previous infarction, heart failure, and tachycardia, i.e., those at highest risk. Data from these trials indicate that ACE inhibitors should generally be started within the first 24 hours, ideally, after thrombolytic therapy has been completed and blood pressure has stabilized. When there are no patient complications and no evidence of symptomatic or asymptomatic LV dysfunction by four to six weeks, ACE inhibitors can be stopped. ACE inhibitors should not be used if clinically relevant renal failure is present, if there is a history of bilateral stenosis of the renal arteries or if there is known allergy to ACE inhibitors.(4)

The evidence available from the trials on ACE inhibitors may be summarized as follows: Treatment with ACE inhibitors has a beneficial effect in patients selected for the presence of LV dysfunction after AMI and in relatively unselected patients presenting with acute myocardial infarction.(7) The benefit increases in patients with clinical or laboratory evidence of LV dysfunction.

What Are the Criteria for Initial Exclusion and Subsequent Withdrawal or Continuation of Ace Inhibitor Treatment of Ami Patients?

The safety profile of patients treated within 24 hours from the onset of symptoms appears acceptable if the following exclusion criteria(7) are applied:

1. High risk of further serious hemodynamic deterioration (systolic blood pressure < 100 mm Hg)
2. History of clinically relevant renal failure
3. History of bilateral stenosis of the renal arteries
4. Documented allergy to ACE inhibitors

In addition, patients with low systolic blood pressure (100 to 110 mm Hg) in the first four hours after the onset of symptoms should be monitored carefully. No specific additional risk was shown in GISSI-3 or ISIS-4 for elderly patients or women, so ACE inhibitors are not contraindicated in these populations.

Left Ventricular Dysfunction and Heart Failure

The consistency of data on the role of ACE inhibitors from trials in patients with LV dysfunction or heart failure complicating AMI (as in the AIRE, SAVE, and TRACE STUDIES studies) strongly indicates that ACE inhibitors should be given to these patients. For this reason, if at any time after AMI clinical signs and/or symptoms of LV dysfunction occur or are diagnosed instrumentally, treatment should be continued over a period of time. On the other hand, if a patient does not show signs or symptoms of LV dysfunction, it is likely that treatment can be stopped safely after four to six weeks (based on existing evidence from GISSI-3 and ISIS-4). In this case, the patients should ideally be reevaluated after a reasonable period (i.e., four to six months) to check for evidence of LV dysfunction. The appearance of persistent hypotension or clinically relevant renal dysfunction should be considered an indication for ACE inhibitor dose reduction or withdrawal (at least temporarily).

Left Ventricular Remodeling

Angiotensin converting enzyme inhibitors, with their ability to interfere with ventricular remodeling and thus attenuate ventricular dilatation over time, are also of value in selected patients who have recovered from an acute infarction. The clinical result is a lessened likelihood for development of CHF and death. In addition, the likelihood of recurrent MI may also be reduced.

The expression of tissue ACE within the heart probably arises from vascular endothelium. In the setting of myocardial necrosis and fibrosis, relatively high concentrations of ACE can be found in the myocardium compared with normal ventricular myocardium.(8) These observations, coupled with the experience obtained in large randomized clinical trials,(7),(9) have established that use of ACE inhibitors improves long term survival, provided the infarct was large, anterior in location and associated with significant impairment of LV contractility. Specifically, in the SAVE trial, patients received captopril at a mean 11 days after onset of infarction, resulting in an approximate 20% reduction in mortality.(9)

Recurrent Infarction

Some rationale exists for the use of these drugs in all patients after MI, based on the observation in the SAVE trial that the likelihood of recurrent MI was reduced by approximately 25% in treated patients irrespective of infarct location or size.(10) There is also preliminary evidence that patients who express a homozygous deletional form of the ACE gene (dd) have an increased circulating ACE level and are more likely to develop MI than those with the II allele ACE gene.(11) This reasoning is also supported by recent observations that myocardial levels of ACE are also higher in patients expressing the dd gene.(12)

Hypertension

There are a number of relevant points about the treatment of patients with hypertension who also have other cardiovascular diseases.(13) In treating patients with congestive heart failure and hypertension, one should make a clear distinction between diastolic or systolic dysfunction causing the symptoms of congestive heart failure.(14) When systolic dysfunction is present, agents that reduce afterload, such as the ACE inhibitors, have been shown to improve survival, as has a combination of hydralazine and nitrates. For diastolic dysfunction, patients with a thickened, stiff myocardium, there are different therapeutic considerations. An optimal level of ventricular filling pressure must be maintained, diuretics must be used with caution, and vasodilators and ACE inhibitors should not be used unless essential for the control of blood pressure.

Renal Dysfunction

ACE inhibitors have been shown to have renoprotective effects in patients with insulin-dependent diabetes mellitus if microalbuminuria is present. Treatment should be initiated with low doses and then doses should be gradually increased. Patients should be asked about the presence of cough and loss of taste, rash or angioedema. The cough that occurs with ACE inhibitor therapy may be mild and thus discontinuation of the medication may be unnecessary.

Long-Term Prognosis

At present time there is considerable activity in the area of prevention of atherosclerosis-related events using angiotensin-converting enzyme inhibitors. Large trials have demonstrated significant reductions in cardiovascular morbidity and mortality with long-term use of ACE inhibitors in patients with left ventricular dysfunction, heart failure or acute myocardial infarction. Reductions in acute ischemic events (e.g., myocardial infarction, unstable angina and need for early revascularization) were independent of ejection fraction and were greater than would be expected from the small reduction in blood pressure that occurred, suggesting that other patients with coronary artery disease may benefit from ACE inhibitor therapy. This hypothesis is being tested in multiple double-blind, randomized, controlled clinical trials with duration of follow-up of three to five years that will involve approximately 30,000 patients. The trials vary with respect to patient population (e.g., normotensive vs. hypertensive, normolipidemic vs. hyperlipidemic, with diabetes mellitus vs.without diabetes mellitus), angiotensin-converting enzyme inhibitor used and outcome measures.(15) When available, the results of these clinical trials could have very important implications for the role of long term ACE inhibitor therapy for preventing or delaying the development of atherosclerosis-related ischemic events.

Summary

In summary, we believe ACE inhibitors should be used in many patients in the setting of acute coronary syndromes, after myocardial infarction and in those with systolic congestive heart failure. In addition, they have a renoprotective effect in diabetics with proteinuria.

Patients most likely to derive significant benefit include those with:

1. anterior infarction
2. persistent hypertension
3. LV dysfunction (EF < 40%)
4. congestive heart failure.

Routine use of ACE inhibitors in inferior MI with preserved LV function may not be warranted given our present information.