A review of the safety and efficacy of nebivolol in the mildly hypertensive patient

REVIEW A review of the safety and efficacy of nebivolol in the mildly hypertensive patient John Cockcroft Wales Heart Research Institute, University Hospital Heath Park, Cardiff, UK Abstract: Nebivolol is a third generation beta-blocker, which can be distinguished from other beta-blockers by its hemodynamic profile. It combines beta-adrenergic blocking activity with a vasodilating effect mediated by the endothelial L-arginine nitric oxide (NO) pathway. The effects of nebivolol have been compared with other beta-blockers and also with other classes of antihypertensive agents. In general, response rates to treatment are higher, and the frequency and severity of adverse events are either comparable or lower with nebivolol. Nebivolol is also effective in reducing cardiovascular morbidity and mortality in elderly patients with heart failure, regardless of the initial ejection fraction. Endothelium-derived NO is important in the regulation of large arterial stiffness, which in turn is a major risk factor for cardiovascular disease. Treatment with nebivolol increases the release of NO from the endothelium and improves endothelial function, leading to a reduction in arterial stiffness. Decreased arterial stiffness has beneficial hemodynamic effects including reductions in central aortic blood pressure. Unlike first generation beta-blockerrs, vasodilator beta-blockerrs such as nebivolol have favorable hemodynamic effects, which may translate into improved cardiovascular outcomes in patients with hypertension. Keywords: nebivolol, hypertension, heart failure, beta-blocker, nitric oxide, arterial stiffness Introduction Correspondence: John Cockcroft Wales Heart Research Institute, University Hospital Heath Park, Cardiff Cf14 4XN, UK Tel +1 2920 743489 Fax +1 2920 743500 Email Hypertension is a major risk factor for cardiovascular disease, and aggressive reduction of blood pressure can significantly improve cardiovascular outcomes (Staessen et al 2003). However, there is still debate as to whether it is blood pressure reduction per se or the antihypertensive agent used that is most important in terms of improving cardiovascular outcome. The latest guidelines issued by the National Institute for Clinical Excellence (NICE) for England and Wales recommend an angiotensin-converting enzyme inhibitor (or an angiotensin receptor blocker if an ACE inhibitor is not tolerated) as first-line treatment for hypertension in patients less than 55 years old (NICE 2006). In patients over 55 years and in black patients of any age, the recommended first-line therapy is either a calcium channel blocker or a thiazide-type diuretic. The NICE guidelines no longer recommend beta-blockers for the first or second line treatment of hypertension. This recommendation was prompted by two recent meta-analyses which showed that despite reducing blood pressure, beta blockade was not effective in reducing cardiovascular events when compared with either placebo or other antihypertensive agents (Carlberg et al 2004; Lindholm et al 2005). Beta-blockers have also recently been shown to increase the risk of type 2 diabetes, especially if treatment is in combination with a thiazide-type diuretic. However, atenolol was the beta-blocker used in most of these studies and, given the relative lack of clinical outcome data from trials of treating hypertension with beta-blockers other than atenolol, it is unclear whether this conclusion applies to all beta-blockers. Vascular Health and Risk Management 2007:3(6) 909–917 © 2007 Dove Medical Press Limited. All rights reserved 909 Cockcroft Isolated systolic hypertension is associated with increased large artery stiffness, a strong independent predictor of cardiovascular risk. Recently endothelium-derived nitric oxide (NO) has been shown to be involved in the regulation of large arterial stiffness, with a reduced bioavailability of NO production linked to increased arterial stiffness (Kinlay et al 2001; Wilkinson et al 2002; Schmitt et al 2005). Arterial stiffening associated with age and disease has therefore become a new and important therapeutic target in terms of blood pressure reduction and cardiovascular disease prevention. Drugs such as nebivolol that reduce blood pressure and improve endothelial function may be especially useful in this regard and should be considered as an alternative firstline treatment for hypertension and in elderly patients with chronic heart failure. Nebivolol Nebivolol is a third generation beta-blocker, which can be distinguished from other beta-blockers by its hemodynamic profile. The hemodynamic effects of nebivolol are due to its vasodilator properties including a reduction in systemic vascular resistance and an increase in cardiac output (Ritter 2001). It is the most beta-1-selective adrenoceptor antagonist currently in clinical use and has no alpha-1-blocking action (Van Bortel et al 1997). The enantiomers have different pharmacological properties. The d-isomer provides the betablocking component (Van Nueten and De Cree 1998) and both the d- and l-isomers have an endothelial NO-dependent vasodilating effect. Thus racemic nebivolol is needed for the drug to be most effective. Such characteristics are in contrast to those of carvedilol which also has vasodilatory and anti-inflammatory properties, but in this case due to its ability to block alpha1 receptors. The effects of carvedilol on NO bioactivity also remain unclear. Nebivolol is rapidly absorbed after oral administration of a standard 5-mg dose and reaches peak plasma levels between 30 minutes to 2 hours after intake. It is extensively metabolized and excretion is mainly in the feces and urine. The pharmacokinetics of nebivolol are not affected by age. However, the recommended starting dose for patients over 65 years is 2.5 mg a day. This is in line with many other antihypertensive treatments where dosage is lowered for elderly patients. Nebivolol (5 mg) is indicated for the treatment of essential hypertension and, in elderly patients ⭓70 years, for the treatment of stable mild and moderate chronic heart failure in addition to standard therapies. A starting dose of 2.5 mg is suggested in patients over 65 years or in patients with renal insufficiency. 910 Nebivolol combines beta-adrenergic blocking activity with a vasodilating effect via increased NO availability, mediated by the endothelial L-arginine NO pathway, leading to a reduction in peripheral vascular resistance. Treatment with nebivolol also leads to improvements in left ventricular function in patients with heart failure (Uhlir et al 1991; Erdogan et al 2007; Lombardo et al 2006), and arterial compliance (Van Merode et al 1989). Left ventricular function is preserved and left ventricular mass is reduced in hypertensive patients with left ventricular hypertrophy (Stoleru et al 1993). Hypertensive patients are at high risk of coronary artery disease and subsequent impaired cardiac function (Robertson and Ball 1994) an (...truncated)