Abstract and Introduction
Abstract
Purpose. The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of nebivolol are reviewed.
Summary. Nebivolol, a third-generation, highly β1-specific β-blocker, is labeled for the treatment of hypertension in the United States. In addition to its β-blocking effects, nebivolol has been shown to increase endothelin-dependent nitric oxide, giving it a unique peripheral vasodilatory action. Nebivolol is extensively metabolized by cytochrome P-450 isoenzyme 2D6. In patients with heart failure, certain β-blockers antagonize excessive adrenergic stimulation and can slow the progression of the disease. Clinical trials have compared nebivolol at target dosages of 5 and 10 mg once daily with placebo and, in small trials, with carvedilol in the treatment of adults with chronic heart failure. Nebivolol appears to have beneficial effects in patients with heart failure, including improvements in left ventricular ejection fraction, left ventricular volumes, and exercise capacity. In addition, the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure showed a reduction in morbidity and mortality after treatment with nebivolol when compared with placebo, though this effect appeared to be less than that of other β-blockers currently recommended for the treatment of heart failure. Nebivolol was well tolerated in all clinical trials, with the most frequently reported adverse events including bradycardia, hypotension, and dizziness. To date, no large clinical trials have compared nebivolol with currently recommended β-blockers in patients with heart failure.
Conclusion. Nebivolol has beneficial effects in heart failure but cannot be considered equivalent to other currently accepted therapies.
Introduction
Heart failure is a worldwide problem and a growing concern in the United States, currently affecting 5 million Americans, with about 550,000 cases diagnosed annually. The risk of developing heart failure increases greatly with age, as heart failure is the most common discharge diagnosis in patients over the age of 65 years. Further, the incidence of heart failure is on the rise. In 2006, there were over 1 million hospital discharges for heart failure in the United States, an increase of 25% over the previous 10 years. The estimated cost of this disease in the United States in 2009 was $37.2 billion.
Heart failure is a clinical syndrome caused by a progressive worsening of heart function, resulting from an impaired ability of the heart's ventricles to fill (diastolic dysfunction) or pump (systolic dysfunction) sufficiently to meet the body's metabolic needs. Because systolic and diastolic dysfunction share similar causes, most notably hypertension and ischemic heart disease, many patients with heart failure have varying degrees of both systolic and diastolic impairment.
Due to the progressive nature of the disease and an overall decrease in the heart's pumping capacity, the activation of several compensatory mechanisms involving both the adrenergic and renin–angiotensin–aldosterone systems are needed to maintain adequate cardiac output, which is a function of heart rate and stroke volume. In the short-term, these compensatory mechanisms do maintain cardiac output; however, as these mechanisms are sustained, they contribute to further decline in heart function. Increased circulating levels of norepinephrine, for example, increase heart rate and cardiac contractility, but a sustained increase in heart rate ultimately increases myocardial oxygen demand and further increases the workload on the heart. Over time, β1-adrenergic receptors are desensitized to norepinephrine, and increased levels of norepinephrine result in myocyte hypertrophy and necrosis, causing progression of systolic dysfunction, cardiac remodeling, and a cyclic process of continuously worsening heart function.
This article reviews the use of nebivolol in chronic heart failure. A variety of studies have found that β-blocker therapy can improve the prognosis and slow the progression of heart failure. Beta-blockers have several documented beneficial effects in heart failure, most notably their ability to antagonize the negative effects of excessive adrenergic stimulation. This antagonism results in a reduction in myocardial oxygen demand, the inhibition of renin release, the prevention of tachycardia and arrhythmias, and the prevention of myocardial cell hypertrophy and necrosis. Clinical trials have shown that β-blockers improve left ventricular ejection fraction (LVEF), decrease ventricular mass, reverse cardiac remodeling, and reduce overall morbidity and mortality associated with heart failure. However, the beneficial effects of β-blockers are not assumed to be class effects, and current consensus recommendations for the treatment of adults with chronic heart failure indicate that only those β-blockers that have demonstrated beneficial effects in clinical trials should be used. In the United States, bisoprolol, carvedilol, and extended-release metoprolol succinate are recommended for patients with systolic dysfunction by the American Heart Association (AHA) and the American College of Cardiology (ACC). Because β-blockers can acutely worsen heart failure in some patients, they should be initiated in stable patients at low dosages, and the dosage should be increased slowly to the target dosage that has been shown to reduce morbidity and mortality (bisoprolol fumarate 10 mg once daily, metoprolol succinate 200 mg once daily, or carvedilol 25 mg [for patients weighing <85 kg] or 50 mg [for patients weighing ≥85 kg] twice daily). The ACC–AHA consensus recommendations indicate that β-blocker therapy should be initiated in any patient with a history of myocardial infarction or an LVEF of <40%, regardless of the presence of heart failure symptoms. Recommendations of the European Society of Cardiology (ESC) are similar to those issued by AHA/ACC, except that ESC recommendations also include the use of nebivolol, initiated at 1.25 mg (as the hydrochloride salt) daily and adjusted up to 10 mg daily, as a fourth treatment option. Nebivolol was approved for marketing in the United States in 2007 for the treatment of hypertension.