Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1 + 2 in patients with type 2 diabetes

Tissue factor (TF) plays a pivotal role in thrombus formation. Statins and angiotensin converting enzyme inhibitors attenuate expression of TF by distinct mechanism. Therefore, we hypothesized that combined therapy with simvastatin and ramipril may have additive beneficial anti-atherogenic effects to lower TF activity when compared with either drug alone. This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each treatment period. Simvastatin and ramipril monotherapy tended to reduce TF activity (0.53 to 0.46 nM, P = 0.056; 0.54 to 0.50 nM, P = 0.167, respectively) while combined therapy had a significant effect (0.64 to 0.43 nM, P < 0.001). All three therapies significantly reduced prothrombin fragment 1 + 2 (F1 + 2) levels from their respective baselines (P = 0.037, P < 0.001, and P = 0.057, respectively). Combined therapy significantly reduced TF activity and F1 + 2 levels to a greater extent than either simvastatin or ramipril alone (P = 0.029 and P = 0.040 by ANOVA, respectively). Percent changes in TF activity and percent changes in F1 + 2 levels were significantly correlated. All three therapies reduced CD40 ligand levels from their respective baselines (P = 0.098, P < 0.001, and P = 0.002, respectively) with no significant differences among these three therapies (P = 0.204 by ANOVA). Ramipril combined with simvastatin significantly reduces plasma TF activity and F1 + 2 levels to a greater extent than monotherapy with either drug in patients with type 2 diabetes.