Download PDF
Semin Thromb Hemost 2013; 39(05): 515-532
DOI: 10.1055/s-0033-1343892
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Venous Thrombosis Associated with HMG-CoA Reductase Inhibitors

Giuseppe Lippi
1   Dipartimento di Patologia e Medicina di Laboratorio, U.O. di Diagnostica Ematochimica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
,
Emmanuel J. Favaloro
2   Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia
,
Fabian Sanchis-Gomar
3   Department of Physiology, Faculty of Medicine, University of Valencia, Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Valencia, Spain
› Author Affiliations
Further Information

Publication History

Publication Date:
29 April 2013 (online)

    Permissions and Reprints

Abstract

Among the various hypolipidemic drugs, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (also known as “statins”) belong to a heterogeneous class of compounds, sharing an identical hypocholesterolemic effect that develops through direct inhibition of a rate-limiting step in endogenous cholesterol synthesis. Their mechanism of action entails competitive inhibition of HMG-CoA reductase. Several lines of evidence suggest that the pleiotropic effects of statins may also play a role in prevention of venous thrombosis, wherein hypercholesterolemic patients are characterized by enhanced thrombin generation, increased susceptibility to endothelial dysfunction and platelet hyperreactivity, so that limiting or counteracting the burden of one or more of these mechanisms would provide an effective means of prophylaxis. Plausible biological links can also be found between statin therapy and reduction of thrombotic risk, mainly targeting immune system, blood coagulation, endothelium, lipid metabolism, and inflammation. The earlier JUPITER (Justification for the Use of Statins in Primary Prevention) trial provided appealing evidence that the risk of venous thrombosis may be lowered by statins. The results of the following studies and those of recent meta-analyses have, however, questioned this assumption. Currently, it seems thereby cautious to conclude that the use of statins as part of the approach used for preventing venous thromboembolism appears unwarranted. This is due to the existence of controversial clinical evidence, to the large number of patients who would need to be treated to prevent one case of venous thrombosis, as well as to the tangible risk of side effects. More randomized and the larger studies are needed before definitive conclusions can be drawn.

Keywords

venous thrombosis - statin - HMG-CoA reductase inhibitors - C-reactive protein - therapy
 

