Therapeutic Advances in Cardiovascular Disease

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1 459593TAK Therapeutic Advances in Cardiovascular DiseaseFW Germino, Y Lin 2012 Therapeutic Advances in Cardiovascular Disease Original Research Efficacy and tolerability of nebivolol: does age matter? A retrospective analysis of three randomized, placebo-controlled trials in stage I II hypertension Ther Adv Cardiovasc Dis (2012) 6(5) DOI: / The Author(s), Reprints and permissions: journalspermissions.nav F. Wilford Germino, Yuhua Lin, Vojislav Pejović and Lynn Bowen Abstract: Objectives: This retrospective analysis examined the efficacy and tolerability of nebivolol, a ß 1 -selective, vasodilatory β-blocker, in four different age groups of patients with hypertension. Methods: Data were pooled from three 12-week, randomized, placebo-controlled trials (placebo, n = 205; nebivolol [ /40 mg/day], n = 1811) and stratified into age quartiles (Group 1: years; Group 2: years; Group 3: years; Group 4: years). Only patients treated with placebo and the three commonly used nebivolol dosages (5, 10, and 20 mg/day) are presented. Baseline-to-endpoint changes in trough sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR) were analyzed for each age quartile using an analysis of covariance (ANCOVA) model. Tolerability was assessed by means of adverse event (AE) rates. Results: The analysis comprised 205 placebo-treated patients and 1380 patients treated with nebivolol dosages of 5, 10, or 20 mg/day. Older age was associated with higher SBP values at baseline. In all age groups, each of the three most frequently used nebivolol dosages significantly reduced DBP, compared with placebo ( 9.1 to 11.8 mmhg versus 3.4 to 5.9 mmhg; p overall). For SBP, a statistically significant effect versus placebo was observed for all dosages and age groups except for 5 and 10 mg/day in Group 4. Within each group, treatment with nebivolol (all three dosages) and placebo resulted in similar AE rates (nebivolol: %; placebo: %) and AE-related discontinuation rates ( % versus 0 4.3%). In each age group, there were no significant nebivolol-placebo differences in the rates of patients who experienced clinically significant changes or abnormal endpoint levels of metabolic parameters. Conclusions: This retrospective analysis suggests that nebivolol monotherapy is efficacious and well tolerated across various age groups, with the efficacy in reducing SBP somewhat diminishing in patients over 62 years of age. Correspondence to: F. Wilford Germino, MD Department of Internal Medicine, Orland Primary Care Specialists, th Street, Orland Park, IL 60467, USA wgermino@hotmail.com Yuhua Lin, MS Forest Research Institute, Jersey City, NJ, USA Vojislav Pejović, PhD Prescott Medical Communications Group, Chicago, IL, USA Lynn Bowen, PhD* Forest Research Institute, Jersey City, NJ, USA *Lynn Bowen is no longer associated with Forest Research Institute. Keywords: age groups, hypertension, nebivolol Introduction The prevalence of hypertension, a major risk factor for cardiovascular disease [World Health Organization, 2009], is strongly associated with age [Egan et al. 2010; Franklin et al. 1997, 2001]. In the US, hypertension affects approximately 35% (30 million) of those aged between 40 and 59 years and approximately 70% (40 million) of those who are 60 or older [Howden and Meyer, 2011; Egan et al. 2010; Vasan et al. 2002]. In addition to the overall prevalence, age is also associated with the severity and type of hypertension: patients with stage II hypertension comprise 5% of those aged years and 32% of those 80 and older [Qureshi et al. 2005]; in individuals over 65, isolated systolic hypertension is the most common form of high blood pressure [Franklin et al. 2001; Kannel, 2000]

