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Expert consensus document on b-adrenergic receptor blockers

European Heart Journal (2004) 25, 1341–1362 ESC Expert consensus document Expert consensus document on b-adrenergicreceptor blockers The Task Force on Beta-Blockers of the European Societyof Cardiology Task Force Members, Jos on, Chairperson* (Spain), Karl Swedberg (Sweden), John McMurray (UK), Juan Tamargo (Spain), Aldo P. Maggioni (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 (Chairperson) (Italy), Maria Angeles Alonso Garcıa (Spain),Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica 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 Alonso Garcıa (CPG Review Coordinator) (Spain); Diego Ardissino (Italy),Cristina Avendano (Spain), Carina Blomstr€ om-Lundqvist (Sweden), Denis Cl ement (Belgium), Helmut Drexler (Germany), Roberto Ferrari (Italy), Keith A. Fox (UK), Desmond Julian (UK), Peter Kearney (Ireland), Werner Klein(Austria), Lars K€ ober (Denmark), Giuseppe Mancia (Italy), Markku Nieminen (Finland), Witold Ruzyllo (Poland), Maarten Simoons (The Netherlands), Kristian Thygesen (Denmark), Gianni Tognoni (Italy), Isabella Tritto (Italy),Lars Wallentin (Sweden) Table of contents Sexual dysfunction . . . . . . . . . 1345 Classes of recommendations . . . . . . . 1342 Contraindications . . . . . . . . . . 1345 Levels of evidence. . . . . . . . . . . 1342 Drug interactions . . . . . . . . . . 1345 Dosing of b-blockers . . . . . . . . . 1346 Clinical efficacy and use . . . . . . . . . 1346 Acute myocardial infarction (AMI) . . . . . 1346 Classification of b-blockers . . . . . . . 1343 Secondary prevention after Pharmacokinetic properties . . . . . . . 1343 myocardial infarction . . . . . . . . . 1347 Lipophilic drugs. . . . . . . . . . 1344 Non-ST-segment elevation acute coronary Hydrophilic drugs. . . . . . . . . 1344 Balanced clearance drugs . . . . . . 1344 Chronic, stable ischaemic heart disease . . . 1348 Mechanism of action . . . . . . . . . 1344 Heart failure and preserved systolic function 1351 Cardiovascular . . . . . . . . . . 1345 Acute heart failure . . . . . . . . 1351 Sinus tachycardia. . . . . . . . . 1352Supraventricular tachycardias. . . . . 1352Tachycardias in WPW syndrome . . . . 1353Atrial flutter. . . . . . . . . . . 1353Atrial fibrillation . . . . . . . . . 1353 * Corresponding author. Chairperson: Jos Ventricular arrhythmias . . . . . . . 1353 Area 1200, Hospital Universitario Gregorio Mara non, Doctor Esquerdo 46, Prevention of sudden cardiac death. . . . 1353 28007 Madrid. Spain. Tel.: þ34-91-586-8295; fax: þ34-91-586-6672.
E-mail address: (J. L Acute myocardial infarction . . . . . . 1354 0195-668X/$ - see front matter  c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
ESC Expert consensus document treatment and the Level of Evidence as indicated in the Dilated cardiomyopathy . . . . . . . 1354 Hypertrophic cardiomyopathy. . . . . 1354Mitral valve prolapse . . . . . . . . 1354 Classes of Recommendations Myocardial bridging . . . . . . . . 1355Long QT syndrome (LQTS) . . . . . . 1355Catecholaminergic polymorphic ventricular Evidence and/or general agreement that a given procedure/treatment is beneficial, SCD in the normal heart . . . . . . . 1355 useful and effective; Other situations . . . . . . . . . 1355 Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy Aortic dissection . . . . . . . . . . 1356 of the procedure/treatment; Hypertrophic cardiomyopathy . . . . . . 1356 Class IIa: Weight of evidence/opinion is in favour of Prophylactic use in non-cardiac surgery . . . 1356 Vasovagal syncope . . . . . . . . . . 1357 Class IIb: Usefulness/efficacy is less well established b-Blockers during pregnancy . . . . . . 1357 by evidence/opinion; Class III*: Evidence or general agreement that the treatment is not useful/effective and insome cases may be harmful.
*Use of Class III is discouraged by the ESC Guidelines and Expert Consensus documents aim topresent all the relevant evidence on a particular issue in Levels of Evidence order to help physicians to weigh the benefits and risksof a particular diagnostic or therapeutic procedure.
They should be helpful in everyday clinical decision-making.
Level of Evidence A Data derived from multiple ran- A great number of Guidelines and Expert Consensus domised clinical trials or meta- Documents have been issued in recent years by the Eu- ropean Society of Cardiology (ESC) and by different or- Level of Evidence B Data derived from a single ran- ganisations and other related societies. This profusion domised clinical trial or non- can put at stake the authority and validity of guidelines, randomised studies which can only be guaranteed if they have been devel- Level of Evidence C Consensus of opinion of the ex- oped by an unquestionable decision-making process. This perts and/or small studies is one of the reasons why the ESC and others have issuedrecommendations for formulating and issuing Guidelinesand Expert Consensus Documents.
In spite of the fact that standards for issuing good quality Guidelines and Expert Consensus Documents are b-Blocker therapy plays a major role in the treatment of well defined, recent surveys of Guidelines and Expert cardiovascular diseases. For many years b-blockers were Consensus Documents published in peer-reviewed jour- used for their antiischaemic, antiarryhthmic and anti- nals between 1985 and 1998 have shown that methodo- hypertensive properties. More recently, the benefit of logical standards were not complied with in the vast adrenoceptor blockade was also established in patients majority of cases. It is therefore of great importance that with heart failure. The aim of this document is to review guidelines and recommendations are presented in formats the rationale and clinical evidence for the use of b-ad- that are easily interpreted. Subsequently, their imple- renergic blockers in patients with cardiovascular disease.
mentation programmes must also be well conducted.
The members for the Beta-blockers in Cardiovascular The ESC Committee for Practice Guidelines (CPG) su- Disease Task Force were nominated by the Committee for pervises and coordinates the preparation of new Guide- Practice Guidelines (CPG) of the European Society of lines and Expert Consensus Documents produced by Task Cardiology (ESC). A specific literature search was carried Forces, expert groups or consensus panels. The chosen out for original articles in peer review journals included in experts in these writing panels are asked to provide dis- Medline. In addition, the ESC as well as the American Heart closure statements of all relationships they may have Association/American College of Cardiology guidelines which might be perceived as real or potential conflicts of with reference to the use of b-blockers were carefully interest. These disclosure forms are kept on file at the reviewed. Most of the previously made recommendations European Heart House, headquarters of the ESC. The were maintained; some were updated and a few are new Committee is also responsible for the endorsement of according to recent evidence in the literature.
these Guidelines and Expert Consensus Documents or Using recommendations which are graded provides a simple method for guidance. Levels of recommendation The Task Force has classified and ranked the useful- are derived from clinical trials, conducted in selected ness or efficacy of the recommended procedure and/or groups of patients that may not be representative of ESC Expert consensus document broader populations; in fact, patients with contraindica- versible antagonism of the effects of b-adrenergic stim- tions are excluded from clinical trials. Besides, the same uli on various organs (Table 1). Their pharmacological strength of evidence may reflect different clinical bene- effects can be explained from the knowledge of the re- fit: mortality, morbidity, clinical symptoms or combined sponses elicited by these receptors in the various tissues end-points; large or small benefit albeit statistically sig- and the activity of the sympathetic tone.1;2 Thus, nificant; easily obtained or only observed, or lost, after b-blockers have relatively little effect on heart rate and several years of treatment. Finally, in individual cases the contractility in an individual at rest but slow heart rate recommended therapy may only be a treatment option and decrease cardiac contractility when the sympathetic and other alternatives may be equally acceptable or even nervous system is activated, i.e., during exercise or more appropriate. An effort was made to include this information in a relatively short document.
