REDUCED PLATELET-AGGREGATION AFTER FLUVASTATIN THERAPY IS ASSOCIATED WITH ALTERED PLATELET LIPID-COMPOSITION AND DRUG-BINDING TO THE PLATELETS

Aims High plasma cholesterol concentration and increased platelet acti vity are two major risk factors for atherosclerosis. Lovastatin, the l ipophilic drug was shown to inhibit platelet aggregation whereas prava statin, the hydrophilic drug had no such effect. Analysis of the effec t of fluvastatin which is both a lipophilic and hydrophilic drug, on p latelet aggregation was the goal of the present study. Methods Fluvast atin 40 mg daily was administered to 25 patients with hypercholesterol aemia for up to 24 weeks. Normal subjects acted as controls. The influ ence of fluvastatin on plasma lipids and on platelet aggregation and f luidity was studied. The direct effect of fluvastatin on platelets was compared with that of other statins. Results Fluvastatin therapy (40 mg day(-1) laemic patients resulted in a 23% and 29% reduction in plas ma levels of total cholesterol and LDL-cholesterol respectively. Plate let cholesterol/phospholipids molar ratio was reduced by 26% and plate let aggregation was significantly (P < 0.02) reduced by 10% after 4 we eks of fluvastatin treatment. On continuing fluvastatin therapy for ad ditional 20 weeks, no further decrement in plasma LDL cholesterol leve ls or in platelet cholesterol/phospholipid ratio were noted. However, platelet aggregation was further significantly (P < 0.01) reduced by u p to 15%. Incubation of platelets with increasing concentrations of fl uvastatin or lovastatin, demonstrated a dose-dependent reduction in pl atelet aggregation, whereas pravastatin showed no effect. This inhibit ory effect of fluvastatin or lovastatin on platelet aggregation (up to 34% or 22% respectively at a concentration of 1 mu g statin ml(-1)) w as found both in platelet rich plasma and in washed platelet suspensio ns. Fluvastatin and lovastatin (but not pravastatin), seem to share si milar platelet binding sites, as non labelled fluvastatin or lovastati n were able to displace [H-3]-labeled-fluvastatin from its binding sit es on platelets. Conclusions Fluvastatin therapy reduces platelet aggr egation via a dual effect which involves its in vivo hypocholesterolae mic action on platelet cholesterol content, and also a direct effect o f the drug binding to the platelets. The antiatherogenicity of fluvast atin may be related, in addition to its plasma cholesterol lowering ab ility, to its inhibitory effect on platelet activation.