2 Therapeutic Advances in Cardiovascular Disease 6 (5) The changes in hypertension type, severity, and prevalence across age groups pose notable challenges in clinical practice. For example, older age is also associated with an increased prevalence of comorbidities and polypharmacy, whereas younger age is a key determinant of poor therapy adherence [Briesacher et al. 2008; Fischer et al. 2010]. In addition, antihypertensive medication itself is independently associated with a higher risk of adverse events (AEs) such as erectile dysfunction (ED) [Cordero et al. 2010; Düsing, 2005; Ko et al. 2002; Shiri et al. 2007] and orthostatic hypotension (OH) [Cleophas and van Marum, 2003], which may affect quality of life and lead to treatment discontinuation in both younger and older patients [Fogari and Zoppi, 2004]. Therefore, patient age should be carefully taken into consideration when selecting antihypertensive therapy [Carlberg and Nilsson, 2010]. Nebivolol, a ß 1 -selective blocker with vasodilatory properties that are thought to be mediated by nitric oxide (NO) [Münzel and Gori, 2009], is approved in the US for the treatment of hypertension. Nebivolol has been associated with a lower incidence of AEs compared with other β 1 - selective blockers [Ambrosioni and Borghi, 2005], and a number of studies suggest that sexual function in patients with hypertension is not adversely affected by nebivolol therapy [Boydak et al. 2005; Brixius et al. 2007; Cordero et al. 2010; Doumas et al. 2006]. Although available data suggest that treatment with older-generation β-blockers (mainly atenolol) is associated with a reduction of cardiovascular morbidity and mortality in younger (<60 years of age) but not older ( 60 years) patients with uncomplicated hypertension [Khan and McAlister, 2006; Messerli et al. 1998], there are no randomized, prospective, placebo-controlled trials that examined the effects of nebivolol treatment, short or long term, based on patients age. This post hoc analysis evaluated the efficacy and safety of nebivolol monotherapy in a pooled sample from three US registration trials [Greathouse, 2010; Saunders et al. 2007; Weiss et al. 2007], stratified by age quartiles. Methods Data collection All data reported in this publication were pooled from three similarly designed phase III, randomized, double-blind, placebo-controlled, multicenter, parallel group trials: NEB-MD-202 [ClinicalTrials.gov identifier: NCT ; Saunders et al. 2007], NEB-MD-302 [Clinical Trials.gov identifier: NCT ; Weiss et al. 2007], and NEB-MD-305 [ClinicalTrials.gov identifier: NCT ; Greathouse, 2010]. Trials NEB-MD-202 and NEB-MD-302 were conducted in the US; trial NEB-MD-305 was conducted in the US, UK, Belgium, and the Netherlands. Participants and trial design The trial details have been published previously [Greathouse, 2010; Saunders et al. 2007; Weiss et al. 2007]. Participants were adult men and women of any race (except for study NEB-MD-202, which recruited black patients only) with a diagnosis of stage I II hypertension (defined as an average untreated sitting diastolic blood pressure [SiDBP] 95 and 109 mmhg) at randomization (Day 0). Patients were not permitted to participate if they had a body mass index (BMI) 35 kg/m 2 (NEB- MD-202 excluded patients with BMI 40 kg/ m 2 ), secondary or malignant hypertension, history or presence of respiratory problems (asthma, bronchospasm, or chronic obstructive pulmonary disease [COPD]), abnormalities in cardiac rate or rhythm, uncontrolled diabetes (hemoglobin A 1C 10%), a cerebrovascular accident or myocardial infarction within 6 months of screening, heart failure requiring treatment, concomitant therapy with medications that may have affected blood pressure, or hypersensitivity to ß-blockers, or if they were pregnant or nursing. In all three trials, a single-blind placebo run-in phase (2 6 weeks) was followed by a randomized, double-blind, fixed-dose treatment phase in which patients were randomized to receive placebo or nebivolol (NEB-MD-202: 2.5, 5, 10, 20, and 40 mg/day; NEB-MD-302: 1.25, 2.5, 5, 10, 20, and 30/40 mg/day; NEB- MD-305: 5, 10, and 20 mg/day) daily for 12 weeks. In NEB-MD-302, the patients randomized to receive the highest nebivolol dosage (30/40 mg/day) were given 30 mg/day for 2 weeks, at which point the dose was up-titrated to 40 mg/day if their sitting HR remained above 55 bpm. All measurements were performed in triplicate at trough (24 ± 2 hours postdose) and 186

