Beta-blockers in chronic heart failure: What have we learned? What do we still need to know?

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Abstract

Current heart failure guidelines mandate the use of β-blockers in patients with symptomatic systolic heart failure. In the past 12–18 months, there have been several reported advances in our understanding of β-blocker therapy for heart failure. Despite these advances, there remain several unanswered questions with regard to β-blockers. These involve, firstly, clarifying the underlying mechanisms of action of β-blockers; secondly, further analysing patients with systolic heart failure who are not well-studied in major clinical trials (e.g. the elderly); thirdly, investigating unexplored indications for β-blockers in heart failure; and finally, directly examining the clinical relevance of pharmacological differences among agents. The impact of genetic polymorphisms on the response to β-blocker therapy, as well as interaction of these agents with future heart failure therapies, requires extensive investigation.

Introduction

The use of β-blockers for the treatment of chronic heart failure (CHF) has quite literally been a revolution in pharmacological therapy for this condition. These agents had long been contraindicated in the treatment of patients with systolic heart failure, the clinical consequence of impaired myocardial contractile function. However, in the late 1970s and early 1980s, Swedish researchers tested the hypothesis that blockade of chronic sympathetic activation might, in fact, be beneficial in this setting. Decades later, we now have an extensive clinical trials database demonstrating the benefit of these agents in improving prognosis, reducing hospitalisation and, particularly in more severe cases, relieving symptoms (Table 1). This database of placebo-controlled β-blocker trials in CHF is now more extensive than that for angiotensin-converting enzyme (ACE) inhibitors, which are widely accepted as standard therapy for heart failure. The robustness of this data is reflected within current heart failure guidelines, which mandate the use of β-blockers (if tolerated) in patients with mild, moderate and severe symptoms of systolic heart failure, provided the patient has been stabilised and rendered euvolemic (i.e. normal volume status restored).

This review focuses on reported advances in our understanding of β-blocker therapy for CHF. The question is also posed as to what further research is required both to provide additional mechanistic insight into the beneficial effects of these agents and to fill in the remaining gaps in the clinical trials database of β-blockers in this setting.

Section snippets

Sub-group analysis of major heart failure trials

Although there have been no major β-blocker CHF trials published in the past 12–18 months, additional insight has been gained from sub-group analysis of recent large-scale heart failure trials (Table 1). In many cases, these were predefined sub-group analyses, although some post-hoc analyses have also been performed. Sub-group analysis must be interpreted with considerable caution, as patients are generally not randomised within these sub-groups. Nevertheless, these analyses do have the

What do we still need to know?

Despite overwhelming evidence in support of the clinical efficacy of β-blockers in CHF, together with the most recent advances in data (as presented above), there still remain significant gaps in our knowledge of these agents. Thus, there is a clear need for ongoing research to address unanswered questions and to tease out the mechanisms of benefit of β-blockers to better direct therapies in the future.

Conclusions

β-blockers have been a major advance in the pharmacological management of the heart failure patient, and are a tribute to the persistence and mechanistic mind-thought of an early group of Swedish pioneers. They have, however, been slow to be embraced by physicians, particularly because of the ‘baggage’ of the past regarding perceived contraindications in this setting. Furthermore, there remain fears surrounding the tolerability and adverse effects of initiation of these agents, which have

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

References (46)

  • P. Lechat et al.

    Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial

    Circulation

    (2001)
  • J. Wikstrand et al.

    Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomised intervention trial in chronic heart failure (MERIT-HF)

    J. Am. Coll. Cardiol.

    (2002)
  • M.P. Tendera et al.

    Effect of gender on the outcome of patients with severe heart failure treated with carvedilol: results of the COPERNICUS study

    J. Am. Coll. Cardiol.

    (2002)
  • H. Krum et al.

    Impact of additional neurohormonal (NH) antagonism in severe CHF patients already receiving a combination of NH antagonists in COPERNICUS

    Eur. Heart J.

    (2002)
  • P.C. Deedwania et al.

    Efficacy and tolerability of treatment with metoprolol CR/XL in elderly patients with heart failure

    Circulation

    (2001)
  • C.W. Yancy et al.

    Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure

    N. Engl. J. Med.

    (2001)
  • P. Carson et al.

    Effect of carvedilol in black patients with severe chronic heart failure: results of the COPERNICUS study

    Circulation

    (2001)
  • P. Mohacsi et al.

    Should physicians avoid the use of beta-blockers in patients with heart failure who have diabetes? Results of the COPERNICUS study

    Circulation

    (2001)
  • M. Domanski et al.

    The effect of bucindolol in diabetic and non-diabetic patients with advanced heart failure

    Circulation

    (2001)
  • S.S. Gottlieb et al.

    Tolerability of beta-blocker initiation and titration in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)

    Circulation

    (2002)
  • S.S. Gottlieb et al.

    MERIT-HF: tolerability of β-blocker initiation in NYHA II, III, & IV CHF [abstract]

    Circulation

    (2000)
  • H. Krum et al.

    Effect of carvedilol on clinical status early following initiation of therapy in patients with severe chronic heart failure: results of the COPERNICUS study [abstract]

    J. Am. Coll. Cardiol.

    (2002)
  • A. Coletta et al.

    Clinical trials update: highlights of the scientific sessions of The American College of Cardiology 2002: LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL

    Eur. J. Heart Fail.

    (2002)
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