There is overwhelming evidence to support the use of beta-blockers for the treatment of chronic heart failure (CHF).
This flies in the face of what many doctors were taught in medical school. Yet in practice, beta-blockers are straightforward to use and result in symptomatic benefit, as well as a reduction in mortality. More patients have been treated in the beta-blocker heart failure trials than in the angiotensin-converting enzyme (ACE) inhibitor trials, and there is no doubt about the results.
Older physicians were taught that beta-blockers were contraindicated in heart failure, and they are widely perceived to be dangerous drugs that are very difficult to use. Consequently, the overall uptake of beta-blockers in patients with heart failure is low.
The IMPROVEMENT study, which surveyed the management of heart failure by primary care physicians across Europe, found that on average only about 20% of patients received a beta-blocker, compared with about 60% receiving an ACE inhibitor.1
In this article, we explain the rationale behind beat-blocker treatment for CHF, discuss the clinical trial evidence for their use, and suggest guidance for their use in practice.
In response to heart failure, the body attempts to restore perfusion pressure, particularly to the kidneys, by producing a variety of vasoactive substances with predominantly vasoconstrictor and salt and water retaining properties. Thus, the renin-angiotensin system is activated, as is the sympathetic nervous system.
The neurohormonal hypothesis of progression in heart failure emphasises the potential adverse effects of this response. ACE inhibitors have been one of the major successes of heart failure management. By analogy, inhibiting sympathetic activation might be helpful.
Drugs that mimic the action of sympathetic activation to increase the inotropic state of the heart increase mortality in patients with heart failure.2–4
Sympathetic activation can be deleterious for the failing heart in a number of ways:
- It causes vasoconstriction, and thus an increase in afterload, and increases heart rate
- High levels of catecholamines are arrhythmogenic and may cause cardiac myocyte necrosis
- Catecholamines also facilitate and enhance the actions of other vasoconstrictor agents, such as angiotensin II and aldosterone.
The precise mechanism of benefit with beta-blockers, as with ACE inhibitors, is uncertain. Beta-blockers may improve myocardial function either by protecting cardiac myocytes from direct catecholamine toxicity or by slowing the heart, which improves contractile function, increases diastolic coronary blood flow and reduces myocardial oxygen demand.
Beta-blockers also have potent anti-ischaemic and anti-arrhythmic effects and reduce the risk of recurrent myocardial infarction.5 With chronic use, haemodynamics6, 7 and left ventricular ejection fraction improve.8
Table 1. Mortality trials of beta-blockers in chronic heart failure
|Drug||Patients (NYHA class)|| |
No. (%) of deaths
|US Carvedilol11||Carvedilol||IHD 48% (II 54%; III 44%)|| |
|CIBIS-II9||Bisoprolol||IHD 50%b (III 83%; IV 17%)|| |
|MERIT-HF10||Metoprolol||IHD 65% (II 41%; III 56%)|| |
|BESTc||Bucindolol||(III 92%; IV 8%)|| |
|COPERNICUSc||Carvedilol||(All III and IV)|| |
a Not designed as a mortality study; b In 40% of patients in CIBIS II, the underlying cause of heart failure was not known; c The data from BEST and COPERNICUS have not yet been published; The mortality rates quoted are the crude data for the trials, not annualised mortality rates; IHD = ischaemic heart disease; NYHA class = New York Heart Association classification of heart failure
The BEST study13 is discussed below.
In the CIBIS-II trial9 bisoprolol was compared with placebo in patients with moderately severe heart failure, and was stopped early because of its pronounced beneficial effects. The target dose was 10mg daily, but this was reached by only 42% of patients.
In the MERIT-HF trial10 controlled-release metoprolol was compared with placebo in patients with predominantly class II and III heart failure. Again, the trial was stopped early. The target dose was 200mg once daily, and was reached by 64% of patients.
These studies had set out to examine the effects of beta-blockade in moderate to severe heart failure, but had in fact failed to recruit many patients at the severe end of the spectrum, reflecting investigators' caution about giving beta-blockers to patients with severe heart failure.
The question remained as to whether beta-blockers are suitable for treating severely affected patients. The COPERNICUS study was designed to examine the effects of carvedilol in class IV heart failure, and was again stopped early.
Full data from the study are not yet published, but the dramatic beneficial effect was seen even in the most severely affected patients. Remarkably, in this population with rather severe heart failure, 74% of patients were titrated to the target dose of carvedilol.
