Subscribe to RSS
DOI: 10.1055/s-0037-1613861
Effects of Fluvastatin and Bezafibrate Combination on Plasma Fibrinogen, t-plasminogen Activator Inhibitor and C Reactive Protein Levels in Coronary Artery Disease Patients with Mixed Hyperlipidaemia (FACT Study)
Publication History
Received
29 June 1999
Accepted after revision
14 December 1999
Publication Date:
08 December 2017 (online)
Summary
Aim of the study
We studied the effects of fluvastatin and bezafibrate in monotherapy and in combination on plasma fibrinogen, t-plasminogen activator inhibitor (PAI-1) and C reactive protein (CRP) in patients with coronary artery disease (CAD) and mixed hyperlipidaemia
Design
In this randomised, double blind, multicentre trial 333 patients with stable angina pectoris or previous myocardial infarction or coronary revascularisation and mixed hyperlipidaemia (LDL-cholesterol 135-250 mg/dl and triglycerides (TG) 180-400 mg/dl) were randomised to fluvastatin 40 mg, bezafibrate 400 mg, fluvastatin 20 mg + bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24 weeks.
Result
Plasma fibrinogen significantly decreased after treatment with the combinations fluvastatin+bezafibrate (−14 and −16%) and with bezafibrate monotherapy (−9%). No significant reduction was observed after fluvastatin monotherapy (−4%). No significant changes were observed in PAI-1 and CRP plasma levels. Combination therapy significantly decreased both LDL-C and TG, and significantly increased HDL-C.
Conclusions
The combined effects on fibrinogen and plasma lipids achieved by fluvastatin and bezafibrate combination treatment might be more useful than the simple reduction of cholesterol in preventing ischaemic cardiovascular disease.
-
References
- 1 Shepherd J, Cobbe SM, Ford I. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301-7.
- 2 Sacks FM, Pfeffer MA, Moye LA. et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001-9.
- 3 The Scandinavian Simvastatin Survival Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9.
- 4 Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a metaanalysis and review of the literature. Ann Intern Med 1993; 118: 956-63.
- 5 Heinrich J, Balleisen L, Schulte H, Assman G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54-9.
- 6 Ridker PM. Fibrinolytic and inflammatory markers for arterial occlusion: the evolving epidemiology of thrombosis and hemostasis. Thromb Haemost 1997; 78: 53-9.
- 7 Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW. for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
- 8 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. for the PLAT Group. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients A case control study. Arterioscler Thromb 1993; 13: 1412-7.
- 9 Lagrand WK, Visser CA, Hermens WT, Niessen HWM, Verheugt FWA, Wolbink GJ, Hack CE. C-reactive protein as a cardiovascular risk factor. More than an epiphenomenon?. Circulation 1999; 100: 96-102.
- 10 Welty FK, Mittleman MA, Wilson PWF, Sutherland PA, Matheney TH, Lipinska I, Muller JE, Levy D, Tofler GH. Hypobetalipoproteinemia is associated with low levels of hemostatic risk factors in the Framingham offspring population. Circulation 1997; 95: 825-30.
- 11 Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, Athyrou VV, Kontopoulos AG. Effect of atorvastatin versus simvastatin on lipid profile and plasma fibrinogen in patients with hypercholesterolaemia. A pilot, randomised, double-blind, dose-titrating study. Clin Drug Invest 1998; 16: 219-27.
- 12 Beigel Y, Fuchs J, Snir M, Green P, Lurie Y, Djaldetti M. Lovastatin therapy in hypercholesterolemia: effect on fibrinogen, hemorheologic parameters, platelet activity, and red blood cell morphology. J Clin Pharmacol 1991; 31: 512-7.
- 13 Jones P, Kafonek S, Laurova I. et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (The CURVES Study). Am J Cardiol 1998; 81: 582-7.
- 14 Tsuda Y, Satoh K, Kitadai M, Takahashi T, Izumi Y, Hosomi N. Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia. Atherosclerosis 1996; 122: 225-33.
- 15 Wierzbicki AS, Lumb PJ, Semra YK. et al. Effect of atorvastatin on plasma fibrinogen. Lancet 1998; 351: 569-70.
- 16 Kockx M, de Maat MPM, Knipscheer HC, Kastelein JJP, Kluft C, Princen HMG, Kooistra T. Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients. Thromb Haemost 1997; 78: 1167-72.
- 17 Schonfeld G. The effects of fibrates on lipoprotein and haemostatic coronary risk factors. Atherosclerosis 1994; 111: 161-74.
