Using ace inhibitors appropriately -- american family physician

Using ACE Inhibitors Appropriately
DAPHNE P. BICKET, M.D., M.L.S.
University of Pittsburgh Medical Center–McKeesport, McKeesport, Pennsylvania
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 infarc-
tion handout on ACEinhibitors, written by tion, 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 nonfatal), 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. (Am Fam Physician
2002;66:461-8,473. Copyright 2002 American Academy of Family Physicians.)
Richard W. Sloan,M.D., R.PH., coordina- Renin-Angiotensin System
The renin-angiotensin system is systemically and locally driven. The systemic process is trig- Department of FamilyMedicine at York (Pa.)Hospital and clinical in four Americans. According tothe American Heart Association,heart and related diseases areexpected to cost Americans gered by the kidney’s response to decreased more than $329 billion in 2002. An estimated effective blood volume and begins with the 10 million persons in this country are known secretion of renin from the renal cortex. Once to have diabetes and 3.6 million to have renal released, renin cleaves angiotensinogen to disease, incurring annual health care costs of form angiotensin I. This product, in turn, is ton S. Hershey Med-ical Center, Pennsylva- $98 billion and $11 billion, respectively.
catalyzed by angiotensin-converting enzyme, formed primarily in the pulmonary vascula- (ACE) inhibitors have documented clinical ture, into angiotensin II. This potent vasocon- benefits in a variety of clinical situations, the strictor affects tissues and systems throughout disparity between the evidence from clinical tri- the body; research shows that these vasocon- als and bedside medicine is well documented.
strictor effects are attenuated by ACE inhibi- The National Registry of Myocardial Infarc- Local renin-angiotensin systems exist in all patients surviving acute myocardial infarction vascular endothelium. Vascular cells maintain local vasomotor tone homeostasis primarily inhibitors received these life-saving drugs at through the elaboration of angiotensin II and discharge.1 A recent review of patients with nitric oxide, a potent vasodilator. If this asymptomatic left ventricular dysfunction stress, the endothelium can no longer main- (48 percent of eligible candidates) and a greater likelihood of being started on an ACE needs. This phenomenon, termed endothelial inhibitor if under the care of a cardiologist dysfunction, precedes and contributes to ath- rather than a noncardiologist.2 In 2000, Bahit and colleagues3 reviewed actual versus ideal endothelial dysfunction by decreasing the prescribing of drugs for secondary prevention destruction of bradykinin, thereby enhancing after myocardial infarction and estimated that 30,600 lives would be saved annually by offer- Clinical investigations support the benefits of ACE inhibition. The results of the Trial on 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
infarction, stroke, and overt nephropathy with the use of Increased left ventricular mass (through growth factors)Increased myocyte hypertrophy Ace Inhibitors: Formulations
Ten ACE inhibitors presently approved for use in the United States work by competitive inhibition of Increased catecholamines from adrenal medulla angiotensin-converting enzymes. Captopril (Capoten) and Increased sodium reabsorption from proximal tubule enalapril (Vasotec) are off-patent, which makes them more economical. Enalapril is the only one available in intra- venous form, which is called enalaprilat (Vasotec-IV).
Drug formularies may dictate which ACE inhibitor a Benefits of ACE inhibition
physician is able to prescribe because they are thought to Decreased pulmonary artery pressure and capillary wedge pressure 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 Decreased left ventricular massDecreased infarction size being treated and work toward target dosages or clinical Increased cardiac outputIncreased cardiac index Initiating Treatment: Considerations
RENAL INSUFFICIENCY
In patients with renal insufficiency, no creatinine level is an absolute contraindication to ACE inhibitor therapy.
