Placebo Effect and Efficacy of Nebivolol in Patients with Hypertension not Controlled with Lisinopril or Losartan: A Phase IV, Randomized, Placebo-Controlled Trial

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Most patients with hypertension require more than one antihypertensive to achieve blood pressure (BP) control. 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). 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). This study was conducted at 76 outpatient centers in the United States. 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. 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. 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). 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%). 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. This trial (NCT00734630) was funded by Forest Laboratories, Inc.