  • References

  • 1 Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascular disease. Nat Rev Cardiol 2011; 8 (9) 502-512
    CrossrefPubMedGoogle Scholar
  • 2 Gotto Jr AM, Moon JE. Management of cardiovascular risk: the importance of meeting lipid targets. Am J Cardiol 2012; 110 (1) (Suppl): 3A-14A
    CrossrefPubMedGoogle Scholar
  • 3 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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) final report. Circulation 2002; 106 (25) 3143-3421
    PubMedGoogle Scholar
  • 4 Matsuyama H, Sato K, Nakamura Y, Suzuki K, Akiba Y. Modulation of regulatory factors involved in cholesterol metabolism in response to feeding of pravastatin- or cholesterol-supplemented diet in chickens. Biochim Biophys Acta 2005; 1734 (2) 136-142
    CrossrefPubMedGoogle Scholar
  • 5 Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004; 109 (23) (Suppl. 01) III39-III43
    PubMedGoogle Scholar
  • 6 Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ J 2010; 74 (5) 818-826
    CrossrefPubMedGoogle Scholar
  • 7 Stolla D, Dariolia R, Rodondia N. Lipid-lowering therapies and liver enzymes. Kardiovaskuläre Medizin 2009; 12 (9) 239-244
    PubMedGoogle Scholar
  • 8 Pella D, Rybar R, Mechirova V. Pleiotropic effects of statins. Acta Cardiol Sin 2005; 21: 190-198
    PubMedGoogle Scholar
  • 9 Lippi G, Favaloro EJ. Coagulopathies and thrombosis: usual and unusual causes and associations, part VI. Semin Thromb Hemost 2012; 38 (2) 125-128
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Lippi G, Franchini M, Favaloro EJ. Unsuspected triggers of venous thromboembolism—trivial or not so trivial?. Semin Thromb Hemost 2009; 35 (7) 597-604
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008; 34 (8) 747-761
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Tufano A, Coppola A, Cerbone AM, Ruosi C, Franchini M. Preventing postsurgical venous thromboembolism: pharmacological approaches. Semin Thromb Hemost 2011; 37 (3) 252-266
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Lippi G, Favaloro EJ, Cervellin G. Prevention of venous thromboembolism: focus on mechanical prophylaxis. Semin Thromb Hemost 2011; 37 (3) 237-251
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Bikdeli B, Sharif-Kashani B. Prophylaxis for venous thromboembolism: a great global divide between expert guidelines and clinical practice?. Semin Thromb Hemost 2012; 38 (2) 144-155
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Poredos P, Jezovnik MK. Dyslipidemia, statins, and venous thromboembolism. Semin Thromb Hemost 2011; 37 (8) 897-902
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Ray JG, Rosendaal FR. The role of dyslipidemia and statins in venous thromboembolism. Curr Control Trials Cardiovasc Med 2001; 2 (4) 165-170
    CrossrefPubMedGoogle Scholar
  • 17 Goldhaber SZ, Savage DD, Garrison RJ , et al. Risk factors for pulmonary embolism. The Framingham Study. Am J Med 1983; 74 (6) 1023-1028
    CrossrefPubMedGoogle Scholar
  • 18 Goldhaber SZ, Grodstein F, Stampfer MJ , et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277 (8) 642-645
    CrossrefPubMedGoogle Scholar
  • 19 Kawasaki T, Kambayashi J, Ariyoshi H, Sakon M, Suehisa E, Monden M. Hypercholesterolemia as a risk factor for deep-vein thrombosis. Thromb Res 1997; 88 (1) 67-73
    CrossrefPubMedGoogle Scholar
  • 20 McColl MD, Sattar N, Ellison J , et al. Lipoprotein (a), cholesterol and triglycerides in women with venous thromboembolism. Blood Coagul Fibrinolysis 2000; 11 (3) 225-229
    PubMedGoogle Scholar
  • 21 Nowak-Göttl U, Junker R, Hartmeier M , et al. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood. Circulation 1999; 100 (7) 743-748
    CrossrefPubMedGoogle Scholar
  • 22 von Depka M, Nowak-Göttl U, Eisert R , et al. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000; 96 (10) 3364-3368
    CrossrefPubMedGoogle Scholar
  • 23 Lippi G, Bassi A, Brocco G, Manzato F, Marini M, Guidi G. Lipoprotein(a) concentration is not associated with venous thromboembolism in a case control study. Haematologica 1999; 84 (8) 726-729
