Yes, a number of beta-blockers are effective in lowering blood pressure (strength of recommendation [SOR]: A, multiple, consistent randomized controlled trials [RCTs]). Cardioselective beta-blockers do not alter lung function studies for patients with chronic obstructive pulmonary disease (COP D) or reversible airway disease (SOR: A, meta-analysis of RCTs). Propranolol and timolol have greater risks of causing fatigue as a side effect (SOR: A, meta- analysis of RCTs). Recent meta-analyses have stirred debate on the effectiveness of the agents in preventing adverse outcomes. The level of evidence has reached the point where the practice of using beta-blockers as monotherapy should be questioned (SOR : C, expert opinion)

Hitchcock, Kristin

Sontheimer, Daniel

University of Missouri: MOspace

312	 vol 56, No 4 / april 2007  The Journal of family PracTiceCliniCal iNquiries From the Family Physicians Inquiries NetworkDaniel Sontheimer, MD, MBaCox Family Medicine Residency, Springfield, MoKristin Hitchcock, MSiNorthwestern University,  Evanston, ILAre	there	big	differences		among	beta-blockers	in	treating	essential	hypertension?evidence-based answerYes, a number of beta-blockers are effective in lowering blood pressure (strength of recommendation [sor]: a, multiple, consistent randomized controlled trials [rCTs]). Cardioselective beta-blockers do not alter lung function studies for patients with chronic obstructive pulmonary disease (CopD) or reversible airway disease (sor: a, meta-analysis of rCTs).  propranolol and timolol have greater risks of causing fatigue as a side effect (sor: a, meta-analysis of rCTs). recent meta-analyses have stirred debate on the effectiveness of the agents in preventing adverse outcomes. The level of evidence has reached the point where the practice of using beta-blockers as monotherapy should be questioned (sor: c, expert opinion).clinical commentaryBeta-blocker debate may be irrelevant when these drugs are taken with other antihypertensivesDefinitive evidence has demonstrated reduced risk of cardiovascular events with beta-blockers as a primary antihypertensive agent for patients with concurrent coronary heart disease. However, using a beta-blocker as a primary antihypertensive for patients without such compelling indications is now considered controversial. in 2006, the uK’s National institute for Health and Clinical excellence published a clinical guideline for hypertension1 in which beta-blockers are no longer preferred as a routine initial therapy for hypertension and are reserved as alternative agents after diuretics, angiotensin-converting enzyme (aCe) inhibitors, angiotensin receptor blockers (arBs), and calcium channel blockers.  This recommendation was based on results from meta-analyses that suggest beta-blockers, especially atenolol, may not be as cardioprotective as other antihypertensives. This has been confirmed by a 2007 Cochrane analysis.2 Despite a half-life of only 6 to 7 hours, atenolol is nearly always dosed once daily, while carvedilol and metoprolol have half-lives of 6 to 10 and 3 to 7 hours, respectively, and are dosed at least twice daily. it is possible that the controversy with beta-blockers arises because atenolol should really be a twice-daily drug.  in clinical practice, most patients with hypertension need more than one agent to attain goal blood pressure values. The debate over whether one beta-blocker is better or worse may be clinically irrelevant when beta-blockers are used in combination with another antihypertensive.Joseph Saseen, PharmD, FCCP, BCPSuniversity of Colorado Health sciences Centerfast trackThe debate over whether one beta-blocker is better or worse may be irrelevant when beta-blockers are used with another antihypertensiveopyright® Dowden Health Medi   For personal use onlyFor mass reproduction, content licensing and permissions contact Dowden Health Media.fast trackwww.jfponline.com  vol 56, No 4 / april 2007 313z	Evidence	summaryNumerous trials have shown that beta-blockers lower blood pressure for patients with hypertension. No head-to-head tri-als of beta-blockers have been conducted that reveal differences in terms