AHFS Class:

• Angiotensin-Converting Enzyme Inhibitors 24:32.04

Generic Name(s):

• Captopril

• Captopril and Hydrochlorothiazide

Captopril is an angiotensin-converting enzyme (ACE) inhibitor.1,3,4,5

Hypertension

Captopril is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.115,317,1200 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.115

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 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.501,502,504,1200,1213 However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines.501,502,503,504,1200 This variability is due, in part, to differences in the guideline development process and the types of studies (e.g., randomized controlled studies only versus a range of studies with different study designs) included in the evidence reviews.501,502,503,515,1200 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).501,502,503,504,515,1200,1201 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.388,389,501,502,523,1202

Disease Overview

Worldwide, hypertension is the most common modifiable risk factor for cardiovascular events and mortality.1205 The lifetime risk of developing hypertension in the US exceeds 80%, with higher rates observed among African Americans and Hispanics compared with whites or Asians.1200 The systolic blood pressure and diastolic blood pressure values defined as hypertension (see Blood Pressure Classification under Uses: Hypertension) in a 2017 multidisciplinary guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations (subsequently referred to as the 2017 ACC/AHA hypertension guideline in this monograph)1200 are lower than those defined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines,500 which results in an increase of approximately 14% in the prevalence of hypertension in the US.1200,1222 However, this change in definition results in only a 2% increase in the percentage of patients requiring antihypertensive drug therapy because nonpharmacologic treatment is recommended for most adults now classified by the 2017 ACC/AHA hypertension guideline as hypertensive who would not meet the JNC 7 definition of hypertension.500,1200,1222 Among US adults receiving antihypertensive drugs, approximately 53% have inadequately controlled blood pressure according to current ACC/AHA treatment goals.1206

Cardiovascular and Renal Sequelae

The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.502,1200 The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors.1200 It is important that very high blood pressure be managed promptly to reduce the risk of target organ damage.1200 The higher the blood pressure, the more likely the development of myocardial infarction (MI), heart failure, stroke, and renal disease.502,1200 For adults 40-70 years of age, each 20-mm Hg increment in systolic blood pressure or 10-mm Hg increment in diastolic blood pressure doubles the risk of developing cardiovascular disease across the entire blood pressure range of 115/75 to 185/115 mm Hg.1200,1238 For those older than 50 years of age, systolic blood pressure is a much more important risk factor for developing cardiovascular disease than is diastolic blood pressure.502 The rapidity with which treatment is required depends on the patient's clinical presentation (presence of new or worsening target organ damage) and the presence or absence of cardiovascular complications; the 2017 ACC/AHA hypertension guideline states that treatment of very high blood pressure should be initiated within 1 week.1200

Blood Pressure Classification

Accurate blood pressure measurement is essential for the proper diagnosis and management of hypertension.1200,1225,1226 Error in measuring blood pressure is a major cause of inadequate blood pressure control and may lead to overtreatment.1225,1226 Because a patient's blood pressure may vary in an unpredictable fashion, a single blood pressure measurement is not sufficient for clinical decision-making.1200 An average of 2 or 3 blood pressure measurements obtained on 2-3 separate occasions using proper technique should be used to minimize random error and provide a more accurate blood pressure reading.1200 Out-of-office blood pressure measurements may be useful for confirming and managing hypertension.1200 The 2017 ACC/AHA hypertension guideline document (available on the ACC and AHA websites) should be consulted for key steps on properly measuring blood pressure.1200

According to the 2017 ACC/AHA hypertension guideline, blood pressure in adults is classified into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.) The 2017 ACC/AHA hypertension guideline lowers the blood pressure threshold used to define hypertension in the US; previous hypertension guidelines (JNC 7) considered adults with systolic blood pressure of 120-139 mm Hg or diastolic blood pressure of 80-89 mm Hg to have prehypertension, those with systolic blood pressure of 140-159 mm Hg or diastolic blood pressure of 90-99 mm Hg to have stage 1 hypertension, and those with systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 100 mm Hg or higher to have stage 2 hypertension.500,1200 The blood pressure definitions in the 2017 ACC/AHA hypertension guideline are based upon data from studies evaluating the association between systolic blood pressure/diastolic blood pressure and cardiovascular risk and the benefits of blood pressure reduction.1200 Individuals with systolic blood pressure and diastolic blood pressure in 2 different categories should be designated as being in the higher blood pressure category.1200

The blood pressure thresholds used to define hypertension, when to initiate drug therapy, and the ideal target blood pressure values remain controversial.505,506,507,508,515,523,530,1200,1201,1207,1209,1222,1223,1229 The 2017 ACC/AHA hypertension guideline recommends a blood pressure goal of less than 130/80 mm Hg in all adults who have confirmed hypertension and known cardiovascular disease or a 10-year atherosclerotic cardiovascular disease (ASCVD) event risk of 10% or higher; the ACC/AHA guideline also states that this blood pressure goal is reasonable to attempt to achieve in adults with confirmed hypertension who do not have increased cardiovascular risk.1200 The lower blood pressure values used to define hypertension and the lower target blood pressure goals outlined in the 2017 ACC/AHA hypertension guideline are based on clinical studies demonstrating a substantial reduction in the composite end point of major cardiovascular disease events and the combination of fatal and nonfatal stroke when a lower systolic blood pressure/diastolic blood pressure value (i.e., 130/80 mm Hg) was used to define hypertension.521,1210,1223 These lower target blood pressure goals also are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210 A linear relationship has been demonstrated between cardiovascular risk and blood pressure even at low systolic blood pressures (e.g., 120-124 mm Hg).1200,1207,1230 The 2017 ACC/AHA hypertension guideline recommends estimating a patient's ASCVD risk using the ACC/AHA Pooled Cohort equations (available online at [Web]), which are based on a variety of factors including age, race, gender, cholesterol levels, statin use, blood pressure, treatment for hypertension, history of diabetes mellitus, smoking status, and aspirin use.1200,1202 While the 2017 ACC/AHA hypertension guideline has lowered the threshold for diagnosing hypertension in adults, the threshold for initiating drug therapy has only been lowered for those patients who are at high risk of cardiovascular disease.1200,1222 Clinicians who support the 2017 ACC/AHA hypertension guideline believe that these recommendations have the potential to increase hypertension awareness, encourage lifestyle modification, and focus antihypertensive drug initiation and intensification in those adults at high risk for cardiovascular disease.1227

The lower blood pressure goals advocated in the 2017 ACC/AHA hypertension guideline have been questioned by some clinicians who have concerns regarding the guideline's use of extrapolated observational data, the lack of generalizability of some of the randomized trials (e.g., SPRINT) used to support the guideline, the difficulty of establishing accurate representative blood pressure values in typical clinical practice settings, and the accuracy of the cardiovascular risk calculator used in the guideline.1224,1229 Some clinicians state the lower blood pressure threshold used to define hypertension in the 2017 ACC/AHA hypertension guideline is not fully supported by clinical data, and these clinicians have expressed concerns about the possible harms (e.g., adverse effects of antihypertensive therapy) associated with classifying more patients as being hypertensive.1222,1223,1229 Some clinicians also state that using this guideline, a large number of young, low-risk patients would need to be treated in order to observe a clinical benefit,1200,1224 while other clinicians state that the estimated gains in life expectancy attributable to long-term use of blood pressure-lowering drugs are correspondingly greater in this patient population.1200

Treatment Benefits

In clinical trials, antihypertensive therapy has been found to reduce the risk of developing stroke by about 34-40%, MI by about 20-25%, and heart failure by more than 50%.388,390,500,1235 In a randomized, controlled study (SPRINT) that included hypertensive patients without diabetes mellitus who had a high risk of cardiovascular disease, intensive systolic blood pressure lowering of approximately 15 mm Hg was associated with a 25% reduction in cardiovascular disease events and a 27% reduction in all-cause mortality.1210,1219 However, the exclusion of patients with diabetes mellitus, prior stroke, and those younger than 50 years of age may decrease the generalizability of these findings.1210 Some experts estimate that if the systolic blood pressure goals of the 2017 ACC/AHA hypertension guideline are achieved, major cardiovascular disease events may be reduced by an additional 340,000 and total deaths by an additional 156,000 compared with implementation of the JNC 8 expert panel guideline goals but these benefits may be accompanied by an increase in the frequency of adverse events.1228 While there was no overall difference in the occurrence of serious adverse events in patients receiving intensive therapy for blood pressure control (systolic blood pressure target of less than 120 mm Hg) compared with those receiving less intense control (systolic blood pressure target of less than 140 mm Hg) in the SPRINT study, hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure occurred in substantially more patients receiving intensive therapy.1210

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease.379,380,399,400,1236,1237 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.379,380 Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure.1236,1237 The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.1236,1237 See Clinical Benefit of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.

General Considerations for Initial and Maintenance Antihypertensive Therapy

Nonpharmacologic Therapy

Nonpharmacologic measures (i.e., lifestyle/behavioral modifications) that are effective in lowering blood pressure include weight reduction (for those who are overweight or obese), dietary changes to include foods such as fruits, vegetables, whole grains, and low-fat dairy products that are rich in potassium, calcium, magnesium, and fiber (i.e., adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), sodium reduction, increased physical activity, and moderation of alcohol intake.1200 Such lifestyle/behavioral modifications, including smoking cessation, enhance antihypertensive drug efficacy and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.502,504,1200 Lifestyle/behavioral modifications without antihypertensive drug therapy are recommended for individuals classified by the 2017 ACC/AHA hypertension guideline as having elevated blood pressure (systolic blood pressure 120-129 mm Hg and diastolic blood pressure less than 80 mm Hg) and in those with stage 1 hypertension (systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg) who do not have preexisting cardiovascular disease or an estimated 10-year ASCVD risk of 10% or greater.1200

Initiation of Drug Therapy

Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation while also considering cardiovascular risk factors.317,328,379,380,388,389,502,1200,1201 Drug therapy generally is reserved for patients who respond inadequately to nondrug therapies or in whom the degree of blood pressure elevation or coexisting risk factors, especially increased cardiovascular risk, require more prompt or aggressive therapy;317,328,379,380,1200 however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209 Recommendations generally are based on specific blood pressure levels shown in clinical studies to produce clinical benefits and can therefore vary depending on the studies selected for review.502,504,505,507,1200

The 2017 ACC/AHA hypertension guideline and many experts currently state that the treatment of hypertension should be based not only on blood pressure values but also on patients' cardiovascular risk factors.502,1200,1219 For secondary prevention of recurrent cardiovascular disease events in adults with clinical cardiovascular disease or for primary prevention in adults with an estimated 10-year ASCVD risk of 10% or higher, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an average systolic blood pressure of 130 mm Hg or an average diastolic blood pressure of 80 mm Hg or higher.1200 For primary prevention of cardiovascular disease events in adults with a low (less than 10%) estimated 10-year risk of ASCVD, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.1200 After initiation of antihypertensive drug therapy, regardless of the ASCVD risk, the 2017 ACC/AHA hypertension guideline generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg is also recommended for noninstitutionalized ambulatory patients 65 years of age or older.1200 While these blood pressure goals are lower than those recommended for most patients in previous guidelines, they are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210

Most data indicate that patients with a higher cardiovascular risk will benefit the most from tighter blood pressure control; however, some experts state this treatment goal also may be beneficial in those at lower cardiovascular risk.1200 Other clinicians believe that the benefits of such blood pressure lowering do not outweigh the risks in those patients considered to be at lower risk of cardiovascular disease and that reclassifying individuals formerly considered to have prehypertension as having hypertension may potentially lead to use of drug therapy in such patients without consideration of cardiovascular risk.1201,1222,1223,1229 Previous hypertension guidelines, such as those from the JNC 8 expert panel, generally recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients.501 Some clinicians continue to support the target blood pressures recommended by the JNC 8 expert panel because of concerns that such recommendations in the 2017 ACC/AHA hypertension guideline are based on extrapolation of data from the high-risk population in the SPRINT study to a lower-risk population.1223,1224 Also, because more than 90% of patients in SPRINT were already receiving antihypertensive drugs at baseline, data are lacking on the effects of initiating drug therapy at a lower blood pressure threshold (130/80 mm Hg) in patients at high risk of cardiovascular disease.1223 The potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs should be considered when deciding a patient's blood pressure treatment goal.1200,1220,1229

The 2017 ACC/AHA hypertension guideline recommends an ASCVD risk assessment for all adults with hypertension; however, experts state that it can be assumed that patients with hypertension and diabetes mellitus or chronic kidney disease (CKD) are at high risk for cardiovascular disease and that antihypertensive drug therapy should be initiated in these patients at a blood pressure of 130/80 mm Hg or higher.1200 The 2017 ACC/AHA guideline also recommends a blood pressure goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus or CKD.1200 These recommendations are based on a systematic review of high-quality evidence from randomized controlled trials, meta-analyses, and post-hoc analyses that have demonstrated substantial reductions in the risk of important clinical outcomes (e.g., cardiovascular events) regardless of comorbid conditions or age when systolic blood pressure is lowered to less than 130 mm Hg.1200,1213 However, some clinicians have questioned the generalizability of findings from some of the trials (e.g., SPRINT) used to support the 2017 ACC/AHA hypertension guideline.1224 For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease.1209 While benefits of intensive blood pressure control were observed in this patient population, some clinicians have questioned whether these findings apply to younger patients who have a low risk of cardiovascular disease.1223 In patients with CKD in the SPRINT trial, intensive blood pressure management (achieving a mean systolic blood pressure of approximately 122 mm Hg compared with 136 mm Hg with standard treatment) provided a similar beneficial reduction in the composite cardiovascular disease primary outcome and all-cause mortality as in the full patient cohort.1200,1210 Because most patients with CKD die from cardiovascular complications, the findings of this study further support a lower blood pressure target of less than 130/80 mm Hg.1200

Data are lacking to determine the ideal blood pressure goal in patients with hypertension and diabetes mellitus; also, studies evaluating the benefits of intensive blood pressure control in patients with diabetes mellitus have provided conflicting results.521,1200,1213 Clinical studies reviewed for the 2017 ACC/AHA hypertension guideline have shown similar quantitative benefits from blood pressure lowering in hypertensive patients with or without diabetes mellitus.1213 In a randomized, controlled study (ACCORD-BP) that compared a higher (systolic blood pressure less than 140 mm Hg) versus lower (systolic blood pressure less than 120 mm Hg) blood pressure goal in patients with diabetes mellitus, there was no difference in the incidence of cardiovascular outcomes (e.g., composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke).521,1214 However, some experts state that this study was underpowered to detect a difference between the 2 treatment groups and that the factorial design of the study complicated interpretation of the results.1200,1216 Although SPRINT did not include patients with diabetes mellitus, patients in this study with prediabetes demonstrated a similar cardiovascular benefit from intensive treatment of blood pressure as normoglycemic patients.1200 A meta-analysis of data from ACCORD and SPRINT suggests that the findings of both studies are consistent and that patients with diabetes mellitus benefit from more intensive blood pressure control.1202,1217 These data support the 2017 ACC/AHA hypertension guideline recommendation of a blood pressure treatment goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus.1200 Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus.1214 The ADA states that a lower blood pressure goal (e.g., less than 130/80 mm Hg) may be appropriate for patients with a high risk of cardiovascular disease and diabetes mellitus if it can be achieved without undue treatment burden.1214

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension, particularly in high-risk groups (e.g., patients with diabetes mellitus, cardiovascular disease, or cerebrovascular disease; black patients); when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.503,507,515,526,530,1200

Choice of 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.501,502,503,504,1200 The 2017 ACC/AHA hypertension guideline states that an ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, or thiazide diuretic (preferably chlorthalidone) are all acceptable choices for initial antihypertensive drug therapy in the general population of nonblack patients, including those with diabetes mellitus;1200 drugs from any of these classes generally produce similar benefits in terms of overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,1200,1213 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, CKD, or cerebrovascular disease or following myocardial infarction (MI).501,502,523,524,525,526,527,534,535,536,543,1200,1214,1215 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension.)

In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.1200 (See Chronic Kidney Disease under Hypertension: Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, in Uses.) However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).1200,1218 Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.1218 Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.1218

Experts state that in patients with stage 1 hypertension (especially the elderly, those with a history of hypotension, or those who have experienced adverse drug effects), it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target blood pressure.1200 Although some patients can begin treatment with a single antihypertensive agent, starting with 2 drugs in different pharmacologic classes (either as separate agents or in a fixed-dose combination) is recommended in patients with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target blood pressure.1200 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).388,389,1200 Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred.1200 Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided.1200 Many patients who begin therapy with a single antihypertensive agent will subsequently require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal.1200 Experts state that other patient-specific factors, such as age, concurrent medications, drug adherence, drug interactions, the overall treatment regimen, cost, and comorbidities, also should be considered when deciding on an antihypertensive drug regimen.1200 For any stage of hypertension, antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved. (See Follow-up and Maintenance Drug Therapy under Hypertension: General Considerations for Initial and Maintenance Antihypertensive Therapy, in Uses.)

Follow-up and Maintenance Drug Therapy

Several strategies are used for the titration and combination of antihypertensive drugs; these strategies, which are generally based on those used in randomized controlled studies, 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).1200 Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects.1200 After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved.1200 Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs.383,1200 In addition to measuring blood pressure, clinicians should evaluate patients for orthostatic hypotension, adverse drug effects, adherence to drug therapy and lifestyle modifications, and the need for drug dosage adjustments.1200 Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.1200

Captopril can be used for the management of hypertension as initial monotherapy115,130,133,134,135,138,171,172,174,177,317,318 or as a component of a multiple-drug regimen.115 When captopril is used alone but the patient's hypertension does not respond adequately, addition of a thiazide diuretic often adequately controls blood pressure.130,137,138,171 Such combined therapy generally produces additive reduction in blood pressure1,3,4,5,8,10,11,12,14,16,23,24,25,27,28,29,30,31,115,130,137,138 and may permit dosage reduction of either or both drugs and minimize adverse effects while maintaining blood pressure control.127,130,137,138

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. Abrupt withdrawal of captopril therapy results in a gradual return of hypertension; rapid increases in blood pressure have not been reported to date.115

Considerations for Drug Therapy in Patients with Underlying Cardiovascular and 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.167,214,217,502,1200 See Table 2 on Compelling Indications for Drug Classes based on Comorbid Conditions, under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Ischemic Heart Disease

The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics and may include ACE inhibitors and/or β-blockers, with the addition of other drugs such as thiazide diuretics or calcium-channel blockers as necessary to achieve blood pressure goals.523,525 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; in addition, all patients who have survived an MI should be treated with a β-blocker because of the demonstrated mortality benefit of these agents.523,525,527

Heart Failure

While ACE inhibitors as single therapies are not superior to other antihypertensive agents in the reduction of cardiovascular outcomes,501,1200 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.524 (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 MI.247,317,318,524,527 (See Uses: Left Ventricular Dysfunction after Acute Myocardial Infarction.)

