Introduction
Since the mid-late nineties beta-blockade has become one of the pillars of chronic heart failure treatment. Based on a significant and consistent beneficial effect on survival and a reduction of worsening heart failure (HF) in large, placebo-controlled studies performed at that time, beta-blockade has been accepted as mandatory therapy in patients with stable mild, moderate and severe HF. These pivotal studies were, in order of sequence: the US carvedilol programme (carvedilol), CIBIS II (bisoprolol), MERIT-HF (metoprolol), and COPERNICUS (carvedilol) performed in patients with chronic HF and left ventricular (LV) dysfunction [1–4]. Whereas the focus in the first 3 studies was in mild/moderate HF, COPERNICUS was exclusively carried out in patients with severe, albeit stable. HF. In addition, in patients with LV dysfunction and/or HF directly after an acute myocardial infarction, carvedilol also significantly improved survival compared to placebo treatment [5]. A later study, SENIORS, performed in an elderly population irrespective of cardiac function with nebivolol, showed a significant reduction in the primary outcome, a composite of all-cause mortality and hospital admission for HF, but for all-cause mortality alone [6]. In all of these studies background therapy included ACE inhibitors.
As a consequence of these results, carvedilol, bisoprolol, metoprolol succinate and nebivolol have been accepted for the treatment of chronic, stable HF (NYHA II-IV) of ischemic or non-ischemic origin in international guidelines for the treatment of HF [7, 8].
Such guidelines however do not address an important question for the clinician: “which beta-blocker to use”? Are they all similarly effective and equally tolerated, or may there be a preferred beta-blocker for the treatment of chronic heart failure?
Pharmacological properties of beta-blocking drugs
The beta-blockers accepted for HF treatment differ considerably (Table 1). Metoprolol and bisoprolol are beta-1 selective agents. Nebivolol is also a beta-1 selective drug, but has additional vasodilating properties, possibly related to endothelial nitric oxide generation.
In contrast, carvedilol blocks not only the beta-1 receptor, but also the beta-2 and alpha-1 adrenoceptors. In addition, carvedilol has anti-oxidative and anti-endothelin properties.
The question arises whether the different adrenergic blocking activities of these beta-blockers are relevant to their beneficial effect in heart failure. One important direction to answer that question without the need for large controlled studies concerns their individual modulating effect on cardiac remodeling [9].
Beta-blockade and cardiac remodeling
Various mechanisms contribute to cardiac remodeling, including neurohormonal and cytokine activation, inflammation, activation of inducible NO synthase, oxidative stress, apoptosis and ischemia, as well as mechanical factors such as stretch and activation of mechano-sensitive ion channels [10]. These factors do not operate in isolation, but often interrelate. Stretch activates neurohormonal pathways including the renin angiotensin system and the alpha-1 adrenergic system [11]. Sympathetic overactivation may augment cytokine production, which in turn increases inducible NO [12, 13]. The excess NO may then lead to oxyradical formation, oxidative stress and apoptosis. This complex of interactions indicates the potential usefulness of adrenergic blockade, besides other forms of neurohormonal blockade, in modulating cardiac remodeling.
Sympathetic blockade may be particularly important in modulating remodeling for several reasons. Activation of the sympathetic system occurs early after a cardiac insult leading to remodeling, possibly earlier than other neurohormonal systems [14]. Also, in heart failure the cardiac sympathetic tone is excessively high. Sufficiently so that cardiac catecholamine levels become toxic for cardiomyocytes, and may result in cardiac necrosis [15, 16]. De-sensitization of beta-receptors, but also beta-blockade may counteract these effects [17].
Also, high catecholamine levels may induce apoptosis. Beta-blockade counteracts this by increasing anti-apoptotic factors, such as Bcl-2 and Bcl X (S), and by reducing those which are pro-apoptotic (e.g. Bax) [18].
A further mechanism through which beta-blockade may affect remodeling concerns its effect on cardiac metabolism. Sympathetic activation in heart failure promotes the use of free fatty acids instead of carbohydrates for energy production. This means less ATP produced for the same amount of available oxygen. Beta-blockade counteracts this waste of ATP by increasing the dependency on carbohydrates, thus improving ATP availability in the energy-starved failing heart.
