Expert consensus document on b-adrenergic receptor blockers
Expert consensus document on b-adrenergic receptor blockers
Expert consensus document on b-adrenergic receptor blockers
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European Heart Journal (2004) 25, 1341–1362ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g><str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> <strong>on</strong> b-<strong>adrenergic</strong><strong>receptor</strong> <strong>blockers</strong>The Task Force <strong>on</strong> Beta-Blockers of the European Societyof CardiologyTask Force Members, Jose Lopez-Send<strong>on</strong>, Chairpers<strong>on</strong>* (Spain), Karl Swedberg(Sweden), John McMurray (UK), Juan Tamargo (Spain), Aldo P. Maggi<strong>on</strong>i (Italy),Henry Dargie (UK), Michal Tendera (Poland), Finn Waagstein (Sweden), Jan Kjekshus(Norway), Philippe Lechat (France), Christian Torp-Pedersen (Denmark)ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairpers<strong>on</strong>) (Italy), Maria Angeles Al<strong>on</strong>so Garcıa (Spain),Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Ver<strong>on</strong>ica Dean (France), Jaap Deckers(The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), GianfrancoMazzotta (Italy), Keith McGregor (France), Jo~ao Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway).Document Reviewers, Maria Angeles Al<strong>on</strong>so Garcıa (CPG Review Coordinator) (Spain); Diego Ardissino (Italy),Cristina Avendano (Spain), Carina Blomstr€om-Lundqvist (Sweden), Denis Clement (Belgium), Helmut Drexler(Germany), Roberto Ferrari (Italy), Keith A. Fox (UK), Desm<strong>on</strong>d Julian (UK), Peter Kearney (Ireland), Werner Klein(Austria), Lars K€ober (Denmark), Giuseppe Mancia (Italy), Markku Nieminen (Finland), Witold Ruzyllo (Poland),Maarten Simo<strong>on</strong>s (The Netherlands), Kristian Thygesen (Denmark), Gianni Togn<strong>on</strong>i (Italy), Isabella Tritto (Italy),Lars Wallentin (Sweden)Table of c<strong>on</strong>tentsPreamble . . . . . . . . . . . . . . . . . . . . . . . . . . 1342Classes of recommendati<strong>on</strong>s . . . . . . . . . . . . . . 1342Levels of evidence. . . . . . . . . . . . . . . . . . . . . 1342Introducti<strong>on</strong>. . . . . . . . . . . . . . . . . . . . . . . . . 1342Pharmacology. . . . . . . . . . . . . . . . . . . . . . . . 1343Definiti<strong>on</strong> . . . . . . . . . . . . . . . . . . . . . . . . 1343Classificati<strong>on</strong> of b-<strong>blockers</strong> . . . . . . . . . . . . . 1343Pharmacokinetic properties . . . . . . . . . . . . . 1343Lipophilic drugs. . . . . . . . . . . . . . . . . . . 1344Hydrophilic drugs. . . . . . . . . . . . . . . . . . 1344Balanced clearance drugs . . . . . . . . . . . . 1344Mechanism of acti<strong>on</strong> . . . . . . . . . . . . . . . . . 1344Adverse events . . . . . . . . . . . . . . . . . . . . . 1345Cardiovascular . . . . . . . . . . . . . . . . . . . 1345Metabolic . . . . . . . . . . . . . . . . . . . . . . 1345Pulm<strong>on</strong>ary . . . . . . . . . . . . . . . . . . . . . . 1345* Corresp<strong>on</strong>ding author. Chairpers<strong>on</strong>: Jose Lopez-Send<strong>on</strong>, Cardiology,Area 1200, Hospital Universitario Gregorio Mara~n<strong>on</strong>, Doctor Esquerdo 46,28007 Madrid. Spain. Tel.: þ34-91-586-8295; fax: þ34-91-586-6672.E-mail address: jlsend<strong>on</strong>@terra.es (J. Lopez-Send<strong>on</strong>).Central effects . . . . . . . . . . . . . . . . . . . 1345Sexual dysfuncti<strong>on</strong> . . . . . . . . . . . . . . . . . 1345C<strong>on</strong>traindicati<strong>on</strong>s . . . . . . . . . . . . . . . . . . . 1345Drug interacti<strong>on</strong>s . . . . . . . . . . . . . . . . . . . 1345Dosing of b-<strong>blockers</strong> . . . . . . . . . . . . . . . . . 1346Clinical efficacy and use . . . . . . . . . . . . . . . . . 1346Acute myocardial infarcti<strong>on</strong> (AMI) . . . . . . . . . 1346Sec<strong>on</strong>dary preventi<strong>on</strong> aftermyocardial infarcti<strong>on</strong> . . . . . . . . . . . . . . . . . 1347N<strong>on</strong>-ST-segment elevati<strong>on</strong> acute cor<strong>on</strong>arysyndromes . . . . . . . . . . . . . . . . . . . . . . . . 1348Chr<strong>on</strong>ic, stable ischaemic heart disease . . . . . 1348Heart failure . . . . . . . . . . . . . . . . . . . . . . 1349Heart failure and preserved systolic functi<strong>on</strong> 1351Acute heart failure . . . . . . . . . . . . . . . . 1351Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . 1352Sinus tachycardia. . . . . . . . . . . . . . . . . . 1352Supraventricular tachycardias. . . . . . . . . . 1352Tachycardias in WPW syndrome . . . . . . . . 1353Atrial flutter. . . . . . . . . . . . . . . . . . . . . 1353Atrial fibrillati<strong>on</strong> . . . . . . . . . . . . . . . . . . 1353Ventricular arrhythmias . . . . . . . . . . . . . 1353Preventi<strong>on</strong> of sudden cardiac death. . . . . . . . 1353Acute myocardial infarcti<strong>on</strong> . . . . . . . . . . . 13540195-668X/$ - see fr<strong>on</strong>t matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.ehj.2004.06.002
1342 ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g>Heart failure . . . . . . . . . . . . . . . . . . . . 1354Dilated cardiomyopathy . . . . . . . . . . . . . 1354Hypertrophic cardiomyopathy. . . . . . . . . . 1354Mitral valve prolapse . . . . . . . . . . . . . . . 1354Myocardial bridging . . . . . . . . . . . . . . . . 1355L<strong>on</strong>g QT syndrome (LQTS) . . . . . . . . . . . . 1355Catecholaminergic polymorphic ventriculartachycardia . . . . . . . . . . . . . . . . . . . . . 1355SCD in the normal heart . . . . . . . . . . . . . 1355Other situati<strong>on</strong>s . . . . . . . . . . . . . . . . . . 1355Hypertensi<strong>on</strong> . . . . . . . . . . . . . . . . . . . . . . 1355Aortic dissecti<strong>on</strong> . . . . . . . . . . . . . . . . . . . . 1356Hypertrophic cardiomyopathy . . . . . . . . . . . 1356Prophylactic use in n<strong>on</strong>-cardiac surgery . . . . . 1356Vasovagal syncope. . . . . . . . . . . . . . . . . . . 1357b-Blockers during pregnancy . . . . . . . . . . . . 1357References . . . . . . . . . . . . . . . . . . . . . . . . . 1357PreambleGuidelines and <str<strong>on</strong>g>Expert</str<strong>on</strong>g> C<strong>on</strong>sensus <str<strong>on</strong>g>document</str<strong>on</strong>g>s aim topresent all the relevant evidence <strong>on</strong> a particular issue inorder to help physicians to weigh the benefits and risksof a particular diagnostic or therapeutic procedure.They should be helpful in everyday clinical decisi<strong>on</strong>making.A great number of Guidelines and <str<strong>on</strong>g>Expert</str<strong>on</strong>g> C<strong>on</strong>sensusDocuments have been issued in recent years by the EuropeanSociety of Cardiology (ESC) and by different organisati<strong>on</strong>sand other related societies. This profusi<strong>on</strong>can put at stake the authority and validity of guidelines,which can <strong>on</strong>ly be guaranteed if they have been developedby an unquesti<strong>on</strong>able decisi<strong>on</strong>-making process. Thisis <strong>on</strong>e of the reas<strong>on</strong>s why the ESC and others have issuedrecommendati<strong>on</strong>s for formulating and issuing Guidelinesand <str<strong>on</strong>g>Expert</str<strong>on</strong>g> C<strong>on</strong>sensus Documents.In spite of the fact that standards for issuing goodquality Guidelines and <str<strong>on</strong>g>Expert</str<strong>on</strong>g> C<strong>on</strong>sensus Documents arewell defined, recent surveys of Guidelines and <str<strong>on</strong>g>Expert</str<strong>on</strong>g>C<strong>on</strong>sensus Documents published in peer-reviewed journalsbetween 1985 and 1998 have shown that methodologicalstandards were not complied with in the vastmajority of cases. It is therefore of great importance thatguidelines and recommendati<strong>on</strong>s are presented in formatsthat are easily interpreted. Subsequently, their implementati<strong>on</strong>programmes must also be well c<strong>on</strong>ducted.The ESC Committee for Practice Guidelines (CPG) supervisesand coordinates the preparati<strong>on</strong> of new Guidelinesand <str<strong>on</strong>g>Expert</str<strong>on</strong>g> C<strong>on</strong>sensus Documents produced by TaskForces, expert groups or <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> panels. The chosenexperts in these writing panels are asked to provide disclosurestatements of all relati<strong>on</strong>ships they may havewhich might be perceived as real or potential c<strong>on</strong>flicts ofinterest. These disclosure forms are kept <strong>on</strong> file at theEuropean Heart House, headquarters of the ESC. TheCommittee is also resp<strong>on</strong>sible for the endorsement ofthese Guidelines and <str<strong>on</strong>g>Expert</str<strong>on</strong>g> C<strong>on</strong>sensus Documents orstatements.The Task Force has classified and ranked the usefulnessor efficacy of the recommended procedure and/ortreatment and the Level of Evidence as indicated in thetables below:Classes of Recommendati<strong>on</strong>sClass I:Class II:Class IIa:Class IIb:*Use of Class III is discouraged by the ESCLevels of EvidenceIntroducti<strong>on</strong>Evidence and/or general agreement that agiven procedure/treatment is beneficial,useful and effective;C<strong>on</strong>flicting evidence and/or a divergenceof opini<strong>on</strong> about the usefulness/efficacyof the procedure/treatment;Weight of evidence/opini<strong>on</strong> is in favour ofusefulness/efficacy;Usefulness/efficacy is less well establishedby evidence/opini<strong>on</strong>;Class III*: Evidence or general agreement that thetreatment is not useful/effective and insome cases may be harmful.Level of Evidence A Data derived from multiple randomisedclinical trials or metaanalysesLevel of Evidence B Data derived from a single randomisedclinical trial or n<strong>on</strong>randomisedstudiesLevel of Evidence C C<strong>on</strong>sensus of opini<strong>on</strong> of the expertsand/or small studiesb-Blocker therapy plays a major role in the treatment ofcardiovascular diseases. For many years b-<strong>blockers</strong> wereused for their antiischaemic, antiarryhthmic and antihypertensiveproperties. More recently, the benefit ofadrenoceptor blockade was also established in patientswith heart failure. The aim of this <str<strong>on</strong>g>document</str<strong>on</strong>g> is to reviewthe rati<strong>on</strong>ale and clinical evidence for the use of b-<strong>adrenergic</strong><strong>blockers</strong> in patients with cardiovascular disease.The members for the Beta-<strong>blockers</strong> in CardiovascularDisease Task Force were nominated by the Committee forPractice Guidelines (CPG) of the European Society ofCardiology (ESC). A specific literature search was carriedout for original articles in peer review journals included inMedline. In additi<strong>on</strong>, the ESC as well as the American HeartAssociati<strong>on</strong>/American College of Cardiology guidelineswith reference to the use of b-<strong>blockers</strong> were carefullyreviewed. Most of the previously made recommendati<strong>on</strong>swere maintained; some were updated and a few are newaccording to recent evidence in the literature.Using recommendati<strong>on</strong>s which are graded provides asimple method for guidance. Levels of recommendati<strong>on</strong>are derived from clinical trials, c<strong>on</strong>ducted in selectedgroups of patients that may not be representative of
ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> 1343broader populati<strong>on</strong>s; in fact, patients with c<strong>on</strong>traindicati<strong>on</strong>sare excluded from clinical trials. Besides, the samestrength of evidence may reflect different clinical benefit:mortality, morbidity, clinical symptoms or combinedend-points; large or small benefit albeit statistically significant;easily obtained or <strong>on</strong>ly observed, or lost, afterseveral years of treatment. Finally, in individual cases therecommended therapy may <strong>on</strong>ly be a treatment opti<strong>on</strong>and other alternatives may be equally acceptable or evenmore appropriate. An effort was made to include thisinformati<strong>on</strong> in a relatively short <str<strong>on</strong>g>document</str<strong>on</strong>g>.The <str<strong>on</strong>g>document</str<strong>on</strong>g> prepared by the task force was circulatedam<strong>on</strong>g a review board appointed by the ESC andapproved by the Committee for Practice Guidelines ofthe ESC. The final <str<strong>on</strong>g>document</str<strong>on</strong>g> was sent to the EuropeanHeart Journal for a formal peer review.This <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> represents the views of theESC and was arrived at after careful c<strong>on</strong>siderati<strong>on</strong> of theavailable evidence. Health professi<strong>on</strong>als are expected totake them fully into account when exercising their clinicaljudgement. This <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> does not,however, override the individual resp<strong>on</strong>sibility of healthprofessi<strong>on</strong>als to make appropriate decisi<strong>on</strong>s in the circumstancesof the individual patient, in c<strong>on</strong>sultati<strong>on</strong>with that patient, and where appropriate and necessarythe patient’s guardian or carer.PharmacologyDefiniti<strong>on</strong>b-Adrenergic antag<strong>on</strong>ists (b-<strong>blockers</strong>) bind selectively tothe b-adrenoceptors producing a competitive and reversibleantag<strong>on</strong>ism of the effects of b-<strong>adrenergic</strong> stimuli<strong>on</strong> various organs (Table 1). Their pharmacologicaleffects can be explained from the knowledge of the resp<strong>on</strong>seselicited by these <strong>receptor</strong>s in the various tissuesand the activity of the sympathetic t<strong>on</strong>e. 1;2 Thus,b-<strong>blockers</strong> have relatively little effect <strong>on</strong> heart rate andc<strong>on</strong>tractility in an individual at rest but slow heart rateand decrease cardiac c<strong>on</strong>tractility when the sympatheticnervous system is activated, i.e., during exercise orstress.Classificati<strong>on</strong> of b-<strong>blockers</strong>b-Blockers can be broadly classified into (a) n<strong>on</strong>-selective,those producing a competitive blockade of both b 1 - andb 2 -<strong>adrenergic</strong> <strong>receptor</strong>s and (b) those with much higheraffinity for the b 1 than for the b 2 <strong>receptor</strong>s usually calledb 1 -selective (Table 2). 1–4 Selectivity is, however, dosedependentand decreases or disappears when larger dosesare used. Paradoxically, some b-<strong>blockers</strong> can exert a weakag<strong>on</strong>ist resp<strong>on</strong>se (intrinsic sympathomimetic activity(ISA), and can stimulate and block the b-adrenoceptor.Several b-<strong>blockers</strong> have peripheral vasodilator activitymediated via a 1 -adrenoceptor blockade (carvedilol, labetalol),b 2 -<strong>adrenergic</strong> <strong>receptor</strong> ag<strong>on</strong>ism (celiprolol) orvia mechanisms independent of the adrenoceptor blockade(bucindolol, nebivolol). In additi<strong>on</strong>, b-<strong>blockers</strong> can beclassified as lipophilic or hydrophilic.Pharmacokinetic propertiesThere are important pharmacokinetic differences am<strong>on</strong>gb-<strong>blockers</strong> 1–4 (Table 1).Table 1 Effects mediated by b 1 - and b 2 -adrenoceptorsTissue Receptor EffectHeartSA node b 1 , b 2 Increase in heart rateAV node b 1 , b 2 Increase in c<strong>on</strong>ducti<strong>on</strong> velocityAtria b 1 , b 2 Increase in c<strong>on</strong>tractilityVentricles b 1 , b 2 Increase in c<strong>on</strong>tractility, c<strong>on</strong>ducti<strong>on</strong> velocity and automaticityof idioventricular pacemakersArteries b 2 Vasodilati<strong>on</strong>Veins b 2 Vasodilati<strong>on</strong>Skeletal muscle b 2 Vasodilati<strong>on</strong>, increased c<strong>on</strong>tractilityGlycogenolysis, K þ uptakeLiver b 2 Glycogenolysis and gluc<strong>on</strong>eogenesisPancreas (b cells) b 2 Insulin and glucag<strong>on</strong> secreti<strong>on</strong>Fat cells b 1 LipolysisBr<strong>on</strong>chi b 2 Br<strong>on</strong>chodilati<strong>on</strong>Kidney b 1 Renin releaseGallbladder and ducts b 2 Relaxati<strong>on</strong>Urinary bladder detrusor b 2 Relaxati<strong>on</strong>Uterus b 2 Relaxati<strong>on</strong>Gastrointestinal b 2 Relaxati<strong>on</strong>Nerve terminals b 2 Promotes noradrenaline releaseParathyroid glands b 1 , b 2 Parathorm<strong>on</strong>e secreti<strong>on</strong>Thyroid gland b 2 T4 ! T3 c<strong>on</strong>versi<strong>on</strong>SA: Sino-Atrial; AV: Auriculo-Ventricular.
1344 ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g>Table 2 Pharmacological classificati<strong>on</strong> of comm<strong>on</strong>ly used b-<strong>adrenergic</strong> antag<strong>on</strong>ists (b-<strong>blockers</strong>)b-blocker ISA Lipid solubility Peripheral vasodilati<strong>on</strong> i.v. Average daily oral doseI. N<strong>on</strong>-selective (b 1 þ b 2 ) <strong>adrenergic</strong> antag<strong>on</strong>istsCarteolol + Low 2.5–20 mg <strong>on</strong>ce/twice dailyNadolol 0 Low 40–320 mg <strong>on</strong>ce dailyPenbutolol + Moderate 20–80 mg <strong>on</strong>ce/twice dailyPindolol ++ High 10–40 mg twice dailyPropranolol 0 High + 40–180 mg twice dailySotalol 0 Low +Timolol 0 High 5–40 mg twice dailyII. Selective b 1 -<strong>adrenergic</strong> antag<strong>on</strong>istsAcebutolol + Moderate 200–800 mg <strong>on</strong>ce/twice dailyAtenolol 0 Low + 25–100 mg <strong>on</strong>ce dailyBetaxolol 0 Moderate 5–20 mg <strong>on</strong>ce dailyBisoprolol 0 Moderate 2.5–10 mg <strong>on</strong>ce dailyCeliprolol + Moderate + 200–600 mg <strong>on</strong>ce dailyEsmolol 0 Low + Only i.v.Metoprolol 0 High + 50–100 mg <strong>on</strong>ce/twice dailyNevibolol 0 + 2.5–5 mg <strong>on</strong>ce dailyIII. a 1 - and b-<strong>adrenergic</strong> antag<strong>on</strong>istsBucindolol + Moderate + 25–100 mg twice dailyCarvedilol 0 Moderate + 3.125–50 mg twice dailyLabetalol + Low + 200–800 mg twice dailyISA: Intrinsic Sympathomimetic Activity; i.v.: Intravenous administrati<strong>on</strong> possible; AMI: Acute Myocardial Infarcti<strong>on</strong>; CHF: Chr<strong>on</strong>ic Heart Failure.Included <strong>on</strong>ly b-<strong>blockers</strong> with dem<strong>on</strong>strated efficacy <strong>on</strong> clinical outcomes and supporting the guidelines recommendati<strong>on</strong>s.* In some studies there was lack of evidence for peripheral a1 -adrenoceptor blockade during l<strong>on</strong>g-term treatment of heart failure with carvedilol. 229Lipophilic drugsLipophilic drugs (metoprolol, propranolol, timolol) arerapidly and completely absorbed from the gastrointestinaltract but are extensively metabolised in the gut walland in the liver (first pass effect), so that their oralbioavailability is low (10–30%). These drugs may accumulatein patients with reduced hepatic blood flow (i.e.,elderly, c<strong>on</strong>gestive heart failure, liver cirrhosis). Lipophilicdrugs present short eliminati<strong>on</strong> half-lives (1-5 h)and they easily enter the central nervous system (CNS),which may account for a greater incidence of centralside-effects.Hydrophilic drugsHydrophilic drugs (atenolol, esmolol) are absorbed incompletelyfrom the gastrointestinal tract and are excretedunchanged or as active metabolites by the kidney.They have l<strong>on</strong>ger half-lives (6–24 h), and do not interactwith other liver-metabolised drugs. They barely cross theblood–brain barrier. Eliminati<strong>on</strong> half-life is increasedwhen glomerular filtrati<strong>on</strong> rate is reduced (i.e., elderly,renal insufficiency).Balanced clearance drugsBisoprolol has a low first-pass metabolism, enters theCNS and is excreted in equal proporti<strong>on</strong> by hepatic andrenal routes. Carvedilol has a low oral bioavailability dueto an extensive first pass effect. It binds to plasma proteinsand is eliminated by hepatic metabolism. 4 Esmololis an ultra short-acting drug. It is administered i.v. andrapidly hydrolysed by red cell esterases (half-life 9 min). 