ACE = angiotensin-converting enzyme. ACE inhibitors are not nephrotoxic. Baseline serum crea- Information from references 4 and 5. tinine levels of up to 3.0 mg per dL (27 µmol per L) aregenerally considered safe. The manufacturers make rec-ommendations for initiating treatment and suggest titrat-ing the dosage slowly. An increase of 20 percent in the Reversing ENdothelial Dysfunction (TREND) showed serum creatinine level is not uncommon and is not a improved coronary blood flow with the administration of cause for discontinuing the medication. For any higher quinapril.8 The Heart Outcomes Prevention Evaluation increase, the family physician should consider a nephrol- (HOPE) and the Microalbuminuria Cardiovascular and ogist. During the first four weeks of treatment, serum Renal Outcomes-HOPE (MICRO-HOPE) trials have pro- potassium and creatinine levels should be monitored vided evidence of reduced mortality rates, myocardial HYPOTENSION
Hypotension can occur in patients with volume deple- tion or hyponatremia (sodium <130 mEq per L [<130mmol per L]), those taking vasodilators, those in acute DAPHNE P. BICKET, M.D., M.L.S., is geriatric coordinator of the familypractice residency program at University of Pittsburgh Medical Cen- congestive heart failure, and those on dialysis. The under- ter–McKeesport, McKeesport, Pa. She is also a clinical instructor in fam- lying problem should be corrected, starting with a low ily medicine in the Department of Family Medicine at the University of dosage and titrating slowly. Any patient with a high plasma Pittsburgh School of Medicine. Dr. Bicket received her medical degreefrom Wake Forest University School of Medicine, Bowman Gray Cam- renin level is vulnerable to first-dose hypotension, but this pus, Winston-Salem, N.C., where she also completed a residency in effect is transient and unpredictable.12 Hypotension is not family practice. She has a master’s degree in library science.
a reason to discontinue ACE inhibition. Patients should be Address correspondence to Daphne P. Bicket, M.D., M.L.S., Family Prac- rechallenged at one half the previous dosage. If they are tice Residency Program, UPMC McKeesport, 2347 Fifth Ave., Mc- taking a diuretic, the dosage should be reduced or held for Keesport, PA 15132 (e-mail: [email protected]). Reprints arenot available from the author. three days before reattempting therapy.
ACE Inhibitors
ACE inhibitors are not nephrotoxic; no specific Cough occurs in 5 to 20 percent of patients. It is not creatinine level is an absolute contraindication. dose- or brand-related, is more frequent in women thanmen, and is more frequent in blacks than whites. It devel-ops within one week to six months and resolves withinfour days of cessation. Physicians should be aware of a Absolute Contraindications
confounding congestive heart failure cough and remem- Angioneurotic edema, which occurs in 0.1 to 0.2 percent ber that changing to another formulation sometimes of patients, usually develops within the first week of ther- helps. Cough is not a reason to discontinue treatment apy but can occur at any time. This life-threatening adverse unless the patient cannot tolerate it. A few studies have effect also occurs with angiotensin II receptor blockers but looked at the use of nonsteroidal anti-inflammatory drugs to a lesser extent.14 Any patient with a history of angioneu- (NSAIDs), nifedipine (Procardia), cromolyn (Intal), or rotic edema, whether related to an ACE inhibitor, angio- nebulized bupivacaine (Marcaine) for managing cough, tensin receptor blockers, or another cause, should not be given an ACE inhibitor. Other contraindications includepregnancy, renal artery stenosis, and previous allergy to HYPERKALEMIA
Hyperkalemia does not usually occur in renocompetent patients, but those who have renal insufficiency or dia- Indications
betes. Patients who are taking potassium, salt substitutes, Several chronic diseases have been shown to stabilize or potassium-sparing diuretics, beta blockers, and NSAIDs improve with the use of ACE inhibitors (Table 315,16).17 are susceptible. Most clinicians discontinue potassium Family physicians should be familiar with these agents as and potassium-sparing diuretics when starting patients appropriate primary, secondary, and tertiary prevention on ACE inhibitor therapy. Potassium levels should be for these prevalent and disabling chronic diseases.