The document prepared by the task force was circu- lated among a review board appointed by the ESC and Classification of b-blockers approved by the Committee for Practice Guidelines ofthe ESC. The final document was sent to the European b-Blockers can be broadly classified into (a) non-selective, Heart Journal for a formal peer review.
those producing a competitive blockade of both b1- and This consensus document represents the views of the b2-adrenergic receptors and (b) those with much higher ESC and was arrived at after careful consideration of the affinity for the b1 than for the b2 receptors usually called available evidence. Health professionals are expected to b1-selective (Table 2).1–4 Selectivity is, however, dose- take them fully into account when exercising their clin- dependent and decreases or disappears when larger doses ical judgement. This consensus document does not, are used. Paradoxically, some b-blockers can exert a weak however, override the individual responsibility of health agonist response (intrinsic sympathomimetic activity professionals to make appropriate decisions in the cir- (ISA), and can stimulate and block the b-adrenoceptor.
cumstances of the individual patient, in consultation Several b-blockers have peripheral vasodilator activity with that patient, and where appropriate and necessary mediated via a1-adrenoceptor blockade (carvedilol, la- the patient's guardian or carer.
betalol), b2-adrenergic receptor agonism (celiprolol) orvia mechanisms independent of the adrenoceptor block-ade (bucindolol, nebivolol). In addition, b-blockers can be classified as lipophilic or hydrophilic.
b-Adrenergic antagonists (b-blockers) bind selectively to There are important pharmacokinetic differences among the b-adrenoceptors producing a competitive and re- b-blockers1–4 (Table 1).
Effects mediated by b1- and b2-adrenoceptors Increase in heart rate Increase in conduction velocity Increase in contractility Increase in contractility, conduction velocity and automaticityof idioventricular pacemakers Vasodilation, increased contractilityGlycogenolysis, Kþ uptake Glycogenolysis and gluconeogenesis Pancreas (b cells) Insulin and glucagon secretion Gallbladder and ducts Urinary bladder detrusor Promotes noradrenaline release Parathyroid glands Parathormone secretion T4 ! T3 conversion SA: Sino-Atrial; AV: Auriculo-Ventricular.
ESC Expert consensus document Pharmacological classification of commonly used b-adrenergic antagonists (b-blockers) Peripheral vasodilation Average daily oral dose I. Non-selective (b þ b ) adrenergic antagonists 2.5–20 mg once/twice daily 40–320 mg once daily 20–80 mg once/twice daily 10–40 mg twice daily 40–180 mg twice daily 5–40 mg twice daily II. Selective b -adrenergic antagonists 200–800 mg once/twice daily 25–100 mg once daily 5–20 mg once daily 2.5–10 mg once daily 200–600 mg once daily 50–100 mg once/twice daily 2.5–5 mg once daily III. a1- and b-adrenergic antagonistsBucindolol 25–100 mg twice daily 3.125–50 mg twice daily 200–800 mg twice daily ISA: Intrinsic Sympathomimetic Activity; i.v.: Intravenous administration possible; AMI: Acute Myocardial Infarction; CHF: Chronic Heart Failure.
Included only b-blockers with demonstrated efficacy on clinical outcomes and supporting the guidelines recommendations.
* In some studies there was lack of evidence for peripheral a1-adrenoceptor blockade during long-term treatment of heart failure with carvedilol.229 Mechanism of action Lipophilic drugs (metoprolol, propranolol, timolol) are rapidly and completely absorbed from the gastrointesti- The mechanisms of action are diverse, not yet com- nal tract but are extensively metabolised in the gut wall pletely understood and probably with important differ- and in the liver (first pass effect), so that their oral ences between agents. The prevention of the cardiotoxic bioavailability is low (10–30%). These drugs may accu- effects of catecholamines plays a central role.6–8 The mulate in patients with reduced hepatic blood flow (i.e., following mechanisms are also considered: (a) Antihy- elderly, congestive heart failure, liver cirrhosis). Lipo- pertensive action. Associated with a decrease in cardiac philic drugs present short elimination half-lives (1-5 h) output, inhibition of the release of renin and production and they easily enter the central nervous system (CNS), of angiotensin II, blockade of presynaptic a-adrenocep- which may account for a greater incidence of central tors that increase the release of norepinephrine from sympathetic nerve terminals and decrease of cen-tral vasomotor activity.1–9 (b) Anti-ischaemic action Hydrophilic drugs b-blockers decrease myocardial oxygen demand by re- Hydrophilic drugs (atenolol, esmolol) are absorbed in- ducing heart rate, cardiac contractility, and systolic completely from the gastrointestinal tract and are ex- blood pressure.10 In addition, prolongation of diastole creted unchanged or as active metabolites by the kidney.
caused by a reduction in heart rate may increase myo- They have longer half-lives (6–24 h), and do not interact cardial perfusion. (c) Reduction of renin release and with other liver-metabolised drugs. They barely cross the angiotensin II and aldosterone production by blocking of blood–brain barrier. Elimination half-life is increased b1-adrenoceptors on renal juxtaglomerular cells. (d) when glomerular filtration rate is reduced (i.e., elderly, Improvement of left ventricular structure and function, decreasing ventricular size and increasing ejection frac-tion.6–8 b-blockers may improve cardiac function be- Balanced clearance drugs cause they: (i) reduce heart rate, prolong diastolic filling Bisoprolol has a low first-pass metabolism, enters the and coronary diastolic perfusion time, (ii) decrease my- CNS and is excreted in equal proportion by hepatic and ocardial oxygen demands, (iii) improve myocardial en- renal routes. Carvedilol has a low oral bioavailability due ergetics by inhibiting catecholamine-induced release to an extensive first pass effect. It binds to plasma pro- of free fatty acids from adipose tissue, (iv) upregulate teins and is eliminated by hepatic metabolism.4 Esmolol receptors and (v) reduce myocardial is an ultra short-acting drug. It is administered i.v. and oxidative stress.1;11;12 (e) The antiarrhythmic effect, the rapidly hydrolysed by red cell esterases (half-life 9 min).5 result of direct cardiac electrophysiological effects ESC Expert consensus document (reduced heart rate, decreased spontaneous firing of asthma or bronchospastic chronic obstructive pulmonary ectopic pacemakers, slowed conduction and increased disease. In some patients with chronic obstructive pul- refractory period of AV node), reduces the sympathetic monary disease, the potential benefit of using b-blockers drive and myocardial ischaemia, improves baroreflex may outweigh the risk of worsening pulmonary function.
function and prevents catecholamine-induced hypokale- A history of asthma, however, should still be considered mia.13 Other mechanisms include: inhibition of cardiac a contraindication to the use of any b-blocker, but apoptosis mediated via the activation of the b-adrener- chronic obstructive pulmonary disease is not a contra- gic pathway,14 inhibition of platelet aggregation,1 re- indication unless there is a significant reactive airway duction of the mechanical stress imposed on the plaque, preventing plaque rupture, resensitization of the b-ad-renergic pathway and changes in myocardial gene ex- pression, i.e., an increase in sarcoplasmic reticulum Central effects (fatigue, headache, sleep disturbances, calcium ATPase, mRNA and a-myosin heavy chain mRNA insomnia and vivid dreams, depression) are less common and a decrease in b-myosin heavy chain mRNA levels.15 with hydrophilic drugs.24 In some patients the fatigue may Finally, some b-blockers exhibit antioxidant properties be related to a decrease in blood flow to skeletal muscles; and inhibit vascular smooth muscle cell proliferation.4 in other cases, it may be secondary to a central effect.
Sexual dysfunction In some patients b-blockers may cause or aggravate im- In general, b-adrenergic inhibitors are well tolerated, but potence and loss of libido.
serious side-effects may occur, especially when these Abrupt discontinuation of b-blockers after chronic agents are used in large doses.1;2 treatment can lead to rebound symptoms (i.e., hyper-tension, arrhythmias, exacerbated angina).25;26 This in- b-blockers reduce heart rate, decrease the firing rate of adrenoceptors during chronic treatment.
cardiac ectopic pacemakers and slow conduction andincrease the refractory period of the AV node. Thus, they may cause extreme bradycardia and AV block. Theseeffects are seen mainly in patients with impaired sinus The contraindications to initiate b-blocker treatment node function and AV-node conduction and are rare when include asthma, symptomatic hypotension or bradycardia b-blockers are given intravenously to patients with acute and severe decompensated heart failure (see later).
myocardial infarction16 or orally in patients with chronic Contraindications may be relative, in patients in whom heart failure.17 b-blockers decrease tissue blood flow due the benefit of therapy may outweigh the risk of untoward to blockade of vascular b2-receptors and unopposed effects. Chronic obstructive lung disease without bron- stimulation of vascular a-adrenoceptors. As a result, chospastic activity and peripheral vascular disease are they can produce cold extremities and Raynaud's phe- not considered as absolute contraindications and high nomenon and worsen the symptoms in patients with se- risk patients may obtain a significant benefit from this vere peripheral vascular disease.4 However, the clinical therapy.27;28 Patients with heart failure and bradycardia benefits of b-adrenergic antagonists in patients with due to sick sinus node or second or third degree AV-block peripheral vascular disease and coronary artery disease may benefit from pre-treatment with pacemaker in order may be very important.18;19 These side-effects are less to tolerate b-blockers, although this approach has, pronounced with drugs exhibiting vasodilator effects and however, not been formally tested. Diabetes or inter- with selective b1 agents. b-blockers can also increase the mittent lower limb claudication are not absolute con- coronary vasomotor tone, in part because of unopposed traindications for b-blockers use.21;29–31 a-adrenergic mediated vasoconstriction.