Diabetes Mellitus

Experts state that initial treatment of hypertension in adults with diabetes mellitus and hypertension should include any of the usual first-line agents (ACE inhibitors, angiotensin II receptor antagonist, calcium-channel blockers, thiazide diuretics).1200,1214,1215 In adults with diabetes mellitus, hypertension, and albuminuria, treatment with an ACE inhibitor or angiotensin II receptor antagonist may be considered to reduce the progression of kidney disease.1200,1215 While there 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, 334,367,368 in the absence of albuminuria, the risk of progressive kidney disease is low, and ACE inhibitors and angiotensin II receptor antagonists have not demonstrated superior cardioprotection when compared with other first-line agents.1214,1215 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).336,337,338,339,341,349,353,354,501,1214,1215 Most patients with diabetes mellitus will require 2 or more antihypertensive agents to achieve blood pressure control.1200,1215

Chronic Kidney Disease

Hypertensive patients with CKD (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m² or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure.403,501,536,537,543 Use of ACE inhibitors or angiotensin II receptor antagonists may be reasonable in patients with diabetic or nondiabetic CKD (stage 1 or 2 with albuminuria or stage 3 or higher);1200 these drugs have been shown to slow the progression of kidney disease.502,534,535,536,543 Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria.535,536,543 Increases in serum creatinine (up to 30%) may be observed as a result of a decrease in intraglomerular pressure and concurrent reduction in GFR.1200 The 2017 ACC/AHA hypertension guideline states that in patients with less severe kidney disease (i.e., stage 1 or 2 CKD without albuminuria), any of the first-line antihypertensive agents (e.g., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics) can be used for the initial treatment of hypertension.1200 Diuretics also may be useful in the management of CKD, and may potentiate the effects of ACE inhibitors, angiotensin II receptor antagonists, and other antihypertensive agents when used in combination.543

Cerebrovascular Disease

Some experts recommend a blood pressure goal of less than 140/90 mm Hg in patients with ischemic stroke or transient ischemic attack (TIA),526 while others state that a blood pressure goal of less than 130/80 mm Hg may be reasonable.1200 The 2017 ACC/AHA hypertension guideline states that adults not previously treated for hypertension who experience a stroke or TIA and who have an established blood pressure of 140/90 mm Hg or higher should receive antihypertensive therapy within a few days after the event to reduce the risk of recurrent stroke or other vascular events.1200 In patients with a recent lacunar stroke, experts suggest that a 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).518,526,1200 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, available data indicate that an ACE inhibitor, angiotensin II receptor antagonist, thiazide diuretic, or the combination of a thiazide diuretic and an ACE inhibitor may be effective.526,1200 Administration of an ACE inhibitor in combination with a thiazide diuretic has been shown to lower rates of recurrent stroke.394,526

Other Special Considerations for Antihypertensive Drug Therapy

Race

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors.379,380,386,399,400,501,504,1200 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.501 (See Clinical Benefit of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.) However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 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.386

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,115,139,177,178,179,180,181,351 a population associated with low renin hypertension;140,217,218,219 however, this population difference in response does not appear to occur during combined therapy with captopril and a thiazide diuretic.179,193,194,217,218,219,504 In addition, ACE inhibitors appear to produce a higher incidence of angioedema in black patients than in other races studied.102,115,325,326,327,351,379,380,1200

For further information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Renovascular or Malignant Hypertension

Captopril also has been effective in the management of renovascular4,5,7,10,13,14,23,24 or malignant4,5,14,23,24 hypertension and, in some patients, in the management of hypertension associated with chronic renal failure.4,10,14

Hypertensive Crises

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 emergent (hypertensive emergencies).231,232,233,234,235,236,237,238,313,314 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),5,115,231,309 captopril should not be used indiscriminately, and the benefits versus risks of rapidly reducing blood pressure with the drug must be weighed carefully.231,309

Hypertensive urgencies are those situations in which there is a severe elevation in blood pressure without progressive target organ damage.1200 Hypertensive urgencies generally can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen and treatment of anxiety if needed.1200 Experts state that there is no need for rapid reduction of blood pressure in such patients and hospitalization or referral to the emergency department also is unnecessary.1200

Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage.309,310,1200 Such emergencies include hypertensive encephalopathy, acute MI, intracerebral hemorrhage, acute left ventricular failure with pulmonary edema, eclampsia, dissecting aortic aneurysm, unstable angina pectoris, acute ischemic stroke, and acute renal failure.231,309,310,315,1200 Although oral therapy with captopril has been used to rapidly reduce blood pressure in such emergencies,231,232,233,236,315 patients with hypertensive emergencies should be hospitalized and treated initially with appropriate parenteral antihypertensive therapy (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside).233,309,310,502,542,1200

Nephropathy

Captopril may be used in patients with nephropathy, including diabetic nephropathy.141,142,143,187,188,189,263,268,269 Use of ACE inhibitors or angiotensin II receptor antagonists is recommended in the management of diabetic or nondiabetic† CKD to slow progression of the disease.404,534,535,536,543,1232 ACE inhibitors have stabilized or improved effective renal blood flow and glomerular filtration rate and decreased proteinuria in hypertensive115,141,142,143,174,187,188,189,281,323 or normotensive115,162 patients with moderately impaired renal function,141,143,174,323 moderate to severe renal disease,141,323 or diabetic nephropathy.141,142,143,187,188,189,268,334 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.143,144 In general, captopril should be used with caution in patients with impaired renal function,115,118,119,120 especially those with bilateral renal-artery stenosis or renal-artery stenosis in a solitary kidney.86,87,115,117,122,123,124 (See Cautions: Renal Effects and see Cautions: Hematologic Effects, and also see Precautions and Contraindications.) Captopril appears to be ineffective in the management of hypertension in anephric patients.67 (See Pharmacology: Renal and Electrolyte Effects.)

Diabetic Nephropathy

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 diabetes mellitus and diabetic retinopathy.115,262,263,264,265,268,269

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.535,536,1232 Comparative trials evaluating the efficacy of ACE inhibitors and angiotensin II receptor antagonists for improving renal outcomes in diabetic patients are lacking.536 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.536 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.536 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.536 Drugs that inhibit the renin-angiotensin system (i.e., ACE inhibitors, angiotensin II receptor antagonists) 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†;1233,1234 however, experts state that in the absence of albuminuria, the risk of progressive kidney disease is low.1214,1215 Combined therapy with ACE inhibitors and angiotensin II receptor antagonists provides no additional cardiovascular benefit and increases the risk of adverse effects (e.g., impaired renal function, hyperkalemia).1232 The American Diabetes Association (ADA) states that the use of an ACE inhibitor or angiotensin II receptor antagonist is not recommended for the primary prevention of diabetic nephropathy in patients with diabetes mellitus who are normotensive, have normal levels of urinary protein excretion, and have a normal glomerular filtration rate.1232

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.115,262,263,279 Patients with hypertension received hypotensive agents (e.g., diuretics, β-blockers, α-adrenergic blocking agents, vasodilators) as needed.115,262 Overall, patients receiving captopril had a 48% reduction in the risk of doubling of serum creatinine concentration.262 Captopril therapy was especially useful in patients with more advanced renal disease (i.e., baseline serum creatinine exceeding 1.5 mg/dL).262,263 Captopril therapy was associated with a 30% reduction in urinary protein excretion within 3 months115 and was evident throughout the study.115,262,263 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.115,262,263 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.115,262,263,264,265,281,282,283,334

Captopril also has been shown to delay the onset of diabetic nephropathy in normotensive patients with diabetes mellitus and microalbuminuria†.115,264,265,266,267,270 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).115,266 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.115,266 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.115

Heart Failure

Captopril is used in the management of heart failure, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers.115,524,700

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.524,700,701,703 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.524,700 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.524 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.700 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,524 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.700,702 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.700,701,703 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.700 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.700 For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.

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.360,524 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.360

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.333,377,524 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.700

Diuretics are recommended in all patients with heart failure and reduced ejection fraction who have evidence of fluid retention, unless contraindicated, to improve symptoms.524 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.524 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.700 (See Uses: Heart Failure, in Ivabradine 24:04.92.)

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.329,335,350 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.524,700 (See Uses: Heart Failure, in Spironolactone 24:32.20.)

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 MI or acute coronary syndrome.246,247,248,249,250,252,253,254,256,257,262,304,320,524 (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.86,121,372 (See Cautions: Renal Effects.)

Left Ventricular Dysfunction After Acute Myocardial Infarction

Captopril is used to improve survival following acute MI 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.115,524

Studies with various ACE inhibitors have shown that these drugs reduce fatal and nonfatal cardiovascular events in patients with recent MI.527,803,1100 The magnitude of benefit appears to be greatest in certain high-risk patients (e.g., those with an anterior infarct, ejection fraction of 40% or less, heart failure, prior infarction, or tachycardia).527,805,1100 In addition to their effects on mortality, ACE inhibitors also are used to minimize or prevent the development of left ventricular dilatation and dysfunction (ventricular “remodeling”) following acute MI.246,247,249,250,251,252,253,524,527 Evidence regarding the efficacy of such therapy has been somewhat conflicting,246,247,249,250,251,252,253,294,295,297,298,299,300,301,302 particularly when parenteral therapy was initiated early (within 24-48 hours) and included patients with no evidence of baseline dysfunction.246,249,294,295,297,298,301 (See Uses: Left Ventricular Dysfunction After Acute Myocardial Infarction, in Enalaprilat/Enalapril 24:32.04.) However, the preponderance of evidence has shown a benefit of early oral therapy with ACE inhibitors, even in patients with no baseline dysfunction.246,247,250,251,252,253,292,293,294,295,296,297,298,299,300,301,302,303,304 In a multicenter, controlled study involving captopril in which initiation of therapy with the drug was delayed until 3-16 days after acute MI 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.246,247,294,295,298,299,300,301,302 In several other studies in which captopril was initiated within 24 hours to 4 weeks after acute MI, a beneficial effect also was observed, at least in terms of effects on left ventricular volume and/or infarct expansion.246,247,249,250,251,252,253

Current expert guidelines recommend the use of an oral ACE inhibitor within the first 24 hours of acute MI in patients with an anterior infarction, heart failure, or ejection fraction of 40% or less who do not have any contraindications (e.g., hypotension, shock, renal dysfunction).527 While early treatment within the first 24 hours of MI has been shown to be beneficial, ACE inhibitors should be used with caution (and with gradual upward titration) during the initial postinfarction period because of the possibility of hypotension or renal dysfunction.527,1100 ACE inhibitor therapy generally should be continued indefinitely in all patients with left ventricular dysfunction or other compelling indications for use (e.g., hypertension, diabetes mellitus, CKD).525,1100 The benefits of long-term ACE inhibitor therapy are less certain in low-risk patients who have undergone revascularization and are receiving aggressive antilipemic therapy.527

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).246,248,256,524 Captopril has reduced the development of symptomatic heart failure and associated morbidity and mortality in such patients.246,248,524 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.246,248 (See Uses: Asymptomatic Left Ventricular Dysfunction, in Enalaprilat/Enalapril 24:32.04.) If an ACE inhibitor is not tolerated, then an angiotensin II receptor antagonist is recommended as alternative therapy.524

Other Uses

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).367,368,369 (See Uses: Prevention of Cardiovascular Events, in Ramipril 24:32.04.)

Administration

Captopril is administered orally.115 The manufacturer recommends that the drug be taken 1 hour before meals to ensure maximum absorption.115

Extemporaneously Compounded Oral Liquid

An extemporaneously compounded oral liquid formulation of captopril has been prepared.405,406

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid formulation of captopril have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 1239Multidisciplinary expert panels were convened to determine recommended standard concentrations. 1239Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 1239 For additional information on S4S (including updates that may be available), see [Web].1239

Dosage

Dosage of captopril must be adjusted according to the patient's tolerance and response.

Hypertension

Because of the risk of inducing hypotension, initiation of captopril therapy requires consideration of recent antihypertensive therapy, the extent of blood pressure elevation, sodium intake, fluid status, and other clinical circumstances. Except in patients with severe hypertension, it is recommended that other antihypertensive therapy be discontinued, if possible, 1 week before initiating captopril to minimize the possibility of severe hypotension. If captopril therapy is initiated in patients already receiving a diuretic, treatment with the drug should be initiated under close supervision, following the usual dosage and titration recommendations.115

Concomitant sodium restriction may be helpful when captopril is used alone.115

Captopril Therapy

The manufacturer states that the usual initial adult dosage of captopril for the management of hypertension in adults with normal renal function is 25 mg 2 or 3 times daily.115 However, lower initial dosages (e.g., 6.25 mg twice daily to 12.5 mg 3 times daily) may be effective in some patients, particularly in those already receiving a diuretic. Because the reduction in blood pressure may be gradual, most clinicians do not increase dosage during the first 1-2 weeks of captopril therapy. If blood pressure is not adequately controlled after 1-2 weeks, dosage may be increased to 50 mg 2 or 3 times daily.115 Similar dosages generally have been used in the management of hypertension in geriatric patients, although dosages of 6.25-12.5 mg 1-4 times daily have occasionally been used.175 The manufacturer states that it usually is not necessary to exceed a captopril dosage of 150 mg daily; if blood pressure is not adequately controlled after 1-2 weeks at a dosage of 50 mg 3 times daily, a thiazide diuretic should also be administered in a low dosage (e.g., 15 mg of hydrochlorothiazide daily).115 Because the full effect of a combined dose of therapy with captopril and a diuretic may not be attained for 6-8 weeks, dosage of either drug in a combined regimen generally should be increased no more frequently than every 6 weeks, unless the clinical situation requires more rapid adjustment.258 Diuretic dosage may be increased until its maximum usual antihypertensive dose is reached.115 If further reduction of blood pressure is necessary, dosage of captopril may be increased to 100 mg 2 or 3 times daily and, if necessary, to 150 mg 2 or 3 times daily, while continuing diuretic therapy.115 Although a β-adrenergic blocking agent (β-blocker) may be used with captopril, the hypotensive effects are less than additive and this combination is rarely employed. (See Uses: Hypertension.) For further information on dosage of captopril used in combination therapy, see Captopril/Hydrochlorothiazide Fixed-combination Therapy under Dosage: Hypertension. The usual adult maintenance dosage of captopril recommended by the manufacturers is 25-150 mg 2 or 3 times daily,115 and the maximum dosage is 450 mg daily.115

The need for divided (2 or 3 doses) daily dosing of captopril may deter patient compliance and adequate blood pressure control throughout the day;259,316 optimally, the antihypertensive drug or dosage form should provide 24-hour efficacy with once-daily dosing, with at least 50% of the peak antihypertensive effect remaining at the end of the dosing interval.316,388

Clinical experience with captopril in pediatric patients is limited (see Cautions: Pediatric Precautions), and dosage must be carefully titrated. In general, dosage for children has been reduced in proportion to body weight. Some experts have recommended an initial captopril dosage in infants of 0.05 mg/kg 1-4 times daily and an initial dosage of 0.5 mg/kg 3 times daily in children.1150 Some experts state that the drug should be initiated at the low end of the dosage range and the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage (6 mg/kg per day) is reached, or adverse effects occur.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Captopril/Hydrochlorothiazide Fixed-combination Therapy

When combination therapy is required for the management of hypertension, dosage first can be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, the fixed combination may be used.102 Alternatively, certain fixed-combination preparations containing low doses of captopril and hydrochlorothiazide can be used initially, thereby potentiating the antihypertensive effect of either drug alone while minimizing the likelihood of dose-related adverse effects.316 If combination therapy is initiated with the fixed-combination preparation, the initial adult dosage is 25 mg of captopril and 15 mg of hydrochlorothiazide once daily.102,259 Subsequent dosage can be adjusted by administering each drug separately or by advancing the once-daily administered fixed-combination preparation to that containing captopril and hydrochlorothiazide 50 and 15 mg, respectively; 25 and 25 mg, respectively; or 50 and 25 mg, respectively.102,259 The manufacturer states that dosage adjustments generally should be made at 6-week intervals.102 It may be necessary to administer captopril separately in divided doses in order to maintain adequate trough (prior to a dose) blood pressure control.259 Generally, combined dosage of captopril and hydrochlorothiazide in adults should not exceed 150 and 50 mg daily, respectively.102,259

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with ACE inhibitor monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocking agent, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with captopril, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220 (See General Considerations for Initial and Maintenance Antihypertensive Therapy under Uses: Hypertension.)

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Hypertensive Crises

In adults with severe hypertension (e.g., accelerated or malignant hypertension) in whom prompt blood pressure reduction is indicated or in whom temporary discontinuance of current antihypertensive therapy is not practical or desirable, diuretic therapy should be continued, other hypotensive agents should be discontinued, and captopril should be initiated promptly at a dosage of 25 mg 2 or 3 times daily, under close supervision with frequent monitoring of the patient's blood pressure.115

When necessary, dosage of captopril may be increased at intervals of 24 hours or less under continuous supervision until the optimum blood pressure response is attained or 450 mg daily is given; in this regimen, a diuretic such as furosemide may also be necessary.115 If adequate control of blood pressure is not attained initially with captopril alone or in combination with a diuretic, some clinicians believe that temporary, adjunctive therapy with other hypotensive agents may be necessary.

Although acute captopril therapy (e.g., 12.5-25 mg, repeated once or twice if necessary at intervals of 30-60 minutes or longer) has been used orally231,232,236,259 in adults with hypertensive crises†, including those with severe hypertension in whom reduction of blood pressure was considered urgent† (hypertensive urgencies)231,232,259 or an emergency† (hypertensive emergencies), other management methods generally are preferred for patients with these conditions.233,234,235,236,237,238,259,310,502,542,1200 (See Hypertensive Crises under Uses: Hypertension.)