5Mechanism of acti<strong>on</strong>The mechanisms of acti<strong>on</strong> are diverse, not yet completelyunderstood and probably with important differencesbetween agents. The preventi<strong>on</strong> of the cardiotoxiceffects of catecholamines plays a central role. 6–8 Thefollowing mechanisms are also c<strong>on</strong>sidered: (a) Antihypertensiveacti<strong>on</strong>. Associated with a decrease in cardiacoutput, inhibiti<strong>on</strong> of the release of renin and producti<strong>on</strong>of angiotensin II, blockade of presynaptic a-adrenoceptorsthat increase the release of norepinephrine fromsympathetic nerve terminals and decrease of centralvasomotor activity. 1–9 (b) Anti-ischaemic acti<strong>on</strong>b-<strong>blockers</strong> decrease myocardial oxygen demand by reducingheart rate, cardiac c<strong>on</strong>tractility, and systolicblood pressure. 10 In additi<strong>on</strong>, prol<strong>on</strong>gati<strong>on</strong> of diastolecaused by a reducti<strong>on</strong> in heart rate may increase myocardialperfusi<strong>on</strong>. (c) Reducti<strong>on</strong> of renin release andangiotensin II and aldoster<strong>on</strong>e producti<strong>on</strong> by blocking ofb 1 -adrenoceptors <strong>on</strong> renal juxtaglomerular cells. (d)Improvement of left ventricular structure and functi<strong>on</strong>,decreasing ventricular size and increasing ejecti<strong>on</strong> fracti<strong>on</strong>.6–8 b-<strong>blockers</strong> may improve cardiac functi<strong>on</strong> becausethey: (i) reduce heart rate, prol<strong>on</strong>g diastolic fillingand cor<strong>on</strong>ary diastolic perfusi<strong>on</strong> time, (ii) decrease myocardialoxygen demands, (iii) improve myocardial energeticsby inhibiting catecholamine-induced releaseof free fatty acids from adipose tissue, (iv) upregulateb-<strong>adrenergic</strong> <strong>receptor</strong>s and (v) reduce myocardialoxidative stress. 1;11;12 (e) The antiarrhythmic effect, theresult of direct cardiac electrophysiological effects
ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> 1345(reduced heart rate, decreased sp<strong>on</strong>taneous firing ofectopic pacemakers, slowed c<strong>on</strong>ducti<strong>on</strong> and increasedrefractory period of AV node), reduces the sympatheticdrive and myocardial ischaemia, improves baroreflexfuncti<strong>on</strong> and prevents catecholamine-induced hypokalemia.13 Other mechanisms include: inhibiti<strong>on</strong> of cardiacapoptosis mediated via the activati<strong>on</strong> of the b-<strong>adrenergic</strong>pathway, 14 inhibiti<strong>on</strong> of platelet aggregati<strong>on</strong>, 1 reducti<strong>on</strong>of the mechanical stress imposed <strong>on</strong> the plaque,preventing plaque rupture, resensitizati<strong>on</strong> of the b-<strong>adrenergic</strong>pathway and changes in myocardial gene expressi<strong>on</strong>,i.e., an increase in sarcoplasmic reticulumcalcium ATPase, mRNA and a-myosin heavy chain mRNAand a decrease in b-myosin heavy chain mRNA levels. 15Finally, some b-<strong>blockers</strong> exhibit antioxidant propertiesand inhibit vascular smooth muscle cell proliferati<strong>on</strong>. 4Adverse eventsIn general, b-<strong>adrenergic</strong> inhibitors are well tolerated, butserious side-effects may occur, especially when theseagents are used in large doses. 1;2Cardiovascularb-<strong>blockers</strong> reduce heart rate, decrease the firing rate ofcardiac ectopic pacemakers and slow c<strong>on</strong>ducti<strong>on</strong> andincrease the refractory period of the AV node. Thus, theymay cause extreme bradycardia and AV block. Theseeffects are seen mainly in patients with impaired sinusnode functi<strong>on</strong> and AV-node c<strong>on</strong>ducti<strong>on</strong> and are rare whenb-<strong>blockers</strong> are given intravenously to patients with acutemyocardial infarcti<strong>on</strong> 16 or orally in patients with chr<strong>on</strong>icheart failure. 17 b-<strong>blockers</strong> decrease tissue blood flow dueto blockade of vascular b 2 -<strong>receptor</strong>s and unopposedstimulati<strong>on</strong> of vascular a-adrenoceptors. As a result,they can produce cold extremities and Raynaud’s phenomen<strong>on</strong>and worsen the symptoms in patients with severeperipheral vascular disease. 4 However, the clinicalbenefits of b-<strong>adrenergic</strong> antag<strong>on</strong>ists in patients withperipheral vascular disease and cor<strong>on</strong>ary artery diseasemay be very important. 18;19 These side-effects are lesspr<strong>on</strong>ounced with drugs exhibiting vasodilator effects andwith selective b 1 agents. b-<strong>blockers</strong> can also increase thecor<strong>on</strong>ary vasomotor t<strong>on</strong>e, in part because of unopposeda-<strong>adrenergic</strong> mediated vasoc<strong>on</strong>stricti<strong>on</strong>.MetabolicIn patients with insulin-dependent type I diabetes n<strong>on</strong>selectiveb-<strong>blockers</strong> mask some of the warning symptomsof hypoglycaemia (tremor, tachycardia); the other signsof hypoglycaemia (e.g., sweating) are maintained. Aselective b-blocker should therefore be preferred atleast in insulin dependent patients. In any case, theclinical benefit of treatment with b-<strong>blockers</strong> outweighsthe risk, at least after myocardial infarcti<strong>on</strong>. 20;21 In <strong>on</strong>estudy carvedilol decreased the new <strong>on</strong>set diabetes inpatients with heart failure. 22Pulm<strong>on</strong>aryb-<strong>blockers</strong> can lead to a life-threatening increase in airwayresistance and are c<strong>on</strong>traindicated in patients withasthma or br<strong>on</strong>chospastic chr<strong>on</strong>ic obstructive pulm<strong>on</strong>arydisease. In some patients with chr<strong>on</strong>ic obstructive pulm<strong>on</strong>arydisease, the potential benefit of using b-<strong>blockers</strong>may outweigh the risk of worsening pulm<strong>on</strong>ary functi<strong>on</strong>.A history of asthma, however, should still be c<strong>on</strong>sidereda c<strong>on</strong>traindicati<strong>on</strong> to the use of any b-blocker, butchr<strong>on</strong>ic obstructive pulm<strong>on</strong>ary disease is not a c<strong>on</strong>traindicati<strong>on</strong>unless there is a significant reactive airwaydisease. 23Central effectsCentral effects (fatigue, headache, sleep disturbances,insomnia and vivid dreams, depressi<strong>on</strong>) are less comm<strong>on</strong>with hydrophilic drugs. 24 In some patients the fatigue maybe related to a decrease in blood flow to skeletal muscles;in other cases, it may be sec<strong>on</strong>dary to a central effect.Sexual dysfuncti<strong>on</strong>In some patients b-<strong>blockers</strong> may cause or aggravate impotenceand loss of libido.Abrupt disc<strong>on</strong>tinuati<strong>on</strong> of b-<strong>blockers</strong> after chr<strong>on</strong>ictreatment can lead to rebound symptoms (i.e., hypertensi<strong>on</strong>,arrhythmias, exacerbated angina). 25;26 This increasedrisk is related with upregulati<strong>on</strong> of b-adrenoceptors during chr<strong>on</strong>ic treatment.C<strong>on</strong>traindicati<strong>on</strong>sThe c<strong>on</strong>traindicati<strong>on</strong>s to initiate b-blocker treatmentinclude asthma, symptomatic hypotensi<strong>on</strong> or bradycardiaand severe decompensated heart failure (see later).C<strong>on</strong>traindicati<strong>on</strong>s may be relative, in patients in whomthe benefit of therapy may outweigh the risk of untowardeffects. Chr<strong>on</strong>ic obstructive lung disease without br<strong>on</strong>chospasticactivity and peripheral vascular disease arenot c<strong>on</strong>sidered as absolute c<strong>on</strong>traindicati<strong>on</strong>s and highrisk patients may obtain a significant benefit from thistherapy. 27;28 Patients with heart failure and bradycardiadue to sick sinus node or sec<strong>on</strong>d or third degree AV-blockmay benefit from pre-treatment with pacemaker in orderto tolerate b-<strong>blockers</strong>, although this approach has,however, not been formally tested. Diabetes or intermittentlower limb claudicati<strong>on</strong> are not absolute c<strong>on</strong>traindicati<strong>on</strong>sfor b-<strong>blockers</strong> use. 21;29–31Drug interacti<strong>on</strong>sb-<strong>blockers</strong> may show pharmacokinetic and pharmacodynamicinteracti<strong>on</strong>s with other drugs. 32 Aluminium salts,cholestyramine, and colestipol may decrease the absorpti<strong>on</strong>of b-<strong>blockers</strong>. Alcohol, phenytoin, rifampicin,and phenobarbital, as well as smoking, induce hepaticbiotransformati<strong>on</strong> enzymes and decrease plasma c<strong>on</strong>centrati<strong>on</strong>sand eliminati<strong>on</strong> half-lives of lipophilic b-<strong>blockers</strong>. Cimetidine and hydralazine may increase thebioavailability of propranolol and metoprolol by reducinghepatic blood flow. Cauti<strong>on</strong> should be exercised in patientswho are taking verapamil, diltiazem or variousantiarrhythmic agents, which may depress sinus-nodefuncti<strong>on</strong> or AV c<strong>on</strong>ducti<strong>on</strong>. Additive effects <strong>on</strong> blood