of patient-oriented outcomes, such as all-cause mor-tality, in the treatment of hypertension. No	effect	on	lung	function,		but	fatigue	is	a	factorA Cochrane review on the cardioselective beta-blockers atenolol (Tenormin), biso-prolol (Zebeta), and metoprolol (Lopres-sor) found that single-dose and multiple-treatment studies showed no decline in lung function among patients with mild to moderate reversible airway disease or chronic obstructive pulmonary disease.3,4 The analysis was not able to identify any differential effect of these beta-blockers with or without intrinsic sympathomimet-ic activity for patients with lung disease.That said, beta-blockers do have side effects. One meta-analysis found no dif-ference in the development of depression with beta-blocker therapy; however, first-generation beta-blockers (propranolol and timolol) had higher rates of fatigue than did the later beta-blockers.5 They re-ported that the risk of fatigue was only 18 per 1000 patients (95% confidence inter-val [CI], 5–30) and the risk for sexual dys-function was 5 per 1000 patients (95% CI, 2–8) for all beta-blockers as a class. Importantly, they also stratified side-effect findings on the basis of lipophilic vs non-lipophilic and found no difference in side effect frequency.Adverse	outcomes	data		give	reason	to	pauseTwo recent meta-analyses6,7 on beta- blockers have called into question the effectiveness of these agents in pre-venting adverse outcomes in treating hypertension. The first meta-analysis6 reviewed 4 studies that compared atenolol with pla-cebo or no treatment, and 5 that com-pared atenolol with other antihypertensive drugs. They found no outcome differences between atenolol and placebo in the 4 studies, comprising 6825 patients, fol-lowed for a mean of 4.6 years. There was no difference in all-cause mortality (rela-tive risk [RR]=1.01; 95% CI, 0.89–1.15), cardiovascular mortality (RR=0.99; 95% CI, 0.83–1.18), or myocardial infarction (RR=0.99; 95% CI, 0.83–1.19). The risk of stroke appeared to be lower in the aten-olol than in the placebo group (RR=0.85; 95% CI, 0.72–1.01). When atenolol was compared with other antihypertensives, there were no major differences in blood pressure lowering between the treatment arms. The authors found a significantly higher mortality (RR=1.13; 95% CI, 1.02–1.25) with atenolol treatment than with other active treatment, in 5 studies comprising 17,671 patients who were fol-lowed up for a mean of 4.6 years. Stroke was also more frequent with atenolol in comparison with other agents. The second meta-analysis7 covered 13 randomized controlled trials (n=105,951) comparing treatment with beta-blockers with other antihypertensive drugs. Seven studies (n=27,433) were included in a comparison of beta-blockers and placebo or no treatment. The relative risk of stroke was 16% higher for beta-blockers (95% CI, 4%–30%) than for other drugs. No difference was seen for myocardial infarc-tion. When the effect of beta-blockers was compared with that of placebo or no treat-ment, the relative risk of stroke was re-duced by 19% for all beta-blockers (95% CI, 7%–29%). There was no difference for myocardial infarction or mortality. An	age	divide	appears		with	adverse	eventsA subsequent meta-analysis found that beta-blocker therapy in younger patients (less than 60 years of age) is associated with a significant reduction in cardiovas-cular morbidity and mortality.8 Research-ers used data from 145,811 participants in 21 hypertension trials, beta-blockers reduced major cardiovascular outcomes A meta-analysis found that beta-blockers reduced major cardio- vascular outcomes in younger— but not older— patientsfast track314	 vol 56, No 4 / april 2007  The Journal of family PracTiceCliniCal iNquiriesBeta-blockers were inferior to calcium channel blockers, ACE  inhibitors, and ARBs for all-cause mortalityin younger patients (risk ratio=0.86; 95% CI, 0.74–0.99) but not in older patients (risk ratio=0.89; 95% CI, 0.75–1.05). In active comparator trials, beta-blockers demonstrated similar reductions in morbidity and mortality to other an-tihypertensive agents in younger patients (risk ratio=0.97; 95% CI, 