Diabetic Nephropathy

The recommended dosage of captopril for the long-term treatment of diabetic nephropathy is 25 mg 3 times daily.115,262 If adequate control of blood pressure is not attained with captopril alone, additional hypotensive agents (e.g., diuretics, β-blockers, calcium-channel blocking agents) may be administered concomitantly.115

Heart Failure

For the management of symptomatic heart failure, captopril usually is administered in conjunction with other agents such as a cardiac glycoside, a diuretic, and a β-blocker. Captopril therapy must be initiated under very close medical supervision with consideration given to recent diuretic therapy and the possibility of severe sodium and/or fluid depletion.115,524 ACE inhibitor therapy should be initiated with caution in patients with very low systemic blood pressure (systolic blood pressure less than 80 mm Hg), markedly increased serum concentrations of creatinine (greater than 3 mg/dL), bilateral renal artery stenosis, or elevated concentrations of serum potassium (greater than 5 mEq/L).524 Experts recommend that renal function and serum potassium should be assessed within 1-2 weeks of initiation of therapy and periodically thereafter, especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, or azotemia, or in those taking potassium supplements.524

It should be recognized that although symptoms of heart failure may improve within 48 hours after initiating ACE inhibitor therapy in some patients, such improvement usually is not evident for several weeks or months after initiating ACE inhibitor therapy.333 In addition, it should be considered that such therapy may reduce the risk of disease progression even if symptomatic improvement is not evident.333 Therefore, dosages generally should be titrated to a prespecified target (i.e., 150 mg of captopril daily) or highest tolerated dosage rather than according to response.524

The usual initial adult dosage of captopril recommended by the manufacturer for the management of heart failure in patients with normal renal function is 25 mg 3 times daily.115 In patients with normal or low blood pressure who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, an initial dosage of 6.25 or 12.5 mg 3 times daily may minimize the magnitude or duration of the hypotensive effect; titration to the usual daily dosage can then be made within the next several days.115 Dosage is increased gradually according to the patient's tolerance and response.115 After a dosage of 50 mg 3 times daily is reached, further increases in dosage should be delayed when possible for at least 2 weeks to determine if an adequate response occurs.115

Alternatively, the American College of Cardiology (ACC) and American Heart Association (AHA) recommend that captopril be initiated at low dosage (i.e., 6.25 mg 3 times daily) and titrated gradually upward as tolerated to a maximum dosage of 50 mg 3 times daily.524 It has been recommended that therapy with ACE inhibitors be titrated upwards to dosages that have been shown to reduce the risk of cardiovascular events in clinical trials rather than titrating based on a patient's therapeutic response.524 Most patients have an adequate response with 50 or 100 mg 3 times daily.115 The manufacturer states that a maximum dosage of 450 mg daily should not be exceeded.115 Some experts suggest a maximum dosage of 50 mg 3 times daily in patients with chronic heart failure.524

Alternatively, for the management of heart failure in geriatric patients, some clinicians have initiated captopril therapy at a dosage of 6.25 mg twice daily; if necessary, dosage was increased to 25 mg twice daily after 2 weeks and was subsequently increased if heart failure was not adequately controlled after 4 weeks of therapy at this dosage.190 The median dosage after 12 weeks of therapy in these geriatric patients was 75 mg daily in 2 divided doses.190

Left Ventricular Dysfunction After Acute Myocardial Infarction

When used following acute myocardial infarction (MI) in adults with left ventricular dysfunction, the manufacturer states that captopril therapy may be initiated as early as 3 days following MI.115 When this approach is followed, an initial 6.25-mg dose of captopril should be given, followed by 12.5 mg 3 times daily.115 During the next several days, dosage should be increased to 25 mg 3 times daily and then, during the next several weeks as tolerated, dosage should be increased to 50 mg 3 times daily.115 Some clinicians recommend initiation of therapy within the first 24 hours following MI.527 The recommended maintenance dosage for long-term use following MI is 50 mg 3 times daily.115

Dosage in Renal Impairment

If captopril is used in patients with impaired renal function, doses and/or frequency of administration must be modified in response to the degree of renal impairment and the risk of neutropenia must be considered.115,211 (See Cautions: Precautions and Contraindications.) The initial dosage of captopril should be reduced in these patients (i.e., less than 75 mg daily), and dosage should be slowly increased in small increments at 1- to 2-week intervals.115 After the desired therapeutic effect has been attained, dosage should be slowly decreased to the minimum effective level.115 It has been suggested that, after the minimum effective daily dosage has been determined in patients with impaired renal function, the dosing interval may be increased with appropriate dose modification; however, criteria for dosage adjustment have not been clearly established. Some clinicians suggest that patients with creatinine clearances of 10-50 mL/minute can receive 75% of the usual captopril dosage or the usual dose can be administered every 12-18 hours, and that those with creatinine clearances less than 10 mL/minute can receive 50% of the usual dosage or the usual dose can be administered every 24 hours.211 Patients undergoing hemodialysis may require a supplemental dose after dialysis.211

When combination therapy with captopril and hydrochlorothiazide is required for the management of hypertension in patients with impaired renal function, the risk of precipitating hypotension during initiation of combined therapy should be considered. (See Cautions: Cardiovascular Effects and see Precautions and Contraindications.) Dosages of the drugs should be titrated carefully by slowly increasing the dosage of each drug separately in small increments.102 After the desired therapeutic effect has been attained, the manufacturer recommends that the dosing interval be increased and/or the doses decreased until the minimal effective daily dosage has been achieved. If after careful titration of each drug separately it is determined that the optimum maintenance dosage corresponds to the ratio in commercial combination preparation, the fixed combination may be substituted but should be replaced with the individual drugs if subsequent dosage adjustment is necessary.102 If concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic such as furosemide is preferred to a thiazide diuretic.102 Therefore, use of commercially available preparations containing captopril in fixed combination with hydrochlorothiazide is usually not recommended for patients with severe renal impairment.102

Captopril is generally well tolerated in most patients; however, serious adverse effects (e.g., neutropenia, agranulocytosis, proteinuria, aplastic anemia)228,229,230,231,232 have been reported rarely, mainly in patients with renal impairment (especially those with collagen vascular disease). Captopril-induced adverse effects are often alleviated by dosage reduction, occasionally disappear despite continued treatment and without dosage reduction, and are usually reversible following discontinuance of the drug. The most common adverse effects of captopril are rash1,3,5,7,8,11,23,24,25,26,30,31,32,71,115,122,160,210 and loss of taste perception.1,3,5,11,14,26,30,31,71,115,122 Adverse effects requiring discontinuance of captopril therapy occur in about 4-12% of patients.

Hematologic Effects

Neutropenia (less than 1000 neutrophils/mm³) and agranulocytosis, both associated with myeloid hypoplasia, have occurred rarely in patients receiving captopril.3,5,23,115 In addition to myeloid hypoplasia, erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia) were frequently observed in patients with captopril-induced neutropenia; anemia and thrombocytopenia also occurred occasionally in these patients.115 Systemic or oral cavity infections or other effects associated with agranulocytosis occurred in about half of the patients who developed neutropenia.115

Neutropenia has occurred within 3-12 weeks after beginning treatment with captopril.3,115 The risk of captopril-induced neutropenia appears to depend principally on the degree of renal impairment and the presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma). In clinical studies in patients with some degree of renal impairment (serum creatinine concentration of at least 1.6 mg/dL), neutropenia occurred in about 0.2% of patients, a frequency greater than 15 times that in patients with uncomplicated hypertension who have normal renal function.115 Most of the patients with renal impairment received relatively high dosages, particularly in relation to their renal function; in some reports, the neutropenia was associated with concomitant administration of allopurinol while in other reports this association was not apparent.115 In clinical studies, neutropenia has occurred in about 3.7% of patients with collagen vascular disease and renal impairment.115 Neutropenia has also occurred in some patients receiving captopril for the management of heart failure and the risk factors appear to be similar; about 50% of the patients developing neutropenia had impaired renal function and about 75% were receiving procainamide concomitantly.115

Following discontinuance of captopril and other drugs, the neutrophil count generally returned to normal in about 2 weeks.115 Serious infections have been limited to patients with complex clinical conditions.115 Death has occurred in about 13% of patients who developed neutropenia, but almost all deaths occurred in patients with serious illness who had collagen vascular disease, renal failure, and/or heart failure and/or who were receiving immunosuppressive therapy.115 Although a few patients have been rechallenged with captopril (usually with lower dosages) without recurrence,5,56,60 others have reportedly experienced recurrence, even with lower dosages.59 Although a causal relationship to captopril has not been established, anemia (e.g., aplastic, hemolytic) has been reported in some patients receiving the drug.115

Renal Effects

Proteinuria (total urinary proteins exceeding 1 g/day) has occurred in about 0.7% of patients receiving captopril, and nephrotic syndrome occurred in about one-fifth of these patients.115 About 90% of patients who have developed proteinuria during captopril therapy had evidence of prior renal disease and/or received relatively high dosages of the drug (greater than 150 mg daily).115 If proteinuria develops, it usually occurs by the eighth month of treatment with captopril,1,3,46 consists mainly of albumin,3 and is rarely accompanied by increases in BUN or serum creatinine concentrations.1,3,46 Renal biopsies in some patients who developed proteinuria showed that membranous glomerulopathy was present; however, it was not definitely established that this effect was caused by the drug since these patients did not have pretreatment renal biopsies, and membranous glomerulopathy has occurred in hypertensive patients who did not receive the drug. Proteinuria usually subsides or clears within 6 months whether or not captopril therapy is continued; however, in some patients, it may persist.

Deterioration in renal function, manifested as transient increases in BUN and serum creatinine concentrations may occur following administration of captopril, especially in patients with impaired renal function, sodium depletion, or hypovolemia; patients with renovascular hypertension, particularly those with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney;5,86,115,117,122,123,124,207,208,209,372 or patients with chronic or severe hypertension in whom the glomerular filtration rate may decrease transiently.1,115 This effect was usually reversible following discontinuance of captopril and/or diuretic therapy. Acute reversible renal failure also may occur. Renal function should be monitored closely115,117,122,147,173 during the first few weeks of therapy122,147 and periodically thereafter117,173 in patients with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney. (See Cautions: Precautions and Contraindications.) About 5-15% or 15-30% of patients with mild to moderate or severe heart failure, respectively, treated with an angiotensin-converting enzyme (ACE) inhibitor develop substantial elevations of serum creatinine concentrations (e.g., exceeding 5 mg/dL) and BUN.115,206,333 Some patients with heart failure, including those with severe preexisting renal disease, may require discontinuance of ACE inhibitor therapy, including captopril, because of progressively increasing serum creatinine concentration.115,372 The rapidity of onset and magnitude of captopril-induced renal insufficiency in patients with heart failure may depend in part on the degree of sodium depletion.148,156,206,372

Because the renin-angiotensin system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly during therapy with an ACE inhibitor in these patients.121,148,156,206,372 Such drug-induced deterioration is generally well tolerated, and does not usually necessitate discontinuance of effective therapy with the drug when symptomatic improvement of the heart failure occurs.115,121,148 In addition, the magnitude of deterioration in renal function can usually be ameliorated by reducing the dosage of concomitantly administered diuretics and/or by liberalizing dietary sodium intake, since concomitant diuretic therapy and/or sodium restriction potentially increase the role of angiotensin II in maintaining glomerular filtration in these patients.121,148,206,372 In patients in whom renal perfusion pressure is very low and is further reduced by ACE inhibitor therapy, however, deterioration in renal function may be clinically important.86,87,121,206,372 Patients with concomitant underlying diabetes mellitus may be at risk for developing renal insufficiency during ACE inhibitor therapy;206,372 however, ACE inhibitors, including captopril, have been beneficial in the management of diabetic nephropathy.115,262,334

Although a definite causal relationship to captopril has not been established, renal insufficiency, polyuria, oliguria, and urinary frequency have been reported in about 0.1-0.2% of patients.115

Dermatologic and Sensitivity Reactions

The most common adverse effect of captopril is rash,3,5,7,8,11,23,24,25,26,30,31,32,71,115,122,160 which occurs in about 4-7% of patients (depending on renal function and dosage)115 and is usually maculopapular3,7,11,24,31,115 and rarely urticarial.3,26,32,115 Rash is often accompanied by pruritus3,5,24,115 and erythema7,8,30 and sometimes by fever,3,5,7 arthralgia,115 eosinophilia,3,5,7,115 and/or positive antinuclear antibody (ANA) titers.115,160 Eosinophilia and/or positive ANA titers have been reported in 7-10% of patients with captopril-induced rash.115 The rash occurs most frequently on the upper extremities and trunk3,8 but may occur at other sites.3,26,32 It generally occurs during the first 4 weeks of therapy3,23,115 and has occurred rarely within 30 minutes after the initial dose of the drug.3 The rash is usually mild and disappears within a few days after dosage reduction, short-term treatment with an oral antihistamine, and/or discontinuance of the drug.3,8,24,30,31,32,115 In some patients, the rash may disappear despite continued treatment and without dosage adjustment.3,5,8,115 Although the cause has not been clearly determined, it has been suggested that the rash may be a reaction mediated by kinins.5 Pruritus without rash occurs in about 2% of patients receiving captopril.115

Photosensitivity has occurred, and captopril has been associated with reversible, pemphigoid lesions.115 Bullous pemphigoid also has been reported; however, a causal relationship to the drug has not been established.115

Angioedema of the face, mucous membranes, lips, tongue, larynx, glottis, or extremities has occurred in about 0.1% of patients and may be reversible following discontinuance of therapy.115,333 (See Cautions: Precautions and Contraindications.) Intestinal angioedema (occasionally without a prior history of facial angioedema or elevated serum levels of complement 1 [C1] esterase inhibitor) also has been reported in patients receiving ACE inhibitors.115 Intestinal angioedema, which frequently presents as abdominal pain (with or without nausea or vomiting), usually is diagnosed by abdominal CT scan, ultrasound, or surgery; manifestations usually have resolved after discontinuance of the ACE inhibitor.115 Intestinal angioedema should be considered in the differential diagnosis of patients who develop abdominal pain during therapy with an ACE inhibitor.115

Other hypersensitivity reactions have included vasculitis115,221,222,223,224,225 and hypersensitivity pneumonitis, which was associated with eosinophilia and pulmonary infiltrates.220 Rarely, a serum sickness type of reaction with rash or other dermatologic manifestations, fever, myalgia, arthralgia, interstitial nephritis, increased erythrocyte sedimentation rate (ESR), and/or difficulty in breathing has been reported in patients receiving captopril.5,7,16,32,45,115 Alopecia has occurred, but a causal relationship to the drug has not been established.115

Severe, sudden anaphylactoid reactions, which can be fatal, have been reported following initiation of hemodialysis that utilized a high-flux polyacrylonitrile [PAN] membrane (e.g., AN 69^®) in patients receiving an ACE inhibitor.102,115,242,243,244 Manifestations of these reactions included nausea, abdominal cramps, burning, angioedema, and shortness of breath; progression to severe hypotension can develop rapidly.242,243,244 Dialysis should be stopped immediately and aggressive supportive and symptomatic therapy should be initiated as indicated.242 Antihistamines do not appear to be effective in providing symptomatic relief.242 While it currently does not seem to be necessary to exclude the use of ACE inhibitors in patients undergoing hemodialysis that involves PAN membranes, caution should be exercised during concomitant use.242 The mechanism of this interaction has not been established, and the incidence and risk of its occurrence remain to be elucidated.242 In these patients, consideration should be given to using a different type of dialysis membrane or a drug other than an ACE inhibitor.102,115 In addition, anaphylactoid reactions also have been reported in patients undergoing low-density lipoprotein (LDL) apheresis with dextran sulfate absorption, a procedure utilizing devices not approved in the US.115,275,276,277 Manifestations of these reactions included flushing, dyspnea, bradycardia, and hypotension.275,276,277 It has been postulated that these reactions may be associated with accumulation of polypeptides (e.g., bradykinin) since endogenous concentration of such polypeptides may be increased by LDL-apheresis with dextran sulfate and their metabolism may be decreased by ACE inhibitors.115,275,276 To avoid these anaphylactoid reactions, some clinicians recommend withdrawal of ACE inhibitors 12-30 hours before apheresis,275,277 while others state that ACE inhibitors should not be used in patients treated with LDL apheresis.277

Life-threatening anaphylactoid reactions have been reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.102,155,278 When ACE inhibitors were temporarily discontinued 24 hours before desensitization with the venom, anaphylactoid reactions did not recur; however, such reactions recurred after inadvertent rechallenge.102,155,278

Onycholysis159,183 and dystrophic changes in the fingernails182 have occurred rarely in patients receiving captopril. In at least one patient, these changes were associated with other manifestations of zinc deficiency (e.g., alopecia, asteatosis, dysgeusia, cutaneous eruptions).182 Although serum zinc concentrations were within the normal range in this patient, manifestations of zinc deficiency showed some improvement when captopril dosage was reduced and then gradually resolved when supplemental zinc therapy was initiated.182 However, other manifestations of zinc deficiency have been absent and serum zinc concentrations normal in other patients with nail changes,159,183 and the relationship, if any, of these effects to captopril-induced zinc deficiency has not been established.159,183

Effects on Taste

Decrease in taste acuity, or alteration (persistent metallic or salty taste) or loss of taste perception is another common adverse effect of captopril, occurring in about 2-4% of patients (depending on renal function and dosage).3,5,11,14,26,30,31,115 Taste impairment usually occurs during the first 3 months of therapy;3 it is usually reversible within 2-3 months even when captopril therapy is continued.3,24,26,27,115 In some patients, taste impairment has been associated with subsequent weight loss.3,26,115 The mechanism of taste impairment has not been established.5 In patients not receiving captopril, alterations in taste perception have been associated with decreased plasma zinc concentrations, but normal plasma zinc concentrations have been reported in a few patients with captopril-induced taste impairment and these patients did not respond to oral zinc supplements.

Cardiovascular Effects

Excessive hypotension occurs rarely in hypertensive patients receiving captopril.7,115,116,122,149,150,153,174,175,210 Transient decreases in mean blood pressure greater than 20% may occur in about half of patients with heart failure treated with captopril.85,115,116,148,151,152,154,155,156,173,210 Hypotension has required discontinuance of therapy in about 3-5% of patients with heart failure receiving captopril.85,115,151

Captopril-induced hypotension may occasionally be alleviated by initial dosage reduction (i.e., 6.25 or 12.5 mg 3 times daily),85,115,148,173 but hypotension has also occurred after low doses (i.e., a single 6.25-mg dose) of the drug.153,154,155 Orthostatic hypotension appears to occur more frequently during initiation of therapy85,115,116,122,148,151,153,154,155,156 and in patients with sodium depletion,66,85,115,148,149,150,153,156 hypovolemia,66,85,115,116,122,148,149,150,156 markedly elevated plasma renin or angiotensin II concentration,116,122,148,152,153,155 or overdosage.115 Transient hypotension in patients with heart failure or with hypertension may occur after any of the first several doses and usually is well tolerated, producing no symptoms or occasionally associated with brief, mild lightheadedness or dizziness,85,115,122,148,151,152,154,156,173,210 blurred vision,148 syncope,333 and, rarely, bradycardia152,157 or conduction defects.115 One patient with congestive heart failure who had markedly elevated PRA developed fatal refractory ventricular fibrillation, associated with hypotension, following two 6.25-mg doses of captopril.155 Patients who are volume and/or sodium depleted such as those receiving diuretics, especially those in whom diuretic therapy was recently initiated (e.g., patients with severe congestive heart failure),1,5,17,23,25,31,85,115,116,148,154,156 those whose sodium intake is severely restricted, and those who are undergoing dialysis,66,115 may occasionally experience a precipitous reduction of blood pressure within the first 3 hours after the initial dose of captopril.1,17,23,25,31,115 Symptomatic hypotension that occurs later in a course of captopril therapy (e.g., after the first 48 hours) may indicate the presence of sodium depletion (e.g., secondary to restriction of sodium intake or increased diuretic dosage).148,210

Enalapril, another ACE inhibitor, has produced severe hypotension in patients with severe heart failure with or without renal insufficiency, which was occasionally associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure, myocardial ischemia, and/or death.147,156,184 Captopril, which has a shorter duration of action than enalapril, may have a decreased risk associated with these adverse effects.156 Because of the risk of developing severe hypotension and potential compromise of the patient's hemodynamic status, patients with heart failure should be monitored closely for 2 weeks after initiation of captopril therapy115 and whenever dosage of captopril and/or a concomitantly administered diuretic is increased.85,115,154,156

