Effects of four angiotensin II-receptor antagonists on fibrinolysis in postmenopausal women with hypertension

Abstract

Background: Reduced fibrinolysis due to increased concentrations of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of endogenous fibrinolysis, is associated with an increased risk for cardiovascular events. Objective: This study was undertaken to compare the effects of 4 angiotensin II (AII)-receptor antagonists with different pharmacokinetic properties—losartan, valsartan, irbesartan, and candesartan—on levels of PAI-1 antigen in postmenopausal women with hypertension. Methods: Postmenopausal women aged 51 to 60 years with mild to moderate hypertension (diastolic blood pressure [DBP] > 90 mm Hg and ≤105 mm Hg) who were not taking any hormone replacement therapy were studied. Patients with diabetes or obesity and patients who smoked were excluded. After a 2-week placebo washout period, patients were assigned to receive losartan 50 mg, valsartan 80 mg, irbesartan 150 mg, candesartan 8 mg, or placebo for 12 weeks according to a double-blind, randomized, parallel-group design, with a titration for nonresponders after 6 weeks. At the end of the placebo period and 6 and 12 weeks after active treatment, blood pressure, PAI-1 antigen levels, heart rate, and body mass index were measured. Results: A total of 156 patients were randomized to receive losartan (n = 31), valsartan (n = 32), irbesartan (n = 31), candesartan (n = 32), or placebo (n = 30); of these, 140 completed the study. All 4 active treatments significantly reduced DBP and systolic blood pressure, with no significant differences in efficacy between groups. Plasma PAI-1 levels decreased slightly after treatment with losartan (−0.9%) and valsartan (−3.8%) and increased slightly with irbesartan (+10.1%), but these values were not significantly different from placebo. In contrast, candesartan significantly increased PAI-1 values by 33.3% ( P < 0.05 vs placebo). There were no significant changes in heart rate or body mass index in any group. Conclusions: These findings suggest that, despite a comparable antihypertensive efficacy, candesartan differs from the other AII-receptor antagonists studied in that it significantly increases PAI-1 antigen levels. This might be related to its specific pharmacologic characteristics, particularly its insurmountable antagonism of the AII AT1 receptor.