New concepts in managing patients with chronic heart failure: the evolving importance of beta-blockade
* Corresponding author. Tel: +33 1 42 16 16 82; fax: +33 01 42 16 16 88. E-mail address: philippe.lechat{at}psl.ap-hop-paris.fr
The publication of the results of the Cardiac Insufficiency Bisoprolol Study III (CIBIS III) in September 20051,2 marked a turning point in the practical treatment of chronic heart failure (CHF). Up to that point, physicians had no evidence on which to base their treatment strategy; ACE-inhibitor first or beta-blocker first. The only reason for the sequence of medication in current guidelines,3 i.e. an ACE-inhibitor first, is the history of the major beta-blocker trials in CHF, all of which were conducted in patients already receiving standard treatment with ACE-inhibitors and diuretics.
For the first time, CIBIS III showed that starting treatment of stable, mild-to-moderate CHF with a beta-blocker (bisoprolol), followed by the addition of an ACE-inhibitor (enalapril), is as effective and safe as starting with an ACE-inhibitor. The two strategies are clinically comparable. Moreover, a beta-blocker-first strategy may reduce the risk of death, especially in the first year of treatment. CIBIS III challenges the current assumption that treatment of CHF should begin with an ACE-inhibitor followed by a beta-blocker and suggests that physicians should now be free to choose between starting with a beta-blocker or an ACE-inhibitor, according to their clinical judgement in individual patients.
It was with the landmark findings of CIBIS III in mind that the Fourth International CHF Symposium was held in Sorrento on 26 November 2005, and entitled New concepts in managing patients with chronic heart failure: the evolving importance of beta-blockade. The symposium, which was sponsored by Merck, provided a comprehensive overview of the history of beta-blockers in CHF, current knowledge regarding their mode of action, and the findings of the key clinical trials. These trials shifted physicians' perceptions of beta-blockers from contra-indicated agents to an indispensable component of modern CHF management. The reasons for the underprescription of beta-blockers in CHF in Europe were discussed, with some suggestions on how their benefits could be extended to a greater number and wider spectrum of patients. This set the scene for an examination of the rationale underlying CIBIS III and a presentation of its results, which may be confidently expected to change clinical practice. The programme ended with a look into the future of CHF management.
Formal presentations were balanced with informal discussion sessions, giving physicians the opportunity to explore practical issues in the everyday management of CHF. These proceedings provide a record of the presentations at the symposium, and summarizes the expert panel's answers to some of the key questions raised in the discussion sessions.
The symposium reviewed the rapid evolution of medical treatment of CHF over recent years, as the beneficial effects of neurohormonal inhibitors on mortality and morbidity were established by the landmark randomized controlled trials. CIBIS II with bisoprolol4 was the first trial to show a significant reduction in all-cause mortality with a beta-blocker, followed by the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) with metoprolol succinate CR/XL5 and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS) with carvedilol.6 All three trials found a reduction in all-cause mortality of 34–35% when the beta-blocker was added to standard therapy (diuretics, ACE-inhibitors, and optional digitalis glycosides).
As a result of these trials, recent ESC guidelines recommend that beta-blockers should be considered for all patients with stable, mild, moderate, or severe CHF (NYHA classes II–IV) on standard treatment with ACE-inhibitors and diuretics, unless there is a contra-indication.3 However, recent surveys show that, with respect to beta-blockers, many European physicians are not following the guidelines—only about one-third of CHF patients receive beta-blockers, compared with the two-thirds who receive ACE-inhibitors.7,8 Furthermore, the doses of beta-blockers used are low, compared with the targets derived from clinical trials.
