Introduction
Hypertension is a major risk factor for cardiovascular disease, and aggressive reduction of blood pressure can significantly improve cardiovascular outcomes.
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.
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. 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 first line treatment for hypertension and in elderly patients with chronic heart failure.
Byscard (Nebivolol)
Byscard 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. It is the most beta-1-selective adrenoceptor antagonist currently in clinical use and has no alpha-1-blocking action. The enantiomers have different pharmacological properties. The d-isomer provides the beta blocking component 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-infl amatory 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.
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 and arterial compliance. Left ventricular function is preserved and left ventricular mass is reduced in hypertensive patients with left ventricular hypertrophy. Hypertensive patients are at high risk of coronary artery disease and subsequent impaired cardiac function and congestive heart failure. Endothelial dysfunction, characterized by decreased bioavailability of NO, also occurs early in various forms of cardiovascular disease.
NO has powerful antiatherogenic effects and a decrease in NO production is associated with a number of cardiovascular risk factors including hypertension, diabetes mellitus and hypercholesterolemia. Endothelial dysfunction may therefore contribute to the pathogenesis of atherosclerosis in hypertension. Treatment with nebivolol may thus favorably impact on the vascular complications of hypertension either directly by reducing blood pressure or indirectly by increasing the bioavailability of NO. In healthy volunteers, nebivolol (5 mg) decreases systemic vascular resistance with no impairment of left ventricular function. In addition, chronic treatment with nebivolol maintains left ventricular function in healthy volunteers and in patients with hypertension, acutemyocardial infarction and congestive heartfailure.
Central aortic pressure is a strong predictor of cardiovascularmorbidity and mortality but classic beta-blockerssuchas atenolol have little effect on reducing central aortic pulsepressure in hypertensive patients. Studies comparingatenololwith other antihypertensive agents show that althoughdecreases in peripheral blood pressure are similar,treatmentwith atenolol results in significantly less reduction of centralaortic pressure compared with eitherfosinopril. Improvements inarterial stiffness and arterial compliance are also greater withcalcium channel blockers, angiotensin-converting enzymeinhibitors, and angiotensin II receptor blockers comparedwith atenolol.
The lack of efficacy of atenolol in reducing central pressurecan have a direct effect on cardiovascular outcomes. Inthe CAFE study (Williams et al 2006) both brachial and aortic pressures were measured using pulse wave analysis in 2199 patients originally enrolled for the ASCOT trial. Patients treated with amlodipine/perindopril had greater reductions in central aortic systolic pressure and central aortic pulse pressure compared with patients given atenolol/bendrofluazide, even though reductions in brachial blood pressure were similar across the treatment groups. In addition, central aortic pulse pressure was an independent determinant of cardiovascular outcomes and may help to explain why, in the ASCOT trial, clinical outcomes were worse in patients treated with atenolol/bendrofluazide. Atenolol may be less effective at reducing central aortic pressure because of its effects on reducing heart rate which may enhance the effect of wave reflections. The additional vasodilatory effects of nebivolol contribute to a lower reduction in heart rate, and the subsequent decrease in wave reflection together with improvements in arterial stiffness, and endothelial dysfunction may offset such deleterious hemodynamic effects and thus lower central pressure more than atenolol. This may translate clinically into greater reductions in cardiovascular morbidity and mortality than those seen with traditional beta-blockers although this remains as yet unproven.
Clinical efficacy of nebivolol in hypertension
The efficacy of nebivolol monotherapy has been extensively studied in patients with mild to moderate hypertension. Early double-blind, placebo-controlled studies showed significant reductions of blood pressure with a daily dose of 5 mg nebivolol. Nebivolol was equally effective in black patients, with a notable absence of typical side-effects usually associated with beta-blockade. Nebivolol did not impair Quality of life, measured with the Inventory of Subjective Health (ISH), and the frequency of adverse events was similar between nebivolol and placebo. A recent follow-up study was conducted in order to establish whether the reported efficacy and safety of nebivolol can be generalized in a large nationwide study. A total of 6356 patients with mild hypertension were treated with nebivolol for 6 weeks. No serious adverse events occurred during the study, and the occurrence of minor adverse events was very limited. Blood pressure was significantly reduced and the efficacy of nebivolol monotherapy and add-on therapy was similar. Nebivolol was also highly effective in patients with isolated systolic hypertension.