3 FW Germino, Y Lin et al. at peak (2 3 hours postdose). All studies were performed in accordance with the Declaration of Helsinki. Assessments Efficacy and tolerability data presented in this analysis are for the dosages of 5, 10, and 20 mg/ day, which correspond to the doses most commonly used in clinical practice. The efficacy outcomes were changes from baseline in trough sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP), which correspond to primary and secondary measures, respectively, in all three pivotal trials. The following safety and tolerability parameters are reported: AE rates, mean changes from baseline in heart rate (HR) and the levels of metabolic parameters (glucose, triglycerides, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and total cholesterol), and the percentages of patients who had normal glucose levels ( 125 mg/dl) at baseline but high levels (>125 mg/dl) at the end of the trial. (Owing to low incidence, rates for ED and OH were examined for the entire dosage range: /40 mg/day.) Data analysis All data are presented for each age quartile (Group 1: years; Group 2: years; Group 3: years; Group 4: years). BP and HR analyses were based on the intent-totreat (ITT) population and performed using an analysis of covariance (ANCOVA) model with treatment group as factor and baseline values, extensive- or poor-metabolizer status, diabetes status, race, and sex as covariates; missing data were imputed using the last observation carried forward approach (LOCF) approach. The changes from baseline in metabolic parameter levels (both absolute [mg/dl] and relative [%]) were also based on the ITT population (LOCF) and analyzed by means of an ANCOVA model with treatment group as factor and baseline parameter value as a covariate. The proportions of patients who attained high glucose levels were compared by means of the chi-squared test. No adjustments for multiple hypothesis testing were performed. Owing to the post hoc nature of this study, all references to statistical significance are nominal and for exploratory purposes only. AE rates were analyzed using descriptive statistics. Results Baseline characteristics and patient disposition In all three trials, a total of 2016 patients were randomized to receive placebo (n = 205) or nebivolol (n = 1811). Dispositions of patients in each age quartile treated with placebo or nebivolol dosages of 5, 10, or 20 mg/day (n = 1585; 78.6% of total) are summarized in Figure 1. For the individuals treated with 5 20 mg/day nebivolol, the most common reasons for discontinuation by age quartile were loss to follow up (Group 1), consent withdrawal (Groups 2 and 4), and AEs (Group 3) (Figure 1). Discontinuation due to an AE (Figure 1) occurred in 1.8% of patients from Group 1, 1.6% of patients from Group 2, 3.2% of patients from Group 3, and 4.2% of patients from Group 4 (Figure 1). Baseline demographic and clinical characteristics for each age quartile are presented in Table 1. Baseline SBP/DBP values were similar within groups for placebo and 5, 10, and 20 mg/day dosages; of note, baseline SBP values appeared to increase with age (Table 1). Blood pressure and heart rate At week 12, all nebivolol dosages of 5 20 mg/day were significantly more effective than placebo in reducing DBP in all age groups (Figure 2A); all three dosages were also significantly more effective than placebo in reducing SBP in Groups 1, 2, and 3 (Figure 2B). In Group 4, the 20 mg/day dosage was significantly more effective than placebo in reducing SBP (Figure 2B). In all age groups, nebivolol was associated with significant HR reductions (Figure 3). Most frequent treatment-emergent adverse events The most common treatment-emergent AEs (TEAEs) per age quartile, by dose, are summarized in Table 2. In all groups, the most common TEAE was headache. Dizziness, the second most frequent AE in the younger half of the population, appeared to lose its prominence among older participants. Nausea, the third most common AE in the youngest group, appeared to follow a similar trend, whereas the trend seemed to be the opposite for fatigue, which was more prominent among older patients

4 Therapeutic Advances in Cardiovascular Disease 6 (5) Figure 1. Study flow, by age (placebo and selected nebivolol dosages only)

5 FW Germino, Y Lin et al. Table 1. Baseline demographic and clinical characteristics (ITT population). Characteristic Placebo Nebivolol (mg/day) years Number of patients Age, years, mean ± SD 40.2 ± ± ± ± 5.3 Women, n (%) 24 (40.7) 49 (40.8) 59 (43.4) 60 (45.8) Black, n (%) 26 (44.1) 35 (29.2) 43 (31.6) 39 (29.8) Diabetes, n (%) 0 7 (5.8) 9 (6.6) 3 (2.3) BMI 30 kg/m 2, n (%) 29 (49.2) 53 (44.5) 69 (50.7) 57 (43.5) Sitting DBP, mmhg, mean ± SD ± ± ± ± 3.8 Sitting SBP, mmhg, mean ± SD ± ± ± ± 13.9 Stage II hypertension, n (%) 30 (50.8) 57 (47.5) 60 (44.1) 56 (42.7) years Number of patients Age, years, mean ± SD 49.6 ± ± ± ± 2.0 Women, n (%) 32 (61.5) 49 (47.1) 51 (50.0) 42 (39.6) Black, n (%) 23 (44.2) 30 (28.8) 33 (32.4) 30 (28.3) Diabetes, n (%) 3 (5.8) 6 (5.8) 2 (2.0) 8 (7.5) BMI 30, n (%) 27 (51.9) 50 (48.1) 49 (48.0) 43 (40.6) Sitting DBP, mmhg, mean ± SD 99.9 ± ± ± ± 3.9 Sitting SBP, mmhg, mean ± SD ± ± ± ± 13.7 Stage II hypertension, n (%) 23 (44.2) 52 (50.0) 54 (52.9) 62 (58.5) years Number of patients Age, years, mean ± SD 57.6 ± ± ± ± 2.7 Women, n (%) 20 (42.6) 60 (49.2) 55 (51.4) 54 (46.6) Black, n (%) 12 (25.5) 21 (17.2) 22 (20.6) 25 (21.6) Diabetes, n (%) 9 (19.1) 7 (5.7) 12 (11.2) 11 (9.5) BMI 30, n (%) 21 (44.7) 58 (47.5) 34 (31.8) 60 (51.7) Sitting DBP, mmhg, mean ± SD 99.5 ± ± ± ± 3.8 Sitting SBP, (mmhg), mean ± SD ± ± ± ± 12.6 Stage II hypertension, n (%) 22 (46.8) 68 (55.7) 58 (54.2) 68 (58.6) years Number of patients Age, years, mean ± SD 67.2 ± ± ± ± 4.5 Women, n (%) 21 (44.7) 52 (46.0) 50 (43.1) 60 (56.1) Black, n (%) 10 (21.3) 18 (15.9) 9 (7.8) 11 (10.3) Diabetes, n (%) 5 (10.6) 8 (7.1) 12 (10.3) 11 (10.3) BMI 30, n (%) 15 (31.9) 28 (24.8) 36 (31.0) 37 (34.6) Sitting DBP, mmhg, mean ± SD 99.6 ± ± ± ± 3.5 Sitting SBP, (mmhg), mean ± SD ± ± ± ± 14.7 Stage II hypertension, n (%) 35 (74.5) 58 (51.3) 64 (59.8) 55 (47.4) Abbreviations: BMI, body-mass index; DBP, diastolic blood pressure; ITT, intent-to-treat; SBP, systolic blood pressure; SD, standard deviation. Incidence of AEs associated with β- blockers The observed TEAE rates (Table 2), and the fact that no patients discontinued treatment due to ED, indicate that ED was not associated with nebivolol therapy in any age group, No placebotreated patient experienced OH, and the occurrence of OH among nebivolol-treated patients 189

