Coronary heart disease (CHD) remains a major therapeutic challenge in the Western world, and strategies aimed at cholesterol lowering form the mainstay of treatment. Fluvastatin is an established 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ("statin") for the treatment of hypercholesterolemia. Its efficacy and safety have been established in numerous clinical trials. Emerging evidence now indicates that treatment with fluvastatin slows the progression of atherosclerotic CHD and reduces the incidence of cardiovascular morbimor tality in the secondary prevention setting. This effect of fluvastatin cannot be explained by cholesterol lowering alone; nonlipid-related mechanisms (so-called "pleiotropic effects") undoubtedly contribute to a certain extent, and are probably linked to modulation of the mevalonate pathway. This review discusses the experimental evidence regarding the antiath erosclerotic and antithrombotic effects of fluvastatin that may contribute to its beneficial action on disease progression and clinical events. Such effects include decreased expression of adhesion molecules in monocytes and leucocyte-endothelium adherence responses, im munomodulation, prevention of low-density lipoprotein oxidation, inhibition of cholesterol esterification and accumulation, along with effects on smooth muscle cell proliferation and migration. Pleiotropic actions aimed at plaque stabilization (eg, decreased secretion of matrix metalloproteinases by macrophages), together with effects on platelet activity, tissue factor expression, and endothelial function, may contribute to an antithrombotic effect of fluva statin. Taken together, the results of these studies indicate that the effects of fluvastatin, at therapeutic doses, may extend beyond cholesterol lowering.
Stamler J., Wentworth D., Neaton JD, for the MRFIT Research Group.Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Study (MRFIT). JAMA256:2823, 1986
2.
Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults.Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA269:3015, 1993
3.
Cleeman JI, Lenfant C.The National Cholesterol Education Program. JAMA280:2099, 1998
4.
Bucher HC, Griffith LE, Guyatt GHSystemic review on the risk and benefit of different cholesterol-lowering interventions. Arterioscler Thromb Vasc Biol19:187, 1999
5.
Langtry HD, Markham A. Fluvastatin.A review of its use in lipid disorders. Drugs57:583, 1999
6.
Schuster H., Berger J., Luft FCRandomised, double-blind, parallel-group trial of atorvastatin and fluvastatin on plasma lipid levels in patients with untreated hyperlipidaemia. Br J Cardiol5:597, 1998
7.
Serruys PW, Foley DP, Jackson G., et al, on behalf of the FLARE Study Group.A randomized placebo controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty: Final results of the fluvastatin angiographic restenosis (FLARE) trial. Eur Heart J20:58, 1999
8.
Appel S., Dingemanse J.Pharmacokinetic and pharmacodynamic interactions of fluvastatin and their therapeutic implications. Rev Contemp Pharmacother7:167, 1996
9.
Christians U. , Jacobsen W., Floren LCMetabolism and drug interactions of 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar?Pharmacol Ther80:1, 1998
10.
Corsini A., Bellosta S., Baetta R., et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther84:413, 1999
11.
Scandinavian Simvastatin Survival Study Group.Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) . Lancet344:1383, 1994
12.
Shepherd J. , Cobbe SM, Ford I., et al, for the West of Scotland Coronary Prevention Study Group.Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med333:1301, 1995
13.
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 Med335:1001, 1996
14.
Smith SCReview of recent clinical trials of lipid lowering in coronary artery disease . Am J Cardiol80:10H, 1997
15.
The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous vein coronary-artery bypass grafts. N Engl J Med336:153, 1997
16.
Downs JR, Clearfield M., Weis S., et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AF-CAPS/TexCAPS . JAMA279:1615, 1998
17.
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 Med339:1349, 1998
18.
Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol80:278, 1997
19.
Ballantyne CM, Herd JA, Ferlic LL, et al. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation99:736, 1999
20.
Riegger Ajg , Abletshauser C., Ludwig M., et al. The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis144:263, 1999
21.
O'Driscoll G., Green D., Taylor RRSimvastatin, an HMGcoenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation95:1126, 1997
22.
West of Scotland Coronary Prevention Study Group.Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation97:1440, 1998
23.
Goldstein JL, Brown MSRegulation of the mevalonate pathway. Nature343:425, 1990
24.
