Using ACE Inhibitors Appropriately



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When first introduced in 1981, angiotensin-converting enzyme (ACE) inhibitors were indicated only for treatment of refractory hypertension. Since then, they have been shown to reduce morbidity or mortality in congestive heart failure, myocardial infarction, diabetes mellitus, chronic renal insufficiency, and atherosclerotic cardiovascular disease. Pathologies underlying these conditions are, in part, attributable to the renin-angiotensin-aldosterone system. Angiotensin II contributes to endothelial dysfunction, altered renal hemodynamics, and vascular and cardiac hypertrophy. ACE inhibitors attenuate these effects. Clinical outcomes of ACE inhibition include decreases in myocardial infarction (fatal and non-fatal), reinfarction, angina, stroke, end-stage renal disease, and morbidity and mortality associated with heart failure. ACE inhibitors are generally well tolerated and have few contraindications.

Cardiovascular disease affects one in four Americans. According to the American Heart Association, heart and related diseases are expected to cost Americans more than $329 billion in 2002. An estimated 10 million persons in this country are known to have diabetes and 3.6 million to have renal disease, incurring annual health care costs of $98 billion and $11 billion, respectively. Although angiotensin-converting enzyme (ACE) inhibitors have documented clinical benefits in a variety of clinical situations, the disparity between the evidence from clinical trials and bedside medicine is well documented.

The National Registry of Myocardial Infarction 2 found that fewer than one half of patients surviving acute myocardial infarction who were candidates for therapy with ACE inhibitors received these life-saving drugs at discharge.1 A recent review of patients with asymptomatic left ventricular dysfunction revealed an underuse of ACE inhibition (48 percent of eligible candidates) and a greater likelihood of being started on an ACE inhibitor if under the care of a cardiologist rather than a noncardiologist.2 In 2000, Bahit and colleagues3 reviewed actual versus ideal prescribing of drugs for secondary prevention after myocardial infarction and estimated that 30,600 lives would be saved annually by offering ACE inhibitors.

Renin-Angiotensin System

The renin-angiotensin system is systemically and locally driven. The systemic process is triggered by the kidney's response to decreased effective blood volume and begins with the secretion of renin from the renal cortex. Once released, renin cleaves angiotensinogen to form angiotensin I. This product, in turn, is catalyzed by angiotensin-converting enzyme, formed primarily in the pulmonary vasculature, into angiotensin II. This potent vasoconstrictor affects tissues and systems throughout the body; research shows that these vasoconstrictor effects are attenuated by ACE inhibition (Table 1).4,5

TABLE 1

Systemic Effects of Angiotensin II and Benefits of Ace Inhibition

Effects of angiotensin II

Increased norepinephrine (central and peripheral)

Increased oxygen demand

Increased coronary vasoconstriction

Increased preload

Increased afterload

Increased left ventricular mass (through growth factors)

Increased myocyte hypertrophy

Increased extracellular collagen matrix

Increased vessel wall hypertrophy

Increased catecholamines from adrenal medulla

Increased sodium reabsorption from proximal tubule

Increased renal vasoconstriction

Increased renal sympathetic tone

Increased aldosterone

Benefits of ACE inhibition

Decreased pulmonary artery pressure and capillary wedge pressure

Increased coronary blood flow

Increased ventricular relaxation

Decreased left ventricular mass

Decreased infarction size

Decreased reperfusion injury

Increased cardiac output

Increased cardiac index

Decreased platelet aggregation

Decreased proteinuria


ACE = angiotensin-converting enzyme.

Information from references 4 and 5.

TABLE 1   Systemic Effects of Angiotensin II and Benefits of Ace Inhibition

View Table

TABLE 1

Systemic Effects of Angiotensin II and Benefits of Ace Inhibition

Effects of angiotensin II

Increased norepinephrine (central and peripheral)

Increased oxygen demand

Increased coronary vasoconstriction

Increased preload

Increased afterload

Increased left ventricular mass (through growth factors)

Increased myocyte hypertrophy

Increased extracellular collagen matrix

Increased vessel wall hypertrophy

Increased catecholamines from adrenal medulla

Increased sodium reabsorption from proximal tubule

Increased renal vasoconstriction

Increased renal sympathetic tone

Increased aldosterone

Benefits of ACE inhibition

Decreased pulmonary artery pressure and capillary wedge pressure

Increased coronary blood flow

Increased ventricular relaxation

Decreased left ventricular mass

Decreased infarction size

Decreased reperfusion injury

Increased cardiac output

Increased cardiac index

Decreased platelet aggregation

Decreased proteinuria


ACE = angiotensin-converting enzyme.

