February 4, 2010 A new review of the use of beta blockers as second-line therapy for primary hypertension has shown

n that the pattern of blood-pressure lowering for this drug class is different than that of thiazide diuretics [1]. Jenny MH Chen (University of British Columbia, Vancouver) and colleagues report their findings in the Cochrane Database of Systematic Reviews. The common belief is that all classes of drugs lower blood pressure to the same degree. This is the first clear demonstration that that is not the case. "The common belief is that all classes of drugs lower blood pressure to the same degree," Chen told heartwire . "This is the first clear demonstration that that is not the case and it is one of the reasons we undertook these systematic reviews. [Chen and colleagues previously published a review on thiazide diuretics as second-line therapy.] We predicted that because different antihypertensive drug classes lower blood pressure by different mechanisms of action, they would lower blood pressure differently." Chen said the most important finding of their study is that although beta blockers and thiazide diuretics reduce systolic BP to the same degree, "beta blockers reduce diastolic BP to a greater degree and pulse pressure to a lesser degree." The magnitude of the differences is "small, 1-2 mmHg, but it is highly statistically significant and likely clinically significant," she said. Review Covered 20 Randomized Controlled Trials Chen et al reviewed 20 double-blind, randomized controlled trials (RCTs) comparing a beta blocker in combination with another class of antihypertensive drug with that drug alone for 3 to 12 weeks in a total of 3744 patients with primary hypertension. They did not include studies in which beta blockers were added to either angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker therapy because they could not find any such trials. Their objective was to quantify the effect of beta-blocker therapy when added as second-line treatment on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and withdrawals because of adverse events. The BP reduction from adding a beta blocker was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. A reduction in BP was seen when a beta blocker was added to thiazide diuretics or calcium channel blockers at doses as low as 0.25 times the manufacturer's recommended starting dose. The BPlowering effect of beta blockers as a second drug was 6/4 mmHg at the starting dose and 8/6 mmHg at twice the starting dose. Thiazides Lower Pulse Pressure to a Much Greater Degree When the antihypertensive effects of beta blockers from this review were compared with those of thiazide diuretics from Chen et al's previous research, published in October 2009, the researchers identified the difference in effect on diastolic BP, indicating that beta blockers have little or no effect on pulse pressure, whereas "thiazides cause a significant dose-related decrease in pulse pressure," they explain. "This difference in the pattern of BP lowering with beta blockers as compared to thiazides might be the explanation for the fact that beta blockers appear to be less effective at reducing adverse cardiovascular outcomes than thiazide diuretics, particularly in older individuals," they add.

"It is known that pulse pressure is greater and represents a greater risk factor in older patients," Chen explained to heartwire . She said that as a result of the two reviews, she would recommend the use of first-line thiazides, "based on equal or better evidence of effectiveness and lower cost. If, for some reason, a thiazide was not given first-line, we recommend it second-line." Beta Blockers Good for AF and Other Tachyarrhythmias Beta blockers also reduced heart rate by 10 beats per minute at one to two times the starting dose, an effect that is "not surprising," said Chen. "Beta blockers will continue to be useful in settings where a reduction in heart rate is required (eg, atrial fibrillation and other tachyarrhythmias)," she noted. Chen et al also found no increase in withdrawals due to adverse effects with beta blockers in their review, but Chen said this "is probably not a true finding" because this outcome was not reported in 35% of the included trials. References 1. Chen JMH, Heran BS, Perez MI, et al. Blood pressure lowering efficacy of beta blockers as second-line therapy for primary hypertension. Cochrane Database Syst Rev 2010; 1:CD007185. Abstract

Clinical Context
Even when single antihypertensive agents are individualized to each patient's specific condition and titrated to high doses, BP targets are often not achieved with the first drug used for monotherapy. Beta-blockers are in widespread clinical use to treat hypertension, thereby lowering the risk for cardiovascular disease and stroke. These drugs can be used as monotherapy or adjunctive therapy when combined with a variety of antihypertensive agents from different drug classes. Because different classes of antihypertensive drugs have different mechanisms of action, prescribing drugs from more than 1 class may address different mechanisms involved in causing hypertension. Compared with monotherapy, greater decreases in blood pressure may therefore be achieved.