6 Therapeutic Advances in Cardiovascular Disease 6 (5) Figure 3. Effect of nebivolol treatment (5 20 mg/ day) on heart rate, by age group (intent-to-treat population). Comparisons made using an analysis of covariance model with treatment as factor and baseline blood pressure, metabolizer status, diabetes status, sex, and race as covariates. *p < 0.05, **p < 0.01, ***p < 0.001, versus placebo. Abbreviations: HR, heart rate; SE, standard error of the mean. Figure 2. Effect of nebivolol treatment (5 20 mg/ day) on blood pressure, by age group (intent-to-treat population). Comparisons made using an analysis of covariance model with treatment as factor and baseline blood pressure, metabolizer status, diabetes status, sex, and race as covariates. *p < 0.05, **p < 0.01, ***p < 0.001, versus placebo Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure; SE, standard error of the mean. was low (a total of three patients in Groups 1 and 2, all treated with 20 mg/day, and one patient in Group 4 who was taking the 10 mg/day dosage; see Table 2). Two nebivolol-treated patients discontinued the trial due to OH: the patient in Group 4 and one of the patients in Group 2. Metabolic parameters Baseline levels and baseline-to-endpoint changes in metabolic parameters are summarized in Table 3. In Group 1, the only statistically significant metabolic effect of nebivolol (versus placebo) was a decrease in absolute (but not relative) levels of HDL cholesterol in patients randomized to the dosage of 10 mg/day (Table 3). In Group 2, treatment with 5 and 20 mg/day nebivolol appeared to be associated with a decrease in HDL cholesterol levels (both absolute and relative) and also a decrease (absolute and relative) in the levels of LDL and total cholesterol in patients treated with the 5/mg day dosage (Table 3). In Group 3, all three nebivolol dosages were associated with a decrease in HDL cholesterol levels and an increase in the level of triglycerides (Table 3). In Group 4, all metabolic parameters examined appeared to be influenced by at least one nebivolol dosage, ranging from a decrease in the levels of glucose and cholesterol (HDL, LDL, and total) to an increase in the levels of total cholesterol and triglycerides (Table 3). Finally, there were no statistically significant differences in the percentage of patients who had normal blood glucose at baseline but high levels (>125 mg/dl) at endpoint (Group 1: 3.6% [nebivolol, 5 20 mg/day] versus 7.0% [placebo], p = 0.233; Group 2: 4.4% versus 0%, p = 0.134; Group 3: 4.8% versus 2.2%, p = 0.427; Group 4: 3.7% versus 6.7%, p = 0.353). Discussion Study summary Results of this post hoc analysis suggest that nebivolol may be effective in treating patients with stage I II hypertension across various age groups, with the effect on SBP becoming less 190