Information from references 4 and 5.

Local renin-angiotensin systems exist in all vascular endothelium. Vascular cells maintain local vasomotor tone homeostasis primarily through the elaboration of angiotensin II and nitric oxide, a potent vasodilator. If this mechanism becomes impaired by oxidative stress, the endothelium can no longer maintain vasomotor tone in response to local needs. This phenomenon, termed endothelial dysfunction, precedes and contributes to atherosclerosis.6 ACE inhibition attenuates endothelial dysfunction by decreasing the destruction of bradykinin, thereby enhancing production of nitric oxide.5,7

Clinical investigations support the benefits of ACE inhibition. The results of the Trial on Reversing ENdothelial Dysfunction (TREND) showed improved coronary blood flow with the administration of quinapril.8 The Heart Outcomes Prevention Evaluation (HOPE) and the Microalbuminuria Cardiovascular and Renal Outcomes-HOPE (MICRO-HOPE) trials have provided evidence of reduced mortality rates, myocardial infarction, stroke, and overt nephropathy with the use of ramipril.9,10

Ace Inhibitors: Formulations

Ten ACE inhibitors presently approved for use in the United States work by competitive inhibition of angiotensin-converting enzymes. Captopril (Capoten) and enalapril (Vasotec) are off-patent, which makes them more economical. Enalapril is the only one available in intravenous form, which is called enalaprilat (Vasotec-IV). Drug formularies may dictate which ACE inhibitor a physician is able to prescribe because they are thought to be interchangeable. If a choice is possible, physicians should use those agents that have been proved by clinical trials to reduce morbidity and mortality for the condition being treated and work toward target dosages or clinical end points (Table 2).11

TABLE 2

Comparison of Angiotensin-Converting Enzyme Inhibitors

Agent Availability Dosages* Considerations Cost (generic)

Benazepril (Lotensin)

5, 10, 20, 40 mg

HTN

$ 27

Start: 10 mg daily

Target: 20 to 40 mg daily

Maximum: 80 mg daily

Captopril (Capoten)

12.5, 25, 50, 100 mg

HTN

Food decreases absorption, but blood levels do not correlate with blood pressure response

59 to 88 (20 to 68)

25 to 50 mg two or three times daily

CHF

151 (100 to 118)

Start: 6.25 to 25 mg three times daily

Target: 50 to 100 mg three times daily

LVD/MI

Start: 6.25 mg daily

Target: 50 mg three times daily

DN‡

88 (58 to 68)

25 mg three times daily

Maximum: 450 mg daily

Enalapril (Vasotec)

2.5§, 5§, 10, 20 mg

HTN

36 (31 to 32)

Start: 5 mg daily

Range: 10 to 40 mg once daily or in two divided doses

CHF

101 (88 to 91)

Start: 2.5 mg daily

Target: 40 mg daily in two divided doses

ALVD

72 (62 to 64)

Start: 2.5 mg twice daily

Target: 20 mg daily in two divided doses

Maximum: 40 mg daily

Fosinopril (Monopril)

10§, 20, 40 mg

HTN

May cause false low serum digoxin levels Patients with impaired liver function may have elevated plasma levels

29

Start: 10 mg daily

Target: 40 mg daily

CHF

29

Start: 10 mg daily

Target: 20 to 40 mg daily

Maximum: 80 mg daily

Lisinopril (Prinivil§, Zestril)

2.5, 5§, 10, 20, 30, 40 mg

HTN

30

Start: 10 mg daily

Target: 20 to 40 mg daily

CHF

30

Start: 5 mg daily

Target: 20 mg daily

AMI

29

Start: 5 mg daily for two days, then 10 mg daily for six weeks, then re-evaluate

Maximum: 40 mg daily

Moexipril (Univasc)

7.5§, 15§ mg

HTN

20

Start: 7.5 mg daily one hour before meals

Target: 7.5 to 30 mg in one dose or two divided doses one hour before meals

Maximum: 30 mg daily

Perindopril (Aceon)

2§, 4§, 8§ mg

HTN

Cautious administration with gentamicin||

30

Start: 4 mg daily

Target: 4 to 8 mg daily

Maximum: 16 mg daily

Quinapril (Accupril)