Finally, beta-blockers reduce heart rate, which is beneficial in reducing cardiac oxygen consumption, while at the same time, by lengthening the diastolic period, improving oxygen supply. Lengthening of the diastolic period also allows more time for the uptake of calcium by the sarcoplasmatic reticulum, possibly improving cardiac relaxation.
Anti-remodeling properties in heart failure: are all beta-blockers equally effective?
Blockade of all adrenergic receptors should be preferable to selective beta-blocking agents for modulation of cardiac remodeling. Not only the beta-1 receptor, but also the beta-2 and alpha-1 receptor are linked to downstream cellular signaling pathways resulting in cardiac remodeling. Of importance, these pathways are not similar. Consequently, blocking only the beta-1 receptor, leaves the heart unprotected to remodeling signals triggered by stimulation of the other adrenergic receptors (Fig. 1). Myocardial stretch, an important factor in remodeling, is a good example. It increases alpha-adrenergic activation, which may result in cardiac hypertrophy and induce toxic effects on the heart. Furthermore, alpha-adrenergic stimulation may lead to peripheral (including renal) and coronary vasoconstriction with potentially harmful effects, including increased afterload, renal hypoperfusion and myocardial ischemia. Blockade of alpha-adrenergic receptors therefore appears a logical approach in heart failure and would support the use of carvedilol rather than selective beta-adrenergic blockers.
Schematic representation of adrenergic receptors and blockade by selective beta-1 blockers (metoprolol, bisoprolol, nebivolol, beta-1 and -2 blockers (propranolol, bucindolol) and the beta-1 and -2 blocker and alpha-1 adrenergic blocker carvedilol. The latter exerts the most protective effect against cardiac remodeling by blocking all 3 receptors
Beta-2 receptor activation facilitates norepinephrine release from the heart through stimulation of pre-synaptic cardiac beta-2 receptors. In addition, beta -2 stimulation may promote cardiac fibrosis and lead to arrhythmias [19, 20]. Whether these negative effects are offset by the positive effects of beta-2 stimulation on apoptosis is questionable. As beta-2 receptors are percent-wise increased in heart failure, blocking their effects appears a logical step in heart failure treatment and would again favour carvedilol to selective beta-1 blocking drugs, such as metoprolol and bisoprolol. In atrial muscle from patients with non-terminal heart failure, carvedilol was a 13-fold more potent antagonist of the effect of adrenaline on beta-2 receptors than that of noradrenaline on beta-1 receptors [21]. In the same study, carvedilol, but not metoprolol, reduced the sensitivity of atrial muscle to adrenaline and noradrenaline in cardiac tissue from terminal hear failure patients.
Arguably, of the three adrenergic receptors, the beta-1 receptor is probably the most important in regards sympathetic stimulation of cardiac remodeling. This would support specific beta-1 receptor blockade. However, carvedilol, compared to metoprolol, has a tighter binding to the beta-1 receptor and, hence, a longer-lasting effect [22].
Moreover, carvedilol reduces the increased expression of the beta-3 adrenergic receptor in heart failure in contrast to metoprolol, with a more effective improvement of hemodynamics and a greater attenuation of cardiac remodeling [23]. Furthermore, carvedilol stimulates beta-arrestin signaling, a unique mechanism, compared to other beta-blockers, which could contribute to its efficacy in heart failure therapy [24].
Carvedilol as preferred beta-blocker in cardiac remodeling and heart failure—preclinical arguments
Carvedilol protects better against cardiac remodeling and subsequent heart failure than more selective beta-adrenergic blockers. The arguments for this includes its comprehensive blocking of all 3 adrenergic receptors, as indicated above, and its anti-oxidant, anti-apoptotic and anti-endothelin effects.
Compared to metoprolol succinate, carvedilol at dosages that led to comparable heart rate reductions, induced significantly greater improvements of cardiac function in dogs with pacing-induced heart failure, and increased renal, hepatic, and skeletal muscle blood flow [25]. In addition, it improved myocardial glucose uptake (providing better energy conservation) compared to metoprolol, and antagonized the response to exogenous norepinephrine to a greater extent than metoprolol succinate.
