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Efficacy and Safety of Nebivolol and Valsartan as Fixed-Dose Combination in Hypertension: A Randomised, Multicentre Study
Study Questions:
What is the efficacy and safety of a new fixed-dose combination of nebivolol and valsartan compared with monotherapy components and placebo in patients with stage 1 or 2 hypertension?
Methods:
This was a phase 3, randomized, multicenter, placebo-controlled, parallel-group trial. Following a 6-week single-blind placebo run-in phase, patients with stage 1 or 2 hypertension were randomized to receive double-blind treatment with nebivolol (5 mg/day or 20 mg/day) or valsartan (80 mg/day or 160 mg/day) monotherapies, fixed-dose combinations of nebivolol and valsartan (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), or placebo. During weeks 5-8 of the trial, doses were doubled. The primary efficacy endpoint was the change in trough seated diastolic blood pressure from baseline to week 8.
Results:
A total of 4,118 patients were included in the intention-to-treat population. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference, -1.2 mm Hg; 95% confidence interval [CI], -2.3 to -0.1; p = 0.030) and valsartan 320 mg/day (-4.4 mm Hg; 95% CI, -5.4 to -3.3; p < 0.0001). The authors noted the absence of a dose response in the fixed-dose combination groups. Combination therapy was well-tolerated and the rate of experiencing at least one treatment-emergent adverse effect was similar across all groups.
Conclusions:
Compared to monotherapy with nebivolol and valsartan (at the highest approved doses of 40 mg/day and 320 mg/day, respectively), the fixed-dose combination of 20 mg/day nebivolol and 320 mg/day valsartan was associated with greater reductions in diastolic blood pressure without an increase in adverse events.
Perspective:
This is an important randomized trial that establishes the advantage and safety of a fixed-dose combination of beta-blocker and angiotensin-II receptor blocker in patients with stage 1 and 2 hypertension. The US Food and Drug Administration requires the following criteria to be met to approve a combination therapy: superior efficacy (compared to either component administered alone) without any change in tolerability. This combination therapy may be a viable treatment option in appropriately selected patients; however, future studies should examine the impact of combination therapy on clinical endpoints as well.
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