The rational use of β-adrenoceptor blockers in the treatment of heart failure. The changing face of an old therapy

Abstract

Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of antagonists of the adrenergic β-receptor (β-blockers) in heart failure has been the subject of debate for many years. Data from studies of the therapeutic use of β-blockers in patients following acute myocardial infarction suggest that in this circumstance these agents confer at least as much benefit to patients with heart failure as they do to those without. Similarly retrospective analysis of a number of the studies of angiotensin converting enzyme (ACE) inhibitors in heart failure suggest a greater effect of the combination of β-blocker with ACE inhibitor compared with ACE inhibitor alone.

The results of recent prospective, placebo-controlled studies of the addition of β-blocker to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect. β-blocker therapy in these studies was well tolerated and in addition to improved mortality, β-blocker therapy is associated with improved morbidity in terms of progressive heart failure and numbers of hospitalizations.

Initiation of β-blocker therapy in heart failure may be associated with deterioration of cardiac function in the short term. Treatment should be started at a low dose of β-blocker with slow up-titration in a number of steps over several weeks. In spite of the established benefits of ACE inhibition in patients with heart failure, this treatment is under-utilized. Part of this shortfall is due to physicians’ perceptions regarding potential unwanted effects of ACE inhibition. Perceptions regarding unwanted effects of β-adrenoceptor blocker therapy are likely to be at least as great. While β-blockade represents a welcome addition to the therapeutic armoury of physicians caring for patients with heart failure, initiation and stabilization of β-adrenoceptor blocker therapy should be undertaken under specialist supervision.

Introduction

The concept of using β-adrenoceptor blockers in the treatment of heart failure was introduced in the early 1970s. The reaction among cardiologists was generally one of extreme scepticism—β-adrenoceptor blockers were, and to an extent still are, widely regarded as contraindicated in heart failure, the failing myocardium being perceived as dependent upon increased sympathetic input for sustained function. Moreover, most physicians in hospital practice are familiar with the scenario of acute left ventricular failure developing in a patient recently commenced on a β-adrenoceptor blocker, often following acute myocardial infarction (AMI). Thus there is a commonly held belief that β-blockade is contraindicated in all patients in whom there has been even mild, transient heart failure at any time following AMI. These concerns have been extended to the treatment of patients with stable, chronic heart failure.

Over the last 20 years improvements in our understanding of the pathophysiology of heart failure have been reflected in developments in the available treatment options for what is one of the commonest chronic conditions of industrialized society. We have moved from a situation where the treatment goal was simply the relief of symptoms with diuretics and cardiac glycosides to having (theoretically) the ability to improve both mortality and morbidity as it relates to hospitalizations and to patients’ functional capacity. Heart failure is characterized by activation of both the renin-angiotensin system (RAS) and sympathetic nervous system (SNS), responses which are compensatory in the short term but have detrimental long-term effects for the myocardium. Prolonged activation of these systems leads to structural changes in the myocardium, a process of remodelling that worsens myocardial function. Further RAS and SNS activation results, setting up a vicious cycle of neuroendocrine activation. Interruption of this cycle using angiotensin converting enzyme (ACE) inhibitors improves both patients’ functional capacity and their outlook in terms of fatal and nonfatal events. Blockade of the activated SNS ought similarly to have beneficial effects.

The development of the role of ACE inhibition in the treatment of heart failure has been marked by a number of large, well conducted clinical trials in both chronic heart failure [1–3] and in heart failure following AMI [4–6]. All have shown consistent benefits in both mortality and morbidity. Thus we have available an effective treatment. Why then does the search for additional treatments continue? Firstly, it is important to realize the magnitude of the problem of heart failure. Current estimates suggest a prevalence rate of between 3 and 25 cases per 1000 population, rising to 25–130/1000 in those over 65 years [7]. Heart failure accounts for 120 000 hospitalizations and 24 000–36 000 deaths annually in the UK [8]. Secondly, the number of hospitalizations for the condition is rising [9]. Heart failure is primarily a disease of old age and the prevalence of the condition is expected to rise as the proportion of elderly subjects in the population increases. Thirdly, a significant proportion of patients with heart failure do not receive appropriate therapy for a variety of reasons [10, 11]. Finally, in spite of treatment advances, the outlook for the patient with heart failure remains bleak [11] and there is little evidence that prognosis in the community has improved [12].