7 FW Germino, Y Lin et al. Table 2. The most common a and β-blocker associated b TEAEs in each age quartile (ITT population). Placebo Nebivolol (mg/day) Group 1: years Number of patients Any TEAE 16 (27.1) 32 (26.7) 37 (27.2) 55 (42.0) Headache 4 (6.8) 9 (7.5) 6 (4.4) 11 (8.4) Dizziness 1 (1.7) 3 (2.5) 5 (3.7) 6 (4.6) Nausea 1 (1.7) 2 (1.7) 4 (2.9) 7 (5.3) Diarrhea 1 (1.7) 4 (3.3) 3 (2.2) 5 (3.8) Fatigue 0 2 (1.7) 3 (2.2) 6 (4.6) Erectile dysfunction c (2.6) 1 (1.4) Orthostatic hypotension (0.8) Group 2: years Number of patients Any TEAE 13 (25.0) 38 (36.5) 34 (33.3) 38 (35.8) Headache 2 (3.8) 13 (12.5) 9 (8.8) 7 (6.6) Dizziness 1 (1.9) 3 (2.9) 5 (4.9) 5 (4.7) Nasopharyngitis 3 (5.8) 6 (5.8) 3 (2.9) 4 (3.8) Fatigue 2 (3.8) 2 (1.9) 3 (2.9) 6 (5.7) Blood cholesterol increased 0 4 (3.8) 4 (3.9) 0 Diarrhea 1 (1.9) 3 (2.9) 2 (2.0) 3 (2.8) Erectile dysfunction c (2.0) 0 Orthostatic hypotension (1.9) Group 3: years Number of patients Any TEAE 20 (42.6) 27 (22.1) 28 (26.2) 42 (36.2) Headache 1 (2.1) 8 (6.6) 6 (5.6) 9 (7.8) Fatigue 0 2 (1.6) 2 (1.9) 9 (7.8) Nasopharyngitis 4 (8.5) 5 (4.1) 2 (1.9) 3 (2.6) Diarrhea 0 2 (1.6) 1 (0.9) 6 (5.2) Dizziness 1 (2.1) 1 (0.8) 0 6 (5.2) Edema peripheral 0 2 (1.6) 3 (2.8) 2 (1.7) Upper respiratory tract infection 1 (2.1) 2 (1.6) 2 (1.9) 3 (2.6) Erectile dysfunction c 1 (3.7) Orthostatic hypotension Group 4: years Number of patients Any TEAE 17 ( 36.2) 30 ( 26.5) 27 ( 23.3) 29 ( 27.1) Headache 5 (10.6) 11 (9.7) 7 (6.0) 1 (0.9) Fatigue 1 (2.1) 4 (3.5) 3 (2.6) 6 (5.6) Nasopharyngitis 0 3 (2.7) 3 (2.6) 5 (4.7) Upper respiratory tract infection 0 5 (4.4) 0 3 (2.8) Nausea (4.3) 2 (1.9) Erectile dysfunction c (3.1) Orthostatic hypotension (0.9) 0 a Five most common TEAEs are listed for Groups 1 and 4; for Groups 2 and 3, six and seven TEAEs are listed, respectively, since 5 6th and 5 7th most frequent TEAEs in those groups were experienced by the same numbers of nebivolol-treated patients (regardless of dosage). b Erectile dysfunction and orthostatic hypotension only. c Men only. Abbreviations: ITT, intent to treat; TEAE, treatment-emergent adverse event

8 Therapeutic Advances in Cardiovascular Disease 6 (5) Table 3. Baseline-to-endpoint changes in glucose and lipid levels (ITT population). Placebo Nebivolol (mg/day) Group 1: years Glucose n Baseline, mg/dl a 93.7 ± ± ± ± 21.8 Endpoint, mg/dl a 97.5 ± ± ± ± ± ± ± ± 1.3 p value ± ± ± ± 1.3 p value HDL n cholesterol Baseline, mg/dl a 51.3 ± ± ± ± 16.4 Endpoint, mg/dl a 51.8 ± ± ± ± ± ± ± ± 1.0 p value ± ± ± ± 2.2 p value LDL n cholesterol Baseline, mg/dl a ± ± ± ± 35.5 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.5 p value ± ± ± ± 2.3 p value Total n cholesterol Baseline, mg/dl a ± ± ± ± 39.3 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.2 p value ± ± ± ± 1.1 p value Triglycerides n Baseline, mg/dl a ± ± ± ± Endpoint, mg/dl a ± ± ± ± ± ± ± ± 9.7 p value ± ± ± ± 5.2 p value

9 FW Germino, Y Lin et al. Table 3. (Continued) Placebo Nebivolol (mg/day) Group 2: years Glucose n Baseline, mg/dl a 97.9 ± ± ± ± 27.4 Endpoint, mg/dl a 97.9 ± ± ± ± ± ± ± ± 1.9 p value ± ± ± ± 1.6 p value HDL n cholesterol Baseline, mg/dl a 54.5 ± ± ± ± 18.6 Endpoint, mg/dl a 56.2 ± ± ± ± ± ± ± ± 1.0 p value ± ± ± ± 1.8 p value LDL n cholesterol Baseline, mg/dl a ± ± ± ± 38.4 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.2 p value ± ± ± ± 1.9 p value Total n cholesterol Baseline, mg/dl a ± ± ± ± 46.5 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.3 p value ± ± ± ± 1.1 p value Triglycerides n Baseline, mg/dl a ± ± ± ± Endpoint, mg/dl a ± ± ± ± ± ± ± ± 12.3 p value ± ± ± ± 8.6 p value (Continued) 193

