Beta‐blockers as sub‐optimal treatment for hypertension: Time for first‐line therapy revision?

Recent evidence provides growing support to earlier observations by Messerli et al. (1) that beta-blockers might not offer optimal cardiovascular protection for patients with uncomplicated essential hypertension. Firstly, a meta-analysis of Lindholm et al. (2) has shown that beta-blocker treatment of patients with primary hypertension was associated with a substantially higher risk of stroke than treatment with other antihypertensive drugs taken together. This was the case when all beta-blockers were analyzed together and when the studies with atenolol were analyzed separately. Secondly, Bradley et al. (3) recently evaluated to what extent the conclusions made by Lindholm and colleagues relate to comparisons between beta-blockers and specific classes of antihypertensive drugs. They showed that beta-blockers were inferior to calciumchannel blockers in terms of all-cause mortality, stroke and cardiovascular mortality, and to renin–angiotensin system inhibitors for all-cause mortality and stroke. In comparison with diuretics, beta-blockers had similar outcomes, but were less well tolerated. Taken together, these results indicate beta-blockers are not as effective as some other classes of antihypertensive medication in the management of patients with primary hypertension. In the recently updated National Institute for Health and Clinical Excellence guidelines for England and Wales, the indication for beta-blockers has been changed from first-line therapy to use as an additional agent in patients requiring polytherapy (4,5). Therefore, it is not surprising that there are increasing numbers of researchers that question the validity of large-scale studies using atenolol as comparator. In the current issue of Blood Pressure, Dahlöf et al. (6) reviewed the literature to assess the effect of beta-blockers compared with initial placebo or nontreatment for the reduction of cardiovascular events in hypertensive patients, and to re-evaluate atenolol as the comparator in the LIFE study. Beta-blocker-based antihypertensive therapy resulted in a significant risk reduction for combined cardiovascular events (19%, pv0.001), cardiovascular death (15%, p50.037) and stroke (32%, pv0.001). Thus, atenolol was an appropriate comparator at the time when the LIFE study was designed in the early 1990s. Nevertheless, results of LIFE and other recent studies, including the above-mentioned meta-analyses, support using newer comparators in future trials. The sympathetic nervous system is an integral mechanism in the overall regulation of blood pressure. The weight of evidence strongly suggests that sympathetic over-activity is important in the etiology and maintenance of hypertension. Therefore, at first glance it might seem surprising that treatment of hypertension with beta-blockers is not able to provide optimal risk reduction. A possible explanation could be that sympathetic activation is itself a dynamic entity, progressing from one profile to another as the patient ages. Beta1-mediated sympathetic activation of the heart may contribute to the hemodynamic profile of early human hypertension. However, at later stages the sympathetic activation to the heart is of less importance. By contrast, the sympathetic nervous system may augment vascular dysfunction by alpha1 receptor stimulation. Accordingly, the lack of beta-blocker effectiveness in older patients might be at least partially explained through the pathophysiological perspective. Indeed, this concept is supported by the results of recent meta-analysis designed to clarify the efficacy of beta-blockers in different age groups (7). This study has shown that beta-blockers reduce major cardiovascular outcomes in younger patients with hypertension but not in older patients. Under these circumstances, would it be wise to treat younger patients with beta-blockers? One should keep in mind that these patients would require life-long therapy. Hence, it is of particular importance to recognize that long-term antihypertensive Blood Pressure. 2006; 15: 323–324