부산대학교 도서관

BACKGROUND: Most patients with hypertension require more than one antihypertensive to achieve blood pressure (BP) control. OBJECTIVE: The purpose of this trial was to assess the efficacy and tolerability of add-on nebivolol, a vasodilatory β-blocker, in patients with untreated or poorly controlled hypertension, receiving stable therapy with lisinopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin II receptor blocker). STUDY DESIGN: This was a phase IV double-blind, placebo-controlled trial conducted from August 2008 to March 2010 (ClinicalTrials.gov identifier: NCT00734630). Patients entered a 2-week, single-blind, placebo-only washout phase, followed by a 3- to 4-week open-label lead-in phase (lisinopril, 10–20 mg/day, or losartan, 50–100 mg/day), and a 12-week randomized, double-blind add-on treatment phase with placebo or nebivolol (5–40 mg/day). SETTING: This study was conducted at 76 outpatient centers in the United States. PATIENTS: Participants were men and women aged 18–85 years with a diagnosis of primary hypertension and seated trough systolic BP (SBP) at screening in the range of 170–200 mmHg if untreated, 155–180 mmHg if taking 1 antihypertensive medication, or 140–170 mmHg if taking 2 antihypertensive medications. INTERVENTION: The intervention was 12 weeks’ treatment with nebivolol 5–40 mg/day added to a background therapy of lisinopril 10–20 mg/day or losartan 50–100 mg/day. MAIN OUTCOME MEASURES: Primary and secondary efficacy parameters were changes from baseline in seated trough cuff SBP and diastolic BP (DBP) at Week 12, respectively. Tolerability was assessed by monitoring treatment-emergent adverse events (TEAEs). RESULTS: A total of 491 patients were randomized to receive nebivolol (n = 258) or placebo (n = 233). Efficacy analyses were conducted for 256 nebivolol and 232 placebo patients (intent-to-treat population); completion rates were 88.8 % and 85.8 %, respectively. Mean baseline SBP/DBP values were 163.1/98.2 mmHg (nebivolol) and 162.4/96.8 mmHg (placebo). Nebivolol was associated with a non-significant mean ± SD reduction in SBP (−10.1 ± 16.9 mmHg) versus placebo (−7.3 ± 15.9 mmHg, P = 0.093) and significant mean DBP reduction (−7.8 ± 10.1 mmHg vs −3.5 ± 10.6 mmHg, P < 0.001). Subgroup analysis suggested a significant effect on DBP for patients receiving background losartan treatment (−8.1 ± 9.2 mmHg vs −3.1 ± 9.4 mmHg, P < 0.001), but not for those receiving lisinopril (−7.6 ± 10.8 mmHg vs −3.8 ± 11.6 mmHg, P = 0.076). A total of 28 % nebivolol-treated and 22 % placebo-treated patients reported a TEAE, the most frequent being upper respiratory tract infection (4.3 % and 2.1 %, respectively), bradycardia (2.7 % and 0 %), headache (2.3 % and 2.1 %), and nasopharyngitis (2.3 % and 0.9 %). CONCLUSION: These data suggest that nebivolol, when added to lisinopril or losartan, results in an additional BP reduction; however, only the effect on DBP reached statistical significance. A subanalysis suggests that the effect on DBP may be stronger in losartan-treated than lisinopril-treated patients. A relatively strong placebo effect may limit data interpretation. Nebivolol was well tolerated, as there was no difference in TEAEs between nebivolol and placebo. FUNDING: This trial (NCT00734630) was funded by Forest Laboratories, Inc.