The possibility of severe hypotension may be minimized by withholding diuretic therapy and/or increasing sodium intake approximately 3-7 days prior to initiating captopril therapy.115,116,148,153 If hypotension occurs in patients receiving captopril, the patient should be placed in the supine115 or Trendelenburg's152 position; if hypotension is severe, IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered.1,115,149,150,152,153,154 Transient hypotension is not a contraindication to additional doses of captopril, and therapy with the drug can be cautiously reinstated after blood pressure has been stabilized (e.g., with volume expansion).115 Asymptomatic hypotension often does not require specific therapy and may be well tolerated with continued captopril therapy;115,148,173 however, severe hypotension occasionally may require discontinuance of captopril therapy.85,115,151,173,174,177 In patients with heart failure, the reduction in blood pressure stabilizes within 1-2 weeks after starting captopril therapy, and blood pressure generally returns to pretreatment levels within 2 months without a decrease in therapeutic efficacy.115 Hypotension may also occur in captopril-treated patients during major surgery or during anesthesia with agents that produce hypotension.115 This hypotensive effect results from inhibition by captopril of the angiotensin II formation that occurs subsequent to compensatory renin release, and, if it is thought to be caused by captopril, can generally be corrected with fluid volume expansion.115

Tachycardia,8,23,27,115 chest pain,8,115 and palpitations115 have each occurred in about 1% of patients receiving captopril.115 Flushing,115 pallor,115 angina pectoris,13,115 myocardial infarction (MI),5,23,115 Raynaud's phenomenon,14,115 and heart failure115 have been reported rarely. Captopril has also produced hyperkinetic circulation (tachycardia, greatly increased cardiac output, and decreased mean blood transit time) in at least one patient with congestive heart failure.58 Although a causal relationship has not been established, other adverse cardiovascular effects that have been reported in patients receiving captopril include cardiac arrest, cerebrovascular accident and/or insufficiency, rhythm disturbances, and syncope.115

Effects on Potassium

Although small increases in serum potassium concentration occur frequently in patients receiving captopril without a thiazide diuretic, hyperkalemia has occurred rarely.5,7,38,69,70,85,115,122,125,126,162,163,164,177 Patients with impaired renal function or heart failure and patients concomitantly receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes) may be at increased risk of developing hyperkalemia during captopril therapy, especially those with diabetes mellitus;38,85,115,125,126,148,162,163,164,372 serum potassium concentration should be monitored carefully in these patients,126,162,163 and potassium intake should be controlled and therapy with drugs that can increase serum potassium modified or discontinued as necessary.85,115,126,148,156,162,163,372 In a clinical trial in patients with type 1 diabetes mellitus who were receiving captopril for proteinuria, the drug was discontinued in about 2% of patients secondary to hyperkalemia.155 However, hyperkalemia was not reported in another trial in normotensive patients with type 1 diabetes mellitus who were receiving captopril for microalbuminuria.115

Respiratory Effects

Cough115,165,166 has been reported in about 0.5-2% of patients receiving captopril.115 However, cough often is overlooked as a potential adverse effect of ACE inhibitors and may occur more frequently (in about 5-15% of patients).165,166,167,185,186,214 The cough generally is persistent and nonproductive and reversible following discontinuance of the drug.102,115 It has been suggested that accumulation of kinins in the respiratory tract secondary to ACE inhibition may in part be responsible for this cough.102,165,166 Concomitant therapy with a nonsteroidal anti-inflammatory agent (i.e., sulindac) appeared to minimize cough in a few patients, but additional study of the safety (e.g., effects on renal function) of such combined therapy is necessary.212 Dyspnea115 and bronchospasm7,165 have been reported rarely during captopril therapy. Angioedema has occurred in 0.1% of patients receiving captopril, and, if associated with laryngeal edema or angioedema of the tongue or glottis, airway obstruction may occur, and angioedema may be fatal.115 (See Cautions: Precautions and Contraindications.)

Hepatic Effects

Hepatitis (including rare cases of hepatic necrosis), cholestasis, jaundice, and elevations in serum concentrations of hepatic enzymes, alkaline phosphatase, and bilirubin have been reported occasionally but have not been directly attributed to the drug, and rare cases of cholestatic jaundice and of hepatocellular injury (with or without secondary cholestasis) have been associated with captopril therapy.115,370

A clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (which occasionally may be fatal) has been reported rarely in patients receiving ACE inhibitors.102,115,370 The mechanism of this reaction is not known.102,115,370

Other Adverse Effects

Hyponatremia (which may be symptomatic) has been reported occasionally in patients receiving captopril; some of these patients had heart failure or were receiving a low-sodium diet or concomitant diuretics. In at least one patient, gynecomastia occurred while receiving captopril, which was reversible following discontinuance of the drug.115,226

Although a causal relationship has not been established, other adverse effects that have occurred rarely in patients receiving captopril include dry mouth, aphthous ulcers, ulceration of the tongue,57 reversible lymphadenopathy, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, dyspepsia, gastric irritation, peptic ulcer, pancreatitis, glossitis, headache, dizziness, paresthesia, malaise, asthenia, myalgia, myasthenia, ataxia, confusion, depression, nervousness, somnolence, blurred vision, impotence, and insomnia.

Precautions and Contraindications

Captopril may cause serious adverse effects (e.g., neutropenia) and must be used under close supervision, particularly in patients with renal impairment (especially those with collagen vascular disease).115 When the drug is used, the risk of neutropenia and agranulocytosis must be considered.115 When captopril is used as a fixed combination that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with captopril.102

Because cough has been associated with the use of many ACE inhibitors, including captopril,102,115,165,166,167,185,186,214 it should be considered in the differential diagnosis of patients who develop cough during captopril therapy.

The possibility that proteinuria can develop and may progress to nephrotic syndrome in patients receiving captopril should be considered, particularly in those with preexisting renal disease or receiving captopril dosages exceeding 150 mg daily.102,115 (See Cautions: Renal Effects.)

Renal function should be evaluated prior to initiation of captopril therapy, and the drug should be used with caution in patients with renal impairment, particularly those with known or suspected renovascular disease.115 Reduction of captopril dosage, reduction in dosage or discontinuance of diuretic therapy, and/or adequate sodium repletion may be necessary in some patients who develop impaired renal function during captopril therapy; it may be impossible to reduce blood pressure to normal levels and maintain adequate renal perfusion.115,156,206,207,209 Because of an increased risk of reducing renal perfusion to a critically low level, captopril should be used with caution and renal function monitored closely for the first few weeks of therapy in patients with bilateral renal-artery stenosis and in those with renal-artery stenosis in a solitary kidney.86,87,115,117,122,123,124 Serum creatinine and electrolyte concentrations should be evaluated prior to and 1 week following initiation of therapy with ACE inhibitors in patients with heart failure.372 In patients with heart failure who have some degree of renal impairment (baseline serum creatinine concentrations less than 2 mg/dL) or more severe renal impairment (baseline serum creatinine concentrations exceeding 2 mg/dL), an increase in serum creatinine concentration exceeding 0.5 or 1 mg/dL, respectively, should prompt consideration of discontinuing ACE inhibitor therapy while additional renal evaluation and corrective action is undertaken.372 The possibility that ACE inhibitors might precipitate severe, sudden, potentially life-threatening anaphylactoid reactions in patients undergoing hemodialysis involving a high-flux membrane should be considered.102,115,242,243,244,372 (See Cautions: Dermatologic and Hypersensitivity Reactions.)

In patients with collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma) or in those receiving other drugs known to affect leukocytes or immune response, particularly those with coexisting impaired renal function, captopril should be used only after an assessment of the benefits and risks, and then with caution.115 If captopril is administered to patients with any of these conditions and/or with impaired renal function, complete and differential leukocyte counts should be performed prior to initiation of therapy, at approximately 2-week intervals for the first 3 months of therapy, and periodically thereafter.115 In other patients receiving captopril, complete leukocyte counts may be performed at approximately 2-week intervals for the first 3 months of therapy and periodically thereafter; differential leukocyte counts should be performed if the complete leukocyte count is less than 4000/mm³ or half of the pretreatment count.1 If the neutrophil count is less than 1000/mm³, captopril should be discontinued and the patient closely monitored.115 Patients should be instructed to notify their clinician if any signs or symptoms of infection such as fever or sore throat occur.115 If infection is suspected, blood cell counts should be performed immediately.115

Because rare cases of cholestatic jaundice and fulminant hepatic necrosis (sometimes fatal) have occurred in patients receiving ACE inhibitors, including captopril, the drug should be discontinued and patients monitored appropriately if jaundice or marked elevations in hepatic enzymes occur during therapy.102,115,370 (See Cautions: Hepatic Effects.)

Captopril should be used with caution in patients with sodium depletion or hypovolemia, those receiving diuretics, and those undergoing dialysis since severe hypotension may occur.66,85,115,148,149,150,153,156,372 The drug should also be used with caution in patients in whom excessive hypotension may have serious consequences (e.g., patients with coronary or cerebrovascular insufficiency).156 ACE inhibitor therapy should be initiated with caution in patients with very low systemic blood pressure (systolic blood pressure less than 80 mm Hg), markedly increased serum concentrations of creatinine (greater than 3 mg/dL), bilateral renal artery stenosis, or elevated concentrations of serum potassium (greater than 5 mEq/L).524 Experts recommend that treatment with an ACE inhibitor be initiated at low doses and gradually titrated upward as tolerated.524 Patients with heart failure should be closely monitored for the first 2 weeks of therapy and whenever the dosage of captopril and/or the diuretic is increased.115 Patients receiving captopril therapy should be informed that vomiting, diarrhea, excessive perspiration, and dehydration may lead to an exaggerated decrease in blood pressure because of fluid volume reduction; patients should notify their clinician if any of these conditions occurs.115 The possibility that patients with aortic stenosis might be at risk of decreased coronary perfusion when treated with captopril should be considered.

Patients receiving captopril should be warned not to interrupt or discontinue therapy unless instructed by their clinician.115 Patients with heart failure receiving captopril should be cautioned against rapid increases in physical activity.115

Although captopril and penicillamine are not pharmacologically related, many adverse effects (e.g., rash, taste impairment, proteinuria) of these drugs are similar. Because captopril and penicillamine contain sulfhydryl groups and are structurally related, it has been suggested that the common toxicities may in part result from the chemical and structural characteristics of the drugs; however, such a relationship has not been clearly determined. Since therapy with ACE inhibitors has been associated with development of a rare syndrome that usually is manifested initially by cholestatic jaundice that may progress to fulminant hepatic necrosis and occasionally may be fatal, patients receiving an ACE inhibitor, including captopril, who develop jaundice or marked elevations of hepatic enzymes should discontinue the drug and receive appropriate medical follow-up.115 (See Cautions: Hepatic Effects.)

Angioedema may occur in patients receiving an ACE inhibitor (e.g., captopril), and, if associated with laryngeal edema, may be fatal.115 If swelling is confined to the extremities, face, lips, and mucous membranes of the mouth, the condition usually responds without treatment.115 Swelling of the tongue, glottis, or larynx may cause airway obstruction, and appropriate therapy (e.g., epinephrine) should be initiated immediately.115 Patients should be informed that swelling of the face, eyes, lips, tongue, larynx, or extremities or difficulty in breathing or in swallowing may be signs and symptoms of angioedema, and that they should discontinue captopril and notify their clinician immediately if any of these conditions occurs.115 The possibility that patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of developing angioedema while receiving the drugs should be considered.

Captopril is contraindicated in patients with known hypersensitivity to the drug or to another ACE inhibitor (e.g., those who experienced angioedema during therapy with another ACE inhibitor).115,524

Pediatric Precautions

Although there is limited clinical experience with captopril in children, safety and efficacy of the drug in children have not been established; however, pediatric dosage was reported to be comparable or less than dosage used in adults when calculated on the basis of body weight.115 Infants, especially neonates, may have increased susceptibility to captopril-induced adverse hemodynamic effects.115 Excessive, prolonged, and unpredictable decreases in blood pressure and associated complications (e.g., oliguria, seizures) have been reported in children receiving the drug.115 The manufacturer states that captopril should be used in children only when other measures for controlling blood pressure have not been effective.115 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Pregnancy, Fertility, and Lactation

Pregnancy

Fetal and neonatal morbidity and mortality have been reported in at least 50 women who were receiving ACE inhibitors during pregnancy.102,115,239,240,241 Very limited epidemiologic data indicate that the rate of fetal and neonatal morbidity resulting from exposure to ACE inhibitors during the second and third trimesters may be as high as 10-20%.239 Hypotension, reversible or irreversible renal failure, anuria, skull hypoplasia, and/or death were reported in neonates whose mothers had received ACE inhibitors during the second and third trimesters of pregnancy.102,115,239,240,241 Other adverse effects associated with such use included oligohydramnios, presumably due to decreased renal function in the fetus,102,115,240,241 prematurity, fetal death, and patent ductus arteriosus; however, it is not known if these effects were associated with ACE inhibition or underlying maternal disease.102,115 Oligohydramnios has been associated with contractures of the limbs, craniofacial deformities, hypoplasia of the lungs, and intrauterine growth retardation.102,115,239,240

Although fetal exposure limited to the first trimester previously was considered not to be associated with substantial risk,102,115,239,240,245 data from an epidemiologic study have shown that infants whose mothers had taken an ACE inhibitor during the first trimester of pregnancy have an increased risk of major congenital malformations compared with infants who had not undergone first trimester exposure to ACE inhibitors.401,402 The risk of major congenital malformations, primarily affecting the cardiovascular and central nervous systems, was increased by about 2.7 times in infants whose mothers had taken an ACE inhibitor during the first trimester of pregnancy compared with infants who had not undergone such exposure.401 Every effort should be made to discontinue captopril therapy as soon as possible in any woman who becomes pregnant while receiving the drug, regardless of the period of gestation.102,115,240,245,401,402 In addition, all women of childbearing potential who are receiving an ACE inhibitor should be advised to report pregnancy to their clinician as soon as possible.102,115,240 Women of childbearing potential who are receiving an ACE inhibitor also should be advised to inform their clinician if they are planning to become pregnant or think they might be pregnant.402 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.239 Rarely (probably less frequently than once in every 1000 pregnancies), no adequate alternative can be identified; in such rare cases, the woman should be informed of the potential hazard to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.102,115,240 If oligohydramnios is present, captopril therapy should be discontinued, unless use of the drug is considered life-saving for the woman.102,115,240 Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling may be performed, if appropriate, depending on the period of gestation.102,115,240 However, both clinicians and patients should realize that oligohydramnios may not become apparent until after irreversible fetal injury already has occurred.102,115,240,245

Infants exposed in utero to ACE inhibitors should be observed closely for hypotension, oliguria, and hyperkalemia.102,115,240 If oliguria occurs, supportive measures (e.g., administration of fluids and pressor agents) to correct hypotension and renal perfusion should be considered.102,115,240 Exchange transfusion or dialysis may be required to reverse hypotension and/or substitute for impaired renal function.102,115,240 Although captopril may be removed by hemodialysis in adults, it is not known if the drug is removed from circulation of neonates or older children by hemodialysis.115 Peritoneal dialysis is not effective in enhancing the elimination of captopril, and it is not known whether the drug may be removed by exchange transfusion.102,115

Reproduction studies in hamsters and rats using 150 and 625 times the maximum human dosage, respectively, of captopril have not revealed evidence of teratogenic effects.115 However, the drug was associated with a low incidence of craniofacial malformations in rabbits when given at dosages 0.8-70 times the maximum human dosage.102,115 Reduction in neonatal survival occurred in the offspring of rats receiving captopril dosages 400 times the usual human dosage continuously during gestation and lactation,115 and an increased incidence of stillbirths has reportedly occurred in ewes.

Fertility

Reproduction studies in rats using captopril have not revealed evidence of impaired fertility.102,115

Lactation

Captopril is distributed into milk in concentrations about 1% of those in maternal blood.115 Because of the potential for serious adverse reactions to captopril in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.115

Hypotensive Agents and Diuretics

When captopril is administered with diuretics or other hypotensive drugs, the hypotensive effect of captopril is increased. The effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly.

Captopril and diuretics appear to have additive hypotensive effects; however, severe hypotension and reversible renal insufficiency may occasionally occur, especially in volume- and/or sodium-depleted patients. (See Cautions: Cardiovascular Effects.) In addition, the duration of hypotensive effect is extended by concomitant diuretic therapy. The hypotensive effects of captopril and β-adrenergic blocking agents (β-blockers) (e.g., propranolol) are less than additive. Hypotensive drugs that cause release of renin (e.g., diuretics) will increase the hypotensive effect of captopril.115 Reduction of captopril dosage and/or dosage reduction or discontinuance of diuretic therapy may be necessary.116,148 Patients should be monitored closely during initiation and dosage adjustment of concomitant therapy with captopril and a diuretic; in patients already receiving diuretics, the risk of these effects may be minimized by withholding diuretic therapy and/or increasing sodium intake for 3-7 days prior to initiating captopril therapy.115,116,148,153

While captopril may have pharmacodynamic interactions in patients receiving diuretics, use of furosemide concurrently with captopril in patients with renal impairment and hypertension does not alter the pharmacokinetics of captopril.115

Hypotensive drugs that affect sympathetic nervous system activity such as ganglionic blocking agents (e.g., trimethaphan camsylate [no longer commercially available in the US]) or adrenergic neuron blocking agents (e.g., guanethidine sulfate) should be used with caution in patients receiving captopril, since the sympathetic nervous system may be especially important in maintaining blood pressure in patients treated with captopril.115

Vasodilating Agents

Data on the effect of concomitant use of captopril and other vasodilators in the management of heart failure are not currently available.115 Pending accumulation of clinical data on such concomitant use, nitroglycerin or other nitrates or other drugs with vasodilating activity (e.g., hydralazine, prazosin) should be discontinued if possible before starting captopril; if such agents are resumed during captopril therapy, they should be administered with caution and possibly at lower dosage.115

Drugs Increasing Serum Potassium Concentration

Since captopril decreases aldosterone secretion, small increases in serum potassium concentration frequently occur, especially in patients with impaired renal function; hyperkalemia has occurred rarely. Potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes should be used with caution in patients receiving captopril and only if hypokalemia is documented, since hyperkalemia may occur; serum potassium should be monitored carefully.85,115,125,126,148,162,163,164 Dosage of the potassium-sparing diuretic and/or potassium supplement should be reduced or the diuretic and/or supplement discontinued as necessary.85,126,148,162,163 Patients with renal impairment may be at increased risk of hyperkalemia.162 If the patient has received spironolactone at any time up to several months before captopril is administered, serum potassium concentration should be determined frequently when captopril is administered since the potassium-sparing effect of spironolactone may persist. However, angiotensin-converting enzyme (ACE) inhibitors have been administered with low-dosage spironolactone therapy and hyperkalemia was reported rarely.329,331,335 (See Uses: Heart Failure.)

