Drug Criteria & Outcomes
Review: Angiotensin-converting enzyme inhibitors (ACEIs)
By Leigh Ann Kipley, PharmD
College of Pharmacy
The University of Texas at Austin
Introduction
Since their introduction in the 1980s, angiotensin-converting enzyme inhibitors (ACEIs) have helped change treatment strategies for cardiovascular dysfunction. A variety of studies have proved the efficacy of ACEIs in the treatment of hypertension, congestive heart failure (CHF), and myocardial infarction (MI). The ACEIs are structurally heterogeneous in that the functional, or active, side chain binds to angiotensin-converting enzyme. Most of the ACEIs contain a carboxyl side group except for fosinopril and captopril, which have a phosphinyl and sulfhydryl group, respectively. The differences in the binding groups may be responsible for the variable pharmacologic and pharmacokinetic properties of the ACEIs.1
Currently, 10 ACEIs are available in the United States. The older ACEIs, which include captopril and enalapril, are dosed multiple times per day, whereas the newer agents are dosed once daily. Representative formulary ACEIs for the treatment of hypertension and CHF include quinapril (Accupril), fosinopril (Monopril), and lisinopril (Prinivil, Zestril).
In January 2000, the New England Journal of Medicine published the results from the Heart Outcomes Prevention Evaluation (HOPE) Study Investigators, which reported the cardiovascular effects of ramipril (Altace) in high-risk patients.2 As with many clinical trials sponsored by pharmaceutical companies, no head-to-head studies exist, which has resulted in significant interest as to whether these benefits are unique to ramipril or are associated with a class effect.
This review focuses on the differences and similarities between typical formulary agents and ramipril. Two additional ACEIs, captopril (Capoten) and enalapril (Vasotec), also will be included in order to compare and establish clinical effectiveness.
Pharmacology
Mechanism of action
Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II has a variety of physiologic effects, including increasing sodium and water retention, which induces left ventricular remodeling, causing vasoconstriction. Bradykinin also is a substrate of ACE and catalyzes the conversion of bradykinin to inactive peptides. When the ACEI is bound to ACE, binding to angiotensin I and bradykinin is inhibited, and both of the above pathways are inhibited. Reductions in angiotensin II production result in vasodilation, reduced cardiac hypertrophy, and decreased sodium and water retention. When bradykinin is unable to bind to ACE, an alternate degradation pathway inactivates bradykinin to prostaglandin. Since prostaglandin is a vasodilator, further reductions in blood pressure may occur.1,3,4
Binding groups
All of the ACEIs are 2-methylpropionyl-L-proline analogues that differ by specific individual functional groups binding to the zinc
moiety in the ACE binding site. Captopril has a sulfhydryl group, fosinopril has a phosphinyl group, and all of the others have a carboxyl group. The differences in the binding groups lead to variations among the agents. For example, the sulfhydryl group on captopril is believed to be the cause of hypersensitivity reactions. Also, the phosphinyl group on fosinopril is associated with a reduced incidence of cough. Quinapril contains magnesium and has been reported to have more drug interactions.1,3,5
Prodrug
Many ACEIs are prodrugs, which rely on liver metabolism to convert the parent drug to the active drug (denoted with -at at the ending of the chemical name). Ramipril, quinapril, fosinopril, and enalapril are converted by the liver to their active counterpart ramiprilat, quinaprilat, fosinoprilat, and enalaprilat, respectively. Lisinopril is the only agent that does not undergo liver metabolism. Captopril is not a prodrug, but is metabolized by the liver to disulfide metabolites.1,3,5
Lipophilicity
Lipophilicity characteristics vary between the ACEIs. Lisinopril has significantly reduced lipophilicity compared to the other agents, and fosinopril is the most lipophilic of the ACEIs. In vitro studies and animal data suggest that greater lipophilic properties are associated with more efficient ACE inhibition in tissues. However, an ACEI reaching the tissue does not mean the drug will necessarily bind to tissue ACE.
