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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-
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
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 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: firstname.lastname@example.org). Reprints arenot available from the author.
three days before reattempting therapy.
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
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 does not usually occur in renocompetent
patients, but those who have renal insufficiency or dia-
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)
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
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
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
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 2Comparison 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
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.
§—Tablet is scored.
||—Animal studies only.
¶—Heart Outcomes Prevention Evaluation (HOPE) trial.
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 3ACE Inhibitors: Summary of Indications
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,
: 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
Beneficial; start ACE inhibitors at onset of
reduced morbidity and mortality are listed in Table 2
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
: 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
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
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
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
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.
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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20. Fournier A, Pruna A, Esper NE, Makdassi R, Oprisiu R, Westeel PF,
the National Registry of Myocardial Infarction 2. J Am Coll Cardiol
et al. Captopril prevention project—what shall we do about cap-
topril and the risk of stroke? Nephrol Dial Transplant 2000;15:2-5.
2. Kermani M, Dua A, Gradman AH. Underutilization and clinical
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Old Patients with Hypertension-2 study. Lancet 1999;354:1751-6.
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RM. Applying the evidence: opportunity in US for 80,000 additional
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Gilman A, Hardman JG, Limbird LE, eds. Goodman & Gilman’s The
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24. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al.
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CHEE434/821 Fall 2004 Problem Set #2 The drug Hydrochlorothiazide ("Diazide") is sometimes used to regulate blood pressure. However, it is also a diuretic and can cause a substantial increase in urine production. To counter this side effect, the antispasmodic drug Oxybutynin ("Ditropan") is often prescribed as well. However, Oxybutynin is known to increase ocular p