Expired CME Article

Statin Therapy in Rheumatoid Arthritis

Authors: Karen H. Costenbader, MD, MPH, Jonathan S. Coblyn, MD

Abstract

Rheumatoid arthritis, a chronic inflammatory polyarthritis that destroys synovial joints, is associated with systemic as well as local inflammation and with an increased risk of cardiovascular disease and death not fully explained by traditional cardiac risk factors. Statins (HMG-coA reductase inhibitors), medications originally designed to lower cholesterol, have been shown to have powerful effects on decreasing cardiovascular mortality rates in the general and high-risk populations. Not all of this protective benefit appears to be mediated by lowered cholesterol levels. Statins also influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide bioavailability, generation of free radicals, and angiogenesis. Recent studies show that statins may provide mild anti-inflammatory benefit in rheumatoid arthritis, in addition to reducing cardiovascular risk.


Key Points


* Rheumatoid arthritis is associated with systemic as well as local inflammation and with increased risk of cardiovascular disease and death not fully explained by traditional cardiac risk factors.


* Statins (HMG-coA reductase inhibitors), medications originally designed to lower cholesterol, have been shown to have powerful effects on decreasing cardiovascular mortality rates in the general and in high-risk populations.


* Statins also influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide bioavailability, generation of free radicals, and angiogenesis.


* Statins may be ideal drugs for rheumatoid arthritis, providing a mild anti-inflammatory effect and reducing cardiovascular risk.

This content is limited to qualifying members.

Existing members, please login first.

If you have an existing account please login now to access this article or view your purchase options.

Purchase only this article ($15)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. Gabriel SE, Crowson CS, O’Fallon WM. The epidemiology of rheumatoid arthritis in Rochester, Minnesota, 1955–1985. Arthritis Rheum 1999;42:415–420.
 
2. Linos A, Worthington JW, O’Fallon WM, et al. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality. Am J Epidemiol 1980;111:87–98.
 
3. Symmons DP, Barrett EM, Bankhead CR, et al. The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br J Rheumatol 1994;33:735–739.
 
4. Yelin E, Henke C, Epstein W. The work dynamics of the person with rheumatoid arthritis. Arthritis Rheum 1987;30:507–512.
 
5. Yelin E. The costs of rheumatoid arthritis: absolute, incremental, and marginal estimates. J Rheumatol Suppl 1996;44:47–51.
 
6. Pincus T, Callahan LF. Taking mortality in rheumatoid arthritis seriously: predictive markers, socioeconomic status and comorbidity. J Rheumatol 1986;13:841–845.
 
7. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum1994;37:481–494.
 
8. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107:1303–1307.
 
9. del Rincon ID, Williams K, Stern MP, et al. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001;44:2737–2745.
 
10. Maradit-Kremers H, Crowson CS, Nicola PJ, et al. Increased unrecognized coronary heart disease in rheumatoid arthritis: a population-based cohort study [abstract]. Arthritis Rheum 2004;50:S688.
 
11. Turesson C, Jarenros A, Jacobsson L. Increased incidence of cardiovascular disease in patients with rheumatoid arthritis: results from a community based study. Ann Rheum Dis 2004;63:952–5.
 
12. Fischer LM, Schlienger RG, Matter C, et al. Effect of rheumatoid arthritis or systemic lupus erythematosus on the risk of first-time acute myocardial infarction. Am J Cardiol 2004;93:198–200.
 
13. Symmons DP, Jones MA, Scott DL, et al. Long-term mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998;25:1072–1077.
 
14. Yelin E, Wanke LA. An assessment of the annual and long-term direct costs of rheumatoid arthritis: the impact of poor function and functional decline. Arthritis Rheum 1999;42:1209–1218.
 
15. McIntosh E. The cost of rheumatoid arthritis. Br J Rheumatol 1996;35:781–790.
 
16. Miossec P, van den Berg W. Th1/Th2 cytokine balance in arthritis. Arthritis Rheum 1997;40:2105–2115.
 
17. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907–916.
 
18. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–1143.
 
19. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115–126.
 
20. Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation1999;100:2124–2126.
 
21. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979.
 
22. Ridker PM, Buring JE, Shih J, et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:731–733.
 
23. Wallberg-Jonsson S, Johansson H, Ohman ML, et al. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis: a retrospective cohort study from disease onset. J Rheumatol 1999;26:2562–2571.
 
24. Sattar N, McCarey DW, Capell H, et al. Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 2003;108:2957–2963.
 
25. Choi HK, Hernan MA, Seeger JD, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173–1177.
 
26. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349–1357.
 
27. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389.
 
28. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial Investigators. N Engl J Med 1996;335:1001–1009.
 
29. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med1995;333:1301–1307.
 
30. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.
 
31. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149–1158.
 
32. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–1630.
 
33. White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the risk of stroke. N Engl J Med2000;343:317–326.
 
34. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504.
 
35. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685–696.
 
36. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998–3007.
 
37. Mitka M. Guidelines: new lows for LDL target levels. JAMA 2004;292:911–913.
 
38. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239.
 
39. Snow V, Aronson MD, Hornbake ER, et al. Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med2004;140:644–649.
 
40. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:III-39–III-43.
 
