Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension:: An 8-week, randomized, double-blind, parallel-group trial

Background: Combination therapy with at least 2 antihypertensive agents is usually needed to achieve appropriate blood pressure (BP) control in patients with isolated or predominant systolic hypertension. A currently recommended combination is a diuretic added to an angiotensin-receptor blocker. Objective: This was a study of the effects on sitting systolic BP (SBP) of 2 combinations of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension (SBP >= 160 mm Hg and <= 200 mm Hg) with or without other cardiovascular risk factors. Methods: After a placebo run-in period, patients were randomized to receive double-blind treatment with either valsartan 80 mg OD (monotherapy group) or valsartan 160 mg OD (combination-therapy groups) for 4 weeks, followed by forced titration to valsartan 160 mg OD (V160), valsartan 160 mg plus HCTZ 12.5 mg OD (V160+HCTZ12.5), or valsartan 160 mg plus HCTZ 25 mg OD (Vl60+HCTZ25) for an additional 4 weeks. End points were the change in SBP between the groups receivmg combination therapy and the monorherapy group, between-group changes in diastolic BP (DBP), responder rates (SBP < 140 mm Hg or a reduction in SBP of 220 min Hg), and tolerability. Results: A total of 774 patients were randomized to treatment: 261 to V160, 258 to V160+HCTZ12.5, and 255 to V160+HCTZ25. The intent-to-treat population consisted of 767 patients (411 men, 356 women; mean age, 60 years; mean weight, 84 kg; clinic mean [SD] baseline BP, 167.5 [8.1]/93.4 [9.1] mm Hg). All treatments produced significant reductions in SBP from baseline (mean [SD] reduction, 20.7 [15.7] mm Hg with V160,27.9 [13.8] mm Hg with V160+HCTZ12.5, and 28.3 [13.1] mm Hg with V160+HCTZ25; all, P < 0.05). DBP was reduced by 6.6 (8.9) mm Hg in the V160 group and by 10.2 (7.7) and 10.1 (7.8) mm Hg in the V160+HCTZ12.5 and V160+HCTZ25 groups, respectively (all, P < 0.05). The additional reductions in BP with V160+HCTZ25 did not reach statistical significance compared with V160+HCTZ12.5. Responder rates were 56.9% in the V160 group, 74.4% in the V160+HCTZ12.5 group, and 75.0% in the V160+HCTZ25 group (P < 0.05, combination therapy vs monotherapy). Adverse events were reported by 27.5% of patients in the monotherapy group, compared with 28.6% and 34.0% in the groups that received V160+HCTZ12.5 and V160+HCTZ25, respectively; the differences were not significant between treatment groups. Conclusions: Monotherapy with V160 was effective in these patients with stage 2 or 3 systolic hypertension. Significant additional reductions in SBP and DBP and an increase in responder rates were achieved with the addition to V160+HCTZ12.5 and HCTZ25, with no significant effect on tolerability.