Beta-blockers in congestive heart failure

Professor Finn Waagstein
Professor of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden

It has been known for almost 20 years that beta-blockers improve survival as secondary prevention after acute myocardial infarction and in hypertension.[1–4] Post hoc analyses have shown that patients with either large infarcts and compromised left ventricular function or with clinical signs of congestive heart failure during the acute stage of disease are those who benefit most from secondary prevention with beta-blockers.[5,6]
Our first uncontrolled studies with beta-blockers in dilated cardiomyopathy suggested a very positive effect on both symptoms and left ventricular systolic and diastolic function.[7–9] Despite these observations it has been very difficult to carry out trials of sufficient size to conclusively prove the value of beta-blockers in congestive heart failure. One important reason is the difficulty in acceptance of the concept that congestive heart failure should be treated with drugs which suppress contractility when the prevailing treatment has focused on inotropic drugs. Another reason is the fact that in most patients there is a transient depression of cardiac function during initiation of beta-blocker treatment[10] as well as an increase in heart failure symptoms. However, since a conclusive evaluation of inotropic and potent vasodilators showed that their beneficial effect is only temporary and that the long-term effects are harmful with regard to both morbidity and mortality, it has been easier to stimulate renewed interest in beta-blockers in heart failure.[11]
Moreover, longitudinal studies of neuroendocrine activation in heart failure have shown the strong predictive value of catecholamines for mortality and that serum catecholamine concentration is only marginally affected by treatment with angiotensin-converting enzyme (ACE) inhibitors.

Possible mechanisms of action of beta-blockers
At present we are far from knowing why beta-blockers are so effective in congestive heart failure. It is believed that complex mechanisms are involved which include direct haemodynamic effects on heart rate and blood pressure mediated through blockade of beta-adrenergic cardiac receptors, but also through blockade of the central nervous system receptors thereby decreasing sympathetic outflow to the heart, kidney, immune system and peripheral muscles, as well as interaction between catecholamines and other neurohormones such as renin, endothelin and atrial natriuretic peptide. Table 1 shows the possible mechanisms of action of beta-blockers and Table 2 describes the findings after long-term beta-blockade.

Table 1. Possible mechanisms of action of beta-blockers in congestive heart failure.
Table 2. Proven long-term effects of beta-blockers in congestive heart failure.

Clinical effects of beta-blockers
The earliest uncontrolled beta-blocker studies in dilated cardiomyopathy, which often showed dramatic improvement in patients from New York Heart Association (NYHA) class IV to class I, were strongly criticized. One argument countered that the selected population had acute-phase tachycardia and that, given that there was no placebo group, it could not be shown that these patients would not have improved spontaneously. Later studies of cardiac function after withdrawal of beta-blockade showed, however, a consistent pattern of deterioration followed by improvement when treatment was reinstituted.[10,15] The Metoprolol in Dilated Cardiomyopathy (MDC) trial confirmed that there was an improvement in the placebo group but that it was significantly less than that seen in the beta-blocker group.[16] A consistent pattern in most trials was that treatment for at least 3 months was required in order to achieve significant improvement in left ventricular systolic function which could last for at least 12 months, particularly in patients with very poor systolic function.[16]

Tolerability of beta-blockers
When beta-blockers are titrated slowly over 6–12 weeks, starting with doses <10% of the target dose, an excellent tolerability is achieved expressed as a low withdrawal rate during the titration period, which does not differ from that of placebo. The early placebo-controlled studies had an open run-in period of 2–14 days with active drug, excluding those who did not tolerate beta-blockers and consequently had very low withdrawal rates during titration.[16,17] Later studies with no run-in period such as the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II),[18] or with a placebo run-in such as the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF),[19] had a withdrawal rate of around 15%, which did not differ from that of placebo.
If one looks specifically at the risk of developing heart failure there was a strong trend towards less heart failure in the beta-blocker group. Bradycardia, hypotension and dizziness occurred more often in the beta-blocker group but in absolute values affected only about 1% of cases. Those complications should be considered less serious than the increased incidence of worsening heart failure seen in the placebo group.
The rate of complications was highest in NYHA class IV patients in whom hospitalization for heart failure was somewhat higher than in the placebo group during titration of beta-blockers. The total number of hospitalizations in this group over the whole study period was, however, similar to that of the placebo group and there was a trend in both the CIBIS-II and MERIT-HF trials to lower mortality in the beta-blocker groups. The proportion of patients in NYHA class IV is generally low in most trials. Except for the CIBIS-II trial which had 17% of NYHA class IV patients, the proportion is usually <5%. This implies that a large proportion of NYHA class IV patients are excluded from these trials because they are judged unable to tolerate beta-blockers, probably due to the fact that it has not been possible to stabilize them with conventional heart failure treatment with diuretics, ACE inhibitors and digoxin. Patients excluded from beta-blocker treatment often have low blood pressure and more advanced signs of organ failure. Based on evidence from controlled trials we therefore cannot give a general recommendation to treat patients in NYHA class IV with beta-blockers. These patients should be referred for evaluation to specialists with experience in treating patients with beta-blockers. In the right hands, some patients make a remarkable recovery.