Cleophas et al (2001) have assessed the long-term efficacy of nebivolol monotherapy. The study found a greater reduction in blood pressure and a higher percentage of responders after 6 months of nebivolol treatment. Nebivolol was well tolerated and patients reported a better feeling of general well being compared with any previous monotherapies. Although current guidelines recommend the adjustment of antihypertensive drug therapy after 6–8 weeks of treatment (WHO-ISH 1999), such a strategy may not be appropriate for optimal nebivolol treatment. In a 6-week observational study, nebivolol reduced both systolic and diastolic blood pressures and, unlike first generation beta-blockers, there were significant reductions in cholesterol, triglycerides, and blood sugar. Results of studies comparing the efficacy and safety of nebivolol compared with other beta-blockers and other classes of antihypertensive agents generally find response rates to treatment are higher, and the frequency and severity of adverse events are either comparable or lower with nebivolol.
Byscard and other beta-blockers
The antihypertensive effects of nebivolol are similar to those of the classic beta-blockers but the unique hemodynamic profile of nebivolol may contribute to its additional reported benefits. For example, in a double blind, randomized study in patients with untreated essential hypertension, both nebivolol (5 mg/day) and atenolol (100 mg/day) significantly reduced blood pressure to a similar extent. However, nebivolol also significantly reduced heart rate and peripheral resistance and increased stroke volume, leading to a small increase in cardiac output whereas cardiac output was significantly decreased and peripheral resistance increased with atenolol. The improvements in diastolic function with nebivolol highlight its potential use in the treatment of heart failure. A separate double blind, randomized, parallel group trial compared patients treated for 4 weeks with nebivolol(5 mg/day), atenolol (50mg/day), or placebo. Both nebivololand atenolol significantly reduced blood pressure comparedwith placebo whilenebivolol had no orthostatic effectsand was better tolerated than atenolol. Similar results were found whennebivolol wascompared with metoprolol.The unique hemodynamic profile of nebivolol may alsocontribute to the maintenance of exercise capacity comparedwith other beta-blockers. In a double blind, placebocontrolled,cross-over study of exercise tolerance in healthy volunteers given nebivolol (5 mg) or atenolol (100 mg) for 2 weeks, exercise capacity was lower and fatigue higher with atenolol compared with nebivolol. Nebivolol also significantly decreased the total peripheral resistance during exercise compared with placebo.
Byscard and other classes of antihypertensive agents
Nebivolol is an effective antihypertensive agent with a superior tolerability profile in comparison with other classes of antihypertensive agents. In a double-blind study comparing hypertensive patients treated with nebivolol (5 mg) or the angiotensin-converting enzyme inhibitor enalapril (10 mg) for 3 months, the decrease in blood pressure was significantly higher and response rates were higher with nebivolol. The incidence of cough was also higher with enalapril. Although nebivolol (5 mg) and the calcium antagonist nifedipine (20 mg) were equally effective in lowering blood pressure, nebivolol also significantly reduced heart rate and adverse events associated with nifedipine treatment caused a significantly higher number of patients to withdraw from the study compared with nebivolol treated patients. Heart rate was also significantly reduced with nebivolol in a study comparing nebivolol (2.5–5 mg) with the calcium channel blocker amlodipine (5–10 mg) in elderly patients with mild to moderate hypertension. A high heart rate is linked to an increased risk of death in the elderly and so an antihypertensive such as nebivolol that effectively lowers blood pressure and also lowers heart rate has dual benefits in this population. Effects of nebivolol and the angiotensin receptor blocker losartan on quality of life and antihypertensive effects were compared in a double-blind, randomized, parallel group study. Patients with hypertension were treated for 12 weeks with 5 mg of nebivolol or 50 mg of losartan once daily. Quality of life parameters did not differ between the two treatments and although both drugs decreased systolic blood pressure similarly, the decrease in diastolic blood pressure was significantly greater with nebivolol.
Type 2 diabetes
Endothelial dysfunction, leading to decreased bioavailability of NO, is one of the major underlying mechanisms linking cardiovascular risk factors such as hypertension, diabetes mellitus, and dyslipidemia to overt cardiovascular disease (Mason 2006). In addition, tight control of blood pressure is more effective at reducing cardiovascular events than tight control of blood sugar in diabetic patients. Unlike some beta-blockers, nebivolol had no effect on insulin sensitivity and glucose tolerance and may therefore have potential therapeutic benefits in patients with type 2 diabetes, especially as many diabetic patients develop hypertension during the course of their disease.
