Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: putting guidelines into practice

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1 European Journal of Heart Failure Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: putting guidelines into practice John McMurray a,, Alain Cohen-Solal b, Rainer Dietz c, Eric Eichhorn d, Leif Erhardt e, Richard Hobbs f, Aldo Maggioni g, Ileana Pina h, Jordi Soler-Soler i, Karl Swedberg j a Clinical Research Initiatie in Heart Failure, Glasgow, Scotland G11 6NT, UK b L Hopital ˆ Beaujon, Clichy, France c Franz-Volhard-Klinik, Berlin, Germany d VA Hospital, Dallas, TX, USA e Uniersity Hosptial, Malmo, Sweden f Department of Primary Care and General Practice, Birmingham, UK g Research Centre Anmco, Florence, Italy h Uniersity Hospital, Cleeland, USA i Vall d Hebron Uniersity, Barcelona, Spain j Department of Medicine, Sahlgrenska HospitalOstra, Goteborg, Sweden Received 1 June 2001; accepted 25 June 2001 Abstract Surveys of prescribing in both hospitals and primary care have shown delays in translating improved survival data from clinical trials into clinical practice thereby denying patients the benefits of proven treatments, such as the angiotensin converting enzyme inhibitors. This may be due to unfamiliarity with clinical guidelines and concerns about adverse events. Recent trials have shown that substantial improvements in survival are associated with spironolactone and beta-blocker therapy. In order to accelerate the uptake of these treatments, and to ensure that all eligible patients should receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of heart failure. The objective of these recommendations is to provide practical guidance for non-specialists in order to support the implementation of evidenced-based therapy for heart failure. These practical recommendations are meant to supplement rather than replace existing guidelines European Society of Cardiology. All rights reserved. Keywords: Clinical recommendations; Beta-blockers; Angiotensin converting enzyme inhibitors; Spironolactone; Heart failure 1. Introduction Evidence-based medicine is the accepted goal to which doctors should aspire in their clinical practice. Corresponding author. Tel.: ; fax: address: j.mcmurray@bio.gla.ac.uk Ž J. McMurray.. In the past two decades, large, placebo controlled, double-blind trials have been conducted in patients with chronic heart failure using clinically important outcome measures, such as mortality and major morbid events. The trials were designed with adequate patient numbers and length of follow-up to provide the required number of events to ensure the necessary statistical power for unequivocal interpretation of the results. Consequently, there is now evidence $ European Society of Cardiology. All rights reserved. PII: S

2 496 ( ) J. McMurray et al. European Journal of Heart Failure for the safety and efficacy, or otherwise, of a number of medical interventions. It has, nevertheless, become apparent that, in spite of the publication of the results of such clinical trials, the translation of the results into clinical prescribing has been slow and incomplete. Patients are thus denied the benefits of proven interventions, which would increase both the quality and quantity of life. In spite of a number of trials showing significant improvements in survival and reductions in hospitalisations for patients with chronic heart failure Ž CHF. who received angiotensin converting enzyme inhibitors Ž Table 1. 1,2, a number of clinical surveys conducted in different countries both in primary care 3,4 and in hospital practice 57 revealed that substantial proportions of patients who should have been treated with an angiotensin converting enzyme inhibitor were not receiving the treatment. It is not entirely clear what the reasons are for the reluctance of doctors to prescribe angiotensin converting enzyme inhibitors to all patients who should receive them but there does seem to be unreasonable concern about possible adverse effects, such as hypotension or renal insufficiency 4,8. Furthermore, the doses of angiotensin converting enzyme inhibitors used in clinical practice has been lower than the doses used in the clinical trials which were shown to have survival benefits. Whether or not these lower doses would have the same benefits as the higher doses can only be the subject of speculation but the results of the Assessment of Treatment with Lisinopril and Survival Ž ATLAS. trial which compared low and high doses of an angiotensin converting enzyme inhibitor showed that the high dose was significantly better than the low dose in reducing the combined end-point of mortality and hospitalisation 9. In addition to the under-prescribing and under-dosing of angiotensin converting enzyme inhibitors having unfavourable consequences for the patients, there is also an unfavourable impact