Cardiovascular Drugs and Therapy 18 91–93 2004 C 2004 Kluwer Academic Publishers. Manufactured in The United States


EDITORIAL

Do Pharmacological Differences Among Beta-Blockers Affect Their Clinical Efficacy in Heart Failure? Andrea Di Lenarda, Gastone Sabbadini∗ , and Gianfranco Sinagra Department of Cardiology and ∗ Department of Clinical Morphological Technological Sciences, Azienda Ospedaliera “Ospedali Riuniti” and University, Trieste, Italy

Over the last decades, considerable insights into the pathophysiology of heart failure (HF) have been gained to show that the overstimulation of biologically active pathways, primarily the renin-angiotensin-aldosterone and sympatho-adrenergic systems, produces many detrimental effects which in turn play a key role in mediating the progression of the syndrome [1]. Supporting this concept, it is now well-established that drugs which possess the ability to antagonize these up-regulated neurohormonal mechanisms represent the best therapeutic strategy to improve the course of the disease [2]. In the setting of HF due to left ventricular (LV) dilation/systolic dysfunction, beta-blockers have been extensively proven to slow the progression of cardiac remodelling, reduce the need of hospitalisation, and prolong the life expectance in a broad spectrum of patients [3–7]. The 3 major clinical trials on beta-blockade in HF showed a similar effect of bisoprolol [5], metoprolol extended-release [6], and carvedilol [7] in the magnitude of risk reduction for all-cause mortality (34– 35%), sudden cardiac death (41–44%), and all-cause hospitalisations (18–20%). On the other hand, a recent meta-analysis of all 28 randomised controlled trials on beta-blockade in HF suggested a 13% additive survival benefit with the use of non-selective versus β1-selective blocking agents [8]. The deleterious consequences of the prolonged, excessive sympathetic activation in HF are mostly mediated through the β1-adrenoreceptors (the primary target for norepinephrine) [8]. Consistently with this finding, all beta-blockers proven to be effective in HF block the β1-adrenoreceptors [3–7]. However, the proportion of β2-adrenoreceptors [9] as well as the release of epinephrine (the primary β2-adrenoreceptor agonist) result to be increased in the failing heart [10]; moreover, the stimulation of β2-adrenoreceptors facilitates the release of norepinephrine [11], and their responsiveness is enhanced when the β1-adrenoreceptors are blocked [12]. Thus, it cannot be ruled out a contribution of β2-adrenoreceptor mediated effects to catecholamine toxicity in HF. Bisoprolol and metoprolol selectively block the β1adrenoreceptors, whereas carvedilol interferes with a wide variety of mechanisms potentially involved in the

toxicity of sympathetic nervous system, including the blockade of β1, β2, α1-adrenoreceptors, the prevention of β1-adrenoreceptor up-regulation, the suppression of endothelin biosynthesis [13,14]. If multiple mechanisms mediate the deleterious effects of sympathetic nervous system, carvedilol would be expected to provide an incremental survival benefit. On the other hand, it is also possible that the presynaptic β2-adrenoreceptor antagonism of carvedilol, together with its tight binding to the down-regulated β1-adrenoreceptors, could exert an incremental protection against norepinephrine toxicity. The actual controversy is whether all beta-blockers are the same in HF or, alternatively, one agent with proven efficacy should be used preferentially. Given the complex pharmacological profile of beta-blockers, clinicians have been waiting with interest the first head-tohead comparison among 2 distinct agents in the class. Nevertheless, the results of COMET trial [15] have generated some surprise and discussion. COMET was a well-designed and well-conducted study that provided the robust finding that carvedilol treatment is associated with a meaningful survival benefit in comparison with metoprolol tartrate [15]. Randomized treatment with carvedilol or immediaterelease metoprolol was given to 3029 patients with symptomatic HF and LV ejection fraction ≤35% for 58 months. Carvedilol treated group showed a highly significant lower risk of all-cause (−17%, p = 0.0017) and cardiovascular death (−20%, p = 0.0004) in comparison with metoprolol treated group. Carvedilol treatment also significantly reduced the risk of sudden death and vascular events (myocardial infarction, stroke) and prevented new onset diabetes. On the other hand, no significant difference between carvedilol and metoprolol was demonstrated on the need of hospitalisation and on HF symptoms. After the publication of these results, most of the discussion arose about the doses of carvedilol and