In rodents with isoproterenol-induced cardiac hypertrophy and heart failure, carvedilol resulted in a greater reduction of heart weight and increase in cAMP than with metoprolol, despite similar reductions in heart rate [26]. Comparison of the R-and S-enantiomeres of carvedilol further indicated that the reduction in heart weight resulted from alpha-1 blockade and that beta-2 blockade contributed to the improvement of cAMP.
The importance of alpha-adrenergic blockade in remodeling was further indicated in studies by Lai et al, who observed that carvedilol, but not metoprolol or propranolol, suppressed collagen production in norepinephrine-stimulated cardiac fibroblasts [27]. Similar suppressing effects were found with doxasozine, an alpha-blocking agent.
In the presence of increased sympathetic tone carvedilol, but not metoprolol, may provide angiotensin-1 receptor blockade through its alpha-1 adrenergic blocking properties, comparable to the effects of angiotensin receptor blockers, inhibiting the vasoconstrictor effect of angiotensin II on human coronary micro-arteries [28].
The anti-oxidant properties of carvedilol relative to selective beta-1 blockade have been shown in different preclinical models [29–31], and contribute to its anti-apoptotic effect compared to metoproplol. One mechanism here may relate to cellular calcium overload, which precedes apoptosis and is delayed by carvedilol, but not by beta-1 selective or non-selective drugs, including metoprolol and propranolol. However, similar protective effects are found when metoprolol is combined with the anti-oxidant N-acetyl-L-cysteine [30]. In isolated rat hearts calcium overload increased mitochondrial oxygen consumption and oxygen radical production. Both were suppressed by carvedilol, but not by metoprolol [31].
In another study in myocardial tissue from patients with end-stage heart failure carvedilol resulted in better cardiac energy conservation than beta-1 selective blockade with significantly less myofibrillar tension-dependent ATP consumption with chronic treatment with carvedilol as compared to metoprolol [32]. Furthermore, whereas in heart failure post-MI beta-blockade up-regulates reduced SERCA levels and improves cardiac remodeling and impaired cardiac function, these effects are more pronounced with carvedilol than metoprolol [33].
Carvedilol as preferred beta-blocker in cardiac remodeling and heart failure—clinical studies
Do the better effects of carvedilol observed in preclinical studies translate into more pronounced anti-remodeling effects in the clinical situation when compared to beta-1 selective blockade?
In heart failure patients carvedilol exerts a more potent anti-adrenergic effect than metoprolol during stress [34, 35] (Fig. 2). This may partly explain the better anti-remodeling properties of carvedilol observed in most studies which compared it to beta-1 selective blocking agents such as metoprolol.
Comparison of the effect of carvedilol and metoprolol on total body and cardiac norepinephrine spillover in patients with heart failure. Carvedilol reduces norepinephrine spillover but metoprolol has no effect (from ref 35 with permission)
Sanderson et al observed a greater decrease in LV volumes with carvedilol than with metoprolol in heart failure patients [36]. Metra and coworkers reported a significantly greater increase in LV ejection fraction after 1 year treatment with carvedilol compared to metoprolol [37]. In contrast, Kukin et al found similar improvements in LV ejection fraction [38]. However, this was a smaller study over a shorter period. Finally, in a meta-analysis including all available controlled trials Packer and colleagues also found a significantly greater increase in LV ejection fraction with carvedilol than with metoprolol [39].
Taken together, the available studies did indicate a better effect of carvedilol on cardiac remodeling and cardiac function, however, none of these studies was of sufficient size or sufficient duration to allow a comparison of the long-term effects of carvedilol on morbidity and survival compared to beta-1selective blockade.
That information was provided by the COMET study.
