Beta-blockers – versatile and effective
In association with A.Menarini Pharmaceuticals Ireland Ltd – Beta-blockers are one of the most valuable classes of drugs in the therapeutic armamentarium. They have an established place in the management of hypertension in combination with other agents. Beta-blockers also form part of the standard treatment for heart failure. Recent evidence has reinforced the place of beta-blockers in the management of hypertension and heart failure. The 2009 reappraisal of European guidelines on hypertension management notes that the vasodilating beta-blockers such as celiprolol, carvedilol, and nebivolol, appear not to share some of the negative properties described for other compounds.1 Recent studies show that third generation beta-blockers, such as nebivolol and carvedilol, are associated with positive outcomes in elderly patients with CHF – a group that can be poorly tolerant of older beta-blockers. As many people with chronic heart failure also have a history of essential hypertension, beta-blockers can be particularly useful.
Beta-blockers may be under-prescribed for elderly patients with heart failure because of concerns about efficacy and tolerability. First and second-generation beta-blockers are poorly tolerated by the elderly and generally make heart failure worse. However, third generation beta-blockers, which have additional vasodilating properties, are both effective and well-tolerated in this group of patients. In addition, two reviews of this topic have provided detailed analyses and interpretations of the available data. 2,3
Chronic heart failure is a common and disabling condition amongst the elderly. The median age of presentation is more than 75 years. Typically, patients with heart failure have enlarged hearts and reduced left ventricular ejection fractions (LVEF) – ‘systolic heart failure’. There is also a group of patients who have normal-sized hearts and near-normal ejection fractions – a condition commonly described as diastolic heart failure or heart failure with preserved LVEF. This condition is generally a consequence of hypertension, atrial fibrillation or valve disease and is more common in older and female patients.
The treatment of heart failure involves the use of ACE-inhibitors, angiotensin II type 1 receptor antagonists, beta-blockers and aldosterone antagonists. Beta-blockers have been shown to reduce adrenergic drive, improve autonomic balance and reduce wall stress and this provides the rationale for their use in heart failure. Several large, randomised trials have shown that treatment with beta-blockers can reduce the risk of death and hospital admissions for worsening heart failure in patients with low ejection fractions. The average age of patients in such studies was less than 63 years and the majority of the trials excluded patients with left ventricular ejection fraction (LVEF) above 40%. Thus, elderly patients with heart failure with preserved LVEF were not represented in the studies and it may not be reasonable to extrapolate the results to them. Moreover, older patients have reduced beta-adrenoceptor numbers and responsiveness in the myocardium, may be more dependent on sympathetic drive to maintain cardiovascular homeostasis and may respond badly to the peripheral vasoconstriction caused by non-vasodilating beta-blockers. This gives rise to concerns about the efficacy and tolerability of beta-blockers in elderly patients with heart failure and may account for the observed under-prescribing.
Two randomised controlled trials of third-generation beta-blockers have shown positive outcome benefits. The SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation) trial was a parallel-group, randomised, double-blind, multicentre trial comparing nebivolol with placebo, in addition to optimal standard therapy, in elderly patients with heart failure.4 Nebivolol is a beta1-selective adrenoceptor antagonist with vasodilating properties mediated by nitric oxide modulation on epithelial cells. The study included patients over 70 years of age (mean age 76 years) one third of whom had preserved LVEF (LVEF greater than 35%), and was therefore representative of the patients with chronic heart failure who are seen in daily practice. The results showed that nebivolol reduced the risk of all-cause mortality or cardiovascular admission (hazard ratio 0.86, p=0.039). Moreover, the nebivolol appeared to be well-tolerated and 68% of patients were able to reach the maintenance dose of 10mg.5
The COPERNICUS (Carvedilol Prospective Randomised Cumulative Survival Study Group) trial was a randomised, double-blind, placebo-controlled trial of carvedilol in addition to standard heart failure treatment in patients with moderate-severe heart failure who had LVEF of less then 25%.6 The results showed a 24% decrease in the combined risk of death or hospitalisation (95% CI 13-33, p<0.001)). However, the benefit appeared to be smaller in patients over the age of 65 years – as one reviewer noted, “an age group that can hardly be considered elderly in this context”.