5§, 10, 20, 40 mg

HTN

Food decreases absorption

32

Start: 10 mg daily

Target: 80 mg daily

CHF

64

Start: 5 mg twice daily, titrate weekly to 20 to 40 mg in divided doses

Maximum: 80 mg daily

Ramipril (Altace)

1.25, 2.5, 5, 10 mg

HTN

Patients with impaired liver function may have elevated plasma levels

30

Start: 2.5 mg daily

Target: 2.5 to 20 mg daily in one dose or two divided dose

CHF/MI

33

Start: 2.5 mg twice daily

Target: 5 mg twice daily

RR: 10 mg daily¶

Maximum: 20 mg daily

Trandolapril (Mavik)

1§, 2, 4 mg

HTN

Food decreases absorption

24

Start: 1 mg daily (2 mg daily in black patients)

Target: 2 to 4 mg per day

CHF/MI

24

Start: 1 mg daily

Target: 4 mg daily

LVD/MI

24

Start: 1 mg daily

Target: 4 mg daily

Maximum: 8 mg daily


note:Recommendations assume reduction in dosing if hypotension occurs, if the patient is hyponatremic, or if the patient is taking a diuretic.

ALVD = asymptomatic left ventricular dysfunction; AMI = acute myocardial infarction; CHF = congestive heart failure; CHF/MI = heart failure after myocardial infarction; DN = diabetic nephropathy; HTN = hypertension; LVD/MI = left ventricular dysfunction after myocardial infarction; RR = risk reduction of cardiovascular events in at-risk patients.

*—If the patient is taking a diuretic or the creatinine clearance is less than 30 to 40 mL per minute, reduce the starting dose by one half or hold the same dosage for three days before starting ACE inhibitor therapy.

†—Estimated cost to the pharmacist based on average wholesale prices for lowest target dosage level and 30 days of therapy (except where noted), in Red book.

Montvale, N.J.: Medical Economics Data, 2001. Cost to the patient will be higher, depending on prescription filling fee.

‡—Off-label use.

§—Tablet is scored.

∥—Animal studies only.

¶—Heart Outcomes Prevention Evaluation (HOPE) trial.10

Information from Drug facts and comparisons. St. Louis: Facts and Comparisons, 2000, and Physicians' desk reference, 2001. 55th ed. Montvale, N.J.: Medical Economics, 2001.

TABLE 2   Comparison of Angiotensin-Converting Enzyme Inhibitors

View Table

TABLE 2

Comparison of Angiotensin-Converting Enzyme Inhibitors

Agent Availability Dosages* Considerations Cost (generic)

Benazepril (Lotensin)

5, 10, 20, 40 mg

HTN

$ 27

Start: 10 mg daily

Target: 20 to 40 mg daily

Maximum: 80 mg daily

Captopril (Capoten)

12.5, 25, 50, 100 mg

HTN

Food decreases absorption, but blood levels do not correlate with blood pressure response

59 to 88 (20 to 68)

25 to 50 mg two or three times daily

CHF

151 (100 to 118)

Start: 6.25 to 25 mg three times daily

Target: 50 to 100 mg three times daily

LVD/MI

Start: 6.25 mg daily

Target: 50 mg three times daily

DN‡

88 (58 to 68)

25 mg three times daily

Maximum: 450 mg daily

Enalapril (Vasotec)

2.5§, 5§, 10, 20 mg

HTN

36 (31 to 32)

Start: 5 mg daily

Range: 10 to 40 mg once daily or in two divided doses

CHF

101 (88 to 91)

Start: 2.5 mg daily

Target: 40 mg daily in two divided doses

ALVD

72 (62 to 64)

Start: 2.5 mg twice daily

Target: 20 mg daily in two divided doses

Maximum: 40 mg daily

Fosinopril (Monopril)

10§, 20, 40 mg

HTN

May cause false low serum digoxin levels Patients with impaired liver function may have elevated plasma levels

29

Start: 10 mg daily

Target: 40 mg daily

CHF

29

Start: 10 mg daily

Target: 20 to 40 mg daily

Maximum: 80 mg daily

Lisinopril (Prinivil§, Zestril)

2.5, 5§, 10, 20, 30, 40 mg

HTN

30

Start: 10 mg daily

Target: 20 to 40 mg daily

CHF

30

Start: 5 mg daily

Target: 20 mg daily

AMI

29

Start: 5 mg daily for two days, then 10 mg daily for six weeks, then re-evaluate

Maximum: 40 mg daily

Moexipril (Univasc)