Against this background, increasing recognition of the importance of SNS activation in the pathophysiology of the syndrome of heart failure has led to a gradual and increasingly enthusiastic reappraisal of the potential role of β-adrenoceptor blockers in the treatment of the condition. It is only recently with the results of recent large clinical trials that the weight of evidence in favour of a beneficial effect of β-adrenoceptor blockers in heart failure has accumulated.

The rationale for β-blockade in heart failure

Sympathetic nervous system activation plays an important role in circumstances in which an acute increase in cardiac output is required, via increased rate and force of contraction as well as peripheral vasoconstriction. It is clear that where such a response is appropriate, e.g. acute or decompensated heart failure, β-blockade would be inappropriate. Indeed in such circumstances short-term administration of β-agonist agents may be beneficial. However chronic adrenergic stimulation leads to progressive desensitization of the β-receptor signalling pathway via both β-receptor downregulation and increased β-adrenoceptor kinase activity [13] and consequently to uncoupling of the receptor from the second messenger adenylate cyclase and reduced intracellular cAMP [14]. These and numerous other changes are seen in the failing heart. While it is widely accepted that these alterations lead to reduced cardiac reserve and limitation of exercise response, debate continues as to the contribution of changes to intrinsic myocardial function in the resting state, i.e. contractile function in the absence of excess neurohormonal influences [15].

Why should the myocardium adapt with changes which result in downregulation of adrenergic signalling? The observed changes in β-receptor signal transduction in heart failure have the overall effect of protecting the myocardium from chronic sympathetic stimulation. Chronic elevation of catecholamine levels are directly toxic to the myocardium [16] and in experimental situations are associated with the development of a reversible cardiomyopathy [17] (Figure 1). The toxic effects of catecholamines on the myocardium may contribute to a number of the features of heart failure: slowed diastolic reuptake of calcium by the sarcoplasmic reticulum [18], the reduction in reuptake being related to the reduction in contractility [19]; loss of the Bowditch effect, i.e. increased force of contraction with increased rates of stimulation [20]; reduced ventricular filling times; regional sympathetic denervation resulting in wall motion abnormalities and asynchronous ventricular contraction and relaxation [21], the resultant ventricular dysfunction being attenuated by β-blockade [22]. β-adrenergic blockade is accompanied by reversal of a number of these changes including up-regulation in β-receptor expression.

Figure 1.

The postulated relationship between increased catecholamine levels, and the development of heart failure. Increased catecholamine levels have a direct toxic effect on cardiomyocytes which leads to myocardial dysfunction. Elevated catecholamine levels additionally have effects on β-receptor signal transduction which in turn leads to reduced myocardial reserve but which may also contribute to progressive myocardial dysfunction.

As has been pointed out previously [23], all positive inotropic agents other than the calcium sensitizing agents cause increased heart rate and cytoplasmic [Ca²⁺]. To date none of these agents improve, and many worsen, mortality in heart failure although some improve quality of life [24]. β-blockade in the failing heart will theoretically increase diastolic filling time, increase sarcoplasmic reticular uptake of Ca²⁺, restore the normal force-interval relationship and normal adrenoceptor signalling. Reduced β-receptor stimulation will lead to attenuated RAS activity [25]. The overall effect is likely to be one of increased cardiac efficiency. Moreover several neuroendocrine factors in addition to catecholamines and angiotensin II have been implicated in the ventricular remodelling which characterizes heart failure, among them inflammatory cytokines and oxidative stress. Generically, β-blockade may theoretically interfere with such pathways simply by improving myocardial energetics and efficiency. However specific β-adrenoceptor blockers may have ‘unique’ properties which interfere with these mechanisms, e.g. the antioxidant effect of carvedilol [26].

