Captopril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Because captopril can 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 drug was previously reserved for hypertension (usually severe) that was not manageable with maximal therapeutic dosages of other hypotensive agents in combination regimens (e.g., usually a diuretic, a β-adrenergic blocking agent [β-blocker], and a vasodilator) or when such regimens produced intolerable adverse effects. However, clinical experience with low dosages (up to 150 mg daily) has shown captopril to have a favorable benefit-to-risk ratio in the management of mild to moderate hypertension and the drug may currently be used as initial therapy in patients with normal renal function, in whom the risk of adverse hematologic effects is relatively low. In patients with impaired renal function, especially those with collagen vascular disease, captopril should be reserved for patients in whom other antihypertensive agents produce intolerable adverse effects or who do not have an adequate response to combination regimens of antihypertensive agents.
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of 4 classes of antihypertensive agents (angiotensin-converting enzyme [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., lifestyle 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, captopril can be used for the management of hypertension as initial monotherapy or as a component of a multiple-drug regimen. When captopril is used alone 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.
Captopril may be effective in the management of hypertension resistant to other drugs. Although captopril occasionally may be effective alone in patients with severe hypertension, it is usually necessary to use it in conjunction with a diuretic.
(See Drug Interactions: Hypotensive Agents and Diuretics.)
Tolerance to the hypotensive effect of captopril apparently does not occur during long-term administration, particularly if the drug is used with a diuretic. As with other hypotensive agents, treatment with captopril is not curative; after withdrawal of the drug, blood pressure returns to pretreatment levels. Abrupt withdrawal of captopril 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 shown to prevent subsequent heart failure and reduce morbidity and mortality in patients with systolic dysfunction following an acute myocardial infarction. (See Uses: Left Ventricular Dysfunction after Acute Myocardial Infarction.)
ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics have all been recommended for use as 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: 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.
Other Special Considerations for Antihypertensive Therapy
In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers 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 captopril has lowered blood pressure in all races studied, monotherapy with this agent 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 captopril 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
Captopril also has been effective in the management of renovascular or malignant hypertension and, in some patients, in the management of hypertension associated with chronic renal failure.
Captopril has been used orally for rapidly reducing blood pressure in patients with hypertensive crises in whom reduction of blood pressure was considered urgent (hypertensive urgencies) or an emergency (hypertensive emergencies). Because even oral therapy for hypertensive crises can result in profound hypotension and associated adverse cardiovascular effects (e.g., myocardial ischemia or infarction, cerebrovascular hypoperfusion or stroke), captopril should not be used indiscriminately, and the benefits versus risks of rapidly reducing blood pressure with the drug must be weighed carefully.
Hypertensive urgencies are those situations in which there is a severe elevation in blood pressure without progressive target organ damage. Such urgencies include the upper levels of stage 2 hypertension associated with severe headache, shortness of breath, epistaxis, or severe anxiety. Hypertensive urgencies generally can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen or with oral doses of short-acting antihypertensive agents such as captopril followed by several hours of observation; however, there is no evidence suggesting that failure to aggressively reduce blood pressure in these patients is associated with any short-term risk. In fact, overly aggressive management of severe elevations in blood pressure not associated with impending or progressing organ damage can sometimes lead to cumulative hypotensive effects.
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. Although oral therapy with captopril has been used to rapidly reduce blood pressure in such emergencies, patients with hypertensive emergencies should be hospitalized and treated initially with appropriate parenteral antihypertensive therapy (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside).
For further information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
Captopril may be used in patients with nephropathy, including diabetic nephropathy. Use of ACE inhibitors or angiotensin II receptor antagonists is recommended in the management of diabetic or nondiabetic chronic kidney disease to slow progression of the disease. ACE inhibitors have stabilized or improved effective renal blood flow and glomerular filtration rate and decreased proteinuria in hypertensive or normotensive patients with moderately impaired renal function, moderate to severe renal disease, or diabetic nephropathy. Short-term administration of captopril improved blood flow and glomerular filtration rate in some hypertensive patients with moderately impaired renal function; however, long-term captopril therapy has not maintained sustained improvement in renal blood flow and glomerular filtration rate. In general, captopril should be used with caution in patients with impaired renal function, especially those with bilateral renal-artery stenosis or renal-artery stenosis in a solitary kidney.