Both nebivolol and carvedilol have a vasodilator effect that is mediated through nitric oxide release from endothelial cells and is independent of their actions on beta- adrenergic receptors. Kalinowski and colleagues7 demonstrated these effects on renal glomerular endothelial cells and suggested that if this mechanism also proves to be beneficial in other vascular beds then it could offer a fruitful direction for development of pharmacological interventions in cardiovascular disorders, especially those relevant to microcirculation protection.
Some limited evidence for a class effect of third-generation beta-blockers comes from COMET (Carvedilol or Metoprolol European Trial) that compared carvedilol (25mg twice daily) with metoprolol (50mg twice daily) showed a 17% relative risk reduction in mortality with carvedilol.8 The interpretation of these findings is uncertain, as the dose of metoprolol was lower than that used in previous study of metoprolol in heart failure.
Bucindolol is a third generation beta-blocker that also has vasodilating properties. However, in a placebo-controlled trial in heart failure patients its effect did not differ form that of the placebo. The reasons for this lack of effect are not clear.
Reviewers conclude that there are important differences between beta-blockers and that third-generation beta-blockers with vasodilating properties appear to offer some advantages in elderly patients with chronic heart failure. So far, the outcome benefits have only been established prospectively in an elderly CHF population for nebivolol and large RCTs will be required to confirm the beneficial effects in elderly patients with heart failure and preserved LVEF.
Beta blockers and hypertension – preserving renal function
Co-existing hypertension and diabetes increase the risk of developing renal disease and other target organ complications. This group also has a high prevalence of cardiovascular risk factors including dyslipidaemia, microalbuminuria, hyperuricaemia, a thrombotic tendency and left ventricular hypertrophy. Hypertension exacerbates the vascular complications of diabetes including renal disease, coronary heart disease, stroke, peripheral vascular disease, lower extremity amputations and retinopathy. Effective treatment of hypertension in these patients reduces the risks of cardiovascular complications and slows the rate of decline in renal function. There are, therefore, compelling reasons to treat hypertension effectively.
A review of studies that evaluated the impact of treatment strategies designed to achieve the recommended blood pressure goal of less than 130/85 mmHg was undertaken by the National Kidney Foundation in 2000.9 All the trials included were randomised and/or double-blind placebo-controlled with a minimum of two-year follow up and a minimum of 30 patients. The results of the review were then used to formulate guidelines for the management of hypertension in this group of patients.
A key finding of the review was that four of the long-term studies not only affirmed the benefits of using a blood pressure goal of 130/85 mm Hg but also showed that further lowering of blood pressure reduced the cardiovascular event rate further and resulted in greater preservation of renal function. Critically, the UKPDS study concluded that tight blood pressure control conferred a relatively greater impact on CV risk reduction than tight blood glucose control. Accordingly the authors of the review proposed that for individuals with renal impairment and/or diabetes, the blood pressure treatment goal should be 130/80 mm Hg.
Analysis of the antihypertensive treatment required to achieve the lower blood pressure goals showed that an average of 3.2 medications were required (see figure 1).
Figure 1: Average number of different antihypertensive agents needed to achieve lower blood pressure goals in all available trials that randomised for different levels of blood pressure control. (Bakris et al. 20009)
UKPDS UK Prospective Diabetes Study 38.