7.5§, 15§ mg

HTN

20

Start: 7.5 mg daily one hour before meals

Target: 7.5 to 30 mg in one dose or two divided doses one hour before meals

Maximum: 30 mg daily

Perindopril (Aceon)

2§, 4§, 8§ mg

HTN

Cautious administration with gentamicin||

30

Start: 4 mg daily

Target: 4 to 8 mg daily

Maximum: 16 mg daily

Quinapril (Accupril)

5§, 10, 20, 40 mg

HTN

Food decreases absorption

32

Start: 10 mg daily

Target: 80 mg daily

CHF

64

Start: 5 mg twice daily, titrate weekly to 20 to 40 mg in divided doses

Maximum: 80 mg daily

Ramipril (Altace)

1.25, 2.5, 5, 10 mg

HTN

Patients with impaired liver function may have elevated plasma levels

30

Start: 2.5 mg daily

Target: 2.5 to 20 mg daily in one dose or two divided dose

CHF/MI

33

Start: 2.5 mg twice daily

Target: 5 mg twice daily

RR: 10 mg daily¶

Maximum: 20 mg daily

Trandolapril (Mavik)

1§, 2, 4 mg

HTN

Food decreases absorption

24

Start: 1 mg daily (2 mg daily in black patients)

Target: 2 to 4 mg per day

CHF/MI

24

Start: 1 mg daily

Target: 4 mg daily

LVD/MI

24

Start: 1 mg daily

Target: 4 mg daily

Maximum: 8 mg daily


note:Recommendations assume reduction in dosing if hypotension occurs, if the patient is hyponatremic, or if the patient is taking a diuretic.

ALVD = asymptomatic left ventricular dysfunction; AMI = acute myocardial infarction; CHF = congestive heart failure; CHF/MI = heart failure after myocardial infarction; DN = diabetic nephropathy; HTN = hypertension; LVD/MI = left ventricular dysfunction after myocardial infarction; RR = risk reduction of cardiovascular events in at-risk patients.

*—If the patient is taking a diuretic or the creatinine clearance is less than 30 to 40 mL per minute, reduce the starting dose by one half or hold the same dosage for three days before starting ACE inhibitor therapy.

†—Estimated cost to the pharmacist based on average wholesale prices for lowest target dosage level and 30 days of therapy (except where noted), in Red book.

Montvale, N.J.: Medical Economics Data, 2001. Cost to the patient will be higher, depending on prescription filling fee.

‡—Off-label use.

§—Tablet is scored.

∥—Animal studies only.

¶—Heart Outcomes Prevention Evaluation (HOPE) trial.10

Information from Drug facts and comparisons. St. Louis: Facts and Comparisons, 2000, and Physicians' desk reference, 2001. 55th ed. Montvale, N.J.: Medical Economics, 2001.

Initiating Treatment: Considerations

RENAL INSUFFICIENCY

In patients with renal insufficiency, no creatinine level is an absolute contraindication to ACE inhibitor therapy. ACE inhibitors are not nephrotoxic. Baseline serum creatinine levels of up to 3.0 mg per dL (27 μmol per L) are generally considered safe. The manufacturers make recommendations for initiating treatment and suggest titrating the dosage slowly. An increase of 20 percent in the serum creatinine level is not uncommon and is not a cause for discontinuing the medication. For any higher increase, the family physician should consider a nephrologist. During the first four weeks of treatment, serum potassium and creatinine levels should be monitored closely.

HYPOTENSION

Hypotension can occur in patients with volume depletion or hyponatremia (sodium <130 mEq per L [<130 mmol per L]), those taking vasodilators, those in acute congestive heart failure, and those on dialysis. The underlying problem should be corrected, starting with a low dosage and titrating slowly. Any patient with a high plasma renin level is vulnerable to first-dose hypotension, but this effect is transient and unpredictable.12 Hypotension is not a reason to discontinue ACE inhibition. Patients should be rechallenged at one half the previous dosage. If they are taking a diuretic, the dosage should be reduced or held for three days before reattempting therapy.