Drug interactions In patients with insulin-dependent type I diabetes non- selective b-blockers mask some of the warning symptoms b-blockers may show pharmacokinetic and pharmacody- of hypoglycaemia (tremor, tachycardia); the other signs namic interactions with other drugs.32 Aluminium salts, of hypoglycaemia (e.g., sweating) are maintained. A cholestyramine, and colestipol may decrease the ab- selective b-blocker should therefore be preferred at sorption of b-blockers. Alcohol, phenytoin, rifampicin, least in insulin dependent patients. In any case, the and phenobarbital, as well as smoking, induce hepatic clinical benefit of treatment with b-blockers outweighs biotransformation enzymes and decrease plasma con- the risk, at least after myocardial infarction.20;21 In one centrations and elimination half-lives of lipophilic b- study carvedilol decreased the new onset diabetes in blockers. Cimetidine and hydralazine may increase the patients with heart failure.22 bioavailability of propranolol and metoprolol by reducinghepatic blood flow. Caution should be exercised in pa- tients who are taking verapamil, diltiazem or various b-blockers can lead to a life-threatening increase in air- antiarrhythmic agents, which may depress sinus-node way resistance and are contraindicated in patients with function or AV conduction. Additive effects on blood ESC Expert consensus document pressure between b-blockers antagonists and other an- and for the control of hypertension, tachycardia and tihypertensive agents are often observed. Indomethacin arrhythmias (Table 4).33–35 and other non-steroidal antiinflammatory drugs antago- b-blockers limit infarct size, reduce life-threatening nize the antihypertensive effects of b-blockers.
arrhythmias, relieve pain and reduce mortality includingsudden cardiac death.36–43 Two large trials were partic- Dosing of b-blockers ularly relevant to guide the use of b-blockers during thefirst hours of AMI. In the First International Study of In- Appropriate dosing of b-blockers varies with the clinical farct Survival (ISIS-1) trial40 patients within 12 h of evo- characteristics of the patient and the selected b-blocker.
lution were randomised to receive i.v. atenolol followed Table 2 shows the average daily oral doses in patients by oral administration for 7 days, or conventional with hypertension and angina. Table 3 indicates the av- treatment, revealing a significant reduction in mortality erage recommended dose for intravenous use.
at 7 days (3.7% vs. 4.6%; equivalent to 6 lives saved per1000 treated). The benefit was mainly due to a reductionin heart rupture and was evident by the end of day 1 and Clinical efficacy and use sustained at 1 month and 1 year. In the other large study,the Metoprolol in Myocardial Infarction (MIAMI),41 i.v.
The benefit and clinical indications of b-blockers have metoprolol followed by oral administration did not sig- been clearly defined in many cardiovascular conditions nificantly reduce 15-day mortality as compared to pla- and agreement about their potential usefulness has been cebo (4.3–4.9% (ns)). A meta-analysis of 28 early trials of clearly established in many clinical settings. b-Blockers i.v. b-blockers43 revealed an absolute reduction of short- are safe to use when contraindications have been ex- term mortality from 4.3% to 3.7% (7 lives saved/1000 cluded and the appropriate dosage regimen is used.
patients treated). This significant albeit small benefit Abrupt discontinuation should be avoided if possible to was demonstrated before the reperfusion era. Similar prevent withdrawal effects. In case of doubt, specialist findings were reported in a more recent meta-analysis advice is recommended.
of 52 trials, most of them including a small number of The benefit of b-blocker treatment has been well documented in the following conditions: Two trials of randomised i.v. b-blockade were con- ducted after the widespread use of reperfusion therapy Acute Myocardial Infarction (AMI) in AMI,45;46 but the number of events was too small toestablish clear conclusions. In the second Thrombolysis in During the acute phase of myocardial infarction, oral Myocardial Infarction (TIMI-II) trial,45 thrombolysed pa- b-blockers are indicated in all patients without contrain- tients were randomly assigned to early i.v. and oral dications (class I, level of evidence A). Intravenous metoprolol versus oral administration after day 6. Rein- administration should be considered in patients with is- farction and recurrent ischaemia were less frequent in chaemic pain resistant to opiates, recurrent ischaemia the early b-blocker group and when treatment was ad- Intravenous dosing of b-blockers Oral, 50–100 mg/day 0.5 mg/kg over 1–5 min 0.05–0.3 mg/kg/min 2.5–5 mg i.v. bolus over 2 min; up to three doses Oral, 25–100 mg/12 h 0.10–0.20 mg/kg/min oral, 80–240 mg/day Use of b-blockers in AMI: guidelines i.v. administrationFor relief of ischaemic pain To control hypertension, sinus tachycardia Primary prevention of sudden cardiac death Sustained ventricular tachycardia To limit infarct size All patients without contraindications Oral administrationAll patients without contraindications ESC Expert consensus document ministered within 2 h of symptom onset, there was a treat 107 patients for 1 year to avoid one non-fatal reduction of the composite endpoint of death or rein- reinfarction. In the retrospective analysis of the Coop- farction. Data from the US National Registry of Myocar- erative Cardiovascular Project, including over 200,000 dial Infarction 247 showed that immediate b-blocker patients with myocardial infarction, b-blocker use was administration in patients with AMI treated with t-PA associated with a reduction in mortality, independent of reduces the occurrence of intracranial haemorrhage, age, race, presence of pulmonary disease, diabetes, although this benefit is small (0.7% and 1.0%; 3 patients/ blood pressure, ejection fraction, heart rate, renal 1000 treated). However, a post-hoc analysis of the first function and treatment received during hospitalisation Global utilization of streptokinase and t-PA for occluded including myocardial revascularisation.21 coronary arteries (GUSTO-I) trial and a systematic review In the Beta-blocker Heart Attack Trial (BHAT)61 pa- of the available experience do not support the routine, tients were randomised 5–21 days after AMI to receive early, intravenous use of b-blockers,33;44;48 at least when propranolol or placebo. Mortality after a mean follow-up thrombolytic treatment or primary percutaneous inter- of 2 years was reduced by 25% (7% vs. 9.5%) (25 lives vention is performed. New data from the PAMI (Primary saved/1000 treated). In the Norwegian trial,62 patients Angioplasty in AMI) Stent-PAMI, Air-PAMI and CADILLAC were randomly assigned 7–28 days after AMI to receive (Controlled Abciximab and Device Investigation to Lower timolol or placebo; mortality was reduced from 9.8% to Late Angioplasty Complications) trials seems to demon- 7.2%, (26 lives/1000 treated) over a follow-up of 25 strate a reduction in mortality when b-blockers are used months. Sudden cardiac death and reinfarction were also before primary percutaneous interventions.49–51 significantly reduced. Interestingly, the beneficial influ-ence of timolol on survival was sustained for at least 6years.63 In the study of Hjalmarson et al.,64 metoprolol Secondary prevention after myocardial given first intravenously and then orally, mortality at 90 days was reduced by 26%. In the Boissel et al. trial Ace-butolol et Pr evention Secondarie de l'Infartus (APSI) Oral b-blockers are recommended for long-term use trial,65 including high risk patients 2–22 days after AMI, (indefinitely) in all patients who recover from AMI and do there was also a significant 48% reduction in mortality not present contraindications (class I, level of evidence associated with the b-blocker treatment. In the Carve- A) (Table 5).33–35;52–58 b-blockers are underused for this dilol Post Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial including patients 2–21 Several large, long-term trials involving more than days after AMI with reduced left ventricular ejection 35,000 survivors of myocardial infarction have demon- fraction and receiving ACE-I, all-cause mortality was strated that the use of b-blockers in patients recovering lower in the carvedilol group than in the placebo group from an episode of AMI improves survival by 20–25% (12% vs. 15%).66 The significant mortality reductions in through a reduction of cardiac mortality, sudden cardiac heart failure observed with b-blockers and the result of death and reinfarction.43;44;49;61–66 Positive results have the CAPRICORN trial further support the use of these been found in trials comparing propranolol, metoprolol, agents in high risk patients with impaired ventricular timolol, acebutolol and carvedilol with placebo; con- function or failure after infarction and demonstrate that versely, no benefit was demonstrated in trials with the benefit of b-blockers is observed also in patients alprenolol, atenolol, oxprenolol or xamoterol.44 A meta- receiving treatment according to current standards, in- analysis of 82 randomised trials (31 with long-term fol- cluding reperfusion therapy and ACE-I.