Although fosinopril and quinapril are more lipophilic than ramipril, ramipril is the only agent that has been studied in human tissue samples to demonstrate binding to human tissue ACE.5 Unfortunately, the possible clinical benefit of tissue ACE inhibition has yet to be determined. Some researchers hypothesize that an increased ability to inhibit tissue ACE will result in better outcomes. However, additional research is needed to determine if tissue ACE inhibition produces any advantage in the clinical setting.1,5-7
Pharmacokinetics
Absorption
Most of the ACEIs are absorbed rapidly after oral administration, with the exception of lisinopril and fosinopril, which are absorbed slowly. Food can affect the absorption of certain ACEIs. For example, the rate of absorption of ramipril is reduced when taken with food, and the rate and extent of absorption of quinapril are reduced when taken with high-fat food. Food does not alter the rate or extent of absorption of fosinopril or lisinopril.3,8,9
Distribution
Fosinoprilat and quinaprilat are highly protein-bound; therefore, both agents have a small
volume of distribution. Ramipril is only moderately protein-bound, and lisinopril has little protein binding.3,8
Metabolism
As noted above, ramipril, quinapril, fosinopril, and enalapril are converted to the active agents via the liver. Fosinopril has more hepatic metabolic involvement than any of the other ACEIs.3,8,9
Elimination
Quinapril, lisinopril, captopril, and enalapril are eliminated mainly by the kidneys. Fosinopril and ramipril are eliminated 50% and 70%, respectively, by the kidneys.3,5,6,8
FDA-labeled indications
All of the ACEIs of concern in this report are indicated for the treatment of hypertension and CHF. Ramipril, lisinopril, and captopril also are indicated for use after acute MIs. Captopril and enalapril are indicated for left ventricular dysfunction. Only captopril is indicated for use in diabetic nephropathy.1,9
Adverse effects
The most common adverse effects associated with ACEIs include cough, central nervous system effects (headache, dizziness), cardiovascular effects (hypotension, angina, syncope), and elevated serum creatinine and potassium. Less common complications include hypersensitivity reactions (rash, angioedema) and acute renal failure.10
Cough
The cough is described as dry, nonproductive, and irritating. It appears to be more common in women and nonsmokers. In the HOPE trial, 1.9% of patients discontinued treatment with ramipril due to cough.2 Incidence varies, with different sources providing incidence ranging from 0.7% to 48%. Discontinuation rates of ACEI agents due to cough range from 1% to 10%. Researchers believe the cough is due to an accumulation of bradykinin. In a few studies, fosinopril has been shown to have a reduced incidence of cough, perhaps due to the phosphinyl binding group. Switching ACEI agents may or may not reduce the occurrence of cough.2,10-12
Rash
Rash is the most common type of hypersensitivity reaction associated with the ACEIs. Most often, the skin reaction manifests as a pruritic maculopapular eruption. Captopril is the ACEI most commonly associated with rash. Rash also has been reported with ramipril. The incidence of rash has been estimated for quinapril, fosinopril, and lisinopril to be 1.4%, 2.2-9.7%, and 1.3-1.7%, respectively.8,10
Angioneurotic edema (angioedema)
Angioedema rarely occurs (0.1-0.2% of all patients), but it is potentially life-threatening. The rate of occurrence is highest during the first month of treatment and is not dose-related. The incidences of angioedema among the ACEIs are: ramipril, < 1%; quinapril, 0.5-1%; lisinopril, 0.1%; and fosinopril, < 1%. Black Americans are at increased risk of developing angioedema and may experience more severe symptoms.3,8,10
Hyperkalemia
Elevated serum potassium levels have been reported with the use of ACEIs due to the inhibition of aldosterone. The risk of developing hyperkalemia is increased in patients with impaired kidney function and in patients taking potassium supplements or potassium-sparing diuretics. The incidences of hyperkalemia among the ACEIs are: ramipril, ~1%; quinapril, ~2%; lisinopril, ~2%; and fosinopril, ~2.6%.8,10
Acute renal failure