In man, up-regulation of β-receptor expression accompanies the improvement in ventricular function seen with the selective β₁-receptor blocker metoprolol but not that seen in response to the nonselective and vasodilating β-adrenoceptor blocker carvedilol [27]. The implication of this finding is that normalization of β-receptor signalling may not be necessary for the beneficial effect of β-adrenoceptor blockers. However, the history of the use of adrenergic agonists and other inotropic agents in heart failure is a litany of disaster in terms of mortality, which is invariably increased [28]. Thus the evidence on balance suggest changes in β-adrenoceptor signal transduction to be of relevance to the clinical syndrome of heart failure.

β-adrenoceptor blockers in chronic heart failure—historical aspects

The pre-ACE inhibitor era

The first reported use of a β-adrenoceptor blocker in heart failure was the administration of intravenous practolol to a patient with tachycardia in the context of acute pulmonary oedema secondary to cardiomyopathy [29]. A subsequent study examined the response to β-blockade in 28 patients with cardiomyopathy [30]. Left ventricular ejection fraction increased by an average of 30% and markers of both systolic and diastolic function improved. In addition, functional classification improved in 15 and remained stable in 12 patients. Withdrawal of β-adrenoceptor blockade was associated with clinical deterioration in 6 and echocardiographic deterioration in a further 9 patients, changes which were reversed on reintroduction of the β-adrenoceptor blocker [31]. The first placebo-controlled trial, a small pilot study, showed trends favouring low-dose metoprolol [32]. Two larger studies went on to examine the effects of β-blockade on mortality, the Metoprolol in Dilated Cardiomyopathy (MDC) study [33] and the Cardiac Insufficiency Bisoprolol Study (CIBIS) [34].

The MDC study examined the effect of metoprolol on mortality or the need for cardiac transplantation in 383 patients followed for at least 12 months. There was 34% risk reduction associated with metoprolol therapy, due almost entirely to reduced requirement for transplantation with no effect on overall mortality. Measures of quality of life and left ventricular ejection fraction improved and there were fewer hospital admissions or treatment withdrawals in the metoprolol group. The CIBIS study enrolled 641 patients with New York Heart Association (NYHA) functional class III and IV (i.e. moderate to severe) heart failure with a single primary end-point, mortality. Bisoprolol treatment was associated with a nonsignificant 20% reduction in mortality. Once again, functional class was improved and hospitalizations reduced. Retrospective subgroup analysis suggested that the reduction in mortality was greater for those patients whose cardiomyopathy was of nonischaemic origin. However this conclusion is at odds with evidence from studies of β-adrenoceptor blockers post MI, in which these agents reduce mortality in heart failure secondary to coronary artery disease [35].

β-adrenoceptor blocker trials in the ACE inhibitor era

Both MDC and CIBIS were conducted in the pre-ACE inhibitor era. While these trials suggested that β-adrenoceptor blockers are at least safe in heart failure, both trials were equivocal in terms of effects on mortality and did not convince the majority of cardiologists to use β-adrenoceptor blockers in routine clinical practice. Recent years have seen several large studies of β-adrenoceptor blockers in cohorts of patients receiving what would be regarded as ‘optimal’ heart failure treatment, i.e. diuretic and ACE inhibitor, ±digoxin. Interest in these studies has been heightened by advances in drug development and the availability of ‘new’ agents with mixed β-adrenergic and α-adrenergic (and hence vasodilating) activity. A number of studies have now reported, all of which indicate that there is indeed a place for β-adrenoceptor blockers in the treatment of heart failure.