low-up) provides strong evidence for the long-term use Although the benefit of b-blockers is observed in a of b-blockers to reduce morbidity and mortality after broad population after infarction,21;30;67 the benefit of acute MI even if aspirin, fibrinolytics or angiotensin long-term therapy is greatest in high-risk patients (i.e., converting enzyme inhibitors (ACE-I) were co-adminis- those with evidence of large or anterior infarction) and tered.44 An annual reduction of 1.2 deaths in 100 pa- there is continued debate about whether low-risk sub- jects (young, revascularised patients without previous infarction was observed; that is, about 84 patients will infarction, residual ischaemia or ventricular arrhyth- require treatment for 1 year to avoid one death.44 Sim- mias and normal ventricular function) should be trea- ilarly, the annual reduction for reinfarction was 0.9 ted with b-blockers because their long-term prognosis events in 100 treated patients; equivalent to the need to is favourable. Chronic stable ischaemic heart disease Use of b-blockers in secondary prevention after infarction: guidelines All patients without contraindications, indefinitely To improve survival To prevent reinfarction Primary prevention of sudden cardiac death To prevent/treat late ventricular arrhythmias ESC Expert consensus document patients and patients with atherosclerosis (carotid myocardial infarction and stable patients with ischaemia plaque) may benefit from a combined treatment with and previous myocardial infarction. In fact, there are statins and b-blockers.68 Treatment with b-blockers in few studies in patients with unstable angina comparing diabetic patients seems to be more effective than in b-blockers with placebo A meta-analysis suggested that non-diabetics and the risk of complications is negligi- b-blocker treatment was associated with a 13% relative ble.69 Other subgroups at high risk, include late ven- reduction in risk of progression to AMI.76 Although no tricular arrhythmias and post infarction ischaemia, Q significant effect on mortality has been demonstrated in wave and non-Q wave infarctions and elderly patients unstable angina in these relatively small trials, larger also benefit from b-blockers.21;67 Although relative randomised trials of b-blockers in patients with acute or contraindications once may have been thought to pre- recent MI have shown a significant effect on mortal- clude the use of b-blockers in some patients, new ev- ity.43;44 In addition, a retrospective analysis from the idence suggests that the benefits of b-blockers in Cooperative Cardiovascular Project21 indicates that the reducing reinfarction and mortality may actually out- relative risk of death was lower in patients with non-Q weigh its risks, even in patients with (1) insulin de- wave myocardial infarction receiving b-blockers. Pooled pendent diabetes mellitus; (2) chronic obstructive data from 2,894 patients with acute coronary syndromes pulmonary disease; (3) severe peripheral vascular dis- included in five randomised, controlled trials of abcix- ease; (4) PR interval up to 0.24 s; and (5) moderate imab during coronary intervention showed a reduction left ventricular failure.21 It is also emphasized that the of 30 day and 60 day mortality associated with the use use of b-blockers in such patients requires careful of b-blockers.77 There is no evidence that any specific monitoring of the patient to be certain that adverse b-blocking agent is more effective in producing benefi- events do not occur.34 cial effects in unstable angina and oral therapy shouldbe aimed to achieving a target heart rate between 50 Non-ST-segment elevation acute coronary and 60 beats per minute. The intravenous route should be preferred in patients at high risk (class II, level ofevidence B).70;71 b-blockers can increase coronary artery Patients with Acute Coronary Syndromes (ACS) without tone and are contraindicated in vasospastic angina ST-segment elevation should be treated with b-blockers without obstructive lesions.78 as soon as possible, to control ischaemia and preventAMI/reinfarction (class I, level of evidence B).65–67 After Chronic, stable ischaemic heart disease the acute phase, all patients should receive b-blockersduring long term for secondary prevention (class I, level All patients with chronic, stable ischaemic heart disease of evidence A) (Table 6).70;71 should receive long-term treatment with b-blockers to There are few randomised studies with b-blockers in control ischaemia, prevent infarction and improve sur- patients with unstable angina and non-Q wave myocar- vival. This is considered as a class I recommendation, dial infarction,73–75 and the new non-ST- segment ele- level of evidence A in patients with previous myocardial vation ACS terminology makes the analysis of possible infarction and class I, levels of evidence A, B and C (to effect even more difficult. Henceforth, the recommen- control ischaemia, prevent infarction and improve sur- dations are based on small studies in unstable angina as vival, respectively) in the absence of a previous history well as in the evidence in acute ST-segment elevation of infarction (Table 7).33;34;52;53;57;72;79 b-blockers should Use of b-blockers in non-ST-segment elevation ACS: guidelines Early benefit, reduction of ischaemia Early benefit, prevention MI Long-term secondary prevention Use of b-blockers in chronic, stable ischaemic heart disease: guidelines Previous infarctionTo improve survival To reduce reinfarction To prevent/control ischaemia No previous infarctionTo improve survival To reduce reinfarction To prevent/control ischaemia ESC Expert consensus document be considered as the first choice in patients with chronic In the Total Ischaemic Burden Bisoprolol Study (TIBBS)106 angina or ischaemia, and hypertension, previous infarc- bisoprolol was more effective than nifedipine in reducing tion or poor ventricular function.53;57;58;79 They appear to the number and duration of ischaemic episodes in pa- be underused for this indication.80 tients with stable angina. In the International Multicen- b-blockers are highly effective to control exercise- ter Angina Exercise (IMAGE) trial,107 metoprolol was induced angina, improve exercise capacity,81–87 and to more effective than nifedipine in controling exercise reduce or suppress both symptomatic and asymptomatic induced ischaemia.
ischaemic episodes.85;88–91 No clear clinical differenceshave been demonstrated between different b-blockers.
Also, no clinical relevant differences were found whencomparing b-blockers with calcium channel blockers for All patients with stable, mild, moderate and severe the control of ischaemia.92–95 Combination therapy with chronic heart failure from ischaemic or non-ischaemic nitrates and b-blockers may be more effective than ni- cardiomyopathies and reduced left ventricular ejection trates or b-blockers alone.96 b-blockers may also be fraction, in NYHA class II–IV, should be treated with combined with dihydropyridines,97–101 but the combina- b-blockers, unless there is a contraindication (class I, tion with verapamil and diltiazem increases the risk of level of evidence A).55;108 In patients with left ven- bradycardia or AV block.
tricular systolic dysfunction, with or without symp- If possible, b-blockers (and other anti-ischaemic tomatic heart failure following an AMI, long-term drugs) should be withheld for four half-lives (usually b-blockade is recommended in addition to ACE inhibi- about 48 h) when a stress test is planned for the diagnosis tion to reduce mortality (class I, level of evidence and risk stratification of patients with suspected coro- A).55;108 Finally, b-blockers are also recommended in nary artery disease.102 b-blockers should be withdrawn patients with chronic heart failure and preserved left gradually to avoid withdrawal effects.26;103 ventricular function (class IIa, level of evidence C) 108 The effect on prognosis in patients with stable angina (Table 8). b-blockers are underused in patients with has not been specifically studied in large trials, and most heart failure.109 of the information comes from studies in the pre- The evidence of clinical benefit on b-blockers in pa- thrombolytic era, when myocardial revascularisation was tients with chronic heart failure with systolic left ven- more restricted. A history of angina has, however, been tricular dysfunction was demonstrated in a number of present in about 1/3 of patients recruited in post in- small studies and in several, large, prospective, rando- farction studies with b-blockers. The b-blockers pooling mised, placebo controlled trials, including a total of over project67 reported a highly significant reduction in mor- 15,000 patients.110–125 Placebo-controlled mortality tri- tality in this subgroup, and it seems reasonable to assume that b-blockers have the potential to prevent death, es- metoprolol122;123 have been associated with a long-term pecially sudden cardiac death, and myocardial infarction reduction in total mortality, cardiovascular mortality, even when there has been no prior infarction.53;57;79 sudden cardiac death and death due to progression of The effects of b-blockers in patients with stable an- heart failure in patients in functional class II–IV. In these gina without prior MI or hypertension have been inves- studies, b-blocking therapy also reduced hospitalisations tigated in some randomised controlled trials. In the Total (all, cardiovascular and heart failure-related), improved Ischaemic Burden European Trial (TIBET)104, no differ- the functional class and led to less worsening of heart ence was found between atenolol and nifedipine, and in failure than placebo. This beneficial effect has been the Angina Prognosis Study in Stockholm (APSIS)105 the consistently observed in subgroups of different age, clinical outcome was similar in the groups treated with gender, functional class, left ventricular ejection frac- metoprolol and verapamil. In the Atenolol Silent Is- tion and ischaemic or non-ischaemic aetiology, diabetics chaemia Study (ASIST),91 in patients with mild angina, and non-diabetics. Black patients may be an exception, atenolol decreased ischaemic episodes at 6 weeks as since in the BEST trial this ethnic group lacked the ben- compared with placebo and after 1 year there was an efit from b-blocker therapy in heart failure.126 In smaller, improvement in the cardiovascular combined outcomes.
