Beta-Blocker–Induced Heart Rate Lowering, Cardioprotection ...

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JACC Vol. 53, No. 22, 2009 June 2, 2009:2101?7

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. [1]): 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.

*St?phane Laurent, MD, PhD Pierre Boutouyrie, MD, PhD

*Department of Pharmacology and INSERM U970 H?pital Europ?en Georges Pompidou Assistance Publique?H?pitaux de Paris Universit? Paris 5 20, rue Leblanc 75015 Paris France E-mail: stephane.laurent@egp.aphp.fr

doi:10.1016/j.jacc.2008.12.074

Please note: Dr. Laurent has received honoraria and research grants from AstraZeneca, Bayer-Schering, Boehringer-Ingelheim, Chiesi, Daichii-Sankyo, Menarini, MSD, Negma, Novartis, Pfizer, Recordati, and Servier.

Beta-Blocker?Induced Heart Rate Lowering, Cardioprotection, and Hypertension

Bangalore et al. (1) have provided an intriguing observation that cardiovascular (CV) events, including CV death, myocardial infarction, heart failure, stroke, and all-cause death, may be increased in hypertensive patients placed on beta-blockers and that this may be related to the degree of heart rate reduction. They have done this by performing meta-regression analyses to demonstrate the relationship between heart rate and cardiovascular outcomes.

However, the data in their graphs show that the regression lines cross the line of unity. The 1 study that is consistently at or below unity in their graphs is the IPPSH (International Prospective Primary Prevention Study in Hypertension), which compared a beta-blocker with placebo. Similarly, the only other placebocontrolled trial analyzed, STOP (Swedish Trial in Old Patients with Hypertension) (2), shows a relative risk of about 0.9 in Figure 4 of Bangalore et al. (1). This suggests that beta-blockers are not increasing CV events because there is no increase in events in beta-blocker patients compared with placebo patients. The major differences in outcome rates are in the studies comparing betablockers with active controls.

These findings suggest that beta-blockers were less effective at preventing CV events than other antihypertensive agents. The mechanism for this may be evident in Table 2 of Bangalore et al. (1), which shows that beta-blockers resulted in less blood pressure reduction in 5 of 7 active control trials analyzed by the authors, with up to a 9.2-mm Hg difference in systolic blood pressure. This suggests that beta-blockers were simply less effective antihypertensive agents in general. Thus, an alternative interpretation of the authors' findings is not that beta-blockers increase mortality, as has been widely reported in the press, but that beta-blockers are simply less effective antihypertensive agents than diuretics or dihydropyridine calcium-channel blockers. As a result, they are also less effective at preventing hypertension-related cardiovascular events than other medications. The clinical message I would take from this study is that we must remember that the primary goal of antihypertensive treatment is to lower blood pressure and not to lower heart rate.

*Steven S. Khan, MD

*Kaiser-Permanente Hospital, UCLA School of Medicine Cardiology 1526 North Edgemont 2nd Floor Los Angeles, California 90027 E-mail: steven.s.khan@

doi:10.1016/j.jacc.2008.11.065

REFERENCE

1. Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker? induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol 2008;52:1482?9.

REFERENCES

1. Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker? induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol 2008;52:1482?9.

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Correspondence 2105

2. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991;338:1281?5.

Different Metabolic Effects of Selective and Nonselective Beta-Blockers Rather Than Mere Heart Rate Reduction May Be the Mechanisms by Which Beta-Blockade Prevents Cardiovascular Events