10 Therapeutic Advances in Cardiovascular Disease 6 (5) Table 3. (Continued) Placebo Nebivolol (mg/day) Group 3: years Glucose n Baseline, mg/dl a ± ± ± ± 35.0 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 3.8 p value ± ± ± ± 2.7 p value HDL n cholesterol Baseline, mg/dl a 53.1 ± ± ± ± 14.9 Endpoint, mg/dl a 55.9 ± ± ± ± ± ± ± ± 0.7 p value < < ± ± ± ± 1.3 p value < <0.001 LDL n cholesterol Baseline, mg/dl a ± ± ± ± 38.2 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.6 p value ± ± ± ± 2.1 p value Total n cholesterol Baseline, mg/dl a ± ± ± ± 42.6 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.7 p value ± ± ± ± 1.2 p value Triglycerides n Baseline, mg/dl a ± ± ± ± 82.7 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 9.0 p value ± ± ± ± 4.3 p value

11 FW Germino, Y Lin et al. Table 3. (Continued) Placebo Nebivolol (mg/day) Group 4: years Glucose n Baseline, mg/dl a ± ± ± ± 25.0 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 1.5 p value ± ± ± ± 1.3 p value HDL cholesterol LDL cholesterol Total cholesterol n Baseline, mg/dl a 53.1 ± ± ± ± 20.7 Endpoint, mg/dl a 54.7 ± ± ± ± ± ± ± ± 1.1 p value ± ± ± ± 1.4 p value n Baseline, mg/dl a ± ± ± ± 30.4 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.3 p value ± ± ± ± 1.8 p value n Baseline, mg/dl a ± ± ± ± 36.9 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 2.4 p value ± ± ± ± 1.0 p value Triglycerides n Baseline, mg/dl a ± ± ± ± 78.7 Endpoint, mg/dl a ± ± ± ± ± ± ± ± 4.8 p value ± ± ± ± 2.9 p value a Mean ± standard deviation. b Mean ± standard error of the mean. Bold text indicates p < Abbreviations: HDL, high-density lipoprotein; ITT, intent to treat; LDL, low-density lipoprotein

12 Therapeutic Advances in Cardiovascular Disease 6 (5) prominent with age. For all age groups, SBP and DBP were significantly reduced (versus placebo) by the three nebivolol doses most frequently used in clinical practice (5, 10, and 20 mg/day), with the exception of SBP in the oldest quartile, in which nebivolol was significantly more efficacious than placebo for the dosage of 20 mg/day only. Treatment with nebivolol was safe and well tolerated, with an AE profile that was similar across dosages and age groups and variations in glucose and lipid levels that were not clinically significant. In addition, nebivolol treatment was associated with low incidences of ED and OH, regardless of age. Clinical relevance Our data suggest that nebivolol is similarly effective across the entire adult age range in reducing DBP (Figure 2a), but also that its ability to reduce SBP diminishes with advancing age (Figure 2b). That observation, and the fact that the mean baseline SBP, but not DBP, was higher in the oldest quartile compared with other age groups (e.g. Group 4, 158 mmhg; Group 1, 146 mmhg; Table 1), are consistent with previous findings. For example, a post hoc analysis of the data from The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT; N = 33,357) demonstrated that higher baseline SBP and older age are associated with a lower likelihood of achieving BP control [Cushman et al. 2002]. The BP results of our analysis are also partly consistent with the outcomes of a 12-week open-label postmarketing surveillance study of patients with hypertension and diabetes, conducted in Germany (N = 5071) [Ladage et al. 2010]. In that study, nebivolol (5 mg/day, administered as monotherapy [46%] or add-on therapy [54%]) was associated with significant reductions in both SBP and DBP across a range of age groups (<40 years, 40 49, 50 59, 60 69, 70 79, and >80 years), with the effect on both, as opposed to SBP only as in our analysis, diminishing with age [Ladage et al. 2010]. The mechanism for attenuation of the SBP effect of nebivolol in the elderly is most likely based on the fact that hypertension, and particularly the SBP component, in advanced age is driven by endothelial dysfunction and increased arterial stiffness [Safar, 2010], which are also the central physiological features affected by nebivolol s proposed mechanism of action [Münzel and Gori, 2009]. In a situation where arterial stiffness is particularly high, higher doses of nebivolol would likely be required to produce a significant reduction in SBP. On the other hand, low levels of NO [Lyamina et al. 2003] and high levels of asymmetric dimethyl arginine, an inhibitor of NO synthase [Paiva et al. 2008], have been implicated in the pathogenesis of hypertension in younger individuals, which suggests that nebivolol, with its NO-mediated vasodilatory properties [McEniery et al. 2004], would be a well-suited antihypertensive therapy for patients <60 years of age. Prospectively designed randomized studies would be required to assess the physiological differences of response to nebivolol treatment between younger and older patients. With regards to tolerability, the AE profile observed in our analysis suggests two possible trends. As mentioned in the Results section, there appears to be a shift in the AE profile with patients age (e.g. dizziness and fatigue appear to lose and gain prominence with age, respectively). This possible trend appears biologically plausible, as physiological response to medication is expected to show differences between younger and older people. The data also seem to suggest that age may affect dose dependence of certain AEs. For example, in the youngest quartile (Group 1), the rates of most AEs among patients randomized to 20 mg/day nebivolol were consistently higher than those observed among patients receiving dosages of 5 or 10 mg/day; a similar pattern emerged in Group 3, but it was largely absent from Group 2 and Group 4 (Table 2). However, this intermittent effect of age on dose dependence does not seem biologically plausible and is likely an artifact of subdividing the pooled sample. A recent analysis of the entire pooled sample of these three trials suggested an overall dose dependence for fatigue, dizziness, and nausea, but not for other TEAEs [Weiss et al. 2011]. The aforementioned German study did not actively monitor AEs, other than stating the absence of critical findings, based on patient complaints [Ladage et al. 2010], and to best of the authors knowledge, there is no systematic study or review that evaluated β-blocker associated AEs based on patients age. However, a recent cross-sectional observational study of hypertensive men treated with any β-blocker for at least 6 months (N = 1007; mean ± SD age: 57.9 ± 10.9 years) demonstrated that, compared with patients treated with atenolol, bisoprolol, metoprolol, or carvedilol, nebivolol-treated individuals had the lowest rates of ED and the highest scores on all subscales of the International Index of Erectile Dysfunction 196