monitored carefully in patients at risk. Up to 5 percent ofpatients experience serum potassium levels greater than HYPERTENSION
5.7 mEq per L (5.7 mmol per L), and if levels remain Guidelines for the pharmacologic management of hyper- higher than that on repeat testing, ACE inhibitor therapy tension issued by the World Health Organization and the International Society of Hypertension place ACE inhibitorswith diuretics and beta blockers as first-line therapy. The TERATOGENICITY
Sixth Report of the Joint National Committee (1997) Women of childbearing age should be warned to notify removed ACE inhibitors as first-line therapy because they their physicians immediately if they become pregnant had not been shown in clinical trials to reduce all-cause during ACE inhibitor therapy. ACE inhibitors are not con- mortality as had diuretics and beta blockers.18 sidered teratogenic if they are discontinued during the In 1999, the Captopril Prevention Project19 randomized first trimester (class C), but they are considered terato- trial compared the three agents. Captopril and conven- genic in the second and third trimesters (class D).
tional treatment did not differ in cardiovascular endpoints overall; all events except for stroke were lower in Other Considerations
the captopril group. Improper randomization has been Neutropenia occurs rarely and tends to occur in cited as a possible reason for increased stroke rates.20 The patients with renal impairment and concurrent collagen results of the Swedish Trial in Old Patients with Hyper- vascular disease. Lithium toxicity is also rare, but lithium tension-2 study21 showed equal outcomes between the levels should be monitored if the patient is on concurrent lithium therapy. Aortic stenosis and hypertropic car- ACE inhibitors have a side effect profile that may place diomyopathies are considered relative contraindications them above thiazides and beta blockers. They do not affect because of the risk of hypotension from fixed outlet lipid, calcium, or uric acid levels, and are less likely to cause erectile dysfunction than other antihypertensive TABLE 2
Comparison of Angiotensin-Converting Enzyme Inhibitors
Start: 10 mg dailyTarget: 20 to 40 mg dailyMaximum: 80 mg daily Start: 6.25 mg dailyTarget: 50 mg three times daily Start: 5 mg dailyRange: 10 to 40 mg once daily or in Start: 2.5 mg dailyTarget: 40 mg daily in two divided doses Start: 2.5 mg twice dailyTarget: 20 mg daily in two divided dosesMaximum: 40 mg daily Start: 5 mg daily for two days, then 10 mg Start: 7.5 mg daily one hour before meals Target: 7.5 to 30 mg in one dose or two ACE Inhibitors
Target: 4 to 8 mg dailyMaximum: 16 mg daily Start: 5 mg twice daily, titrate weekly to Start: 2.5 mg twice dailyTarget: 5 mg twice daily Start: 1 mg dailyTarget: 4 mg dailyMaximum: 8 mg daily NOTE: Recommendations assume reduction in dosing if hypotension occurs, if the patient is hyponatremic, or if the patient is taking adiuretic. ALVD = asymptomatic left ventricular dysfunction; AMI = acute myocardial infarction; CHF = congestive heart failure; CHF/MI = heart fail-ure after myocardial infarction; DN = diabetic nephropathy; HTN = hypertension; LVD/MI = left ventricular dysfunction after myocardialinfarction; 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 halfor 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 (exceptwhere noted), in Red book. Montvale, N.J.: Medical Economics Data, 2001. Cost to the patient will be higher, depending on prescriptionfilling 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 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, CONGESTIVE HEART FAILURE
rate of progression of heart failure, rate of sudden death orfatal myocardial infarction, and rate of hospital admission. ACE inhibitors are first-line therapy in patients with left Target dosages should be those used in the therapeutic trials.
ventricular systolic dysfunction, as confirmed in multiple Several studies suggest that higher dosages produce greater trials and meta-analyses. Decreases in dyspnea, emergency hemodynamic and prognostic benefit than lower dosages.11 department visits, hospitalizations, disease progression, Myocardial infarction: Beneficial in all patients with anterior death, and the need for diuretics have been proved, as well myocardial infarction or systolic dysfunction. Likely to be beneficial in all others for at least six weeks. Greatest benefits as increases in ejection fraction and exercise tolerance.23 All when started within 24 hours, in patients with more severe patients with systolic dysfunction, even if they are asymp- myocardial damage, and the longer patients take the tomatic, should be considered for treatment with an ACE inhibitor. This consideration mandates wide use of cardiac Left ventricular dysfunction: Beneficial because it delays onset of imaging to identify the presence and type of heart failure.
symptomatic heart failure and reduces cardiovascular events.