Acute renal failure may result from the lack of efferent arteriole vasoconstriction when ACE is inhibited. It is more common in patients with renal artery stenosis or with only a single kidney. ACEIs may reduce glomerular filtration in patients with severe CHF or patients overtreated with diuretics.3,10
Contraindications
Ramipril, quinapril, fosinopril, and lisinopril are contraindicated in individuals with hypersensitivity to the respective agent or any member of the ACEIs class. Because ACEIs are classified Pregnancy Category D in the second and third trimester, use during pregnancy is contraindicated.8,10,13
Warnings
Neutropenia and agranulocytosis
Neutropenia and agranulocytosis have resulted from the use of captopril, enalapril, lisinopril, and quinapril. No data are available indicating that the other ACEIs do not cause neutropenia and agranulocytosis. Monitor patients with renal failure and collagen vascular diseases.8
Angioedema
ACEIs should be avoided in patients who are allergic to any ACEI due to the increased risk of anaphylactic reactions. As noted previously, angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, or larynx has been reported with use of ACEIs.8
Proteinuria
Proteinuria has been reported and most often is associated with captopril.8
Hypotension
ACEI use in severely salt- or volume-depleted individuals may result in excessive hypotension and should be used with caution. Monitor patients for first-dose hypotension during therapy initiation.8
Renal function impairment
Impaired renal function reduces the elimination of lisinopril, ramipril, quinapril, and fosinopril. Treatment with ACEIs has resulted in an increase in blood urea nitrogen and serum creatinine. Drug Facts and Comparisons recommends monitoring renal function in all patients upon initiating ACEI therapy. Dosage adjustments may be needed to avoid accumulation.8
Hepatic function impairment/failure
Hepatic dysfunction can alter clearance of the ACEIs that are metabolized hepatically. Thus, lower doses of fosinopril and ramipril are recommended in patients with hepatic impairment. ACEIs should be discontinued in patients who develop jaundice or marked elevations in hepatic enzymes.8
Elderly
Because elderly patients may have reduced renal function, doses of renally eliminated ACEIs may need to be adjusted. Therefore, dosage reductions are recommended for ramipril, quinapril, and lisinopril. Reduced renal function does not affect the dosing of fosinopril because the agent has dual elimination (renal and hepatic).8
Pregnancy
All of the ACEIs are Pregnancy Category C during the first trimester of pregnancy and Pregnancy Category D during the second and third trimester of pregnancy. ACEI therapy should not be used during any portion of the pregnancy.13
Lactation
Captopril does pass into breast milk and should be avoided by nursing mothers. However, only negligible amounts of enalapril were found in breast milk in several studies. All other ACEIs should be avoided during lactation due to lack of safety studies.13
Children
The safety and efficacy of the ACEIs in pediatric patients have not been established. Captopril has been used in a limited number of instances. Hypotension, oliguria, and seizures rarely have been reported with captopril use in children.8
Precautions
Hyperkalemia
Elevated serum potassium has been reported with use of ACEIs.8
Surgery/anesthesia
Anesthesia use during surgery combined
with ACEI therapy may result in increased hypotension.8
Drug interactions
All ACEIs interact with diuretics/sympathomimetics, resulting in additive hypotension. Additionally, all ACEIs interact with potassium-sparing diuretics, resulting in hyperkalemia. The drugs in this class interact with nonsteroidal anti-inflammatory drugs (NSAIDs), with loss of hypotensive action and deterioration of renal function as effects. All ACEIs also interact with lithium, resulting in lithium toxicity. Quinapril interacts with tetracycline and quinolone antibiotics, resulting in decreased tetracycline absorption and decreased quinolone absorption.5,8,14
Dosing and administration
Dosing and administration of ramipril and other representative ACEIs for hypertension and CHF (respectively) are displayed in the accompanying table.9,15 (See table.)
