ACE inhibitors and ARBs: Their role in the treatment of hypertension

The Seventh Report of the Joint National Committee (JNC 7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has emphasized that the treatment of hypertension is very important to decrease the risk of cardiovascular morbidity and mortality. A higher blood pressure means that there is a greater chance of myocardial infarction (MI), heart failure, stroke, and kidney disease. JNC 7 recommends a thiazide diuretic as first-line treatment for hypertension without compelling indications.1

Recently, there has been great interest in whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in addition to a thiazide diuretic have a role in the initial therapy for all patients who present with hypertension. For patients with cardiovascular risk factors, recent trials have shown that ACE inhibitors in addition to thiazide diuretics and beta blocking agents have resulted in a reduction in the risk of cardiovascular outcomes (MI, stroke, or worsening of heart failure) and progression of renal disease.

It is likely that ACE inhibitors reduce cardiovascular disease risk through ACE blockade and reduction of circulating serum angiotensin II levels. There is, however, an escape mechanism that occurs as a result of long-term ACE inhibition, involving chymase, cathepsin G, and chymase-sensitive angiotensin generation enzyme at the tissue level, which can produce high levels of local angiotensin II.2-4 This local production of angiotensin II has been implicated in atherosclerotic plaque formation and left ventricular hypertrophy by acting on angiotensin I receptors.5,6 Theoretically, there is a possibility that this escape may translate into a risk of cardiovascular morbidity and mortality that ACE inhibitors will not be able to reduce. ARBs, however, specifically antagonize the angiotensin I receptors and thus may provide a more complete blockade of the pathological effects of angiotensin II.5 The question lies in whether ACE inhibitors and ARBs are equal in their effects on hypertension and the reduction of cardiovascular morbidity and mortality. It is also an interesting theory that the combination of an ACE inhibitor and an ARB may lead to a more complete blockade of the effect of angiotensin II. Whether this will translate into a larger reduction in risk factors than either drug could achieve alone remains to be seen. This article reviews the available evidence regarding ACE inhibitors, ARBs, and the combination of the two drug classes for the treatment of hypertension and prevention of cardiovascular disease.

ACE inhibitors

Two main studies recently compared ACE inhibitors with thiazide diuretics for the treatment of hypertension and reduction of the risk of cardiovascular disease. The results were conflicting.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a large, randomized, double-blind study of patients aged 55 years or older with hypertension and one coronary artery disease (CAD) risk factor. A comparison of a thiazide diuretic versus an ACE inhibitor or amlodipine (Norvasc) showed that all three drugs were similar in preventing the primary outcome, fatal CAD or nonfatal MI combined. However, lisinopril (Prinivil, Zestril) showed a statistically significant higher 6-year rate of cardiovascular disease events compared with chlorthalidone (Hygroton). The goal systolic blood pressure was 140 mm Hg. The mean systolic blood pressure was lower in the thiazide group (133.9 mm Hg) than in the ACE inhibitor group (135.9 mm Hg), which was statistically significant.7

The Australian National Blood Pressure 2 trial was similar to ALLHAT. It compared an ACE inhibitor with a thiazide diuretic as first-line antihypertensive therapy in 6,083 patients between the ages of 65 and 84 years with hypertension of at least 160 mm Hg systolic or 90 mm Hg diastolic if the systolic blood pressure was at least 140 mm Hg without recent cardiovascular events. Both groups were treated with other antihypertensive medications equally to achieve the goal blood pressure. There was no difference in the reduction of blood pressure. There was a statistically significant reduction of first-time cardiovascular events, however, in the group treated with enalapril (Vasotec), specifically, a reduction of MIs compared with the thiazide-treated group, particularly for men.8 Hence, contrary to the ALLHAT study, ACE inhibitors proved to be superior to thiazides in reducing cardiovascular risk and more so for men than for women with hypertension. There was no difference in the blood pressure—lowering effects between the two drugs.

The Heart Outcomes Prevention Evaluation study group published a landmark report on the use of ACE inhibitors in not only hypertensive patients but also in patients at high risk for cardiovascular events. A total of 9,297 patients, who were 55 years of age or older and at high risk for a cardiovascular event with evidence of vascular disease plus one other risk factor, were randomly assigned to receive ramipril (Altace) or placebo for 5 years. A significant reduction of MI, stroke, or death from cardiovascular causes occurred in the ramipril group. The beneficial effect of treatment was consistently observed in patients with and without diabetes, in those with and without hypertension at baseline, and in those with and without evidence of cardiovascular disease.9 This suggests that ramipril has beneficial effects on the cardiovascular system in preventing cardiovascular disease independent of its ability to decrease blood pressure.

The Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial was a study of 380 patients with type 2 diabetes and concomitant hypertension.10 The reduction in systolic blood pressure was significantly greater in the amlodipine group compared with the fosinopril (Monopril) group (—19 mm Hg for the amlodipine group versus –13 mm Hg for the fosinopril group; P < .05). The fosinopril group, however, showed a significant reduction in the combined end point of MI, stroke, and hospitalization because of angina.