41. Palinski W, Napoli C. Unraveling pleiotropic effects of statins on plaque rupture. Arterioscler Thromb Vasc Biol 2002;22:1745–1750.
 
42. Palinski W, Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis. J Am Soc Nephrol 2002;13:1673–1681.
 
43. Casey PJ. Protein lipidation in cell signaling. Science 1995;268:221–225.
 
44. Wong B, Lumma WC, Smith AM, et al. Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation. J Leukoc Biol 2001;69:959–962.
 
45. Weber C, Erl W, Weber KS, et al. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 1997;30:1212–1217.
 
46. Liu L, Moesner P, Kovach NL, et al. Integrin-dependent leukocyte adhesion involves geranylgeranylated protein(s). J Biol Chem 1999;274:33334–33340.
 
47. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001;7:687–692.
 
48. Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399–1402.
 
49. Barbato JE, Tzeng E. Nitric oxide and arterial disease. J Vasc Surg 2004;40:187–193.
 
50. Mohacsi A, Magyar J, Tamas B, et al. Effects of endothelins on cardiac and vascular cells: new therapeutic target for the future? Curr Vasc Pharmacol 2004;2:53–63.
 
51. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004;15:1983–1992.
 
52. Suwaidi JA, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948–954.
 
53. Celermajer DS, Sorensen KE, Georgakopoulos D, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.Circulation 1993;88:2149–2155.
 
54. Hashimoto M, Kozaki K, Eto M, et al. Association of coronary risk factors and endothelium-dependent flow-mediated dilatation of the brachial artery. Hypertens Res 2000;23:233–238.
 
55. Tsunekawa T, Hayashi T, Kano H, et al. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation2001;104:376–379.
 
56. O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997;95:1126–1131.
 
57. Fabian E, Varga A, Picano E, et al. Effect of simvastatin on endothelial function in cardiac syndrome X patients. Am J Cardiol 2004;94:652–655.
 
58. Omori H, Nagashima H, Tsurumi Y, et al. Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol 2002;54:395–399.
 
59. Alonso R, Mata P, De Andres R, et al. Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin. Atherosclerosis2001;157:423–429.
 
60. Mason JC, Ahmed Z, Mankoff R, et al. Statin-induced expression of decay-accelerating factor protects vascular endothelium against complement-mediated injury. Circ Res 2002;91:696–703.
 
61. Bacon PA, Raza K, Banks MJ, et al. The role of endothelial cell dysfunction in the cardiovascular mortality of RA. Int Rev Immunol 2002;21:1–17.
 
62. Bacon PA, Stevens RJ, Carruthers DM, et al. Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmun Rev 2002;1:338–347.
 
63. Bijl M. Endothelial activation, endothelial dysfunction and premature atherosclerosis in systemic autoimmune diseases. Neth J Med 2003;61:273–277.
 
64. Wong M, Toh L, Wilson A, et al. Reduced arterial elasticity in rheumatoid arthritis and the relationship to vascular disease risk factors and inflammation. Arthritis Rheum 2003;48:81–89.
 
65. Van Doornum S, McColl G, Jenkins A, et al. Screening for atherosclerosis in patients with rheumatoid arthritis: comparison of two in vivo tests of vascular function. Arthritis Rheum 2003;48:72–80.
 
66. Forster A, Frey D, Hermann F, et al. Simvastatin improves endothelial function in rheumatoid arthritis [abstract]. Arthritis Rheum 2004;50:S178.
 
67. Stanislaus R, Pahan K, Singh AK, et al. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci Lett 1999;269:71–74.
 
68. Aktas O, Waiczies S, Smorodchenko A, et al. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 2003;197:725–733.
 
69. Youssef S, Stuve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002;420:78–84.
 
70. Endres M, Laufs U, Huang Z, et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A1998;95:8880–8885.
 
71. Bea F, Blessing E, Bennett B, et al. Simvastatin promotes atherosclerotic plaque stability in apoE-deficient mice independently of lipid lowering. Arterioscler Thromb Vasc Biol 2002;22:1832–1837.
 
72. Sparrow CP, Burton CA, Hernandez M, et al. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arterioscler Thromb Vasc Biol2001;21:115–121.
 
73. Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 2003;170:1524–1530.
 
74. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins.Science 1999;286:1946–1949.
 
75. Maeda T, Matsunuma A, Kurahashi I, et al. Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells. J Cell Biochem 2004;92:458–471.
 
76. Song C, Guo Z, Ma Q, et al. Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells. Biochem Biophys Res Commun 2003;308:458–462.
 
77. LaCroix AZ, Cauley JA, Pettinger M, et al. Statin use, clinical fracture, and bone density in postmenopausal women: results from the Women’s Health Initiative Observational Study. Ann Intern Med 2003;139:97–104.
 
78. Pasco JA, Kotowicz MA, Henry MJ, et al. Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study. Arch Intern Med 2002;162:537–540.
 
79. Sirola J, Honkanen R, Kroger H, et al. Relation of statin use and bone loss: a prospective population-based cohort study in early postmenopausal women. Osteoporos Int 2002;13:537–541.
 