| Table | |||
| Initial Dose | Maintenance Dose | Maximum Dose | |
| Ramipril | |||
| Hypertension | 2.5 mg q d | 2.5-20 mg q d | 20 q d |
| CHF | 1.25-2.5 mg bid | 5 mg bid | 5 mg bid |
| Quinipril | |||
| Hypertension | 10 mg q d | 20-80 mg q d | 80 mg q d |
| CHF | 5 mg bid | 10-40 mg q d | 40 mg q d |
| Fosinopril | |||
| Hypertension | 10 mg q d | 20-80 mg q d | 80 mg q d |
| CHF | 10 mg q d | 20-40 mg q d | 40 mg q d |
| Lisinopril | |||
| Hypertension | 10 mg q d | 20-40 mg q d | 40 mg q d |
| CHF | 5 mg q d | 5-40 mg q d | 40 mg q d |
Dosing adjustments need to be made in patients with renal impairment and in the elderly. Patients on ramipril with a creatinine clearance (ClCr) of 10-50 mL/min should receive 50-75% of the normal dose. If ClCr is less than 10 mL/min, they should receive only 25-50% of the normal dose. Patients on quinapril should be given 75-100% of the normal dose if ClCr is 10-50 mL/min, and 75% of the normal dose of ClCr is less than 10 mL/min. No adjustment is necessary for fosinopril if ClCr is greater than 10 mL/min; patients on dialysis should receive 20-50% of the normal dose of fosinopril. Patients receiving lisinopril should receive 50-75% of the normal dose if ClCr is 10-50 mL/min; 25-50% of the normal dose if ClCr is less than 10 mL/min; and 50% of the normal dose if on hemodialysis.9,15
Typical formulary agents (quinapril, fosinopril, lisinopril) compared to ramipril
Pharmacology
All of these agents have a common mechanism of action. Ramipril, quinapril, and lisinopril have carboxyl binding groups, whereas fosinopril has a phosphinyl binding group. Lisinopril is the only agent that is not a prodrug; therefore, lisinopril does not rely on the liver for metabolic conversion and activation.
Fosinopril is the most lipophilic, whereas lisinopril is the least lipophilic. Greater lipophilicity has been reported to be associated with more efficient ACE inhibition in tissue. Unfortunately, no data are available to substantiate this claim. Although the lipophilic agents reach the tissue, no data exist suggesting increased ACE tissue inhibition. Ramipril is the only ACEI studied that has been shown to bind to tissue ACE in humans.
Pharmacokinetics
Administering ramipril and quinapril with food reduces the absorption; however, fosinopril and lisinopril absorption is not affected by food. Quinapril and fosinopril are highly protein-bound and subsequently have a small volume of distribution. Ramipril is only moderately protein-bound, whereas lisinopril has little protein binding. Quinapril is mainly eliminated by the kidney, and is activated only by the liver. Fosinopril has equal hepatic and renal clearance. Ramipril has more kidney than liver clearance. Lisinopril is solely eliminated by the kidney and has no hepatic metabolism.
Dosing adjustments
All of the ACEIs included in this discussion are eliminated renally to some extent, and adjusting doses depends on the agent and the patient’s renal function. Fosinopril does have an equal amount of hepatic involvement and does not need to be adjusted until the patient undergoes hemodialysis. Because many elderly patients are renally and/or hepatically impaired and more sensitive to reductions in blood pressure, dosage adjustments are recommended.
Indications
Ramipril has the same indications as lisinopril, which include hypertension, CHF, and acute MI. Quinapril and fosinopril are indicated only for hypertension and CHF.
Adverse effects
Fosinopril is least likely to cause cough, perhaps because of the phosphinyl group.
Drug interactions
Because quinapril contains magnesium, drug interactions exist with concurrent tetracycline and quinolone therapy. Ramipril, fosinopril, and lisinopril are associated with the classic ACEI drug interactions, which include diuretics, potassium-sparing diuretics, NSAIDs, and lithium.
Dosing
Most of the ACEIs included in this review are dosed once daily in hypertension and CHF. Ramipril is dosed once daily for hypertension and twice daily for CHF.
Efficacy
No head-to-head trials have been performed comparing the agents discussed in this review and ramipril. Therefore, clinical effectiveness can only be estimated using captopril and enalapril as surrogate markers. Clinical trials have demonstrated that ramipril is as effective as enalapril and captopril in treating hypertension and CHF. In addition, quinapril, fosinopril, and lisinopril have been shown to be as effective as enalapril and captopril.
Frishman and colleagues performed a placebo- controlled study of 403 patients evaluating the efficacy of quinapril vs. captopril vs. placebo.16 Results showed that quinapril had equal efficacy to captopril. Gavazzi and colleagues studied the efficacy of quinapril vs. captopril in CHF in a double-blind, randomized, parallel study with 156 patients.17 Results showed quinapril to be as efficacious as captopril in CHF.