Dose-effect relationship
A linear relation between the final dose and improvement in ejection fraction and mortality was found in a prospective study of carvedilol in heart failure. It has to be emphasized, however, that a less favourable response may be seen in patients who cannot tolerate a high beta-blocker dose. It can therefore not be concluded that the beta-blocker dose is the only factor which decides the response. In later trials there have been attempts to reach the highest possible tolerated dose which gives a high degree of beta-blockade. For example, in the CIBIS-II trial the target dose was twice that of the CIBIS-I trial and in the MERIT-HF trial the target dose was one-third higher than that of the MDC trial.

Importance of baseline heart rate and decrease in heart rate
Since the early studies with beta-blockers included patients with tachycardia the prevailing opinion was that (1) patients with tachycardia had a better response than patients with a normal or a low heart rate and that (2) the degree of improvement was related to the degree of reduction of heart rate. Analyses of the CIBIS-I trial with bisoprolol showed, however, no consistent pattern on which to base this assumption.[21] In the MERIT-HF Trial19 there was no difference in survival between those in the lowest tertile for heart rate and those in the highest two tertiles for heart rate. This finding suggests that mechanisms other than reduction in heart rate play an important role for improved survival.

Role of heart failure aetiology
For a long time it was believed that improvement could only be achieved in patients with dilated cardiomyopathy. A contributing factor to this belief was that more dramatic improvement could be achieved in dilated cardiomyopathy because treatment with beta-blockers was started at the same time as ACE inhibitors and it was thought that it might have been a myocarditis which healed during the treatment period. The first patients with ischaemic cardiomyopathy who had been treated with beta-blockers already had irreversible damage caused by an infarction and therefore did not have the same potential for improvement compared with the patients with dilated cardiomyopathy.[22] Later studies confirmed that patients in the beta-blocker group with less pronounced damage often improved significantly while patients in the placebo group remained unchanged.[23] Later studies also showed that there is no difference in survival between ischaemic and non-ischaemic heart failure,[8,19] which is in agreement with the post hoc analyses of secondary prophylaxis after myocardial infarction in subgroups with heart failure or impaired left ventricular function.[2,3,6]

Combined treatment of heart failure
There was no combined treatment with ACE inhibitors in the early beta-blocker studies, which shows that patients can be improved by beta-blockers alone. A direct comparison between captopril and metoprolol in dilated cardiomyopathy showed that metoprolol caused a more marked improvement in left ventricular function.24 In the MDC trial, on the other hand, ejection fraction was increased when the beta-blocker was combined with ACE inhibitors compared with metoprolol alone. It cannot be assessed from this study whether this was due to the fact that ACE inhibitors were given only to patients with more serious failure or whether treatment with ACE inhibitors was just a matter of chance. A prospective, randomized study is needed to answer this question.
The same argument applies for combined treatment with digoxin. Even if digoxin was shown to reduce morbidity and mortality from heart failure in the DIG study, one cannot draw the conclusion that combined treatment is to be preferred. Ad hoc analyses from studies with carvedilol imply reduced morbidity and mortality when treatment was combined with digoxin compared with carvedilol alone.[25] Again, however, this interpretation may be criticized since there is no guarantee that the risk profile was identical in the two treatment groups. A prospective, randomized study is therefore required.
Should treatment be combined with spironolactone in NYHA groups III and IV? This question may possibly be answered after a thorough analysis of the Randomized Aldactone Evaluation Study.[26] Even if this seems to be the case, since the mechanisms will differ from that of ACE inhibitors and beta-blockers, one has to perform a prospective, randomized study to answer the question correctly and to obtain a measure of the possible gain in mortality reduction by the combined treatment.

Treatment of NYHA class IV patients with beta-blockade
In all the reported studies there have been few patients in NYHA class IV (<5%), which means that many NYHA class IV patients are judged to be unable to tolerate beta-blockade since they have not been stabilized by conventional treatment with diuretics, ACE inhibitors and digoxin. Such patients have often proven to have very low blood pressure and signs of organ failure.
A nominal reduction in deaths was seen in the treatment groups in both the CIBIS-II and the MERIT-HF trials, but this reduction is not significant even when the data from both studies are pooled. Thus, based on these studies one cannot issue a general treatment recommendation since considerable experience will be needed to master any complication that might be caused by the treatment. An ongoing trial with captopril given to these patients might be able to answer this question. At present it is not possible to issue a general recommendation that NYHA class patients should be treated with beta-blockers. These patients should be taken care of by specialists with experience in beta-blockade.
A possible alternative use of beta-blocker treatment in this group of seriously ill patients was proposed by the Bristow group.[27] These investigators stabilized patients who were unable to tolerate beta-blockade using the phosphodiesterase inhibitor enoximone. They claimed to have successfully enabled patients to tolerate metoprolol after slow down-titration of enoximone treatment.[27] This alternative treatment must, however, be tested in a randomized study.

