Q J Med 1999; 92: 673-678
© 1999 Association of Physicians
Commentary papers |
Beta-blockers for heart failure–time to think the unthinkable?
From the Departments of Cardiovascular Medicine and Cardiology, John Radcliffe Hospital, Oxford, UK
Dr C.H. Davies, Department of Cardiology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201-3098, USA
Introduction
Heart failure accounts for 5% of acute medical admissions in the UK and its incidence is rising as the population ages.1 The natural history is characterized by inexorable progression, with a steady attrition of patients from terminal pump failure or sudden death. Despite wider and earlier use of angiotensin-converting-enzyme (ACE) inhibitors, the outlook remains poor, with 40–50% mortality within 5 years among patients suffering from mild-to-moderate heart failure, rising to 70–80% in more advanced heart failure.2 The notion that ß-blockers may confer substantial prognostic benefits in chronic heart failure will seem counterintuitive and even inconceivable to generations of clinicians brought up with the strict doctrine that these agents are harmful to patients with impaired ventricular function. Nevertheless, a compelling weight of evidence now supports such a radical and unprecedented U-turn in clinical practice. This evidence has emerged in three distinct phases: early reports and hypothesis-generating studies, followed by medium-sized randomized trials and most recently, definitive mortality trials.
Hypothesis-generating studies
The traditional dogma that ß-adrenoceptor antagonists worsen heart failure was first questioned by Waagstein in 1975.3 Over the next decade, a succession of small studies appeared to confirm that ß-blockers are tolerated in over 90% of patients with stable chronic heart failure if introduced gradually, and result in consistent improvements in left ventricular function, haemodynamic indices and exercise tolerance.4 Furthermore, post hoc analysis of secondary prevention trials after myocardial infarction indicated that the prognostic benefits of ß-blockade were greatest among those patients with evidence of left ventricular dysfunction.5
Potential mechanisms of action—changing paradigms in heart failure
These encouraging findings initially attracted little interest, as they flew in the face of a traditional `haemodynamic' model of the pathogenesis of heart failure which emphasized the primacy of mechanical factors (impaired pump function, vasoconstriction and fluid retention). However, such a paradigm could not account for the demonstration that inotropic agents which act via stimulation of the ß-adrenergic pathway produce only transient haemodynamic benefits in heart failure patients, and increased mortality.6,7 Indeed, experience with the partial ß1 antagonist xamoterol, which also shortened survival in severe heart failure,8 suggests that even minor degrees of ß-adrenoceptor stimulation may be deleterious. To unravel the apparent paradox, whereby acute adrenergic stimulation improves myocardial performance but chronic stimulation worsens prognosis, has required a shift to a `neuroendocrine' model of heart failure. In this, impaired pump function is initially compensated for by increases in sympathetic drive,9 angiotensin and endothelins,10 but with time these and other neuroendocrine factors mediate adverse changes in myocardial structure, function and electrical stability (Figure 1
). Thus a progressive cycle of deterioration is initiated,11 which leads to worsening clinical heart failure and/or arrhythmogenesis (i.e. sudden death). Pharmacological blockade of this vicious cycle with neuroendocrine antagonists may result in a transient deterioration, but is ultimately the only way to prevent progressive ventricular dysfunction and to modify the unfavourable natural history of chronic heart failure. Moreover, experience with ACE inhibitors suggests that antagonism of a single endocrine axis in isolation is insufficient to prevent longer-term deterioration.12
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The precise mechanisms of ß-blocker action remain uncertain, but can be considered at haemodynamic, cellular, electrical and peripheral levels.
Haemodynamic mechanisms
Numerous studies have demonstrated an increase in ejection fraction following the introduction of ß-blockers in patients with heart failure (reviewed in reference 4). It has been suggested that this effect could just be the result of bradycardia (if cardiac output is maintained, reduced heart rate must be accompanied by an increase in stroke volume and ejection fraction). However, studies using atrial pacing to achieve matched rates13 have confirmed that the improvement is independent of heart rate, and is temporally dissociated from the onset of bradycardia.14 The meticulous echocardiographic studies performed in the Australia/New Zealand Carvedilol Trial demonstrated reductions in both left ventricular end systolic and diastolic dimensions following ß-blocker treatment, but with significantly greater reduction in systolic volumes.15 Reducing systole relative to diastole produces an obligate increase in ejection fraction, and this represents an increase in myocardial contractility. In addition, there is some evidence that ß-blockade might improve the ventricular inco-ordination that is a frequent accompaniment of heart failure.16 Diastolic dysfunction is a common accompaniment to systolic dysfunction, with effective ventricular filling time reduced to <200 ms in approximately 25% of patients,17 and bradycardia would be predicted to increase the relative time available for ventricular filling.