Goldstein and associates evaluated the efficacy of fosinopril vs. enalapril in a double-blind, randomized study of hypertension in 214 patients.18 Results showed fosinopril was equal in efficacy to enalapril. Zannad and co-workers conducted a double-blind study of the efficacy of fosinopril vs. enalapril in 254 patients with CHF.19 Results showed fosinopril more efficacious than enalapril. Nami and colleagues performed a randomized, double-blind study of response rates of monotherapy for hypertension in 80 patients.20 Study drugs included ramipril, lisinopril, quinapril, and enalapril. Results showed ramipril was equal to lisinopril, which was greater than quinapril, which was greater than enalapril in response rate.
Manthey and colleagues studied the efficacy of ramipril vs. enalapril in CHF in a randomized, double-blind study of 15 patients.21 Results indicate that ramipril is equal to enalapril in efficacy. deGraeff and associates evaluated the efficacy of ramipril vs. captopril in a randomized, double-blind study of 12 patients with CHF.22 Results showed that ramipril has a slower onset and longer duration of action than captopril. Acanfora and co-workers conducted a study of the efficacy of quinapril vs. captopril in their double-blind, randomized study of CHF in 131 patients.23 Results showed quinapril to be equally efficacious to captopril.
The HOPE trial 2
Study design
A randomized, placebo-controlled, double-blind, two-by-two factorial multicenter clinical trial evaluated ramipril and vitamin E in high-risk patients with evidence of vascular disease or diabetes plus one other cardiovascular risk factor and with no known evidence of low ejection fraction or heart failure.
Patients
Inclusion criteria included age of at least 55 years, history of coronary artery disease, stroke, peripheral vascular disease, or diabetes, and at least one other cardiovascular risk factor (hypertension, elevated total cholesterol, low HDL, cigarette smoking, or documented microalbuminuria). Exclusion criteria include noncompliance during run-in phase, history of heart failure,
low ejection fraction (0.40), prior use of ACEI or vitamin E, uncontrolled hypertension, overt nephropathy, or an MI or stroke within four weeks of study commencement. A total of 10,576 patients were eligible for the study.
Timeline
The study ran from September 1994 to March 1999. Originally, the study was to last five years, but after 4.5 years, evidence clearly demonstrated the beneficial effects of ramipril and the study was terminated.
Sites
Patients were recruited from 129 centers in Canada, 27 centers in the United States, 76 centers in 14 western European countries, 30 centers in Argentina and Brazil, and five centers in Mexico.
Sponsorship
The study was funded by the Medical Research Council of Canada, Hoechst Marion Roussel, AstraZeneca, King Pharmaceuticals, Natural Source Vitamin E Association, Negma, and the Heart and Stroke Foundation of
Ontario.
Interdisciplinary review board
The review board at each institution approved the protocol.
Treatment groups
Ramipril 10 mg q d or Ramipril placebo q d
+ Vitamin E 400 IU q d or Vitamin E placebo q d
Primary endpoints
MI, stroke, or death from cardiovascular causes.
Secondary endpoints
Death from any cause, revascularization, hospitalization for unstable angina or heart failure, and complications related to diabetes.
Methods
All eligible patients participated in a run-in phase before the study began. Patients received 2.5 mg ramipril once daily for seven to 10 days, followed by matching placebo for 10-14 days. More than 1,000 patients were excluded due to noncompliance, adverse effects, abnormal serum creatinine or potassium levels, or withdrawal of consent. Of the remaining 9,541 patients, 48% were randomly assigned to receive 10 mg ramipril every day, while another 48% were assigned to receive placebo every day. The remaining 2% received low-dose 2.5 mg ramipril daily.
