Comparison of Nebivolol Monotherapy Versus Nebivolol in Combination With Other Antihypertensive Therapies for the Treatment of Hypertension

Comparison of Nebivolol Monotherapy Versus Nebivolol in Combination With Other Antihypertensive Therapies for the Treatment of Hypertension Vasilios Papademetriou, MD* Nebivolol is a novel, ␤1-adrenergic receptor blocker with vasodilatory properties mediated through the activation of the L-arginine/nitric oxide pathway. Short-term randomized clinical trials have demonstrated that nebivolol has antihypertensive efficacy benefits comparable to other ␤ blockers but with a favorable safety and tolerability profile. The long-term safety and efficacy results of oral nebivolol (5, 10, or 20 mg) 1 time/day, as monotherapy or in combination with other antihypertensive agents, were assessed in a double-blind, multicenter, 9-month extension study of 3 phase III, double-blind, 3-month trials in patients with stage I to II hypertension (mean sitting diastolic blood pressures [BPs] >95 and <109 mm Hg). Patients were eligible for entry if they had completed 1 of 3 feeder trials of nebivolol monotherapy (1.25 to 40 mg) 1 time/day. Dose titration and use of additional antihypertensive agents were used to achieve a diastolic BP goal of <90 mm Hg. The primary efficacy end point was change in diastolic BP at trough compared with baseline of the feeder study. Of the 845 patients entering this study, 607 patients (72%) were receiving nebivolol monotherapy, 206 patients (24%) were taking nebivolol plus diuretic, 21 patients (2%) were taking nebivolol plus calcium channel blocker, and 11 patients (1%) were taking nebivolol plus other antihypertensive medication at study end. Patients receiving nebivolol monotherapy had decreases in diastolic and systolic BPs of 15.0 and 14.8 mm Hg, respectively. More than 78% of patients were responders to nebivolol monotherapy, and 65% were responders to combination with a diuretic. Overall incidence of adverse events in the extension study was comparable to that seen in the feeder studies and decreased over time. In conclusion, the results demonstrate that nebivolol is a safe and effective antihypertensive therapy that provides long-term BP-lowering effects with a favorable tolerability profile. © 2009 Published by Elsevier Inc. (Am J Cardiol 2009;103: 273–278)

In short-term randomized clinical trials, nebivolol has demonstrated antihypertensive efficacy benefits that are comparable to other ␤ blockers, but with a more favorable safety and tolerability profile.1– 6 Nebivolol received approval for treatment of hypertension in December 2007 in the United States and is approved in ⬎50 other countries outside North America. A long-term, open-label study performed outside the United States in patients with stage I to II hypertension has demonstrated that nebivolol is safe and effective, with blood pressure (BP)-lowering effects increasing over time.7 I report the long-term safety and efficacy results of oral nebivolol 1 time/day, as monotherapy or in combination with other antihypertensive agents, in a 9-month extension study of 3 phase III, double-blind, 3-month trials, conducted in a mainly United States population of patients with stage I to II hypertension.8 –10

Hypertension Research, Veterans Administration, and Georgetown University Medical Centers, Washington, D.C. Manuscript received July 13, 2008; revised manuscript received and accepted August 22, 2008. *Corresponding author: Tel: 202-745-8334; fax: 202-745-8636. E-mail address: [email protected] (V. Papademetriou). 0002-9149/09/$ – see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.amjcard.2008.08.063