The Appropriate Blood Pressure Control in Diabetes (ABCD) trial11 and the Swedish Trial in Old Patients (STOP)12 showed similar results in the comparison of ACE inhibitors with calcium channel blocking agents. In the STOP study, ACE inhibitors were also compared with beta blocking agents and diuretics. There was no difference in the occurrence of fatal and nonfatal MI between the ACE inhibitor or beta blocker and diuretic groups.

In the Captopril Prevention Project, patients with hypertension were randomly assigned to receive captopril (Capoten) or conventional therapy (a beta blocker, diuretic, or both). No difference was shown in the risk of MI

in the captopril or the beta blocker-diuretic groups. There was, however, a blood pressure difference at baseline between the two study groups, which has been criticized.12

ACE inhibitors, therefore, have consistently been shown to be superior to long-acting calcium channel blocking agents for preventing cardiovascular disease. There is insufficient evidence, however, to suggest that ACE inhibitors are better or worse than beta blocking agents and thiazide diuretics in treating hypertension and reducing the risk of cardiovascular morbidity and mortality.

The effect of ACE inhibitors on prevention of cerebrovascular disease has also been studied. The Perindopril Protection Against Recurrent Stroke Study was a randomized trial comparing a perindopril (Aceon)-based blood pressure—lowering regimen with placebo among 6,105 individuals with previous stroke or transient ischemic attacks.13 The treatment groups included combination therapy with perindopril and indapamide (Lozol) or a combination of placebos, which made up the first subgroup. Single-agent therapy with only perindopril or a single placebo made up the second subgroup. The primary outcome was total stroke (fatal and nonfatal). The results suggested that active treatment significantly reduced total stroke compared with placebo (relative risk reduction, 28%; 95% confidence interval, 17%–38%). The reduction in stroke was significant in the group that received combination therapy with perindopril and indapamide and not in the group that received therapy with only perindopril.13 The stroke risk was not discernibly different between the groups administered single-drug therapy with perindopril compared with a single placebo agent. Compared with those assigned to placebo, blood pressure (systolic/diastolic) reductions among those treated with combination therapy (12.3/5.0 mm Hg) were about twice as great as those among participants treated with a single drug (4.9/2.8 mm Hg). The reductions in the risk of stroke were similar for hypertensive and nonhypertensive individuals.

This study suggested that the most important factor in reducing the risk of stroke was the reduction in blood

pressure with the help of two blood pressure-lowering agents. It did not suggest that the ACE inhibitor, when administered alone, reduced blood pressure or the occurrence of stroke significantly. Hence, the ACE inhibitor did not exhibit beneficial effects independent of blood pressure reduction. The reductions in outcomes were similar for both hypertensive and non-hypertensive patients.

ACE inhibitors are becoming first-line therapy for hypertensive and nonhypertensive patients with evidence of diabetic nephropathy. An ACE inhibitor had a favorable effect on the progression of diabetic nephropathy in a trial comparing captopril with a pla-cebo in 409 insulin-dependent diabetic patients with a proteinuria level of 500 mg/day or greater and a serum creatinine level of 2.5 mg/dL or less.14 The primary end point was a doubling of the baseline creatinine level. The serum creatinine level doubled in 25 patients in the captopril group (n = 207) compared with 43 patients in the placebo group (P = .007). The reduction in the risk of doubling the baseline serum creatinine level was 48% in the captopril group overall. There were an equal number of patients with hypertension in the captopril and placebo groups. The difference in blood pressure control between the two groups was

statistically insignificant. This suggests that the effect of captopril on the decline in renal function was inde-

pendent of its effects on blood pressure. These renoprotective effects seem to be the result of the ability to reduce proteinuria and other processes in the kidney that hasten the progression of nephropathy.

ARBs and hypertension

There have been few large studies comparing ARBs with other therapies that are standard for the treatment of hypertension and reduction of the risk of cardiovascular morbidity and death. The Losartan Intervention for Endpoint Reduction in Hypertension study was a double-blind, randomized, parallel-group trial of 9,193 patients aged 55 to 80 years with essential hypertension (sitting blood pressure of 160—200/

95—115 mm Hg) and left ventricular hypertrophy based on electrocardiographic criteria. The patients were assigned to losartan (Cozaar, Hyzaar)-based or atenolol-based therapy for 4 years or until 1,040 patients had the primary event being measured (death, MI, or stroke).

The results showed that the decrease in systolic blood pressure at the last visit before the end point occurred was 30.3 mm Hg (18.5%) and 29.1 mm Hg (19.2%) in the losartan and atenolol groups, respectively (P = .017). The primary composite end point (death, MI, or stroke) occurred in 508 of 4,605 patients (11%) in the losartan group and in 588 of 4,588 patients (13%) in the atenolol group, with an adjusted hazard ratio of 0.87 (P = .021).7 There was also a significant reduction of death due to cardiovascular disease, fatal and nonfatal stroke, and MI in the losartan group.