1346 ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g>pressure between b-<strong>blockers</strong> antag<strong>on</strong>ists and other antihypertensiveagents are often observed. Indomethacinand other n<strong>on</strong>-steroidal antiinflammatory drugs antag<strong>on</strong>izethe antihypertensive effects of b-<strong>blockers</strong>.Dosing of b-<strong>blockers</strong>Appropriate dosing of b-<strong>blockers</strong> varies with the clinicalcharacteristics of the patient and the selected b-blocker.Table 2 shows the average daily oral doses in patientswith hypertensi<strong>on</strong> and angina. Table 3 indicates the averagerecommended dose for intravenous use.Clinical efficacy and useThe benefit and clinical indicati<strong>on</strong>s of b-<strong>blockers</strong> havebeen clearly defined in many cardiovascular c<strong>on</strong>diti<strong>on</strong>sand agreement about their potential usefulness has beenclearly established in many clinical settings. b-Blockersare safe to use when c<strong>on</strong>traindicati<strong>on</strong>s have been excludedand the appropriate dosage regimen is used.Abrupt disc<strong>on</strong>tinuati<strong>on</strong> should be avoided if possible toprevent withdrawal effects. In case of doubt, specialistadvice is recommended.The benefit of b-blocker treatment has been well<str<strong>on</strong>g>document</str<strong>on</strong>g>ed in the following c<strong>on</strong>diti<strong>on</strong>s:Acute Myocardial Infarcti<strong>on</strong> (AMI)During the acute phase of myocardial infarcti<strong>on</strong>, oralb-<strong>blockers</strong> are indicated in all patients without c<strong>on</strong>traindicati<strong>on</strong>s(class I, level of evidence A). Intravenousadministrati<strong>on</strong> should be c<strong>on</strong>sidered in patients with ischaemicpain resistant to opiates, recurrent ischaemiaand for the c<strong>on</strong>trol of hypertensi<strong>on</strong>, tachycardia andarrhythmias (Table 4). 33–35b-<strong>blockers</strong> limit infarct size, reduce life-threateningarrhythmias, relieve pain and reduce mortality includingsudden cardiac death. 36–43 Two large trials were particularlyrelevant to guide the use of b-<strong>blockers</strong> during thefirst hours of AMI. In the First Internati<strong>on</strong>al Study of InfarctSurvival (ISIS-1) trial 40 patients within 12 h of evoluti<strong>on</strong>were randomised to receive i.v. atenolol followedby oral administrati<strong>on</strong> for 7 days, or c<strong>on</strong>venti<strong>on</strong>altreatment, revealing a significant reducti<strong>on</strong> in mortalityat 7 days (3.7% vs. 4.6%; equivalent to 6 lives saved per1000 treated). The benefit was mainly due to a reducti<strong>on</strong>in heart rupture and was evident by the end of day 1 andsustained at 1 m<strong>on</strong>th and 1 year. In the other large study,the Metoprolol in Myocardial Infarcti<strong>on</strong> (MIAMI), 41 i.v.metoprolol followed by oral administrati<strong>on</strong> did not significantlyreduce 15-day mortality as compared to placebo(4.3–4.9% (ns)). A meta-analysis of 28 early trials ofi.v. b-<strong>blockers</strong> 43 revealed an absolute reducti<strong>on</strong> of shorttermmortality from 4.3% to 3.7% (7 lives saved/1000patients treated). This significant albeit small benefitwas dem<strong>on</strong>strated before the reperfusi<strong>on</strong> era. Similarfindings were reported in a more recent meta-analysisof 52 trials, most of them including a small number ofpatients. 44Two trials of randomised i.v. b-blockade were c<strong>on</strong>ductedafter the widespread use of reperfusi<strong>on</strong> therapyin AMI, 45;46 but the number of events was too small toestablish clear c<strong>on</strong>clusi<strong>on</strong>s. In the sec<strong>on</strong>d Thrombolysis inMyocardial Infarcti<strong>on</strong> (TIMI-II) trial, 45 thrombolysed patientswere randomly assigned to early i.v. and oralmetoprolol versus oral administrati<strong>on</strong> after day 6. Reinfarcti<strong>on</strong>and recurrent ischaemia were less frequent inthe early b-blocker group and when treatment was ad-Table 3 Intravenous dosing of b-<strong>blockers</strong>Drug Loading dose Maintenance doseAtenolol 5 þ 5 mg Oral, 50–100 mg/dayEsmolol 0.5 mg/kg over 1–5 min 0.05–0.3 mg/kg/minLabetalol 20 mg in 2 min 2–10 mg/minMetoprolol 2.5–5 mg i.v. bolus over 2 min; up to three doses Oral, 25–100 mg/12 hPropranolol 0.15 mg/kg 0.10–0.20 mg/kg/min oral, 80–240 mg/dayTable 4 Use of b-<strong>blockers</strong> in AMI: guidelinesSetting/indicati<strong>on</strong> Class Level Ref.i.v. administrati<strong>on</strong>For relief of ischaemic pain I B 33, 34To c<strong>on</strong>trol hypertensi<strong>on</strong>, sinus tachycardia I B 33Primary preventi<strong>on</strong> of sudden cardiac death I B 35Sustained ventricular tachycardia I C 33Supraventricular tachyarrhythmias I C 33, 34To limit infarct size IIa A 33All patients without c<strong>on</strong>traindicati<strong>on</strong>s IIb A 33Oral administrati<strong>on</strong>All patients without c<strong>on</strong>traindicati<strong>on</strong>s I A 33, 34
ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> 1347ministered within 2 h of symptom <strong>on</strong>set, there was areducti<strong>on</strong> of the composite endpoint of death or reinfarcti<strong>on</strong>.Data from the US Nati<strong>on</strong>al Registry of MyocardialInfarcti<strong>on</strong> 2 47 showed that immediate b-blockeradministrati<strong>on</strong> in patients with AMI treated with t-PAreduces the occurrence of intracranial haemorrhage,although this benefit is small (0.7% and 1.0%; 3 patients/1000 treated). However, a post-hoc analysis of the firstGlobal utilizati<strong>on</strong> of streptokinase and t-PA for occludedcor<strong>on</strong>ary arteries (GUSTO-I) trial and a systematic reviewof the available experience do not support the routine,early, intravenous use of b-<strong>blockers</strong>, 33;44;48 at least whenthrombolytic treatment or primary percutaneous interventi<strong>on</strong>is performed. New data from the PAMI (PrimaryAngioplasty in AMI) Stent-PAMI, Air-PAMI and CADILLAC(C<strong>on</strong>trolled Abciximab and Device Investigati<strong>on</strong> to LowerLate Angioplasty Complicati<strong>on</strong>s) trials seems to dem<strong>on</strong>stratea reducti<strong>on</strong> in mortality when b-<strong>blockers</strong> are usedbefore primary percutaneous interventi<strong>on</strong>s. 49–51Sec<strong>on</strong>dary preventi<strong>on</strong> after myocardialinfarcti<strong>on</strong>Oral b-<strong>blockers</strong> are recommended for l<strong>on</strong>g-term use(indefinitely) in all patients who recover from AMI and d<strong>on</strong>ot present c<strong>on</strong>traindicati<strong>on</strong>s (class I, level of evidenceA) (Table 5). 33–35;52–58 b-<strong>blockers</strong> are underused for thisindicati<strong>on</strong>. 59–60Several large, l<strong>on</strong>g-term trials involving more than35,000 survivors of myocardial infarcti<strong>on</strong> have dem<strong>on</strong>stratedthat the use of b-<strong>blockers</strong> in patients recoveringfrom an episode of AMI improves survival by 20–25%through a reducti<strong>on</strong> of cardiac mortality, sudden cardiacdeath and reinfarcti<strong>on</strong>. 43;44;49;61–66 Positive results havebeen found in trials comparing propranolol, metoprolol,timolol, acebutolol and carvedilol with placebo; c<strong>on</strong>versely,no benefit was dem<strong>on</strong>strated in trials withalprenolol, atenolol, oxprenolol or xamoterol. 44 A metaanalysisof 82 randomised trials (31 with l<strong>on</strong>g-term follow-up)provides str<strong>on</strong>g evidence for the l<strong>on</strong>g-term useof b-<strong>blockers</strong> to reduce morbidity and mortality afteracute MI even if aspirin, fibrinolytics or angiotensinc<strong>on</strong>verting enzyme inhibitors (ACE-I) were co-administered.44 An annual reducti<strong>on</strong> of 1.2 deaths in 100 patientstreated with b-<strong>blockers</strong> after myocardialinfarcti<strong>on</strong> was observed; that is, about 84 patients willrequire treatment for 1 year to avoid <strong>on</strong>e death. 44 Similarly,the annual reducti<strong>on</strong> for reinfarcti<strong>on</strong> was 0.9events in 100 treated patients; equivalent to the need totreat 107 patients for 1 year to avoid <strong>on</strong>e n<strong>on</strong>-fatalreinfarcti<strong>on</strong>. In the retrospective analysis of the CooperativeCardiovascular Project, including over 200,000patients with myocardial infarcti<strong>on</strong>, b-blocker use wasassociated with a reducti<strong>on</strong> in mortality, independent ofage, race, presence of pulm<strong>on</strong>ary disease, diabetes,blood pressure, ejecti<strong>on</strong> fracti<strong>on</strong>, heart rate, renalfuncti<strong>on</strong> and treatment received during hospitalisati<strong>on</strong>including myocardial revascularisati<strong>on</strong>. 21In the Beta-blocker Heart Attack Trial (BHAT) 61 patientswere randomised 5–21 days after AMI to receivepropranolol or placebo. Mortality after a mean follow-upof 2 years was reduced by 25% (7% vs. 9.5%) (25 livessaved/1000 treated). In the Norwegian trial, 62 patientswere randomly assigned 7–28 days after AMI to receivetimolol or placebo; mortality was reduced from 9.8% to7.2%, (26 lives/1000 treated) over a follow-up of 25m<strong>on</strong>ths. Sudden cardiac death and reinfarcti<strong>on</strong> were alsosignificantly reduced. Interestingly, the beneficial influenceof timolol <strong>on</strong> survival was sustained for at least 6years. 63 In the study of Hjalmars<strong>on</strong> et al., 64 metoprololgiven first intravenously and then orally, mortality at 90days was reduced by 26%. In the Boissel et al. trial Acebutololet Preventi<strong>on</strong> Sec<strong>on</strong>darie de l’Infartus (APSI)trial, 65 including high risk patients 2–22 days after AMI,there was also a significant 48% reducti<strong>on</strong> in mortalityassociated with the b-blocker treatment. In the CarvedilolPost Infarct Survival C<strong>on</strong>trol in Left VentricularDysfuncti<strong>on</strong> (CAPRICORN) trial including patients 2–21days after AMI with reduced left ventricular ejecti<strong>on</strong>fracti<strong>on</strong> and receiving ACE-I, all-cause mortality waslower in the carvedilol group than in the placebo group(12% vs. 15%). 66 The significant mortality reducti<strong>on</strong>s inheart failure observed with b-<strong>blockers</strong> and the result ofthe CAPRICORN trial further support the use of theseagents in high risk patients with impaired ventricularfuncti<strong>on</strong> or failure after infarcti<strong>on</strong> and dem<strong>on</strong>strate thatthe benefit of b-<strong>blockers</strong> is observed also in patientsreceiving treatment according to current standards, includingreperfusi<strong>on</strong> therapy and ACE-I.Although the benefit of b-<strong>blockers</strong> is observed in abroad populati<strong>on</strong> after infarcti<strong>on</strong>, 21;30;67 the benefit ofl<strong>on</strong>g-term therapy is greatest in high-risk patients (i.e.,those with evidence of large or anterior infarcti<strong>on</strong>) andthere is c<strong>on</strong>tinued debate about whether low-risk subjects(young, revascularised patients without previousinfarcti<strong>on</strong>, residual ischaemia or ventricular arrhythmiasand normal ventricular functi<strong>on</strong>) should be treatedwith b-<strong>blockers</strong> because their l<strong>on</strong>g-term prognosisis favourable. Chr<strong>on</strong>ic stable ischaemic heart diseaseTable 5 Use of b-<strong>blockers</strong> in sec<strong>on</strong>dary preventi<strong>on</strong> after infarcti<strong>on</strong>: guidelinesSetting/indicati<strong>on</strong> Class Level Ref.All patients without c<strong>on</strong>traindicati<strong>on</strong>s, indefinitely I A 33, 34, 52–57To improve survival I A 33, 52–53To prevent reinfarcti<strong>on</strong> I A 33, 52–53Primary preventi<strong>on</strong> of sudden cardiac death I A 35To prevent/treat late ventricular arrhythmias IIa B 33, 35