controlled studies b-blockade has been shown to improve Use of b-blockers in chronic heart failure: guidelines All stable patients, with symptomatic heart failure and reduced LVEF, functional class II–IV (to prolong survival)LVSD without symptoms after AMI LVSD without symptoms, no previous MI Chronic HF with preserved systolic function (to reduce heart rate) Acute, compensated heart failure after AMI Patient stable after acutely decompensated chronic heart failure AMI: Acute Myocardial Infarction; LVEF: Left Ventricular Ejection Fraction; LVSD: Left Ventricular Systolic Dysfunction.
ESC Expert consensus document ventricular function.115–127 Exercise capacity may also risk of the secondary end-point of death from cardio- improve114 as well as symptoms and quality of life,17 but vascular causes was lower in the bucindolol group (HR, these effects usually are marginal and have not been 0.86; 0.74–0.99), as well as rehospitalisation secondary to worsening heart failure. In a subgroup analysis, there b-blockers with placebo.128 was a survival benefit in non-black patients.
In the second Cardiac Insufficiency Bisoprolol Study Overall, the NNT for approximately 1 year with a (CIBIS-2)121 symptomatic patients in NYHA class III or IV, b-blocker in mainly NYHA class II/III (mild-moderate) CHF with left-ventricular ejection fraction of 35% or less, is 28 to prevent 1 death and 16 to prevent 1 death or receiving standard therapy with diuretics and ACE-in- hospitalisation (based on MERIT-HF) and in moderate to hibitors, were randomly assigned to receive bisoprolol or severe CHF (mainly class III/IV) these numbers are 18 and placebo during a mean follow of 1.3 years. The study was 13, respectively (based on COPERNICUS).
stopped early because bisoprolol showed a significant Although a reduction in mortality and hospitalisation mortality benefit (11.8% vs. 17.3%) (55 lives saved/1000 has been demonstrated with several b-blockers in chronic treated; Number Needed to Treat (NNT) for 1.3 year to heart failure, a class-effect has not been established. No save 1 life ¼ 18). There were significantly fewer sudden benefit on survival was observed with bucindolol cardiac deaths among patients on bisoprolol than in (BEST),130 although bucindolol was associated with a those on placebo (3.6% vs. 6.3%). Treatment effects were reduction in cardiovascular mortality and myocardial independent of the severity or cause of heart failure.
infarction.131 A direct comparison of two different b- In the Metoprolol Randomised Intervention Trial blockers (metoprolol vs. carvedilol) has been assessed in (MERIT-HF)122 patients with chronic heart failure in NYHA the Carvedilol Or Metoprolol European Trial (COMET).132 functional class II–IV and ejection fraction 40% and In this study patients with chronic heart failure and re- stabilised with optimum standard therapy, were ran- duced left ventricular ejection fraction were treated with domly assigned metoprolol CR/XL or placebo. This study carvedilol (targed 25 mg bid) or metoprolol tartrate was also stopped early on the recommendation of the (targed 50 mg bid). After a mean follow-up of 58 months independent safety committee after a mean follow-up of all cause mortality was lower in the carvedilol group (34% 1 year. All-cause mortality was lower in the metoprolol vs. 40%) (HR 0.83; CI 0.74–0.93), equivalent to an NNT to group than in the placebo group (7.2%, per patient-year save one life ¼ 59; and this finding was consistent through of follow-up vs. 11.0%) (38 lives saved/1000 treated; predefined groups. No differences in re-hospitalisation number needed to treat (NNT) for 1 year to save 1 life were observed between groups. The results of this study ¼ 28). There was also a 41% reduction in sudden cardiac suggest that carvedilol is superior to metoprolol to extend death and 49% reduction in deaths from worsening heart life in heart failure patients. However, in this trial the formulation of metoprolol was different from the one In the Carvedilol Prospective Randomised Cumulative used in the MERIT-HF trial (tartrate vs. slow release suc- Survival (COPERNICUS) study,124 cinate) and the target dose was lower (50 mg/12 h vs. 100 symptoms of heart failure at rest or on minimal exertion, mg/12 h, equivalent to 130 mg/day of tartrate). In any clinically euvolemic, and with an ejection fraction of case, the COMET trial illustrates that selection of a b- <25% were randomly assigned to placebo or carvedilol blocker and the dose used may have a significant impact for a mean period of 10.4 months. The study also ter- on the outcome of patients with heart failure. Accord- minated prematurely after observing a significant re- ingly only bisoprolol, metoprolol in the formulation and duction in mortality: the cumulative risk for death at 1 dose used in MERIT-HF and carvedilol are recommended year was 18.5% in the placebo group and 11.4% in the for the treatment of patients with heart failure.
carvedilol group (71 lives saved/1000 treated; number Further data are needed to establish the effects of needed to treat for 10.4 months to save 1 life (NNT) ¼ b-blocking agents in certain demographic groups, such as 18). As in the previous studies, there was a reduction in elderly subjects (>75 years), certain racial subsets and hospitalisations and sudden cardiac death. In a post hoc patients with atrial fibrillation. In SENIORS the effect of analysis from CIBIS II and MERIT-HF including high risk b-blockade (nevibolol) in the elderly patient with heart patients with ejection fraction <25% and NYHA class III failure is investigated. In another study, CIBIS-3, biso- and IV similar findings were observed.121;129 prolol will be used first, followed by the administration In the CAPRICORN trial66 patients with left-ventricular of ACE-inhibitors.
ejection fraction of <40% early after an episode of AMI As b-blocker action may be biphasic with long-term were randomly assigned to carvedilol or placebo. After a improvement, possibly preceded by initial worsening, mean follow-up of 1.3 years, all-cause mortality alone b-blockers should be initiated under careful control. The was lower in the b-blocker group (12% vs. 15%), although initial dose should be small and increased slowly and no differences were observed in rehospitalisation rate.
progressively to the target dose used in the large clinical In the Beta-blocker Evaluation of Survival (BEST) trials. Uptitration should be adapted to the individual Trial130 patients with chronic heart failure and reduced response. b-blockers may reduce blood pressure and left ventricular ejection fraction were assigned to buc- heart rate excessively, may temporarily induce myocar- indolol or placebo. The study was stopped prematurely dial depression and precipitate heart failure. In addition, because of lack of differences in total mortality after 2 b-blockers may initiate or exacerbate asthma and induce years of follow-up (33% vs. 30% in the placebo and buc- peripheral vasoconstriction. Table 9 indicates the rec- indolol groups, respectively; p ¼ 0:16). Nevertheless, the ommended procedure for the use of b-blockers in clinical ESC Expert consensus document Practical guidance on using b-adrenergic blockers in heart failure (modified from Ref. 133) Who should receive b-blocker therapy All patients with chronic, stable heart failure Without contraindications (symptomatic hypotension or bradicardia, asthma) What to promiseTreatment is primarily prophylactic against death and new hospitalisations for cardiovascular reasons. Some patients willexperience improvement of symptoms.