Ross R.Atherosclerosis—an inflammatory disease. N Engl J Med340:115, 1999
25.
Steinberg D., Pathasarathy S., Carew TE, et al. Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med320:915, 1989
26.
Ip JH, Fuster V., Badimon L., et al. Syndromes of accelerated atherosclerosis: Role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol15:1667, 1990
27.
Suzumura K. , Yasuhara M., Tanaka K., et al. Protective effect of fluvastatin sodium (XU-62-320), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro. Biochem Pharmacol57:697, 1999
28.
Yamamoto A. , Hoshi K., Ichihara K.Fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, scavenges free radicals and inhibits lipid peroxidation in rat liver microsomes. Eur J Pharmacol361:143, 1998
29.
Hussein O., Schlezinger S., Rosenblat M., et al. Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL. Atherosclerosis128:11, 1997
30.
Leonhardt W. , Kurktschiev T., Meissner D., et al. Effects of fluvastatin therapy on lipids, antioxidants, oxidation of low density lipoproteins and trace metals . Eur J Clin Pharmacol53:65, 1997
31.
Aviram M., Hussein O., Rosenblat M., et al. Interactions of platelets, macrophages, and lipoproteins in hypercholesterolemia: Antiatherogenic effects of HMG-CoA reductase inhibitor therapy. J Cardiovasc Pharmacol31:39, 1998
32.
Keidar S., Kaplan M., Aviram M.Angiotensin II modified LDL is taken up by macrophages via the scavenger receptor, leading to cellular cholesterol accumulation. Arterioscler Thromb16:97, 1996
33.
Keidar S., Kaplan M., Shapira H., et al. Low density lipoprotein isolated from patients with essential hypertension exhibits increased propensity for oxidation and enhanced uptake by macrophages: A possible role for angiotensin II. Atherosclerosis104:71, 1994
34.
Mitani H., Bandoh T., Ishikawa J., et al. Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits. Br J Pharmacol119:1269, 1996
35.
de Graaf J. , Hendriks JC, Demacker PN, et al. Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment. Arterioscler Thromb13:712, 1993
36.
Galeano NF, Al-Haideri M., Keyserman F., et al. Small dense low density lipoprotein has increased affinity for LDL-receptor-independent cell surface binding sites: A potential mechanism for increased atherogenicity. J Lipid Res39:1263, 1998
37.
Gardner CD, Fortmann SP, Krauss RMAssociation of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA276:875, 1996
38.
Lamarche B. , Tchernof A., Moorjani S., et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation95:69, 1997
39.
März W., Scharnagl H., Abletshauser C., et al. Effect of fluvastatin on small dense low density lipoproteins in postmenopausal women with an atherogenic lipoprotein phenotype [abstract] . XIth International Symposium on Atherosclerosis , Paris, France, October 1997
40.
Superko HR, Krauss RM, DiRicco C.Effect of fluvastatin on low-density lipoprotein peak particle diameter. Am J Cardiol80:78, 1997
41.
Anggard E.Nitric oxide: Mediator, murderer and medicine. Lancet343:1199, 1994
42.
Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet340:1111, 1992
43.
Casino PR, Kilcoyne CM, Cannon RO III, et al. Impaired endothelium-dependent vascular relaxation in patients with hypercholesterolemia extends beyond the muscarinic receptor. Am J Cardiol75:40, 1995
44.
John S., Sclaich M., Langenfeld M., et al. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients. Circulation87:211, 1998
45.
Romano M., Marulli C., Mezzetti A., et al. Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients [abstract]. 71st Scientific Sessions of theAmerican Heart Association, Dallas, TX, November 1998
46.
Anderson TJ , Uehata A., Gerhard MD, et al. Close relation of endothelial function in the coronary and peripheral circulations. J Am Coll Cardiol26:1235, 1995
47.
Sieberlink Hmj , van Boven A.Cholesterol lowering in primary prevention improves coronary flow reserve and coronary vascular resistance [abstract] . 71st Scientific Sessions of the American Heart Association, Dallas, TX, November 1998
48.
Eichstädt HW , Eskötter H., Hoffmann I., et al. Improvement of myocardial perfusion by short-term fluvastatin therapy in coronary artery disease. Am J Cardiol76:122A, 1995
49.