Three groups of patients with very severe heart failure were analysed:
- Left ventricular ejection fraction (LVEF) <20% and hospitalisation for heart failure in the year before study entry – mortality rate reduced by 42% with carvedilol
- LVEF 15% and hospitalised three or more times during the preceding year for worsening heart failure – mortality rate reduced by 36% with carvedilol
- Patients with fluid retention, those who were in hospital at study entry, and those who had received intravenous therapy with a positive inotropic or vasodilator drug within 2 weeks, or had been hospitalised three or more times during the previous year – mortality rate reduced by 50% with carvedilol.
Large studies with a primary end-point of all-cause mortality have included 11 622 patients – more patients than in the trials of ACE inhibitors for heart failure. The evidence in favour of beta-blockers is now overwhelming.
Morbidity can be difficult to measure objectively. Smaller studies have shown improvements in quality of life scores in beta-blocker treated patients,14,15 but there have been inconsistent findings in formal measures of exercise capacity.15,16
An additional benefit of beta-blockade is prevention of worsening of heart failure symptoms rather than direct improvement of symptoms.
One important objective measurement of morbidity is hospitalisation: both CIBIS-II and MERIT-HF reported significant reductions in both all-cause hospitalisation and hospitalisation for worsening heart failure.
Which beta-blocker to use in heart failure remains a controversial issue. Not all beta-blockers are the same, and it cannot be argued that the survival benefit is a 'class effect': for example, xamoterol, a beta-blocker with pronounced sympathomimetic properties, causes a worse outcome than placebo.17
More recently, the BEST study of bucindolol in patients with NYHA class III/IV heart failure13 showed no significant reduction in mortality. Many explanations have been suggested. The most plausible are as follows:
- Bucindolol has excessive sympathomimetic activity18
- The patients had too severe heart failure (although COPERNICUS contradicts this)
- There was a preponderance of African-American subjects. African-Americans may be less responsive to beta-blockers.
The trial evidence favours bisoprolol, metoprolol and carvedilol. Bisoprolol and metoprolol are both beta1-selective antagonists. Cardiac beta2 receptors are more common in heart failure, and thus a non-selective agent may be preferable.
Carvedilol is a non-selective beta-blocker. It is also an alpha-antagonist, thus causing vasodilation, and may be better tolerated than beta1-selective antagonists, especially when first given. Carvedilol also has anti-oxidant properties, although the clinical relevance of this is not clear at present.
Other beta-blockers, such as nebivolol,19 have vasodilating properties. The SENIORS study will compare the effects of nebivolol vs placebo in patients aged more than 70 years with signs of CHF and LVEF <35% or EF >35%with a cardiac abnormality and a hospital admission with heart failure within the previous year.
The ongoing COMET study of carvedilol vs metoprolol will help to resolve the issue of whether one beta-blocker is better than another.
When correctly used, beta-blockers are well tolerated. Withdrawal rates in clinical trials are similar in the active and placebo groups.
The most important general instruction is that a very low initiation dose should be used, with small increments at infrequent intervals. Even in the COPERNICUS trial in very severe heart failure, 74% of patients reached the target dose of carvedilol.
Appropriate dosing schedules are shown in table 2, below. When initiating a beta-blocker and when uptitrating, patients should be warned that they may feel transiently more breathless and require an increase in diuretic dose for a few days. Other problems such as bradycardia and hypotension may occur, and patients need to be able to contact the hospital if their symptoms worsen.
The only patients who should not receive beta-blockade are those:
- With a conventional contraindication, such as proven reversible airways obstruction
- With oedema
- Receiving intravenous inotropic therapy.
All other patients should be considered candidates for treatment.
Even patients with chronic obstructive pulmonary disease may benefit as the airways obstruction is often fixed. This group have to be monitored carefully for worsening airways obstruction and be warned to stop treatment and seek urgent advice if their breathing deteriorates abruptly.
If a patient has an episode of acute pulmonary oedema the beta-blocker should be stopped temporarily and re-initiated at half the previous dose once the episode is treated. Where a patient cannot tolerate a dose of beta-blocker, the dose should be reduced to the previously tolerated level. A little beta-blocker is better than none at all.
Heart failure is a common illness, and the most common cause of medical admission to hospital.20
National and international bodies produce guidelines on the management of heart failure, but these can swiftly be overtaken by advancing trial evidence. For example, the European Society of Cardiology guidelines recommend beta-blockers for mild to moderate heart failure only.21
Most physicians in both primary and secondary care will care for many patients with CHF, and should therefore keep themselves up to date with heart failure management, and have a route of referral to specialist services for the accurate diagnosis of heart failure and to assist in its treatment according to local requirements. Integrated care pathways between primary and secondary care need to be forged.