The COMET study
The Carvedilol or Metoprolol European Trial (COMET) evaluated the effects of carvedilol (25 mg BID) and metoprolol tartrate (50mg BID) in a randomized, double-blind, parallel design in patients with chronic heart failure, NYHA class II–IV and LV ejection fraction <35%, on standard heart failure therapy including diuretics and ACE inhibitors [40]. To be included, patients had to be hospitalized for cardiovascular reasons in the year preceding randomization. The study was event-driven, lasting until 1,020 deaths had occurred. 3,029 patients were included, 1,511 receiving carvedilol and 1,518 metoprolol. The study duration was long, 58 months, reflecting the beneficial effects of beta-blocking agents in general in heart failure. Nevertheless, there was a clear benefit of carvedilol compared to metoprolol with a 17% greater reduction in all-cause death compared to the effect of metoprolol, p = 0.0017 (Fig. 3). It reduced annual mortality from 10.0% to 8.3% and prolonged median survival by 1.4 years compared to metoprolol. Cardiovascular deaths were reduced by 20% (p = 0.0004), sudden death by 19% (p = 0.022), heart failure death by 13% (p = 0.07) and stroke death by 66% (p = 0.0006), all relative to the effects of metoprolol. The greater reduction in mortality with carvedilol compared to metoprolol persisted in all pre-specified subgroups, including, age, sex, LV ejection fraction, ischemic vs non-ischemic etiology, heart rate and blood pressure at baseline. In contrast, the co-primary endpoint all-cause death and all-cause hospitalisation did not differ between carvedilol and metoprolol groups, but all pre-defined secondary endpoints showed a significantly better effect of carvedilol.
Total mortality in COMET. Carvedilol significantly improves survival by 17% relative to the effect of metoprolol (from ref 40 with permission)
After 4 months of treatment, there was a minimal, but significant difference in the effect on heart rate, 1.6 beat/minute less in the carvedilol group. A subsequent analysis of heart rate and blood pressure at 4 months treatment did however show a consistent treatment benefit of carvedilol, irrespective of whether heart rates were below or above median heart rate and above or below median systolic blood pressure [41]. Similarly, in view of the suggestion that by using metoprolol tartrate rather than succinate, the dose of metoprolol could have been an issue, patients on and below target dose at 4 months were compared showing again a consistent better effect of carvedilol compared to metoprolol, irrespective of dose. The latter observation accords to previous comparative studies between metoprolol tartrate (in a similar dose as used in COMET) and metoprolol succinate, which showed a comparable effect on heart rate [42]. Moreover, the MERIT-HF trial in patients on a high dose and low dose of metoprolol succinate had the same outcome (although patients were not randomised into those groups)[43]. After myocardial infarction there was no difference in 5 year outcome between metoprolol tartrate (41% on 100 mg once daily, 46% on 200 mg) and succinate (49% on 100 mg, 28% on 200 mg) [44].
Thus, the results of COMET provide a clear distinction between the better clinical effects of carvedilol as compared to beta-1 selective blockers, i.c. metoprolol, in patients with chronic heart failure, and cannot be explained by differences in heart rate, blood pressure or dose.
What more can we learn from COMET?
Vasculo-protective properties of carvedilol
In COMET, several vascular endpoints were studied, including cardiovascular death, stroke, stroke death, MI and unstable angina.
MIs were reported in 69 carvedilol and 94 metoprolol patients (HR 0.71, CI 0.52 = 0.97, p = 0.03) (Fig. 4 ) [45]. Cardiovascular death or non-fatal MI combined were reduced by 19% in carvedilol, compared to metoprolol (p = 0.0009). Unstable angina was reported as an adverse event by 29% less carvedilol patients (0.049). Also, strokes were 21% less in the carvedilol group, and a stroke or MI combined in 25% less carvedilol patients (=0.015). Fatal MI or fatal stroke were reported in 34 carvedilol and in 72 metoprolol patients (HR 0.46, CI 0.31–0.69, p = 0.0002). Also, death following a non-fatal MI or stroke occurred significantly less in the carvedilol group (37%, p = 0.0086). Of importance, these effects were generally observed early in the study. It can be concluded that carvedilol improves vascular outcomes more than metoprolol and that these results suggest a ubiquitous protective effect of carvedilol against major vascular events.
Vasculoprotective effects of carvedilol in COMET. Carvedilol significantly reduces acute myocardial infarction and unstable angina by 29% compared to metoprolol
This effect is probably dependent on different mechanisms.