Methods Patients were eligible for entry if they had completed 1 of 3 randomized, double-blind, placebo-controlled, 12week, dose-ranging feeder trials of nebivolol monotherapy 1 time/day (1.25 to 40 mg, total number of patients 2,020). This was a double-blind, multicenter, parallel-group, doseranging, 9-month extension study. Patients were derived from 3 3-month feeder studies conducted at 123 centers, primarily in the United States (105 sites) but also in Europe (18 sites). Inclusion and exclusion criteria for the 3 feeder studies have been described elsewhere. Studies were conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki. The protocol and written informed consent forms were reviewed and approved by a central institutional review board/independent ethics committee before enrollment of any patients in the study. All patients provided written, informed consent before receiving any study medication. Patients were assessed on the last visit of the feeder study (day 0 of extension study) and on weeks 4, 13, 26, and 39 (study end; Figure 1). All patients received nebivolol monotherapy (5, 10, or 20 mg) 1 time/day, based on sitting diastolic BP, heart rate, and study drug dose received during the feeder study. www.AJConline.org

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Figure 1. Study design and patient disposition. *Nebivolol dose based on average sitting heart rate and diastolic BP and on dose in previous study. †Before amendment 1, level 1 and 2 adjunct therapies were thiazide or a thiazide-like diuretic with triamterene, respectively; after amendment 1, level 1 and 2 adjunct therapies were a calcium channel blocker (CCB; amlodipine 5 and 10 mg, respectively). ‡Nebivolol dose and addition of level 1 or 2 adjunct therapies based on average sitting heart rate and diastolic BP and on dose assigned at previous visit. EU ⫽ European Union; US ⫽ United States.

The initial dose of nebivolol and/or use of adjunct therapy were determined by a treatment algorithm that took into consideration patients achieving a sitting diastolic BP ⱕ90 mm Hg, a sitting heart rate ⱖ55 beats/min measured at trough drug plasma level (approximately 24 ⫾ 2 hours after dose), and the nebivolol dose assigned at the previous clinic visit. After 4 weeks of therapy, patients not responding to the initial dose of nebivolol monotherapy (average sitting diastolic BP ⱖ90 mm Hg) received a higher dose of nebivolol and/or a thiazide/thiazide-like diuretic or amlodipine 5 mg; this was designated as “level 1” adjunct therapy. On subsequent visits, if nebivolol plus level 1 therapy did not achieve goal BP and heart rate, a thiazide/thiazide-like diuretic with triamterine or amlodipine 10 mg was added to nebivolol, designated as “level 2” therapy. If a patient was prescribed 2 allowable adjunct medications concurrently (levels 1 and 2), the second adjunct medication was considered a “rescue” medication. To simplify analysis, patients were divided into 4 groups on each visit: nebivolol monotherapy (5 to 20 mg), nebivolol plus diuretic, nebivolol plus calcium channel blocker (amlodipine), or nebivolol plus other antihypertensive medication. Treatment group assignment was based on the treatment taken by a patient during the visit interval. Numbers in

each group varied at each visit, because treatment assignment could be adjusted. Patients were not subject to dietary controls. Patients and investigators remained blinded to nebivolol dose throughout the extension study. Compliance was assessed by pill at each visit. Patients taking ⬍90% of their medication were designated noncompliant. The primary objective of the study was to determine the long-term efficacy and safety of nebivolol in patients with stage I to II hypertension. The primary efficacy end point was change in average sitting diastolic BP measured at trough (approximately 24 ⫾ 2 hours after dose) at the end of the 9-month extension phase compared with the baseline of the feeder study. Secondary end points included change from feeder study baseline in mean standing and supine diastolic BPs, trough sitting, standing, and supine systolic BPs, and diastolic and systolic BPs taken at peak drug plasma concentration (approximately 2 to 3 hours after dose) in the sitting, supine, and standing positions, measured at the end of the extension phase. Responders were defined as patients achieving a trough sitting diastolic BP at study end of ⱕ90 mm Hg or with an absolute decrease of ⱖ10 mm Hg compared with the baseline of the feeder study.