80. Wang PS, Solomon DH, Mogun H, et al. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 2000;283:3211–3216.
 
81. van Staa TP, Wegman S, de Vries F, et al. Use of statins and risk of fractures. JAMA2001;285:1850–1855.
 
82. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 2004;363:2015–2021.
 
83. Kloppenburg M, Breedveld FC, Terwiel JP, et al. Minocycline in active rheumatoid arthritis: a double-blind, placebo-controlled trial. Arthritis Rheum 1994;37:629–636.
 
84. Kanda H, Yokota K, Kubo K, et al. Simvastatin reduces the disease activity in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2004;50:S387.
 
85. Kanda H, Hamasaki K, Kubo K, et al. Anti-inflammatory effect of simvastatin in patients with rheumatoid arthritis. J Rheumatol 2002;29:2024–2026.
 
86. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004;363:1607–1608.
 
87. Leonardi CL. Efalizumab in the treatment of psoriasis. Dermatol Ther 2004;17:393–400.
 
88. Klareskog L, Hamsten A. Statins in rheumatoid arthritis: two birds with one stone? Lancet2004;363:2011–2012.
 
89. Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000;6:1004–1010.
 
90. Vincent L, Chen W, Hong L, et al. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett 2001;495:159–166.
 
91. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998;279:1643–1650.
 
92. Rosenson RS. Current overview of statin-induced myopathy. Am J Med 2004;116:408–416.
 
93. Chong PH, Seeger JD, Franklin C. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med 2001;111:390–400.
 
94. de Denus S, Spinler SA, Miller K, et al. Statins and liver toxicity: a meta-analysis. Pharmacotherapy2004;24:584–591.
 
95. Davidson MH. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance.Expert Opin Drug Saf 2004;3:547–557.
 
96. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
 
97. Stevens RJ, Kothari V, Adler AI, et al. The UKPDS risk engine: a model for the risk of coronary heart disease in type II diabetes (UKPDS 56). Clin Sci (Lond) 2001;101:671–679.
 
98. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998;101:2711–2719.
 
99. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998;273:24266–24271.
 
100. Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129–1135.
 
101. Bonetti PO, Wilson SH, Rodriguez-Porcel M, et al. Simvastatin preserves myocardial perfusion and coronary microvascular permeability in experimental hypercholesterolemia independent of lipid lowering.J Am Coll Cardiol 2002;40:546–554.
 
102. Wilson SH, Herrmann J, Lerman LO, et al. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering. Circulation2002;105:415–418.
 
103. Wilson SH, Simari RD, Best PJ, et al. Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering. Arterioscler Thromb Vasc Biol 2001;21:122–128.
 
104. Wassmann S, Laufs U, Baumer AT, et al. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species.Hypertension 2001;37:1450–1457.
 
105. Laufs U, Gertz K, Huang P, et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000;31:2442–2449.
 
106. Kimura M, Kurose I, Russell J, et al. Effects of fluvastatin on leukocyte-endothelial cell adhesion in hypercholesterolemic rats. Arterioscler Thromb Vasc Biol 1997;17:1521–1526.
 
107. Romano M, Diomede L, Sironi M, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest 2000;80:1095–1100.
 
108. Inoue I, Goto S, Mizotani K, et al. Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells.Life Sci 2000;67:863–876.
 
109. Pahan K, Sheikh FG, Namboodiri AM, et al. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 1997;100:2671–2679.
 
110. Ito T, Ikeda U, Shimpo M, et al. HMG-CoA reductase inhibitors reduce interleukin-6 synthesis in human vascular smooth muscle cells. Cardiovasc Drugs Ther 2002;16:121–126.
 
111. Laufs U, Marra D, Node K, et al. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem 1999;274:21926–21931.
 
112. Guijarro C, Blanco-Colio LM, Ortego M, et al. 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res1998;83:490–500.
 
113. Fukumoto Y, Libby P, Rabkin E, et al. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of Watanabe heritable hyperlipidemic rabbits. Circulation2001;103:993–999.
 
114. Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001;103:926–933.
 
115. Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta1993;1165:335–338.
 
116. Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 2001;108:1429–1437.
 
117. Colli S, Eligini S, Lalli M, et al. Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997;17:265–272.
 
118. Baetta R, Camera M, Comparato C, et al. Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering.Arterioscler Thromb Vasc Biol 2002;22:692–698.
 
119. Essig M, Nguyen G, Prie D, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells: role of geranylgeranylation and Rho proteins.Circ Res 1998;83:683–690.
 
120. Wada H, Mori Y, Kaneko T, et al. Hypercoagulable state in patients with hypercholesterolemia: effects of pravastatin. Clin Ther 1992;14:829–834.
 
121. Isaacsohn JL, Setaro JF, Nicholas C, et al. Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels. Am J Cardiol 1994;74:735–737.
 
122. Davidson M, McKenney J, Stein E, et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia: Atorvastatin Study Group I. Am J Cardiol1997;79:1475–1481.
 
123. Mitropoulos KA, Armitage JM, Collins R, et al. Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids: the Oxford Cholesterol Study Group. Eur Heart J 1997;18:235–241.