1350 ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g>ventricular functi<strong>on</strong>. 115–127 Exercise capacity may alsoimprove 114 as well as symptoms and quality of life, 17 butthese effects usually are marginal and have not beenc<strong>on</strong>sistently dem<strong>on</strong>strated in all trials comparingb-<strong>blockers</strong> with placebo. 128In the sec<strong>on</strong>d Cardiac Insufficiency Bisoprolol Study(CIBIS-2) 121 symptomatic patients in NYHA class III or IV,with left-ventricular ejecti<strong>on</strong> fracti<strong>on</strong> of 35% or less,receiving standard therapy with diuretics and ACE-inhibitors,were randomly assigned to receive bisoprolol orplacebo during a mean follow of 1.3 years. The study wasstopped early because bisoprolol showed a significantmortality benefit (11.8% vs. 17.3%) (55 lives saved/1000treated; Number Needed to Treat (NNT) for 1.3 year tosave 1 life ¼ 18). There were significantly fewer suddencardiac deaths am<strong>on</strong>g patients <strong>on</strong> bisoprolol than inthose <strong>on</strong> placebo (3.6% vs. 6.3%). Treatment effects wereindependent of the severity or cause of heart failure.In the Metoprolol Randomised Interventi<strong>on</strong> Trial(MERIT-HF) 122 patients with chr<strong>on</strong>ic heart failure in NYHAfuncti<strong>on</strong>al class II–IV and ejecti<strong>on</strong> fracti<strong>on</strong> 40% andstabilised with optimum standard therapy, were randomlyassigned metoprolol CR/XL or placebo. This studywas also stopped early <strong>on</strong> the recommendati<strong>on</strong> of theindependent safety committee after a mean follow-up of1 year. All-cause mortality was lower in the metoprololgroup than in the placebo group (7.2%, per patient-yearof follow-up vs. 11.0%) (38 lives saved/1000 treated;number needed to treat (NNT) for 1 year to save 1 life¼ 28). There was also a 41% reducti<strong>on</strong> in sudden cardiacdeath and 49% reducti<strong>on</strong> in deaths from worsening heartfailure.In the Carvedilol Prospective Randomised CumulativeSurvival (COPERNICUS) study, 124 patients who hadsymptoms of heart failure at rest or <strong>on</strong> minimal exerti<strong>on</strong>,clinically euvolemic, and with an ejecti<strong>on</strong> fracti<strong>on</strong> of
ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> 1351Table 9 Practical guidance <strong>on</strong> using b-<strong>adrenergic</strong> <strong>blockers</strong> in heart failure (modified from Ref. 133)Who should receive b-blocker therapy All patients with chr<strong>on</strong>ic, stable heart failure Without c<strong>on</strong>traindicati<strong>on</strong>s (symptomatic hypotensi<strong>on</strong> or bradicardia, asthma)What to promiseTreatment is primarily prophylactic against death and new hospitalisati<strong>on</strong>s for cardiovascular reas<strong>on</strong>s. Some patients willexperience improvement of symptoms.When to start No physical evidence of fluid retenti<strong>on</strong> (use diuretics accordingly) Start ACE-I first if not c<strong>on</strong>traindicated In stable patients, in the hospital or in outpatient clinics NYHA class IV/severe CHF patients should be referred for specialist advice Review treatment. Avoid verapamil, diltiazem, antiarrhythmics, n<strong>on</strong>-steroidal anti-inflamatory drugsBeta-blocker Bisoprolol, carvedilol or metoprololDose Start with a low dose Increase dose slowly. Double dose at not less than 2 weekly intervals Aim for target dose (see above) or, if not tolerated, the highest tolerated doseStarting dose mgTarget dose mgBisoprolol 1.25 <strong>on</strong>ce daily 10 <strong>on</strong>ce dailyCarvedilol 3.125 twice daily 25–50 twice dailyMetoprolol CR/XL 12.5–25 <strong>on</strong>ce daily 200 <strong>on</strong>ce dailyM<strong>on</strong>itoring M<strong>on</strong>itor for evidence of heart failure symptoms, fluid retenti<strong>on</strong>, hypotensi<strong>on</strong> and bradycardia Instruct patients to weigh themselves daily and to increase their diuretic dose if weight increasesProblem solving Reduce/disc<strong>on</strong>tinue b-blocker <strong>on</strong>ly if other acti<strong>on</strong>s were ineffective to c<strong>on</strong>trol symptoms/sec<strong>on</strong>dary effects Always c<strong>on</strong>sider the reintroducti<strong>on</strong> and/or uptitrati<strong>on</strong> of the b-blocker when the patient becomes stable Seek specialist advice if in doubt.Symptomatic hypotensi<strong>on</strong> (dizziness, light headedness and/or c<strong>on</strong>fusi<strong>on</strong>) Rec<strong>on</strong>sider need for nitrates, calcium channel <strong>blockers</strong> and other vasodilators If no signs/symptoms of c<strong>on</strong>gesti<strong>on</strong> c<strong>on</strong>sider reducing diuretic doseWorsening symptoms/signs (increasing dyspnoea, fatigue, oedema, weight gain) Double dose of diuretic or/and ACE-I. Temporarily reduce the dose of b-<strong>blockers</strong> if increasing diuretic dose does not work Review patient in 1–2 weeks; if not improved seek specialist advice If serious deteriorati<strong>on</strong> halve dose of b-blocker Stop b-blocker (rarely necessary; seek specialist advice)Bradycardia ECG to exclude heart block C<strong>on</strong>sider pacemaker support if severe bradycardia or AV block or sick sinus node early after starting b-<strong>blockers</strong> Review need, reduce or disc<strong>on</strong>tinue other heart rate slowing drugs, e.g., digoxin, amiodar<strong>on</strong>e, diltiazem Reduce dose of b-blocker. Disc<strong>on</strong>tinuati<strong>on</strong> rarely necessarySevere decompensated heart failure, pulm<strong>on</strong>ary oedema, shock Admit patient to hospital Disc<strong>on</strong>tinue b-blocker if inotropic support is needed or symptomatic hypotensi<strong>on</strong>/bradycardia is observed If inotropic support is needed, levosimendan may be preferredCHF: C<strong>on</strong>gestive Heart Failure; NYHC: New York Heart Associati<strong>on</strong>.practice and lists the c<strong>on</strong>traindicati<strong>on</strong>s. Detailed practicalguidance <strong>on</strong> the use of b-<strong>blockers</strong> in heart failurecan be found elsewhere. 133Heart failure and preserved systolic functi<strong>on</strong>There is a paucity of data regarding the possible benefitof b-<strong>blockers</strong> in patients with heart failure and preservedsystolic left ventricular functi<strong>on</strong>. Accordingly, the recommendeduse of b-<strong>blockers</strong> in these patients is empirical,based mainly <strong>on</strong> the possible benefit of reducingheart rate and improving myocardial ischaemia.Acute heart failureThere are no randomised clinical trials with b-<strong>blockers</strong>in acute heart failure targeted to improve the acutec<strong>on</strong>diti<strong>on</strong>. In the Gothenburg study i.v. metoprolol or
1352 ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g>placebo was initiated early after an AMI and followed byoral therapy for three m<strong>on</strong>ths. Patients with newsymptoms of heart failure were less frequently found inthe metoprolol group, and in patients with signs ofpulm<strong>on</strong>ary c<strong>on</strong>gesti<strong>on</strong> with basal rales and/or i.v. furosemide,metoprolol therapy reduced mortality andmorbidity. 134 In the COPERNICUS trial, b-blocker therapystarted early after acute decompensati<strong>on</strong> of chr<strong>on</strong>icheart failure was associated with a l<strong>on</strong>g-term reducti<strong>on</strong>in mortality. 124 In the CAPRICORN trial patients withheart failure or left ventricular dysfuncti<strong>on</strong> randomisedearly after AMI also received benefit from b-blockertherapy. 66 As recommended in the ESC acute heartfailure guidelines. 135 Patients with acute overt heartfailure including more than basal pulm<strong>on</strong>ary rales,b-<strong>blockers</strong> should be used cautiously. In these patients,if <strong>on</strong>going ischaemia and tachycardia are present, intravenousmetoprolol can be c<strong>on</strong>sidered. (class IIb, levelof evidence C). However, in patients with AMI whostabilise after acute heart failure, b-<strong>blockers</strong> should beinitiated early (class IIa, level of evidence B). In patientswith chr<strong>on</strong>ic heart failure b-<strong>blockers</strong> should be initiatedwhen the patient has stabilised after the acute episode(usually after 4 days) (class I, level of evidence A). Theoral initial dose of bisoprolol, carvedilol or metoprololshould be small and increased slowly and progressivelyto the target dose used in the large clinical trials. Uptitrati<strong>on</strong>should be adapted to individual resp<strong>on</strong>se. Patients<strong>on</strong> b-<strong>blockers</strong> admitted due to worsening heartfailure, should be c<strong>on</strong>tinued <strong>on</strong> this therapy in generalunless inotropic support is needed but dose could bereduced if signs of excessive dosages are suspected (lowheart rate and hypotensi<strong>on</strong>).Arrhythmias (Table 10)Sinus tachycardiaSinus tachycardia is not a primary disorder and treatmentshould be directed to the underlying cause. In selectedindividuals b-<strong>blockers</strong> can be used to slow heartrate 136;137 (class I, level of evidence C) (e.g., if a fastheart rate produces symptoms) and are especially indicatedin situati<strong>on</strong>s of anxiety, after myocardial infarcti<strong>on</strong>,in patients with heart failure, hyperthyroidism andhyperdynamic b-<strong>adrenergic</strong> state. 