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Table 1 Patient baseline* demographics by treatment† (population: intent-to-treat) Parameter

Age (yrs) Mean ⫾ SD ⬍65 ⱖ65 Sex Men Women Race Black Nonblack No diabetes Body mass index‡ (kg/m2) Mean ⫾ SD ⬍30 ⱖ30 Sitting systolic BP (mm Hg), mean ⫾ SD Sitting diastolic BP (mm Hg), mean ⫾ SD Sitting heart rate (beats/min), mean ⫾ SD

Nebivolol Nebivolol ⫹ Monotherapy Diuretic (n ⫽ 607) (n ⫽ 206)

Total (n ⫽ 845)

52.7 ⫾ 11.5 503 (82.9%) 104 (17.1%)

54.1 ⫾ 10.1 53.0 ⫾ 11.2 172 (83.5%) 702 (83.1%) 34 (16.5%) 143 (16.9%)

311 (51.2%) 296 (48.8%)

125 (60.7%) 451 (53.4%) 81 (39.3%) 394 (46.6%)

133 (21.9%) 474 (78.1%) 568 (93.6%)

54 (26.2%) 197 (23.3%) 152 (73.8%) 648 (76.7%) 194 (94.2%) 792 (93.7%)

29.1 ⫾ 4.1 358 (59.0%) 249 (41.0%) 151 ⫾ 14

29.6 ⫾ 4.1 29.3 ⫾ 4.1 116 (56.3%) 490 (58.0%) 90 (43.7%) 355 (42.0%) 155 ⫾ 16 152 ⫾ 14

99 ⫾ 3

100 ⫾ 4

99 ⫾ 4

73 ⫾ 8

73 ⫾ 9

73 ⫾ 9

* Baseline at start of feeder studies. Treatment classification at end of study. ‡ Body mass index is the baseline weight in kilograms divided by the square of the baseline height in meters.

Figure 2. Mean change in sitting BP (at trough) from baseline to end of study for the nebivolol monotherapy group (intent-to-treat population, observed cases). SiDBP ⫽ sitting diastolic BP; SiSBP ⫽ sitting systolic BP.

†

Efficacy and safety measurements were recorded at each visit. BP was recorded as the mean of 3 readings measured using a calibrated mercury sphyngomanometer and appropriately sized cuff in supine, sitting, and standing positions at trough and peak drug plasma levels. Safety was assessed by monitoring of adverse events (AEs), vital signs, physical examination (including body weight), electrocardiograms, and laboratory assessments (chemistry panel, hematologic profile, and urinalysis). The incidence of AEs was recorded at each study visit and included day ranges, namely “up to week 4” (day ⱕ60, includes all AEs up to day 60, AEs continued from the feeder studies, and all AEs with unknown dates), week 13 (includes all AEs during days 61 to 144), week 26 (includes all AEs during days 145 to 228), and week 39 (includes all AEs occurring day ⱖ229). Incidence and numbers of AEs were based on all AEs recorded during the extension study, which included AEs with a start date after the first dose of nebivolol in this study and ongoing AEs with start dates in the feeder studies. Changes from baseline in the lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides) were also monitored throughout the extension study. Routine clinical chemistry, hematology, and urinalysis were performed on day 0 and week 39 (first and last visits). In addition, blood glucose and electrolytes were measured at weeks 13 and 26. Because the cohort of this study was self-selected, no formal statistical comparisons were made. Changes from baseline of the feeder studies to the end of the 9-month extension were summarized by treatment group for overall

