Enalapril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Enalaprilat is used in the management of hypertension when oral therapy is not practical. Because captopril, another angiotensin-converting enzyme (ACE) inhibitor, may cause serious adverse effects (e.g., neutropenia, agranulocytosis), particularly in patients with renal impairment (especially those with collagen vascular disease) or in patients receiving immunosuppressive therapy, the possibility that similar adverse effects may occur with enalapril or enalaprilat should be considered since current experience is insufficient to rule out such risk. Enalapril has occasionally been used without recurrence of adverse effect in patients who developed intolerable adverse effects (i.e., rash, taste disturbances) during captopril therapy. Further studies are needed to evaluate the possible risks associated with the long-term use of enalapril. The hypotensive efficacy of enalapril in hypertensive patients is similar to that of captopril or β-adrenergic blocking agents (β-blockers). Enalapril may have a greater effect on systolic blood pressure at rest (but not with exercise) than do β-blockers, but additional study is necessary to establish the comparative efficacy of enalapril and β-blockers.
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of 4 classes of antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics); data from clinical outcome trials indicate that lowering blood pressure with any of these drug classes can reduce the complications of hypertension and provide similar cardiovascular protection. However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines. Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs). Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.
Considerations in Initiating Antihypertensive Therapy
Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., life-style modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.
While the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended antihypertensive drug therapy in all patients with systolic/diastolic blood pressure of 140/90 mm Hg or higher who fail to respond to lifestyle/behavioral modifications, other experts, including the panel members appointed to the Eighth Joint National Committee (JNC 8 expert panel), recommend a higher systolic blood pressure threshold for older individuals (e.g., the JNC 8 expert panel recommends a threshold of 150 mm Hg for patients 60 years of age or older).
In addition, there is some variation in the blood pressure thresholds and treatment goals recommended for patients with diabetes mellitus or chronic kidney disease. In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had blood pressures of 130/80 mm Hg or higher; however, current hypertension management guidelines generally recommend the same blood pressure threshold of 140/90 mm Hg for initiating antihypertensive drug therapy in these individuals as for the general population of patients without these conditions, although a lower goal (e.g., less than 130/80 mm Hg) may still be considered.
Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension; when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies. For additional details,
Antihypertensive drug therapy generally should be initiated gradually and titrated at intervals of approximately 2-4 weeks to achieve the target blood pressure. The goal is to reduce blood pressure to levels below the threshold used for initiating drug therapy. Addition of a second drug should be initiated when use of monotherapy in adequate dosages fails to achieve goal blood pressure. Some experts state that initial antihypertensive therapy with a combination of drugs may be considered in patients with systolic/diastolic blood pressure greater than 20/10 mm Hg above goal blood pressure. Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly). Initial combined therapy may be particularly useful in patients with markedly high baseline blood pressures and those with additional risk factors.
Initial Drug Therapy
In current hypertension management guidelines, ACE inhibitors are recommended as one of several preferred drugs for the initial treatment of hypertension; other options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as heart failure, ischemic heart disease, diabetes mellitus, chronic kidney disease, or cerebrovascular disease or following myocardial infarction.
(See Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors under Uses: Hypertension.)
Follow-up and Maintenance Therapy
Several strategies are recommended for the titration and combination of antihypertensive drugs; these strategies include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination). In patients who fail to respond adequately to initial monotherapy with an ACE inhibitor, the JNC 8 expert panel states that a thiazide diuretic or a calcium-channel blocker may be added. If goal blood pressure is not achieved with maximum dosages of these 2 drugs, a third antihypertensive agent from one of the recommended drug classes may be added; if more than 3 drugs are required, other antihypertensive agents (e.g., β-blockers, aldosterone antagonists, centrally acting agents) may be considered. Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects. If the blood pressure goal cannot be achieved using the above recommended strategies, consultation with a hypertension specialist should be considered.
