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Do β-blockers have a role in treating hypertension?

YES

Finlay A. McAlister, MD FRCPC MSc
Associate Professor in the Division of General Internal Medicine at the University of Alberta in Edmonton

Correspondence to: Dr Nadia Khan, Centre for Health Evaluation and Outcomes Sciences, 620B—1081 Burrard St, St Paul’s Hospital, Vancouver, BC V6Z 1Y6; telephone 604 266-0961; fax 604 266-0962; e-mail nakhan{at}shaw.ca

The 2006 Canadian Hypertension Education Program recommendations¹ continue to list β-blockers as appropriate first-line therapy for uncomplicated hypertension in those younger than 60 years (but not for those older than 60). A recent, widely publicized meta-analysis, however, reported that β-blocker use was associated with increased risk of stroke,² sparking great controversy about the role of these agents in treating hypertension. Many family physicians are now facing the following questions.

1. Do β-blockers have any role in treatment of hypertension?
   
2. If patients are stable and well controlled on β-blocker therapy, should their therapy be changed?
   

Pathophysiology of hypertension

Efficacy of β-blockers might differ by age, given the differences in the pathophysiology of hypertension in younger and older patients. Younger patients tend to develop hypertension with high sympathetic drive and cardiac output but normal arterial compliance—a state attenuated by β-adrenergic blockade. Older patients generally have systolic hypertension with increased arterial stiffness. Thus, agents having little effect on arterial compliance, such as β-blockers, would be expected to be less beneficial for older patients.

Clinical trial evidence

These differences in efficacy according to age have largely been borne out in clinical trials. Messerli et al published a meta-analysis of hypertension trials that evaluated β-blockers in patients older than 60.³ From a pooled analysis of 10 trials published before 1999 (N=16164), they found that β-blockers were not significantly different from placebo in reducing cardiovascular mortality and all-cause mortality. Because of these data, the Canadian hypertension guidelines¹ have recommended that β-blockers not be used as initial monotherapy for uncomplicated hypertension among the elderly. The guidelines have continued, however, to endorse β-blockers for elderly patients with congestive heart failure or a history of myocardial infarction (MI) or symptomatic angina and as second- or third-line agents for patients with uncontrolled hypertension.

In their meta-analysis, Lindholm et al pooled together 18 trials (N = 106 460) evaluating β-blocker use regardless of patient age.² In this analysis, there was no difference in risk of MI or death. While β-blockers were associated with reduced risk of stroke (reduced relative risk [RR] 19%, 95% confidence interval [CI] 7% to 29%) in placebo-controlled trials, this was less than the 32% reduction seen with other antihypertensive agents in placebo-controlled trials.⁴ In trials comparing one antihypertensive agent with another, patients assigned β-blockers had a 16% higher risk of stroke than patients taking other antihypertensives did.

Given the plausible differences in β-blocker efficacy according to age, however, we re-analyzed all β-blocker hypertension trials according to age of participants.⁵ In trials where the average age was older than 60, β-blockers were associated with increased risk of stroke, MI, or death compared with other antihypertensives (RR 1.07, 95% CI 1.00–1.14), largely driven by an 18% increase (95% CI 7%–30%) in risk of stroke. Among trials where the average age of patients was younger than 60, there was no difference in the composite outcome of stroke, MI, or death between patients taking β-blockers and those taking other agents (RR 0.97, 95% CI 0.88–1.07).

Tolerability and side effect profile

Like all antihypertensive agents, β-blockers can have adverse effects. Contrary to popular belief, however, β-blockers are generally well tolerated and do not impair quality of life.⁶ They do have several contraindications, including moderate or severe asthma, but they appear to be safe for patients with chronic obstructive pulmonary disease with minor airway reversibility and those with sick sinus syndrome or high-degree atrioventricular block. While studies demonstrate adverse effects on insulin resistance and lipid profile, newer β-blockers with vasodilatory effects, such as carvedilol, have neutral effects on insulin sensitivity and lipid profile.⁷ Meta-analyses also report no significant increases in depressive symptoms⁸ or in exacerbation of claudication for patients with peripheral arterial disease.⁹ Although β-blockers are associated with fatigue and sexual dysfunction, the absolute risks are fairly small (fatigue, 18 per 1000 patients; sexual dysfunction, 5 per 1000).

Conclusion

Do β-blockers have any role in the treatment of hypertension?
Although β-blockers should not be used for first-line monotherapy in elderly patients with hypertension, they remain reasonable first-line treatment for patients younger than 60 with uncomplicated hypertension or for patients of any age with heart failure, symptomatic angina, or MI within the previous 2 years, and they remain reasonable add-on agents for patients with uncontrolled hypertension.

If patients are stable and well controlled on β-blocker therapy, should their therapy be changed?
While no trial data directly answer this question, hypertension studies collectively demonstrate that the most important factor in improving outcomes is achieving good blood pressure control; choice of agent is less important.¹⁰

KEY POINTS β-Blockers are appropriate first-line treatment for patients younger than 60 with uncomplicated hypertension or for patients of any age with heart failure, symptomatic angina, or myocardial infarction within the previous 2 years. β-Blockers are reasonable add-on agents for patients with uncontrolled hypertension. Hypertension studies collectively demonstrate that the most important factor in improving outcomes is achieving good blood pressure control; choice of agent is less important.

 

Acknowledgment

Dr Khan is a GENESIS (Canadian Institutes of Health Research [CIHR] and Heart and Stroke Foundation of Canada) young investigator, a CIHR New Investigator, and a St Paul’s Hospital Foundation New Investigator. Dr McAlister is supported by the Alberta Heritage Foundation for Medical Research, CIHR, and the University of Alberta/Merck Frosst/Aventis Chair in Patient Health Management.

References

1. Khan NA, McAlister FA, Rabkin SW, Padwal R, Feldman RD, Campbell NR, et al. The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension. Part II—therapy. Can J Cardiol 2006;22(7):583-93.[Medline]
2. Lindholm LH, Carlberg B, Samuelsson O. Should βblockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545-53.[Medline]
3. Messerli FH, Grossman E, Goldbourt U. Are β–blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279:1903-7.[Abstract/Free Full Text]
4. Psaty BP, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003;289:2534-44.[Abstract/Free Full Text]
5. Khan N, McAlister FA. Re-examining the efficacy of β-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006;174:1737-42.[Abstract/Free Full Text]
6. Dobre D, van Jaarsveld CH, Dejongste MJ, Haaijer Ruskamp FM, Ranchor AV. The effect of beta-blocker therapy on quality of life in heart failure patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2007;16(2):152-9.[Medline]
7. Jacob S, Rett K, Henriksen EJ. Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of β-blocking agents? Am J Hypertens 1998;11:1258-65.[Medline]
8. Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. β-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288:351-7.[Abstract/Free Full Text]
9. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med 1991;151(9):1769-76.[Abstract/Free Full Text]
10. Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003;21:1055-76.[Medline]

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