COUGH

Cough occurs in 5 to 20 percent of patients. It is not dose- or brand-related, is more frequent in women than men, and is more frequent in blacks than whites. It develops within one week to six months and resolves within four days of cessation. Physicians should be aware of a confounding congestive heart failure cough and remember that changing to another formulation sometimes helps. Cough is not a reason to discontinue treatment unless the patient cannot tolerate it. A few studies have looked at the use of nonsteroidal anti-inflammatory drugs (NSAIDs), nifedipine (Procardia), cromolyn (Intal), or nebulized bupivacaine (Marcaine) for managing cough, but further studies are needed.13

HYPERKALEMIA

Hyperkalemia does not usually occur in renocompetent patients, but those who have renal insufficiency or diabetes. Patients who are taking potassium, salt substitutes, potassium-sparing diuretics, beta blockers, and NSAIDs are susceptible. Most clinicians discontinue potassium and potassium-sparing diuretics when starting patients on ACE inhibitor therapy. Potassium levels should be monitored carefully in patients at risk. Up to 5 percent of patients experience serum potassium levels greater than 5.7 mEq per L (5.7 mmol per L), and if levels remain higher than that on repeat testing, ACE inhibitor therapy should be discontinued.

TERATOGENICITY

Women of childbearing age should be warned to notify their physicians immediately if they become pregnant during ACE inhibitor therapy. ACE inhibitors are not considered teratogenic if they are discontinued during the first trimester (class C), but they are considered teratogenic in the second and third trimesters (class D).

Other Considerations

Neutropenia occurs rarely and tends to occur in patients with renal impairment and concurrent collagen vascular disease. Lithium toxicity is also rare, but lithium levels should be monitored if the patient is on concurrent lithium therapy. Aortic stenosis and hypertropic cardiomyopathies are considered relative contraindications because of the risk of hypotension from fixed outlet obstruction.

Absolute Contraindications

Angioneurotic edema, which occurs in 0.1 to 0.2 percent of patients, usually develops within the first week of therapy but can occur at any time. This life-threatening adverse effect also occurs with angiotensin II receptor blockers but to a lesser extent.14 Any patient with a history of angioneurotic edema, whether related to an ACE inhibitor, angiotensin receptor blockers, or another cause, should not be given an ACE inhibitor. Other contraindications include pregnancy, renal artery stenosis, and previous allergy to ACE inhibitors.

Indications

Several chronic diseases have been shown to stabilize or improve with the use of ACE inhibitors (Table 315,16).17 Family physicians should be familiar with these agents as appropriate primary, secondary, and tertiary prevention for these prevalent and disabling chronic diseases.

TABLE 3

ACE Inhibitors: Summary of Indications

Hypertension: Beneficial with added benefits in selected subgroups. HOPE Trial10 showed primary prevention of cardiovascular end points in diabetic patients older than 55 years with one other cardiac risk factor.

Congestive heart failure: Beneficial with increased benefit in those with more severe systolic dysfunction. Reduces mortality, rate of progression of heart failure, rate of sudden death or fatal myocardial infarction, and rate of hospital admission. Target dosages should be those used in the therapeutic trials. Several studies suggest that higher dosages produce greater hemodynamic and prognostic benefit than lower dosages.11

Myocardial infarction: Beneficial in all patients with anterior myocardial infarction or systolic dysfunction. Likely to be beneficial in all others for at least six weeks. Greatest benefits when started within 24 hours, in patients with more severe myocardial damage, and the longer patients take the medication.15

Left ventricular dysfunction: Beneficial because it delays onset of symptomatic heart failure and reduces cardiovascular events.

Diabetic nephropathy: Beneficial; start ACE inhibitors at onset of microalbuminuria in all diabetic patients. Some small studies have shown slowing of onset of microalbuminuria in nonalbuminuric patients; whether this affects outcome is not known.

Risk reduction for cardiovascular events in at-risk patients: Beneficial; Heart Outcomes Prevention Evaluation (HOPE) and Microalbuminuria Cardiovascular and Renal Outcomes-HOPE (MICRO-HOPE) trials offer good evidence.10

Definitions16

Beneficial: Effectiveness has been demonstrated by clear evidence from randomized controlled trials, and expectation of harms is small compared with the benefit.

Likely to be beneficial: Interventions for which effectiveness is less well established than it is for those listed under ”beneficial.”


note:Benefits ascribed are the opinion of the author of this article.

ACE = angiotensin-converting enzyme.

Information from references 10, 11, 15 and 16.

TABLE 3   ACE Inhibitors: Summary of Indications

View Table

TABLE 3

ACE Inhibitors: Summary of Indications

Hypertension: Beneficial with added benefits in selected subgroups. HOPE Trial10 showed primary prevention of cardiovascular end points in diabetic patients older than 55 years with one other cardiac risk factor.