Cardiac Glycosides

A study in healthy men revealed no evidence of a pharmacokinetic interaction between captopril and digoxin.115 However, studies in patients with heart failure indicate that serum digoxin concentrations may increase by about 15-30% when captopril and digoxin are used concomitantly.198,199,200 Such increases may result from decreased renal clearance (probably both glomerular filtration and tubular secretion) of digoxin198,200 and, possibly, displacement of the glycoside from tissue-binding sites by captopril-induced increases in serum potassium.198 Captopril has been administered concomitantly with digoxin in patients with heart failure without unusual adverse effects157,173,198,199 or apparent increased risk of cardiac glycoside toxicity.198,199,200 It has been postulated that captopril-induced increases in serum potassium may offset the potential toxic effects of increased serum digoxin concentrations.198,200 Reduction in digoxin dosage does not appear to be necessary when captopril is initiated;198 however, serum digoxin concentrations should be monitored and the patient observed for signs of glycoside toxicity when the drugs are used concomitantly.198,200 Further studies are needed to determine the clinical importance of this potential interaction.200

Nonsteroidal Anti-inflammatory Agents

Because ACE inhibitors may promote kinin-mediated prostaglandin synthesis and/or release, 5,9,30,77,104,114,364 concomitant administration of drugs that inhibit prostaglandin synthesis (e.g., aspirin, ibuprofen) may reduce the blood pressure response to ACE inhibitors, including captopril.283,284,285,286,287,288,289,290,364 Limited data indicate that concomitant administration of ACE inhibitors with nonsteroidal anti-inflammatory agents (NSAIAs) occasionally may result in acute reduction of renal function;285,291 however, the possibility cannot be ruled out that one drug alone may cause such an effect.285,364 Blood pressure should be monitored carefully when an NSAIA is initiated in patients receiving ACE inhibitor therapy; in addition, clinicians should be alert for evidence of impaired renal function.285 Some clinicians suggest that if a drug interaction between an ACE inhibitor and an NSAIA is suspected, the NSAIA should be discontinued, or a different hypotensive agent used or, alternatively, the dosage of the hypotensive agent should be modified.285,286

Aspirin and other NSAIAs also can attenuate the hemodynamic actions of ACE inhibitors in patients with heart failure.333,364 Because ACE inhibitors share and enhance the effects of the compensatory hemodynamic mechanisms of heart failure, with aspirin and other NSAIAs interacting with the compensatory mechanisms rather than with a given ACE inhibitor per se, these desirable mechanisms are particularly susceptible to the interaction and a subsequent potential loss of clinical benefits.364 As a result, the more severe the heart failure and the more prominent the compensatory mechanisms, the more appreciable the interaction between NSAIAs and ACE inhibitors.364 Even if optimal dosage of an ACE inhibitor is used in the treatment of heart failure, the potential cardiovascular and survival benefit may not be seen if the patient is receiving an NSAIA concomitantly.333 In several multicenter studies, concomitant administration of a single 350-mg dose of aspirin in patients with heart failure inhibited favorable hemodynamic effects associated with ACE inhibitors, attenuating the favorable effects of these drugs on survival and cardiovascular morbidity.333,359,364 However, these findings have not been confirmed by other studies. 333,363,364 In one retrospective analysis of pooled data, patients who received an ACE inhibitor concomitantly with aspirin (160- 325 mg daily) during the acute phase following myocardial infarction (MI) had proportional reductions in 7- and 30-day mortality rates comparable to patients who received an ACE inhibitor alone.363,364 Some clinicians have questioned the results of this study because of methodologic concerns (e.g., unsubstantiated assumptions about aspirin therapy [dosage, time of initiation, duration]; disparate distribution of patients).363,364 Although it has been suggested that patients requiring long-term management of heart failure avoid the concomitant use of ACE inhibitors and aspirin (and perhaps substitute another platelet-aggregation inhibitor for aspirin [e.g., clopidogrel, ticlopidine]),364 many clinicians state that existing data are insufficient to recommend a change in the current prescribing practices of clinicians concerning the use of aspirin in patients receiving therapy with an ACE inhibitor.333,706

Antacids

Concomitant oral administration of captopril and antacids may decrease the rate and extent of GI absorption of captopril.197,201 Oral administration of a single, 50-mg dose of captopril 15 minutes after an oral dose of an antacid containing magnesium carbonate and aluminum and magnesium hydroxides resulted in a 40-45% decrease in captopril bioavailability, and a delay and decrease in peak serum concentrations of the drug.197,201 However, there is some evidence that this potential interaction may not be clinically important,197,201 but additional study is necessary.201

Probenecid

Concomitant administration of probenecid may increase blood concentrations of captopril and its metabolites, probably through decreased tubular secretion of captopril and subsequently increased metabolism of the drug (the latter effect probably occurring indirectly as a result of decreased renal clearance of the drug).203,204,205,213 Prolongation of ACE inhibition by captopril213 and possible subsequent potentiation of clinical and toxic effects of the drug may occur during concomitant therapy,203,213 but the potential for such interaction has not been fully elucidated.203,204

Other Drugs

Neuropathy reportedly developed in 2 patients receiving captopril and cimetidine; however, further documentation of this potential interaction is necessary.

Initiation of captopril therapy has been associated with unexplained hypoglycemia in several diabetic patients whose diabetes had been controlled with insulin or oral antidiabetic agents.101 Testing in these patients indicated that captopril may increase insulin sensitivity; the mechanism of this effect is not known.101 The risk of precipitating hypoglycemia should be considered when captopril therapy is initiated in diabetic patients.101

Lithium and an ACE inhibitor (e.g., captopril) should be used concomitantly with caution and serum lithium concentrations should be monitored frequently since elevated serum lithium concentrations and lithium toxicity have occurred following concomitant therapy with the drugs.115 The risk of lithium toxicity in patients receiving captopril may be increased in patients who are also receiving diuretic therapy.115

Laboratory Test Interferences

Captopril may cause false-positive results in urine acetone determinations54,115 using sodium nitroprusside reagent.54

Pharmacology

The mechanism(s) of action of captopril has not been fully elucidated. The drug appears to reduce blood pressure in hypertensive patients and produce beneficial hemodynamic effects in patients with heart failure mainly by suppressing the renin-angiotensin-aldosterone system.

Effects on Renin-Angiotensin-Aldosterone System

Captopril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) by competing with the physiologic substrate (angiotensin I) for the active site of angiotensin-converting enzyme (ACE); the affinity of the drug for ACE is approximately 30,000 times greater than that of angiotensin I.

Inhibition of ACE results in decreased plasma angiotensin II concentrations and, consequently, blood pressure may be reduced in part through decreased vasoconstriction. Plasma renin activity (PRA) increases, possibly as a result of loss of feedback inhibition (mediated by angiotensin II) on the release of renin from the kidneys and/or stimulation of reflex mechanisms via baroreceptors (as a result of the decrease in blood pressure). It has been suggested that the hypotensive effect of ACE inhibitors may in part result from a local effect (e.g., in vascular wall).104,105,106,107,108,109,110,111 By decreasing local angiotensin II production, ACE inhibitors may decrease vascular tone by reducing direct angiotensin II-induced vasoconstriction and/or angiotensin II-induced increases in sympathetic activity.104,105,106,107,108 The hypotensive effect of captopril persists longer than inhibition of ACE in blood; it is not known whether ACE is inhibited longer in vascular endothelium than in blood.

Captopril alone is apparently more effective in reducing blood pressure in patients with high or normal renin hypertension. The drug also may lower blood pressure in patients with low renin hypertension, but these patients are unlikely to respond unless a diuretic is given in conjunction with captopril. A positive correlation between pretreatment PRA and short-term reduction in blood pressure with captopril has been reported4,5,10,14,16,26 and is particularly evident when data from a large number of patients are combined;3,5 the magnitude of the initial decrease in blood pressure appears to be proportional to the pretreatment PRA.5,21,31,77 Although some clinicians have reported a positive correlation between pretreatment PRA and long-term response to captopril, such a correlation has not been consistently found and remains to be clearly established. Some clinicians believe that an individual pretreatment PRA is not useful in predicting a response to captopril because of the wide interpatient variation in PRA values. Since captopril increases PRA, renin profiling should not be performed during captopril therapy.

Decreases in plasma angiotensin II concentrations lead to decreased aldosterone secretion from the adrenal cortex and, therefore, decreased plasma aldosterone concentrations and decreased urinary aldosterone excretion. However, there is increasing evidence to suggest that plasma aldosterone concentrations may not decrease during therapy with usual dosages of ACE inhibitors in some patients and may return to pretreatment levels in others during prolonged therapy.329,335,340,343,344,345,346,347,348,358 It has been suggested that the addition of spironolactone, a drug that competitively inhibits the physiologic effects of aldosterone, appears to augment the suppressive effect of ACE inhibitors on aldosterone.329,330,331,332,335,340,342 The hypotensive effect of captopril may result in part from decreased sodium and water retention as a result of the reduction in aldosterone secretion.3,5,63

Effects on Catecholamines and Autacoids

Circulating plasma norepinephrine concentration is not affected by captopril, and the drug does not inhibit the increase in plasma norepinephrine concentration that results from orthostatic reflexes.16,17,26 However, by inhibiting angiotensin II formation, ACE inhibitors may affect catecholamine release and reuptake by noradrenergic nerve endings104 and/or may decrease vascular sensitivity to vasopressors.104,112,113 There is some evidence that high doses of ACE inhibitors may inhibit presynaptic norepinephrine release and postsynaptic α₂-adrenoceptor activity, thereby interfering with sympathetic reflexes, but the clinical importance of this finding is not known since dosages tested in animals substantially exceed usual human hypotensive dosages.103,104,112

Because ACE also degrades the vasodilator bradykinin, it has been suggested that inhibition of ACE by captopril may cause accumulation of bradykinin in plasma or tissues with resultant vasodilation.4,5,7,10,104,106 However, the effects of captopril on plasma bradykinin concentration have varied, possibly because of the difficulties in measuring bradykinin; the contribution of bradykinin-mediated effects to the hypotensive action of captopril remains to be clearly established. It has been suggested that prostaglandins also may mediate some of the pharmacologic effects of captopril, since there is some evidence that the drug may increase prostaglandin production or release;5,9,30,104,114 prostaglandin release may in part result from increased concentrations of bradykinin.77 Some clinicians have reported that captopril may control blood pressure in patients with renovascular hypertension without affecting urinary excretion of prostaglandin E₂. However, the effects of captopril on prostaglandins have been inconsistent, and further evaluation is necessary to determine the importance of any prostaglandin-mediated effects. (See Drug Interactions: Nonsteroidal Anti-Inflammatory Agents.)

Cardiovascular Effects

In hypertensive patients, captopril reduces blood pressure by decreasing total peripheral resistance with no change or an increase in heart rate, stroke volume, or cardiac output; these effects are independent of pretreatment blood pressure or cardiac output. The drug causes arterial and possibly venous dilation. Captopril generally decreases systolic and diastolic blood pressure by 15-25%; blood pressure is decreased to about the same extent in both the supine and standing positions. Orthostatic hypotension and tachycardia occur infrequently but are more common in sodium-depleted or hypovolemic patients.1,5,17,23,25,31 (See Cautions: Cardiovascular Effects.) Plasma volume has been reported to be unchanged or slightly increased.3,4,23 Animal studies indicate that captopril does not have a direct effect on vascular smooth muscle.3 The drug appears to have no direct effect on baroreceptor sensitivity3,5 although reflex stimulation may occur during captopril therapy.

In patients with heart failure, captopril decreases total peripheral resistance, pulmonary vascular resistance, pulmonary capillary wedge pressure, and mean arterial and right atrial pressures. Cardiac index, cardiac output, stroke volume, and exercise tolerance are increased in these patients; heart rate decreases or is unchanged. The drug may also cause regional redistribution of blood flow, principally increasing renal blood flow with slight or no increase in flow in the forearm or hepatic vasculature, respectively.169

Renal and Electrolyte Effects

Renal blood flow may increase but glomerular filtration rate is usually unchanged during captopril therapy. In some patients, however, both BUN and serum creatinine concentrations have occasionally increased.86,115,118,119,206 Increased BUN and serum creatinine occur more frequently in patients with preexisting renal impairment,86,115,118 in those receiving concomitant therapy with a diuretic,86,116,120,123,206,207,208 and in those with heart failure.115,121 In patients with heart failure and renal perfusion pressures less than 70 mm Hg, changes in creatinine clearance induced by 1-3 months of captopril therapy have varied linearly and inversely with pretreatment PRA; however, creatinine clearance was not substantially affected by the drug in patients with renal perfusion pressures of 70 mm Hg or greater.121 Transient increases in BUN and serum creatinine concentrations are more frequent in patients with renovascular hypotension than in hypertensive patients with normal renal function.86,117,122,123,124 In addition, renal function can markedly deteriorate during therapy with an ACE inhibitor in patients with preexisting, severely compromised renal function.86,87,117 (See Cautions: Renal Effects.) Although anephric patients may respond to captopril immediately following hemodialysis (i.e., when hypovolemia exists), they apparently do not respond to the drug when fluid repleted.65,66,67

Small increases in serum potassium concentration may occur secondary to captopril-induced decreases in aldosterone secretion,1,3,4,5,7,14,17,21,23,25,26,28,115,125,126 especially in patients with impaired renal function.1,115,125,126 Concomitant administration of thiazide diuretics generally offsets this increase.127,130 Captopril apparently does not cause sodium retention. Urinary sodium excretion may be increased during the first 2-3 days of captopril therapy.10,23

Other Effects

Serum prolactin concentration has been reported to increase during captopril therapy.

Pharmacokinetics

Absorption

Approximately 60-75% of an oral dose of captopril is rapidly absorbed from the GI tract in fasting healthy individuals or hypertensive patients.19,20,84,115 Food may decrease absorption of captopril by up to 25-40%,1,3,115,191,195,196,197,202 although there is some evidence that this effect is not clinically important.191,192,195 Following oral administration of a single 100-mg dose of captopril in fasting healthy individuals in one study, average peak blood drug concentrations of 800 ng/mL were attained in 1 hour.19

The hypotensive effect of a single dose of orally administered captopril may be apparent within 15 minutes5,6,16,23 and is usually maximal in 1-2 hours.1,3,10,15,16,17,21,24,29 The duration of action is generally 2-6 hours but appears to increase with increasing doses and has been prolonged up to 12 hours in some patients receiving high doses. The reduction in blood pressure may be gradual, and several weeks of therapy may be required before the full effect of the drug is achieved.1,3,5,16,21,28 The reduction in blood pressure observed with the initial dose of captopril has been reported by some clinicians to be positively correlated with the reduction in blood pressure achieved by long-term therapy with the drug.21,29 Some clinicians have observed a triphasic hypotensive effect during the first 1-2 weeks of therapy: the initial blood pressure reduction in the first few days is followed by a period lasting 3-9 days during which blood pressure increases toward pretreatment levels or remains stable, and then, a further reduction in blood pressure occurs. Because of the apparent resistance that may occur, increases in captopril dosage are usually avoided in the first 1-2 weeks of therapy since the eventual reduction in blood pressure does not reflect the response observed during this period. After withdrawal of the drug, blood pressure gradually returns to pretreatment levels within 1-7 days; rebound hypertension has not been reported to date.

Distribution

Animal studies indicate that captopril is rapidly distributed into most body tissues, except the CNS.1,5 Captopril crosses the placenta in humans and is distributed into milk in concentrations about 1% of maternal blood concentrations.115

Captopril is approximately 25-30% bound to plasma proteins,1,3,22 mainly albumin.3

Elimination

The elimination half-life of unchanged captopril appears to be less than 2 hours in patients with normal renal function.115 The elimination half-life of captopril and its metabolites is correlated with creatinine clearance and increases to about 20-40 hours in patients with creatinine clearances less than 20 mL/minute3 and as long as 6.5 days in anuric patients.5,22

About half the absorbed dose of captopril is rapidly metabolized, mainly to captopril-cysteine disulfide and the disulfide dimer of captopril.3,5,19 In vitro studies suggest that captopril and its metabolites may undergo reversible interconversions.3 It has been suggested that the drug may be more extensively metabolized in patients with renal impairment than in patients with normal renal function.3,22

Captopril and its metabolites are excreted in urine.3,19,20,22,115 Renal excretion of unchanged captopril occurs principally via tubular secretion.170,204 In patients with normal renal function, more than 95% of an absorbed dose is excreted in urine in 24 hours;3,19,115 about 40-50% of the drug excreted in urine is unchanged captopril and the remainder is mainly the disulfide dimer of captopril and captopril-cysteine disulfide.3,115 In one study in healthy individuals, about 20% of a single dose of captopril was recovered in feces in 5 days, apparently representing unabsorbed drug.3,19 Captopril is removed by hemodialysis.1,3

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. ER Squibb & Sons, Inc. Capoten^® prescribing information. Princeton, NJ; 1981 Mar.

3. ER Squibb & Sons, Inc. Capoten^® (captopril) monograph. Princeton, NJ; 1981 Apr.

4. Atkinson AB, Robertson JIS. Captopril in the treatment of clinical hypertension and cardiac failure. Lancet . 1979; 2:836-9. [PubMed 90928]

5. Heel RC, Brogden RN, Speight TM et al. Captopril: a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs . 1980; 20:409-52. [PubMed 7009133]

6. Ferguson RK, Turini GA, Brunner HR et al. A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet . 1977; 1:775-8. [PubMed 66571]

7. Gavras H, Brunner HR, Turini GA et al. Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ 14225 in man. N Engl J Med . 1978; 298:991-5. [PubMed 205788]

8. Larochelle P, Genest J, Kuchel O et al. Effect of captopril (SQ 14225) on blood pressure, plasma renin activity and angiotensin I converting enzyme activity. Can Med Assoc J . 1979; 121:309-16. [PubMed 223756]

9. Swartz S, Williams GH, Hollenberg NK et al. Increase in prostaglandins during converting enzyme inhibition. Clin Sci . 1980; 59(Suppl):133-5S.

10. Brunner HR, Gavras H, Waeber B et al. Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med . 1979; 90:19-23. [PubMed 217289]

11. Johnston CI, Millar JA, McGrath BP et al. Long-term effects of captopril (SQ 14225) on blood-pressure and hormone levels in essential hypertension. Lancet . 1979; 2:493-6. [PubMed 90216]

12. McCaa CS, Langford HG, Cushman WC et al. Response of arterial blood pressure, plasma renin activity and aldosterone concentration to long-term administration of captopril to patients with severe, treatment-resistant malignant hypertension. Clin Sci . 1979; 57(Suppl):371-3S.

13. Fagard R, Amery A, Reybrouck T et al. Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients. Am J Cardiol . 1980; 46:295-300. [PubMed 6250392]

14. Maruyama A, Ogihara T, Naka T et al. Long-term effects of captopril in hypertension. Clin Pharmacol Ther . 1980; 28:316-23. [PubMed 6996895]

15. Mimran A, Brunner HR, Turini GA et al. Effect of captopril on renal vascular tone in patients with essential hypertension. Clin Sci . 1979; 57(Suppl):421-3S. [PubMed 519950]

16. Case DB, Atlas SA, Laragh JH et al. Clinical experience with blockade of the renin-angiotensin-aldosterone system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in hypertensive patients. Prog Cardiovasc Dis . 1978; 21:195-206. [PubMed 214819]

17. Morganti A, Pickering TG, Lopez-Ovejero JA et al. Endocrine and cardiovascular influences of converting enzyme inhibition with SQ 14225 in hypertensive patients in the supine position and during head-up tilt before and after sodium depletion. J Clin Endocrinol Metab . 1980; 50:748-54. [PubMed 6245101]

19. Kripalani KJ, McKinstry DN, Singhvi SM et al. Disposition of captopril in normal subjects. Clin Pharmacol Ther . 1980; 27:636-41. [PubMed 6989546]

20. McKinstry DN, Kripalani KJ, Migdalof BH et al. The effect of repeated administration of captopril (CP) on its disposition in hypertensive patients. Clin Pharmacol Ther . 1980; 27:270-1.

