Combination therapy versus monotherapy as initial treatment for stage 2 hypertension: A prespecified subgroup analysis of a community-based, randomized, open-label trial

Background: Current guidelines suggest consideration of initial combination therapy for patients with stage 2 hypertension, but rates of hypertension treatment and control in clinical practice vary according to age, race, sex, and body mass index (BMI). Objective: This was a prespecified subgroup analysis of one of the primary efficacy end points-mean change in systolic blood pressure (SBP) at 6 weeks-in a previously published community-based, randomized, open-label trial comparing valsartan monotherapy with valsartan/hydrochlorothiazide (HCTZ) combination therapy as initial treatment for high-risk patients with stage 2 hypertension. Methods: Eligible participants with stage 2 hypertension (SBP >= 160 min Hg and/or diastolic blood pressure [DBP] >= 100 mm Hg) were treated with valsartan 160 mg/d or valsartan/HCTZ 160/12.5 mg/d for 2 weeks, followed by forced titration to valsartan 320 mg/d or valsartan/HCTZ 320/12.5 mg/d for an additional 4 weeks. In addition to the primary blood pressure end point (change in SBP at 6 weeks), secondary blood pressure end points at 6 weeks included changes in DBP and the proportion of patients achieving a blood pressure control threshold of < 140/90 mm Hg (< 130/80 mm Hg for patients with diabetes), as recommended by the Seventh Report of the joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). The subgroups of interest were women, blacks, Hispanics, the elderly (age >= 65 years), patients with diabetes, smokers, and lean, overweight, and obese subjects (BMI < 25, 25-< 30, and 30 kg/m(2), respectively). Results: The randomized trial included 1668 patients (756 [45.3%] female, 392 [23.5%] black, 109 [6.5%] Hispanic, 220 [13.2%] elderly, 970 of 1641 [59.1%] obese, 166 [10.0%] with diabetes, 467 [28.0%] smokers) with stage 2 hypertension. Among those allocated to combination therapy compared with monotherapy, the mean (SD) change in SBP at 6 weeks was -27.4 (18.5) and -19.3 (17.7) mm Hg in women, -21.4 (17.6) and -12.6 (18.5) min Hg in black subjects, -21.7 (17.6) and -16.3 (16.5) min Hg in Hispanic subjects, -25.5 (20.2) and -16.9 (17.9) mm Hg in the elderly, and -23.6 (18.1) and -15.9 (16.2) mm Hg in obese subjects. With the exception of the results for Hispanics, all comparisons of combination therapy and monotherapy were statistically significant (P <= 0.01). A higher proportion of those receiving valsartan/HCTZ compared with valsartan monotherapy reached the JNC 7-defined blood pressure goal (44.5% vs 29.1%, respectively; P < 0.001). This pattern was seen consistently in most subgroups analyzed, including men (41.8% vs 27.9%; P < 0.001), women (47.8% vs 30.5%; P < 0.001), white subjects (46.4% vs 33.8%; P < 0.001), black subjects (41.8% vs 19.1%; P < 0.001), those aged < 65 years (44.6% vs 29.7%; P < 0.001), those aged >= 65 years (43.9% vs 24.5%; P = 0.004), overweight subjects (49.0% vs 31.2%; P < 0.001), and obese subjects (41.4% vs 26.0%; P < 0.001). In the entire study cohort, patients assigned to combination therapy had a significantly higher incidence of dizziness compared with those assigned to monotherapy (8.5% vs 4.7%; P = 0.002); however, there was no statistically significant difference in the frequency of adverse events between treatment groups in the pre-specified subgroups. Conclusions: Across various subgroups of patients with stage 2 hypertension, combination therapy was consistently associated with a significantly greater reduction in SBP than monotherapy. With the exception of a significantly greater increase in dizziness compared with monotherapy, combination therapy was well tolerated.