numbers and percentages of patients. Descriptive statistics (mean, SD, and 95% confidence intervals [CIs]) for change from baseline of the feeder studies to the end of the 9-month extension were summarized for all continuous efficacy parameters by visit and treatment group. BP parameters were also displayed across time. The sample size was calculated to enable detection of AEs during long-term exposure. It was assumed that ⱖ240 patients would be exposed to nebivolol (combined groups of 5, 10, or 20 mg) for a period of 1 year. With this number of patients, there was ⬎95% chance that AEs with a frequency ⱖ1.3% would occur. Therefore, 240 patients was the minimum number required for the conduct of the study, but actual enrollment was dependent on how many patients successfully completed the feeder studies and volunteered to participate in the long-term extension study. Results A total of 2,016 patients were randomized in the 3 feeder studies. Of those, 1,738 (86.2%) completed the studies, 169 patients in the placebo arm and 1,569 patients in the nebivolol arm. Of the 845 patients entering the 9-month extension study (Figure 1), 81 (9.6%) had previously received placebo and 764 (90.4%) had previously received nebivolol in the feeder studies. Patients entering the 9-month extension study had a mean age of 53 years, about ½ of them were men (53.4%), and most were nonblack (76.7%; Table 1). The nebivolol plus amlodipine and nebivolol plus other antihypertensive medication groups did exhibit some differences in baseline demographics compared with the other groups. These differences may be due to the small sample in the latter 2 groups (n ⫽ 21 and 11, respectively) and therefore will not be discussed further.

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The American Journal of Cardiology (www.AJConline.org) Table 2 Summary of the most frequently reported adverse events for all treatment groups (n ⫽ 845) AE*

Figure 3. Responder rates at the end of the 9-month extension study by treatment (intent-to-treat population, observed cases). A responder was defined as a patient whose average trough sitting diastolic BP was ⬍90 mm Hg at the end of the study (last visit after baseline with no missed appointments) or had decreased by ⱖ10 mm Hg from the baseline of the feeder study; treatment classification was based on treatment at the end of study. ‡Includes only patients with no missing results.

By the end of the study, 607 patients (72%) were receiving nebivolol monotherapy, 206 patients (24%) were taking nebivolol plus diuretic, 21 patients (2%) were taking nebivolol plus amlodipine, and 11 patients (1%) were taking nebivolol plus other antihypertensive medication. Only 1.1% of the 845 patients received a second adjunctive antihypertensive medication. Patient compliance with the treatment regimen was high, from 92.0% in the nebivolol plus diuretic group, 94.8% for the nebivolol monotherapy group, to 100% in the nebivolol plus amlodipine and nebivolol plus other antihypertensive medication groups. Nebivolol-treated patients demonstrated significant and sustained decreases in BP compared with baseline, and pressures remained lowered throughout the duration of the extension study. The largest decrease in BP was observed in the nebivolol monotherapy group. At study end, mean diastolic and systolic BPs were decreased by 15.0 mm Hg (95% CI ⫺15.9 to ⫺14.1) and 14.8 mm Hg (95% CI ⫺16.6 to ⫺13.1), respectively (Figure 2). Patients treated with nebivolol plus diuretic also demonstrated significant decreases in BP. In this group diastolic and systolic BPs were decreased by ⫺12.0 mm Hg (95% CI ⫺13.2 to ⫺10.8) and ⫺16.2 mm Hg (95% CI ⫺19.0 to ⫺13.4), respectively. Similar results were obtained for the nebivolol monotherapy and nebivolol plus diuretic groups for trough and peak supine, standing, and sitting diastolic BP and systolic BP. These decreases in BP were observed regardless of race, gender, age, or body mass index. There were too few patients in the nebivolol plus amlodipine and nebivolol plus other antihypertensive medication groups to draw any meaningful efficacy conclusions, although similar trends were noted. Overall, 74% of nebivolol-treated patients and 65.5% of nebivolol plus diuretic treated patients responded to treatment (trough sitting diastolic BP at study end ⱕ90 mm Hg or decrease from baseline ⱖ10 mm Hg; Figure 3). A post hoc analysis assessed response rates in patients entering the long-term extension study who had received placebo during the feeder studies and in those nebivolol-treated patients who remained uncontrolled at the end of the feeder studies. Of the 19 placebo-treated patients entering the extension study, 63.2% responded to nebivolol treatment. Of the 130

