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Nebivolol for Hypertension
Abstract & Commentary
By Michael H. Crawford, MD
Source: Papademetriou V. Comparison of nebivolol monotherapy versus nebivolol in combination with other antihypertensive therapies for the treatment of hypertension. Am J Cardiol. 2009;109:273-278.
Nebivolol is a new beta 1 selective blocker with vasodilatation properties via activation of the L-arginine/nitric oxide pathway. Short-term studies, and a long-term, open-label study, have shown excellent efficacy and safety in stages 1-11 hypertension. Papademetriou presents the results of a nine-month extension of three trials of nebivolol monotherapy vs placebo, where patients were titrated with nebivolol monotherapy or other agents. The protocol involved dose titration of nebivolol monotherapy (5, 10, or 20 mg/day in a single dose) or the addition of other drugs (thiazide diuretic, amlodipine, others) until diastolic blood pressure was < 90 mmHg and trough heart rate was > 55 beats/min. The primary endpoint was trough diastolic blood pressure at the end of nine months. Of the 1,738 patients who completed the three-feeder studies, 845 entered the nine-month extension study. During the feeder study, 90% were on nebivolol and 10% were on placebo. Men and women were about evenly divided, and about a quarter were African-American. The patients were distributed into four groups: nebivolol alone (607); nebivolol plus diuretic (206); nebivolol plus calcium channel blocker (21); and nebivolol plus other meds (11). Compliance was high-ranging, from 92%-100% across the four groups.
Results: Patients on nebivolol monotherapy exhibited the greatest decrease in blood pressure (15 mmHg for systolic and diastolic pressure); 78% of the patients achieved goal blood pressure. The pressures remained decreased throughout the study period. Among those on nebivolol plus diuretic, 65% reached goal blood pressure. More than half the patients reported some adverse event, but none exceeded 5% incidence. Whether all were related to the drug is difficult to say since there was no placebo arm in the long-term study. Adverse events usually attributed to beta blockers were low; one patien developed sexual dysfunction, five bradycardia, 39 fatigue (4.6%), and 25 dizziness (3%). Serious adverse events were rare (2%). Papademetriou concluded that nebivolol alone, or in combination with other antihypertensive drugs, is a safe and effective long-term antihypertensive therapy.
Nebivolol is a relatively new addition to our antihypertensive armamentarium, having been approved by the FDA in December 2007. This study adds to the long-term experience with this drug. It is a unique, highly cardio-selective beta 1 blocker that also increases nitric oxide production, which results in vasodilation. Whether these properties explain the low incidence of traditional beta-blocker adverse effects is unknown. Nebivolol does not appear to significantly affect metabolic parameters such as blood glucose levels.
Nebivolol is a potent antihypertensive agent with average systolic blood pressure decreases of 14-16 mmHg in this study across all groups. It may seem strange that monotherapy resulted in more people achieving target blood pressure goals as compared to combination therapy with diuretics (78% vs 65%, respectively), but those on diuretics were nebivolol monotherapy failures. Also, no particular subgroup did better on nebivolol (age, sex, race, or BMI). Although the study was complex, it was really a study of a nebivolol-based approach, with other drugs added as you would in the real world. Remarkably, only 3% of the subjects discontinued therapy because of adverse events, and serious adverse events were rare.
A major limitation of this study is that the patients were already selected for being tolerant of nebivolol. Only 10% of the subjects were previously on placebo in the lead in studies. This increases the likelihood that nebivolol will be tolerated. However, it does not necessarily select patients for their blood pressure response to the drug. Thus, despite this limitation for assessing drug tolerance and safety, efficacy seems well proven. If the low adverse event profile, especially of typical beta-blocker side effects, is maintained in real world practice, nebivolol could be a positive addition to our antihypertensive armamentarium.