Beta-adrenoceptor antagonism has been shown unequivocally to be of benefit to almost all patients with CHF due to left ventricular systolic dysfunction. They are not widely used yet as they are generally perceived to be dangerous drugs in heart failure, yet their use improves quality of life and reduces mortality dramatically.
The general reluctance to use beta-blockers has to be overcome. Heart failure is so common that primary care physicians will be asked to take on the initiation of treatment for many patients. The clinical evidence is robust and patients should not be denied this life-enhancing therapy.
- Witte K, Thackray S, Clark AL, Cooklin M, Cleland JGF. Clinical trials update. Eur J Heart Failure 2000: in press
- Packer M, Carver JR, Rodeheffer RJ et al for the PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991; 325: 1468-75.
- Cohn JN, Goldstein SO, Greenberg BH et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med 1998; 339: 1810-16.
- Dies F, Krell M, Whitlow P. Intermittent dobutamine in ambulatory outpatients with chronic cardiac failure. Circulation 1986; 74 (Suppl 2): 39.
- Cleland JGF, Bristow M, Erdmann E, Remme WJ, Swedberg K, Waagstein F. Beta-blocking agents in heart failure. Should they be used and how? Eur Heart J 1996; 17: 1629-39.
- Ferro G, Duilio C, Spinaelli L, Spadafora M, Guarnaccia F, Condorelli M. Effects of beta-blockade on the relation between heart rate and ventricular diastolic perfusion time during exercise in systemic hypertension. Am J Cardiol 1991; 68: 1101-3.
- Eichhorn EJ, Heesch CM, Barnett JH et al. Effects of metoprolol on myocardial function and energetics in patients with non-ischaemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1994; 24: 1310-20.
- Packer M, Colucci WS, Sackner-Bernstein JD et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE trial. Circulation 1996; 94: 2793-9.
- CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9-13.
- MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001-7.
- Packer M, Bristow MR, Cohn JN et al for the US carvedilol study group. The effects of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349-55.
- Packer M. The COPERNICUS study. 22nd Congress of the European Society of Cardiology. Amsterdam, August 2000.
- The BEST Steering Committee: Design of the Beta-blocker Evaluation Survival Trial (BEST). Am J Cardiol 1995; 75: 1220-3.
- A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation 1994; 90: 1765-73.
- Waagstein F, Bristow MR, Swedberg K et al for the MDC Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993; 342: 1441-6.
- Packer M, Colucci WS, Sackner-Bernstein JD et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation 1996; 94: 2793-9.
- The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1-6.
- Maack C, Cremers B, Flesch M, Hoper A, Sudkamp M, Bohm M. Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium. Br J Pharmacol 2000; 130: 1131-9.
- Cockcroft JR, Chowienczyk PJ, Brett SE et al. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther 1995; 274: 1067-71.
- Brown A, Cleland JGF. Influence of concomitant disease on patterns of hospitalisations in patients with heart failure from Scottish hospitals in 1995. Eur Heart J 1998; 19: 1063–9.
- The Task Force of the Working Group on Heart Failure of the European Society of Cardiology. The treatment of heart failure. Eur Heart J 1997; 18: 736-53.
The National Service Framework (NSF) for Coronary Heart Disease states that all patients with heart failure should receive a 'full package of appropriate investigation and treatment'.1 Those with suspected heart failure should be offered investigation such as electrocardiography or echocardiography to confirm or refute the diagnosis.
The NSF recommends that in patients with confirmed heart failure, the cause should be identified and treatments 'most likely to both relieve symptoms and reduce their risk of death should be offered'.
One of the treatments recommended for clinical management is beta-blockers.
Theoretically, we have the drugs to treat CHF and the evidence (outlined in Clark and Cleland's article), so what is stopping us?
The primary obstacle may well be our training. When I sat finals, giving a negative inotrope in CHF would have guaranteed a re-sit.
This is not only an educational issue, but also a cultural one, and may be the rock upon which all of this founders.
Concern regarding side-effects will undoubtedly inhibit some GPs, but a greater worry to most will be the workload implications.
Most GPs find it difficult enough to keep up with the demands generated by clinical governance, rising public expectation, out-of-hours pressures, etc., without actively looking for extra work.
The idea of reviewing patients fortnightly – many of whom will be housebound, and thus require a visit – may not seem worthwhile.
- First, there needs to be a widespread education campaign to explain to clinicians not only that b-blockers work in CHF, but also why they work.
- Second, the Government must fund the work properly, and remove the numbing constraints of unified budgets so that diligent, caring GPs do not, once again, have to foot the bill in terms of increased workload and reduced income.
- DoH. National Service Framework for Coronary Heart Disease. London: March 2000.