As noted above, treatment duration was set at five years. Upon study initiation, patients were assigned to receive ramipril or placebo at 2.5 mg dose every day for one week, 5 mg every day for the next three weeks, and 10 mg every day thereafter. All patients were also randomized to receive 400 IU vitamin E or placebo daily. The SECURE trial reports the results of the vitamin E companion study and the low-dose ramipril substudy.24 Follow-up visits were scheduled at one month, six months, and every six months thereafter. At each visit, data were collected on the outcome events, compliance, and adverse effects. Each patient was continued on all other non-ACEI medications prior to study initiation. The MICRO-HOPE, a substudy of the HOPE trial, reported the effects of ramipril on the cardiovascular and microvascular outcomes in diabetic patients, and the results will be discussed later in this review.25
Statistics
A total of 9,000 patients were required to achieve a 4% event rate per year for five years, with 90% power to detect a 13.5% reduction in relative risk. Data were analyzed on an intention-to-treat basis. Survival curves were estimated according to Kaplan-Meier procedure, and treatments were compared with use of the log-rank test. All analyses were stratified for randomization to vitamin E or placebo.
Results
At baseline, patients in the ramipril group had blood pressure of 139/79 mmHg vs. 139/79 mmHg for patients in the placebo group. At one month, ramipril and placebo group blood pressures were 133/76 mmHg and 137/78 mmHg, respectively. At two years, blood pressures measured 135/76 and 138/78 mmHg, respectively. By the end of the study, ramipril patients measured 136/76 mmHg, and placebo group patients measured 139/77 mmHg.
Upon study completion, a 22% relative risk reduction of the combined primary outcome of cardiovascular death, MI, and stroke was observed.
Microalbuminuria, Cardiovascular and Renal Outcomes (MICRO-HOPE) substudy 25
The HOPE study included a substudy focusing on effects of ramipril on cardiovascular and microvascular outcomes in diabetic patients. A total of 3,577 people were eligible for the substudy, based on the same inclusion and exclusion criteria as the HOPE trial.2 The primary endpoints also were the same as the HOPE trial, including cardiovascular death, MI, or stroke. Similarly, the secondary endpoints were identical to the HOPE trial. Upon substudy completion, a 25% relative risk reduction of the combined primary outcome of cardiovascular death, MI, and stroke was observed.
At baseline, patients in the ramipril group had blood pressure of 142/80 mmHg vs. 142/79 mmHg for patients in the placebo group. At one month, ramipril and placebo group blood pressures were 136/77 mmHg and 141/79 mmHg, respectively. At two years, blood pressures measured 139/77 and 142/78 mmHg, respectively. By the end of the study, ramipril patients measured 140/77 mmHg, and placebo group patients measured 142/77 mmHg.
Discussion of results from HOPE and MICRO-HOPE
The changes in the primary outcomes in the HOPE trial between the placebo treated group and the ramipril treated group were:
- CV death: 8.1% vs. 6.1% (26% risk reduction);
- MI: 12.3% vs. 9.9% (20% risk reduction);
- stroke: 4.9% vs. 3.4% (32% risk reduction).
The MICRO-HOPE trial specifically looked at the same endpoints in a subset patient population of diabetics and showed the following outcomes:
- CV death: 9.7 vs. 6.2 (37% risk reduction);
- MI: 12.9% vs. 10.2% (22% risk reduction);
- stroke: 6.1% vs. 4.2% (33% risk reduction).
The ramipril-treated group had a slight advantage with better blood pressure control. This independent factor (lower blood pressure in the ramipril group) is estimated by the drug manufacturer to have accounted for 5-7% of the risk reductions shown above.26
Although no other ACEIs were evaluated in the HOPE trial, the drug manufacturer does not believe that these benefits can be expected to be an ACEI class effect. To refute the class-effect concept, the pharmaceutical company proposes that ramipril has increased lipophilicity. Lipophilicity is said to improve tissue binding, which might confer better end-organ protection. Unfortunately, there have been few direct head-to-head trials comparing ACEIs that are highly tissue-bound to those with more limited tissue binding. In situations where such comparisons have occurred, the results do not convincingly support the claim of overall superiority for lipophilic ACEIs.
Conclusions
While simple reductions in blood pressure in the ACEI-treated group can explain about 20% of the overall benefits in the primary outcome measures of the HOPE and MICRO-HOPE trials, there remains an additional level of benefit. Without any direct comparison within the HOPE or MICRO-HOPE studies, the likelihood that this benefit represents a "class effect" cannot be excluded. Despite the lack of a provable theory as to why ramipril would uniquely result in these outcomes, the fact remains that no other ACEI has shown these results at this point in time.
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25. 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; 355:253-259.
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