Clinical efficacy of nebivolol in chronic heart failure
A large, randomized, double-blind, placebo-controlled study (SENIORS study), has assessed the effects of nebivolol on mortality and morbidity in elderly patients
≥70 yearswith a history of heart failure. Patientswere started on adose of 1.25 mg nebivolol once daily andtitrated to a target dose of 10 mg over a mean of seven weeks. Although nebivolol did not significantly reduce mortality, the composite risk of all cause mortality or cardiovascular hospital admission (time to first event) was significantly reduced by 15% with nebivolol compared with placebo. This risk reduction was lower than that seen in previous trials with other beta-blockers. However, a sub-analysis of data from patients most similar to patients of these earlier trials showed the risk reduction to increase to 27%. Such results indicate that nebivolol has comparable benefits to those of other beta-blockers studied in heart failure. The benefits of treatment appeared after 6 months and the risk reduction increased if treatment was continued. The benefits of beta-blockade were independent of the initial ejection fraction and were observed even in patients with mild left ventricular dysfunction or preserved ventricular function. The vasodilating effects specific to nebivolol may help to improve tolerability in elderly patients with heart failure and support the use of this particular beta-blocker to treat heart failure in an elderly population.
Safety and tolerability
Nebivolol is well-tolerated in patients with hypertension. In clinical trials, reported adverse events are mostly mild to moderate in nature with an incidence similar to that observed with placebo. Meta-analysis of the incidence of adverse events in double-blind, a placebo-controlled trial finds the occurrence of adverse events to be no different with nebivolol compared with placebo and doses of up to 30 mg (6 times the recommended dose) have been well tolerated. Adverse events typical of classical beta-blockers are lower with nebivolol. Classical beta-blockers may also alter plasma lipids in a potentially adverse manner (Cruickshank and Prichard 1987) whereas patients treated for 3 months with up to 10 mg daily nebivolol show no changes in plasma total cholesterol, triglycerides, lipoproteins, and apolipoproteins. Quality of life, assessed using the Inventory of Subjective Health, is not impaired with nebivolol treatment and in general is similar to that reported with both atenolol and losartan.
In the SENIORS study in elderly patients with chronic heart failure, the tolerability of nebivolol was similar to placebo. Drug-related adverse events were typical of those associated with beta-blockers and included hypotension, bradycardia and dizziness.
Endothelial function and the role of nitric oxide
The vascular endothelium modulates the tone and structure of the blood vessel smooth muscle by releasing various vasoactive and relaxing factors. One of the most important appears to be NO, a potent endogenous smooth muscle dilator, synthesized from the amino acid L-arginine, via the action of the constitutive enzyme nitric oxide synthase. NO regulates basal vascular tone and blood pressure and also has powerful antiatherogenic properties. Endothelial dysfunction, manifested by reduced arterial vasodilation, is linked to abnormalities of the L-arginine/NO pathway resulting in decreased bioavailability of NO. Such dysfunction can therefore predispose to atherogenesis and may represent a link between conditions associated with increased cardiovascular risk (including diabetes, hypercholesterolemia and hypertension) and the development of overt cardiovascular disease. Nebivolol can improve endothelial function directly via an effect on the endothelial L-arginine/NO pathway. Nebivolol relaxes pre-contracted canine coronary artery strips only if the endothelium is intact (Stoleru et al 1993) and this vasorelaxant effect is antagonized by nitro-L-arginine, an inhibitor of NO production, implying that the effect is mediated via release of endothelium-derived NO. Similar findings have been reported in vivo in a human vascular bed. Infusion of nebivolol into the brachial artery of healthy volunteers resulted in vasodilation and an increase in forearm blood flow by an average of 90% whereas atenolol had no effect. The vasodilator effect was significantly reduced with co-infusion of L-NMMA and this inhibition was abolished by L-arginine, the substrate for NO production, suggesting that the L-arginine/nitric oxide pathway was involved. Similar effects of nebivolol have also been demonstrated in experiments of nebivolol infusion into superficial hand veins and in patients with hypertension. Oral nebivolol, but not atenolol, can also improve both basal and stimulated NO release relative to placebo in patients with essential hypertension. The improvements in endothelial function, secondary to release of NO, seen with nebivolol are of particular importance in black patients. This patient group has a reduced bioavailability of NO and alterations in endothelial function which may contribute to the greater susceptibility to cardiovascular disease observed in black patients. Pre-treatment with nebivolol of endothelial cells from black patients can increase NO bioavailability to levels similar to those in endothelial cells from white patients thereby helping to reverse endothelial dysfunction.
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