on the costs incurred in managing heart failure 10. A large trial of spironolactone vs. placebo in patients with moderate to severe heart failure, already receiving diuretic and angiotensin converting enzyme inhibitor therapy, showed improved survival and reduced hospitalisation in the group treated with spironolactone Ž Table but no information is available at present as to the uptake of spironolactone into prescribing practice. The recent publications of four large clinical trials of beta-blockers in patients with chronic heart failure 1216 have shown that when the beta-blocker therapy was added to standard therapy which included both diuretic and angiotensin converting enzyme inhibitor, significant improvements in survival and re- ductions in hospitalisations were achieved Table Need for practical guidance The speed and extent of uptake of angiotensin converting enzyme inhibitors as a treatment for chronic heart failure has been repeatedly shown to be disappointing in many countries 37. Beta-blockers usage after myocardial infarction is similarly unsatisfactory and this is also likely to be the case in chronic heart failure There does, therefore, appear to be the need for a practical tool to facilitate the implementation of evidence based therapy. 2. Development of recommendations On the assumption that the reluctance of doctors to prescribe the angiotensin converting enzyme inhibitors and beta-blockers reflects a lack of practical, easy-to-follow advice on dosing, both initiation and maintenance and identification of potential problems, with clear recommendations on how to handle these if they should arise, a group of clinicians with expertise in the diagnosis and management of heart failure met recently. The output of this meeting was a step-wise, concise set of clinical recommendations for each of Table 1 Events prevented per 1000 patients years of treatment Hospital admissions ACE-I Ž. 1 beta-blockers Ž. 2 Spironolactone Ž. 3 digoxin Ž. 4 Ž Any cause Deaths Ž. 1 Based on the treatment arm of the SOLVD Ž. 2, average follow-up, 3.5 years Ž. 2 Based on the MERIT-HF study Ž14,15., average follow-up 1 year Ž. 3 Based on the RALES trial Ž11., average follow-up 2 years Ž. 4 Based on the DIG trial Ž32., average follow-up 3 years Note: Ž. a shorter follow-up tends to exaggerate benefit, Ž. b absolute benefit is a function of absolute risk, RALES recruited much higher risk patients Ž NYHA class IIIIV. than the other trials Žmainly NYHA class IIIII and Ž c. digoxin, beta-blockers and spironolactone have largely been evaluated in addition to ACE inhibitors.

3 ( ) J. McMurray et al. European Journal of Heart Failure Table 2 Practical guidance on the use of ACE inhibitors in patients with CHF due to left ventricular systolic dysfunction Why? Two major randomised trials Ž CONSENSUS I and SOLVD-T. and a meta-analysis of smaller trials have conclusively shown that ACE inhibitors increase survival, reduce hospital admissions and improve NYHA class and quality of life in patients with all grades of symptomatic CHF. Other major randomised trials in patients with systolic dysfunction after acute myocardial infarction Ž SAVE, AIRE, TRACE. have shown that ACE inhibitors increase survival. In patients with heart failure Ž ATLAS., the composite end-point of death or hospital admission was reduced by higher doses of ACE inhibitor compared to lower doses. ACE inhibitors have also been shown to delay or prevent the development of symptomatic CHF in patients with asymptomatic left ventricular systolic dysfunction. In whom and when? Indications: Potentially all patients with CHF 1st line treatment Ž along with beta-blockers. in patients with NYHA class I-IV CHF Contraindications: History of angioneurotic oedema Cautionsseek specialist adice: Significant renal dysfunction Ž creatinine 2.5 mgdl or 221 moll. or hyperkalaemia Ž K 5.0 mmoll. Symptomatic or severe asymptomatic hypotension Ž systolic BP 90 mmhg. Drug interactions to look out for: K supplementsk sparing diuretics Ž including spironolactone. a NSAIDS, angiotensin receptor blockers Low salt substitutes with a high K content Where? In the community for most patients Exceptions: see CAUTIONSSPECIALIST ADVICE above Which ace inhibitor and what dose? Starting dose Ž mg. Target dose Ž mg. Captopril 6.25 thrice daily thrice daily Enalapril 2.5 twice daily 1020 twice daily Lisinopril once daily 3035 once daily Ramipril 2.5 once daily 5 twice daily or 10 once daily Trandolapril 1.0 once daily 4 once daily How to use? Start with a low dose Ž see above. Double dose at not less than 2 weekly intervals Aim for target dose Ž see above. or, failing that, the highest tolerated dose Remember some ACE inhibitor is better than no ACE inhibitor Monitor blood chemistry Ž urea, creatinine, K. and blood pressure When to stop up-titrationdown-titration; see PROBLEM SOLVING Advice to patient? Explain expected benefits Ž see WHY?. Treatment is given to improve symptoms, to prevent worsening of CHF and to increase survival Symptoms improve within a few weeks to a few months Advise patients to report principal adverse effects i.e. dizzinesssymptomatic hypotension, cough Problem solving Asymptomatic low blood pressure does not usually require any change in therapy Symptomatic hypotension: If dizziness, light-headedness andor confusion and a low blood pressure reconsider need for