- 18 Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. for the Cholesterol and Recurrent Events (CARE) Investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999; 100: 230-5.
- 19 Pauciullo P, Mancini M, Mariani M, Cortellaro M, Paoletti R. on behalf of the FACT Study Centers. Treatment of mixed hyperlipidemia in CAD patients with fluvastatin and bezafibrate in monotherapy and combination. 71st Congress of the European Atherosclerosis Society, May 26-29 1999, Athens.
- 20 Pauciullo P, Borgnino C, Paoletti R, Mariani M, Mancini M. on behalf of the FACT Study Centers. Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT Study). Atherosclerosis, in press.
- 21 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-46.
- 22 Herd JA, Ballantyne CM, Farmer JA, Ferguson JJ, Jones PH, West MS, Gould KL, Gotto AM. for the LCAS Investigators. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 1997; 80: 278-86.
- 23 De Faire U, Ericsson CG, Grip L, Nilsson J, Svane B, Hamsten A. Retardation of coronary atherosclerosis: the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and other angiographic trials. Cardiovasc Drugs Ther 1997; 11: 257-63.
- 24 Papadakis JA, Ganotakis ES, Jagroop IA, Winder AF, Mikhailidis DP. Statin + fibrate combination therapy. Fluvastatin with bezafibrate or ciprofibrate in high risk patients with vascular disease. Int J Cardiol 1999; 69: 237-44.
- 25 Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia. Thromb Haemost 1993; 70: 241-3.
- 26 Almer LD, Kjellstrom T. The fibrinolytic system and coagulation during bezafibrate treatment of hypertriglyceridemia. Atherosclerosis 1986; 61: 81-5.
- 27 Niort G, Bulgarelli A, Pagano A. Effect of short-term treatment with bezafibrate on plasma fibrinogen, fibrinopeptide A, platelet activation and blood filterability in atherosclerotic hyperfibrinogenemic patients. Atherosclerosis 1988; 71: 113-9.
- 28 Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996; 347: 849-53.
- 29 Koppensteiner R, Minar E, Ehringer H. Effect of lovastatin on hemorrheology in type II hyperlipoproteinemia. Atherosclerosis 1990; 85: 53-8.
- 30 Mc MCarthy. Lipid-lowering therapy may reduce thrombotic risk. Lancet 1997; 349: 703.
- 31 Lacoste L, Lam JYT, 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.
- 32 The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 ng/dL) plus two additional atherosclerotic risk factors. Am J Cardiol 1993; 72: 1031-7.
- 33 Heistad DD, Armstrong ML. Sick vessel syndrome: can atherosclerotic arteries recover?. Circulation 1994; 89: 2447-50.
- 34 Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-5.
- 35 Meade TW, Mellows S, Brozovic M. et al. Haemostatic function and ischemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 02: 533-7.
- 36 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease The Framingham Study. JAMA 1987; 258: 1183-6.
- 37 Cortellaro M, Boschetti C, Cofrancesco E, Zanussi C, Catalano M, de Gaetano G, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Della AVolpe, Polli E. and the PLAT study group: The PLAT study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients. Principal results. Arterioscler Thromb 1992; 12: 1063-70.
- 38 Heinrich J, Assmann G. Fibrinogen and cardiovascular risk. J Cardiovascular Risk 1995; 02: 197-205.
- 39 Anderson JL, Carlquist JF, Muhlestein JB, Horne BD, Elmer SP. Evaluation of C-reactive protein, an inflammatory marker, and infectious serology as risk factors for coronary artery disease and myocardial infarction. JACC 1998; 32: 35-41.
- 40 Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham Study. Am Heart J 1987; 113: 1006-10.
- 41 Haverkate F, Thompson SG, Pyke SDM, Gallimore JP, Pepys MB. for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997; 349: 462-6.
- 42 Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1996; 336: 973-9.
- 43 Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet 1987; 02: 986-8.
- 44 The Writing Group for the Estradiol Clotting Factors Study. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo controlled study. Thromb Haemost 1996; 75: 476-80.
- 45 Goldbout U, Behar S, Reicher-Reiss H. et al. Rationale and design of a secondary prevention trial of increasing serum HDL cholesterol and reducing triglycerides after myocardial infarction in patients with clinically manifest atherosclerotic heart disease (The Bezafibrate Infarction Prevention Study). Am J Cardiol 1993; 71: 909-15.
- 46 The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/ progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273: 199-208.