Die effek van simvastatien, 'n HMG-KoA-reduktase-inhibeerder op die hemostatiese balans in hipercholesterolemiese pasiënte

Abstract

The effect of simvastatin, a HMG-CoA reductase inhibitor, on the haemostatic balance in hypercholesterolaemic patients.

Coronary heart disease (CHO) is an important cause of mortality and morbidity for a large proportion of the economically active persons in South Africa. Two hundred and twenty six out of each 100000 deaths amongst Asians, 11 O out of each 100000 deaths amongst coloureds, 139 out of each 100000 deaths amongst whites and 11 out of each 100000 deaths amongst Africans can be ascribed to CHO. The prevalence of familial hypercholesterolaemia (FH) amongst the Afrikaner is unusually high and is estimated to be 1 in 70. FH is characterised by elevated levels of low density lipoprotein cholesterol (LOL-C). The use of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors is the most effective way to lower high LOL-C levels in these patients. Previously reported primary and secondary prevention trials have shown that the use of HMG-CoA reductase inhibitors may reduce cardiovascular as well as all-cause mortality. Increased levels of plasma fibrinogen has been shown to be a CHO risk factor to the same or even greater extent than cholesterol. Hypercholesterolaemia is also associated with increased fibrinogen levels. Studies on the effect of HMG-CoA reductase inhibitors on plasma fibrinogen levels and other haemostatic variables have yielded conflicting results. The objective of this study was to study the treatment effects of the HMG-CoA reductase inhibitor, simvastatin, on the haemostatic balance in 29 unrelated FH patients. Twenty nine FH patients, 12 men and 17 women, were treated with 10 mg simvastatin daily for 4 weeks and then with 20 mg simvastatin for 1 O weeks. Serum lipids and various safety parameters were monitored throughout the study. The following haemostatic variables were measured: fibrinogen, antithrombin Ill, thrombin-antithrombin complex (TAT), d-dimer, az-antiplasmin, plasmin-az- antiplasmin complex (PAP}, tissue plasminogen activator and plasminogen activator inhibitor-1 . Women had significantly higher concentrations of fibrinogen (3.31 [0.99] g/L vs 2. 75 [0.75] g/L}, PAP (0.39 [0.39] mg/L vs 0.21 [0.13] mg/L) and d-dimer (12.0 [10.6] µg/L vs 3.90 [4.40] µg/L) than men. As was exp!3cted, simvastatin treatment significantly reduced LDL-C in both men (7.54 [3.12] mmol/L to 4.81 [0.92] mmol/L) and women (7.34 [1 .81] mmol/L to 5.11 [1.03] mmol/L). Simvastatin treatment significantly increased plasma fibrinogen levels in men (2.82 [0.67] g/L to 3.19 [0. 7 4] g/L) but not in women. This finding suggests that the hyperfibrinogenaemia associated with hypercholesterolaemia in FH patients is probably not caused by an abnormal lipid profile. The increases in fibrinogen in men were accompanied by compensatory profibrinolytic changes in the TAT:PAP ratio, a marker of the haemostatic balance. This study provides evidence that possible adverse changes in plasma fibrinogen in men, as a result of lipid lowering treatment with simvastatin occurs. This is accompanied by compensatory profibrinolytic changes in men. The clinical implications of this finding requires further investigation. The haemostatic system in men and women appears to respond differently to simvastatin therapy and may be influenced by different factors. The haemostatic balance in women appears to be at a "higher" level of activity that in men.