137;138 In patients withpheochromocytoma, b-<strong>blockers</strong> are also effective toc<strong>on</strong>trol sinus tachycardia, but if given al<strong>on</strong>e hypertensivecrisis can occur sec<strong>on</strong>dary to unopposed a-<strong>receptor</strong>mediated c<strong>on</strong>stricti<strong>on</strong>. 139Supraventricular tachycardiasb-<strong>blockers</strong> are effective for suppressing atrial prematurebeats and c<strong>on</strong>trolling heart rate and c<strong>on</strong>versi<strong>on</strong> of focalatrial tachycardia, as well as preventing its recurrence,in many instances the result of increased sympathetict<strong>on</strong>e 140 such as after surgery (class I, level of evidence C)(Table 10). 137 On the c<strong>on</strong>trary, multifocal atrial tachycardiais frequently associated with severe obstructivelung disease, in which case b-<strong>blockers</strong> are ineffective andc<strong>on</strong>traindicated. AV nodal reciprocating tachycardias,the most comm<strong>on</strong> form of paroxismal supraventriculartachycardia, also resp<strong>on</strong>ds well to i.v. administrati<strong>on</strong> ofpropranolol, metoprolol, atenolol, sotalol or timolol,with a reducti<strong>on</strong> in heart rate, c<strong>on</strong>versi<strong>on</strong> to sinusrhythm or facilitating the success of vagal manoeuvres137;141–145 (class I, level of evidence C). b-<strong>blockers</strong> arealso useful for the preventi<strong>on</strong> of recurrent episodes. OralTable 10 Use of b-<strong>blockers</strong> in arrhythmias: guidelinesSetting/indicati<strong>on</strong> Class Level Ref.Supraventricular arrhythmiasSinus tachycardia I C 137Focal atrial tachycardia, for cardioversi<strong>on</strong> IIa C 137Focal atrial tachycardia, for preventi<strong>on</strong> of recurrence I B 137Atrioventricular nodal reciprocating tachycardia I C 137Focal juncti<strong>on</strong>al tachycardia IIa C 137N<strong>on</strong>-paroxysmal juncti<strong>on</strong>al tachycardia IIa C 137WPW with symptomatic arrhythmias IIa C 137Atrial flutterRate c<strong>on</strong>trol of atrial flutter, poorly tolerated IIa C 137Rate c<strong>on</strong>trol of atrial flutter, well tolerated I C 137Atrial fibrillati<strong>on</strong> (ESC/AHA/ACC)Preventi<strong>on</strong> (post AMI, HF, HTA, post surgery, post c<strong>on</strong>versi<strong>on</strong> to sinus rhythm) I A 136Chr<strong>on</strong>ic c<strong>on</strong>trol of heart rate I B 136Acute c<strong>on</strong>trol of heart rate I A 136C<strong>on</strong>versi<strong>on</strong> to sinus rhythm IIa B 136Combinati<strong>on</strong> with digoxin, for heart rate c<strong>on</strong>trol IIa A 136Acute c<strong>on</strong>trol of HR in heart failure IIb C 136Ventricular arrhythmiasC<strong>on</strong>trol of arrythmias early after AMI (i.v.) I A 33C<strong>on</strong>trol of arrythmias late after AMI I A 33, 35, 52, 56, 57Preventi<strong>on</strong> of sudden cardiac death in heart failure and after MI I A 137
ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> 1353administrati<strong>on</strong> of b-<strong>blockers</strong> is very effective to preventparoxysmal tachycardias precipitated by emoti<strong>on</strong> or exercise.146 Oral propranolol, atenolol, nadolol, and sotalolwere found to be effective in the l<strong>on</strong>g term prophylactictreatment of patients with paroxysmal supraventriculartachycardias 145 (class I, level of evidence C). 137b-<strong>blockers</strong> are also recommended for the treatment ofother forms of supraventricular tachycardias, includingfocal juncti<strong>on</strong>al tachycardia and n<strong>on</strong>-paroxysmal juncti<strong>on</strong>altachycardia 137 (Table 10).Tachycardias in WPW syndromeb-<strong>blockers</strong> may be effective in some patients with supraventriculararrhythmias in the presence of WPW, ifthe accessory pathway is incapable of rapid anterogradec<strong>on</strong>ducti<strong>on</strong> as dem<strong>on</strong>strated in an electrophysiologicalstudies. 137;145 However, b-<strong>blockers</strong> may cause very seriousadverse events. b-<strong>blockers</strong>, as well as digitalis andcalcium channel <strong>blockers</strong>, do not block the accessorypathway and may even enhance c<strong>on</strong>ducti<strong>on</strong>, resulting ina very rapid ventricular resp<strong>on</strong>se which may lead to severehypotensi<strong>on</strong> or cardiac arrest. 136;147–149 For thisreas<strong>on</strong>s, b-<strong>blockers</strong> are c<strong>on</strong>traindicated in arrhythmiasassociated with WPW syndrome. b-<strong>blockers</strong> are alsoc<strong>on</strong>traindicated in patients with sick sinus or bradycardia/tachycardiasyndrome, as sinus arrest with syncopemay occur. 145Atrial flutterb-<strong>blockers</strong> are not effective for c<strong>on</strong>versi<strong>on</strong> of atrialflutter to sinus rhythm but may be effective for ventricularrate c<strong>on</strong>trol, for this reas<strong>on</strong> they are indicated instable patients (class I, level of evidence C). 137Atrial fibrillati<strong>on</strong>b-<strong>blockers</strong> may be effective to prevent episodes of AtrialFibrillati<strong>on</strong> (AF), to c<strong>on</strong>trol heart rate, to revert atrialfibrillati<strong>on</strong> to sinus rhythm and to maintain sinus rhythmafter it is restored (Table 10). 136Preventi<strong>on</strong>. The incidence of atrial fibrillati<strong>on</strong> is lower inpatients receiving b-<strong>blockers</strong>. This effect has been observedin randomised studies in patients with heart failure,during sec<strong>on</strong>dary preventi<strong>on</strong> after acute myocardialinfarcti<strong>on</strong>, in hypertensi<strong>on</strong> and after elective n<strong>on</strong>-cardiacsurgery. 136C<strong>on</strong>trol of heart rate. Propranolol, atenolol, metoprolol,or esmolol may be given i.v. to acutely c<strong>on</strong>trolthe rate of ventricular resp<strong>on</strong>se to AF in specific settings,especially in states of high <strong>adrenergic</strong> t<strong>on</strong>e (e.g.,postoperatively), but i.v. administrati<strong>on</strong> in heart failureis not recommended. b-<strong>blockers</strong> have also provedto be effective in patients with AF complicating thyrotoxicosis,AMI, chr<strong>on</strong>ic stable cor<strong>on</strong>ary artery disease150;151 and during pregnancy. 152 For acute c<strong>on</strong>trol ofheart rate, intravenous esmolol is the recommendedagent. 136;153For l<strong>on</strong>g-term use, b-blockade is a safe therapy toc<strong>on</strong>trol heart rate in AF patients and antag<strong>on</strong>ises theeffects of increased sympathetic t<strong>on</strong>e. In seven of 12comparis<strong>on</strong>s with placebo, b-<strong>blockers</strong> were effective inc<strong>on</strong>trolling resting heart rate. The effect was drugspecific, with sotalol, nadolol and atenolol being themost efficacious. 150 Atenolol provided better c<strong>on</strong>trol ofexercise-induced tachycardia than digoxin al<strong>on</strong>e. 154Combinati<strong>on</strong>s of several agents may often be requiredto achieve adequate rate c<strong>on</strong>trol, but care should betaken to avoid excessive slowing. In general, the combinati<strong>on</strong>of digoxin and b-<strong>blockers</strong> appears to be moreeffective than either digoxin or b-blocker al<strong>on</strong>e andbetter than the combinati<strong>on</strong> of digoxin and calciumchannel <strong>blockers</strong>. 155–158C<strong>on</strong>versi<strong>on</strong> to sinus rhythm. There are few randomisedstudies exploring the efficacy of b-<strong>blockers</strong> to revert AFto sinus rhythm or to maintain sinus rhythm. Onerandomised, open-label, crossover study showed thatatenolol was as effective as sotalol and better thanplacebo at suppressing episodes of AF, reducing theirdurati<strong>on</strong> and associated symptoms. 150 In AF after n<strong>on</strong>cardiacsurgery, intravenous esmolol produced a morerapid c<strong>on</strong>versi<strong>on</strong> to sinus rhythm than did intravenousdiltiazem, 151 , but other antiarrhythmic drugs arepreferred for cardioversi<strong>on</strong> of AF to sinus rhythm. 136b-<strong>blockers</strong> may also reduce subacute recurrences afterc<strong>on</strong>versi<strong>on</strong> to sinus rhythm, 151 bisoprolol being as effectiveas sotalol 159 and carvedilol 160 to maintain sinusrhythm after AF.Ventricular arrhythmiasb-<strong>blockers</strong> are effective in the c<strong>on</strong>trol of ventriculararrhythmias related to sympathetic activati<strong>on</strong>, includingstress-induced arrhythmias, AMI, perioperative andheart failure, including the preventi<strong>on</strong> of suddencardiac death (class I, level of evidence A) 33;35;52;56;57(Table 10). Most b-<strong>blockers</strong> have proved effective toreduce the number of ventricular premature beats. Insustained ventricular tachycardia, b-<strong>blockers</strong> includingpropanolol, sotalol, metoprolol and oral atenolol havebeen effective to suppress the tachycardia, but theexperience is limited and there is a lack of c<strong>on</strong>trolledstudies. Success of b-blocker to treat VF is anecdotal.161 On the c<strong>on</strong>trary, b-<strong>blockers</strong> have proven to bevery efficacious to prevent arrhythmias leading to suddencardiac death in different c<strong>on</strong>diti<strong>on</strong>s, includingacute and chr<strong>on</strong>ic myocardial ischaemia, heart failureand cardiomyopathies.Preventi<strong>on</strong> of sudden cardiac deathThere is clear evidence dem<strong>on</strong>strating that the benefitderived from b-blocker treatment in part is the c<strong>on</strong>sequenceof a reducti<strong>on</strong> in sudden cardiac death (SCD).Accordingly, b-<strong>blockers</strong> are clearly indicated in the primaryand sec<strong>on</strong>dary preventi<strong>on</strong> of SCD in differentclinical settings and guidelines have been established33;35;162;163 (Table 11). However, it should bestressed that for sec<strong>on</strong>dary preventi<strong>on</strong> of sudden cardiacdeath and in particular in the presence of severe leftventricular dysfuncti<strong>on</strong>, the use of b-<strong>blockers</strong> does not
