Placebo effect and efficacy of nebivolol in patients with hypertension not controlled with lisinopril or losartan: a phase IV, randomized, placebo-controlled trial

Am J Cardiovasc Drugs. 2013 Apr;13(2):129-40. doi: 10.1007/s40256-013-0010-y.


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 ( 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.

Publication types

  • Clinical Trial, Phase IV
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenergic beta-1 Receptor Antagonists / administration & dosage
  • Adrenergic beta-1 Receptor Antagonists / adverse effects
  • Adrenergic beta-1 Receptor Antagonists / therapeutic use*
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage
  • Angiotensin II Type 1 Receptor Blockers / adverse effects
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use*
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Benzopyrans / administration & dosage
  • Benzopyrans / adverse effects
  • Benzopyrans / therapeutic use*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Ethanolamines / administration & dosage
  • Ethanolamines / adverse effects
  • Ethanolamines / therapeutic use*
  • Female
  • Humans
  • Hypertension / drug therapy*
  • Lisinopril / administration & dosage
  • Lisinopril / adverse effects
  • Lisinopril / therapeutic use*
  • Losartan / administration & dosage
  • Losartan / adverse effects
  • Losartan / therapeutic use*
  • Male
  • Middle Aged
  • Nebivolol
  • Treatment Outcome
  • United States
  • Young Adult


  • Adrenergic beta-1 Receptor Antagonists
  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Benzopyrans
  • Ethanolamines
  • Nebivolol
  • Lisinopril
  • Losartan

Associated data