Address for correspondence: Andrea Di Lenarda, MD, Department of Cardiology, Azienda Ospedaliera “Ospedali Riuniti”, Strada di Fiume 447, 34100 Trieste, Italy. Tel.: +39/040/3994865; Fax: +39/040/3994878; E-mail: [email protected]

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metoprolol used in the trial and the differences in the pharmacological profile between the 2 drugs. First of all, it has to be recognised that, whereas not representing the optimal ones for HF treatment, the doses of carvedilol and metoprolol are those usually administered to HF patients in the “real-world”. Secondly, “the slightly lower resting heart rate observed with carvedilol is consistent with a modestly greater degree of beta-blockade with this agent” [16] and probably cannot completely explain the large survival benefit shown by carvedilol in this trial. Finally, due to its longer half-life, carvedilol may exert a more constant degree of β1-adrenoreceptor blockade than metoprolol immediate-release [17], whereas substantial betablockade is present for much of the day-time also in patients treated with metoprolol [8]. As underlined by Cohn [18], cardiologists would have been probably more confident with the results of COMET trial by the demonstration of similar positive results on surrogate end-points. These data, not available from COMET, come from previous comparative studies, showing a significantly greater beneficial effect with carvedilol than with metoprolol tartrate on LV systolic function and remodelling [19–21]. Indeed, how beta-blockers work has yet to be fully elucidated and new data are accumulating about the pharmacological differences between distinct agents in the class. In one study recently conducted by Kindermann et al. [22] on healthy volunteers, carvedilol showed a beta-blocking effect far beyond its elimination from plasma. This effect could be due to an atypical binding of carvedilol to the beta-adrenoreceptors and could be relevant in clinical practice preventing the beta-blocker rebound phenomenon. Additional information on pharmacological differences existing between beta-blockers used in clinical practice comes now from the study by Stoschitzky et al. [23], published in this issue of Cardiovascular Drugs and Therapy. The Authors show that, while bisoprolol (similarly to atenolol and propranolol) is taken up into, and released from, adrenergic cells together with norepinephrine and epinephrine during exercise and in general during maximal sympathetic activation, plasma concentration of carvedilol and nebivolol does not change during exercise. Thus, the human body seems to handle carvedilol and nebivolol differently from other beta-blockers, being the plasma concentration of the 2 drugs not affected by changes in sympathetic drive. According to these findings, it is also possible that pharmacodynamic half-life of some beta-blockers (as propranolol, atenolol and bisoprolol, but not nebivolol and carvedilol) could be prolonged since some drug could be still present in adrenergic cells when not detectable in plasma. Thus, as suggested by the Authors, carvedilol and nebivolol concentration at adrenoreceptor level might be in the therapeutic range all the time, while the therapeutic concentration of other betablockers might be reached only when sympathetic drive

is high. Finally, nebivolol and carvedilol concentration at their site of action might be in closer relation to plasma concentration than that of other β-blocker such as propranolol, atenolol and bisoprolol. Given the complex and still partially unknown pharmacological profile of beta-blockers, actually we cannot reach any firm conclusion about the clinical relevance of the pharmacological differences existing among the agents in the class. Nevertheless, we can state that only beta-blockers shown to be effective in HF (bisoprolol, metoprolol, carvedilol) should be used in this setting at the highest tolerated dose. Based on the results of COMET trial, carvedilol should be preferred to metoprolol tartrate for HF treatment. The hypothesis that bisoprolol and metoprolol extended-release may exert similar clinical benefits than carvedilol should be the aim of future investigations.

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