Congestive heart failure: Beneficial with increased benefit in those with more severe systolic dysfunction. Reduces mortality, rate of progression of heart failure, rate of sudden death or fatal myocardial infarction, and rate of hospital admission. Target dosages should be those used in the therapeutic trials. Several studies suggest that higher dosages produce greater hemodynamic and prognostic benefit than lower dosages.11

Myocardial infarction: Beneficial in all patients with anterior myocardial infarction or systolic dysfunction. Likely to be beneficial in all others for at least six weeks. Greatest benefits when started within 24 hours, in patients with more severe myocardial damage, and the longer patients take the medication.15

Left ventricular dysfunction: Beneficial because it delays onset of symptomatic heart failure and reduces cardiovascular events.

Diabetic nephropathy: Beneficial; start ACE inhibitors at onset of microalbuminuria in all diabetic patients. Some small studies have shown slowing of onset of microalbuminuria in nonalbuminuric patients; whether this affects outcome is not known.

Risk reduction for cardiovascular events in at-risk patients: Beneficial; Heart Outcomes Prevention Evaluation (HOPE) and Microalbuminuria Cardiovascular and Renal Outcomes-HOPE (MICRO-HOPE) trials offer good evidence.10

Definitions16

Beneficial: Effectiveness has been demonstrated by clear evidence from randomized controlled trials, and expectation of harms is small compared with the benefit.

Likely to be beneficial: Interventions for which effectiveness is less well established than it is for those listed under ”beneficial.”


note:Benefits ascribed are the opinion of the author of this article.

ACE = angiotensin-converting enzyme.

Information from references 10, 11, 15 and 16.

HYPERTENSION

Guidelines for the pharmacologic management of hypertension issued by the World Health Organization and the International Society of Hypertension place ACE inhibitors with diuretics and beta blockers as first-line therapy. The Sixth Report of the Joint National Committee (1997) removed ACE inhibitors as first-line therapy because they had not been shown in clinical trials to reduce all-cause mortality as had diuretics and beta blockers.18

In 1999, the Captopril Prevention Project19 randomized trial compared the three agents. Captopril and conventional treatment did not differ in cardiovascular end points overall; all events except for stroke were lower in the captopril group. Improper randomization has been cited as a possible reason for increased stroke rates.20 The results of the Swedish Trial in Old Patients with Hypertension-2 study21 showed equal outcomes between the three drug classes.

ACE inhibitors have a side effect profile that may place them above thiazides and beta blockers. They do not affect lipid, calcium, or uric acid levels, and are less likely to cause erectile dysfunction than other antihypertensive agents.14 There is evidence from several trials that fasting glucose levels, glycosylated hemoglobin levels, and rates of new diagnoses of type 2 diabetes are lower in patients randomized to ACE inhibitor therapy than in those taking placebo. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial will evaluate prospectively whether this ACE inhibitor prevents diabetes.22 Treatment goals for blood pressure include 140/90 mm Hg (or less) in patients without comorbidities, 130/80 mm Hg (or less) in patients with diabetes (2001 American Diabetes Association [ADA] Guidelines) and 125/75 mm Hg (or less) in those with end organ damage.

CONGESTIVE HEART FAILURE

ACE inhibitors are first-line therapy in patients with left ventricular systolic dysfunction, as confirmed in multiple trials and meta-analyses. Decreases in dyspnea, emergency department visits, hospitalizations, disease progression, death, and the need for diuretics have been proved, as well as increases in ejection fraction and exercise tolerance.23 All patients with systolic dysfunction, even if they are asymptomatic, should be considered for treatment with an ACE inhibitor. This consideration mandates wide use of cardiac imaging to identify the presence and type of heart failure.

Target dosages used in the clinical trials that showed reduced morbidity and mortality are listed in Table 2.11 Starting doses should be determined individually and based on clinical status (i.e., blood pressure, serum sodium level) and comorbidities (i.e., age, renal insufficiency). When the dosage is titrated up, the diuretic dosage will probably need to be decreased.