One reason why many CHF patients do not receive a beta-blocker may be physicians' concerns about the tolerability of multi-drug regimens, especially in elderly patients and those with co-morbidities. However, beta-blockers are as effective in these patients as in the overall CHF population. Indeed, because of their high morbidity and mortality, elderly CHF patients are among those who can benefit most from treatment. However, it is not always easy in practice to up-titrate both an ACE-inhibitor and a beta-blocker towards recommended targets. Studies show that the first-initiated drug stands a better chance of being up-titrated to the target, which tends to favour ACE-inhibitors vs. beta-blockers.8–10 This is one reason why CIBIS III sought to evaluate the efficacy and tolerability of a beta-blocker-first strategy.
Another key argument for early beta-blockade is that most mortality in early CHF is due to sudden death, which is better prevented by beta-blockers than ACE-inhibitors. Furthermore, sympathetic activation appears earlier in CHF than that of the renin–angiotensin system, which suggests that beta-blockade might be an earlier priority than ACE-inhibition. Moreover, beta-blockade reduces the risk of decreased renal function in patients receiving ACE-inhibitors, and eliminates the risk of angiotensin II escape. Before the publication of CIBIS III, two small studies with surrogate endpoints had suggested that initiation of beta-blockade before ACE-inhibition might be more beneficial than an ACE-inhibitor-first strategy.11,12 Furthermore, a recent meta-analysis indicated that the magnitude of the prognostic benefit conferred by beta-blockers in the absence of ACE-inhibitors is similar to that of ACE-inhibitors alone.13
However, changes in clinical practice should be based, where possible, on the results of large randomized controlled trials. CIBIS III was the first such trial to compare the effects of a beta-blocker-first strategy with that of an ACE-inhibitor first on the ‘hard’ endpoints of mortality and hospitalization. It showed that the bisoprolol-first and enalapril-first groups were comparable with regard to the primary endpoint, all-cause mortality or hospitalization, and all secondary endpoints. Moreover, bisoprolol-first showed a trend towards improved early survival (31% reduction in 1-year mortality, P=0.065). This suggests that during early treatment of CHF, before combination therapy can be initiated, a beta-blocker-first strategy might be predicted to improve survival, allowing a greater number of patients to subsequently benefit from combined beta-blockade and ACE-inhibition, as well as other drugs and interventions.
Compared with earlier landmark beta-blocker trials, CIBIS III was notable for including patients more representative of the ‘real-life’ CHF population—elderly (mean age 72), with mild-to-moderate CHF (NYHA class II and III), and left ventricular ejection fraction 
35%.1 Inclusion criteria were broad enough to allow many patients with co-morbidities such as diabetes to take part. The study also used a slow-dose titration with the aim of minimizing side-effects, a particular concern in frail elderly patients. Thus, physicians can be confident that the results of CIBIS III are applicable to the patients whom they manage in their everyday practice.
Although analysis of CIBIS III did not identify any subgroups that benefited more than others from a beta-blocker-first strategy, it may be speculated that early initiation of a beta-blocker is particularly appropriate in patients considered to be at increased risk of sudden cardiac death. It might also be appropriate to initiate and up-titrate a beta-blocker before an ACE-inhibitor in patients with tachycardia, ischaemic heart disease, and in those who would not be expected to tolerate high doses of both agents. The daily practice of some physicians will probably change as a result of CIBIS III, and the evidence may be incorporated into some national guidelines in the near future. These proceedings provide a picture of the place of beta-blockers in CHF management today, and an insight into their potential for the future.
Thanks to Merck KGaA, Germany, for the financial grant that made this symposium possible. Special thanks to Sigrid Körner (Commercial Unit Cardiometabolic Care) and Wilfried R. Meyer (Medical Affairs Cardiometabolic Care). Thanks also to Jane Fraser, Isabella Schmele (Merck KGaA), and European Heart Journal staff.
Footnotes
Paper presented at the Fourth International CHF Symposium, Sorrento, 26 November 2005 
1 Department of Cardiology, Lund University, University Hospital, Malmö, Sweden
2 Service de Pharmacologie, Hopital Pitié-Salpetriere, 47 Boulevard de l'Hôpital, 75013 Paris, France
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