0.88–1.07) but not in older patients (risk ratio=1.06; 95% CI, 1.01–1.10), with the excess risk being particularly marked for strokes (risk ratio=1.18; 95% CI, 1.07–1.30). The pri-mary outcome researchers evaluated was a composite of stroke, myocardial infarc-tion, and death. Calcium	channel	blockers	beat	beta-blockers	in	recent	reviewFinally, a more recent systematic review found beta blockers to be inferior to cal-cium channel blockers and renin-angio-tensin system inhibitors (ACE inhibitors or ARBs) for major endpoints of all-cause mortality, coronary heart disease, stroke, total cardiovascular events, and cardio-vascular mortality.9 This review found beta-blockers had similar outcomes as diuretics but were less well tolerated than diuretics (RR= 1.80; 95% CI, 1.33–2.42) or renin-angiotensin system inhibitors (RR=1.41; 1.29–1.54). Thirteen trials with 91,561 par-ticipants, meeting inclusion criteria, compared beta-blockers with placebo (4 trials; n=23,613), diuretics (5 trials; n=18,241), calcium-channel blockers (4 trials; n=44,825), and renin-angiotensin system inhibitors (3 trials; n=10,828). Compared with placebo, beta-blockers re-duced the risk of stroke (RR=0.80; 95% CI, 0.66–0.96) with a marginal fall in to-tal cardiovascular events (RR=0.88; 95% CI, 0.79–0.97), but did not affect all-cause mortality (RR=0.99, 0.88–1.11), coro-nary heart disease (RR=0.93, 0.81–1.07), or cardiovascular mortality (RR=0.93, 0.80–1.09). The effect on stroke was less than that of calcium-channel block-ers (RR=1.24, 1.11–1.40) and renin-an-giotensin system inhibitors (RR=1.30, 1.11–1.53). The effect on total cardiovas-cular events was less than that of calcium- channel blockers (RR=1.18, 1.08–1.29).Recommendations	from	othersThe Joint National Committee on Hyper-tension (JNC-7) states that excellent clin-ical trial data demonstrate that lowering blood pressure with beta-blockers (and several other drug classes) will reduce the complications of hypertension.10 The European Society of Cardiol-ogy recommends beta-blockers as the first choice for antihypertensive therapy, alone or in combination, for patients with previ-ous myocardial infarction, ischemic heart disease, arrhythmias or heart failure, as-ymptomatic left ventricular dysfunction, diabetes, or high risk of coronary disease, based on the efficacy of these drugs in these patient populations.11 nreferences 1.  Hypertension: Management of hypertension in adults in primary care. london: royal College of physicians; June 2006. available at www.nice.org.uk/CG034. ac-cessed on March 7, 2007.  2.  Wiysonge C, Bradley H, Mayosi B, et al. Beta-block-ers for hypertension. Cochrane Database Syst Rev 2007; (1):CD002003. 3.  salpeter s, ormiston T, salpeter e, Wood-Baker r. Cardioselective beta-blockers for CopD. Cochrane Database Syst Rev 2005; (4):CD003566.  4.  salpeter s, ormiston T, salpeter e. Cardioselective beta-blockers for reversible airway disease. Cochrane Database Syst Rev 2002; (4):CD002992. 5.  Ko DT, Hebert pr, Coffey Cs, sedrakyan a, Curtis Jp, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002; 288:351–357.  6.  Carlberg B, samuelsson o, lindholm lH. atenolol in hypertension: is it a wise choice? Lancet 2004; 364:1684–1689.  7.  lindholm lH, Carlberg B, samuelsson o. should beta blockers remain first choice in the treatment of primary hypertension? a meta-analysis. Lancet 2005; 366:1545–1553.  8.  Khan N, Mcalister Fa. re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006; 174:1737–1742.  9.  Bradley Ha, Wiysonge Cs, volmink Ja, et al. How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? systematic review and meta-analysis. J Hypertens 2006; 24:2131–2141.  10.  Chobanian av, Bakris Gl, Black Hr, et al. seventh report of the Joint National Committee on prevention, Detection, evaluation, and Treatment of High Blood pressure. Hypertension 2003; 42:1206–1252.  11.  lopez-sendon J, swedberg K, McMurray J, et al. ex-pert consensus document on beta-adrenergic recep-tor blockers. Eur Heart J 2004; 25:1341–1362.

Are there big differences among beta-blockers in treating essential hypertension?

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