Beta-blockade in CHF: from contraindication to indication
1 Pierre et Marie Curie University, Department of Pharmacology, Paris, F-75012, France
2 AP-HP, Saint-Antoine Hospital, Division of Clinical Pharmacology, Paris, F-75012, France
3 INSERM–AP-HP, Clinical Investigation Center, CIC-9304, Hôpital St-Antoine, 184, rue du Faubourg Saint-Antoine, Paris, F-75012, France
* Corresponding author. Tel: +33 1 49 28 22 00; fax: +33 1 49 28 28 13. E-mail address: christian.funck-brentano{at}sat.aphp.fr
When beta-blockers were first introduced, they were initially tested in chronic heart failure (CHF) at full doses and without slow upward titration. In this context, they rapidly became contraindicated in CHF because of their negative inotropic properties. Later, however, it became clear that sympathetic activation was closely associated with CHF and that the degree of activation was, to some extent, proportional to the severity of left ventricular dysfunction. This suggested that beta-blockers should be beneficial in CHF, but in practice they were still avoided, despite a small number of encouraging early uncontrolled studies. It was not until the 1990s that large randomized controlled trials provided unequivocal proof of the mortality and morbidity benefits of beta-blockade with bisoprolol, controlled-release metoprolol succinate, and carvedilol. In the landmark studies, the beta-blocker, given on top of standard treatment, consistently reduced the all-cause mortality by 34–35%, with very good tolerability. Beta-blockade also reduced cardiovascular mortality, sudden cardiac death, and death due to progression of heart failure, reduced hospitalizations (all-cause, cardiovascular, and worsening heart failure), and improved NYHA functional class. All the landmark trials were performed with a very low initial dose of the beta-blocker (compared with the dose used in patients without CHF), with a slow individualized upward titration towards full beta-blockade. Such a progressive and individualized method of administration appears to be critical for the transformation of beta-blockers from contraindicated agents in CHF to agents that are not only indicated, but considered a critical component of standard treatment.
Key Words: Dose-response • Side-effects • Bisoprolol • Carvedilol • Metoprolol • Dose titration
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