Total Headache Fatigue† Upper respiratory tract infection, NOS Arthralgia Nasopharyngitis Dizziness Sinusitis, NOS Urinary tract infection Blood triglycerides increased C-reactive protein increased Cough Edema peripheral Nausea Bronchitis, NOS Dyspepsia Blood glucose increased Blood cholesterol increased Hypercholesterolemia aggravated Insomnia Back pain Hypercholesterolemia Hyperlipidemia

Incidence 461 (54.6%) 46 (5.4%) 39 (4.6%) 33 (3.9%) 32 (3.8%) 31 (3.7%) 25 (3.0%) 21 (2.5%) 21 (2.5%) 20 (2.4%) 20 (2.4%) 15 (1.8%) 15 (1.8%) 14 (1.7%) 14 (1.7%) 13 (1.5%) 13 (1.5%) 11 (1.3%) 11 (1.3%) 11 (1.3%) 10 (1.2%) 9 (1.1%) 9 (1.1%)

NOS ⫽ not otherwise specified. * For each event, a patient was classified only 1 time. † Typical ␤-blocker–associated AE.

nebivolol-treated patients who were nonresponders in the feeder studies, 61.5% responded at the end of the extension study. Nebivolol monotherapy alone or in combination with a diuretic resulted in a decrease of heart rate by ⫺7.7 or ⫺8.5 beats/min, respectively. Overall, nebivolol 5 to 20 mg administered 1 time/day was safe and well tolerated. Although 54.6% of patients reported ⱖ1 AE, most reported events were minor and nonspecific (Table 2). Drug-related AEs requiring discontinuation were few and serious AEs rare. The most commonly reported side effect was headache (5.4%), and the incidence decreased over time from 3.4% at day 28 to 0.5% at day 273. The incidence of AEs commonly attributed to ␤ blockers was low. Over the duration of the study, 1 patient (0.1%) reported sexual dysfunction, 5 patients (0.6%) developed bradycardia, 39 patients (4.6%) reported fatigue, and 25 patients (3.0%) reported dizziness. The incidence of reported AEs was, in general, higher in patients taking combination therapy compared with nebivolol monotherapy. During the last study visit, however, the incidence of AEs was similar in the 2 larger groups; for nebivolol monotherapy the incidence was 15.6% (78/275) versus 18.5% for the nebivolol plus diuretic group. Serious AEs were rare. Overall, 17 patients (2.0%) developed 19 serious AEs: 12 patients were receiving nebivolol monotherapy, 4 were taking nebivolol plus diuretic, and 1 was taking nebivolol plus other antihypertensive medications. Two patients (0.2%) developed serious AEs possibly or definitely related to the study drug; 1 patient taking nebivolol plus diuretic had right upper arm quadrant pain, which was possibly related to the study drug and resolved with treatment. One patient taking nebivolol monotherapy

Systemic Hypertension/Long-Term Antihypertensive Therapy With Nebivolol Table 3 Mean change from baseline to end of study in laboratory parameters associated with cardiovascular risk* Laboratory Parameter (mg/dl) Total cholesterol No. of patients Baseline mean Mean ⌬ from baseline ⫾ SE Low-density lipoprotein cholesterol No. of patients Baseline mean Mean ⌬ from baseline ⫾ SE High-density lipoprotein cholesterol No. of patients Baseline mean Mean ⌬ from baseline ⫾ SE Triglycerides No. of patients Baseline mean Mean ⌬ from baseline ⫾ SE Glucose No. of patients Baseline mean Mean ⌬ from baseline ⫾ SE

Nebivolol Monotherapy

Nebivolol ⫹ Diuretic

265 210 ⫺1.2 ⫾ 1.8

124 213 1.1 ⫾ 2.9

218 121 1.4 ⫾ 1.7

96 124 1.3 ⫾ 2.9

231 56 ⫺5.4 ⫾ 0.6

103 54 ⫺5.0 ⫾ 1.0

265 164 23.6 ⫾ 6.5

124 179 27.1 ⫾ 15.4

265 105 0.7 ⫾ 1.2

124 101 7.4 ⫾ 1.6

⌬ ⫽ change. * Intention to treat, observed cases.

