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Prof. Kurt Stoschitzky,
Recommendations for beta-blocker use in arterial hypertension have evolved in the last decade but have not made it clear whether they should be first-intention drugs or not. The latest generation seems appropriate in the treatement of essential hypertension and offer fewer side-effects. Nevertheless, there are pros and cons for each drug within each generation and class, to be weighed for each patient.
When a hypertensive patient also suffers from angina pectoris, post-myocardial infarction, heart failure, tachyarrhythmias, glaucoma and/or is pregnant, the indication for beta-blockers is clear whereas it is not when these additional conditions are not present. Accordingly, there are no “pros and cons" for and/or against the class of beta-blockers as a whole or even for and/or against single substances of this class of drugs since both effects and side effects may differ largely between different beta-blockers (Table). Therefore, pros and cons of beta-blockers in arterial hypertension should be seen both between different patients as well as between different beta-blockers.
The indications for beta-blockers (and diuretics) in arterial hypertension have evolved in the last decade
In 2003, the “Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure” (JNC VII), published its recommendation that a “thiazide diuretic should be used in the drug treatment for most" but “there are also excellent clinical trial data providing evidence that lowering blood pressure with other classes of drugs, including ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers and calcium channel blockers (CCBs) also reduces the complications of hypertension.” (1) In 2004, the Task Force on Beta-Blockers of the European Society of Cardiology (2) state that “beta-blockers may be considered first choice therapy, alone or in combination, in patients with previous myocardial infarction, ischaemic heart disease, arrhythmias or heart failure, asymptomatic left ventricular dysfunction, diabetes or high risk of coronary disease, based on the efficacy of these drugs on these patient populations (class I, level of evidence A)”. The 2007 Guidelines for the management of arterial hypertension state that “drug treatment can be initiated with thiazide diuretics, ARBs, and beta-blockers” (3) The same year, authors of a Seminar on Essential Hypertension published in the Lancet (4) wrote that “we beg to differ and think that in uncomplicated hypertension, diuretics and β-blockers should no longer be considered for first-line treatment”, In 2008 a paper in the Journal of Hypertension (4) stated that “the enthusiasm for the primary use of β-blockers in hypertension is waning, contrary to the egalitarian views of the ESC-ESH”, A recent task force document of the European Society of Hypertension (5) writes “the 2007 ESC/ESH guidelines conclusion that diuretics, ACE inhibitors, calcium antagonists, angiotensin receptor antagonists, and β-blockers can all be considered suitable for initiation of antihypertensive treatment as well as for its maintainance.”
At this point, it is rather unclear whether or not beta-blockers are indicated as a first choice in patients with essential arterial hypertension.
It might be most appropriate in this context, as presented in a recent issue of the ESC e-Journal of Cardiology Practice (6) to consider that “beta-blockers are not all equal members of one family of drugs. They should be recognised as individual substances with their own qualities and be used according to individual features, needs and demands of every single patient”.
Three generations for different needs
There are 3 currently available generations of beta-blockers
Atenolol beta-blockers : higher mortality Secondly, a meta-analysis (7) reported that atenolol more particularly caused significantly higher mortality than other active treatment whereas non-atenolol beta-blockers showed a (non-significant) tendency to decrease both mortality and myocardial infarction compared to other antihypertensives (8). Authors conclude that “results cast doubts on atenolol as a suitable drug for hypertensive patients.” Even though atenolol showed higher mortality, most outcome studies in arterial hypertension have used atenolol as a reference drug for beta-blockers (because it might be easier to win a match when you can choose a weak opponent?”) and consequently other antihypertensives are found “better” than beta-blockers. Clinical studies in arterial hypertension using atenolol as a beta-blocker might be doubtful, and therefore this drug is not further discussed in the present manuscript. Third generation beta-blockers appear suitable for essential hypertension Beta-blockers are still questioned in the treatment of essential arterial hypertension, particularly since they may cause metabolic side effects such as increases in plasma levels of glucose and lipids. (2) However, recent ESC/ESH Guidelines for the management of arterial hypertension (3) emphasise that “this may not apply to vasodilator beta-blockers, such as carvedilol and nebivolol, which have less or no metabolic action, and their use entails an even reduced incidence of new-onset diabetes compared with classical beta-blockers. Third generation beta-blockers, carvedilol and nebivolol, clearly differ from those of the 1st and 2nd generation since they do not show unfavourable metabolic side effects.” Third generation beta-blockers offer fewer side effects Fourthly, also according to the recent ESC/ESH Guidelines for the management of arterial hypertension, (3) beta-blockers should be used in patients with arterial hypertension and added angina pectoris, post-myocardial infarction, heart failure, tachyarrhythmias, glaucoma and/or pregnancy. In hypertensives without one of the added above-mentioned conditions, it is less clear whether or not beta-blockers are among first choice drugs. In general, beta-blockers may show side effects such as bradycardia, AV block, bronchoconstriction, vasoconstriction, erectile dysfunction and sleep disturbances (the latter caused by a decrease in nocturnal production of melatonin). (2,9) However, most side effects are caused only by 1st generation drugs (propranolol) and 2nd generation drugs (metoprolol, bisoprolol) and not by 3rd generation drugs (carvedilol, nebivolol).