When to start No physical evidence of fluid retention (use diuretics accordingly) Start ACE-I first if not contraindicated 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, non-steroidal anti-inflamatory drugsBeta-blocker  Bisoprolol, carvedilol or metoprolol Dose 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 dose 3.125 twice daily 25–50 twice daily 12.5–25 once daily Monitoring Monitor for evidence of heart failure symptoms, fluid retention, hypotension and bradycardia Instruct patients to weigh themselves daily and to increase their diuretic dose if weight increases Problem solving Reduce/discontinue b-blocker only if other actions were ineffective to control symptoms/secondary effects Always consider the reintroduction and/or uptitration of the b-blocker when the patient becomes stable Seek specialist advice if in doubt.
Symptomatic hypotension (dizziness, light headedness and/or confusion) Reconsider need for nitrates, calcium channel blockers and other vasodilators If no signs/symptoms of congestion consider reducing diuretic dose Worsening symptoms/signs (increasing dyspnoea, fatigue, oedema, weight gain) Double dose of diuretic or/and ACE-I.
 Temporarily reduce the dose of b-blockers if increasing diuretic dose does not work Review patient in 1–2 weeks; if not improved seek specialist advice If serious deterioration halve dose of b-blocker Stop b-blocker (rarely necessary; seek specialist advice) Bradycardia ECG to exclude heart block Consider pacemaker support if severe bradycardia or AV block or sick sinus node early after starting b-blockers Review need, reduce or discontinue other heart rate slowing drugs, e.g., digoxin, amiodarone, diltiazem Reduce dose of b-blocker. Discontinuation rarely necessary Severe decompensated heart failure, pulmonary oedema, shock Admit patient to hospital Discontinue b-blocker if inotropic support is needed or symptomatic hypotension/bradycardia is observed If inotropic support is needed, levosimendan may be preferred CHF: Congestive Heart Failure; NYHC: New York Heart Association.
practice and lists the contraindications. Detailed prac- ommended use of b-blockers in these patients is empir- tical guidance on the use of b-blockers in heart failure ical, based mainly on the possible benefit of reducing can be found elsewhere.133 heart rate and improving myocardial ischaemia.
Heart failure and preserved systolic function Acute heart failure There is a paucity of data regarding the possible benefit There are no randomised clinical trials with b-blockers of b-blockers in patients with heart failure and preserved in acute heart failure targeted to improve the acute systolic left ventricular function. Accordingly, the rec- condition. In the Gothenburg study i.v. metoprolol or ESC Expert consensus document placebo was initiated early after an AMI and followed by Arrhythmias (Table 10) oral therapy for three months. Patients with newsymptoms of heart failure were less frequently found in Sinus tachycardia the metoprolol group, and in patients with signs of Sinus tachycardia is not a primary disorder and treatment pulmonary congestion with basal rales and/or i.v. furo- should be directed to the underlying cause. In selected semide, metoprolol therapy reduced mortality and individuals b-blockers can be used to slow heart morbidity.134 In the COPERNICUS trial, b-blocker therapy rate136;137 (class I, level of evidence C) (e.g., if a fast started early after acute decompensation of chronic heart rate produces symptoms) and are especially indi- heart failure was associated with a long-term reduction cated in situations of anxiety, after myocardial infarc- in mortality.124 In the CAPRICORN trial patients with tion, in patients with heart failure, hyperthyroidism and heart failure or left ventricular dysfunction randomised hyperdynamic b-adrenergic state.137;138 In patients with early after AMI also received benefit from b-blocker pheochromocytoma, b-blockers are also effective to therapy.66 As recommended in the ESC acute heart control sinus tachycardia, but if given alone hypertensive failure guidelines.135 Patients with acute overt heart crisis can occur secondary to unopposed a-receptor failure including more than basal pulmonary rales, b-blockers should be used cautiously. In these patients,if ongoing ischaemia and tachycardia are present, in- travenous metoprolol can be considered. (class IIb, level b-blockers are effective for suppressing atrial premature of evidence C). However, in patients with AMI who beats and controlling heart rate and conversion of focal stabilise after acute heart failure, b-blockers should be atrial tachycardia, as well as preventing its recurrence, initiated early (class IIa, level of evidence B). In patients in many instances the result of increased sympathetic with chronic heart failure b-blockers should be initiated tone140 such as after surgery (class I, level of evidence C) when the patient has stabilised after the acute episode (Table 10).137 On the contrary, multifocal atrial tachy- (usually after 4 days) (class I, level of evidence A). The cardia is frequently associated with severe obstructive oral initial dose of bisoprolol, carvedilol or metoprolol lung disease, in which case b-blockers are ineffective and should be small and increased slowly and progressively contraindicated. AV nodal reciprocating tachycardias, to the target dose used in the large clinical trials. Up- the most common form of paroxismal supraventricular titration should be adapted to individual response. Pa- tachycardia, also responds well to i.v. administration of tients on b-blockers admitted due to worsening heart propranolol, metoprolol, atenolol, sotalol or timolol, failure, should be continued on this therapy in general with a reduction in heart rate, conversion to sinus unless inotropic support is needed but dose could be rhythm or facilitating the success of vagal manoeu- reduced if signs of excessive dosages are suspected (low vres137;141–145 (class I, level of evidence C). b-blockers are heart rate and hypotension).
also useful for the prevention of recurrent episodes. Oral Use of b-blockers in arrhythmias: guidelines Supraventricular arrhythmiasSinus tachycardia Focal atrial tachycardia, for cardioversion Focal atrial tachycardia, for prevention of recurrence Atrioventricular nodal reciprocating tachycardia Focal junctional tachycardia Non-paroxysmal junctional tachycardia WPW with symptomatic arrhythmias Atrial flutterRate control of atrial flutter, poorly tolerated Rate control of atrial flutter, well tolerated Atrial fibrillation (ESC/AHA/ACC)Prevention (post AMI, HF, HTA, post surgery, post conversion to sinus rhythm) Chronic control of heart rate Acute control of heart rate Conversion to sinus rhythm Combination with digoxin, for heart rate control Acute control of HR in heart failure Ventricular arrhythmiasControl of arrythmias early after AMI (i.v.) Control of arrythmias late after AMI 33, 35, 52, 56, 57 Prevention of sudden cardiac death in heart failure and after MI ESC Expert consensus document administration of b-blockers is very effective to prevent comparisons with placebo, b-blockers were effective in paroxysmal tachycardias precipitated by emotion or ex- controlling resting heart rate. The effect was drug ercise.146 Oral propranolol, atenolol, nadolol, and sotalol specific, with sotalol, nadolol and atenolol being the were found to be effective in the long term prophylactic most efficacious.150 Atenolol provided better control of treatment of patients with paroxysmal supraventricu- exercise-induced tachycardia than digoxin alone.154 lar tachycardias145 (class I, level of evidence C).137 Combinations of several agents may often be required b-blockers are also recommended for the treatment of to achieve adequate rate control, but care should be other forms of supraventricular tachycardias, including taken to avoid excessive slowing. In general, the com- focal junctional tachycardia and non-paroxysmal junc- bination of digoxin and b-blockers appears to be more tional tachycardia137 (Table 10).
effective than either digoxin or b-blocker alone andbetter than the combination of digoxin and calcium Tachycardias in WPW syndrome b-blockers may be effective in some patients with su- praventricular arrhythmias in the presence of WPW, if Conversion to sinus rhythm. There are few randomised the accessory pathway is incapable of rapid anterograde studies exploring the efficacy of b-blockers to revert AF conduction as demonstrated in an electrophysiological to sinus rhythm or to maintain sinus rhythm. One studies.137;145 However, b-blockers may cause very seri- randomised, open-label, crossover study showed that ous adverse events. b-blockers, as well as digitalis and atenolol was as effective as sotalol and better than calcium channel blockers, do not block the accessory placebo at suppressing episodes of AF, reducing their pathway and may even enhance conduction, resulting in duration and associated symptoms.150 In AF after non- a very rapid ventricular response which may lead to se- cardiac surgery, intravenous esmolol produced a more vere hypotension or cardiac arrest.136;147–149 For this rapid conversion to sinus rhythm than did intravenous reasons, b-blockers are contraindicated in arrhythmias associated with WPW syndrome. b-blockers are also preferred for cardioversion of AF to sinus rhythm.136 contraindicated in patients with sick sinus or bradycar- b-blockers may also reduce subacute recurrences after dia/tachycardia syndrome, as sinus arrest with syncope conversion to sinus rhythm,151 bisoprolol being as effec- tive as sotalol159 and carvedilol160 to maintain sinusrhythm after AF.