reported sexual dysfunction, which was deemed definitely related to the study drug and resolved spontaneously after withdrawal from the study. One patient (0.1%) taking nebivolol monotherapy developed bradycardia and peripheral edema that was considered probably related to the study drug, and the patient was withdrawn from the study. There were no clinically relevant differences observed in the incidence of AEs in subgroup analyses by gender, ethnicity (black versus nonblack), and age (⬍65 versus ⱖ65 years). Obese patients (body mass index ⱖ30 kg/m2) had a slightly higher incidence of AEs over the 4 intervals compared with nonobese patients (body mass index ⬍30 kg/m2), although this difference was not significant. There was a slight increase in blood glucose in the nebivolol monotherapy group from baseline to study end, and a slightly greater increase in blood glucose was observed in the nebivolol plus diuretic group; however, neither change was statistically significant (Table 3). Mean levels of triglycerides and cholesterol (including low-density lipoprotein cholesterol and high-density lipoprotein cholesterol) changed little during the extension study, and none of these changes were considered clinically significant. Discussion Results from this study indicate that oral nebivolol 1 time/day at doses from 5 to 20 mg is safe and effective when used for treatment of stage I to II hypertension over a period of 9 months. Nebivolol was safe and effective as monotherapy or in combination with other antihypertensive drugs. More than 78% of patients were responders to nebivolol monotherapy, and 65% were responders to combination with a diuretic. At first glance, it appears strange

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that fewer patients responded to the combination of nebivolol plus diuretic compared with monotherapy, but this can easily be explained if we take into consideration that patients who progressed to combination were the nonresponders to monotherapy. The absolute systolic and diastolic BP decrease in all treatment groups was 14 to 16 mm Hg, which is similar to or better than what is usually seen in similarly designed hypertension trials. Approximately 2⁄3 of the patients who had received placebo or who were nonresponders on nebivolol treatment in the feeder studies became responders in the extension study. Response rates were similar across the board and in all subgroups of the study population, suggesting that nebivolol can be used in all patients with stage I to II hypertension regardless of age, race, gender, or body mass index. AEs that could be attributed to study drug were few. Because there was no placebo arm in the present study, no comparisons can be made, but previously published studies have indicated that the side effect profile of nebivolol is similar to placebo.3,8 –12 Overall incidence of AEs in the extension study was comparable to that seen in the feeder studies and decreased over time. Most events reported were mild to moderate in intensity. Incidence of treatment-related AEs was also low and tended to decrease over time. In addition, discontinuation due to AEs was very low (3.1%) and patient compliance was high (94.3%) over the study period. The efficacy and safety results of this trial are similar to those in previously published work in Europe; nebivolol was shown to be effective and well tolerated in the treatment of hypertension.1– 6 In a long-term, 6-month study, conducted in 3,741 hypertensive patients, the BP-lowering effects of nebivolol were consistent over the duration of treatment, and nebivolol was well tolerated, with a low incidence of ␤-blocker–associated AEs.7 The present study was designed to allow for individualized treatment of hypertension and to adhere to the Joint National Committee 7 guidelines, which recommend the use of ⬎1 antihypertensive drug to maintain strict BP control.13 In keeping with these guidelines, investigators were allowed to prescribe a second antihypertensive drug, which could be administered according to a prespecified treatment algorithm or by investigator choice. Although the study yielded a large number of treatment groups that ultimately complicated data analysis, this treatment approach may mimic a “real-world” clinical situation. Thus, the present data may offer insight into long-term nebivolol use in routine clinical practice. The findings of this trial further expand the database on nebivolol with its unique mechanism of action. Nebivolol is a highly cardioselective ␤1-adrenoceptor blocking agent with vasodilatory properties attributed to its ability to increase nitric oxide bioavailability in the vascular endothelium.8 –11,14 –17 Together these effects likely contribute to the efficacy and tolerability profile of nebivolol. They may also explain the low incidence of ␤-blocker–associated AEs (e.g., sexual dysfunction, fatigue, and depression) reported in this study. Several recent publications have provided more information on the efficacy, tolerability, and mechanism of action of nebivolol.8 –13,18,19 Concerns surrounding the association of traditional ␤ blockers (e.g., atenolol and metoprolol) with increased risk

