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Beta-blockers no longer recommended for first-line treatment of uncomplicated hypertension
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Beta adrenergic receptor antagonists have been recognized as an option for the treatment of hypertension for more than 25 years.
Joint National Committee 7 hypertension treatment guidelines recognize beta blockers as one of five first-line therapy options. However, their use for uncomplicated hypertension has recently decreased due to concerns over increased morbidity and mortality demonstrated in a number of clinical trials as well as metaanalyses. Most notably, a 2007 Cochrane metaanalysis included 13 trials that compared beta blockers with placebo, diuretics, calcium channel blockers, and renin angiotensin system blockers. Atenolol was used in more than 75% of the beta-blocker-treated patients, which mirrors current practice. When the beta-blocker arms were compared with placebo, there was no benefit in all-cause mortality reduction. Increased occurrence of CVD and stroke was noted when beta- blockers were compared to CCB or RAS blockers. Additionally, patients receiving beta-blockers were more likely to experience adverse metabolic events and other side effects which may have further worsened outcomes.
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Whether beta-blockers are as effective as other agents when evaluating BP lowering, and whether BP reduction conferred by beta-blockade is effective in preventing adverse CV events has been questioned.
In INVEST, 22,576 patients with hypertension and CAD were followed for a mean 2.7 years. The researchers compared atenolol plus hydrochlorothiazide dosed twice daily with verapamil SR plus trandolapril also dosed twice daily. BP lowering and adverse CV outcomes were the same.
However, in the LIFE trial, losartan with add-on HCTZ demonstrated superior BP lowering and CV outcome prevention compared with once-daily atenolol with add-on HCTZ. That trial included 9,193 patients with hypertension and left ventricular hypertrophy.
Similarly, ASCOT, which enrolled 19,257 patients at high risk for hypertension and compared atenolol plus bendroflumethiazide with amlodipine plus perindopril, was stopped early; this was primarily due to increased mortality in the atenolol group. Overall, there was significantly greater BP reduction in the amlodipine group.
Like in LIFE, in ASCOT all drugs were dosed once daily. CAFE, an ASCOT substudy of 2,199 patients, evaluated central aortic pressure and observed substantial reductions in central aortic and pulse pressures in the amlodipine-treated group compared with the atenolol-treated group. This difference remained constant throughout the four-year study evaluation. In a post hoc analysis, central pulse pressure was significantly associated with the composite outcome, total CV events and development of renal impairment. While the result of CAFE suggests drug therapy that lowers central aortic pressure may be more relevant to the CV endpoint measure than brachial BP measurement, it is not possible to know whether the BP differences observed in ASCOT and CAFE were due to the once-daily dosing of atenolol (serum half life is about six to seven hours), or the superior BP reduction of amlodipine.
Although beta-blockers have fallen out of favor as first-line agents in those with uncomplicated hypertension, there will likely continue to be a role for beta-blockers in the treatment of patients with hypertension combined with chronic stable angina, HF or who are post-MI. Additionally, the role of long-acting beta-blockers and beta-blockers that have mixed receptor sites for activation, or have vasodilating effects, requires further investigation in long-term studies to definitively address the appropriate use of these agents and their clinical benefit.
In 2007, the European Society of Hypertension/European Society of Cardiology stopped endorsing beta-blockers in patients with hypertension and without angina, HF, tachyarrhythmias, glaucoma or prior MI. In the United States, we await updated guidelines from the JNC for treatment of hypertension which may contain similar recommendations to avoid use of beta-blockers as first-line treatment for uncomplicated hypertension.
Mary Parker, PharmD, BCPS (AQ Cardiology) is Director of Cardiovascular Risk Reduction Clinics at LeBauer HeartCare in Greensboro, NC.
Rhonda Cooper-DeHoff, PharmD, MS, Associate Professor, University of Florida College of Pharmacy, Gainesville, is Cardiology Today’s regular Pharmacology Consult columnist and a member of the CHD and Prevention section of Cardiology Today’s Editorial Board.