Preferred beta-blockers for the treatment of heart failure

Introduction

Beta-adrenergic receptor blockers play an important role in the management of cardiovascular disease, including hypertension, ischemic heart disease and chronic heart failure. They differ, though, in beta-selectivity, vasodilation properties, and other ancillary features.

Recently, third generation, vasodilating, beta-blockers were introduced into practice.

• Carvedilol is a non-selective beta-blocker with additional alpha1-blocking and antioxidant activities.
• Nebivolol is a novel beta-blocker with both a greater degree of selectivity for beta-1 adrenergic receptors than other agents in this class and an ability to stimulate endothelial nitric oxide production, leading to vasodilation and other potential clinical effects.

I - CARVEDILOL

1) Mechanisms and clinical effects

Third generation beta blockers have distinctive vasodilator activity.

1. The first example of this group, labetolol is non-selective.
2. Carvedilol blocks the beta-1 receptors 2-3 times more than alpha-1 receptors.
3. Bucindolol is a non-selective agent and blocks the alpha receptors as well. 

The vasodialtor effect of these three agents is obtained via the blockade of the alpha receptors. However nebivolol shows a highly selective beta-1 blocking effects and confers an endothelium dependent vasodilatation via activation of L-arginin/NO pathway.

Carvedilol:

• is a third generation lipophylic beta blocker with antioxydant properties which block both beta-1 and alpha-1 adrenergic receptors(1). Its affinity to beta-1 receptors is 2-3 times much higher than alpha-1 receptors.
• has S and R enantiomeres and both have equal alpha blocking effects but S enantiomere shows stronger beta blockade (2).

After oral administration, absorption is fast and reaches maximum plasma concentration within 1-2 hours. The plasma half-life is 7-10 hours, and should be given twice daily. As it is metabolised mainly by the liver, the pharmacokinetics are changed in liver diseases.

Unlike traditional beta blockers carvedilol :

• has a positive effect on renal hemodynamics.
• increases renal blood flow and decreases microalbuminuria (3,4).
• has a neutral effect on insulin resistance, triglyceride and cholesterol (5).

2) Clinical Trials

• In the COMET trial (Carvedilol Or Metoprolol European Trial) the carvedilol group showed a lower probability of new diabetes development (6).
  The vasodilator effect of carvedilol increases the insulin dependent glucose influx into the myocytes and increases insulin sensitivity. Traditional beta blockers on the other hand may cause peripheral vasoconstriction and disturb the glucose utilisation in the periphery and reduces insulin sensitivity (7).

Its distinctive features allow different applications and usage and there are several trials for various conditions.

• A Meta-analysis of 36 clinical trials which included 3412 patients showed that 25 mg carvedilol decreased systolic blood pressure by 9.6 % and diastolic blood pressure by 10.7 % (2). Unlike other beta blockers, carvedilol preserves the cardiac output and reduces the peripheral resistance in hypertensive patients.
• The CAPRICORN study was designed to explore the beneficial effects of carvedilol in post myocardial infarction patients with depressed left ventricular function (EF< 40 %) . When added to standard treatment including ACE-inhibitors, the carvedilol groupe showed a 23 % reduction in all cause mortailty (8).
• Apart from the two second generation beta blockers metoprolol and bisoprolol, carvedilol has also been shown to be effective in heart failure to reduce morbidity and mortality. The US Carvedilol study reported a 65 % mortality reduction in Class III or IV patients with heart failure when carvedilol added on usual care including digoxin, diuretics and ACE inhibitors (9).
• However this particular study had a small number of Class IV patients and the COPERNICUS study was set up to investigate the effects of carvedilol in Class III and IV patients and revealed a 35 % reduction in all cause mortality (10).
• The COMET trial’s aim was to point out the differences between a second generation beta blocker metoprolol (tartrate) and a third generation beta blocker carvedilol in heart failure patients in nearly a five years follow-up.
  The study ended up with a 17 % reduction in total mortality by carvedilol and the difference was present in all the sub-groups except for women, probably due to the relatively small number of women in the study.
• The results of COMET have been interpreted in different ways. The first possibility is the difference between the molecules. However some authors criticised using the metoprolol tartrate in relatively low dose to compare carvedilol as metoprolol succinate was shown to be effective in reducing mortality in the MERIT-HF trial (11).
• Despite the fact that carvedilol distinctively blocks the rapidly depolarised sodium channels and L-type calcium channels there is no data to prove the difference in the antiarrhythmic efficacy of carvedilol as compared to the other beta blockers.

There is some evidence suggesting the preventive effects of carvedilol for nitrate tolerance (12).
Side effects include rare vertigo, tiredness and headache. Erectile dysfunction may also be a problem.