Thus, enalapril can be used for the management of hypertension as initial monotherapy or as a component of a multiple-drug regimen. When enalapril alone is used but the hypertension does not respond adequately, addition of a thiazide diuretic often adequately controls blood pressure. Such combined therapy generally produces additive reduction in blood pressure and may permit dosage reduction of either or both drugs and minimize adverse effects while maintaining blood pressure control.
Enalapril may be effective in the management of hypertension resistant to other drugs. Although enalapril occasionally may be effective alone in patients with severe hypertension, it is usually necessary to use the drug in conjunction with a diuretic.
(See Drug Interactions: Hypotensive Agents and Diuretics.)Enalapril has been used in some diabetic hypertensive patients with no adverse effect on control or therapy of diabetes; however, hypoglycemia has occasionally occurred when the drug was used in patients whose diabetes had been controlled with insulin or oral hypoglycemic agents. (See Drug Interactions: Other Drugs.)
Tolerance to the hypotensive effect of enalapril apparently does not occur during long-term administration, particularly if the drug is used with a diuretic.
IV enalaprilat may be used in the management of hypertension when oral therapy is not practical. Enalaprilat generally produces a prompt reduction in blood pressure, usually without an orthostatic response, and with a slight reduction in heart rate. Occasional hypotension, or symptomatic postural hypotension in volume-depleted patients, might be anticipated. Enalaprilat also has been used effectively to control blood pressure in adults with severe hypertension or hypertensive emergencies
(see Hypertensive Crises under Uses: Hypertension)and in a small number of neonates with severe hypertension.
As with other antihypertensive agents, treatment with enalapril or enalaprilat is not curative; after withdrawal of the drug, blood pressure returns to pretreatment levels. Abrupt withdrawal of enalapril or enalaprilat therapy results in a gradual return of hypertension; rapid increases in blood pressure have not been reported to date.
Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors
Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.
Ischemic Heart Disease
The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics. Many experts recommend the use of an ACE inhibitor (or an angiotensin II receptor antagonist) and/or a β-blocker in hypertensive patients with stable ischemic heart disease because of the cardioprotective benefits of these drugs; all patients who have survived a myocardial infarction should be treated with a β-blocker because of the demonstrated mortality benefit of these agents. Other antihypertensive drugs such as calcium-channel blockers or thiazide diuretics may be added to the regimen as necessary to achieve blood pressure goals.
While ACE inhibitors as single therapies are not superior to other antihypertensive agents in the reduction of cardiovascular outcomes, ACE inhibitors, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers, have been shown to reduce morbidity and mortality in patients with existing heart failure.
(See Uses: Heart Failure.)ACE inhibitors also have been used to prevent subsequent heart failure and reduce morbidity and mortality in patients with systolic dysfunction following acute myocardial infarction. (See Uses: Left Ventricular Dysfunction after Myocardial Infarction.)
ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics have all been recommended for initial antihypertensive therapy in patients with diabetes mellitus, although certain agents may be preferred. Results of several studies indicate that adequate control of blood pressure in patients with type 2 diabetes mellitus reduces the development or progression of complications of diabetes (e.g., death related to diabetes, stroke, heart failure, microvascular disease). There also is evidence demonstrating the benefits of ACE inhibitors in reducing the development or progression of microvascular or macrovascular complications in hypertensive patients with type 1 or type 2 diabetes mellitus. The American Diabetes Association (ADA) states that the antihypertensive regimen of patients with diabetes and hypertension should include an ACE inhibitor or angiotensin II receptor antagonist because of the cardiovascular benefits of these drugs; the renoprotective effect of these drugs provides another compelling reason for their use in diabetic patients who may have albuminuria or renal insufficiency.
(See Uses: Diabetic Nephropathy.)If additional blood pressure control is required, a calcium-channel blocker or thiazide diuretic may be added. Because ACE inhibitors and angiotensin II receptor antagonists tend not to be as effective in black patients, some experts recommend a thiazide diuretic or a calcium-channel blocker as the initial antihypertensive drug of choice in black patients with diabetes. (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.)
