Are ARBs better than ACE-inhibitors?

Summarized by Robert W. Griffith, MD
May 7, 2002 (Reviewed: July 16, 2004)

Introduction

It was in the early 1970s that Brunner, Laragh and Gavras first outlined the role of angiotensin II in the pathogenesis of hypertensive vascular damage. They showed that excess angiotensin caused damage to the myocardium and renal parenchyma, independent of its elevation of blood pressure; and that subjects with high blood pressure but low renin levels were less likely to have heart attacks or strokes than those with high renin levels. Thirty years later we are defining the clinical role of the first angiotensin receptor blockers (ARBs); Brunner and Gavras have recently summarized the progression of our knowledge in this area, up to this point.

Effective medical treatment of hypertension has been available for the last 50 years, and with each new class of drugs introduced there has been a reduction in the frequency and severity of adverse effects. This is extremely important, as antihypertensive therapy is, for the most part, a lifelong effort without motivation provided by obvious symptoms of the disease. In comparative studies, attention has mainly been directed at the side-effect profiles of the candidates. With the arrival of the angiotensin-converting enzyme (ACE) inhibitors and the selective angiotensin-type-1-receptor blockers (ARBs) the safety profiles are almost as good as can be expected for effective medications. However, there is still a lot to be learned about their full cardiovascular profile.

Some recent studies led to the view that there were no advantages of ACE inhibitors over thiazides or beta-blockers with regard to mortality and morbidity in hypertensive patients. However, when patients with higher absolute cardiovascular risk are examined, differences emerge. ACE inhibitors, in placebo-controlled studies, have been shown to be more effective than older antihypertensives in patients with coronary heart disease, congestive cardiac failure, diabetic nephropathy, and stroke; head-to-head comparisons were not reported, however. ARBs have provided similar results for diabetic nephropathy and congestive cardiac failure.

The LIFE study results

The concept that blockade of the renin-angiotensin system can provide benefits beyond merely lowering blood pressure gets further support from the LIFE study.¹ In this trial, over 9,000 hypertensive patients with left ventricular hypertrophy were given an ARB (losartan) or a beta-blocker (atenolol) for at least 4 years. Not only did the ARB prevent more cardiovascular morbidity and mortality - chiefly with respect to stroke - than the beta-blocker for a similar reduction in blood pressure, but also it was associated with a significantly decreased frequency of new-onset diabetes.

About 13% of the LIFE study population had diabetes at entry into the study.² Analysis of the results from this subset showed that all-cause mortality was reduced by 39%, cardiovascular mortality by 37%, and congestive heart failure by 40% in the losartan group, compared with the results for atenolol. Findings for stroke and myocardial infarction were less impressive.

Measurements of left ventricular hypertrophy (Cornell voltage-duration product and Sokolow-Lyon measured on ECG) showed that losartan treatment was associated with a greater regression of hypertrophy, compared with atenolol treatment. This was seen in both the total study population (in those who had these parameters measured) and in the diabetic subset. The finding is not totally surprising, as angiotensin II is a myocardial growth factor, and an independent risk factor for cardiovascular disease.

Stroke was an endpoint that was particularly lessened with the ARB. It was not related to thiazide use - patients in both treatment arms took hydrochlorothiazide equally - nor was it apparently associated with the presence of atrial fibrillation. The finding fits with the observed greater reduction in ventricular hypertrophy, which is itself an independent risk factor for cerebrovascular events.

The decrease in the numbers of new-onset diabetes in the losartan group may represent, in fact, a relative increase in the atenolol group; beta-blockers are known to decrease insulin sensitivity, and therefore increase the likelihood of the development of the metabolic syndrome (Syndrome X).

Other recent studies

Brunner and Gavras reference previous studies of ACE inhibitors in hypertensive patients showing their benefits with respect to cardiovascular events. Similar results to those in the LIFE study have been reported for the HOPE study, which employed the ACE inhibitor ramipril, and the CAPPP study, which used captopril. There is little doubt that both ACE inhibitors and ARBs have similar effects on raised blood pressure, as well as other angiotensin II-related conditions, like left ventricular hypertrophy. Although they haven't been compared head-to-head, both ACE inhibitors and ARBs have the ability to provide a degree of renal protection in patients with type 2 diabetes and diabetic nephropathy. And one ARB, valsartan, has proved to be valuable in congestive heart failure, providing additional benefit when added to an ACE inhibitor.

Conclusions

To quote Brunner and Gavras, "To date, all evidence suggests that the beneficial effects of ACE inhibitors can be duplicated with ARBs without the nuisance of side effects". The chief ACE-inhibitor side effect that falls under the rubric 'nuisance' is a dry, persistent cough. Different studies have shown that candesartan, eprosartan, losartan and valsartan have virtually no potential to cause cough in subjects who developed cough with an ACE inhibitor. On the other hand, in these studies in hypertensive patients, the beneficial effects of the ACE inhibitors and the ARBs on blood pressure were virtually identical.

Other possible differences between ACE inhibitors and ARBs remain to be teased out in future studies. In the meantime, it seems safe to conclude that the benefits of both drug classes are extremely similar, their actions beyond lowering blood pressure are also similar, but they differ in that the ACE inhibitors have the propensity to cause an irritating dry cough.

Source

• Angiotensin blockade for hypertension: a promise fulfilled. HR. Brunner, H. Gavras, Editorial. Lancet, 2002, vol. 359, pp. 990--991

Footnotes
1. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. B. Dahlof, RB. Devereux, SE. Kjeldsen,  et al., Lancet, 2002, vol. 359, pp. 995--1003
2. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. LH. Lindholm, H. Ibsen, B. Dahlof,  et al., Lancet, 2002, vol. 359, pp. 1004--1010

Related Links
Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure
Angiotensin-Receptor Antagonists in Type 2 Diabetes
Getting a Handle on Syndrome-X

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