II -  NEBIVOLOL

1) Mechanisms and clinical effects

Nebivolol is :

• a selective beta-1 adrenergic receptor blocker with nitric oxide dependent vasodilator and antioxidant effects.
  It is a mixture of D and L isomeres. D-nebivolol is a selective beta-1 antagonist while L-nebivolol is responsible for the nitric oxide dependent vasodilator effect.
• Its negative inotropic effect is lower than metoprolol and carvedilol and does not have any membrane stabilising or intrinsic sympathomimetic effects. It is mainly metabolised by the liver (13-15). Clinical trials showed neutral effects on lipid and glucose metabolism.
• causes a dose dependent nitric-oxide related renal artery dilatation and increases glomerular filtration rate, urine flow and sodium chloride excertion (16-17).

2) Clinical trials

• Nebivolol as an antihypertensive agent was tested in 6376 patients in whom a significant reduction both in systolic and diastolic blood pressure has been achieved. Nebivolol was well tolerated and had neutral metabolic effects (18). The studies comparing nebivolol (5 mg) with losartan (50 mg), lisinopril (10-40 mg), amlodipin (5-10 mg) and nifedipin (20mg bid) showed no inferiority of nebivolol in terms of both systolic and diastolic blood pressure reduction(19).
• Nitric oxide behaves as an endogenous inhibitor of platelet aggregation in the platelets and nebivolol inhibits platelet aggregation triggered by adenosine diphospate and collagen (20). It has also been shown Nebivolol inhibits proliferation of human coronary endothelial cells, aortic smooth muscle cells and smooth muscle cells via nitric oxide delivery (21).
• Nebivolol has been tried extensively in patients with heart failure. In one study nebivolol has been demonstrated to reduce the heart rate and increase ejection fraction, decrease left ventricular end diastolic pressure, pulmonary capillary pressure and peripheral vascular resistance in patients with Class I-II heart failure patients with an ejection fraction lower than 24 % in a three months' follow-up (22). Nebivolol has also favorable effects on diastolic compliance (23).
• The SENIORS study was designed to investigate the effects of nebivolol in the elderly (<70 years ) with heart failure with or without low ejection fraction in both genders The previous beta blockers in heart failure trials (US-Carvedilol and COPERNICUS with carvedilol, MERIT-HF with metoprolol and CIBIS II with bisoprolol) had not included elderly patients.
  
  Over 2000 patients were included in the study and with up to 10 mg nebivolol in 21 months follow-up a significant reduction in the composite end point of all-cause mortality and heart failure hospitalisations was achieved(p=0.039).
  (24). Interestingly enough, all cause mortality did not reach statistical significance. However when the patients were younger than 75 years and with an ejection fraction lower than 35 % were analysed, a 38 % reduction in all cause mortality was achieved and this was similar to the previous beta blocker heart failure trials. This study showed that nebivolol could be recommended to the elderly patients with heart failure without considering the ejection fraction.

III – Other Third Generation Beta-Blockers

LABETOLOL

Blocks the alpha-1, beta-1 and beta-2 receptors and alpha-1 receptor blokade is responsible for the vasodilator effect. It has a partial agonist effect and is metabolised mainly by the liver.

BUCINDOLOL

Bucindolol is a non-selective and lipophilic beta blocker with a higher affinity then beta receptors. Vasodilator effects seem to be due to direct alpha-1 blockade(2).

BEST (Beta-Blocker Evaluation of Survival Trial) failed to show any benefit of bucindolol for total mortality in Class III-IV heart failure patients when added to the usual care (25). In the Class IV patients bucindolol even increased the composite end point of death and heart failure hospitalisations in six-months follow-up. The annual mortality for Class IV patients in the placebo group of the BEST study was 28 % which was higher than CIBIS (20 %), COPERNICUS (19 %) and MERIT-HF (25 %) studies. It has been suggested that the Class IV patients in BEST study were much sicker than the other studies and this contributed to the less beneficial effect of bucindolol in the BEST study.

CELIPROLOL

Celiprolol is a third generation beta blocker with a weak beta-2 agonist activity and weak alpha 2 blocker and direct smooth muscle relaxing properties. It reduces peripheral vascular resistance and has similar antihypertensive effects to metoprolol, propronalol, atenolol and pindolol. In a study on heart failure patients comparing metoprolol, placebo and celiprolol, both drugs were well tolerated but celiprolol did not show any additional benefit (26,27).

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Conclusion:

All beta blockers are not the same in their effects. Although it seems that their antihypertensive efficacy is a class effect, it may not be easy to consider their beneficial effects in heart failure as a class effect. Moreover their metabolic effects are also different, third generation beta blockers being more neutral or positive.

Carvedilol and nebivolol are the third generation beta blockers of choice for heart failure together with the second generation beta blockers bisoprolol and metoprolol succinate.