b-blockers are not effective for conversion of atrial Ventricular arrhythmias flutter to sinus rhythm but may be effective for ven- b-blockers are effective in the control of ventricular tricular rate control, for this reason they are indicated in arrhythmias related to sympathetic activation, includ- stable patients (class I, level of evidence C).137 ing stress-induced arrhythmias, AMI, perioperative andheart failure, including the prevention of sudden Atrial fibrillation cardiac death (class I, level of evidence A)33;35;52;56;57 b-blockers may be effective to prevent episodes of Atrial (Table 10). Most b-blockers have proved effective to Fibrillation (AF), to control heart rate, to revert atrial reduce the number of ventricular premature beats. In fibrillation to sinus rhythm and to maintain sinus rhythm sustained ventricular tachycardia, b-blockers including after it is restored (Table 10).136 propanolol, sotalol, metoprolol and oral atenolol have Prevention. The incidence of atrial fibrillation is lower in been effective to suppress the tachycardia, but the patients receiving b-blockers. This effect has been ob- experience is limited and there is a lack of controlled served in randomised studies in patients with heart fail- studies. Success of b-blocker to treat VF is anec- ure, during secondary prevention after acute myocardial dotal.161 On the contrary, b-blockers have proven to be infarction, in hypertension and after elective non-car- very efficacious to prevent arrhythmias leading to sud- den cardiac death in different conditions, includingacute and chronic myocardial ischaemia, heart failure Control of heart rate. Propranolol, atenolol, meto- prolol, or esmolol may be given i.v. to acutely controlthe rate of ventricular response to AF in specific set- Prevention of sudden cardiac death tings, especially in states of high adrenergic tone (e.g.,postoperatively), but i.v. administration in heart fail- There is clear evidence demonstrating that the benefit ure is not recommended. b-blockers have also proved derived from b-blocker treatment in part is the conse- to be effective in patients with AF complicating thy- quence of a reduction in sudden cardiac death (SCD).
rotoxicosis, AMI, chronic stable coronary artery dis- Accordingly, b-blockers are clearly indicated in the pri- ease150;151 and during pregnancy.152 For acute control of mary and secondary prevention of SCD in different heart rate, intravenous esmolol is the recommended clinical settings and guidelines have been estab- lished33;35;162;163 (Table 11). However, it should be For long-term use, b-blockade is a safe therapy to stressed that for secondary prevention of sudden cardiac control heart rate in AF patients and antagonises the death and in particular in the presence of severe left effects of increased sympathetic tone. In seven of 12 ventricular dysfunction, the use of b-blockers does not ESC Expert consensus document Use of b-blockers in the prevention of sudden cardiac death: guidelines Primary prevention Primary prevention, in presence of HF or LV Primary prevention, during and post-MI Resuscitated VT/VF, spontaneous sustained VT Primary or secondary prevention Dilated cardiomyopathy Primary or secondary prevention Myocardial bridging Primary prevention Primary prevention – symptomatic Secondary prevention – b-blockers+ICD Primary prevention – asymptomatic Catecholaminergic VT Primary or secondary prevention RV cardiomyopathy Primary prevention Patients with implantable defibrillators Secondary prevention HF: Heart Failure; LV: Left Ventricle; MI: Myocardial Infarction; RV: Right Ventricle; VT: Ventricular Tachycardia; BP: Blood Pressure.
preclude the identification and appropriate treatment of benefit from b-blockers in mortality reduction, including ischaemia and the use of implantable defibrillators.35;163 SCD and are indicated in all patients for the prevention ofSCD (Class I, level of evidence A)35 (Table 11). A consis- Acute myocardial infarction tent contribution to the improved outcome by these The use of b-blockers in AMI has been already discussed.
drugs is related to a substantial reduction (between 40% For the prevention of VF, i.v. b-blockers are indicated in and 55%) in SCD rates.115;122;172 The recent introduction of patients with ventricular arrythmias33 (class I, level of new therapies, such as thrombolytics, ACE-Inhibitors, evidence A) (Table 11). SCD secondary to VF is very aldosterone receptor blockers as well as concomitant an acute coronary revascularisation or aspirin does not appear to limit the b-blockers increase the threshold for VF during acute independent benefit on clinical outcome provided by ischaemia and a decrease in VF was demonstrated in b-blockers, as suggested by the evidence of risk reduc- some placebo controlled trials with metoprolol, atenolol tions between 30% and 50%.21 and propranolol very early after onset of symp-toms.39;168;169 In a randomised study including 735 pa- Dilated cardiomyopathy tients within 4 h after the onset of chest pain, treated There are no specific studies demonstrating the benefit of with intravenous propranolol followed by oral adminis- b-blockers for the prevention of sudden cardiac death in tration, VF occurred in two patients in the b-blocker dilated cardiomyopathy, but the reduction in mortality group and in 14 of the control group (p < 0:06).39 Also, was similar in patients with ischemic or non-ischaemic i.v. metoprolol in patients with AMI significantly reduced heart failure115; accordingly, b-blockers are recom- the number of VF episodes.39 However, in other large mended for the prevention of sudden cardiac death in this studies, including the ISIS-2 and MIAMI40;41 no significant population (class I, level of evidence B)35;163 (Table 11).
decrease in the incidence of VF was noted. Besides, inthe thrombolytic era, there is a lack of controlled studies exploring the effect of early b-blocker administration on Sudden cardiac death secondary to ventricular arrhyth- the incidence of VF, and the benefit of early intravenous mias is frequent in patients with hypertrophic cardio- administration of b-blockers to prevent VF is question- myopathy, especially during exercise and in the presence able in patients treated with reperfusion therapy.33 After acute myocardial infarction, the efficacy of b-blockers may improve symptoms, the currently avail- b-blockers is related to a reduction in all-cause mortality able data do not support the routine use of b-blockers in and sudden cardiac death and their use is recommended the prevention of sudden cardiac death in these pa- in all patients for the primary prevention of sudden car- diac death (class I, level of evidence A)33;35;163 (Table 11).
A recent analysis of 31 b-blockers trials170 showed that 13 Mitral valve prolapse trials reported data on reduction of SCD, which was re- Mitral valve prolapse is usually benign; its link with SCD duced from 51% to 43% in patients treated with b-blockers has been suggested but never conclusively demon- vs. the untreated group. In the CAPRICORN trial in post MI strated.35 No prospective studies have ever been con- patients with left ventricular dysfunction, there was a ducted with b-blockers or antiarrhythmic drugs in this trend toward SCD reduction in the carvedilol group.66 condition. Accordingly, no data are available to defineprophylactic interventions that may reduce the risk of SCD. However, b-blocking agents are generally consid- Patients with a history of congestive heart failure 67 or ered as first choice therapy in symptomatic patients.
depressed left ventricular function171 show the greatest Yet, the routine or selective use of b-blockers to prevent ESC Expert consensus document sudden cardiac death in patients with mitral valve pro- recurrence with antiarrhythmic agents and b-blockers lapse is not recommended.35 The Brugada syndrome186 is an arrhythmogenic dis- Myocardial bridging order associated with high risk of SCD caused by rapid Although it is considered as a benign condition, patients polymorphic ventricular arrhythmias mainly occurring at with myocardial bridging may present with ischaemia and rest or during sleep in individuals with a structurally in some cases ventricular arrhythmias and sudden cardiac normal heart. The occurrence of cardiac arrest at 3 year death.177 Symptoms usually improve with b-blockers.178 follow-up may be as high as 30%. The disease is charac- This information is based on a limited number of small terised by transient right bundle branch block and observational studies (class IIa, level of evidence C).35 ST-segment elevation in leads V1–V3. The efficacy of b-blockers in this condition has not been investigated.