Beneficial outcome data from large clinical trials of this last generation are still missing. You find in the Table seen below the main "pros and cons" of the most frequently used beta-blockers (propranolol, metoprolol, bisoprolol, carvedilol and nebivolol) (2,5,6,10-16)
additional alpha-blockade no inhibition of nocturnal melatonin no release from adrenergic cells reduction of oxidative stress positive effects in
1. Chobanian AV, Bakris GL, Black HR, and others. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII). Hypertension 2003; 42: 1206-1252
2. The Task Force on Beta-Blockers of the European Society of Cardiology. Expert consensus document on β-adrenergic receptor blockers. Eur Heart J 2004; 25: 1341-1362
3. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension and of the European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension. Eur Heart J 2007; 28: 1462-1536
4. Opie LH. Beta-blockade should not be among several choices for initial therapy of hypertension. J Hypertension 2008; 28: 161-163
5. Mancia G, Laurent S, Agabiti-Rosei, and others. Reapprasial of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertension 2009; 27: 2121-2158
6. Stoschitzky K. Individual beta-blockers for individual patients. ESC e-journal of cardiology practice 2008; 6: 19
7. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004; 364: 1684-1689
8. Lindholm LH, Carlberg B, Samuelsson O. Should Beta-blockers remain first choice in the treatment of arterial hypertension? A meta-analysis. Lancet 2005; 366: 1545-1553
9. Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W. Influence of beta-blockers on melatonin release. Eur J Clin Pharmacol 1999; 55: 111-115
10. Dandona P, Ghanim H, Brooks BP. Antioxidant activity of carvedilol in cardiovascular disease. J Hypertension 2007; 25: 731-741
11. del Colle S, Morello F, Rabbia F, et al. Antihypertensive drugs and the sympathetic nervous system. J Cardiovasc Pharmacol 2007; 50: 487-496
12. Maffei A, di Pardo A, Carangi R, Carullo P, Poulet R, Gentile MT, Vecchione C, Lembo G. Hypertension 2007; Nebivolol induces nitric oxide release in the heart through inducible nitric oxide synthase activation. 50: 652-656
13. Cutler JA, Davis BR. Thiazide-type diuretics and β-adrenergic blockers as first-line drug treatments for hypertension. Circulation 2008; 117: 2691-2705
14. Messerli FH, Bangalore R, Julius S. Risk/benefit assessment of β-blockers and diuretics precludes their use for first-line therapy in hypertension. Circulation 2008; 117: 2706-2715
15. Mason RP, Giles TD, Sowers JR. Evolving mechanisms of action of beta-blockers: Focus on Nebivolol. J Cardiovasc Pharmacol 2009; 54: 123-128
16. Galderisi M, d’Errico A, Sidiropulos M, Innelli P, de Divitiis O, de Simone G. Nebivolol induces parallel improvement of left ventricular filling pressure and coronary flow reserve in uncomplicated arterial hypertension. J Hypertension 2009; 27: 2108-2115
Kurt Stoschitzky, FESC Nucleus Member of the ESC Working Group on Cardiovascular Pharmacology and Drug Therapy Abteilung für Kardiologie Universitätsklinik für Innere Medizin Auenbruggerplatz 15 A-8036 Graz, Austria Phone: +43-316-385-80261 Fax: +43-316-385-3733 e-mail: firstname.lastname@example.org