A Randomized, Multicenter, Double-blind, Placebo-controlled, 3 × 3 Factorial Design, Phase II Study to Evaluate the Efficacy and Safety of the Combination of Fimasartan/Amlodipine in Patients With Essential Hypertension.

PURPOSE: The objective of this study was to evaluate the efficacy and safety of a fimasartan/amlodipine combination in patients with hypertension and to determine the optimal composition for a future single-pill combination formulation. METHODS: This Phase II study was conducted by using a randomized, multicenter, double-blind, placebo-controlled, 3 × 3 factorial design. After a 2-week placebo run-in period, eligible hypertensive patients (with a sitting diastolic blood pressure [SiDBP] between 90 and 114 mm Hg) were randomized to treatment. They received single or combined administration of fimasartan at 3 doses (0, 30, and 60 mg) and amlodipine at 3 doses (0, 5, and 10 mg) for 8 weeks. The primary efficacy end point was the change in SiDBP from baseline and at week 8; secondary end points included the change in SiDBP from baseline and at week 4 and the changes in sitting systolic blood pressure from baseline and at weeks 4 and 8. Treatment-emergent adverse events (AEs) were also assessed. FINDINGS: 420 Korean patients with mild to moderate hypertension were randomly allocated to the 9 groups. Mean (SD) SiDBP changes in each group after 8 weeks were as follows: placebo, -6.0 (8.5) mm Hg; amlodipine 5 mg, -10.6 (9.2) mm Hg; amlodipine 10 mg, -15.9 (7.2) mm Hg; fimasartan 30 mg, -10.1 (9.1) mm Hg; fimasartan 60 mg, -13.0 (10.0) mm Hg; fimasartan 30 mg/amlodipine 5 mg, -16.2 (8.5) mm Hg; fimasartan 30 mg/amlodipine 10 mg, -19.5 (7.5) mm Hg; fimasartan 60 mg/amlodipine 5 mg, -16.6 (6.9) mm Hg; and fimasartan 60 mg/amlodipine 10 mg, -21.5 (8.3) mm Hg. All treatment groups produced significantly greater reductions in blood pressure compared with the placebo group. In addition, all combination treatment groups had superior reductions in blood pressure compared with the monotherapy groups. In the combination treatment groups, doubling fimasartan dose in the given dose of amlodipine did not show further BP reduction, whereas doubling amlodipine dose showed significantly further BP reduction in the given dose of fimasartan. During the study period, 75 (17.9%) of 419 patients experienced 110 AEs. Ninety-five AEs were mild, 9 were moderate, and 6 were severe in intensity. Eight patients discontinued the study due to AEs. There was no significant difference in incidence of AEs among groups (P = 0.0884). The most common AE was headache (12 patients [2.9%]), followed by dizziness (11 patients [2.6%]) and elevated blood creatine phosphokinase levels (6 patients [1.4%]). IMPLICATIONS: Fimasartan combined with amlodipine produced superior blood pressure reductions and low levels of AEs compared with either monotherapy. Therefore, a single-pill combination with fimasartan 60 mg/amlodipine 10 mg will be developed. ClinicalTrials.gov: NCT01518998.

Age-associated increase in arterial stiffness measured according to the cardio-ankle vascular index without blood pressure changes in healthy adults.

AIM: The cardio-ankle vascular index (CAVI) reflects arterial stiffness from the aorta to the ankle, independent of blood pressure (BP). We investigated the age-stratified CAVI in healthy, normotensive individuals to evaluate the effects of age on arterial stiffness. METHODS: The CAVI and peripheral BP were determined in healthy, normotensive Koreans 20 to 79 years of age. The subjects had no history of cardiovascular disease and did not take any medications for hypertension, diabetes mellitus or dyslipidemia (N = 1,380; 44.1% in men). RESULTS: The mean systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were 117, 75 and 42 mmHg, respectively. The CAVI increased linearly with age and was determined using the following equation: CAVI = 5.0 + 0.048 × age (year) in men (r(2) = 0.395, p < 0.001), CAVI = 4.8 + 0.045 × age (year) in women (r(2) = 0.450, p < 0.001). However, SBP, DBP and PP did not change progressively with age. Age emerged as the major determinant of the CAVI in a stepwise multiple regression analysis (r(2) change = 43.1%). CONCLUSIONS: The CAVI scores increased with age in the healthy, normotensive individuals, whereas SBP, DBP and PP did not. Age was the dominant risk factor for the progression of arterial stiffness. These data suggest that the CAVI is a sensitive marker of the arterial aging process, above and beyond conventional upper arm BP.