21. Case DB, Atlas SA, Laragh JH et al. Use of first-dose response or plasma renin activity to predict the long-term effect of captopril: identification of triphasic pattern of blood pressure response. J Cardiovasc Pharmacol . 1980; 2:339-46. [PubMed 6156332]

22. Rommel AJ, Pierides AM, Heald A et al. Captopril elimination in chronic renal failure. Clin Pharmacol Ther . 1980; 27:282.

23. Ferguson RK, Vlasses PH. Clinical pharmacology and therapeutic applications of the new oral angiotensin converting enzyme inhibitor, captopril. Am Heart J . 1981; 101:650-6. [PubMed 6261570]

24. Ferguson RK, Vlasses PH, Koplin JR et al. Captopril in severe treatment-resistant hypertension. Am Heart J . 1980; 99:579-85. [PubMed 6989221]

25. Brunner HR, Waeber B, Wauters JP et al. Inappropriate renin secretion unmasked by captopril (SQ 14,225) in hypertension of chronic renal failure. Lancet . 1978; 2:704-7. [PubMed 80634]

26. MacGregor GA, Markandu ND, Roulston JE et al. Essential hypertension: effect of an oral inhibitor of angiotensin-converting enzyme. Br Med J . 1979; 2:1106-9. [PubMed 229941]

27. Atkinson AB, Brown JJ, Lever AF et al. Combined treatment of severe intractable hypertension with captopril and diuretic. Lancet . 1980; 2:105-8. [PubMed 6105291]

28. White NJ, Rajagopalan B, Yahaya H et al. Captopril and furosemide in severe drug-resistant hypertension. Lancet . 1980; 2:108-10. [PubMed 6105292]

29. Koffer H, Vlasses PH, Ferguson RK et al. Captopril in diuretic-treated hypertensive patients. JAMA . 1980; 244:2532-5. [PubMed 7001071]

30. Swartz SL, Williams GH, Hollenberg NK et al. Endocrine profile in the long-term phase of converting-enzyme inhibition. Clin Pharmacol Ther . 1980; 28:499-508. [PubMed 6250761]

31. Jenkins AC, McKinstry DN. Review of clinical studies of hypertensive patients treated with captopril. Med J Aust . 1979; 2(Suppl):32-7.

32. Friedlander D. Captopril and propranolol in mild and moderate essential hypertension: preliminary report. N Z Med J . 1979; 90:146-9. [PubMed 386192]

38. Dzau VJ, Colucci WS, Williams GH et al. Sustained effectiveness of converting-enzyme inhibition in patients with severe congestive heart failure. N Engl J Med . 1980; 302:1373-9. [PubMed 6246425]

42. Lopez-Ovejero JA, Saal SD, D'Angelo WA et al. Reversal of vascular and renal crises of scleroderma by oral angiotensin-converting-enzyme blockade. N Engl J Med . 1979; 300:1417-9. [PubMed 220537]

43. D'Angelo WA, Lopez-Ovejero JA, Saal SD et al. Early versus late treatment of scleroderma renal crisis and malignant hypertension with captopril. Arthritis Rheum . 1980; 23:664.

44. Whitman HH, Case DB, Botstein G et al. Variable response to oral converting enzyme blockade in hypertensive scleroderma patients. Arthritis Rheum . 1980; 23:762-3.

45. Hoorntje SJ, Weening JJ, Kallenberg CGM et al. Serum-sickness-like syndrome with membranous glomerulopathy in patient on captopril. Lancet . 1979; 2:1297.

46. Case DB, Atlas SA, Mouradian JA et al. Proteinuria during long-term captopril therapy. JAMA . 1980; 244:346-9. [PubMed 6993700]

54. Warren SE. False-positive urine ketone test with captopril. N Engl J Med . 1980; 303:1003-4. [PubMed 6997747]

56. Case DB, Whitman HH III, Laragh JH et al. Successful low dose captopril rechallenge following drug-induced leucopenia. Lancet . 1981; 1:1362-3.

57. Nicholls MG, Maslowski AH, Ikram H et al. Ulceration of the tongue—a complication of captopril therapy. Ann Intern Med . 1981; 94:659. [PubMed 7015949]

58. Fouad FM, Salcedo EE, Saragoca M et al. Hyperkinetic circulation associated with captopril therapy for congestive heart failure. N Engl J Med . 1981; 305:405-6. [PubMed 7019709]

59. Forslund T, Borgmastars H, Fyhrquist F. Captopril-associated leukopenia confirmed by rechallenge in patient with renal failure. Lancet . 1981; 1:166. [PubMed 6109854]

60. Edwards CRW, Drury P, Penketh A et al. Successful reintroduction of captopril following neutropenia. Lancet . 1981; 1:723. [PubMed 6110936]

63. Harris C, Smith GH. Captopril. Drug Intell Clin Pharm . 1981; 15:932-9. [PubMed 7040022]

65. Man In't Veld AJ, Wenting GJ, Schalerkamp MADH. Does captopril lower blood pressure in anephric patients? Br Med J . 1979; 2:1110.

66. Man In't Veld AJ, Schicht IM, Derkx FHM et al. Effects of an angiotensin-converting enzyme inhibitor (captopril) on blood pressure in anephric subjects. Br Med J . 1980; 280:288-90. [PubMed 6986949]

67. Leslie BR, Case DB, Sullivan JF et al. Absence of blood-pressure lowering effect of captopril in anephric patients. Br Med J . 1980; 280:1067-8. [PubMed 6992919]

69. Grossman A, Eckland D, Price P et al. Captopril: reversible renal failure with severe hyperkalemia. Lancet . 1980; 1:712. [PubMed 6103125]

70. Warren SE, O'Connor DT. Hyperkalemia resulting from captopril administration. JAMA . 1980; 244:2551-2. [PubMed 7001073]

71. Anon. Captopril: benefits and risks in severe hypertension. Lancet . 1980; 2:129-30. [PubMed 6105297]

77. Vidt DG, Bravo EL, Fouad FM. Captopril. N Engl J Med . 1982; 306:214-9. [PubMed 7033784]

84. Duchin KL, Singhvi SM, Willard DA et al. Captopril kinetics. Clin Pharmacol Ther . 1982; 31:452-8. [PubMed 7037265]

85. Romankiewicz JA, Brogden RN, Heel RC et al. Captopril: an update review of its pharmacological properties and therapeutic efficacy in congestive heart failure. Drugs . 1983; 25:6-40. [PubMed 6218982]

86. Hricik DE, Browning PJ, Kopelman R et al. Captopril-induced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl J Med . 1983; 308:373-6. [PubMed 6337327]

87. Blythe WB. Captopril and renal autoregulation. N Engl J Med . 1983; 308:390-1. [PubMed 6337329]

101. Ferriere M, Lachkar H, Richard JL et al. Captopril and insulin sensitivity. Ann Intern Med . 1985; 102:134-5. [PubMed 3881067]

102. Par Pharmaceutical, Inc. Capozide^® (captopril and hydrochlorothiazide) 25/15, 25/25, 50/15, 50/25 prescribing information. Spring Valley, NY; 2002 Jul.

103. De Jonge A, Wilffert B, Kalkman HO et al. Captopril impairs the vascular smooth muscle contraction mediated by postsynaptic α₂-adrenoceptors in the pithed rat. Eur J Pharmacol . 1981; 74:385-6. [PubMed 6271562]

104. Dzau VJ. Significance of the vascular renin-angiotensin pathway. Hypertension . 1986; 8:553-9. [PubMed 3013773]

105. Riley LJ Jr, Vlasses PH, Ferguson RK. Clinical pharmacology and therapeutic applications of the new oral converting enzyme inhibitor, enalapril. Am Heart J . 1985; 109:1085-9. [PubMed 2986440]

106. Antonaccio MJ, Asaad M, Rubin B et al. Captopril: factors involved in its mechanism of action. In: Horovitz ZP, ed. Angiotensin converting enzyme inhibitors. Baltimore-Munich: Urban/Schwarzenberg; 1981:161-80.

107. Unger T, Ganten D, Lang RE et al. Is tissue converting enzyme inhibition a determinant of the antihypertensive efficacy of converting enzyme inhibitors? Studies with the two different compounds, Hoe 498 and Mk 421, in spontaneously hypertensive rats. J Cardiovasc Pharmacol . 1984; 6:872-80. [PubMed 6209494]

108. Unger T, Ganten D, Lang RE et al. Persistent tissue converting enzyme inhibition following chronic treatment with Hoe498 and MK421 in spontaneously hypertensive rats. J Cardiovasc Pharmacol . 1985; 7:36-41. [PubMed 2580148]

109. Cohen ML, Kurz KD. Angiotensin converting enzyme inhibition in tissue from spontaneously hypertensive rats after treatment with captopril or MK-421. J Pharmacol Exp Ther . 1982; 220:63-9. [PubMed 6273529]

110. Velletri P, Bean BL. The effects of captopril on rat aortic angiotensin-converting enzyme. J Cardiovasc Pharmacol . 1982; 4:315-25. [PubMed 6175817]

111. Okamura T, Miyazaki M, Inagami T et al. Vascular renin-angiotensin system in two-kidney, one clip hypertensive rats. Hypertension . 1986; 8:560-5. [PubMed 3013774]

112. Antonaccio MJ, Kerwin L. Pre- and post junctional inhibition of vascular sympathetic function by captopril in SHR: implication of vascular angiotensin II in hypertension and antihypertensive actions of captopril. Hypertension . 1981; 3(Suppl I):I54-62. [PubMed 6167515]

113. Imai Y, Abe K, Seino M et al. Attenuation of pressor responses to norepinephrine and pitressin and potentiation of pressor response to angiotensin II by captopril in human subjects. Hypertension . 1982; 4:444-51. [PubMed 7040234]

114. Moore TJ, Crantz FR, Hollenberg NK et al. Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Hypertension . 1981; 3:168-73. [PubMed 6260645]

115. Par Pharmaceutical, Inc. Capoten^® (captopril) tablets prescribing information. Spring Valley, NY; 2003 Jun.

116. Hansten PD, Horn JR. Angiotensin converting enzyme (ACE) inhibitors captopril (Capoten) enalapril (Vasotec). Drug Interact Newsl . 1986; 6(Updates):U17-8.

117. Schreiber MJ Jr, Fang LST. Renal failure associated with captopril. JAMA . 1983; 250:31.

118. Steinman TI, Silva M. Acute renal failure, skin rash, and eosinophilia associated with captopril therapy. Am J Med . 1983; 75:154-6. [PubMed 6222649]

119. Verbeelen DL, deBoel S. Reversible acute on chronic renal failure during captopril treatment. BMJ . 1984; 289:20-1. [PubMed 6428648]

120. Murphy BF, Whitworth JA, Kincaid-Smith P. Renal insufficiency with combinations of angiotensin converting enzyme inhibitors and diuretics. BMJ . 1984; 288:844-5. [PubMed 6322905]

121. Packer M, Lee WH, Kessler PD. Preservation of glomerular filtration rate in human heart failure by activation of the renin-angiotensin system. Circulation . 1986; 74:766-74. [PubMed 3019586]

122. Frohlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med . 1984; 144:1441-4. [PubMed 6233948]

123. Watson ML, Bell GM, Muir AL et al. Captopril/diuretic combinations in severe renovascular disease: a cautionary note. Lancet . 1983; 2:404-5. [PubMed 6135901]

124. Jackson B, Matthews PG, McGrath BP et al. Angiotensin converting enzyme inhibition in renovascular hypertension: frequency of reversible renal failure. Lancet . 1984; 1:225-6. [PubMed 6198567]

125. Zanella MT, Mattei E Jr, Draibe SA et al. Inadequate aldosterone response to hyperkalemia during angiotensin converting enzyme inhibition in chronic renal failure. Clin Pharmacol Ther . 1985; 38:613-7. [PubMed 2998675]

126. Textor SC, Bravo EL, Fouad FM et al. Hyperkalemia in azotemic patients during angiotensin-converting enzyme inhibition and aldosterone reduction with captopril. Am J Med . 1982; 73:719-25. [PubMed 6291388]

127. Santucci A, Aguglia F, de Mattia G et al. Long-term captopril treatment in moderate to severe hypertension. Br J Clin Pharmacol . 1982; 14(Suppl 2):775-9.

128. Irvin JD, Viau JM. Safety profiles of the angiotensin converting enzyme inhibitors captopril and enalapril. Am J Med . 1986; 81(Suppl 4C):46-50. [PubMed 3022584]

129. Gavras I, Gavras H. Clinical utility of angiotensin converting enzyme inhibitors in hypertension. Am J Med . 1986; 81(Suppl 4C):28-31. [PubMed 3022582]

130. Weinberger MH. Comparison of captopril and hydrochlorothiazide alone and in combination in mild to moderate essential hypertension. Br J Clin Pharmacol . 1982; 14(Suppl 2):127S-31. [PubMed 6753893]

131. Anon. Drugs for hypertension. Med Lett Drugs Ther . 1984; 26:107-12. [PubMed 6150424]

132. Moser M. Initial treatment of adult patients with essential hypertension. Part 1: why conventional stepped-care therapy of hypertension is still indicated. Pharmacotherapy . 1985; 5:189-95. [PubMed 2863806]

133. Kaplan NM. Initial treatment of adult patients with essential hypertension. Part 2: alternating monotherapy is the preferred treatment. Pharmacotherapy . 1985; 5:195-200. [PubMed 4034407]

134. Bauer JH. Stepped-care approach to the treatment of hypertension: is it obsolete? (unpublished observations)

135. World Health Organization/International Society of Hypertension Fourth Mild Hypertension Conference. 1986 guidelines for the treatment of mild hypertension: memorandum from the WHO/ISH. Hypertension . 1986; 8:957-61.

137. Andren L, Karlbert B, Ohman P et al. Captopril and atenolol combined with hydrochlorothiazide in essential hypertension. Br J Clin Pharmacol . 1982; 14(Suppl 2):107-11S. [PubMed 7104162]

138. Stumpe KO, Overlack A, Kolloch R et al. Long-term efficacy of angiotensin-converting enzyme inhibition with captopril in mild-to-moderate essential hypertension. Br J Clin Pharmacol . 1982; 14(Suppl 2):121-6S.

139. Veterans Administration Co-operative Study Group On Antihypertensive Agents. Racial differences in response to low-dose captopril are abolished by the addition of hydrochlorothiazide. Br J Clin Pharmacol . 1982; 14(Suppl 2):97-101S. [PubMed 7049210]

140. Chrysant SG, Danisa K, Kem DC et al. Racial differences in pressure, volume and renin interrelationships in essential hypertension. Hypertension . 1979; 1:136-41. [PubMed 399939]

141. Bauer JH, Reams GP. Antihypertensive treatment in patients with renal disease: control of glomerular hypertension. Kidney . (in press)

142. Taguma Y, Kitamotoa Y, Futaki G et al. Effect of captopril on heavy proteinuria in azotemic diabetics. N Engl J Med . 1985; 313:1617-20. [PubMed 3906398]

143. Bauer JH. Role of angiotensin converting enzyme inhibitors in essential and renal hypertension. Am J Med . 1984; 77(Suppl 2A):43-51. [PubMed 6206722]

144. Bauer JH, Reams GP. Renal effects of angiotensin converting enzyme inhibitors in hypertension. Am J Med . 1986; 81(Suppl 4C):19-27. [PubMed 3022581]

145. Thind GS, Johnson A, Bhatnagar D et al. A parallel study of enalapril and captopril and 1 year of experience with enalapril treatment in moderate-to-severe essential hypertension. Am Heart J . 1985; 109:852-8. [PubMed 2984913]

146. Cooper RA. Captopril associated neutropenia: who is at risk? Arch Intern Med . 1983; 143:659-60. Editorial.

147. Merck Sharp & Dohme. Vasotec^® (enalapril maleate) prescribing information. West Point, PA; 1985 Dec.

148. Packer M, Kessler PD, Gottlieb SS. Adverse effects of converting-enzyme inhibition in patients with severe congestive heart failure: pathophysiology and management. Postgrad Med J . 1986; 62(Suppl 1):179-82. [PubMed 3022272]

149. McMurray J, Matthews DM. Effect of diarrhoea on a patient taking captopril. Lancet . 1985; 1:581. [PubMed 2857931]

150. Benett PR, Cairns SA. Captopril, diarrhoea, and hypotension. Lancet . 1985; 1:1105. [PubMed 2860320]

151. Captopril Multicenter Research Group. ACE-inhibitor captopril in refractory congestive heart failure. J Am Coll Cardiol . 1983; 2:755. [PubMed 6350401]

152. Cleland J, McAlpine H, Semple P et al. First dose hypotension with angiotensin converting enzyme inhibitors in heart failure. Br Heart J . 1985; 53:672-3.

153. Hodsman GP, Isles CG, Murray GD et al. Factors related to first dose hypotensive effect of captopril: prediction and treatment. BMJ . 1983; 286:832-4. [PubMed 6403103]

154. Cody RJ, Franklin KW, Laragh JH. Postural hypotension during tilt with chronic captopril and diuretic therapy of severe congestive heart failure. Am Heart J . 1982; 103:480-4. [PubMed 7039281]

155. LaBarre TR, O'Connell JB, Gunnar RM. Captopril therapy for severe CHF: hypotensive response in presence of markedly elevated PRA. Am Heart J . 1982; 103:308-10. [PubMed 7034517]

156. Packer M, Lee WH, Yushak M et al. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med . 1986; 315:847-53. [PubMed 3018566]

157. Ader R, Chatterjee K, Ports T et al. Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulation . 1980; 61:931-7. [PubMed 6244906]

158. Chrysant SG, Dunn M, Marples D et al. Severe reversible azotemia from captopril therapy. Report of three cases and review of the literature. Arch Intern Med . 1983; 143:437-41. [PubMed 6338847]

159. Borders JV. Captopril and onycholysis. Ann Intern Med . 1986; 105:305-6. [PubMed 3524344]

160. Goodfield MJ, Millard LG. Severe cutaneous reactions to captopril. BMJ . 1985; 290:1111. [PubMed 3157419]

161. Rahmat J, Gelfand RL, Gelfand MC et al. Captopril-associated cholestatic jaundice. Ann Intern Med . 1985; 102:56-8. [PubMed 3881069]

162. Hansten PD, Horn JR. Captopril (Capoten) interactions. Drug Interact Newsl . 1985; 5(Updates):U10-1.

163. Burnakis TG, Mioduch JM. Combined therapy with captopril and potassium supplementation. Arch Intern Med . 1984; 144:2371-2. [PubMed 6391404]

164. Vlasses PH, Ferguson RK, Chatterjee K. Captopril: clinical pharmacology and benefit-to-risk ratio in hypertension and congestive heart failure. Pharmacotherapy . 1982; 2:1-17. [PubMed 6765388]

165. Sesoko S, Kaneko Y. Cough associated with the use of captopril. Arch Intern Med . 1985; 145:1524. [PubMed 3896184]

166. Semple PF, Herd GW. Cough and wheeze caused by inhibitors of angiotensin-converting enzyme. N Engl J Med . 1986; 314:61. [PubMed 2999601]

167. Reviewers' comments on enalapril maleate (personal observations); 1986 Nov.

168. Packer M, Medina N, Yushak M. Relation between serum sodium concentration and the hemodynamic and clinical responses to converting enzyme inhibition with captopril in severe heart failure. J Am Coll Cardiol . 1984; 3:1035-43. [PubMed 6323565]

169. Creager MA, Halperin JL, Bernard DB et al. Acute regional circulatory and renal hemodynamic effects of converting-enzyme inhibition in patients with congestive heart failure. Circulation . 1981; 64:483-9. [PubMed 6266691]

170. Singhui SM, Duchin KL, Willard DA et al. Renal handling of captopril: effect of probenecid. Clin Pharmacol Ther . 1982; 32:182-9. [PubMed 7047044]

171. Croog SH, Levine S, Testa MA et al. The effects of antihypertensive therapy on the quality of life. N Engl J Med . 1986; 314:1657-64. [PubMed 3520318]

172. Chobanian AV. Antihypertensive therapy in evolution. N Engl J Med . 1986; 314:1701-2. [PubMed 3713773]

173. The Captopril Multicenter Research Group I. A cooperative study of captopril in congestive heart failure: hemodynamic effects and long-term response. Am Heart J . 1985; 110:439-47. [PubMed 3895877]

174. Jenkins AC, Dreslinski GR, Tadros SS et al. Captopril in hypertension: seven years later. J Cardiovasc Pharmacol . 1985; 7(Suppl 1):S96-101. [PubMed 2580185]

175. Jenkins AC, Knill JR, Dreslinski GR. Captopril in the treatment of the elderly hypetensive patient. Arch Intern Med . 1985; 145:2029-31. [PubMed 3904655]

177. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Low-dose captopril for the treatment of mild to moderate hypertension. I. Results of a 14-week trial. Arch Intern Med . 1984; 144:1947-53. [PubMed 6237623]

178. Drayer JI, Weber MA. Monotherapy of essential hypertension with a converting-enzyme inhibitor. Hypertension . 1983; 5(Suppl 2):III108-13.

