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ABSTRACT & COMMENTARY
By Michael H. Crawford, MD
Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study. This article originally appeared in the
September 2014 issue of Clinical Cardiology Alert.
SOURCE: Makani H, et al. Antihypertensive efficacy of angiotensin receptor blockers as monotherapy as evaluated by ambulatory blood pressure monitoring: A meta-analysis. Eur Heart J 2014;35:1732-1742.
Angiotensin receptor blockers (ARBs) are often
used as first-line therapy for the treatment of systemic hypertension because of their perceived efficacy and relatively low incidence of adverse effects. However, there are contradictory reports about the efficacy of individual agents in this class, especially losartan. Thus, these investigators from New York City performed a meta-analysis of studies of ARBs used as monotherapy that employed 24-hour ambulatory blood pressure (BP) monitoring to assess antihypertensive efficacy. The randomized clinical trials included had to have no uptitration of the drugs, so they could clearly compare maximum recommended doses to half-maximum and quarter maximum doses of the ARBs. Also, trial duration had to be at least 1 month and no other classes of antihypertensives could be given. Also, none of the subjects could have severe hypertension. They identified 62 trials that met these criteria that enrolled more than 15,000 patients with a mean treatment duration of 10 weeks.
Reduction in systolic BP averaged 10 mmHg and diastolic BP averaged 7 mmHg at 25% maximum doses. At 50% maximum doses, systolic BP decreased 12 mmHg and diastolic BP 8 mmHg. At maximum doses, systolic BP dropped 13 mmHg and diastolic BP dropped 8 mmHg. When 25% maximum dose was compared to 50% maximum dose, there was a significant further reduction of systolic BP (P = 0.04) but not diastolic BP (P = 0.08). When comparing 50% to maximum dose, there was no significant reduction in systolic or diastolic BP.
Studies that compared losartan to other ARBs showed that losartan at 50% maximum dose (50 mg/day) lowered BP less than other ARBs (differences 2.5 mmHg systolic and 1.8 mmHg diastolic). Also, maximum dose losartan (100 mg/day) lowered BP less than maximum doses of other ARBs (differences 3.9 mmHg systolic and 2.2 mmHg diastolic). Sensitivity analyses showed no evidence of publication bias and no differences in outcomes based on study duration or number of subjects. The authors concluded that this comprehensive analysis of 62 studies of monotherapy at a fixed dose of ARBs showed a shallow dose response curve and that losartan was consistently inferior to other ARBs.
This analysis shows that ARBS as monotherapy have a similar efficacy as most other antihypertensive drugs; a 10-15 mmHg reduction in systolic BP and 5-10 mmHg in diastolic BP. Surprisingly, uptitrating the dose four-fold had little further effect. This is also consistent with other studies that have shown that combining drugs from two different classes of agents is approximately five times more effective than doubling the dose of one drug. The only exception to this rule appears to be calcium channel blockers, which seem to be more potent than most other agents in comparison studies, with maximum systolic BP lowering effects of up to 20 mmHg. Another reason not to uptitrate antihypertensive agents is to avoid dose-related side effects. This is a particular concern with thiazide diuretics, calcium blockers, and beta-blockers, but not with ARBs. Thus, for all these reasons, combination therapy at well-tolerated doses seems to trump uptitration of monotherapy.
The conclusion that losartan is the least effective of the ARBs has been demonstrated in other clinical studies and in vitro studies of angiotensin II receptor blocking effects. However, the absolute differences shown in this study were modest. Until recently, losartan was the only ARB available as a generic. Now that generic versions of other ARBs are becoming available, I predict the use of losartan will decrease in the United States.
Meta-analyses do have weaknesses. For example, no adjustments for adherence to therapy were made, but drug discontinuation rates are usually low with ARBs. Also, there were insufficient data to compare all the ARBs head to head. In addition, the population of patients studied all had mild-to-moderate hypertension and none had severe hypertension. Although not an ideal study, it supports the shift toward using combination therapy in moderately severe hypertension and the marketing of drug combination pills for hypertension treatment.