4 498 ( ) J. McMurray et al. European Journal of Heart Failure Table 2 Continued b nitrates, calcium channel blockers and other vasodilators If no signssymptoms of congestion consider reducing diuretic dose If these measures do not solve problem seek specialist advice Cough: Cough is common in patients with CHF, many of whom have smoking related lung disease Cough is also a symptom of pulmonary oedema which should be excluded when a new or worsening cough develops ACE inhibitor induced cough rarely requires treatment discontinuation When a very troublesome cough does develop Ž e.g. one stopping the patient sleeping. and can be proven to be due to ACE inhibition Ž i.e. recurs after ACE inhibition withdrawal and rechallenge. substitution of an angiotensin receptor blocker can be considered Worsening renal function: Some rise in urea Ž blood urea nitrogen., creatinine and K is to be expected after initiation of an ACE inhibitor; if the increase is small and asymptomatic no action is necessary An increase in creatinine of up to 50% above baseline, or to 3 mgdl Ž 266 moll., which ever is the smaller, is acceptable An increase in K to 6.0 mmoll is acceptable If urea, creatinine or K do rise excessively consider stopping concomitant nephrotoxic drugs Ž e.g. NSAIDs., non-essential vasodilators Ž e.g. calcium antagonists, nitrates., K supplementsretaining agents Ž triamterene, amiloride. and, if no signs of congestion, reducing the the dose of diuretic If greater rises in creatinine or K than those outlines above persist despite adjustment of concomitant medications the dose of the ACE inhibitor should be halved and blood chemistry rechecked, if there is still an unsatisfactory response specialist advice should be sought If K rises to 6.0 mmoll or creatinine increases by 100% or to above 4 mgdl Ž354 moll. the dose of ACE inhibitor should be stopped and specialist advice sought Blood chemistry should be monitored serially until K and creatinine have plateaued NB: it is very rarely necessary to stop an ACE inhibitor and clinical deterioration is likely if treatment is withdrawn; ideally, specialist advice should be sought before treatment discontinuation a Avoid unless essential. b Calcium channel blockers should be discontinued unless absolutely essential e.g. for angina or hypertension. beta-blockers, angiotensin converting enzyme inhibitors and spironolactone based on the questions which a physician is likely to ask when considering treatment options: why should the treatment be given; in whom and when; where Ž in which setting.; which agent and what dose; how to use; advice to patient; and problem solving. These practical recommendations are not meant to replace existing guidelines 2031, but rather offer a tool to facilitate their implementation. 3. Practical recommendations The recommendations start from the assumption that the physician has made a clinical diagnosis of heart failure and may have initiated diuretic treatment for treating the symptoms and signs associated with salt and water overload. Step 1 requires that the presence of left ventricular systolic dysfunction is confirmed using echocardiography, radionuclide ventriculography or radiological left ventricular angiography. These investigations are regarded as definitive and must be regarded as representing the minimum standard of care. Step 2 requires the initiation of first-line therapy which, for all patients with heart failure due to left ventricular systolic dysfunction, consists of an angiotensin converting enzyme inhibitor Žfor New York Heart Association classes IIV. and a beta-blocker Ž for New York Heart Association classes IIV., unless these are contra-indicated. It is important that contra-indications and cautions are observed. It is recommended that the angiotensin converting enzyme inhibitor is initiated first, followed by the beta-blocker, that both are initially introduced at low doses and then up-titrated slowly, and that both are titrated to the target doses used in the clinical trials checking tolerability and blood chemistry. The objective is to treat patients with both an angiotensin converting enzyme inhibitor and a beta-blocker, both, ideally given at the target doses used in the large randomised trials. It was, however, the panel s view that lower doses of both treatment were still likely to be of value and should be used if larger doses are not tolerated.