13 FW Germino, Y Lin et al. (encompassing domains of erectile function, orgasmic function, sexual desire, satisfaction with intercourses, and global satisfaction) [Cordero et al. 2010]. The results of our study are in agreement with these findings, as ED was experienced by only one placebo-treated man and five nebivolol-treated men. In the three trials that were pooled in our analysis [Greathouse, 2010; Saunders et al. 2007; Weiss et al. 2007], the observed rates of ED (0.5% of men) and OH (0.2%) were relatively low. (OH is a phenomenon that has been estimated to occur in 5 33% of the elderly and may be caused by various antihypertensive medications, including β-blockers [Verhaeverbeke and Mets, 1997].) Such results are in agreement with previously published data indicating that nebivolol treatment is associated with lower AE rates compared with other β 1 -selective blockers [Ambrosioni and Borghi, 2005], other β-blockers in general, and other antihypertensive medications [Van Bortel et al. 2008], that it does not adversely affect sexual functioning [Boydak et al. 2005; Brixius et al. 2007; Doumas et al. 2006], and that it actually may result in positive pressor effects (i.e. reduced chances of OH) in elderly patients with mild hypertension [Cleophas et al. 2002]. In our data set, there were no statistically significant nebivolol-placebo differences in the rates of clinically significant metabolic changes, abnormal levels of metabolic parameters, or the rates of patients who attained blood glucose levels 125 mg/dl. However, we did observe a pattern of statistically significant changes in metabolic parameter levels in each age quartile, corresponding to variations from baseline of <5% for glucose and cholesterol, and <30% for triglycerides (Table 3). If one focuses on relative changes only (which facilitates comparisons and may be more relevant from the clinical standpoint), the vast majority of significant changes occurred in the three oldest quartiles (Table 3). The most consistent significant change was a decrease in HDL cholesterol levels by 3 4% in patients treated with nebivolol (Groups 2, 3, and 4), compared with 2 3% increase in patients treated with placebo (Table 3). The second most consistent change was an increase in triglyceride levels of 16 29% in nebivolol-treated patients (significance observed in Groups 3 and 4), compared with changes in the range from 5% to 1% among placebo-treated patients (Table 3). The remaining significant relative changes were observed in the oldest quartile (LDL and total cholesterol), and include variations from 0.3% to 1.9%, relative to baseline, among nebivolol-treated patients. The HDL cholesterol and triglyceride changes appear consistent and do suggest a real phenomenon. This effect is also mentioned in the prescribing information for nebivolol, which states that in controlled monotherapy trials, the drug was associated with a decrease in HDL cholesterol [Forest Laboratories, 2011]. The statistically significant increases in LDL and total cholesterol, observed in the oldest quartile, are even smaller in magnitude and less consistent than the HDL cholesterol changes; therefore, it seems reasonable to speculate that their impact on cardiovascular risk would be minimal. Of note, the German study reported statistically significant improvements on a number of metabolic parameters (HbA1c, triglycerides, HDL cholesterol, LDL cholesterol), and across all age groups examined [Ladage et al. 2010], which is consistent with the results of several previous trials that demonstrated neutral or beneficial metabolic effects of nebivolol [Fonseca, 2010]. A prospective, appropriately designed trial would be needed to investigate the metabolic effects of nebivolol treatment in regard to age. Limitations This was a post hoc analysis; therefore, all p values and references to statistical significance are nominal and for exploratory purposes only. In addition, in all three trials, patients were included based on their DBP values [Greathouse, 2010; Saunders et al. 2007; Weiss et al. 2007]. Such inclusion criteria would not be appropriate for a trial in which participants age corresponded to that in our oldest quartile, since at that age isolated systolic hypertension would be expected to be dominant [Franklin et al. 1997, 2001; Kannel, 2000]. Furthermore, in a sample closer to reallife situation, the percentages of patients with stage II hypertension in Groups 1 3 would be expected to be lower than those observed in our data set [Qureshi et al. 2005], and would be expected to steadily increase with age [Qureshi et al. 2005], which also appears not to be the case with our data (Table 1: Group 1, 45.5%; Group 2, 52.6%; Group 3, 55.1%; Group 4, 55.4%). Finally, the primary studies included in this analysis were not powered to detect efficacy and safety differences by age, particularly those related to ED and OH