1354 ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g>Table 11 Use of b-<strong>blockers</strong> in the preventi<strong>on</strong> of sudden cardiac death: guidelinesDisease/setting Indicati<strong>on</strong> Class Level Ref.AMI Primary preventi<strong>on</strong> I A 33Post-MIPrimary preventi<strong>on</strong>, in presence of HF or LV I A 35, 163dysfuncti<strong>on</strong>Post-MI Primary preventi<strong>on</strong>, during and post-MI I A 35, 163Post-MI Resuscitated VT/VF, sp<strong>on</strong>taneous sustained VT IIa C 33, 35, 163Heart failure Primary or sec<strong>on</strong>dary preventi<strong>on</strong> I A 35Dilated cardiomyopathy Primary or sec<strong>on</strong>dary preventi<strong>on</strong> I B 35, 163Myocardial bridging Primary preventi<strong>on</strong> IIa C 35L<strong>on</strong>g QT syndrome Primary preventi<strong>on</strong> – symptomatic I B 35L<strong>on</strong>g QT syndrome Sec<strong>on</strong>dary preventi<strong>on</strong> – b-<strong>blockers</strong>+ICD I C 35L<strong>on</strong>g QT syndrome Primary preventi<strong>on</strong> – asymptomatic IIa C 35Catecholaminergic VT Primary or sec<strong>on</strong>dary preventi<strong>on</strong> IIa C 35RV cardiomyopathy Primary preventi<strong>on</strong> IIb C 35Patients with implantable defibrillators Sec<strong>on</strong>dary preventi<strong>on</strong> IIa C 35, 163HF: Heart Failure; LV: Left Ventricle; MI: Myocardial Infarcti<strong>on</strong>; RV: Right Ventricle; VT: Ventricular Tachycardia; BP: Blood Pressure.preclude the identificati<strong>on</strong> and appropriate treatment ofischaemia and the use of implantable defibrillators. 35;163Acute myocardial infarcti<strong>on</strong>The use of b-<strong>blockers</strong> in AMI has been already discussed.For the preventi<strong>on</strong> of VF, i.v. b-<strong>blockers</strong> are indicated inpatients with ventricular arrythmias 33 (class I, level ofevidence A) (Table 11). SCD sec<strong>on</strong>dary to VF is veryfrequent after an acute cor<strong>on</strong>ary occlusi<strong>on</strong>. 164–167b-<strong>blockers</strong> increase the threshold for VF during acuteischaemia and a decrease in VF was dem<strong>on</strong>strated insome placebo c<strong>on</strong>trolled trials with metoprolol, atenololand propranolol very early after <strong>on</strong>set of symptoms.39;168;169 In a randomised study including 735 patientswithin 4 h after the <strong>on</strong>set of chest pain, treatedwith intravenous propranolol followed by oral administrati<strong>on</strong>,VF occurred in two patients in the b-blockergroup and in 14 of the c<strong>on</strong>trol group (p < 0:06). 39 Also,i.v. metoprolol in patients with AMI significantly reducedthe number of VF episodes. 39 However, in other largestudies, including the ISIS-2 and MIAMI 40;41 no significantdecrease in the incidence of VF was noted. Besides, inthe thrombolytic era, there is a lack of c<strong>on</strong>trolled studiesexploring the effect of early b-blocker administrati<strong>on</strong> <strong>on</strong>the incidence of VF, and the benefit of early intravenousadministrati<strong>on</strong> of b-<strong>blockers</strong> to prevent VF is questi<strong>on</strong>ablein patients treated with reperfusi<strong>on</strong> therapy. 33After acute myocardial infarcti<strong>on</strong>, the efficacy ofb-<strong>blockers</strong> is related to a reducti<strong>on</strong> in all-cause mortalityand sudden cardiac death and their use is recommendedin all patients for the primary preventi<strong>on</strong> of sudden cardiacdeath (class I, level of evidence A) 33;35;163 (Table 11).A recent analysis of 31 b-<strong>blockers</strong> trials 170 showed that 13trials reported data <strong>on</strong> reducti<strong>on</strong> of SCD, which was reducedfrom 51% to 43% in patients treated with b-<strong>blockers</strong>vs. the untreated group. In the CAPRICORN trial in post MIpatients with left ventricular dysfuncti<strong>on</strong>, there was atrend toward SCD reducti<strong>on</strong> in the carvedilol group. 66Heart failurePatients with a history of c<strong>on</strong>gestive heart failure 67 ordepressed left ventricular functi<strong>on</strong> 171 show the greatestbenefit from b-<strong>blockers</strong> in mortality reducti<strong>on</strong>, includingSCD and are indicated in all patients for the preventi<strong>on</strong> ofSCD (Class I, level of evidence A) 35 (Table 11). A c<strong>on</strong>sistentc<strong>on</strong>tributi<strong>on</strong> to the improved outcome by thesedrugs is related to a substantial reducti<strong>on</strong> (between 40%and 55%) in SCD rates. 115;122;172 The recent introducti<strong>on</strong> ofnew therapies, such as thrombolytics, ACE-Inhibitors,aldoster<strong>on</strong>e <strong>receptor</strong> <strong>blockers</strong> as well as c<strong>on</strong>comitantrevascularisati<strong>on</strong> or aspirin does not appear to limit theindependent benefit <strong>on</strong> clinical outcome provided byb-<strong>blockers</strong>, as suggested by the evidence of risk reducti<strong>on</strong>sbetween 30% and 50%. 21Dilated cardiomyopathyThere are no specific studies dem<strong>on</strong>strating the benefit ofb-<strong>blockers</strong> for the preventi<strong>on</strong> of sudden cardiac death indilated cardiomyopathy, but the reducti<strong>on</strong> in mortalitywas similar in patients with ischemic or n<strong>on</strong>-ischaemicheart failure 115 ; accordingly, b-<strong>blockers</strong> are recommendedfor the preventi<strong>on</strong> of sudden cardiac death in thispopulati<strong>on</strong> (class I, level of evidence B) 35;163 (Table 11).Hypertrophic cardiomyopathySudden cardiac death sec<strong>on</strong>dary to ventricular arrhythmiasis frequent in patients with hypertrophic cardiomyopathy,especially during exercise and in the presenceof left ventricular outflow obstructi<strong>on</strong>. 163 Thoughb-<strong>blockers</strong> may improve symptoms, the currently availabledata do not support the routine use of b-<strong>blockers</strong> inthe preventi<strong>on</strong> of sudden cardiac death in these patients.21;35;173–176Mitral valve prolapseMitral valve prolapse is usually benign; its link with SCDhas been suggested but never c<strong>on</strong>clusively dem<strong>on</strong>strated.35 No prospective studies have ever been c<strong>on</strong>ductedwith b-<strong>blockers</strong> or antiarrhythmic drugs in thisc<strong>on</strong>diti<strong>on</strong>. Accordingly, no data are available to defineprophylactic interventi<strong>on</strong>s that may reduce the risk ofSCD. However, b-blocking agents are generally c<strong>on</strong>sideredas first choice therapy in symptomatic patients.Yet, the routine or selective use of b-<strong>blockers</strong> to prevent
ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g> 1355sudden cardiac death in patients with mitral valve prolapseis not recommended. 35Myocardial bridgingAlthough it is c<strong>on</strong>sidered as a benign c<strong>on</strong>diti<strong>on</strong>, patientswith myocardial bridging may present with ischaemia andin some cases ventricular arrhythmias and sudden cardiacdeath. 177 Symptoms usually improve with b-<strong>blockers</strong>. 178This informati<strong>on</strong> is based <strong>on</strong> a limited number of smallobservati<strong>on</strong>al studies (class IIa, level of evidence C). 35L<strong>on</strong>g QT syndrome (LQTS)Prol<strong>on</strong>gati<strong>on</strong> of the QT interval not sec<strong>on</strong>dary to ischaemiaor drugs is associated with life-threatening ventriculararrhythmias, sometimes exercise or stressrelated. 179;180 b-Blockers are usually c<strong>on</strong>sidered indicatedbut there is a lack of prospective, placebo-c<strong>on</strong>trolledstudies. In the largest of the retrospective analyses,c<strong>on</strong>ducted in 233 LQTS patients, all symptomatic forsyncope or cardiac arrest, mortality 15 years after thefirst syncope was 9% for the patients treated by anti<strong>adrenergic</strong>therapy (b-<strong>blockers</strong> and/or left cardiac sympatheticdenervati<strong>on</strong>) and close to 60% in the group nottreated or treated with miscellaneous therapies. 181 Thesedata support the benefit of b-<strong>blockers</strong>, however, they d<strong>on</strong>ot provide total protecti<strong>on</strong> and especially for the patientswith a history of cardiac arrest the risk of SCD remainsunacceptably high. In symptomatic patients the useof b-<strong>blockers</strong> is c<strong>on</strong>sidered a class I with a level of evidenceB, in asymptomatic patients a class IIa, level ofevidence C 35 (Table 11).Catecholaminergic polymorphic ventriculartachycardiaThis clinical entity is characterised by <strong>adrenergic</strong>ally inducedpolymorphic ventricular tachycardia in the absenceof structural cardiac abnormalities and a familialhistory of syncope and SCD occurs in approximately <strong>on</strong>ethird of the cases. 182;183 The arrhythmias are reproducibleduring exercise stress test or during isoproterenolinfusi<strong>on</strong>. 183 At the present time b-<strong>blockers</strong> seem to bethe <strong>on</strong>ly therapy that may be effective. 183 Retrospectiveanalysis of the few published cases, shows SCD in 10.5%and 48% of patients with and without b-blocker therapy,respectively. 