Guethlin M. , Kasel AM, Coppenrath K., et al. Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin. Circulation99:475, 1999
50.
Watanabe T. , Fan J.Atherosclerosis and inflammation mononuclear cell recruitment and adhesion molecules with reference to the implication of ICAM-I/LFA-1 pathway in atherogenesis. Int J Cardiol66(Suppl 1):S45, 1998
51.
Niwa S., Totsuka T., Hayashi S.Inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line. Int J Immunopharmacol18:669, 1996
52.
Kimura M., Kurose I., Russell J., et al. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats. Arterioscler Thromb Vasc Biol17:1521, 1997
53.
Rothe G., Herr A., Stöhr J., et al. A more mature phenotype of blood mononuclear phagocytes is induced by fluvastatin treatment in hypercholesterolemic patients with coronary artery disease. Atherosclerosis144(1):251, 1999
54.
Madej A., Kalina Z., Okopie B., et al. The release of tumor necrosis factor-alpha by cultured macrophages from hyperlipidemic patients treated with fluvastatin [abstract]. Eur J Clin Pharmacol52(Suppl):76, 1997
55.
Galis ZS, Muszynski M., Sukhova GK, et al. Cytokinestimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res75:181, 1994
56.
Saren P., Welgus HG, Kovanen PTTNF-α and IL-1β selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol157:4159, 1996
57.
Bernini F., Didoni G., Bonfadini G., et al. Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages. Atherosclerosis104:19, 1993
58.
Kathawala FGHMG-CoA reductase inhibitors: An exciting development in the treatment of hyperlipoproteinemia. Med Res Rev11:121, 1991
59.
Corsini A., Raiteri M., Soma MR, et al. Pathogenesis of atherosclerosis and the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Am J Cardiol76:21 A, 1995
60.
Corsini A., Bernini F., Quarato P., et al. Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Cardiology87:458, 1996
Maltese WAPost-translational modification of proteins by isoprenoids in mammalian cells . FASEB J4:3319, 1990
63.
Bellosta S. , Bernini F., Ferri N., et al. Direct vascular effects of HMG-CoA reductase inhibitors. Atherosclerosis137 (Suppl):S101, 1998
64.
Rogler G., Lackner KJ, Schmitz G.Effects of fluvastatin on growth of porcine and human vascular smooth muscle cells in vitro. Am J Cardiol76:114A, 1995
65.
Corsini A., Mazzotti M., Raiteri M., et al. Relationship between mevalonate pathway and arterial myocyte proliferation: In vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis101:117, 1993
66.
Soma MR, Donetti E., Parolini C., et al. HMG CoA reductase inhibitors: In vivo effects on carotid intimal thickening in normocholesterolemic rabbits. Arterioscler Thromb Vase Biol13:571, 1993
67.
Soma MR, Parolini C., Donetti E., et al. Inhibition of isoprenoid biosynthesis and arterial smooth muscle cell proliferation. J Cardiovasc Pharmacol25(Suppl 4):S20, 1995
68.
Bandoh T., Mitani H., Niihashi M., et al. Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery. Eur J Pharmacol315:37, 1996
69.
Shiomi M., Ito T., Tsukada T., et al. Effect of fluvastatin sodium on the smooth muscle cells in atherosclerotic plaques. Arzneim Forsch48:680, 1998
70.
Corsini A., Pazzucconi F., Pfister P., et al. Inhibition of proliferation of arterial smooth muscle cells by fluvastatin. Lancet348:1584, 1996
71.
Corsini A., Pazzucconi F., Arnaboldi L., et al. Direct effects of statins on the vascular wall. J Cardiovasc Pharmacol31:773, 1998
72.
Weintraub WS , Boccuzzi SJ, Klein JL, on behalf of the Lovastatin Restenosis Trial Study Group.Lack of effect of lovastatin on restenosis after coronary angioplasty. N Engl J Med331:1331, 1994
73.
Bertrand ME , McFadden EP, Fruchart JC, for the PREDICT Trial Investigators.Effects of pravastatin on angiographic restenosis after coronary balloon angioplasty. J Am Coll Cardiol30:863, 1997
74.
Smith SCRisk-reduction therapy: The challenge to change. Circulation93:2205, 1996
75.