14 Therapeutic Advances in Cardiovascular Disease 6 (5) Conclusions These data suggest that nebivolol is an efficacious and well-tolerated antihypertensive monotherapy across various age ranges; however, the efficacy in reducing SBP in the elderly appears to require higher nebivolol dosages (i.e. 20 mg/ day), and the drug may be associated with a small decrease in HDL cholesterol levels in patients >45 years of age. The rates of ED and OH seen in our pooled analysis suggest that nebivolol may represent a well-tolerated treatment in patients who are at a particular risk for these AEs. Longerterm, active-comparator trials would be useful to further examine the potential benefit of this therapy in selected populations, relative to other commonly used antihypertensive medications. Funding This work was sponsored by Forest Research Institute, a subsidiary of Forest Laboratories, Inc., the US marketer of nebivolol. Conflict of interest statement F. Wilford Germino is a member of the speakers bureaus at Bristol-Myers Squibb Company, Pfizer Pharmaceuticals, Takeda, and Forest Laboratories, and has received grant support from Novartis Pharmaceutical Corporation, Forest Research Institute, and Daiichi-Sankyo. Yuhua Lin is an employee of Forest Research Institute; at the time of writing and submission of the manuscript, Lynn Bowen was also a Forest Research Institute employee. Vojislav Pejović is an employee of Prescott Medical Communications Group, a contractor of Forest Research Institute. References Ambrosioni, E. and Borghi, C. (2005) 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 12: Boydak, B., Nalbantgil, S., Fici, F., Nalbantgil, I., Zoghi, M., Ozerkan, F. et al. (2005) A randomised comparison of the effects of nebivolol and atenolol with and without chlorthalidone on the sexual function of hypertensive men. Clin Drug Investig 25: Briesacher, B., Andrade, S., Fouayzi, H. and Chan, K. (2008) Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy 28: Brixius, K., Middeke, M., Lichtenthal, A., Jahn, E. and Schwinger, R. (2007) Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men. Clin Exp Pharmacol Physiol 34: Carlberg, B. and Nilsson, P. (2010) Hypertension in the elderly: what is the goal blood pressure target and how can this be attained? Curr Hypertens Rep 12: Cleophas, T., Grabowsky, I., Niemeyer, M., Makel, W. and van der Wall, E. (2002) Paradoxical pressor effects of beta-blockers in standing elderly patients with mild hypertension: a beneficial side effect. Circulation 105: Cleophas, T. and van Marum, R. (2003) Age-related decline in autonomic control of blood pressure: implications for the pharmacological management of hypertension in the elderly. Drugs Aging 20: Cordero, A., Bertomeu-Martinez, V., Mazon, P., Facila, L., Bertomeu-Gonzalez, V., Conthe, P. et al. (2010) Erectile dysfunction in high-risk hypertensive patients treated with beta-blockade agents. Cardiovasc Ther 28: Cushman, W., Ford, C., Cutler, J., Margolis, K., Davis, B., Grimm, R. et al. (2002) Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich) 4: Doumas, M., Tsakiris, A., Douma, S., Grigorakis, A., Papadopoulos, A., Hounta, A. et al. (2006) Beneficial effects of switching from beta-blockers to nebivolol on the erectile function of hypertensive patients. Asian J Androl 8: Düsing, R. (2005) Sexual dysfunction in male patients with hypertension: influence of antihypertensive drugs. Drugs 65: Egan, B., Zhao, Y. and Axon, R. (2010) US trends in prevalence, awareness, treatment, and control of hypertension, JAMA 303: Fischer, M., Stedman, M., Lii, J., Vogeli, C., Shrank, W., Brookhart, M. et al. (2010) Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med 25: Fogari, R. and Zoppi, A. (2004) Effect of antihypertensive agents on quality of life in the elderly. Drugs Aging 21: Fonseca, V. (2010) Effects of beta-blockers on glucose and lipid metabolism. Curr Med Res Opin 26:

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