Chronic Kidney Disease
Hypertensive patients with chronic kidney disease (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure. Use of ACE inhibitors or angiotensin II receptor antagonists is recommended in patients with diabetic or nondiabetic chronic kidney disease; these drugs have been shown to slow the progression of kidney disease, but evidence of a cardiovascular benefit is not as clear. Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria. Although ACE inhibitors and angiotensin II receptor antagonists generally are not recommended as the drugs of first choice for initial antihypertensive therapy in black patients, some experts suggest that these drugs be used for their renoprotective effects in black patients with chronic kidney disease and proteinuria because of the high likelihood that these patients will progress to end-stage renal disease. Diuretics also may be useful in the management of chronic kidney disease, and may potentiate the effects of ACE inhibitors, angiotensin II receptor antagonists, and other antihypertensive agents when used in combination.
Blood pressure goals in patients with ischemic stroke or transient ischemic attack (TIA) should be individualized, but generally are similar to those recommended for the general population (i.e., systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg). In patients with a recent lacunar stroke, the American Heart Association (AHA) and the American Stroke Association (ASA) suggest that a lower systolic blood pressure goal of 130 mm Hg may be reasonable based on results of a randomized open-label study (the Secondary Prevention of Small Subcortical Strokes [SPS3] trial). Although experts state that the optimal choice of drug for the management of hypertension in patients with a previous TIA or ischemic stroke is uncertain, the available data indicate that a diuretic or the combination of a diuretic and an ACE inhibitor may be used. Administration of an ACE inhibitor in combination with a thiazide diuretic has been shown to lower recurrent stroke rates.
Hypertension Associated with Scleroderma Renal Crisis
Enalapril has been effective for the management of hypertension associated with scleroderma renal crisis in a limited number of patients who were unable to tolerate captopril because of adverse effects. Maintenance therapy with enalapril (5-30 mg daily) controlled blood pressure in these patients and was accompanied by improvement in renal function. Some clinicians consider ACE inhibitors the drugs of choice for this condition.
Other Special Considerations for Antihypertensive Therapy
In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with ACE inhibitors. In a prespecified subgroup analysis of the ALLHAT study, a thiazide-type diuretic was more effective than an ACE inhibitor in improving cerebrovascular and cardiovascular outcomes in black patients; when compared with a calcium-channel blocker, the ACE inhibitor was less effective in reducing blood pressure and was associated with a 51% higher rate of stroke. However, such diminished response to an ACE inhibitor is largely eliminated when the drug is administered concomitantly with a thiazide diuretic or calcium-channel blocker. In addition, some experts state that when use of ACE inhibitors is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.
Although enalapril has lowered blood pressure in all races studied, monotherapy with enalapril has produced a smaller reduction in blood pressure in black hypertensive patients, a population associated with low renin hypertension; however, this population difference in response does not appear to occur during combined therapy with enalapril and a thiazide diuretic. In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.
Renovascular or Malignant Hypertension
Enalapril also has been effective in the management of renovascular or malignant hypertension, renal hypertension secondary to renal-artery stenosis, and, in some patients, hypertension associated with chronic renal failure. In addition to the drugs' hypotensive effect, ACE inhibitors also have stabilized or improved effective renal blood flow and glomerular filtration rate and decreased proteinuria in some hypertensive patients with moderately impaired renal function, moderate to severe renal disease, or diabetic nephropathy. However, enalapril should be used with caution in patients with impaired renal function, especially those with bilateral renal-artery stenosis or with renal-artery stenosis in a solitary kidney.
(See Cautions: Renal Effectsand see Hematologic Effectsand see Precautions and Contraindications.)
Enalaprilat has been used effectively to reduce blood pressure in adults with severe hypertension or hypertensive emergencies.
Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage. Such emergencies include hypertensive encephalopathy, acute myocardial infarction, intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, eclampsia, dissecting aortic aneurysm, and unstable angina pectoris. Patients with hypertensive emergencies require hospitalization and are treated initially with an appropriate parenteral agent. Elevated blood pressure alone, in the absence of manifestations or other evidence of target organ damage, rarely requires emergency therapy.