Diuretics, while essential for controlling volume overload, do not confer mortality reduction like the first-line therapies of ACE inhibition and beta blockade. The one exception to this is spironolactone (Aldactone), which has shown mortality reduction in Class III and IV heart failure.24

MYOCARDIAL INFARCTION

In 1996 and 1999, the American Heart Association advocated the administration of an ACE inhibitor to all patients presenting with acute anterior myocardial infarction and/or clinical heart failure in the absence of hypotension or other contraindications. The guidelines recommend starting within the first 24 hours and continuing therapy indefinitely for anterior infarctions and left ventricular dysfunction.25

A pragmatic approach is to give ACE inhibitors to all patients with acute myocardial infarction who are clinically stable and to continue that therapy indefinitely in those with anterior myocardial infarction or systolic dysfunction. Others should be re-evaluated for continuation of therapy at four to six weeks.15

DIABETES MELLITUS

ACE inhibitors slow the onset of diabetic nephropathy in patients with microalbuminuria and type 1 diabetes.26 Normotensive, nonalbuminuric diabetics also have a slower onset of nephropathy; however, the ADA currently does not recommend ACE inhibitors as primary prevention in these patients, and there is no evidence that this practice affects outcomes.27,28

In the MICRO-HOPE trial, patients with diabetes and one cardiac risk factor were studied; subjects were titrated to 10 mg a day of ramipril or placebo. The study was stopped prematurely because of the significant decrease in combined primary outcomes in patients taking ramipril. Total cardiovascular end points were reduced by 25 percent (95 percent confidence interval, 12 to 36; P = 0.0004); these included myocardial infarction (22 percent), cerebrovascular accident (33 percent), cerebrovascular death (37 percent), total mortality (24 percent), revascularization (17 percent) and overt nephropathy (24 percent).10 Ramipril was approved by the U.S. Food and Drug Administration in November 2000 for primary prevention of cardiovascular events in at-risk patients.

A meta-analysis of four trials including 1,123 patients with type 2 diabetes showed improved outcomes in those taking ACE inhibitors as opposed to other antihypertensive agents.29 The authors noted in their conclusions that atenolol (Tenormin) may be equivalent to captopril and that further studies are needed in regard to these two agents. Figure 1 represents the risk reduction as calculated in this meta-analysis.29 It will be rare for a patient with diabetes not to meet the criteria for ACE inhibition in the year 2002.

FIGURE 1.

Risk reduction from angiotensin-converting enzyme inhibition in diabetics; a meta-analysis of randomly controlled trials. (RR = relative risk, CI = confidence interval; ABCD = Appropriate Blood Pressure Control in Diabetes; CAPPP = Captopril Prevention Project; FACET = Fosinopril Versus Amlodipine Cardiovascular Events Trial; UKPDS = U.K. Prospective Diabetes Study)

Reprinted with permission from Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care 2000;23:891.

View Large


FIGURE 1.

Risk reduction from angiotensin-converting enzyme inhibition in diabetics; a meta-analysis of randomly controlled trials. (RR = relative risk, CI = confidence interval; ABCD = Appropriate Blood Pressure Control in Diabetes; CAPPP = Captopril Prevention Project; FACET = Fosinopril Versus Amlodipine Cardiovascular Events Trial; UKPDS = U.K. Prospective Diabetes Study)

Reprinted with permission from Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care 2000;23:891.


FIGURE 1.

Risk reduction from angiotensin-converting enzyme inhibition in diabetics; a meta-analysis of randomly controlled trials. (RR = relative risk, CI = confidence interval; ABCD = Appropriate Blood Pressure Control in Diabetes; CAPPP = Captopril Prevention Project; FACET = Fosinopril Versus Amlodipine Cardiovascular Events Trial; UKPDS = U.K. Prospective Diabetes Study)

Reprinted with permission from Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care 2000;23:891.

RENAL INSUFFICIENCY

ACE inhibitors in nondiabetic patients with nephropathy are more effective than other antihypertensives at slowing progression to end-stage renal disease.30 The Ramipril Efficacy in Nephropathy (REIN) study30 (treatment goal: diastolic blood pressure less than 90 mm Hg) and the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) study30 (treatment: benazepril, in a dosage of 10 mg daily) demonstrated improved renal survival. Even in normotensive patients with nondiabetic proteinuria, the EUCLID study group demonstrated slowing of progression of renal disease.27 Unless contraindicated, ACE inhibitors should be used in patients with renal insufficiency of any cause with a goal blood pressure of 125/75 mm Hg in those with more than 1,000 mg per 24 hours (1 g per 24 hours) proteinuria.30

Angiotensin Receptor Blockers

Angiotensin receptor blockers (ARBs) are a promising adjunct to ACE inhibitors because angiotensin II is synthesized through other pathways. A recent meta-analysis of ARBs in heart failure concluded that ACE inhibitors are superior to ARBs in reducing hospitalization and all-cause mortality. The combination of both agents was superior to ACE inhibitors alone for reducing hospitalizations but not mortality.31 As single agents, ARBs have not been shown to be superior to ACE inhibitors and are an expensive alternative when the former are not tolerated.

