• Luis M Ruilope, Ettore Malacco, Yasser Khder, Albert Kandra, Gerd Bönner, and Daniela Heintz.
• Hypertension Unit, Hospital 12 de Octubre, 28041 Madrid, Spain. ruilope@ad-hocbox.com
• Clin Ther. 2005 May 1;27(5):578-87.

BackgroundRecent antihypertensive treatment guidelines recommend greater use of combination therapies.ObjectivesThe primary objective of this study was to determine whether combination therapy with valsartan 160 mg plus hydrochlorothiazide (HCTZ) 25 mg OD would be more effective than monotherapy with amlodipine 10 mg OD in reducing systolic blood pressure (SBP) in patients with moderate (stage II) hypertension and > or =1 other cardiovascular risk factor or concomitant condition. A secondary objective was to assess the effects of the study treatments on circulating markers of endothelial dysfunction and vascular inflammation.MethodsThis was a multicenter, randomized, double-blind, active-controlled, 24-week study. After a 2-week, single-blind, placebo run-in period, patients were randomized to 3 groups, 2 of them receiving valsartan 160 mg OD and 1 receiving amlodipine 5 mg OD. At week 4, HCTZ 12.5 mg OD was added to valsartan in one of the treatment groups (V+HCTZ12.5), HCTZ 25 mg OD was added to the other (V+HCTZ25), and the amlodipine dose was force-titrated to 10 mg OD (A10). The primary efficacy variable was change in mean sitting SBP at week 24. Other variables were changes in mean sitting diastolic blood pressure (DBP) and mean pulse pressure (PP) from baseline, and response rate (systolic response defined as mean sitting SBP <140 mm Hg or a reduction in mean sitting SBP of > or =20 mm Hg from baseline; diastolic response defined as mean sitting DBP <90 mm Hg or a reduction in mean sitting DBP of > or =10 mm Hg from baseline). Changes in the following markers of endothelial dysfunction were determined at baseline and weeks 4, 12, and 24 in all randomized patients from the participating European and South African centers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular tissue plasminogen activator (t-PA) antigen, and oxidized low-density lipoprotein (LDL).ResultsThe study enrolled 1088 patients with moderate hypertension (mean age, 61 years; 82% white; 53% women). The intent-to-treat population consisted of 1079 patients: 357 in the V+HCTZ12.5 group, 363 in the V+HCTZ25 group, and 359 in the A10 group. At baseline, the groups were comparable in terms of blood pressure and most other characteristics; the only statistically significant difference between groups was in the proportion of patients aged > or =65 years, which was lower in the amlodipine group (P = 0.01). At the end of the study, the least squares mean (SD) changes from baseline in mean sitting SBP were 27.1 (13.7), 29.7 (13.7), and 27.6 (13.8) mm Hg in the V+HCTZ12.5, V+HCTZ25, and A10 groups, respectively, with corresponding percent changes of 16%, 18%, and 17% (P < 0.05, V+HCTZ25 vs A10). The changes in mean sitting DBP did not differ significantly between groups. The reductions in PP were 17.5 (11.3), 18.7 (11.3), and 16.9 (11.3) mm Hg, with percent changes of 24%, 26%, and 23% (P < 0.05, V+HCTZ25 vs A10). Significant reductions in t-PA antigen were observed in both combination-therapy groups compared with the amlodipine monotherapy group at week 12 (P < 0.05); the reductions remained significant through the end of the study in the V+HCTZ12.5 group. There was a significant reduction in IL-6 and hs-CRP at week 12 with V+HCTZ25 compared with A10 (P < 0.05). Oxidized LDL values were reduced by approximately 10% with all treatments. Rates of total adverse events were significantly lower with the valsartan-based treatments compared with amlodipine monotherapy (49.7%, 49.6%, and 67.5% with V+HCTZ12.5, V+HCTZ25, and A10, respectively; P < 0.05). Rates of total discontinuations were a respective 10.1%, 9.0%, and 24.5%, and discontinuation rates due to AEs were 4.2%, 3.5%, and 18.2%. Leg edema was more common with amlodipine monotherapy than with the valsartan-based combinations (P < 0.05).ConclusionIn this group of patients with moderate hypertension and > or =1 other cardiovascular risk factor or concomitant condition, similar and greater antihypertensive effects were seen with the fixed-dose combinations of valsartan 160 mg and HCTZ 12.5 and 25 mg OD, respectively, compared with amlodipine 10 mg OD, with significantly lower rates of treatment-related adverse events and possible beneficial effects on vascular markers.

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