(See Cautions: Renal Effectsand see Cautions: Hematologic Effects, and also see Precautions and Contraindications.)Captopril appears to be ineffective in the management of hypertension in anephric patients. (See Pharmacology: Renal and Electrolyte Effects.)
Captopril is used in the management of diabetic nephropathy manifested by proteinuria (urinary protein excretion exceeding 500 mg per 24 hours) in patients with type 1 (insulin dependent, IDDM) diabetes mellitus and diabetic retinopathy.
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 per 24 hours) or higher (exceeding 300 mg per 24 hours) levels of urinary albumin excretion. Comparative trials evaluating the efficacy of ACE inhibitors and angiotensin II receptor antagonists for improving renal outcomes in diabetic patients are lacking. Evidence supporting use of ACE inhibitors generally is based on studies in patients with type 1 diabetes mellitus, while evidence supporting use of angiotensin II receptor antagonists generally is based on studies in patients with type 2 diabetes mellitus. Findings from these studies indicate that both drug classes delay progression of increased urinary albumin excretion in patients with diabetes mellitus and also may slow the decline in renal function. Because the available data are consistent, some experts suggest that the effects of both drug classes in improving renal outcomes in patients with diabetes mellitus and proteinuria are likely to be similar. Drugs that inhibit the renin-angiotensin system (i.e., ACE inhibitors, angiotensin II receptor antagonists) also have been shown to delay the onset of albuminuria in patients with type 2 diabetes mellitus and hypertension who have normal levels of urinary albumin excretion. Although combined therapy with ACE inhibitors and angiotensin II receptor antagonists appears to have additive effects in reducing albuminuria, such combinations provide no additional cardiovascular benefit and increase the risk of adverse effects (e.g., impaired renal function, hyperkalemia).
In a multicenter, controlled study in hypertensive and normotensive individuals who had type 1 diabetes mellitus for at least 7 years, diabetic retinopathy, proteinuria, and a serum creatinine concentration of 2.5 mg/dL or less, deterioration in renal function was substantially less pronounced in patients receiving long-term captopril therapy (median: 3 years [range: 1.8-4.8 years]) than in those receiving placebo. Patients with hypertension received hypotensive agents (e.g., diuretics, β-blockers, α-adrenergic blocking agents, vasodilators) as needed. Overall, patients receiving captopril had a 48% reduction in the risk of doubling of serum creatinine concentration. Captopril therapy was especially useful in patients with more advanced renal disease (i.e., baseline serum creatinine exceeding 1.5 mg/dL). Captopril therapy was associated with a 30% reduction in urinary protein excretion within 3 months and was evident throughout the study. In addition, patients receiving captopril had a 50% reduction in the risk of death and need for dialysis or renal transplantation, particularly in those with more advanced renal disease. It has been suggested that captopril and other ACE inhibitors may slow the progression of renal nephropathy by a mechanism independent of its antihypertensive properties.
Captopril also has been shown to delay the onset of diabetic nephropathy in normotensive patients with diabetes mellitus and microalbuminuria. In multicenter controlled studies in normotensive patients with type 1 diabetes mellitus, retinopathy, and microalbuminuria (20-200 mcg/minute), treatment with captopril (50 mg twice daily) for 2 years was associated with a substantial reduction in the risk of developing diabetic nephropathy (based on progression of microalbuminuria to proteinuria). In one study, albumin excretion rate increased from a mean baseline value of 52 to 76 mcg/minute at 2 years in patients receiving placebo, while rates determined at the same time points in patients receiving captopril decreased from 52 to 41 mcg/minute. While clinical studies indicate that treatment with captopril can postpone the development of diabetic nephropathy in normotensive type 1 diabetic patients with microalbuminuria, the long-term clinical benefit of reducing the progression of microalbuminuria to proteinuria has not been determined.
Captopril is used in the management of 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. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [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. In patients with prior or current symptoms of chronic heart failure with reduced LVEF, 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 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 sacubitril/valsartan, an ARNI, 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 and 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.
