Author + information
- Stéphane Laurent, MD, PhD⁎ ( and )
- Pierre Boutouyrie, MD, PhD
- ↵⁎Department of Pharmacology and INSERM U970, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Université Paris 5, 20, rue Leblanc, 75015 Paris, France
In their recently published article, Bangalore et al. (1) concluded, from a meta-regression analysis of 9 studies including a total of 34,096 patients taking beta-blockers as first-line therapy and 30,139 patients taking other antihypertensive agents, that beta-blocker–associated reduction in heart rate increased the risk of myocardial infarction, cardiovascular events, and death for hypertensive patients. The authors suggested, as a mechanism, that “pharmacologically induced bradycardia leads to dyssynchrony or uncoupling between outgoing and reflected wave, thereby elevating central aortic pressure.” They referred to the CAFE (Conduit Artery Functional End Point) study, which showed a higher central aortic systolic blood pressure after atenolol-based treatment than after amlodipine-based treatment, and to the main ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study showing a better predictive value for cardiovascular events of amlodipine-based treatment than atenolol-based treatment. Although appealing, their conclusion that beta-blockers are deleterious through the reduction in heart rate, thus increasing central pulse pressure, may be too simplistic and not supported by data.
Indeed, although the authors pointed out that resting heart rate was an independent risk factor for cardiovascular morbidity and mortality for hypertensive patients, they did not analyze the influence of baseline heart rate in their meta-analysis, a major confounding factor. We performed a similar meta-regression analysis in the same set of studies. We first checked that we obtained similar results concerning the influence of heart rate, measured at the end of the trial in the beta-blocker group, on the relative risk of myocardial infarction (Fig. 3 of Bangalore et al. ): the equation derived from our analysis (y = 2.593 – 0.0237x; p = 0.0072) was very close to the equation (y = 2.5794 – 0.0235x; p < 0.0001) found by Bangalore et al. (1). We further analyzed the influence of heart rate, measured at baseline in the beta-blocker group, on the relative risk of myocardial infarction, and found a significant relationship (y = 3.864 – 0.0380x; p < 0.0001). The lower the heart rate at baseline, the higher the relative risk of myocardial infarction. Importantly, the slope of the later equation (baseline heart rate) was 1.6-fold higher (p < 0.001) than that of the former one (heart rate at the end of the trial). These results suggest that heart rate at baseline (i.e., before any administration of beta-blocker) is a better predictor of myocardial infarction than heart rate at the end of the trial. The relative risk for myocardial infarction was higher than unity when baseline heart rate was lower than 75.4 beats/min, and lower than unity when heart rate was higher than this value.
Thus, heart rate at baseline may have acted as a confounding factor in the analysis performed by Bangalore et al. (1). This suggests that reduction in heart rate may not be the main mechanism through which beta-blockers devoid of vasodilating properties, particularly atenolol, exert deleterious effects on the cardiovascular system, and demonstrate less effect than other antihypertensive agents for preventing cardiovascular events. Indeed, in contrast to vasodilating agents like calcium-channel blockers and renin-angiotensin system blockers, atenolol does not reduce total peripheral resistance and sympathetic drive, and fails to induce the long-term remodeling of large and small arteries that is required for structural improvement of arterial stiffness and resistance and the reduction in wave reflection and central aortic blood pressure.
Please note: Dr. Laurent has received honoraria and research grants from Astra-Zeneca, Bayer-Schering, Boehringer-Ingelheim, Chiesi, Daichii-Sankyo, Menarini, MSD, Negma, Novartis, Pfizer, Recordati, and Servier.
- American College of Cardiology Foundation