Hypertension Therapy—Becoming More Interesting!

Abstracts & Commentary

Synopsis: In patients with hypertension and LVH, despite equal blood pressure lowering effects, losartan reduced cardiovascular events more than atenolol. These effects were more pronounced in diabetics.

Sources: Dahlof B, et al. Lancet. 2002;359:995-1003; Lindholm LH, et al. Lancet. 2002;359:1004-1010.

Two new publications suggest that specific choice of agent for control of blood pressure may be more important than previously believed. One of the largest trials in hypertension therapy, cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE), a randomized trial against atenolol, tested the hypothesis that interference with the renin-angiotensin system (RAS) may be as important as blood pressure control in reducing cardiovascular morbidity and mortality. The primary hypothesis of this study is that a selective angiotensin-II type 1 receptor blocker (ARB) would be more effective in reducing cardiovascular (CV) morbidity and mortality than the beta blocker atenolol in hypertensive patients with ECG evidence of left ventricular hypertrophy (LVH). The study was multinational, and enrolled 9193 subjects age 55-80 with essential hypertension, randomized to either losartan or atenolol. "Entry" baseline sitting blood pressure (BP) was 160-200/95-115 mm Hg. Patients had to have ECG LVH. The primary end point was a combination of CV death, myocardial infarction (MI), and stroke. Other secondary end points were assessed. Trial duration was a minimum of 4 years. Initiation of drug therapy was stepwise; all patients received hydrochlorothiazide (HCTZ) 12.5 mg. If blood pressure control was not adequate on the maximum dose of each drug (losartan or atenolol 100 mg daily plus HCTZ up to 25 mg), other agents could be added. A substudy indicated that most individuals had LVH on echocardiography. The trial was stopped when sufficient prespecified primary end points occurred. Patients enrolled between 1995-1997 from all Scandinavian countries, Iceland, the United Kingdom, and the United States. The 2 groups were closely matched in all characteristics; mean follow-up was 4.8 years. More than 80% of individuals were maintained on the initial study drug. The daily mean dose of losartan was 82 mg; atenolol 79 mg.

Results: Blood pressure was reduced in both groups to a comparable level by 40/17 mm Hg. Blood pressure at the last visit was 144/81 in both groups. Half of all subjects had a final sitting BP of £ 140/90. The adjusted primary end point demonstrated a 13% risk reduction with losartan, with curve separation beginning early and continuing in year 5-6, P = 0.02. Stroke outcome was robustly reduced by losartan with a 25% RR decrease, P = 0.001. ECG LVH was decreased more with losartan. Of interest, the ARB reduced the incidence of new diabetes during the study by 25%. Overall event rates were more than 2% per year, (11% for losartan and 15% for atenolol); thus, these subjects meet high-risk criteria defined by the NCEP-ATP-III scoring system. MI was not reduced in the ARB group. Dahlof and colleagues believe that LIFE is the first study to demonstrate a major clinical end point difference between 2 active treatment groups in hypertension, and stress that the comparable BP lowering effects within the 2 cohorts indicate that the ARB has additional protection against stroke beyond reducing BP. They state that although MI incidence did not differ between the 2 groups, atenolol presumably provided the cardioprotection common to all beta blockers, thus indicating an equivalent ARB protective effect. They suggest that the benefit of losartan "could result from increased protection against the detrimental effects of angiotensin II."

In a companion report, the LIFE investigators analyzed the large number of diabetics in the study. These results are actually more robust than those in the primary study. In this study, 1195 diabetics (13% of entire study) who met LIFE criteria were enrolled. Mean age was 67 and blood pressure was 177/96. At follow-up of 4.7 years, BP reduction was comparable of 18/11 mm Hg, to a mean final pressure of 147/79. The primary end point was reduced by 24%, P = 0.031. Cardiovascular mortality was reduced by 37%, P = 0.028, and all-cause mortality by 39%, P = 0.002. Compared to the majority of LIFE subjects without diabetes, the diabetic patients had a higher BMI, coronary risk score, and prevalence of cardiovascular disease. In addition, baseline BP was slightly higher. A primary end point occurred in 20% of the diabetics. Reduction of stroke or MI was not different between the 2 groups. Heart failure admissions were reduced by 41% with losartan, P = 0.019. As in the entire LIFE study, fewer adverse events occurred with losartan. Albuminuria was less frequent in the ARB group. In addition, ECG LVH was considerably less with losartan than atenolol. Lindholm and associates note that in the 20% of diabetics not previously with hypertensive therapy, the results were even more impressive. They suggest that "lowering blood pressure may be even more important than glucose control in diabetics." Other studies in diabetics, but not all, including CAPPP and HOPE, are compatible with these results. Lindholm et al again stress the detrimental role of angiotensin II, and note that LVH is a risk marker for increased morbidity and mortality in diabetic patients.

Comment by Jonathan Abrams, MD

LIFE is a landmark study in some respects, as it convincingly demonstrates that an agent that interferes with the angiotensin cascade with equivalent BP lowering to a beta blocker, has no downside and confers a small but definite reduction in morbidity, most of which is stroke. The data in the diabetics are even more robust, and consistent with the results of captopril in diabetic patients in CAPP. The HOPE study also enrolled a larger number of diabetics, not all hypertensive, who had an additional major CAD risk factor. In HOPE, patients at high vascular risk responded favorably to interference with the RAS provided by the ACE inhibitor ramipril. HOPE was not a comparative trial with another active agent, but did demonstrate that in high-risk patients, interfering with A-II is a big plus!

There was no reduction in MI in either the main cohort or in the diabetic subanalysis. The primary end point was reduced to 18% with losartan vs. 23% with atenolol; the CV mortality was 6% vs. 10%; both statistically significant. These data support that standard treatment of hypertension should include an ACE inhibitor or ARB based on the HOPE and LIFE trials. In the hypertensive diabetic, using either of these drug classes would appear to be mandatory, and HOPE suggests that an ACE inhibitor should also be used for diabetics those who do not have hypertension. Approximately half of type II diabetics will have hypertension, which imparts a substantial augmentation of CV risk. Dahlof et al’s contention that equivalence of MI events between the 2 drugs suggests that losartan is cardioprotective is interesting. Stroke reduction is an important end point itself, and LIFE is very good news in this regard. Diabetics in LIFE were at an even greater risk, as indicated by their higher event rates compared to nondiabetics. The reduction of new diabetes in LIFE and in HOPE suggests possible improvement of insulin resistance and/or anti-inflammatory actions are features of these 2 related drug classes.

Dr. Abrams, MD is Professor of Medicine, Division on Cardiology, University of New Mexico, Albuquerque.