Treatment with Simvastatin and Low-dose Aspirin Depresses Thrombin Generation in Patients with Coronary Heart Disease and Borderline-high Cholesterol Levels

Jacek Musiał; Anetta Undas; Robert Undas; Jan Brożek; Andrzej Szczeklik

doi:10.1055/s-0037-1615701

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 85(02): 221-225
DOI: 10.1055/s-0037-1615701

Review Article

Schattauer GmbH

Treatment with Simvastatin and Low-dose Aspirin Depresses Thrombin Generation in Patients with Coronary Heart Disease and Borderline-high Cholesterol Levels

Jacek Musiał

¹Dept. of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

,

Anetta Undas

¹Dept. of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

,

Robert Undas

¹Dept. of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

,

Jan Brożek

¹Dept. of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

,

Andrzej Szczeklik

¹Dept. of Medicine, Jagiellonian University School of Medicine, Krakow, Poland

› Institutsangaben

Abstract

Summary

Aspirin and statins are beneficial in coronary heart disease across a broad range of cholesterol levels. We assessed the effects of low-dose aspirin (75 mg daily) on thrombin generation in patients with coronary heart disease and average blood cholesterol levels. We also investigated whether in patients with borderline-high cholesterol level who have been already taking aspirin, additional treatment with simvastatin would affect thrombin generation.

Seven-day treatment with low-dose aspirin decreased thrombin generation ex vivo only in patients with total cholesterol 5.2 mmol/L. In patients with higher cholesterol levels aspirin had no effect. In these patients, already taking low-dose aspirin, additional three-month simvastatin treatment resulted in a reduction of thrombin generation. This demonstrates that low-dose aspirin depresses thrombin generation only in subjects with desirable blood cholesterol levels, while in others, with borderline-high cholesterol, thrombin formation is being reduced following the addition of simvastatin.

Keywords

Aspirin - simvastatin - thrombin generation

Volltext

Referenzen

References
1 Scandinavian Simvastatin Survival Study Group.. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9.
2 Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM. for the AFCAPS/ TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA 1998; 279: 1615-22.
3 The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349-57.
4 Davi G, Ganci A, Averna M, Giammarresi C, Barbagallo C, Catalano I, Cala A, Notarbartolo A. Thromboxane biosynthesis, neutrophil and coagulative activation in type IIa hypercholesterolemia. Thromb Haemost 1995; 74: 1015-9.
5 Alessandri C, Basili S, Maurelli M, Bracaglia D, Andreozzi P, Pergolini M, Cordova C. Relationship between prothrombin activation fragment F1+2 and serum cholesterol. Haemostasis 1996; 26: 214-219.
6 Hennekens CH, Dyken ML, Fuster V. Aspirin as a therapeutic agent in cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation 1997; 96: 2751-3.
7 Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330: 1287-94.
8 Kessels H, Béguin S, Andree H, Hemker HC. Measurement of thrombin generation in whole blood – the effect of heparin and aspirin. Thromb Haemost 1994; 72: 78-83.
9 Szczeklik A. Thrombin generation in myocardial infarction and hypercholesterolemia: effects of aspirin. Thromb Haemost 1995; 74: 77-80.
10 Wallen NH, Ladjevardi M. Influence of low- and high-dose aspirin treatment on thrombin generation in whole blood. Thromb Res 1998; 92: 189-94.
11 Kyrle PA, Westwick J, Scully MF, Kakkar VV, Levis GP. Investigation of the interaction of blood platelets with the coagulation system at the site of plug formation ex vivo in man. Effect of low-dose aspirin. Thromb Haemost 1987; 57: 62-69.
12 Szczeklik A, Musiaĺ J, Undas A, Gajewski P, Góra P, Swadźba J, Jankowski M. Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in subjects with marked hypercholesterolemia. J Am Coll Cardiol 1999; 33: 1286-93.
13 Szczeklik A, Krzanowski M, Gora P, Radwan J. Antiplatelet drugs and generation of thrombin in clotting blood. Blood 1992; 80: 2006-11.
14 Mielke CH. Measurement of the bleeding time. Thromb Haemost 1984; 52: 210-211.
15 Aoki I, Aoki N, Kawano K, Shimoyama K, Maki A, Homori M, Yanagisawa A, Yamamoto M, Kawai Y, Ishikawa K. Platelet-dependent thrombin generation in patients with hyperlipidemia. J Am Coll Cardiol 1997; 30: 91-6.
16 Eichinger S, Wolz M, Nieszpaur-Los M, Schneider B, Lechner K, Eichler HG, Kyrle PA. Effects of low molecular weight heparin (Fragmin) and of unfractionated heparin on coagulation activation at the site of plug formation in vivo. Thromb Haemost 1994; 72: 831-5.
17 Weiss JH, Lages B. Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding time wounds. Blood 1988; 71: 629-35.
18 Szczeklik A, Musial J, Undas A, Swadzba J, Gora PF, Piwowarska W, Duplaga M. Inhibition of thrombin generation by aspirin is blunted in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1996; 16: 948-54.
19 Lacoste L, Lam JY, Hung J, Letchacovski G, Solymoss CB, Waters D. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation 1995; 92: 3172-7.
20 DiGarbo V, Cordova R, Avellone G. Increased thrombin formation and complement activation in patients with type IIA hyperlipoproteinemia: effects of simvastatin treatment. Curr Therapeut Res 1997; 58: 706-23.
21 Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996; 348: 1079-82.
22 Broijersen A, Hamsten A, Silveira A, Fatah K, Goodall AH, Eriksson M, Angelin B, Hjemdahl P. Gemfibrozil reduces thrombin generation in patients with combined hyperlipidaemia, without influencing plasma fibrinogen, fibrin gel structure or coagulation factor VII. Thromb Haemost 1996; 76: 171-6.
23 Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997; 17: 265-72.
24 Ferro D, Basili S, Alessandri C, Mantovani B, Cordova C, Violi F. Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia. Lancet 1997; 350: 1222.
25 Aikawa M, Voglic SJ, Sugiyama S, Rabkin E, Taubman MB, Fallon JT, Libby P. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation 1999; 100: 1215-22.
26 O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126-31.
27 John S, Schlaich M, Langenfeld M, Weihprecht H, Schmitz G, Weidinger G, Schmeider RE. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients. A randomized, placebo-controlled, double-blind study. Circulation 1998; 98: 211-6.
28 Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lamas S. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression on endothein-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998; 101: 2711-9.
29 Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 1129-35.