5 ( ) J. McMurray et al. European Journal of Heart Failure Table 3 Practical guidance on the use of beta-blockers in patients with CHF due to left ventricular systolic dysfunction Why? Several major randomised controlled trials Ž i.e. USCP, CIBIS II, MERIT-HF, COPERNICUS. have shown, conclusively, that beta-blockers increase survival, reduce hospital admissions and improve NHYA class and quality of life when added to standard therapy Ž diuretics, digoxin and ACE inhibitors. in patients with stable mild and moderate CHF and in some patients with severe CHF. One other trial Ž BEST.33did not show a reduction in all cause mortality but did report a reduction in cardiovascular mortality and is other wise broadly consistent with the aforementioned studies. The recent CAPRICORN Study showed a reduction in mortality with carvedilol in post-myocardial infarction patients with reduced left ventricular systolic dysfunction 34, In whom and when? Indications: Contraindications: Cautionsseek specialist adice: Drug interactions to look out for: Where? Potentially all patients with stable mild and moderate CHF; patients with severe CHF should be referred for specialist advice 1st line treatment Ž along with ACE inhibitors. in patients with stable NYHA class IIV CHF, start early as possible in course of disease Asthma Severe Ž NYHA class IV. CHF Current or recent Ž 4 weeks. exacerbation of CHF e.g. hospital admission with worsening CHF Heart block or heart rate 60min. Persisting signs of congestion: raised jugular venous pressure, ascites, marked peripheral oedema Verapamildiltiazem Ž should be discontinued. Amiodarone In the community in stable patients ŽNYHA class IVsevere CHF patients should be referred for specialist advice. Not in unstable patients hospitalised with worsening CHF Other exceptions: see CAUTIONSSEEK SPECIALIST ADVICE Which beta-blocker and what dose? Only three beta-blockers have shown to reduce mortality in heart failure. There is evidence that some betablockers may be ineffective. The benefits of beta-blockers cannot be assumed to be a class effect in heart failure Starting dose ( mg) Target dose ( mg) Bisoprolol 1.25 once daily 10 once daily Carvedilol twice daily 2550 twice daily Metoprolol CRXL once daily 200 once daily How to use? Start with a low dose Ž see above. Double dose at not less than 2 weekly intervals Aim for target dose Ž see above. or, failing that, the highest tolerated dose Remember some beta-blocker is better than no beta-blocker Monitor HR, BP, clinical status Ž symptoms, signs, especially signs of congestion, body weight. Check blood chemistry 12 weeks after initiation and 12 weeks after final dose titration A specialist CHF nurse may assist with patient education, follow-up Ž in personby telephone. and dose uptitration When to down-titratestop up-titration, see PROBLEM SOLVING Advice to patient? Explain expected benefits Ž see WHY?. Emphasise that treatment given as much to prevent worsening of CHF as to improve symptoms, beta-blockers also increase survival If symptomatic improvement occurs, this may develop slowly 36 months or longer Temporary symptomatic deterioration may occur Ž estimated 2030% of cases. during initiationup-titration phase Advise patient to report deterioration Ž see PROBLEM SOLVING. and that deterioration Žtiredness, fatigue, breathlessness. can usually be easily managed by adjustment of other medication; patients should be advised not to stop beta-blocker therapy without consulting their physician Patients should be encouraged to weigh themselves daily Žafter waking, before dressing, after voiding, before eating. and to increase their diuretic dose should their weight increase, persistently Ž 2 days., by kg