Target dosages used in the clinical trials that showed Diabetic nephropathy: Beneficial; start ACE inhibitors at onset of reduced morbidity and mortality are listed in Table 2.11 microalbuminuria in all diabetic patients. Some small studies Starting doses should be determined individually and have shown slowing of onset of microalbuminuria in based on clinical status (i.e., blood pressure, serum nonalbuminuric patients; whether this affects outcome is not known.
sodium level) and comorbidities (i.e., age, renal insuffi-ciency). When the dosage is titrated up, the diuretic Risk reduction for cardiovascular events in at-risk patients: Beneficial; Heart Outcomes Prevention Evaluation (HOPE) and dosage will probably need to be decreased.
Microalbuminuria Cardiovascular and Renal Outcomes-HOPE Diuretics, while essential for controlling volume overload, (MICRO-HOPE) trials offer good evidence.10 do not confer mortality reduction like the first-line therapies of ACE inhibition and beta blockade. The one exception to Beneficial: Effectiveness has been demonstrated by clear this is spironolactone (Aldactone), which has shown mor- evidence from randomized controlled trials, and expectation tality reduction in Class III and IV heart failure.24 of harms is small compared with the benefit.
Likely to be beneficial: Interventions for which effectiveness is less MYOCARDIAL INFARCTION
well established than it is for those listed under ”beneficial.” In 1996 and 1999, the American Heart Association advo- cated the administration of an ACE inhibitor to all patients NOTE: Benefits ascribed are the opinion of the author of this article. presenting with acute anterior myocardial infarction ACE = angiotensin-converting enzyme. and/or clinical heart failure in the absence of hypotension Information from references 10,11, 15 and 16. or other contraindications. The guidelines recommendstarting within the first 24 hours and continuing therapyindefinitely for anterior infarctions and left ventriculardysfunction.25 agents.14 There is evidence from several trials that fasting A pragmatic approach is to give ACE inhibitors to all glucose levels, glycosylated hemoglobin levels, and rates of patients with acute myocardial infarction who are clini- new diagnoses of type 2 diabetes are lower in patients ran- cally stable and to continue that therapy indefinitely in domized to ACE inhibitor therapy than in those taking those with anterior myocardial infarction or systolic dys- placebo. The Diabetes Reduction Assessment with function. Others should be re-evaluated for continuation Ramipril and Rosiglitazone Medication (DREAM) trial will evaluate prospectively whether this ACE inhibitorprevents diabetes.22 Treatment goals for blood pressure DIABETES MELLITUS
include 140/90 mm Hg (or less) in patients without ACE inhibitors slow the onset of diabetic nephropathy comorbidities, 130/80 mm Hg (or less) in patients with in patients with microalbuminuria and type 1 diabetes.26 diabetes (2001 American Diabetes Association [ADA] Normotensive, nonalbuminuric diabetics also have a Guidelines) and 125/75 mm Hg (or less) in those with end slower onset of nephropathy; however, the ADA currently does not recommend ACE inhibitors as primary preven- Acute Myocardial Infarction
Cardiovascular Events
All-Cause Mortality
FIGURE 1. Risk reduction from angiotensin-converting enzyme inhibition in diabetics; a meta-analysis of randomly con-trolled 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. Prospec-tive Diabetes Study) Reprinted with permission from Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits ofACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes. Diabetes Care 2000;23:891. tion in these patients, and there is no evidence that thispractice affects outcomes.27,28 RENAL INSUFFICIENCY
In the MICRO-HOPE trial, patients with diabetes and ACE inhibitors in nondiabetic patients with nephropathy one cardiac risk factor were studied; subjects were titrated are more effective than other antihypertensives at slowing to 10 mg a day of ramipril or placebo. The study was progression to end-stage renal disease.30 The Ramipril Effi- stopped prematurely because of the significant decrease in cacy in Nephropathy (REIN) study30 (treatment goal: dias- combined primary outcomes in patients taking ramipril.
