Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect.

Lipid-lowering with statins reduces blood thrombogenicity. However, it is unknown whether this is purely due to LDL-cholesterol reduction, or it is related to a statin or agent specific effect. We investigated the relationship between reduction in blood thrombogenicity and the magnitude of low-density lipoprotein cholesterol (LDL-C) during pravastatin therapy. We prospectively followed for 6 months 57 hyperlipidemic patients who initiated therapy with pravastatin, and 36 patients who were randomized into placebo plus diet. Pravastatin-treated patients were grouped according to the LDL-C reduction at 6 months; (i) "adequate LDL-C reduction": LDL-C reduction >30% from baseline or LDL-C<125 mg/dl (n = 38; LDL-C reduction 74 +/- 4 mg/dl; 6-month LDL-C 119 +/- 5 mg/dl); (ii) "inadequate LDL-C reduction": neither of the above criteria (n = 19; LDL-C reduction 31 +/- 5 mg/dl; 6-month LDL-C 158 +/- 6 mg/dl). Placebo patients were divided into those "with LDL-C reduction" (n = 17, mean reduction 21 +/- 5 mg/dl) and those "without LDL reduction" (n = 19). The following parameters were altered at 6 months in both patients with "adequate" and "inadequate" LDL-C reduction: (1) tissue plasminogen activator decreased by 1.4 +/- 0.4 and 1.5 +/- 0.5 ng/ml respectively (p = NS); (2) plasminogen activator inhibitor-1 decreased by 8.7 +/- 2.0 and 10.1 +/- 2.7 ng/ml respectively (p = NS); (3) thrombus formation under dynamic flow conditions decreased by 3.5 +/- 0.9 and 2.8 +/- 1.2 microm2 x 10(3) respectively (p = NS). In contrast, no significant changes from baseline were noted in placebo-treated patients, regardless of their LDL-C reduction category, and multivariate analysis eliminated LDL-C reduction as an independent predictor of reduction in thrombogenicity. Therefore, the reduction in thrombogenicity was not proportional to the magnitude of LDL-C reduction suggesting that a class or agent specific property is primarily responsible for the pro-fibrinolytic/antithrombotic effects observed.

Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin.

Thrombotic risk in hyperlipidemic women and its response to lipid therapy is unknown. We prospectively studied 28 men and 29 women with high low-density lipoprotein (LDL) cholesterol during 6 months of therapy with pravastatin. Women had significantly higher high-density lipoprotein (HDL) cholesterol (54.2 +/- 1.7 vs 39.5 +/- 2.2 mg/dl, p <0.01), lower prevalence of coronary artery disease (41% vs 67%, p = 0.04), and otherwise similar baseline characteristics compared with men. Both genders achieved a 33% reduction in LDL at 6 weeks (188 +/- 6 to 133 +/- 5 mg/dl) and maintained similar LDL levels throughout the study. Systemic hemostatic markers and thrombus formation under dynamic flow conditions were evaluated at baseline, and at 3 and 6 months of follow-up. Prothrombin fragment F1.2, a marker of thrombin generation, was higher in women versus men at baseline (2.4 +/- 0.2 vs 1.4 +/- 0.3 nmol/L, p = 0.02). The levels decreased in women to 2.0 +/- 0.3 nmol/L at 3 months and to 1.6 +/- 0.2 nmol/L at 6 months (p <0.045, analysis of variance), whereas it remained unchanged in men. Plasminogen activator inhibitor-I significantly decreased at 3 and 6 months of follow-up: by 12.6% and 18.7%, respectively, in women, and by 18.8% and 23.5%, respectively, in men. Similarly, tissue plasminogen activator decreased significantly by 7.4% in women and 11.8% in men at 6 months compared with baseline. Fibrinogen showed an increase in both genders at follow-up. Thrombus formation was similar at baseline between the 2 genders, and decreased at 3 and 6 months compared with baseline by 12.5% and 29.5% in women, and by 18.6% and 19.4% in men (p <0.04 at 6 months vs baseline in both men and women). Other markers, including C-reactive protein, fibrinopeptide A, D-dimer, and factor VIIa, did not differ between genders and did not change with therapy. Thus, despite higher HDL, and lower incidence of coronary disease, women with high LDL had a comparable thrombotic and/or fibrinolytic profile to men and even evidence of increased thrombin generation at baseline. Blood thrombogenicity was reduced with pravastatin in both genders; in addition, thrombin generation was gradually reduced in women to a level similar to that of men by 6 months of follow-up.

Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile.

OBJECTIVES: The study sought to determine the effects of lipid-lowering with pravastatin on the systemic fibrinolytic profile and on thrombus formation under dynamic flow conditions. BACKGROUND: Lowering cholesterol (C) decreases clinical events in coronary artery disease (CAD) patients, but an analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted. METHODS: We prospectively studied 93 stable patients with untreated low-density lipoprotein cholesterol (LDL-C) >145 mg/dl. The CAD patients received pravastatin, and non-CAD patients were randomized to pravastatin versus placebo (double-blind). Thrombus formation upon an injured vascular surface was assessed in a substudy of 40 patients with a previously validated ex vivo perfusion chamber system. Systemic hemostatic markers and thrombus formation were evaluated at baseline, three and six months. RESULTS: Placebo produced no changes in either the lipid profile, any of the hemostatic markers, or the ex vivo thrombus formation. Both pravastatin groups (CAD and non-CAD) showed decreased LDL-C by 30% within 6 weeks (188 to 126 mg/dl, p < 0.001 vs. baseline), and decreased plasminogen activator inhibitor-1 at 3- and 6-month follow-up compared to baseline (15% to 18% decrease at 3 months and 21% to 23% at 6 months). For the tissue plasminogen activator antigen, CAD and non-CAD groups showed significant decreases at 6 months compared to baseline (10% and 13%, respectively). No significant changes were observed with treatment in d-dimer, fibrinopeptide A, prothrombin fragment F1.2, factor VIIa, von Willebrand factor, or C-reactive protein. Fibrinogen levels were significantly increased at 6 months compared to baseline, though still below the upper normal limit. In the perfusion chamber substudy, there was a decrease in thrombus area in non-CAD patients treated with pravastatin at both 3 and 6 months compared to baseline (by 21% and 34%, respectively). The CAD patients showed decreases in thrombus formation by 13% at 3 months, and by 16% at 6 months. The change in LDL-C- correlated modestly with the change in thrombus formation (r = 0.49; p < 0.01). CONCLUSIONS: Pravastatin therapy significantly decreased thrombus formation and improved the fibrinolytic profile in patients with and without CAD. These early effects may, in part, explain the benefit rendered in primary and secondary prevention of CAD.

The efficacy and safety of pravastatin in patients aged 60 to 85 years with low-density lipoprotein cholesterol > 160 mg/dl.

This study demonstrated that pravastatin 20 mg once daily significantly lowered total cholesterol (by 19%) and LDL cholesterol by 25%.