6 500 ( ) J. McMurray et al. European Journal of Heart Failure Table 3 Continued Problem solving Worsening symptomssigns Ž e.g. increasing dyspnoea, fatigue, oedema, weight gain.: If increasing congestion double dose of diuretic andor halve dose of beta-blocker Žif increasing diuretic does not work. If marked fatigue Ž andor bradycardia, see below. half dose of beta-blocker Ž rarely necessary. Review patient in 12 weeks; if not improved seek specialist advice If serious deterioration halve dose of beta-blocker or stop this treatment Ž rarely necessary.; seek specialist advice Low heart rate: If 50 beatsmin and worsening symptoms halve dose beta-blocker or, if severe deterioration, stop beta-blocker Ž rarely necessary. Review need for other heart rate slowing drugs e.g. digoxin, amiodarone, diltiazem Arrange ECG to exclude heart block Seek specialist advice Asymptomatic low blood pressure: Does not usually require any change in therapy Symptomatic hypotension: If dizziness, light-headedness andor confusion and a low blood pressure reconsider need for nitrates, calcium channel blockers and other vasodilators If no signssymptoms of congestion consider reducing diuretic dose If these measures do not solve problem seek specialist advice NB: beta-blockers should not be stopped suddenly unless absolutely necessary Žthere is a risk of a rebound increase in myocardial ischaemiainfarction and arrhythmias.; ideally specialist advice should be sought before treatment discontinuation These recommendations are set out in more detail in Table 2 for angiotensin converting enzyme inhibitors and Table 3 for beta-blockers. Step 3 requires the addition of second-line therapy for those patients in whom there are persisting signs and symptoms of heart failure ŽNew York Heart Association class IIIIV., consisting of spironolactone and digoxin. Again, it is important that contraindications and cautions are observed, that spironolactone is initiated first followed by digoxin, that both are initiated at a low dose and then uptitrated checking tolerability and blood chemistry. The recommendations for spironolactone are set out in Table 4. Digoxin is included in this summary as one large trial showed that it reduced the need for hospital admission, particularly for worsening heart failure, though this treatment had no effect on survival, either positive or negative Ž Table Digoxin may still have a special role in the patient with atrial fibrillation when rapid control of the ventricular rate is needed Žwhich cannot be achieved with cautious introduction and up-titration of a beta-blocker.. Initial treatment with digoxin should not preclude subsequent introduction of a beta-blocker. Digoxin can be withdrawn if an excessive bradycardia develops during combined digoxin beta-blocker treatment although combined use of digoxin and beta-blockers may be required for optimal ventricular rate control Conclusions Under-prescribing and under-dosing of therapeutic interventions which have significantly reduced both mortality and morbidity in patients with chronic heart failure in controlled clinical trials is a persisting problem. Consequently, this under-treatment denies patients the benefits of these interventions and has an adverse health economic effect in terms of increased hospitalisations. The preparation of these concise and practical clinical recommendations for the prescribing of angiotensin converting enzyme inhibitors and beta-blockers should provide doctors with the confidence to practise evidence-based medicine in their patients with chronic heart failure. This would improve not only the outcomes for the individual patient but also reduce the burden on health care systems. References 1 CONSENSUS Study Group. Effect of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316: The Study of Left Ventricular Dysfunction Ž SOLVD. Investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:

7 ( ) J. McMurray et al. European Journal of Heart Failure Table 4 Practical guidance on the use of spironolactone in patients with CHF due to left ventricular systolic dysfunction Why? The RALES study showed that low dose spironolactone increased survival, reduced hospital admissions and improved NYHA class when added to standard therapy Ždiuretic, digoxin, ACE inhibitor and, in a minority of cases, a beta-blocker. in patients with severe Ž NYHA class III or IV. CHF. In whom and when? Indications: Potentially all patients with symptomatically moderately severe or severe CHF Second line therapy Ž after ACE inhibitors and beta-blockers. in patients with NYHA class IIIIV CHF Cautionsseek specialist adice: Significant renal dysfunction Ž creatinine 221 moll or 2.5 mgdl. Significant hyperkalaemia Ž K 5.0 mmoll. Drug interactions to look out for: ACE inhibitors, angiotensin receptor blockers, other potassium sparing diuretics Žbeware combination preparations e.g. frusemide plus amiloride