Acute enalaprilat therapy (e.g., 1.25-5 mg IV, repeated every 6 hours as necessary) is one of several parenteral regimens currently recommended for rapidly reducing blood pressure in patients with hypertensive crises in whom reduction of blood pressure is considered an emergency. However, reduction of blood pressure in a prompt but controlled manner may be more easily achieved with short-acting antihypertensive agents administered by continuous IV infusion (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside), and some clinicians state that such agents generally are preferred.
Enalaprilat also has been used for rapid reduction of blood pressure in pediatric patients 1-17 years of age with hypertensive urgencies or emergencies.
The risks of overly aggressive therapy in any hypertensive crisis must always be considered, as excessive falls in blood pressure may precipitate renal, cerebral, or coronary ischemia.
Enalapril is used in the management of symptomatic heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers.
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. In patients with prior or current symptoms of chronic heart failure with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI (e.g., sacubitril/valsartan) in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure with reduced LVEF (New York Heart Association [NYHA] class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality. However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.
Some clinicians state that ACE inhibitors usually are prescribed in clinical practice at dosages lower than those determined as target dosages in clinical trials, although results of several studies suggest that high dosages are associated with greater hemodynamic, neurohormonal, symptomatic, and prognostic benefits than lower dosages. Results of a large, randomized, double-blind study (Assessment of Treatment with Lisinopril and Survival [ATLAS] study) in patients with heart failure (NYHA class II-IV) indicate that high lisinopril dosages (32.5-35 mg daily) were associated with a 12% lower risk of death or hospitalization for any cause and 24% fewer hospitalizations for heart failure than low dosages (2.5-5 mg) of the drug.
Once ACE inhibitor therapy is initiated for heart failure, it generally is continued indefinitely, if tolerated, since withdrawal of an ACE inhibitor may lead to clinical deterioration. Patients with NYHA class II or III heart failure who are tolerating therapy with an ACE inhibitor may be switched to therapy containing an ARNI to further reduce morbidity and mortality; however, the ARNI should not be administered concomitantly with an ACE inhibitor or within 36 hours of the last dose of an ACE inhibitor.
Current evidence supports the use of ACE inhibitors and β-blocker therapy to prevent development of left ventricular dilatation and dysfunction (''ventricular remodeling'') in patients with heart failure.
(See Uses: Asymptomatic Left Ventricular Dysfunction.)The addition of other agents such as diuretics, cardiac glycosides, aldosterone antagonists, and/or sinoatrial modulators in the management of heart failure should be individualized. Unless contraindicated, diuretics are recommended in all patients with heart failure and reduced ejection fraction who have evidence of fluid retention to improve symptoms. Digoxin may be beneficial to patients with heart failure with reduced ejection fraction to decrease hospitalization for heart failure, especially in those with persistent symptoms despite treatment with guideline-directed medical therapy. The addition of a sinoatrial modulator (i.e., ivabradine) is recommended in selected patients with chronic heart failure and reduced LVEF who are already receiving guideline-directed medical therapy, to reduce heart failure-related hospitalizations.
Results of a randomized, multicenter, double-blind, placebo-controlled study (Randomized Aldactone Evaluation Study [RALES]) indicate that addition of low-dosage spironolactone (25-50 mg daily) to standard therapy (e.g., an ACE inhibitor and a loop diuretic with or without a cardiac glycoside) in patients with severe (NYHA class IV within 6 months before enrollment and NYHA class III or IV at the time of enrollment) heart failure and an LVEF of 35% or less, was associated with decreases in overall mortality and hospitalization (for worsening heart failure) rates of approximately 30 and 35%, respectively, compared with standard therapy and placebo. Based on the results of RALES and other studies, ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure (NYHA class II-IV) and reduced LVEF (35% or less) who are already receiving standard therapy to reduce morbidity and mortality.