tolic blood pressure less than 90 mm Hg) and the Total cardiovascular end points were reduced by 25 percent Angiotensin-Converting Enzyme Inhibition in Progressive (95 percent confidence interval, 12 to 36; P = 0.0004); these Renal Insufficiency (AIPRI) study30 (treatment: benazepril, included myocardial infarction (22 percent), cerebrovascu- in a dosage of 10 mg daily) demonstrated improved renal lar accident (33 percent), cerebrovascular death (37 per- survival. Even in normotensive patients with nondiabetic cent), total mortality (24 percent), revascularization proteinuria, the EUCLID study group demonstrated slow- (17 percent) and overt nephropathy (24 percent).10 ing of progression of renal disease.27 Unless contraindi- Ramipril was approved by the U.S. Food and Drug Admin- cated, ACE inhibitors should be used in patients with renal istration in November 2000 for primary prevention of car- insufficiency of any cause with a goal blood pressure of diovascular events in at-risk patients.
125/75 mm Hg in those with more than 1,000 mg per 24 A meta-analysis of four trials including 1,123 patients with type 2 diabetes showed improved outcomes in thosetaking ACE inhibitors as opposed to other antihyperten- Angiotensin Receptor Blockers
sive agents.29 The authors noted in their conclusions that Angiotensin receptor blockers (ARBs) are a promising atenolol (Tenormin) may be equivalent to captopril and adjunct to ACE inhibitors because angiotensin II is synthe- that further studies are needed in regard to these twoagents. Figure 1 represents the risk reduction as calculatedin this meta-analysis.29 It will be rare for a patient with ACE inhibitors slow progression to end-stage renal diabetes not to meet the criteria for ACE inhibition in the disease in nondiabetic patients with nephropathy. ACE Inhibitors
sized through other pathways. A recent meta-analysis of 15. Gersh BJ. Optimal management of acute myocardial infarction at ARBs in heart failure concluded that ACE inhibitors are the dawn of the next millennium. Am Heart J 1999;138(2 pt 2):S188-202.
superior to ARBs in reducing hospitalization and all-cause 16. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm mortality. The combination of both agents was superior to AJ, et al. Effect of losartan compared with captopril on mortality ACE inhibitors alone for reducing hospitalizations but not in patients with symptomatic heart failure: randomised trial—theLosartan Heart Failure Survival Study ELITE II. Lancet 2000;355: mortality.31 As single agents, ARBs have not been shown to be superior to ACE inhibitors and are an expensive alter- 17. Barton S, ed. Clinical evidence. London, U.K.: BMJ Publishing native when the former are not tolerated.
18. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
The author indicates that she does not have any conflicts of inter- McLean, Va.: International Medical Publishing, 1997; NIH publica- est. Sources of funding: none reported. 19. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition com-pared with conventional therapy on cardiovascular morbidity and 1. Barron HV, Michaels AD, Maynard C, Every NR. Use of mortality in hypertension: the Captopril Prevention Project angiotensin-converting enzyme inhibitors at discharge in patients (CAPPP) randomised trial. Lancet 1999;353:611-6.
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2. Kermani M, Dua A, Gradman AH. Underutilization and clinical 21. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, et benefits of angiotensin-converting enzyme inhibitors in patients al. Randomised trial of old and new antihypertensive drugs in elderly with asymptomatic left ventricular dysfunction. Am J Cardiol patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751-6.
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