Diuretics are recommended in all patients with heart failure and reduced ejection fraction who have evidence of fluid retention, unless contraindicated, 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 manufacturer states that most experience from controlled studies has been with combined captopril, cardiac glycoside, and diuretic therapy; however, the manufacturer also states that the beneficial effect of captopril does not require concomitant cardiac glycoside 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 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 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 captopril with improvement in cardiac function indexes, symptomatic relief, improved functional capacity, and increased exercise tolerance. In some studies, improvement in cardiac function indexes and exercise tolerance were sustained for up to 6 months. In some patients, beneficial effects have been sustained for up to 1 year or longer. Captopril also has been effective in conjunction with cardiac glycosides and diuretics in the management of heart failure resistant to or inadequately controlled by cardiac glycosides, diuretics, and vasodilators.
ACE inhibitors also are used to prevent symptomatic heart failure in patients with ACCF/AHA stage B heart failure
(see Uses: Asymptomatic Left Ventricular Dysfunction)and have been shown to reduce mortality after myocardial infarction or acute coronary syndrome. (See Uses: Left Ventricular Dysfunction after Acute Myocardial Infarction.)
In patients with heart failure in whom renal perfusion is severely compromised, the renin-angiotensin system appears to substantially contribute to preservation of glomerular filtration; therefore, therapy with an ACE inhibitor may adversely affect renal function in such patients.
(See Cautions: Renal Effects.)
Left Ventricular Dysfunction after Acute Myocardial Infarction
Captopril is used in an effort to improve survival following acute myocardial infarction in clinically stable patients with left ventricular dysfunction (manifested as an ejection fraction of 40% or less) and to reduce the incidence of overt heart failure and subsequent hospitalizations for heart failure in these patients. ACE inhibitors have been shown to reduce mortality rates in diabetic patients with left ventricular dysfunction, and the American College of Cardiology (ACC) and the AHA recommend use of these drugs in diabetic patients with acute coronary syndromes (i.e., unstable angina or non-ST-segment elevation myocardial infarction).
ACE inhibitors, including captopril, have been used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular ''remodeling'') 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 captopril and other ACE inhibitors (e.g., lisinopril, zofenopril [not commercially available in the US]), even in patients with no baseline dysfunction, one large study involving enalapril therapy initiated within 24 hours of infarction (parenteral enalaprilat followed by oral enalapril) found little if any early (within several months) benefit, particularly in terms of survival, from such therapy. However, in a multicenter, controlled study involving captopril in which initiation of therapy with the drug was delayed until 3-16 days after acute myocardial infarction and limited to patients with low ejection fractions (40% or less), long-term (mean: 42 months; range: 24-60 months) therapy with the drug was associated with a reduction in overall mortality as well as a reduction in morbidity and mortality secondary to cardiovascular causes. In addition, in a large, controlled, long-term (average: 15 months; range: 6-46 months) study, ramipril (another ACE inhibitor) was associated with a reduction in overall mortality as well as in the risk of progression to severe heart failure and heart failure-associated hospitalization when given within an average of 5 (range: 2-9) days following acute myocardial infarction in patients who had clinical signs of heart failure. In several other studies involving captopril in which the drug was initiated within 24 hours to 4 weeks after acute myocardial infarction, a beneficial effect also was observed, at least in terms of effects on left ventricular volume and/or infarct expansion.
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 involved in healing) combined with a rapid decrease in blood pressure associated with the initial administration of IV 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 such 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 ACE inhibitor 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. ()
Asymptomatic Left Ventricular Dysfunction
ACE inhibitors have been used to attenuate left ventricular enlargement and prevent progression to symptomatic dysfunction in asymptomatic patients with heart failure (ACCF/AHA stage B heart failure). Captopril has reduced the development of symptomatic heart failure and associated morbidity and mortality in such patients. The drug's beneficial effect in preventing the development of symptomatic heart failure in these patients 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. If an ACE inhibitor is not tolerated, then an angiotensin II receptor antagonist is recommended as alternative therapy.
Captopril has been shown to increase digital circulation in one patient with Raynaud's phenomenon and decrease the orthostatic sodium and water retention in several women with idiopathic edema. Therefore, it has been suggested that the drug may be useful in the treatment of these conditions; however, additional evaluation is necessary.
ACE inhibitors have been used to reduce the risk of cardiovascular events in patients 55 years of age or older who are at high risk for cardiovascular events (e.g., diabetes mellitus, history of cardiovascular disease, stroke, peripheral vascular disease, dyslipidemia, smoking, microalbuminuria, hypertension).