    PubMedGoogle Scholar
  • 24 Ignatescu M, Kostner K, Zorn G , et al. Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension. Thromb Haemost 1998; 80 (2) 231-232
    PubMedGoogle Scholar
  • 25 Evans NS, Green D. ASH evidence-based guidelines: statins in the prevention of venous thromboembolism. Hematology (Am Soc Hematol Educ Program) 2009; 273-274
    PubMedGoogle Scholar
  • 26 Glynn RJ, Danielson E, Fonseca FA , et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360 (18) 1851-1861
    CrossrefPubMedGoogle Scholar
  • 27 Ramcharan AS, Van Stralen KJ, Snoep JD, Mantel-Teeuwisse AK, Rosendaal FR, Doggen CJ. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis. J Thromb Haemost 2009; 7 (4) 514-520
    CrossrefPubMedGoogle Scholar
  • 28 Sørensen HT, Horvath-Puho E, Søgaard KK , et al. Arterial cardiovascular events, statins, low-dose aspirin and subsequent risk of venous thromboembolism: a population-based case-control study. J Thromb Haemost 2009; 7 (4) 521-528
    CrossrefPubMedGoogle Scholar
  • 29 Li L, Sun T, Zhang P, Tian J, Yang K. Statins for primary prevention of venous thromboembolism. Cochrane Database Syst Rev 2011; (12) CD008203
    PubMedGoogle Scholar
  • 30 Herrington DM, Vittinghoff E, Lin F , et al; HERS Study Group. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002; 105 (25) 2962-2967
    CrossrefPubMedGoogle Scholar
  • 31 Ray JG, Mamdani M, Tsuyuki RT, Anderson DR, Yeo EL, Laupacis A. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med 2001; 161 (11) 1405-1410
    CrossrefPubMedGoogle Scholar
  • 32 Agarwal V, Phung OJ, Tongbram V, Bhardwaj A, Coleman CI. Statin use and the prevention of venous thromboembolism: a meta-analysis. Int J Clin Pract 2010; 64 (10) 1375-1383
    CrossrefPubMedGoogle Scholar
  • 33 Squizzato A, Galli M, Romualdi E , et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J 2010; 31 (10) 1248-1256
    CrossrefPubMedGoogle Scholar
  • 34 Lacut K, Le Gal G, Abalain JH, Mottier D, Oger E. Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: role of drug induced homocysteinemia?. Thromb Res 2008; 122 (3) 314-319
    CrossrefPubMedGoogle Scholar
  • 35 Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol 2009; 67 (1) 99-109
    CrossrefPubMedGoogle Scholar
  • 36 Huerta C, Johansson S, Wallander MA, García Rodríguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 2007; 167 (9) 935-943
    CrossrefPubMedGoogle Scholar
  • 37 Doggen CJ, Lemaitre RN, Smith NL, Heckbert SR, Psaty BM. HMG CoA reductase inhibitors and the risk of venous thrombosis among postmenopausal women. J Thromb Haemost 2004; 2 (5) 700-701
    CrossrefPubMedGoogle Scholar
  • 38 Yang CC, Jick SS, Jick H. Statins and the risk of idiopathic venous thromboembolism. Br J Clin Pharmacol 2002; 53 (1) 101-105
    CrossrefPubMedGoogle Scholar
  • 39 The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975; 231 (4) 360-381
    CrossrefPubMedGoogle Scholar
  • 40 Keech A, Simes RJ, Barter P , et al; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366 (9500) 1849-1861
    CrossrefPubMedGoogle Scholar
  • 41 Freeman DJ, Robertson M, Ford I , et al. Risk factors for the development of incident venous thrombotic events in the prospective study of pravastatin in the elderly at risk (PROSPER). (Abstract) Platelets 2007; 18 (Suppl. 01) S18
    PubMedGoogle Scholar
  • 42 Yang CC, Kao CC. Cardiovascular diseases and the risk of venous thromboembolism: a hospital-based case-control study. J Chin Med Assoc 2007; 70 (3) 103-109
    CrossrefPubMedGoogle Scholar
  • 43 Rodriguez AL, Wojcik BM, Wrobleski SK, Myers Jr DD, Wakefield TW, Diaz JA. Statins, inflammation and deep vein thrombosis: a systematic review. J Thromb Thrombolysis 2012; 33 (4) 371-382
    CrossrefPubMedGoogle Scholar
  • 44 Khemasuwan D, Divietro ML, Tangdhanakanond K, Pomerantz SC, Eiger G. Statins decrease the occurrence of venous thromboembolism in patients with cancer. Am J Med 2010; 123 (1) 60-65
    CrossrefPubMedGoogle Scholar