179. Holland OB, von Kuhnert L, Campbell WB et al. Synergistic effect of captopril with hydrochlorothiazide for the treatment of low-renin hypertensive black patients. Hypertension . 1983; 5:235-9. [PubMed 6337951]

180. Moser M, Lunn J. Responses to captopril and hydrochlorothiazide in black patients with hypertension. Clin Pharmacol Ther . 1982; 32:307-12. [PubMed 7049502]

181. Weinberger MH. Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients. J Cardiovasc Pharmacol . 1985; 7(Suppl 1):S52-5. [PubMed 2580177]

182. Smit AJ, Hoountje SJ, Donker AJ. Zinc deficiency during captopril treatment. Nephron . 1983; 34:196-7. [PubMed 6348568]

183. Brueggemeyer CD, Ramirez G. Onycholysis associated with captopril. Lancet . 1984; 1:1352-3. [PubMed 6145047]

184. Di Carlo L, Chatterjee K, Parmley WW et al. Enalapril: a new angiotensin-converting enzyme inhibitor in chronic heart failure: acute and chronic hemodynamic evaluations. J Am Coll Cardiol . 1983; 2:865-71. [PubMed 6313787]

185. Webb D, Benjamin N, Collier J et al. Enalapril-induced cough. Lancet . 1986; 2:1094. [PubMed 2877240]

186. Cruickshank JM. Antihypertensive therapy and quality of life. N Engl J Med . 1987; 316:53.

187. Hommel E, Parving HH, Mathiesen E et al. Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy. BMJ . 1986; 293:467-70. [PubMed 3091164]

188. Bjorck S, Nyberg G, Mulec H et al. Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy. BMJ . 1986; 293:471-4. [PubMed 3017501]

189. O'Hare JA. Captopril and diabetic proteinuria: a correction. N Engl J Med . 1987; 316:52. [PubMed 3785349]

190. Murphy PJ, van der Cammen T, Malone-Lee J. Captopril in elderly patients with heart failure. BMJ . 1986; 293:239-40. [PubMed 3089469]

191. Ohman KP, Kagedal B, Larsson R et al. Pharmacokinetics of captopril and its effects on blood pressure during acute and chronic administration and in relation to food intake. J Cardiovasc Pharmacol . 1985; 7(Suppl 1):S20-4. [PubMed 2580171]

192. Salvetti A, Pedrinelli R, Magagna A et al. Influence of food on acute and chronic effects of captopril in essential hypertensive patients. J Cardiovasc Pharmacol . 1985; 7(Suppl 1):S25-9. [PubMed 2580172]

193. MacGregor GA, Markandu ND, Banks RA et al. Captopril in essential hypertension; contrasting effects of adding hydrochlorothiazide or propranolol. BMJ . 1982; 284:693-6. [PubMed 6802291]

194. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Racial differences in response to low-dose captopril are abolished by the addition of hydrochlorothiazide. Br J Clin Pharmacol . 1982; 14(Suppl): 97-101S.

195. Kubo SH, Cody RJ. Clinical pharmacokinetics of the angiotensin converting enzyme inhibitors: a review. Clin Pharmacokinet . 1985; 10:377-91. [PubMed 2994938]

196. Singhvi SM, McKinstry DN, Shaw JM et al. Effect of food on the bioavailability of captopril in healthy subjects. J Clin Pharmacol . 1982; 22:135-40. [PubMed 7040498]

197. Mantyla R, Mannisto PT, Vuorela A et al. Impairment of captopril bioavailability by concomitant food and antacid intake. Int J Clin Pharmacol Ther Toxicol . 1984; 22:626-9. [PubMed 6389377]

198. Cleland JGF, Dargie HJ, Pettigrew A et al. The effects of captopril on serum digoxin and urinary urea and digoxin clearances in patients with congestive heart failure. Am Heart J . 1986; 112:130-5. [PubMed 3524169]

199. Cleland JGF, Dargie HJ, Hodsman GP et al. Interaction of digoxin and captopril. Br J Clin Pharmacol . 1983; 17:214P.

200. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1987(Oct):204a.

201. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1987(Jul):125a.

202. Williams GM, Sugerman AA. The effect of a meal, at various times relative to drug administration, on the bioavailability of captopril. J Clin Pharmacol . 1982; 22:18A.

203. Mangini RJ, ed. Drug interaction facts. St. Louis: JB Lippincott Co; 1987(Jul):127.

204. Singhvi SM, Duchin KL, Willard DA et al. Renal handling of captopril: effect of probenecid. Clin Pharmacol Ther . 1982; 32:182-9. [PubMed 7047044]

205. Johnston CI, Arnolda L, Hiwatari M. Angiotensin-converting enzyme inhibitors in the treatment of hypertension. Drugs . 1984; 27:271-7. [PubMed 6323123]

206. Packler M, Lee WH, Medina M et al. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern Med . 1987; 106:346-54. [PubMed 3028221]

207. Hricik DE. Captopril-induced renal insufficiency and the role of sodium balance. Ann Intern Med . 1985; 103:222-3. [PubMed 3893255]

208. Spital A. Captopril-induced renal insufficiency. Ann Intern Med . 1986; 104:126. [PubMed 3510053]

209. Hricik DE. Captopril-induced renal insufficiency. Ann Intern Med . 1986; 104:126. [PubMed 3510053]

210. The Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA . 1988; 259:539-44. [PubMed 2447297]

211. Bennett WM, Aronoff GR, Golper TA et al. Drug prescribing in renal failure: dosing guidelines for adults. Philadelphia: American College of Physicians; 1987:36-7.

212. Nicholls MG, Gilchrist NL. Sulindac and cough induced by converting enzyme inhibitors. Lancet . 1987; 1:872. [PubMed 2882285]

213. Drummer OH, Thompson J, Hooper R et al. Effect of probenecid on the disposition of captopril dimer in the rat. Biochem Pharmacol . 1985; 34:3347-51. [PubMed 2994681]

214. Ollivier JP, Ducrocq MB, Droniou J. Un effet secondaire des inhibiteurs de l'enzyme de conversion: la toux. Presse Med . 1987; 16:759-61. [PubMed 3035534]

216. The Expert Panel (coordinated by the National Heart, Lung, and Blood Institute). Report of the Joint National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med . 1988; 148:36-69. [PubMed 3422148]

217. Ferguson RK, Vlasses PH, Rotmensch HH. Clinical applications of angiotensin-converting enzyme inhibitors. Am J Med . 1984; 77:690-8. [PubMed 6091446]

218. Kostis JB. Angiotensin converting enzyme inhibitors. II. Clinical use. Am J Med . 1988; 116(6 Part 1):1591-1605.

219. Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. N Engl J Med . 1988; 319:1517-25. [PubMed 3054561]

220. Schatz PL, Mesologites D, Hyun J et al. Captopril-induced hypersensitivity lung disease: an immune-complex-mediated phenomenon. Chest . 1989; 95:685-7. [PubMed 2522035]

221. Miralles R, Pedro-Botet J, Farré M et al. Captopril and vasculitis. Ann Intern Med . 1988; 109:514.

222. Edwards IR, Coulter DM, Beasley DMG et al. Captopril: 4 years of post marketing surveillance of all patients in New Zealand. Br J Clin Pharmacol . 1987; 23:529-36. [PubMed 3297125]

223. Goodfield MJD, Millard LG, Banks DC et al. Extended use of captopril. Lancet . 1984; 2:517. [PubMed 6147571]

224. Laaban J, Marie JP, Wallach D et al. Eur Heart J . 1987; 8:319.

225. Guillevin L, Le Roux G, Breau JL. Vasculitis: case report. Ann Med Interne . 1987; 138:658-9.

226. Markusse HM, Meyboom RHB. Gynaecomastia associated with captopril. BMJ . 1988; 296:1262-3.

227. Al Mahdy H, Boswell GV. Captopril-induced oesophagitis. Eur J Clin Pharmacol . 1988; 34:95. [PubMed 3282896]

228. Kim CR, Maley MB, Mohler ER Jr. Captopril and aplastic anemia. Ann Intern Med . 1989; 111:187-8. [PubMed 2662851]

229. Strair RK, Mitch WE, Faller DV et al. Reversible captopril-associated bone marrow aplasia. Can Med Assoc J . 1985; 132:320-2. [PubMed 3882212]

230. ACE-inhibitors: contraindicated in pregnancy. WHO Drug Information . 1990; 4:23.

231. Gifford RW Jr. Management of hypertensive crises. JAMA . 1991; 266:829-35. [PubMed 1865522]

232. Komsuoglu B, Sengun B, Bayram A et al. Treatment of hypertensive urgencies with oral nifedipine, nicardipine, and captopril. Angiology . 1991; 42:447-54. [PubMed 2042792]

233. Angeli P, Chiesa M, Caregaro L et al. Comparison of sublingual captopril and nifedipine in immediate treatment of hypertensive emergencies. Arch Intern Med . 1991; 151:678-82. [PubMed 2012448]

234. Guerrera G, Melina D, Capaldi L et al. Sublingually administered captopril versus nifedipine in hypertension emergencies. (Spanish; with English abstract.) Minerva Cardioangiol . 1990; 38:37-44.

235. Ceyhan B, Karaaslan Y, Caymaz O et al. Comparison of sublingual captopril and sublingual nifedipine in hypertensive emergencies. Jpn J Pharmacol . 1990; 52:189-93. [PubMed 2179605]

236. Moritz RD, de Queiroz LP, Pereira MR et al. Comparative study of the use of nifedipine and captopril in hypertensive emergencies. (Portuguese; with English abstract.) Arq Bras Cardiol . 1989; 52:323-6.

237. Guerrera G, Melina D, Capaldi L et al. Usefulness of sublingual captopril in hypertensive emergencies: preliminary results. (Spanish; with English abstract.) Cardiologia . 1989; 34:167-71.

238. del Castillo AC, Rodriguez M, Gonzalez E et al. Dose-response effect of sublingual captopril in hypertensive crises. J Clin Pharmacol . 1988; 28:667-70. [PubMed 3063729]

239. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull . 1992; 22:2.

240. Joint letter of Bristol-Myers Squibb Company; Ciba-Geigy Corporation, Pharmaceutical Division; Hoechst-Roussel Pharmaceuticals Inc; ICI Pharmaceutical Group, ICI Americas Inc; Merck Human Health Division; Parke-Davis, Division of Warner-Lambert Company. Important warning information regarding use of ACE inhibitors in pregnancy. 1992 Mar 16.

241. Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors. Obstet Gynecol . 1992; 80:429-32. [PubMed 1495700]

242. US Food and Drug Administration. Severe allergic reactions associated with dialysis and ACE inhibitors. FDA Med Bull . 1992; 22:4.

243. Parnes EL, Shapiro WB. Anaphylactoid reactions in hemodialysis patients treated with the AN69 dialyzer. Kidney Int . 1991; 40:1148-52. [PubMed 1762316]

244. Tielemans C, Madhoun P, Lenaers M et al. Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors. Kidney Int . 1990; 38:982-4. [PubMed 2266684]

245. Bristol-Myers Squibb. Princeton, NJ: Personal communication.

246. Cohn JN. The prevention of heart failure—a new agenda. N Engl J Med . 1992; 327:725-7. [PubMed 1495526]

247. Pfeffer MA, Braunwald E, Moyé LA et al for the SAVE Investigators Group. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargment Trial. N Engl J Med . 1992; 327:669-77. [PubMed 1386652]

248. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med . 1992; 327:685-91. [PubMed 1463530]

249. Swedberg K, Held P, Kjekshus J et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian enalapril survival study II (Consensus II). N Engl J Med . 1992; 327:678-84. [PubMed 1495520]

250. Sharpe N, Smith H, Murphy J et al. Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition. Lancet . 1991; 337:872-6. [PubMed 1672967]

251. Oldroyd KG, Pye MP, Ray SG et al. Effects of early captopril administration on infarct expansion, left ventricular remodeling and exercise capacity after acute myocardial infarction. Am J Cardiol . 1991; 68:713-8. [PubMed 1892076]

252. Sharpe N, Murphy J, Smith H et al. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet . 1988; 1:255-9. [PubMed 2893080]

253. Pfeffer MA, Lamas GA, Vaughan DE et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med . 1988; 319:80-6. [PubMed 2967917]

254. Kjekshus J, Swedberg K, Snappin S. Effects of enalapril on long-term mortality in severe congestive heart failure. Am J Cardiol . 1992; 69:103-7. [PubMed 1729857]

255. Scott AA, Purohit DM. Neonatal renal failure: a complication of maternal antihypertensive therapy. Am J Obstet Gynecol . 1989; 160:1223-4. [PubMed 2543224]

256. Braunwald E. ACE inhibitors—a cornerstone of the treatment of congestive heart failure. N Engl J Med . 1991; 325:351-3. [PubMed 2057038]

257. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med . 1991; 325:293-302. [PubMed 2057034]

258. E. R. Squibb and Sons, Inc. Capozide^® (captopril-hydrochlorothiazide) tablets prescribing information. In: Physicians' desk reference. 46th ed. Montvale, NJ: Medical Economics Company Inc; 1992(Suppl A):A116.

259. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med . 1993; 153:154-83. [PubMed 8422206]

260. Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med . 1993; 153:149-52. [PubMed 8422205]

261. Alderman MH. Which antihypertensive drugs first—and why! JAMA . 1992; 267:2786-7. Editorial.

262. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med . 1993; 329:1456-62. [PubMed 8413456]

263. Remuzzi G, Ruggenenti P. Slowing the progression of diabetic nephropathy. N Engl J Med . 1993; 329:1496-7. [PubMed 8413463]

264. Anon. Captopril for diabetic nephropathy. Med Lett Drugs Ther . 1994; 36:46-7. [PubMed 8177138]

265. Kasiske VL, Kalil RSN, Ma JZ et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med . 1993; 118:129-138. [PubMed 8416309]

266. Viberti G, Mogensen CE, Groop LC et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA . 1994; 271:275-9. [PubMed 8295285]

267. Mathiesen ER, Hommel E, Giese J et al. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ . 1991; 303:81-7. [PubMed 1860008]

268. Bakris GL. Angiotensin-converting enzyme inhibitors and progression of diabetic nephropathy. Ann Intern Med . 1993; 118:643-4. [PubMed 8452332]

269. Fournier A, Lalau JD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med . 1994; 330:937. [PubMed 8114873]

270. Dawnay A, Lipkin GW. ACE inhibition and diabetic nephropathy. BMJ . 1991; 303:1400. [PubMed 1810297]

271. Baker DW, Konstam MA, Bottorff M et al. Management of heart failure. JAMA . 1994; 272:1361-6. [PubMed 7933398]

272. Young JB. Angiotensin-converting enzyme inhibitors in heart failure: new strategies justified by recent clinical trials. Int J Cardiol . 1994; 43:151-63. [PubMed 8181869]

273. Sharpe N. ACE inhibitors versus diuretics: when to choose which drug? Cardiovasc Drugs Ther . 1993; 7:877-9. Abstract.

274. Riegger GA. The effects of ACE inhibitors on exercise capacity in the treatment of congestive heart failure. J Cardiovasc Pharmacol . 1990; 15(Suppl 2):S41-6.

275. Agishi T. Anion-blood contact reaction (ABC reaction) in patients treated by LDL apheresis with dextran sulfate-cellulose column while receiving ACE inhibitors. JAMA . 1994; 271:195-6. [PubMed 7695665]

276. Olbricht CJ, Schaumann D, Fischer D. Anaphylactoid reactions, LDL apheresis with dextran sulphate, and ACE inhibitors. Lancet . 1992; 340:908-9. [PubMed 1357312]

277. Keller C, Grützmacher P, Bahr F et al. LDL-apheresis with dextran sulphate and anaphylactoid reactions to ACE inhibitors. Lancet . 1993; 341:60-1. [PubMed 8093314]

278. Tunon-de-Lara JM, Villanueva P, Marcos M et al. ACE inhibitors and anaphylactoid reactions during venom immunotherapy. Lancet . 1992; 340:908. [PubMed 1357311]

279. Bristol-Myers Squibb, Princeton, NJ: Personal communication.

280. Ravid M, Savin H, Jutrin I et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med . 1993; 118:577-81. [PubMed 8452322]

281. Björck S, Mulec H, Johnsen SA et al. Renal protective effect of enalapril in diabetic nephropathy. BMJ . 1992; 304:339-43. [PubMed 1540729]

282. Cook J, Daneman D, Spino M et al. Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus. J Pediatr . 1990; 117:39-45. [PubMed 2196359]

283. McNeil. Motrin^® (ibuprofen suspension, chewable tablets, caplets) prescribing information. Fort Washington, PA; 1994 Dec.

284. Abe K, Ito T, Sato M et al. Role of prostaglandin in the antihypertensive mechanisms of captopril in low renin hypertension. Clin Sci . 1980; 59:141-4s.

285. Angiotensin-converting enzyme inhibitor interactions: nonsteroidal anti-inflammatory drugs (NSAIDs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:131-2.

286. ACE inhibitors/indomethacin. In: Tatro DS, Olin BR, Hebel SK et al. Drug interaction facts. St. Louis: JB Lippincott Co; 1992(April):28.

287. Salvetti A, Abdel-Haq B, Magagna A et al. Indomethacin reduces the antihypertensive action of enalapril Clin Exp Hypertens . 1987; 9:559-67.