Difference in effect between beta-blockers
A great number of beta-blockers have been shown to improve myocardial function (Table 3): beta1-selective blockers with various degrees of selectivity, unselective beta-blockers, beta-blockers with a certain degree of intrinsic activity and beta-blockers with vasodilatory activity. 

Table 3. Beta-blockers proven to improve ejection fraction in chronic heart failure.

Beta-blockers with marked intrinsic activity have been shown to worsen survival despite improvement in heart function.[28] There are only a few studies in which different beta-blockers were directly compared and no significant differences in effect on ejection fraction were seen. The problem with these direct studies is that one cannot be sure whether equipotent doses were given. There is a dose-dependent effect on heart function, morbidity and survival. Some of the new beta-blockers, the so-called third generation beta-blockers, have been shown in experimental studies to differ in antioxidative capacity from the first and second generation beta-blockers. It is therefore argued that the third generation beta-blockers are better at counteracting ischaemic cell death and apoptosis in humans. More recent direct comparisons of the antioxidative effect in humans cannot, however, confirm that such differences exist.[13] It has also been stated that blockade of both beta1- and beta2-receptors at the same time would give better protection against sudden cardiac death than beta1receptor blockade alone. The two large studies, CIBIS-II and MERIT-HF, using selective beta-blockers, demonstrated a marked effect on sudden cardiac death; a prospective, randomized study of carvedilol, using death as a predefined endpoint, needs to be performed. A third study using a third generation unselective dilated beta-blocker, bucindolol, has been stopped prematurely without reaching a conclusion regarding its effect on survival.
In an ongoing survival study which directly compares carvedilol and metoprolol, it is hoped that the differences in effect will be elucidated. Unfortunately, in this study a lower dose of short-acting metoprolol has been used as a target dose compared with that used in earlier studies. The calculated median target dose may be as low as 50% of the total dose of 159 mg of slow-release metoprolol used in the MERIT-HF study. One can therefore question whether the two beta-blockers have been given in equipotent doses.

Supplementary therapy in those at high risk of arrhythmias
Even if beta-blockers markedly diminish the risk of sudden cardiac death they do not entirely eliminate it. Amiodarone has been suggested as an alternative. Placebo-controlled studies on amiodarone have not, however, shown clear-cut positive effects on total mortality even if death from arrhythmia is reduced. A meta-analysis demonstrated 10% reduced mortality,[29] the most marked effect being in patients simultaneously treated with beta-blockade. ICD-30, which causes a more marked decrease in mortality in high-risk patients compared with beta-blockers and treatment with amiodarone, should therefore be used as a supplementary treatment in selected populations.

Table 4. Comparison between the two survival studies, CIBIS-II[18] and MERIT-HF.[19]

Effects on survival
There are presently two large placebo-controlled studies using the predefined primary endpoints of ‘death’ and ‘combined death and hospitalization’ (Table 4, Figures 1–4). These two studies correlate surprisingly well with regard to effect and tolerability despite the fact that the CIBIS-II trial, which included only NYHA class III and IV patients, demonstrated approximately 50% higher placebo mortality than the MERIT-HF trial.

Figure 1. Subgroup mortality in the CIBIS-II trial.[18] DCM, dilated cardiomyopathy. EF, ejection fraction; MI, myocardial infarction; HR, heart rate; BP, blood pressure.

Figure 3. Kaplan-Meier survival curve in the CIBIS-II trial.[18]
Figure 4. Kaplan-Meier survival curve in the MERIT-HF trial.[19]

Comparable effects were seen in the different NYHA functional classes, in ischaemic and non-ischaemic heart failure and between different age groups in both the CIBIS-II and the MERIT-HF trials. The MERIT-HF trial demonstrated an effect on mortality that was independent of baseline blood pressure, heart rate and ejection fraction. The most impressive findings in both trials were the great number of sudden cardiac deaths in NYHA functional classes II and III and the marked effect on sudden death. This emphasizes the fact that ACE inhibitors alone do not provide sufficient protection against sudden cardiac death and it confirms the great effect on sudden death which has been previously demonstrated in post-infarction trials using beta-blockers. It should be stressed that none of these heart failure studies should be considered as post-infarction studies since, for example, only 14% of the infarct patients in the MERIT-HF trial were included within 6 months of an acute myocardial infarction.

Conclusion
More than 6600 patients with heart failure treated with beta-blockers or placebo have clearly demonstrated that beta-blockade as a supplement to ACE inhibitors or angiotensin I receptor blockade should be standard treatment of heart failure in patients with depressed systolic left ventricular function <0.40. This combination of treatment can achieve a 34% reduction in total mortality. Tolerance is excellent since there is no difference in withdrawal rate from placebo and the number of readmissions for heart failure is significantly reduced.

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