ARBs, similar to ACE inhibitors, have also been studied in hypertensive patients for the prevention of stroke. The Study on Cognition and Prognosis in the Elderly was a randomized controlled trial of candesartan (Atacand) versus placebo in 4,964 elderly patients with mild to moderately increased blood pressure. Outcomes measured were a composite of cardiovascular death, nonfatal stroke, and nonfatal MI. In the candesartan group, there was a modest, statistically nonsignificant reduction in major cardiovascular events (10.9%) and a marked reduction in nonfatal stroke (27.8%; P = .04).15

ACE inhibitors have been shown to slow the progression of nephropathy in insulin-dependent diabetic patients, but these agents are not tolerated well by all patients, mainly because of dry cough and angioedema. There are trials, however, that suggest that angiotensin receptor antagonists have a similar effect on the progression of chronic renal disease, which is most likely independent of its effects on blood pressure.

ARBs have been extensively studied in chronic kidney disease. Similar to ACE inhibitors, ARBs have shown a substantial reduction in the progression of nephropathy to chronic kidney disease and end-stage renal disease, especially in diabetic patients, compared with placebo and calcium channel blocking agents such as amlodi-pine.13,16,17 These effects seem to be independent of blood pressure reduction.

ACE inhibitors, ARBs, or both?

It has been shown in previous trials that both ACE inhibitors and ARBs are equally effective in reducing both sitting systolic and diastolic blood pressure. ARBs are associated with a significantly lower incidence of cough compared with ACE inhibitors.18 Earlier in this article, the effects of treatment with ACE inhibitors or ARBs compared with placebo or other standard hypertensive therapy (beta blocking agent, calcium channel blocker, or thiazide diuretic) were examined. Both ACE inhibitors and ARBs showed a survival benefit in reducing cardiovascular mortality, stroke, and nephropathy, but ACE inhibitors seemed to show more benefit than ARBs for the treatment of heart failure.

The debate, however, seems to be whether an ARB can be used in place of an ACE inhibitor for treatment of hypertension and for the reduction of cardiovascular mortality. Going one step further would be to investigate whether combining ACE inhibitors and ARBs would translate into a better survival benefit than either drug used alone.

The Evaluation of Losartan in the Elderly (ELITE) II study was based on the previous smaller ELITE study, which compared captopril with losartan in patients with heart failure. Results showed an unexpected survival benefit of losartan as a result of a reduction in sudden cardiac death. The ELITE II trial evaluated 3,152 patients with heart failure and an ejection fraction below 40% who were randomly assigned to receive losartan or captopril. There was no significant difference between groups in the primary end point, which was all-cause mortality or sudden cardiac death. There were, however, significantly fewer discontinuations of losartan because of adverse effects.19

To this date, there appears to be only one ongoing trial comparing ACE inhibitors with ARBs, or a combination of the two, in hypertensive patients, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). This trial is comparing cardiovascular outcomes in patients receiving telmi-sartan (Micardis), ramipril, or a combination of the two drugs. The patients are older than 55 years of age and have a history of CAD, stroke or recent (> 7 days and < 1 year) transient ischemic attack, peripheral vascular disease, or diabetes with target end-organ damage, such as microalbuminuria, ankle brachial index below 0.8, or left ventricular hypertrophy. This is not primarily a hypertension study, however, and patients with uncontrolled hypertension (> 160/100 mm Hg) are excluded. The primary end points are death caused by MI, acute MI, stroke, and hospitalization due to congestive heart failure.20 Preliminary data from this study have not yet been released.

Discussion

The inhibition of the deleterious effects of angiotensin continues to play a major role in antihypertensive therapy. The previous discussion suggests that substantial data seem to support the use of ACE inhibitors to reduce cardiovascular morbidity and mortality in hypertensive and nonhypertensive patients. There is insufficient evidence to state that ACE inhibitors are better than diuretics or beta blocking agents for uncomplicated hypertension. In patients with hypertension and with risk factors for CAD and cerebrovascular disease, however, there is sufficient evidence to suggest that an ACE inhibitor should be added to first-line therapy for hypertension to reduce mortality from MI and stroke.

There is not yet enough evidence to consider an ARB as monotherapy for the initial treatment of patients with hypertension and cardiovascular risk factors. Current studies suggest that ARBs, unlike ACE inhibitors, do not reduce mortality due to cardiovascular disease, but they are recommended by JNC 7 either as initial therapy or as additions to the therapeutic regimen when certain compelling indications are present. These indications include heart failure, diabetes, and chronic kidney disease. For the treatment of hypertensive patients with congestive heart failure, the evidence is stronger for ACE

inhibitors compared with ARBs in preventing the progression of the disease, but both are considered suitable as first-line treatment.

Conclusion

More head-to-head studies are needed to compare the benefits of ACE inhibitors with those of ARBs and to assess the combination of the two classes of drugs for the treatment of hypertension and the reduction of cardiovascular mortality. Ongoing trials, such as the ONTARGET trial, will provide more data to resolve these issues.