The effect of the nonselective, vasodilating β-adrenoceptor blocker carvedilol was investigated in two large clinical trials. The US Carvedilol Heart Failure Trials Programme recruited 1094 patients, with heart failure of various aetiologies, to receive placebo or carvedilol with follow-up for 7–15 months [36]. The overall mortality rate with carvedilol (target dose 50–100 mg per day) was 3.2%, compared with 7.8% with placebo, a 65% reduction in the risk of death which reflected reductions in both sudden death and death from progressive heart failure. Moreover, carvedilol treatment was associated with a 27% reduction in the risk of hospitalization. Over the study as a whole 7.8% of the placebo group and 5.7% of the carvedilol group discontinued study medication due to adverse reactions. Similar results were seen in the parallel Australia/New Zealand Heart Failure Research Collaborative Group Trial [37]. In this study, carvedilol (target dose 50 mg per day) or placebo was added to standard therapy in 415 patients with ischaemic cardiomyopathy who were followed for 18–24 months. Carvedilol treatment was associated with a 25% reduction in mortality and 26% reduction combined end-point of death and hospitalization.

What of the selective β-adrenergic receptor antagonists? The data for these agents are at least as convincing as that from the studies with carvedilol. The second Cardiac Insufficiency Bisoprolol Study (CIBIS II) and The Metoprolol Randomised Intervention Trial in Heart Failure (MERIT-HF) together represent the largest randomised trials of β-adrenoceptor blockers, and indeed two of the largest treatment trials of any agent, yet conducted in heart failure. CIBIS-II examined the effect of the selective β₁-receptor antagonist bisoprolol or placebo on all-cause mortality in 2647 symptomatic patients with stable, moderate to severe (NYHA Class III or IV) heart failure. The study was stopped early following the second interim data analysis [38]. Bisoprolol was associated with improvements in all-cause mortality (11.8% vs 17.3% placebo, P < 0.0001), cardiovascular deaths (P = 0.0049), all-cause hospitalization (P = 0.0006), and hospitalization for worsening heart failure (P < 0.0001) (Figure 2). Interestingly, the target dose of 10 mg bisoprolol per day was reached in 42% of patients randomised to active treatment, 7.5 mg daily in a further 11% and 5 mg daily in 13%. CIBIS-II was unable to demonstrate any difference in treatment efficacy based upon the aetiology of heart failure.

Figure 2.

Cumulative survival curves according to treatment with bisoprolol or placebo in the CIBIS-II study. (Reproduced from [38] with permission. © The Lancet 1999).

Similarly the Metoprolol Randomised Intervention Trial in Heart Failure (MERIT-HF) study was terminated early due to the finding of a strong beneficial effect of the β-adrenoceptor blocker, in this case a long acting formulation of the β₁-selective agent metoprolol [39]. The study objectives were to examine the effect of metoprolol on total mortality and on the combined end-point of all-cause mortality and hospitalization. The study recruited 3991 patients with symptomatic heart failure and left ventricular ejection fraction ≤40%. Metoprolol was initiated at a dose of 12.5 mg or 25 mg once daily and titrated to a maximum of 200 mg once daily on four or five steps over 8 weeks. Metoprolol reduced all cause mortality by 35% and there was also a reduction in the combined end-point of mortality and hospitalization.

One recent β-adrenoceptor blocker trial has shown a disappointing result. The BEST trial using bucindolol has very recently been terminated prematurely on the advice of the safety monitoring board. This decision was made due to there being no apparent benefit of bucindolol on survival rather than any harmful effect. Further details of this trial are awaited but the patient population, primarily NYHA III and IV heart failure, may explain the apparently incongruous result. The results of additional trials in this area are awaited: COMET (carvedilol compared with metoprolol) and COPERNICUS (carvedilol in NYHA IV heart failure).

β-adrenoceptor blockers in heart failure following MI

There is good evidence supporting a beneficial effect from early intravenous β-blockade and long-term oral β-blockade after MI [40, 41]. In spite of the unequivocal evidence of their beneficial effects on mortality, the use of β-adrenoceptor blockers post MI varies markedly. A recent study in 11 European countries revealed differences among countries in terms of the use of iv (0.5%–54%) and oral (34%–77%) β-blockade after MI [42]. The estimated shortfall in β-adrenoceptor blocker use, i.e. that proportion of patients with no evident contraindication but discharged not taking a β-adrenoceptor blocker was 20% overall with a range of 6–38% among countries.