Accordingly, b-blockers are not currently recommended Long QT syndrome (LQTS) in this condition.35 Prolongation of the QT interval not secondary to ischae- mia or drugs is associated with life-threatening ventric-ular related.179;180 b-Blockers are usually considered indicated b-blockers are also indicated in patients with pacemakers but there is a lack of prospective, placebo-controlled and implantable defibrillators for secondary prevention studies. In the largest of the retrospective analyses, (class IIb and IIa, respectively, level of evidence C).35 conducted in 233 LQTS patients, all symptomatic forsyncope or cardiac arrest, mortality 15 years after the first syncope was 9% for the patients treated by antiad-renergic therapy (b-blockers and/or left cardiac sympa- b-Blockers are indicated in the treatment of hyperten- thetic denervation) and close to 60% in the group not sion (class I, level of evidence A)46;52;53 (Table 12). In- treated or treated with miscellaneous therapies.181 These travenous b-blockers can be used to treat hypertensive data support the benefit of b-blockers, however, they do emergencies. Current guidelines strongly recommend not provide total protection and especially for the pa- reduction of blood pressure to different levels according tients with a history of cardiac arrest the risk of SCD re- to the risk profile (the higher the risk the lower the ideal mains unacceptably high. In symptomatic patients the use blood pressure)52;56–58;187–189, and in most patients the of b-blockers is considered a class I with a level of evi- appropriate control requires the use of two or more an- dence B, in asymptomatic patients a class IIa, level of tihypertensive medications. Although the primary ob- evidence C35 (Table 11).
jective in hypertensive patients is the control of bloodpressure levels, pharmacological treatment should also Catecholaminergic polymorphic ventricular reduce morbidity and mortality and the selection of a specific drug should be based on the patient profile.58 This clinical entity is characterised by adrenergically in- Thus, b-blockers may be considered as the first choice duced polymorphic ventricular tachycardia in the ab- therapy, alone or in combination, in patients with pre- sence of structural cardiac abnormalities and a familial vious myocardial infarction, ischaemic heart disease, history of syncope and SCD occurs in approximately one arrhythmias or heart failure, asymptomatic left ventric- third of the cases.182;183 The arrhythmias are reproduc- ular dysfunction, diabetes or high risk of coronary dis- ible during exercise stress test or during isoproterenol ease, based on the efficacy of these drugs on these infusion.183 At the present time b-blockers seem to be the only therapy that may be effective.183 Retrospective analysis of the few published cases, shows SCD in 10.5% In early studies, treatment of hypertension with b- and 48% of patients with and without b-blocker therapy, blockers was associated with an improvement in long- respectively.183 Although this finding is not conclusive term outcomes, including a reduction in mortality,190–192 given the lack of controlled studies, b-blockers are rec- stroke193–195 and heart failure.193 In the Swedish Trial in ommended for the primary and secondary prevention of Old Patients with hypertension (STOP-Hypertension SCD (class IIa, level of evidence C).35 trial),190 all cause mortality and sudden cardiac deathwas lower in the b-blocker (metoprolol, pindolol or SCD in the normal heart atenolol) than in the placebo group. In the MAPHY Idiopathic VF occurs in up to 8% of victims of SCD.184 study192, comparing metoprolol with thiazide, blood According to the UCARE European registry, prevention of pressure reduction was similar in both groups, but mor- Use of b-blockers in the treatment of hypertension: guidelines After MI, in ischaemia, tachyarrythmias, heart failure MI: Myocardial Infarction; BP: Blood Pressure.
ESC Expert consensus document tality was lower in the metoprolol group. This benefit of force in the aortic wall. For this purpose b-blockers are b-blockers compared with diuretics was not observed in considered the drug of choice in patients with aortic other studies. In the Medical Research Council (MRC) dissection although this therapeutic approach has not trial191 atenolol failed to reduce cardiovascular events as been tested in randomised clinical trials. Intravenous compared to placebo or diuretics in hypertensive pa- b-blockers (propranolol, metoprolol, atenolol, labetalol tients without previous myocardial infarction, angina and and esmolol) should be preferred to achieve rapid con- heart failure. In the HAPPHY study,194 b-blockers trol of blood pressure and can be used under careful (metoprolol, atenolol or propranolol) did not improve control of blood pressure, heart rate and end-organ the clinical outcome as compared with diuretics. In a perfusion. The recommended doses are indicated in Ta- meta-analysis193 b-blockers were effective in preventing ble 3 but have to be individually adjusted according to stroke and heart failure when compared with placebo but the obtained response.193;194;203 While b-blocking agents not with diuretics.
are usually adequate in most patients, combination with In more recent trials, b-blockers were equally effica- intravenous sodium nitroprusside may be required for cious to reduce blood pressure and cardiovascular risk when compared with calcium channel blockers196 andACE-inhibitors.196–199 In a meta-analysis, including the UK Prospective Diabetes Study (UKPDS) (atenolol vs. cap-topril), STOP-Hypertension-2 (diuretics or b-blockers vs.
Hypertrophic cardiomyopathy is a complex disease with a broad spectrum of manifestations and risk profile. Al- blockers), CAPP (diuretics or b-blockers vs. captopril) though b-blockers, including propranolol, atenolol, and NORDIL (thiazide or b-blocker vs. diltizem), ACE-in- metoprolol, sotalol or nadolol have been successfully hibitors offered a similar cardiovascular protection as used to relieve symptoms, improve physical capacity, compared with diuretics or b-blockers and calcium control heart rate, treat arrhythmias, treat heart failure channel blockers provided an extra 13% reduction in the and prevent sudden cardiac death in patients with and risk of stroke but the risk of infarction was 19% higher without evidence of left ventricular outflow obstruction, than with b-blockers or diuretics.200 their use has not been clearly standardised.176 Also, The Losartan Intervention For Endpoint reduction in there is no proof that prophylactic drug therapy in hypertension (LIFE) study compared the angiotensin II asymptomatic patients to prevent or delay progression of inhibitor losartan with atenolol in hypertensive patients congestive symptoms and improve prognosis.
with left ventricular hypertrophy but without myocardialinfarction or stroke within the previous 6 months, anginapectoris requiring treatment with b-blockers and heart Prophylactic use in non-cardiac surgery failure or left ventricular ejection fraction of 6 40%.
Losartan was associated with a greater reduction in b-Blockers are indicated in high cardiac risk patients, stroke as compared atenolol (5% vs. 6.7%) over a mean with present or past history of ischaemia, arrhythmias or follow up of 8.4 years. Mortality and myocardial infarc- hypertension controlled by b-blockers and in patients tion was similar in both groups.201 with ischaemia in perioperative testing submitted toelective non-cardiac surgery (specially vascular surgery), Aortic dissection to prevent ischaemic events and arrhythmias (class I,level of evidence A). Also, b-blockers are indicated for b-blockers are indicated to lower blood pressure in pa- the treatment of perioperative hypertension, ischaemia tients with suspected or diagnosed aortic dissection and arrhythmias identified preoperatively and previously (class I, level of evidence C) (Table 13).202 untreated (class IIa, level of evidence (B) (Table 14).54 b-blockers reduce blood pressure and pulse pressure Perioperative b-blocker therapy in high risk patients is (systolic/diastolic pressure difference), which reflect the In several studies, the preoperative administration of b-blockers was associated with better control of blood Use of b-blockers in aortic dissection: guidelines pressure206;207 and a reduction in perioperative ischae- mia204;206–212 and arrhythmias.213;214 There is also evi- To lower blood pressure dence that patients with high risk for coronary heartdisease have a better outcome if treated with b-blockers Use of b-blockers in non-cardiac surgery: guidelines High cardiac risk (history of ischaemia, arrhythmias, hypertension, or stress induced ischaemia, to reduce ischaemic events and arrhythmias Preoperative use to control ischaemia, hypertension, arrhythmias Treatment of peroperative ischaemia, hypertension and arrhythmias ESC Expert consensus document during hospitalisation for non-cardiac surgery, including 5. Benfield P, Sorkin EM. Esmolol. A preliminary review of its pharma- a reduction in mortality and cardiovascular complica- codynamic and pharmacokinetic properties and therapeutic effi-cacy. Drugs 1987;33:392–412.
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The Lilly Suicides by Richard DeGrandpre1 William Forsyth met and married his wife June in 1955. After two years of military service in West Germany, Bill left with June to Los Angeles, where Bill had grown up. Soon after arriving, Bill bought several Volkswagens and started a rental car business near the LA airport. Times were tough at first, but the business

An in vitro ischemic penumbral mimic perfusate increases nadph oxidase-mediated superoxide production in cultured hippocampal neurons

An in vitro ischemic penumbral mimic perfusate increasesNADPH oxidase-mediated superoxide production in culturedhippocampal neurons Matthew E. PameSameh S. Qingbo , J. Cameron ,Xiang Q. , Laura L. , Gabriel G. aDepartment of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, CA 92093, USAbDepartment of Anesthesiology, University of California San Diego, La Jolla, CA 92093, USAcSchool of Medicine, Department of Geriatric Medicine, University of California San Diego, La Jolla, CA 92093, USAdDepartment of Neuroscience, University of California San Diego, La Jolla, CA 92093, USAeThe Rady Children's Hospital-San Diego, San Diego, CA 92123, USA