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of insulin insensitivity and new-onset diabetes20 do not appear to be present with newer, vasodilating ␤ blockers.21–24 These differences have been recognized in recent guidelines that specifically state that vasodilating ␤ blockers appear to exhibit few, if any, unfavorable effects on metabolic parameters compared with traditional ␤ blockers.25,26 Indeed, there were no significant changes in blood glucose compared with placebo in the 3 nebivolol monotherapy feeder studies,8 –10 and this outcome was sustained in the present study. The incremental increase in blood glucose observed in the nebivolol plus diuretic group has been observed in previous studies with the addition of diuretics.27–29 Acknowledgment: The author acknowledges Strategic Medical Initiatives for providing editorial support; editorial support was funded by Forest Laboratories, Jersey City, New Jersey. 1. Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension. Am J Cardiol 2003;92:344 –348. 2. Czuriga I, Riecansky I, Bodnar J, Fulop T, Kruzsicz V, Kristof E, Edes I, for the NEBIS Investigators Group. Comparison of the new cardioselective beta-blocker nebivolol with bisoprolol in hypertension: the Nebivolol, Bisoprolol Multicenter Study (NEBIS). Cardiovasc Drugs Ther 2003;17:257–263. 3. Grassi G, Trevano FQ, Facchini A, Toutouzas T, Chanu B, Mancia G. Efficacy and tolerability profile of nebivolol vs atenolol in mild-tomoderate essential hypertension: results of a double-blind randomized multicentre trial. Blood Press Suppl 2003;2:35– 40. 4. Van Nueten L, Lacourciere Y, Vyssoulis G, Korlipara K, Marcadet DM, Dupont AG, Robertson JI. Nebivolol versus nifedipine in the treatment of essential hypertension: a double-blind, randomized, comparative trial. Am J Ther 1998;5:237–243. 5. Van Nueten L, Schelling A, Vertommen C, Dupont AG, Robertson JI. Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial. J Hum Hypertens 1997;11:813– 819. 6. Van Nueten L, Taylor FR, Robertson JI. Nebivolol vs atenolol and placebo in essential hypertension: a double-blind randomised trial. J Hum Hypertens 1998;12:135–140. 7. Cleophas TJ, Grabowsky I, Niemeyer MG, Makel WN, van der Wall EE. Long-term efficacy of nebivolol monotherapy in patients with hypertension. Curr Ther Res Clin Exp 2001;62:451– 461. 8. Greathouse M. A randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study to assess the efficacy and safety of nebivolol in patients with stage I or II hypertension. Clin Cardiol 2008. In press. 9. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens (Greenwich) 2007;9:866 – 875. 10. Weiss RJ, Weber MA, Carr AA, Sullivan WA. A randomized, doubleblind, placebo-controlled parallel-group study to assess the efficacy and safety of nebivolol, a novel beta-blocker, in patients with mild to moderate hypertension. J Clin Hypertens (Greenwich) 2007;9:667– 676. 11. Ambrosioni E, Borghi C. Tolerability of nebivolol in head-to-head clinical trials versus other cardioselective beta-blockers in the treatment of hypertension: a meta-analysis. High Blood Press Cardiovasc Prev 2005;12:27–35. 12. Gradman A. Safety and tolerability of nebivolol: a pooled safety analysis comparing typical ␤-blocker–associated adverse events with placebo. J Clin Hypertens (Greenwich) 2008;10(suppl A):A120.

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