183 Although this finding is not c<strong>on</strong>clusivegiven the lack of c<strong>on</strong>trolled studies, b-<strong>blockers</strong> are recommendedfor the primary and sec<strong>on</strong>dary preventi<strong>on</strong> ofSCD (class IIa, level of evidence C). 35SCD in the normal heartIdiopathic VF occurs in up to 8% of victims of SCD. 184According to the UCARE European registry, preventi<strong>on</strong> ofrecurrence with antiarrhythmic agents and b-<strong>blockers</strong>failed. 185The Brugada syndrome 186 is an arrhythmogenic disorderassociated with high risk of SCD caused by rapidpolymorphic ventricular arrhythmias mainly occurring atrest or during sleep in individuals with a structurallynormal heart. The occurrence of cardiac arrest at 3 yearfollow-up may be as high as 30%. The disease is characterisedby transient right bundle branch block andST-segment elevati<strong>on</strong> in leads V1–V3. The efficacy of b-<strong>blockers</strong> in this c<strong>on</strong>diti<strong>on</strong> has not been investigated.Accordingly, b-<strong>blockers</strong> are not currently recommendedin this c<strong>on</strong>diti<strong>on</strong>. 35Other situati<strong>on</strong>sb-<strong>blockers</strong> are also indicated in patients with pacemakersand implantable defibrillators for sec<strong>on</strong>dary preventi<strong>on</strong>(class IIb and IIa, respectively, level of evidence C). 35Hypertensi<strong>on</strong>b-Blockers are indicated in the treatment of hypertensi<strong>on</strong>(class I, level of evidence A) 46;52;53 (Table 12). Intravenousb-<strong>blockers</strong> can be used to treat hypertensiveemergencies. Current guidelines str<strong>on</strong>gly recommendreducti<strong>on</strong> of blood pressure to different levels accordingto the risk profile (the higher the risk the lower the idealblood pressure) 52;56–58;187–189 , and in most patients theappropriate c<strong>on</strong>trol requires the use of two or more antihypertensivemedicati<strong>on</strong>s. Although the primary objectivein hypertensive patients is the c<strong>on</strong>trol of bloodpressure levels, pharmacological treatment should alsoreduce morbidity and mortality and the selecti<strong>on</strong> of aspecific drug should be based <strong>on</strong> the patient profile. 58Thus, b-<strong>blockers</strong> may be c<strong>on</strong>sidered as the first choicetherapy, al<strong>on</strong>e or in combinati<strong>on</strong>, in patients with previousmyocardial infarcti<strong>on</strong>, ischaemic heart disease,arrhythmias or heart failure, asymptomatic left ventriculardysfuncti<strong>on</strong>, diabetes or high risk of cor<strong>on</strong>ary disease,based <strong>on</strong> the efficacy of these drugs <strong>on</strong> thesepatient populati<strong>on</strong>s (class I, level of evidenceA). 52;56;57;188In early studies, treatment of hypertensi<strong>on</strong> with b-<strong>blockers</strong> was associated with an improvement in l<strong>on</strong>gtermoutcomes, including a reducti<strong>on</strong> in mortality, 190–192stroke 193–195 and heart failure. 193 In the Swedish Trial inOld Patients with hypertensi<strong>on</strong> (STOP-Hypertensi<strong>on</strong>trial), 190 all cause mortality and sudden cardiac deathwas lower in the b-blocker (metoprolol, pindolol oratenolol) than in the placebo group. In the MAPHYstudy 192 , comparing metoprolol with thiazide, bloodpressure reducti<strong>on</strong> was similar in both groups, but mor-Table 12 Use of b-<strong>blockers</strong> in the treatment of hypertensi<strong>on</strong>: guidelinesSetting/indicati<strong>on</strong> Class Level Ref.To c<strong>on</strong>trol BP I A 52, 56, 57After MI, in ischaemia, tachyarrythmias, heart failure I A 52, 57, 188MI: Myocardial Infarcti<strong>on</strong>; BP: Blood Pressure.
1356 ESC <str<strong>on</strong>g>Expert</str<strong>on</strong>g> <str<strong>on</strong>g>c<strong>on</strong>sensus</str<strong>on</strong>g> <str<strong>on</strong>g>document</str<strong>on</strong>g>tality was lower in the metoprolol group. This benefit ofb-<strong>blockers</strong> compared with diuretics was not observed inother studies. In the Medical Research Council (MRC)trial 191 atenolol failed to reduce cardiovascular events ascompared to placebo or diuretics in hypertensive patientswithout previous myocardial infarcti<strong>on</strong>, angina andheart failure. In the HAPPHY study, 194 b-<strong>blockers</strong>(metoprolol, atenolol or propranolol) did not improvethe clinical outcome as compared with diuretics. In ameta-analysis 193 b-<strong>blockers</strong> were effective in preventingstroke and heart failure when compared with placebo butnot with diuretics.In more recent trials, b-<strong>blockers</strong> were equally efficaciousto reduce blood pressure and cardiovascular riskwhen compared with calcium channel <strong>blockers</strong> 196 andACE-inhibitors. 196–199 In a meta-analysis, including the UKProspective Diabetes Study (UKPDS) (atenolol vs. captopril),STOP-Hypertensi<strong>on</strong>-2 (diuretics or b-<strong>blockers</strong> vs.ACE-inhibitors vs. dihydropiridine calcium channel<strong>blockers</strong>), CAPP (diuretics or b-<strong>blockers</strong> vs. captopril)and NORDIL (thiazide or b-blocker vs. diltizem), ACE-inhibitorsoffered a similar cardiovascular protecti<strong>on</strong> ascompared with diuretics or b-<strong>blockers</strong> and calciumchannel <strong>blockers</strong> provided an extra 13% reducti<strong>on</strong> in therisk of stroke but the risk of infarcti<strong>on</strong> was 19% higherthan with b-<strong>blockers</strong> or diuretics. 200The Losartan Interventi<strong>on</strong> For Endpoint reducti<strong>on</strong> inhypertensi<strong>on</strong> (LIFE) study compared the angiotensin IIinhibitor losartan with atenolol in hypertensive patientswith left ventricular hypertrophy but without myocardialinfarcti<strong>on</strong> or stroke within the previous 6 m<strong>on</strong>ths, anginapectoris requiring treatment with b-<strong>blockers</strong> and heartfailure or left ventricular ejecti<strong>on</strong> fracti<strong>on</strong> of 6 40%.Losartan was associated with a greater reducti<strong>on</strong> instroke as compared atenolol (5% vs. 6.7%) over a meanfollow up of 8.4 years. Mortality and myocardial infarcti<strong>on</strong>was similar in both groups. 201Aortic dissecti<strong>on</strong>b-<strong>blockers</strong> are indicated to lower blood pressure in patientswith suspected or diagnosed aortic dissecti<strong>on</strong>(class I, level of evidence C) (Table 13). 202b-<strong>blockers</strong> reduce blood pressure and pulse pressure(systolic/diastolic pressure difference), which reflect theTable 13 Use of b-<strong>blockers</strong> in aortic dissecti<strong>on</strong>: guidelinesSetting/indicati<strong>on</strong> Class Level Ref.To lower blood pressure I C 202force in the aortic wall. For this purpose b-<strong>blockers</strong> arec<strong>on</strong>sidered the drug of choice in patients with aorticdissecti<strong>on</strong> although this therapeutic approach has notbeen tested in randomised clinical trials. Intravenousb-<strong>blockers</strong> (propranolol, metoprolol, atenolol, labetaloland esmolol) should be preferred to achieve rapid c<strong>on</strong>trolof blood pressure and can be used under carefulc<strong>on</strong>trol of blood pressure, heart rate and end-organperfusi<strong>on</strong>. The recommended doses are indicated in Table3 but have to be individually adjusted according tothe obtained resp<strong>on</strong>se. 193;194;203 While b-blocking agentsare usually adequate in most patients, combinati<strong>on</strong> withintravenous sodium nitroprusside may be required forsevere hypertensi<strong>on</strong>.Hypertrophic cardiomyopathyHypertrophic cardiomyopathy is a complex disease with abroad spectrum of manifestati<strong>on</strong>s and risk profile. Althoughb-<strong>blockers</strong>, including propranolol, atenolol,metoprolol, sotalol or nadolol have been successfullyused to relieve symptoms, improve physical capacity,c<strong>on</strong>trol heart rate, treat arrhythmias, treat heart failureand prevent sudden cardiac death in patients with andwithout evidence of left ventricular outflow obstructi<strong>on</strong>,their use has not been clearly standardised. 176 Also,there is no proof that prophylactic drug therapy inasymptomatic patients to prevent or delay progressi<strong>on</strong> ofc<strong>on</strong>gestive symptoms and improve prognosis.Prophylactic use in n<strong>on</strong>-cardiac surgeryb-Blockers are indicated in high cardiac risk patients,with present or past history of ischaemia, arrhythmias orhypertensi<strong>on</strong> c<strong>on</strong>trolled by b-<strong>blockers</strong> and in patientswith ischaemia in perioperative testing submitted toelective n<strong>on</strong>-cardiac surgery (specially vascular surgery),to prevent ischaemic events and arrhythmias (class I,level of evidence A). Also, b-<strong>blockers</strong> are indicated forthe treatment of perioperative hypertensi<strong>on</strong>, ischaemiaand arrhythmias identified preoperatively and previouslyuntreated (class IIa, level of evidence (B) (Table 14). 54Perioperative b-blocker therapy in high risk patients isunderutilized. 205In several studies, the preoperative administrati<strong>on</strong> ofb-<strong>blockers</strong> was associated with better c<strong>on</strong>trol of bloodpressure 206;207 and a reducti<strong>on</strong> in perioperative ischaemia204;206–212 and arrhythmias. 213;214 There is also evidencethat patients with high risk for cor<strong>on</strong>ary heartdisease have a better outcome if treated with b-<strong>blockers</strong>Table 14 Use of b-<strong>blockers</strong> in n<strong>on</strong>-cardiac surgery: guidelinesSetting/indicati<strong>on</strong> Class Level Ref.High cardiac risk (history of ischaemia, arrhythmias, hypertensi<strong>on</strong>, or stress inducedI A 54ischaemia, to reduce ischaemic events and arrhythmiasPreoperative use to c<strong>on</strong>trol ischaemia, hypertensi<strong>on</strong>, arrhythmias I A 54Treatment of peroperative ischaemia, hypertensi<strong>on</strong> and arrhythmias IIa B 54
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