  • 45 Lacut K, Oger E, Le Gal G , et al. Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study. Fundam Clin Pharmacol 2004; 18 (4) 477-482
    CrossrefPubMedGoogle Scholar
  • 46 Momi S, Impagnatiello F, Guzzetta M , et al. NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties. Eur J Pharmacol 2007; 570 (1-3) 115-124
    CrossrefPubMedGoogle Scholar
  • 47 Pai M, Evans NS, Shah SJ, Green D, Cook D, Crowther MA. Statins in the prevention of venous thromboembolism: a meta-analysis of observational studies. Thromb Res 2011; 128 (5) 422-430
    CrossrefPubMedGoogle Scholar
  • 48 Resh M, Mahmoodi BK, Navis GJ, Veeger NJ, Lijfering WM. Statin use in patients with nephrotic syndrome is associated with a lower risk of venous thromboembolism. Thromb Res 2011; 127 (5) 395-399
    CrossrefPubMedGoogle Scholar
  • 49 Delluc A, Tromeur C, Le Moigne E , et al. Lipid lowering drugs and the risk of recurrent venous thromboembolism. Thromb Res 2012; 130 (6) 859-863
    CrossrefPubMedGoogle Scholar
  • 50 Delluc A, Malécot JM, Kerspern H , et al. Lipid parameters, lipid lowering drugs and the risk of venous thromboembolism. Atherosclerosis 2012; 220 (1) 184-188
    CrossrefPubMedGoogle Scholar
  • 51 Macchia A, Laffaye N, Comignani PD , et al. Statins but not aspirin reduce thrombotic risk assessed by thrombin generation in diabetic patients without cardiovascular events: the RATIONAL trial. PLoS ONE 2012; 7 (3) e32894
    CrossrefPubMedGoogle Scholar
  • 52 Rahimi K, Bhala N, Kamphuisen P , et al. Effect of statins on venous thromboembolic events: a meta-analysis of published and unpublished evidence from randomised controlled trials. PLoS Med 2012; 9 (9) e1001310
    CrossrefPubMedGoogle Scholar
  • 53 Freeman DJ, Robertson M, Brown EA , et al. Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). BMC Geriatr 2011; 11: 8
    CrossrefPubMedGoogle Scholar
  • 54 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 AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279 (20) 1615-1622
    CrossrefPubMedGoogle Scholar
  • 55 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 (19) 1349-1357
    CrossrefPubMedGoogle Scholar
  • 56 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360 (9326) 7-22
    CrossrefPubMedGoogle Scholar
  • 57 Sever PS, Dahlöf B, Poulter NR , et al; ASCOT investigators. 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 (9364) 1149-1158
    CrossrefPubMedGoogle Scholar
  • 58 Fellström B, Holdaas H, Jardine AG , et al; Assessment of Lescol in Renal Transplantation Study Investigators. Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial. Kidney Int 2004; 66 (4) 1549-1555
    CrossrefPubMedGoogle Scholar
  • 59 Colhoun HM, Betteridge DJ, Durrington PN , et al; CARDS investigators. 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 (9435) 685-696
    CrossrefPubMedGoogle Scholar
  • 60 Asselbergs FW, Diercks GF, Hillege HL , et al; Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110 (18) 2809-2816
    CrossrefPubMedGoogle Scholar
  • 61 Koren MJ, Hunninghake DB. ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol 2004; 44 (9) 1772-1779
    PubMedGoogle Scholar
  • 62 Wanner C, Krane V, März W , et al; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353 (3) 238-248
    CrossrefPubMedGoogle Scholar
  • 63 Cowell SJ, Newby DE, Prescott RJ , et al; Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005; 352 (23) 2389-2397
    CrossrefPubMedGoogle Scholar
  • 64 Nakamura H, Arakawa K, Itakura H , et al; MEGA Study Group. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006; 368 (9542) 1155-1163
    CrossrefPubMedGoogle Scholar
  • 65 Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006; 29 (7) 1478-1485
    CrossrefPubMedGoogle Scholar
  • 66 Amarenco P, Bogousslavsky J, Callahan III A , et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355 (6) 549-559
    CrossrefPubMedGoogle Scholar
  • 67 Kjekshus J, Apetrei E, Barrios V , et al; CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357 (22) 2248-2261
    CrossrefPubMedGoogle Scholar
  • 68 Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 2006; 47 (2) 332-337