288. Fujita T, Yamashita N, Yamashita K. Effect of indomethacin on antihypertensive action of captopril in hypertensive patients. Clin Exp Hypertens . 1981; 3:939-52. [PubMed 7026199]

289. Moore TJ, Crantz FR, Hollenberg NK et al. Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. Hypertension . 1981; 3:168-73. [PubMed 6260645]

290. Silberbauer K, Stanek B, Templ H. Acute hypotensive effect of captopril in man modified by prostaglandin synthesis inhibition. Br J Clin Pharmacol . 1982; 14(Suppl 2):87:93S.

291. Seelig CB, Maloley PA, Campbell JR. Nephrotoxicity associated with concomitant ACE inhibitor and NSAID therapy. South Med J . 1990; 83:1144-8. [PubMed 2218652]

292. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet . 1994; 343:1115-22. [PubMed 7910229]

293. Ambrosioni E, Borghi C, Magnani B for the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med . 1995; 332:80-5. [PubMed 7990904]

294. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet . 1993; 342:821-8. [PubMed 8104270]

295. Ball SG, Hall AS, Murray GD. Angiotensin-converting enzyme inhibitors after myocardial infarction: indications and timing J Am Coll Cardiol . 1995; 25(Suppl):42-6S. (IDIS 350026)

296. ISIS-4 Collaborative Group. Fourth international study of infarct survival: protocol for a large simple study of the effects of oral mononitrate, of oral captopril, and intravenous magnesium. Am J Cardiol . 1991; 68:87-100D.

297. Simoons ML. Myocardial infarction: ACE inhibitors for all? for ever? Lancet . 1994; 344:279-81. Editorial.

298. Anon. An ACE inhibitor after a myocardial infarction. Med Lett Drugs Ther . 1994; 36:69-70. [PubMed 8035753]

299. Ertl G, Jugdutt B. ACE inhibition after myocardial infarction: can megatrials provide answers? Lancet . 1994; 344:1068-9.

300. Ertl G. Angiotensin converting enzyme inhibitors in angina and myocardial infarction: what role will they play in the 1990s? Drugs . 1993; 46:209-18.

301. Purcell H, Coats A, Fox K et al. Improving outcome after acute myocardial infarction: what is the role of ACE inhibitors? Br J Clin Pract . 1995; 49:195-9. (IDIS 349780)

302. Ball SG, Hall AS. What to expect from ACE inhibitors after myocardial infarction. Br Heart J . 1994; 72(Suppl):S70-4.

303. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet . 1995; 345:669-85. [PubMed 7661937]

304. Chinese Cardiac Study Collaborative Group. Oral captopril versus placebo among 13 634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet . 1995; 345:686-7. [PubMed 7885123]

305. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.

306. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.

307. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA . 1995; 274:620-5. [PubMed 7637142]

308. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation . 1995; 92:1079-82. Editorial.

309. Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med . 1990; 323:1177-83. [PubMed 2215596]

310. Gales MA. Oral antihypertensives for hypertensive urgencies. Ann Pharmacother . 1994; 28:352-8. [PubMed 8193426]

311. Grossman E, Messerli FH, Grodzicki T et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA . 1996; 276:1328-31.

312. Rehman F, Mansoor GA, White WB. “Inappropriate” physician habits in prescribing oral nifedipine capsules in hosptalized patients. Am J Hypertens . 1996; 9:1035-9. [PubMed 8896658]

313. Pascale C, Zampaglione B, Marchisio M. Management of hypertensive crisis: nifedipine in comparison with captopril, clonidine, and furosemide. Curr Ther Res . 1992; 51:9-18.

314. Wu SG, Lin SL, Shiao WY et al. Comparison of sublingual captopril, nifedipine and prazosin in hypertensive emergencies during hemodialysis. Nephron . 1993; 65:284-7. [PubMed 8247194]

315. Abdelwahab W, Frishman W, Landau A. Management of hypertensive urgencies and emergencies. J Clin Pharmacol . 1995; 35:747-62. [PubMed 8522630]

316. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

317. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]

318. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]

320. Garg R, Yusuf S for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA . 1995; 273:1450-6. [PubMed 7654275]

322. Klahr S, Levey AS, Beck GJ et al for the Modification of Diet in Renal Disease Study Group. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med . 1994; 330:877-84. [PubMed 8114857]

323. Maschio G, Alberti D, Jannin G et al for the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med . 1996; 334:939-45. [PubMed 8596594]

324. Giatras I, Lau J, Levey AS et al for the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med . 1997; 127:337-45. [PubMed 9273824]

325. Vaseretic^® (enalapril maleate-hydrochlorothiazide) tablets prescribing information. In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996 (Suppl A):A121-2.

326. Merck & Co. Vasotec^® I.V. (enalaprilat) prescribing information. In: Physicians; desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996 (Suppl A):A122.

327. Merck & Co. Vasotec^® tabelts (enalapril maleate) prescribing information. In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996 (Suppl A):A122.

328. Whelton PK, Appel LJ, Espeland MA et al. for the TONE Collaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA . 1998; 279:839-46. [PubMed 9515998]

329. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med . 1999; 341(10): 709-17. [PubMed 10471456]

330. The RALES Investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the randomized aldosterone evaluation study [RALES]). Am J Cardiol . 1996; 78:902-7. [PubMed 8888663]

331. Zannad F. Angiotensin-converting enzyme inhibitor and spironolactone combination therapy: new objectives in congestive heart failure treatment.). Am J Cardiol . 1993; 71:34A-9A. [PubMed 8422003]

332. Dahlstrom U, Karlsson E. Captopril and spironolactone therapy for refractory congestive heart failure. Am J Cardiol . . 1993; 71:29A-33A. [PubMed 8422001]

333. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol . 1999; 83:9A-38A.

334. American Diabetes Association. Clinical Practice Recommendations 2003. Position Statement. Diabetic nephropathy. Diabetes Care . 2003; 26(Suppl 1):S94-8.

335. Weber KT. Aldosterone and spironolactone in heart failure. N Engl J Med . 1999;341:753-5. Editorial. [PubMed 10471464]

336. Genuth S. United Kingdom prospective diabetes study results are in. J Fam Pract . 1998; 47:(Suppl 5):S27.

337. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med . 1998; 15:895-6. [PubMed 9827842]

338. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ . 1998; 317:703-13. [PubMed 9732337]

339. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes . 1998; 106:369-72. [PubMed 9831300]

340. Struthers AD. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail . 1996;2: 47-54. [PubMed 8798105]

341. Tatti P, Pahor M, Byington RP et al. Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care . 1998; 21:597-603. [PubMed 9571349]

342. Staessen J, Lijnen P, Fagard R et al. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocr. 1981;91:457-65. [PubMed 7035596]

343. Semplicini A, Rossi GP, Bongiovi S et al. Time course changes in blood pressure, aldosterone and body fluids during enalapril treatment: a double-blind randomized study vs hydrochlorothiazide plus propranolol in essential hypertension. Clin Exp Pharmacol Physiol . 1986; 13:17-24. [PubMed 3011329]

344. MacFadyen RJ, Lee AF, Morton JJ et al. How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart . 1999; 82:57-61.

345. Struthers AD. Why does spironolactone improve mortality over and above an ACE inhibitor in congestive heart failure? Br J Clin Pharmacol . 1999; 47:479-82.

346. Johnston CI, Jackson BJ, Larmour I et al. Plasma enalapril levels and hormonal effects after short- and long-term administration in essential hypertension. Br J Clin Pharmacol . 1984; 18(Suppl 2):233-9S.

347. Sanchez RA, Marco E, Gilbert HB et al. Natriuretic effect and changes in renal haemodynamics induced by enalapril in essential hypertension. Drugs . 1985; 30(Suppl 1):49-58. [PubMed 2994987]

348. Hodsman GP, Brown JJ, Cumming AM et al. Enalapril in the treatment of hypertension with renal artery stenosis. BMJ . 1983; 287:1413-7. [PubMed 6315126]

349. American Diabetes Association. The United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; 1998 Sep 15 from American Diabetes Association web site ([Web]).

350. Anon. Spironolactone for heart failure. Med Lett Drugs Ther . 1999; 41:81-2. [PubMed 10505071]

351. Mylan Pharmaceuticals. Captopril tablets prescribing information 1998 Mar. In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:1958-61.

352. Weiner B, Kraus DM, Clifton GD et al. ASHP therapeutic guidelines on angiotensin-converting-enzyme inhibitors in patients with left ventricular dysfunction. Am J Health-Syst Pharm . 1997; 54:299-313. [PubMed 9028424]

353. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ . 1998; 317:713-20. [PubMed 9732338]

354. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust . 1998; 169:511-2.

357. Apothecon. Captopril/Hydrochlorothiazide tablets prescribing information. Princeton, NJ; 1997 Mar.

358. Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther . 1995; 9:145-9. [PubMed 7786835]

359. Aspirin interactions: captopril. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1997:62-3.

360. Packer M, Poole-Wilson PA, Armstrong PW et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation . 1999; 100:2312-8. [PubMed 10587334]

361. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]

362. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]

363. Latini R, Tognoni G, Maggioni AP et al. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin. J Am Coll Cardiol . 2000; 35:1801-7. [PubMed 10841227]

364. Hall D. The aspirin-angiotensin-converting enzyme inhibitor tradeoff: to halve and halve not. J Am Coll Cardiol . 2000; 35:1808-12. [PubMed 10841228]

365. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: A consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]

366. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet . 1998; 351:1755-62. [PubMed 9635947]

367. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care . 2003; 26(Suppl. 1):S80-2.

368. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet . 2000; 355: 253-9.

369. Niskanen L, Hender T, Hansson L et al. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/β-blocker-based treatment regimen. Diabetes Care . 2001; 24:2091-6. [PubMed 11723089]

370. Schattner A, Kozak N, Friedman J. Captopril-induced jaundice: report of 2 cases and a review of 13 additional reports in the literature. Am J Med Sci . 2001; 322:236-40. [PubMed 11678523]

372. Schoolwerth AC, Sica DA, Ballermann BJ et al. Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation . 2001; 104:1985-91. [PubMed 11602506]

373. Morgensen CE, Neldman S, Tikkanen I et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ . 2000; 321:1440-4. [PubMed 11110735]

375. Williams MA, Fleg JL, Ades PA et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ≥ 75 years of age). An American Heart Association Scientific Statement from the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac rehabilitation, and Prevention. Circulation . 2002; 105:1735-43. [PubMed 11940556]

376. Williams CL, Hayman LL, Daniels SR et al. Cardiovascular health in childhood: a statement for health professional from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation . 2002; 106:143-60. [PubMed 12093785]

377. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol . 2001. From ACC website. [Web]

379. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-60. [PubMed 12479770]

380. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]

381. Frohlich ED. Treating hypertension—what are we to believe? N Engl J Med . 2003; 348:639-401.

383. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) . 2002;4:393-404. [PubMed 12461301]

384. Black HR, Elliott WJ, Neaton JD et al. Baseline characteristics and elderly blood pressure control in the CONVINCE trial. Hypertension . 2001; 37:12-18. [PubMed 11208750]

385. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care . 2003; 26(Suppl 1):S80-2.

386. Douglas JG, Bakris GL, Epstein M et al. Management of high blood pressure in African Americans: Consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med . 2003; 163:525-41. [PubMed 12622600]

388. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.

389. Reviewers' comments (personal observations) on the Thiazides General Statement 40:28.

390. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs. Lancet . 2000;356:1955-64. [PubMed 11130523]

391. Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA . 2003;289:2073-2082. [PubMed 12709465]

392. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE). Lancet . 2002;359:995-1003. [PubMed 11937178]

393. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med . 2000;342:145-153. [PubMed 10639539]

394. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet . 2001;358:1033-41. [PubMed 11589932]

395. Wing LMH, Reid CM, Ryan P, et al, for Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med . 2003;348:583-92. [PubMed 12584366]

396. Sica DA, Elliott WJ. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in combination: theory and practice. J Clin Hypertens (Greenwich) . 2001; 3:383-7. [PubMed 11723362]

397. Carter B for the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Personal communication.

398. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. The Fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics . 2004;114(Suppl 2):555-76. [PubMed 15286277]

399. Wright JT, Dunn JK, Cutler JA et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA . 2005; 293:1595-607. [PubMed 15811979]

400. Neaton JD, Kuller LH. Diuretics are color blind. JAMA . 2005; 293:1663-6. [PubMed 15811986]

401. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med . 2006; 354:2443-51. [PubMed 16760444]

402. Food and Drug Administration. FDA public health advisory: angiotensin-converting enzyme inhibitor (ACE inhibitor) drugs and pregnancy. From FDA website ([Web]).

403. National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis . 2002; 39(Suppl 2):S1-246.

404. Kidney Disease: Improving Global Outcomes (KDIGO) Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Inter Suppl . 2013: 3:1-150.

405. Nahata MC, Morosco RS, Hipple TF. Stability of captopril in liquid containing ascorbic acid or sodium ascorbate. Am J Hosp Pharm. 1994 Jul 1;51(13):1707-8. PMID: 7942898.

406. Nahata MC, Morosco RS, Hipple TF. Stability of captopril in three liquid dosage forms. Am J Hosp Pharm. 1994 Jan 1;51(1):95-6. PMID: 8135269.

500. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). Bethesda, MD: National Institutes of Health; 2004 Aug. (NIH publication No. 04-5230.)

501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]

502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]

503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]

504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]

505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]

506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]

507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]

508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]

510. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet . 1997; 350:757-64. [PubMed 9297994]

511. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res . 2008; 31:2115-27. [PubMed 19139601]

515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]

518. SPS3 Study Group, Benavente OR, Coffey CS et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet . 2013; 382:507-15. [PubMed 23726159]

521. ACCORD Study Group, Cushman WC, Evans GW et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med . 2010; 362:1575-85. [PubMed 20228401]

522. Patel A, ADVANCE Collaborative Group, MacMahon S et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet . 2007; 370:829-40. [PubMed 17765963]

523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.

524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.

525. Smith SC, Benjamin EJ, Bonow RO et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation . 2011; 124:2458-73. [PubMed 22052934]

526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]

527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013; 127:e362-425.

528. Pfeffer MA, Swedberg K, Granger CB et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet . 2003; 362:759-66. [PubMed 13678868]

530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]

531. . Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet . 2000; 355:253-9. [PubMed 10675071]

534. Qaseem A, Hopkins RH, Sweet DE et al. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med . 2013; 159:835-47. [PubMed 24145991]

535. Taler SJ, Agarwal R, Bakris GL et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis . 2013; 62:201-13. [PubMed 23684145]

536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.

537. Levey AS, de Jong PE, Coresh J et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int . 2011; 80:17-28. [PubMed 21150873]

541. Perk J, De Backer G, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J . 2012; 33:1635-701. [PubMed 22555213]

542. Marik PE, Varon J. Hypertensive crises: challenges and management. Chest . 2007; 131:1949-62. [PubMed 17565029]

543. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. K/DOQI Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease (2002). From National Kidney Foundation website. [Web]

700. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation . 2016; 134:e282-93.

701. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J . 2016; 37:2129-200. [PubMed 27206819]

702. McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med . 2014; 371:993-1004. [PubMed 25176015]

703. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther . 2016; 41:119-27. [PubMed 26992459]

706. Massie BM. Aspirin use in chronic heart failure: what should we recommend to the practitioner?. J Am Coll Cardiol . 2005; 46:963-6. [PubMed 16168276]

803. Lamas GA, Escolar E, Faxon DP. Examining treatment of ST-elevation myocardial infarction: the importance of early intervention. J Cardiovasc Pharmacol Ther . 2010; 15:6-16. [PubMed 20061507]

805. Reed GW, Rossi JE, Cannon CP. Acute myocardial infarction. Lancet . 2017; 389:197-210. [PubMed 27502078]

1100. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014; 130:e344-426.

1150. Flynn JT, Kaelber DC, Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics . 2017; 140 [PubMed 28827377]

1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol . 2017; [PubMed 29146535]

1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]

1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]

1205. Aronow WS, Frishman WH. Implications of the New National Guidelines for Hypertension. Cardiol Rev . 2018 Mar/Apr; 26:55-61. [PubMed 29419560]

1206. Benjamin EJ, Virani SS, Callaway CW et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation . 2018; 137:e67-e492. [PubMed 29386200]

1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]

1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]

1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]

1213. Reboussin DM, Allen NB, Griswold ME et al. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol . 2017; [PubMed 29146534]

1214. American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetes 2018. Diabetes Care . 2018; 41:S86-S104. [PubMed 29222380]

1215. de Boer IH, Bangalore S, Benetos A et al. Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care . 2017; 40:1273-1284. [PubMed 28830958]

1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]

1217. Perkovic V, Rodgers A. Redefining Blood-Pressure Targets--SPRINT Starts the Marathon. N Engl J Med . 2015; 373:2175-8. [PubMed 26551394]

1218. Messerli FH, Bangalore S, Bavishi C et al. Angiotensin-converting enzyme inhibitors in hypertension: to use or not to use?. J Am Coll Cardiol . 2018; 71:1474-1482. [PubMed 29598869]

1219. Karmali KN, Lloyd-Jones DM. Global risk assessment to guide blood pressure management in cardiovascular disease prevention. Hypertension . 2017; 69:e2-e9. [PubMed 28115516]

1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]

1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]

1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]

1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]

1225. Einstadter D, Bolen SD, Misak JE et al. Association of repeated measurements with blood pressure control in primary care. JAMA Intern Med . 2018; 178(6):858-60. [PubMed 29710186]

1226. Baron RB. Treating blood pressure correctly by measuring it correctly. JAMA Intern Med . 2018; 178(6):860-1. [PubMed 29710072]

1227. Muntner P, Carey RM, Gidding S et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. Circulation . 2018; 137(2):109-18. [PubMed 29133599]

1228. Bundy JD, Mills KT, Chen J et al. Estimating the association of the 2017 and 2014 hypertension guidelines with cardiovascular events and deaths in US adults. An analysis of national data. JAMA Cardiol . Published online ahead of print May 23, 2018; [PubMed 29800138]

1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]

1230. Vasan RS, Larson MG, Leip EP et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med . 2001; 345(18):1291-7. [PubMed 11794147]

1232. American Diabetes Association. 10. Microvascular complications and foot care: standards of medical care in diabetes 2018. Diabetes Care . 2018; 41:S86-S104. [PubMed 29222381]

1233. Remuzzi G, Macia M, Ruggeneti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J Am Soc Nephrol . 2006; 17(Suppl 2):S90-7. [PubMed 16565256]

1234. Haller H, Ito S, Izzo JL Jr. et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. NEJM . 2011; 364:907-17. [PubMed 21388309]

1235. Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension . 2000;35:539-543. [PubMed 10679494]

1236. Leenen FHH, Nwachuku CE, Black HR et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium-channel blocker versus angiotensin-converting enzyme inhibitor in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Hypertension . 2006; 48:374-84. [PubMed 16864749]

1237. Messerli FH, Staessen JA. Amlodipine better than lisinopril: how one randomized clinical trial ended fallacies from observational studies. Hypertension . 2006; 48:359-61. [PubMed 16894055]

1238. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality. Lancet . 2002;360:1903-13. [PubMed 12493255]

1239. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]