The circumstance in which a physician finds a patient in acute left ventricular failure soon after the initiation of β-adrenoceptor blocker therapy is most pertinent to the patient who has recently suffered AMI. The growing appreciation of the role of ACE inhibitors in patients with clinical evidence of heart failure after MI has led to the current position in which many physicians make a choice, i.e. ACE inhibitor for the patient with any sign of heart failure, β-adrenoceptor blocker for the patient without such evidence. The evidence for this being the correct course of action is lacking, but equally there are as yet no completed trials of β-adrenoceptor blockers following MI in the thrombolytic, ACE inhibitor era. The results of ongoing studies, such as the CAPRICORN study with carvedilol are awaited. For the moment we will review the data from previous studies and from the trials of ACE inhibitors in heart failure.

The Beta-adrenoceptor blocker Heart Attack Trial (BHAT) studied the effect of oral propranolol or placebo commenced from 5 to 21 days after MI. Nearly 4000 patients were enrolled and followed up for 2–4 years. Propranolol was associated with beneficial effects on both mortality [43] and morbidity [44]. Interestingly, the benefits were greater in those patients with evidence of heart failure at the time of randomization. Total mortality in patients with heart failure was 13.3% for propranolol, 18.4% for placebo, a relative risk reduction of 27%. For those without heart failure the figures were 5.9% and 7.8% for propranolol and placebo, respectively, a risk reduction of 25%. The risk reductions in terms of sudden death (47% in those with heart failure, 13% in those without) and cardiovascular mortality (32% in those with heart failure, 21% in those without) were relatively greater for patients with heart failure. Once again β-adrenoceptor blocker treatment was well tolerated, with 7% of patients in each treatment arm developing heart failure. Withdrawals due to heart failure were greater in the propranolol group (4.3% compared with 1.6% for placebo) but only in those patients with a prior history of heart failure [44]. The Metoprolol in Acute Myocardial Infarction [MIAMI] trial [45] also demonstrated a clear early benefit of oral β-blockade once again with the most dramatic effect in patients with heart failure.

Although no formal trial has compared the combination of β-adrenoceptor blocker plus ACE inhibitor to ACE inhibitor alone, either in chronic heart failure or in heart failure after AMI, it is interesting to look at the data from some of ACE inhibitor trials. In TRACE [6] the relative risk reduction seen with trandolapril was greater in those patients taking a β-adrenoceptor blocker (Table 1). In SAVE a retrospective subgroup analysis indicated that coadministration of a β-adrenoceptor blocker with captopril was associated with 26% reduction in 1-year mortality, 30% reduction in mortality over the trial as a whole, and 21% reduction in the incidence of severe heart failure [46]. Similar findings have recently been published from the AIRE study, in which coadministration of a β-adrenoceptor blocker with ramipril was associated with a reduction in risk of death of over 30% and of severe or resistant heart failure of over 40% [47]. This was true for patients with transient clinical evidence of heart failure and those higher risk patients with persisting signs. (Figure 3). None of the ACE inhibitor studies was designed to investigate the hypothesis that the combination of β-adrenoceptor blocker plus ACE inhibitor is superior to ACE inhibitor alone. Nonetheless, as in chronic heart failure, these studies are consistent in indicating an added benefit from β-blockade in addition to ACE inhibition following MI.

Table 1.

Deaths during the TRACE study [6] according to treatment with or without β-adrenoceptor blocker. 95% CI = 95% confidence intervals.

Figure 3.

Cumulative survival curves according to β-adrenoceptor blocker treatment in patients with transient heart failure (–––) or persistent heart failure (—–) in the AIRE study. (Reproduced from [47] with permission. © BMJ Publishing Group 1999).

β-adrenoceptor blocker for heart failure—who, when, how and how much?