The Author

DAPHNE P. BICKET, M.D., M.L.S., is geriatric coordinator of the family practice residency program at University of Pittsburgh Medical Center–McKeesport, McKeesport, Pa. She is also a clinical instructor in family medicine in the Department of Family Medicine at the University of Pittsburgh School of Medicine. Dr. Bicket received her medical degree from Wake Forest University School of Medicine, Bowman Gray Campus, Winston-Salem, N.C., where she also completed a residency in family practice. She has a master's degree in library science.

Address correspondence to Daphne P. Bicket, M.D., M.L.S., Family Practice Residency Program, UPMC McKeesport, 2347 Fifth Ave., McKeesport, PA 15132 (e-mail: bicketdp@msx.upmc.edu). Reprints are not available from the author.

The author indicates that she does not have any conflicts of interest. Sources of funding: none reported.

REFERENCES

1. Barron HV, Michaels AD, Maynard C, Every NR. Use of angiotensin-converting enzyme inhibitors at discharge in patients with acute myocardial infarction in the United States: data from the National Registry of Myocardial Infarction 2. J Am Coll Cardiol. 1998;32:360–7.

2. Kermani M, Dua A, Gradman AH. Underutilization and clinical benefits of angiotensin-converting enzyme inhibitors in patients with asymptomatic left ventricular dysfunction. Am J Cardiol. 2000;86:644–8.

3. Bahit MC, Granger CB, Alexander KP, Kramer J, Lapointe NM, Califf RM. Applying the evidence: opportunity in US for 80,000 additional lives saved per year. Retrieved online August 2001.

4. Jackson EK, Garrison JC. Renin and angiotensin. In: Goodman LS, Gilman A, Hardman JG, Limbird LE, eds. Goodman & Gilman's The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, Health Professions Division, 1996:733–58.

5. Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR, et al. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation. 1994;90:2056–69.

6. Anderson TJ. Assessment and treatment of endothelial dysfunction in humans. J Am Coll Cardiol. 1999;34:631–8.

7. Parmley WW. Evolution of angiotensin-converting enzyme inhibition in hypertension, heart failure, and vascular protection. Am J Med. 1998;105:S27–31.

8. Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996;94:258–65.

9. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53.

10. The Heart Outcomes Prevention Evaluation 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.

11. Physicians' desk reference, 2001. 55th ed. Montvale, N.J.: Medical Economics, 2001.

12. Katzung BG. Basic & clinical pharmacology. 8th ed. Stamford, Conn.: Appleton & Lange, 2001:172–4.

13. Drug facts and comparisons. St. Louis: Facts and Comparisons, 2001:504–9.

14. Gifford RW Jr. Antihypertensive therapy. Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium antagonists. Med Clin North Am. 1997;81:1319–33.

15. Gersh BJ. Optimal management of acute myocardial infarction at the dawn of the next millennium. Am Heart J. 1999;138(2 pt 2):S188–202.

16. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582–7.

17. Barton S, ed. Clinical evidence. London, U.K.: BMJ Publishing Group, 2001(5):xiv.

18. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. McLean, Va.: International Medical Publishing, 1997; NIH publication no. 98-4080.

19. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611–6.

20. Fournier A, Pruna A, Esper NE, Makdassi R, Oprisiu R, West-eel PF, et al. Captopril prevention project—what shall we do about captopril and the risk of stroke?. Nephrol Dial Transplant. 2000;15:2–5.

21. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354:1751–6.

22. Yusef S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffen-buttel BH, et al. Ramipril and the development of diabetes. JAMA. 2001;286:1882–5.

23. American College of Cardiology. 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. Am J Cardiol. 1999;83:1A–38A.

24. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–17.

25. Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, et al. 1999 update: ACC/AHA guidelines for the management of patient with acute myocardial infarction: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation. 1999;100:1016–30.

26. American Diabetes Association Clinical Practice Recommendations 2001. Diabetes Care. 2001;24(suppl 1):S1–133.

27. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID study group. Lancet. 1997;349:1787–92.

28. Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med. 1998;128(12 pt 1):982–8.

29. Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care. 2000:23:888–92.

30. Bakris GL. Improving prognosis of nondiabetic chronic renal insufficiency: the role of ACE inhibitors. Kidney Int (In press).

31. Jong P, Demers C, McKelvie RS, Liu PP. Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2002;39:463–70.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.



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