We read with interest the article by Bangalore et al. (1), who analyzed in 9 trials the role of pharmacologic reduction of heart rate (HR) using beta-blockers in preventing cardiovascular events in patients with hypertension. Beta-blocker?induced lower HR was associated with greater mortality and morbidity risk. As the basis of worse outcomes with "beta-blockers," the authors recognize only an increase in central aortic/pulse pressure with pharmacologic HR lowering. Even though they acknowledge that the beta-blocker used in the studies was mainly atenolol, and hence, any extrapolation of these results to other beta-blockers should be done with caution, the whole paper and the accompanying editorial just generically refer to "beta-blockade." In fact, the mechanisms by which beta-blockers improve prognosis in different cardiac contexts are probably multiple. Improved energy efficiency seen with some beta-blockers (2) could be one of the reasons for better survival observed with their use (3). Additionally, central inhibition of sympathetic activity with moxonidine in heart failure, despite a significant reduction of HR, has been associated with increased mortality (4). In fact, moxonidine has been shown to alter myocardial metabolism (5). This could be the reason for the failure of central sympathetic inhibition to prevent deaths in patients with heart failure and also indicates that the predominant mechanism of action of "effective" beta-blockers is probably related to mechanisms other than mere HR reduction. In fact, apart from reducing HR, atenolol and most selective beta-blockers impair endothelial function, decrease insulin sensitivity, and increase lipid levels (6), all conditions that may worsen the global risk profile. Conversely, new generation beta-blockers have been seen to improve metabolism and endothelial function (7). Therefore, HR reduction in itself, especially if associated with a bulk of deleterious metabolic and vascular effects, is definitely not enough to improve prognosis. The alarm created by the Bangalore et al. (1) paper should be clearly confined to selective beta-blockers and not generically extended to the whole drug class.

*Gabriele Fragasso, MD Michela Cera, MD Alberto Margonato, MD

*Istituto Scientifico San Raffaele, Milan, Italy Clinical Cardiology-Heart Failure Clinic via Olgettina 60 Milan 20132 Italy E-mail: gabriele.fragasso@hsr.it

doi:10.1016/j.jacc.2008.12.075

REFERENCES

1. Bangalore S, Sawhney S, Messerli FH. Relation of beta-blocker? induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol 2008;52:1482?9.

2. Podbregar M, Voga G. Effect of selective and nonselective betablockers on resting energy production rate and total body substrate utilization in chronic heart failure. J Cardiac Fail 2002:8:369 ?78.

3. Poole-Wilson P, Swedberg K, Cleland J, et al., Carvedilol or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7?13.

4. Wiltse C, Wright T, for the MOXCON Investigators. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003;5:659-66.

5. Mobini R, Jansson PA, Bergh CH, Sharing Tang M, Waagstein F, Andersson B. Influence of central inhibition of sympathetic nervous activity on myocardial metabolism in chronic heart failure: acute effects of the imidazoline I1-receptor agonist moxonidine. Clin Sci 2006;110: 329 ?36.

6. Lithell HO. Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care 1991;14:203?9.

7. Celik T, Iyisoy A, Kursaklioglu H, et al. Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients. J Hypertens 2006;24:591? 6.

Beta-Blockers and Hypertension

Bangalore et al. (1) state that unlike results from post-myocardial infarction and congestive heart failure studies, a beta-blocker? induced low heart rate (HR) in hypertension is associated with an increase in death rate and cardiovascular (CV) events. This conclusion is highly misleading.

In post-myocardial infarction and congestive heart failure studies, the benefit from beta-1 blockade arises from decreased work of the heart (via reduced HR and blood pressure), reduced ventricular fibrillation risk, and a reduction in catecholamine-induced (beta-1) cardiac necrosis and apoptosis (2); thus, intrinsic sympathomimetic activity reduces efficacy (2). The situation with hypertension is complex, as diastolic hypertension in the young/middle-aged arises from a link with obesity (3) and high sympathetic nerve activity plus raised cardiac output (2). In contrast, isolated systolic hypertension arises in the elderly via a decrease in vascular compliance (3).

The 3 main contributor trials in the Bangalore et al. (1) study were the ASCOT (Anglo-Scandinavian Cardiac Outcomes), LIFE (Losartan Intervention for Endpoint Reduction in Hypertension), and INVEST (International Verapamil SR Trandolapril Study) studies in elderly patients with hypertension, which involved moderately beta-1 selective atenolol as the first-line choice. Atenolol does not improve vascular compliance (2), so it does not lower central systolic pressure; indeed first-line atenolol slightly increases central pressure (4), possibly linked to partial beta-2 block-

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