Introduction Directory UMM :Data Elmu:jurnal:A:Atherosclerosis:Vol150.Issue2.Jun2000:

Atherosclerosis 150 2000 429 – 436 Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia FACT study Paolo Pauciullo a, , Carlo Borgnino b , Rodolfo Paoletti c , Mario Mariani d , Mario Mancini a a Department of Clinical and Experimental Medicine, Medical School of the Uni6ersity ‘ Federico II ’ , Via S. Pansini 5 , 80131 Naples, Italy b Medical Department, No6artis Farma S.p.A., Origgio, Italy c Institute of Pharmacological Sciences, Uni6ersity of Milan, Milan, Italy d Department of Cardiology, Angiology and Pneumology, Uni6ersity of Pisa, Pisa, Italy Received 26 July 1999; received in revised form 22 November 1999; accepted 7 January 2000 Abstract Preliminary data suggest that fluvastatin may be safely combined with fibrates. The Fluvastatin Alone and in Combination Treatment Study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease and mixed hyperlipidaemia. A total of 333 patients were randomly allocated in this multicentre double-blind trial to receive 40 mg fluvastatin alone n = 80, 400 mg bezafibrate n = 86, 20 mg fluvastatin + 400 mg bezafibrate n = 85 or 40 mg fluvastatin + 400 mg bezafibrate n = 82 for 24 weeks. Low-density lipoprotein LDL-cholesterol decreased \ 20 in all fluvastatin-containing regimens, with significantly greater decreases compared with bezafibrate alone P B 0.001. Bezafibrate alone and fluvastatin + bezafibrate combinations resulted in greater increases in high-density lipoprotein HDL- cholesterol and decreases in triglycerides compared with fluvastatin alone P B 0.001. Fluvastatin 40 mg + bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-cholesterol of 24, a decrease in triglycerides of 38 and an increase in HDL-cholesterol of 22. All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy, or between combination regimens. No clinically relevant liver aspartate aminotransferase or alanine aminotransferase ASAT or ALAT greater than three times the upper limit of normal or muscular creatine phosphokinase CPK greater than four times the upper limit of normal laboratory abnormalities were reported. This large study shows 40 mg fluvastatin in combination with 400 mg bezafibrate to be highly effective and superior to either drug given as monotherapy in mixed hyperlipidaemia, and to be safe and well tolerated. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords : Hyperlipidaemia; LDL cholesterol; Triglyceride; Fluvastatin; Bezafibrate; Combination therapy www.elsevier.comlocateatherosclerosis

1. Introduction

Hypercholesterolaemia is well established as a major risk factor in the development of atherosclerosis and coronary artery disease [1,2]. Treatment of hypercholes- terolaemia with 3-hydroxy-3-methlyglutaryl coenzyme A HMG-CoA reductase inhibitors statins reduces the incidence of fatal and non-fatal myocardial infarc- tion by 30 – 35 with fewer coronary revascularisation procedures and fewer strokes [3 – 8]. Statins are cur- rently the most potent and best-tolerated agents for lowering low-density lipoprotein LDL-cholesterol. Considerable evidence is now accumulating showing triglycerides to be an independent risk factor for coro- nary artery disease [9,10]. Triglyceride reduction by bezafibrate has been shown to slow progression of coronary atherosclerosis independently from LDL- cholesterol lowering in dyslipidaemic patients after my- ocardial infarction [11]. In patients with mixed hyperlipidaemia, treatment should therefore aim at normalising both LDL-choles- terol and triglyceride levels. In these patients, a combi- This work has been carried out on behalf of the FACT Study Centers. Corresponding author. Tel.: + 39-81-74620112303; fax: + 39- 81-5466152. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 0 0 0 0 3 7 9 - 8 nation of a statin and a fibrate would be a rational approach, as fibrates are more effective than statins in reducing triglycerides and also in increasing high-den- sity lipoprotein HDL-cholesterol [12]. However, combining statins and fibrates has not been recom- mended because episodes of rhabdomyolysis have fol- lowed concomitant use of lovastatin or simvastatin and gemfibrozil [13 – 16]. Small studies to date suggest that a combination of fluvastatin and bezafibrate [17,18] or gemfibrozil, [19,20] is well tolerated with no evidence of any clini- cally significant interactions. The Fluvastatin Alone and in Combination Treatment FACT Study was performed to examine the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease CAD and mixed hyperlipidaemia.

2. Patients and methods