Cellular mechanisms
At a structural level, chronic elevation of catecholamine levels and their metabolites is directly toxic to cardiac myocytes, producing depletion of high energy phosphates, free radical generation, cytokine expression and accelerated apoptosis in animal models18–20 and focal myocarditis in patients with phaeochromocytoma.21 Autoantibodies against the ß1-adrenoceptor occur in heart failure, and are associated with impaired cardiac function, and this effect might be attenuated by ß-blockade.22 At a functional level, a flattening of the force-frequency relationship is a fundamental characteristic of heart failure23—contraction is normal at lower stimulation rates, but fails to increase and may even decline with increases in heart rate.24 Beta-blockade would be predicted to restrict heart rate to the optimal portion of the rate-output relationship and to thus improve myocardial efficiency. The effects on intracellular cAMP of long term ß-adrenoceptor antagonism in a situation of chronic catecholamine excess are difficult to predict,25 and as yet poorly understood (for example ß-receptor up-regulation occurs with metoprolol but not with carvedilol26). From a receptor perspective, the relative increase in ß2-adrenoceptors that occurs in heart failure27 and the ß2-up-regulation that occurs following administration of a selective ß1 antagonist28 would support the use of non-selective antagonists, although the practical importance remains uncertain. Interestingly, a recent small-scale comparison found no differences between carvedilol and metoprolol in terms of exercise tolerance, ejection fraction or free radical activity over a 6-month period.29
Electrical mechanisms
Almost half of patients with heart failure succumb to sudden (presumed arrhythmic) death, and among those with coronary disease, the mechanism is ventricular tachyarrhythmia in 80% of cases. Catecholamines increase abnormal automaticity, triggered activity and re-entry in diseased myocardium (reviewed in reference 30) and ß-blockers would be expected to reduce the occurrence of lethal arrhythmias, a finding supported by a reduction in sudden death in recent studies.31
Peripheral mechanisms
Increased sympathetic tone (measured by sympathetic nerve traffic) may contribute to reduced blood flow to active muscle and thus towards the impaired exercise capacity in heart failure.32 This effect is attenuated by ß-blockade,33 providing a mechanism for the increases in maximum O2 uptake observed during long-term metoprolol treatment.34
Medium-sized randomized trials
The neuroendocrine paradigm provided a clearer rationale for the use of ß-blockers in combination with ACE inhibitors, and this renewed interest led to a second phase of medium-sized, randomized controlled trials of ß-blockers in stable chronic heart failure. The Metoprolol in Dilated Cardiomyopathy (MDC),35 Cardiac Insufficiency Bisoprolol Study-I (CIBIS-I)36 and Australia/New Zealand15 trials all demonstrated haemodynamic improvements and reduced hospitalization rates for acute heart failure, but were underpowered to detect an effect on survival. Crucially, these studies confirmed the feasibility and safety of ß-blocker therapy in general heart failure populations to a still sceptical cardiology community and thus paved the way for a third phase of `mega-trials'.
Mortality trials
The first of these, the US Carvedilol trial (USC),37 was published in 1996. Carvedilol is a non-selective ß1-, ß2- and α-antagonist with anti-oxidant properties.38 USC was an amalgam of four smaller studies with a total of 1094 patients and, in common with all of the mortality trials, was stopped ahead of schedule by its safety committee. Although USC demonstrated a 67% mortality reduction (3.2% vs. 7.8%), the confidence intervals were wide (39–80%) because of the small number of deaths before the trial was stopped. Furthermore, patients had to tolerate carvedilol during a 2-week run-in prior to randomization, and deaths during this period were excluded—hardly an accurate reflection of clinical practice. These uncertainties meant that few were willing to commit patients to ß-blocker therapy on the basis of this trial alone. The next trial, CIBIS-II,31 studied the selective ß1-antagonist bisoprolol in 2647 patients with moderate and severe heart failure (95% receiving an ACE inhibitor) followed for a median of 1.3 years with a mortality reduction of 34% (11.8% vs. 17.3%) and a parallel reduction in hospital admissions due to heart failure. Contrary to earlier suggestions, this benefit was achieved in patients with heart failure secondary to coronary artery disease as well as those with non-ischaemic cardiomyopathies. Finally, the MERIT-HF trial used the selective antagonist metoprolol in slow-release form in 3991 patients with predominantly mild or moderate heart failure.39 This too was stopped prematurely, with preliminary results demonstrating a 35% mortality reduction.
These studies provide compelling evidence that ß-blockers confer significant benefits both in terms of mortality and quality of life for patients with heart failure in addition to those already obtained with ACE inhibitors, with meta-analyses confirming a 36% relative mortality reduction.40,41 Indeed, the case for the routine addition of ß-blockers to ACE inhibitors in heart failure is now at least as strong as for the use of ACE inhibitors themselves (treatment of 78 patients for 1 year with ACE inhibitors prevents one death, whereas only 29 patients have to be treated to prevent one death with ß-blockers41).
Practical implications for heart failure therapy
Translating these findings into routine clinical practice is likely to prove a major challenge. Patient selection (Table 1) requires a baseline echocardiogram as an ejection fraction <35%31,42 to 40%39 was an entry criterion in the mortality trials. This in itself produces an obstacle to the use of ß-blockers as, at present, only a third of patients suspected of having heart failure in the UK undergo echocardiography,43 and clinical diagnosis alone may be incorrect in 30–45% of cases.44,45 Patients should have been established on an ACE inhibitor and clinically stable in the preceding 6 weeks. The key to success is the use of very low starting doses followed by gradual up-titration every 2–3 weeks46 (see Figure 2 for the protocols used in the major trials). Although theoretical arguments about the merits of individual ß-blockers in heart failure remain unresolved pending the results of the COMET trial, only carvedilol currently has a product license for an ultra-low dose preparation (3.125 mg bd) in the UK and USA.
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Patients and their general practitioners should be aware that there may be a transient mild deterioration in their condition over the first few months,14 and that the goals of ß-blockers are related more to reducing mortality and hospital admissions than improvements in exercise tolerance.47–49 It is in helping patients to persevere through these first few months of treatment that the support of their general practitioner is crucial. Overcoming our preconceptions about the use of ß-blockers in heart failure and introducing them into clinical practice might seem an impossible challenge, yet recent experience in Italy suggests that following a concerted effort, over half of patients with heart failure were receiving ß-blockers.50
In conclusion, there are several obstacles to be overcome before the potential benefits of ß-blockers in heart failure can be fully realized. Based on earlier experience with ACE inhibitors, their use may be limited initially to specialist centres but will become more widespread as confidence grows. However, the potential therapeutic gains are such that this is a challenge we can no longer ignore.
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