The evidence for the beneficial effect of β-blockade in heart failure is now overwhelming. However the prospect of commencing β-adrenoceptor blocker therapy in these patients is one which will be viewed with some trepidation by many physicians, particularly nonspecialists. Comments made following trials of new therapies include the remark that the patients included in the trials are not representative of those met in everyday practice: for example the elderly and those with serious concomitant illnesses are common in the latter and rather less so in the former. To some extent these criticisms are valid. For instance few patients over 75 years of age were included in the major ACE inhibitor trials yet such individuals constitute a large proportion of the heart failure population (48). Further to this, there is good evidence that a significant proportion of patients with heart failure do not currently receive an ACE inhibitor (11, 49). At least part of this shortfall can be attributed to physicians’ perceptions regarding the potential adverse effects of ACE inhibition (49). If this is the current status of a therapy with which the majority of physicians have considerable experience, then can we expect them to accept a change in their practice which involves a treatment which until now has been perceived as contraindicated? Moreover most patients with heart failure are not under the care of cardiologists or physicians with particular interest and experience in this area. The uptake of such a change in practice is likely to be slow.

Each of the recently reported studies of β-blockade in chronic heart failure is characterized by (1) the inclusion of patients with primarily mild to moderate heart failure; (2) the inclusion of patients with ‘stable’ heart failure and (3) a slow dose-titration procedure.

Mild to moderate heart failure

The vast majority of the patients included in the recent β-adrenoceptor blocker trials had ‘mild to moderate’ heart failure, i.e. NYHA functional class II and III symptoms. This refers to their functional capacity and the patients were by and large ambulant and self-caring. Those with the most severe restriction of activities of daily living were a minority in CIBIS II (17%) and in the US carvedilol programme (19%). It should be remembered that levels of impairment of functional capacity and of left ventricular function are poorly correlated. Thus the finding of severe impairment of ventricular function on echocardiography should not in itself prevent the physician from considering β-adrenoceptor blocker therapy.

It is of note however, that in CIBIS-II, although the relative risk of death in patients receiving bisoprolol did not differ according to disease severity at baseline, the confidence intervals for the group with NYHA IV include a relative risk of 1. The US Carvedilol study included very few patients with NYHA IV and this study did not report the effect of therapy according to NYHA class. The study does however, report that benefit was similar irrespective of left ventricular ejection fraction. To date there is insufficient experience with β-adrenoceptor blockers in patients with severe symptoms to recommend their routine use in this group and β-blockade should certainly be initiated under specialist supervision in these patients.

‘Stable’ heart failure

Heart failure is a condition of relapse and remission, the latter usually coming about in response to a change in treatment. As discussed previously, at times of decompensation the failing heart is likely to be dependent on increased adrenergic input and β-blockade may be detrimental. Concomitant cardiovascular therapy in both CIBIS II and MERIT-HF were unchanged for 2 weeks prior to initiation of β-adrenoceptor blocker. Stability in terms of functional status and symptoms was also required. In clinical practice this translates into maximizing the patient's clinical condition prior to initiation of β-blockade—the patient should be free of signs of cardiac decompensation, i.e. elevated JVP, pulmonary rales or oedema, peripheral oedema, resting tachycardia. In addition they should be taking an appropriate dose of ACE inhibitor and diuretic. Patients intolerant of ACE inhibitor should be taking another effective vasodilator regimen, ideally the combination of nitrate and hydrallazine.

Slow dose-titration

Physicians wish to see their patients stabilized on therapeutic doses of a recently prescribed medication as quickly as possible. Experience with β-adrenoceptor blockers in the past has suggested that sudden inhibition of adrenergic input to the myocardium can be detrimental and even catastrophic. Each of the recent studies has employed a regimen of initiation β-blockade at a low dose with subsequent slow dose titration: CIBIS II commenced bisoprolol at 1.25 mg for 2 weeks with incremental steps to 2.5 mg and 3.75 mg each for 2 weeks and to 5 mg and 7.5 mg for 4 weeks each before the final step to 10 mg daily; MERIT-HF commenced metoprolol CR/XL at 12.5 or 25 mg (depending upon functional class) with incremental steps to 25, 50, 100 and 200 mg daily over a total of 8 weeks; the US carvedilol programme initiated therapy with an open-label phase of carvedilol 6.25 mg twice daily for two weeks, increasing if tolerated at this stage to 12.5, 25 and 50 mg, each twice daily, over 2–10 weeks.