Many patients with heart failure respond to enalapril with improvement in cardiac function indexes, symptomatic (e.g., dyspnea, fatigue) relief, improved functional capacity, and increased exercise tolerance. In some studies, improvement in cardiac function indexes and exercise tolerance were sustained for up to 4 months. In some patients, beneficial effects have been sustained for up to 2-21 months. Enalapril also has been effective in conjunction with cardiac glycosides and diuretics for the management of heart failure resistant to or inadequately controlled by cardiac glycosides, diuretics, and vasodilators. In a multicenter, placebo-controlled study in patients with severe heart failure (NYHA class IV), the addition of enalapril to the therapeutic regimen (which included cardiac glycosides, diuretics, and/or vasodilators) was associated with a 40% reduction in overall mortality at 6 months and a 31% reduction at 12 months compared with patients who did not receive an ACE inhibitor, although the incidence of sudden cardiac death did not differ. In addition, there was a substantial improvement in NYHA functional class for patients receiving enalapril in this study. Follow-up of surviving patients 2 years after completion of the blinded, placebo-controlled phase showed a carry-over effect of enalapril on mortality reduction despite the availability of enalapril therapy for all surviving patients (whether treated initially with the drug or not) and the poorer clinical condition of the initial enalapril-treated group at the outset of follow-up; during follow-up, the carry-over effect on mortality reduction of initial enalapril therapy persisted for 15 months.
In 2 multicenter, controlled studies, enalapril substantially reduced mortality in patients with mild to moderate heart failure (NYHA class I-III) when added to a conventional therapeutic regimen (most commonly cardiac glycosides and diuretics); in these patients, enalapril therapy also may substantially reduce the rate of hospitalization. In one of these studies, the reduction in mortality was substantially greater with enalapril than with combined hydralazine and isosorbide dinitrate, although the latter regimen produced substantially greater improvement in exercise performance and left ventricular function. The beneficial effects of enalapril on reduction in mortality may result from a delay in worsening of heart failure, although other mechanisms (e.g., on causes of sudden death) may be involved. Analysis of the results of these studies according to racial subgroup indicates that white patients had substantially greater reductions in blood pressure and the risk of hospitalization for heart failure than black patients receiving similar dosages of enalapril.
(See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.)However, the risk of death in either racial subgroup was not altered by enalapril therapy.
It has not been determined whether addition of a vasodilator (e.g., hydralazine) to an ACE inhibitor is more effective than an ACE inhibitor alone. The efficacy of enalapril appears to be similar to that of captopril. However, because of enalapril's relatively long duration of action compared with captopril, enalapril may produce more prolonged hypotensive effects, particularly at high dosages, which potentially could result in adverse cerebral and renal effects. In addition, because the renin-angiotensin system appears to substantially contribute to preservation of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, therapy with an ACE inhibitor in such patients may adversely affect renal function.
(See Cautions: Renal Effects.)
ACE inhibitors also are used in patients with ACCF/AHA stage B heart failure
(see Uses: Asymptomatic Left Ventricular Dysfunction)to prevent symptomatic heart failure and have been shown to reduce mortality after myocardial infarction or acute coronary syndrome. (See Uses: Left Ventricular Dysfunction after Acute Myocardial Infarction.)
Asymptomatic Left Ventricular Dysfunction
Enalapril is used in clinically stable asymptomatic patients with left ventricular dysfunction (manifested as an ejection fraction of 35% or less) in an effort to decrease the rate of development of overt heart failure and subsequent hospitalizations for heart failure in these patients. AHA recommends use of ACE inhibitors in these patients. Experts recommend that all asymptomatic patients with reduced LVEF (ACCF/AHA stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality. If ACE inhibitors are not tolerated, then an angiotensin II receptor antagonist is recommended as an alternative.