Libby P., Aikawa M.New insights into plaque stabilisation by lipid lowering. Drugs56(Suppl 1):9, 1998
76.
Brown BG, Zhao XQ, Sacco DE, et al. Arteriographic view of treatment to achieve regression of coronary atherosclerosis and to prevent plaque disruption and clinical cardiovascular events. Br Heart J69:S48, 1993
77.
Richardson PD, Davies MJ, Born Gvr.Influence of plaque configuration and stress distribution on fissuring or coronary atherosclerotic plaques. Lancetii:941, 1989
78.
Libby P.Molecular basis of acute coronary syndromes. Circulation91:2844, 1995
79.
Bellosta S. , Via D., Canavesi M., et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol18:1671, 1998
80.
Tremoli E., Maderna P., Colli S., et al. Increased platelet sensitivity and thromboxane B2 formation in type-II hyperlipoproteinaemic patients. Eur J Clin Invest14:329, 1984
81.
DiMinno G., Silver MJ, Cerbone AM, et al. Increased fibrinogen binding to platelets from patients with familial hypercholesterolaemia. Arteriosclerosis6:203, 1986
82.
Eynard AR, Tremoli E., Caruso D., et al. Platelet formation of the 12-hydroxyeicosatetraenoic acid and thromboxane B2 is increased in type IIa hypercholesterolemic subjects. Atherosclerosis60:61, 1986
83.
Reilly IA, Doran JB, Smith B., et al. Increased thromboxane biosynthesis in a human preparation of platelet activation: Biochemical and functional consequences of selective inhibition of thromboxane synthase. Circulation73:1300, 1986
84.
Davi G., Ganci G., Averna M., et al. Thromboxane biosynthesis, neutrophil and coagulative activation in type IIa hypercholesterolemia. Thromb Haemost74:1015, 1995
85.
Fuhrman B., Brook JG, Aviram M.Proteins derived from platelet alpha granules modulate the uptake of oxidized low density lipoprotein by macrophages. Biochim Biophys Acta1127:15, 1992
86.
Aviram M., Danker G., Brook JGPlatelet secretory products increase LDL oxidation, enhance its uptake by macrophages and reduce its fluidity. Arteriosclerosis10:559, 1990
87.
Blache D., Pfister P., Durand P.Fluvastatin reduces platelet activity in vitro [abstract]. XIth International Symposium on Atherosclerosis, Paris, France, October 1997
88.
Hussein O., Rosenblat M., Schlezinger S., et al. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet composition and drug binding to platelets. Br J Clin Pharmacol44:77, 1997
89.
Milani M., Cimminiello C., Merlo B., et al. Effects of fluvastatin and pravastatin on lipid profiles and thromboxane production in type IIa hypercholesterolemia. Am J Cardiol76:51 A, 1995
90.
Huhle G., Abletshauser C., Mayer N., et al. Reduction of platelet activity markers in type II hypercholesterolaemic patients by a HMG-CoA-reductase inhibitor. Thromb Res95:229, 1999
91.
Ridker PM, Vaughan DE, Stampfer MJ, et al. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet341:1165, 1993
92.
Ridker PM, Hennekens CH, Stampfer MJ, et al. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet343:940, 1994
93.
Bevilacqua M., Bettica P., Milani M., et al. Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease. Am J Cardiol79:84, 1997
94.
Nemerson Y.Tissue factor and hemostasis. Blood71:1, 1988
95.
Wilcox JN, Smith KM, Schwartz SM, et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA86:2839, 1989
96.
Colli S., Eligini S., Lalli M., et al. Vastatins inhibit tissue factor in cultured human macrophages: A novel mechanism of protection against atherosclerosis. Arterioscler Thromb Vasc Biol17:265, 1997
97.
Tan KC, Janus ED, Lam KSEffects of fluvastatin on prothrombotic and fibrinolytic factors in type 2 diabetes mellitus. Am J Cardiol84:934, 1999
98.
Ambrosi P., Aillaud MR, Habib G., et al. Treatment with fluvastatin decreases soluble thrombomodulin in cardiac transplant patients [abstract]. 71st Congress of the European Atherosclerosis Society, Athens , Greece, May 1999