This type of regimen has implications for both patient and physician. It implies a requirement to review the patient at regular intervals over a fairly short time. This may lead to the patient being initiated and remaining on low dose therapy, a scenario familiar to physicians who initiate ACE inhibitors in hospital and intend up-titration to occur in the community. On the other hand, a regimen of slow dose titration can allow the physician time to alter and amend concomitant treatments, including diuretics, in the face of changes in patient status. This leads us to the question of what to do if the patient shows signs of decompensated heart failure after commencement of β-adrenoceptor blocker. In each of the studies discussed above, treatment withdrawal due to worsening heart failure was very infrequent, in particular in patients receiving active therapy. However the studies do not report the incidence of the requirement for alteration of concomitant medication during dose-titration. In all of the studies the recommendation was made that in the event of the patient developing signs of cardiac decompensation following initiation of therapy, concomitant medications ought to be titrated before the dose of β-adrenoceptor blocker was reduced or therapy withdrawn. This would indeed be reasonable as far as diuretics are concerned but it should be emphasized that the dose of ACE inhibitor should not be reduced to allow that of β-adrenoceptor blocker to be increased.

Finally, how much β-adrenoceptor blocker should we give? As with the ACE inhibitors, we ought to aim for the maximum tolerated dose within the schedule utilized in the relevant clinical trial. This would be 10 mg once daily for bisoprolol, 200 mg once daily for metoprolol CR/XL and 50 mg twice daily for carvedilol (US Trial). The median dose of each agent was 45 mg daily of carvedilol in the US trial, and 10 mg daily for bisoprolol. The mean daily dose of metoprolol CR/XL in the MERIT-HF trial was 159 mg. There is no data to suggest superiority of any one β-adrenoceptor blocker.

Overall we suggest that β-blockade should be initiated under the care of individual physicians with an interest in heart failure and experience in the use of β-adrenoceptor blockers in this condition. These may or may not be cardiologists. For the time being it is not recommended that β-blockade is initiated in primary care. Such recommendations imply the necessity for patients with heart failure to be identified and assessed for the appropriateness of β-blockade. This has implications for all physicians to actively seek to identify individual patients. Specialist heart failure clinics are becoming more common and represent an appropriate environment for assessment of the patient both prior to and after initiation of therapy. It is our own experience that specialist nurses are invaluable in this respect. As with ACE inhibitors it is likely that the initiation and titration of β-adrenoceptor blocker therapy will become more generalized with time.

The early days of ACE inhibitor treatment saw patients being admitted to hospital for initiation of therapy. None of the studies of β-blockade in heart failure had this as a requirement. However a short observation period following each dose titration is advisable—this may again be perceived as a difficulty and a reason not to up-titrate the dose of drug. Similarly, exacerbations of heart failure may occur during which temporary withdrawal of β-adrenoceptor blocker may be indicated. Physicians active in this area will have to make provision for these requirements.

Conclusions

The case for a beneficial effect of β-blockade in patients with stable, chronic heart failure is now established. The available data pertains largely to patients with (symptomatically) mild to moderate heart failure. With the exception of the BEST study, each of the studies reported to date has shown benefit in terms of morbidity and mortality. Initiation and maintenance of β-adrenoceptor blocker in heart failure presents logistical and management problems. However for a large proportion of patients with heart failure, β-blockade is now indicated and physicians looking after such patients should strive to initiate therapy in as many as possible. This can be done in an out-patient setting but does require regular review during dose titration. β-adrenoceptor blockers are to the specialist a welcome addition to the armoury of medications available for the treatment of patients with heart failure. Innovative concepts regarding the treatment of this important condition are spreading from the use of treatments previously thought unusable to the provision of appropriate services in the form of specialist clinics and nurses. Whether or not the convincing results of a number of large, well conducted β-adrenoceptor blocker trials are translated into clinical practice remains to be seen.