Enalapril's beneficial effect in preventing the development of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction may result either from relieving symptoms that otherwise would have become apparent or from slowing the progression of asymptomatic ventricular dysfunction to overt, symptomatic disease. In a multicenter, placebo-controlled study in patients with left ventricular dysfunction who did not have symptomatic heart failure (NYHA class I and II) and were not being treated for such at initiation of ACE inhibitor therapy, enalapril reduced the incidence of heart failure and rate of related hospitalizations relative to those receiving placebo during an average of 37.4 months of follow-up. Patients with higher ejection fractions and black patients appeared to benefit less from enalapril therapy than those with lower fractions and white patients, respectively. The effect of enalapril in preventing the development of heart failure was evident within 3 months after initiation of the drug and continued to increase for the remaining study period (approximately 3 years). Mortality rates increased substantially in patients who developed overt heart failure, suggesting the possibility of a secondary benefit on prognosis from prevention of symptomatic progression. In a follow-up study, treatment with enalapril for 3-4 years led to a sustained improvement in survival (11-12 years) in patients with reduced LVEF, including those who were asymptomatic at baseline.
Left Ventricular Dysfunction after Acute Myocardial Infarction
ACE inhibitors, including enalapril and enalaprilat, have been used to minimize or prevent the development of left ventricular dilatation and dysfunction following acute myocardial infarction. However, evidence regarding the efficacy of such therapy has been somewhat conflicting, particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline dysfunction. While the preponderance of evidence (including a large, multinational, multicenter study) has shown a benefit of early oral therapy involving other ACE inhibitors, even in patients with no baseline dysfunction, one large study involving parenteral and oral enalapril found little if any early (within several months) benefit, particularly in terms of survival, from such therapy. In this multicenter, controlled study, IV enalaprilat (followed by oral enalapril) was initiated within 24 hours of the onset of chest pain associated with acute myocardial infarction and continued for up to approximately 6 months; there was no evidence of improved survival from enalapril therapy during the 6-month period after myocardial infarction and, in some patients, an actual worsening of heart failure was observed. In addition, enalapril therapy was associated with a substantial risk of hypotensive episodes, and long-term mortality was higher among patients who experienced hypotension with the first dose of enalapril than among other patients receiving the drug or among those who experienced hypotension with placebo. The lack of survival benefit observed in this study applied overall as well as to subgroups of patients (e.g., those with Q-wave infarction, anterior infarction, previous infarction, or current infarction complicated by pulmonary edema or heart failure). The results of this study are in contrast to other studies involving other ACE inhibitors initiated within 24 hours to 4 weeks after acute myocardial infarction in which a beneficial effect was observed, in terms of effects on left ventricular volume, infarct expansion, and/or survival.
The reason for the differences in potential benefit observed between studies involving enalapril and those involving other ACE inhibitors (e.g., captopril, lisinopril, ramipril) is unclear, but the lack of benefit in the enalapril study may have resulted in part from an early adverse effect of ACE inhibition (e.g., inhibition of angiotensin II-stimulated protein synthesis involved in healing) combined with a rapid decrease in blood pressure associated with the initial administration of enalaprilat and with an inadequate period of follow-up to detect a delayed beneficial effect. While use of parenteral ACE inhibitors during the early postinfarction period is not recommended, an oral ACE inhibitor should be initiated (starting with low doses) and titrated upward gradually during the initial postinfarction period. Early treatment with an ACE inhibitor following myocardial infarction has been shown to be beneficial in patients with or without left ventricular dysfunction or heart failure, although the benefits of these drugs appear to be greatest in patients with anterior myocardial infarction or evidence of prior infarction, heart failure, or tachycardia. Some clinicians state that ACE inhibitor therapy generally can be discontinued if there are no patient complications or evidence of symptomatic or asymptomatic left ventricular dysfunction by 4-6 weeks postinfarction in patients in whom such therapy was initiated prophylactically. However, long-term therapy with oral ACE inhibitors has been used to prevent cardiovascular events in patients with diabetes mellitus or a history of cardiovascular disease or myocardial infarction.
Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. The usual precautions of ACE inhibitor or angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed. For additional information on the use of ACE inhibitors in the treatment of diabetic nephropathy, see