ABCD Appropriate Blood Pressure Control in Diabetes Trial
MDRD Modification of Dietary Protein in Renal Disease
HOT Hypertension Optimal Treatment Trial
AASK African American Study of Kidney Disease
The working group proposed a treatment paradigm to provide the “least intrusive” control of blood pressure in people with renal insufficiency and /or diabetes. (see figure 2) In this scheme, beta-blockers are added, provided that the pulse rate is above 84 beats/minute if ACE-inhibitor, diuretic and calcium channel blocker (CCB) combinations have failed to control blood pressure adequately. Beta-blockers can be substituted for CCBs in patients with angina, heart failure or arrhythmias.
There is now a trend for increasing use of fixed-dose combination treatments for hypertension,10which supports the working group’s recommendation for multiple BP treatments when attempting to reach the blood pressure goal.
Figure 2: Suggested treatment paradigm to provide the “least intrusive” control of blood pressure in people with renal insufficiency and /or diabetes (Bakris et al 20009)
A suggested paradigm by which blood pressure goals in people with renal insufficiency and/or diabetes can be achieved by the least intrusive means possible. Note that initiation of this paradigm is suggested for people without other documented pre-existing problems (e.g. angina, heart failure) in which many of the medications suggested in the schema may already be used. #Everyone with diabetes and/or renal insufficiency should be instructed on lifestyle modifications as per the JNC VI. Everyone, however, should be started on therapy if blood pressure is greater than 130/85 mmHg. Note that, if BP is <15/10 mmHg above goal (130/80 mmHg), then ACE inhibitor alone may be used. ^ACE inhibitor should be the same if two different fixed-dose combinations are used.*Nondihydropyridine CCBs (verapamil, diltiazem have been shown to reduce both CV mortality, proteinuria, and diabetic nephropathy progression independent of an ACE inhibitor). Beta blockers may be substituted for calcium channel blockers if the patient has angina, heart failure, or arrhythmia necessitating their use. Beta-blockers with proven efficacy to reduce CV events and the lowest side-effect profile are preferred. Note that use of a beta-blocker with a nondihydropyridine CCB should be avoided in the elderly and those with conduction abnormalities. Otherwise, such combinations are safe and particularly effective for lowering blood pressure. Note that other agents, such as minoxidil, hydralazine, and clonidine or methyldopa, can also be used as adjunctive agents to help achieve goal blood pressure. Clonidine should NOT be used with beta-blockers for numerous reasons, not the least of which is a high likelihood of severe bradycardia.
Beta blockers are versatile and valuable agents in the management of cardiovascular disease. Understanding of how to use beta-blockers effectively has increased in recent years and this should ensure that more patients can benefit from treatment with these agents.
1. Mancia G, Laurent S, Agabiti-Roseic E et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27:2121–2158
2. Coats AJS. β-Adrenoceptor antagonists in elderly patients with chronic heart failure: Therapeutic potential of third-generation agents. Drugs and Aging 2006; 23: 93-99
3. Dobre D, Haaijer-Ruskamp FM, Voors A & van Veldhuisen D. β-Adrenoceptor antagonists in elderly patients with heart failure: A critical review of their efficacy and tolerability. Drugs and Aging 2007; 24: 1031-1044
4. Shibata MC, Flather MD, Böhm M et al. Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisations in Seniors with Heart Failure (SENIORS): rationale and design. In J Cardiol 2002;86: 77-85
5. Flather MD, Shibata MC, Coats AJ et al., SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular admission in elderly patients with heart failure. Eur Heart J 2005;26: 215-25
6. Packer M, Coats AJ, Fowler MB et al. Carvedilol Prospective Randomised Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344:1651-8
7. Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, Jankowski M, Martyniec L, Angielski S, Malinski T. Third-Generation β-Blockers Stimulate Nitric Oxide Release From Endothelial Cells Through ATP Efflux. A Novel Mechanism for Antihypertensive Action. Circulation 2003; 107: 2747-2752
8. Poole-Wilson PA, Swedberg K, Cleland JG et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003; 362: 7-13
9. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000 ; 36: 646-61
10. IMS Data, 2012
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Author: Christine Clark revised 19th Sept 2012