    CrossrefPubMedGoogle Scholar
  • 69 Tavazzi L, Maggioni AP, Marchioli R , et al; Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372 (9645) 1231-1239
    CrossrefPubMedGoogle Scholar
  • 70 Crouse III JR, Raichlen JS, Riley WA , et al; METEOR Study Group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007; 297 (12) 1344-1353
    CrossrefPubMedGoogle Scholar
  • 71 Feldman HH, Doody RS, Kivipelto M , et al; LEADe Investigators. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010; 74 (12) 956-964
    CrossrefPubMedGoogle Scholar
  • 72 Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. ASTRONOMER Investigators. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010; 121 (2) 306-314
    CrossrefPubMedGoogle Scholar
  • 73 Fassett RG, Robertson IK, Ball MJ, Geraghty DP, Coombes JS. Effect of atorvastatin on kidney function in chronic kidney disease: a randomised double-blind placebo-controlled trial. Atherosclerosis 2010; 213 (1) 218-224
    CrossrefPubMedGoogle Scholar
  • 74 Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357 (9256) 577-581
    CrossrefPubMedGoogle Scholar
  • 75 de Lemos JA, Blazing MA, Wiviott SD , et al; Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292 (11) 1307-1316
    CrossrefPubMedGoogle Scholar
  • 76 Nissen SE, Tuzcu EM, Schoenhagen P , et al; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291 (9) 1071-1080
    CrossrefPubMedGoogle Scholar
  • 77 Cannon CP, Braunwald E, McCabe CH , et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350 (15) 1495-1504
    CrossrefPubMedGoogle Scholar
  • 78 LaRosa JC, Grundy SM, Waters DD , et al; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352 (14) 1425-1435
    CrossrefPubMedGoogle Scholar
  • 79 Pedersen TR, Faergeman O, Kastelein JJ , et al; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294 (19) 2437-2445
    CrossrefPubMedGoogle Scholar
  • 80 Armitage J, Bowman L, Wallendszus K , et al; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010; 376 (9753) 1658-1669
    CrossrefPubMedGoogle Scholar
  • 81 Rosendaal FR. Statins and venous thrombosis: a story too good to be true?. PLoS Med 2012; 9 (9) e1001311
    CrossrefPubMedGoogle Scholar
  • 82 Ridker PM, Cannon CP, Morrow D , et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352 (1) 20-28
    CrossrefPubMedGoogle Scholar
  • 83 Ridker PM, Danielson E, Fonseca FA , et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21) 2195-2207
    CrossrefPubMedGoogle Scholar
  • 84 Lippi G, Favaloro EJ, Montagnana M, Franchini M. C-reactive protein and venous thromboembolism: causal or casual association?. Clin Chem Lab Med 2010; 48 (12) 1693-1701
    CrossrefPubMedGoogle Scholar
  • 85 Perez A, Bartholomew JR. Interpreting the JUPITER trial: statins can prevent VTE, but more study is needed. Cleve Clin J Med 2010; 77 (3) 191-194
    CrossrefPubMedGoogle Scholar
  • 86 Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med 2010; 48 (6) 749-756
    CrossrefPubMedGoogle Scholar
  • 87 Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005; 25 (2) 287-294
    PubMedGoogle Scholar
  • 88 Kinlay S. Potential vascular benefits of statins. Am J Med 2005; 118 (Suppl 12A) 62-67
    CrossrefPubMedGoogle Scholar
  • 89 Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45: 89-118
    CrossrefPubMedGoogle Scholar
  • 90 Yoshida M. Potential role of statins in inflammation and atherosclerosis. J Atheroscler Thromb 2003; 10 (3) 140-144
    CrossrefPubMedGoogle Scholar
  • 91 Wierzbicki AS, Poston R, Ferro A. The lipid and non-lipid effects of statins. Pharmacol Ther 2003; 99 (1) 95-112
    CrossrefPubMedGoogle Scholar
  • 92 Davignon J. Pleiotropic effects of pitavastatin. Br J Clin Pharmacol 2012; 73 (4) 518-535
    CrossrefPubMedGoogle Scholar
  • 93 Mihos CG, Salas MJ, Santana O. The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review. Cardiol Rev 2010; 18 (6) 298-304
    CrossrefPubMedGoogle Scholar
  • 94 Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J Gen Med 2011; 4: 261-271
    PubMedGoogle Scholar