Which Drugs Have Truly Safe and Effective Effects?

Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ. 2006;174:1737-1742. Abstract
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. Abstract
Beevers DG. The end of beta blockers for uncomplicated hypertension? Lancet. 2005;366:1510-1512.
Khan NA, McAlister FA, Rabkin SW, et al. The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part II - Therapy. Can J Cardiol. 2006;22:583-593. Abstract
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Beta-Blockers Safe for Younger Patients, Canadian Researchers Say

Just as it appears that beta-blockers are "dead in the water" as first-line antihypertensive agents, a new meta-analysis suggests this may not be true for all age groups, or for all risks. And are statins antihypertensive agents? Another meta-analysis, from the 2006 European Society of Hypertension (ESH) meeting in Madrid, Spain, suggests they are. Meanwhile, one of the safest antihypertensive drug classes, angiotensin-converting enzyme (ACE) inhibitors, may be unsafe in pregnancy, but effective against cancer. And rounding out the news this month, positive airway pressure is effective, hawthorn may be effective, and if frog slime proves effective, Brazil wants compensation.

A new meta-analysis of beta-blockers as first-line therapy for hypertension confirms that they should not be used in older patients (age > 60 years) who do not have another indication for these agents such as heart failure, post myocardial infarction (MI), or symptomatic coronary disease. However, unlike several other notable investigators in the field, Nadia Khan, MD, MSc (University of British Columbia, Vancouver, Canada) and Finlay A. McAlister, MD, MSc (University of Alberta, Edmonton, Canada), say that the evidence supports the use of beta-blockers as first-line therapy in younger patients without contraindications or prior intolerance to thiazide diuretics. In younger patients, beta-blockers are associated with a significant reduction in cardiovascular morbidity and mortality, Drs. Khan and McAlister note.

Their meta-analysis is published in the June 6 issue of the Canadian Medical Association Journal.^[1] Its conclusions challenge those of Lars Hjalmar Lindholm, MD (Umea University, Sweden) and colleagues, who have published several meta-analyses on the same topic. The most recent, which appeared in 2005,^[2] involved data pooled from 18 randomized trials from which it was concluded that there is an excess risk of stroke associated with beta-blockers compared with other classes of antihypertensive drugs, and that beta-blockers should not remain one of the first-choice options for the treatment of hypertension. The accompanying editorial^[3] suggested that this might mark "the end of beta-blockers for uncomplicated hypertension."

Drs. Khan and McAlister believe that the conclusion was flawed, because "not all randomized hypertension trials relevant to this question were included in the meta-analysis, and Prof. Lindholm and colleagues focused on an individual endpoint (stroke), rather than the composite outcome usually reported in hypertension clinical trials, 'major cardiovascular outcomes,' ie, stroke, MI, or death." In addition, they "inappropriately pooled data from trials involving people in their 70s and 80s with those from trials involving people in their 40s and 50s." The pathophysiology of hypertension differs in older and younger patients, they say.

Drs. Khan and McAlister organized their meta-analysis according to different age groups. The primary outcome was a composite of stroke, MI, and death. They identified 32 randomized controlled trials that evaluated the efficacy of beta-blockers as first-line therapy for hypertension in preventing major cardiovascular outcomes. The trials were published between 1982 and 2004 and involved a total of 145,811 participants. Both authors independently evaluated the eligibility of all trials. Trials enrolling older (mean age at baseline ≥ 60 years) patients were separated from those enrolling younger (mean age < 60 years) patients.

On the basis of this analysis, in placebo-controlled trials, beta-blockers reduced major cardiovascular outcomes in younger patients by 14% (risk ratio [RR] 0.86, 95% confidence interval [CI] 0.74-0.99), but not in older patients (RR 0.89, 95% CI 0.75-1.05). In active comparator trials, beta-blockers demonstrated efficacy similar to that of other antihypertensive agents in younger patients (RR 0.97, 95% CI 0.88-1.07), but not in older patients (RR 1.06, 95% CI 1.01-1.10), with the excess risk being particularly marked for strokes (RR 1.18, 95% CI 1.07-1.30).

Their findings confirm those of Prof. Lindholm and colleagues that beta-blockers are associated with an increased risk of stroke compared with other antihypertensive agents, but the excess risk was largely driven by data from trials enrolling older patients, the Canadian researchers conclude. Younger patients randomly assigned to beta-blockers had rates of cardiovascular death, MI, or stroke similar to those in patients assigned to other antihypertensive agents, and "beta-blockers were more efficacious than placebo in these patients," they say.

There is robust evidence from a set of trials enrolling over 30,000 hypertensive patients to refute the claim that beta-blockers are less beneficial than other antihypertensive agents, they say, and "this supports the 2006 Canadian Hypertension Education Program Recommendations^[4] that beta-blockers should remain one of the recommended drug classes in the therapeutic armamentarium for younger hypertensive patients." Drs. Khan and McAlister are lead authors of the Canadian guidelines.

Prof. Lindholm himself appears to remain unconvinced by their arguments. At the recent 16th Annual Scientific Meeting of the European Society of Hypertension (ESH), held June 12-15 in Madrid, Spain, he declared that "regardless of age, beta-blockers should not [his emphasis] remain first choice in the treatment of primary hypertension, whereas diuretics, calcium antagonists, and ACE inhibitors may be so" [sic].^[5] He had tried, unsuccessfully, to persuade the Canadians of this, he added.