or triamterene., potassium supplements Ž e.g. KCl. NSAIDs Low salt substitutes with a high potassium content Where? In the community or in hospital Exceptions, see CAUTIONSSEEK SPECIALIST ADVICE Which dose? Starting dose Ž mg. Target dose Ž mg. 25 mg once daily or on alternate days 2550 mg once daily How to use? Start at 25 mg once daily Check blood chemistry at 1, 4, 8 and 12 weeks; 6, 9 and 12 months, 6 monthly thereafter If K rises to between 5.5 and 6.0 mmoll or creatinine rises to 2.5 mgdl Ž 221 moll. reduce dose to 25 mg on alternate days and monitor blood chemistry closely If K rises to 6.0 mmoll or creatinine to 4.0 mgdl Ž 354 moll. stop spironolactone and seek specialist advice Advice to patient? Explain expected benefits Ž see WHY?. Treatment is given to improve symptoms, prevent worsening of CHF and to increase survival Symptom improvement occurs within a few weeks to a few months of starting treatment Avoid NSAIDs not prescribed by a physician Ž self-purchased over the counter treatment e.g. ibuprofen. Temporarily stop spironolactone if diarrhoea andor vomiting and contact physician Problem solving Worsening renal functionhyperkalaemia: See HOW TO USE? section Major concern is hyperkalaemia Ž 6.0 mmoll. though this was uncommon in RALES; a high normal potassium may be desirable in CHF patients, especially if taking digoxin It is important to avoid other K retaining drugs Ž e.g. K sparing diuretics. and nephrotoxic agents Ž e.g. NSAIDs. Some low salt substitutes have a high K content Male patients may develop breast discomfort andor gynaecomastia 3 Mair FS, Crowleu TS, Brundred PE. Prevalence, aetiology and management of heart failure in general practice. Br J Gen Pract 1996;46: Houghton A, Cowley A. Why are angiotensin converting enzyme inhibitors under-utilised in the treatment of heart failure by general practitioners? Int J Cardiol 1997;59: Philbin EF, Andreou C, Rocco TA, Lynch LJ, Baker SL. Patterns of angiotensin-converting enzyme inhibitors use in congestive heart failure in two community hospitals. Am J Cardiol 1996;77: Smith NL, Psaty BM, Pitt B, Garg R, Gottdiener JS, Heckbert SR. Temporal patterns in the medical treatment of

8 502 ( ) J. McMurray et al. European Journal of Heart Failure congestive heart failure with angiotensin-converting enzyme inhibitors in older adults, 1989 through Arch Intern Med 1998;158: Reis SE, Holubkov R, Edmundosicz D et al. Treatment of patients admitted to the hospital with congestive heart failure: speciality-related disparities in practice patterns and outcomes. J Am Coll Cardiol 1997;30: Hobbs FDR, Wilson S, Jones MI, Allan TF, Tobias R. European survey of primary care physician perceptions and practice in heart failure diagnosis and management ŽEuro-HF- Study.. Eur Heart J 2000;21: Packer M, Poole-Wilson PA, Armstrong PW, Cleland JGF, Horowitz JD. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100: Berry C, Murdoch DR, McMurray JJ. Economics of chronic heart failure. Eur J Heart Fail 2001;3Ž. 3 : Pitt B, Zannad F, Remme WJ et al. The effect of sprionolactone on morbidity and mortality in patients with severe heart failure. N Eng J Med 1999;341: Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334: The Cardiac Insufficiency Bisoprolol Study II Ž CIBIS-II.: a randomised trial. Lancet 1999;359: Hjalmarson A, Goldstein S, Fagerberg B et al. Effect of metoprolol CRXL in chronic heart failure: metoprolol CRXL randomised intervention trial in congestive heart failure Ž MERIT-HF.. Lancet 1999;353: Hjalmarson A, Goldstein S, Fagerberg B et al. Effects of controlled-release metoprolol on total mortality, hospitalisations, and well-being in patients with heart failure ŽMERIT- HF.. MERIT-HF Study Group. J Am Med Assoc 2000;283: Packer M, Coats AJ, Fowler MB, et al. Effects of carvedilol on survival in severe chronic heart failure. 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The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336: A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;31; 344Ž 22.: Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001;5; 357Ž 9266.: Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JGF. Carvedilol alone or in combination with digoxin for the management of atrial fibrilation in patients with heart failure? Eur Heart J 2000;21:123. Abstract.