Study Highlights
The goal of the study was to determine the effects of beta-blockers given as a second-line drug in adult patients with primary hypertension. Specific effects studied were on SBP, DBP, heart rate, and withdrawals because of adverse effects. The reviewers searched CENTRAL (the Cochrane Library 2009, Issue 2), MEDLINE (1966 Aug 2009), EMBASE (1988 - Aug 2009), and references of retrieved articles and reviews. Selection criteria were double-blind RCTs of a beta-blocker plus a drug from another class of antihypertensive drugs vs that drug alone. Studies were included if trial duration was 3 to 12 weeks and subjects were patients with primary hypertension. For each included study, 2 reviewers independently extracted the data and evaluated trial quality.

The reviewers identified 20 double-blind RCTs meeting inclusion criteria. These RCTs enrolled a total of 3744 patients with hypertension (baseline BP, 158/102 mmHg; mean trial duration, 7 weeks). To estimate the effect of adding a beta-blocker as the second drug on lowering BP, the reviewers compared the difference in BP reduction between the combination and monotherapy groups. Adding a beta-blocker to thiazide diuretics or calcium channel blockers was associated with a decrease in BP, even at doses as low as 0.25 times the maker's recommended starting dose. Reduction in BP when a beta-blocker was added as a second drug was 6/4 mm Hg at 1 times the starting dose and 8/6 mm Hg at 2 times the starting dose, or an approximately 30% additional reduction when the dose was doubled. Adding a beta-blocker as second-line therapy did not appear to change SBP and DBP variability. When given at 1 to 2 times the starting dose, beta-blockers were associated with a decrease in heart rate by 10 beats/minute. This review showed no statistically significant increase in withdrawals from adverse effects of beta-blockers. However, 35% of the included RCTs did not report withdrawals from adverse effects. When the BP-lowering effect of beta-blockers from this review was compared vs that of thiazide diuretics from a previous Cochrane review, second-line beta-blockers reduced SBP by the same amount as second-line thiazide diuretics but had a greater effect on DBP. Because of the different effect on DBP, beta-blockers have little or no effect on pulse pressure, whereas thiazides cause a significant dose-related decrease in pulse pressure. Limitations of this study include lack of data on the effect of adding beta-blockers to other classes of antihypertensive drugs and incomplete and possibly selective outcome reporting bias for heart rate and withdrawals because of adverse effects.

Clinical Implications
A Cochrane systematic review showed that adding a beta-blocker as second-line antihypertensive therapy reduced BP vs placebo in a dose-related fashion at a dose range of 0.25 to 2 times the recommended starting dose. Second-line beta-blockers had little or no effect on pulse pressure or BP variability. Second-line beta-blockers reduced resting heart rate by 10 beats/minute at 1 and 2 times the starting dose. Although second-line beta-blockers did not statistically significantly increase withdrawals for adverse effects, 35% of trials did not report this outcome.

CME Test

According to the systematic Cochrane review by Chen and colleagues, which of the following statements about the effects of beta-blockers given as a second-line drug on BP in adult patients with primary hypertension is not correct? Reduction in BP when a beta-blocker was added as a second drug was 6/4 mm Hg at 1 times the starting dose Reduction in BP when a beta-blocker was added as a second drug was 8/6 mm Hg at 2 times the starting dose

At doses of 0.25 times the maker's recommended starting dose, no BP-lowering effect was observed Adding a beta-blocker as second-line therapy did not appear to change SBP and DBP variability According to the systematic Cochrane review by Chen and colleagues, which of the following statements about the effects of beta-blockers given as a second-line drug on heart rate and withdrawals because of adverse effects in adult patients with primary hypertension is correct? When given at the starting dose, beta-blockers were not associated with a decrease in heart rate When given at 2 times the starting dose, beta-blockers were associated with a decrease in heart rate by 5 beats/minute Beta-blockers were associated with a significant increase in withdrawals because of adverse effects Beta-blockers had little or no effect on pulse pressure
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