The vascular endothelium contains both beta-1 and -2 as well as alpha-1 receptors. Blockade of all 3 adrenergic receptors by carvedilol provides for better endothelium-dependent vasodilatation than more selective beta-blockers [46]. Carvedilol, but not metoprolol results in vasodilatation and better improves endothelial function [47]. Anti-oxidative properties of carvedilol may contribute to improving free-radical induced endothelial dysfunction, whereas anti-apoptotic effects could contribute to a reduction of myocardial injury and infarct size following ischemia-reperfusion [48–55]. These properties may also affect atherosclerosis formation [56].
Finally, carvedilol, suppresses norepinephrine release from the ischemic heart, which is likely to contribute to better anti-ischemic effects, vaso-dynamics and, possibly vasculo-protection by the drug [57].
Carvedilol and diabetes mellitus
In COMET, diabetic events occurred in 22% less carvedilol patients than in metoprolol patients (p = 0.039) [58]. New onset diabetes was diagnosed in 10.4% versus 12.6% cases in the carvedilol and metoprolol treatment groups, respectively (HR 0.78, p = 0.048). Patients with diabetes at baseline had an increased mortality, compared to non-diabetics (45.3% versus, 33.9%). Both diabetics and non-diabetics at baseline had a similar reduction in mortality with carvedilol compared to metoprolol (15% and 18%, respectively). Thus, whereas there was a high prevalence and incidence of diabetes in COMET patients, new onset diabetes was more likely to occur during treatment with metoprolol than during treatment with carvedilol.
In the Gemini study, in patients with diabetes and hypertension, in patients not taking insulin sensitizers, metoprolol tartrate significantly worsened insulin resistance, an effect not seen with carvedilol [59]. Similarly, in patients after an MI, carvedilol improved insulin resistance [60]. In the latter study, carvedilol also reduced total cholesterol and LDL levels to a greater extent than metoprolol. Reductions in triglycerides, total cholesterol and non-HDL levels were also reported to be significantly greater with carvedilol than with metoprolol in the GEMINI study [61], whereas a different report of the latter study indicated more weight gain with metoprolol than carvedilol [62].
Taken together, carvedilol may also be a better choice than metoprolol in heart failure in combination with determinants of the metabolic syndrome.
Which is the preferred beta-blocker in patients with chronic obstructive lung disease?
The respiratory system is characterized by a significant predominance of beta-2 receptors, particularly present in the alveoli, where they regulate gas exchange efficacy. Obviously, beta-1 selective blockers may have a different effect than carvedilol. Recent studies indicate that a beta-1 selective agent will result in a slightly higher peak VO2 than carvedilol, although probably not clinically relevant, except in patients with a low lung diffusion (DLco). Carvedilol reduces DLco to some extent, whereas bisoprolol does not, in heart failure patients [63].
Previous studies by the same group indicate that carvedilol has no effect on lung volumes and DLco in patients with heart failure without obstructive airway disease [64]. Another study suggests that a sizeable number of HF patients with COPD or asthma tolerate carvedilol for a relatively long period [65]. Part of this may be due to the concomitant alpha-adrenergic blocking properties and resulting bronchodilatation of carvedilol, although this is as yet speculative. Beta-blockers are not contra-indicated in the presence of lung function impairment, but their use should be guided by lung function tests and knowledge of the pharmacological properties of the specific beta-blocker [66]. In any case, it would appear wise to choose a beta-1selective blocker in patients with reversible obstructive airway disease or during exacerbation of COPD.
Conclusion
There is ample evidence from pre-clinical and clinical studies that carvedilol has more pronounced anti-remodeling effects in heart failure than selective beta-blocking agents, more specifically the beta-1 selective blocking drugs metoprolol and bisoprolol.
The significant difference in efficacy is due to a combination of factors, including the comprehensive blockade of all 3 adrenergic receptors by carvedilol, and its anti-oxidative, anti-apoptotic and anti-endothelin effects.
As a result, in the COMET study carvedilol led to a significant and clinically relevant improvement of survival, better well-being, less new onset diabetes and significantly less vascular events including MI and stroke.
Taken together, these results clearly indicate that carvedilol is the preferred beta-blocker in the treatment of chronic heart failure.
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Remme, W.J. Which Beta-Blocker is Most Effective in Heart Failure?. Cardiovasc Drugs Ther 24, 351–358 (2010). https://doi.org/10.1007/s10557-010-6247-7
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DOI: https://doi.org/10.1007/s10557-010-6247-7