Usefulness of Statins for Prevention of Venous Thromboembolism

Accepted Manuscript Title: Usefulness of Statins for Prevention of Venous Thromboembolism Author: Patricia Chaffey, Mary Thompson, Ajit D. Pai, Ali R. Tafreshi, Javad Tafreshi, Ramdas G. Pai PII: DOI: Reference:

S0002-9149(18)30260-1 https://doi.org/10.1016/j.amjcard.2018.02.024 AJC 23154

To appear in:

The American Journal of Cardiology

Received date: Accepted date:

29-12-2017 6-2-2018

Please cite this article as: Patricia Chaffey, Mary Thompson, Ajit D. Pai, Ali R. Tafreshi, Javad Tafreshi, Ramdas G. Pai, Usefulness of Statins for Prevention of Venous Thromboembolism, The American Journal of Cardiology (2018), https://doi.org/10.1016/j.amjcard.2018.02.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Usefulness of Statins For Prevention of Venous Thromboembolism Patricia Chaffey, PharmDa, Mary Thompson, PharmDa, Ajit D Pai, BAa, Ali R Tafreshi, BSb, Javad Tafreshi, PharmDc, and Ramdas G Pai MDd

a

b

Loma Linda University School of Pharmacy, Loma Linda, CA

University of Southern California School of Medicine, Los Angeles, CA c

d

Marshall B. Ketchum University College of Pharmacy, Fullerton, CA

University of California Riverside School of Medicine, Riverside, CA.

Running head: Statins for VTE prevention

Corresponding author: Javad Tafreshi, PharmD, BCPS-AQ Cardiology, FAHA, APh Professor and Associate Dean for Academic Affairs Marshall B. Ketchum University College of Pharmacy 2575 Yorba Linda Blvd. Fullerton, CA 92831-1699 Phone: 714.872.5693 Fax: 714.872.5706 [email protected]

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Abstract: Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, is common with an annual incidence of 1-5 per 1000, resulting in major morbidity, mortality and increased health care costs. It is more common in the elderly, obese, those with cancer, those undergoing surgery and those with prior VTE. Strategy to reduce its occurrence has important public health implications. Pleotropic effects of statins may have beneficial effects on a number of potential targets associated with VTE. Statins have excellent safety profile and seem to be associated with beneficial effects in VTE in case control studies, large observational studies, meta-analyses and a randomized trial. In conclusion, after critically reviewing the clinical data supporting statin use in the prevention of VTE, we presented clinical recommendations for the use of statins in reducing VTE occurrence, especially in high-risk situations.

Key words: Statins, venous thromboembolism

Introduction Venous thromboembolism (VTE) that includes deep venous thrombosis (DVT) and pulmonary embolism (PE) is common with an annual incidence of 1-5 per 1000, resulting in major morbidity, mortality and increased health care costs (1,2). It is the third most common disorder in the western population after myocardial infarction and stroke despite being grossly underdiagnosed (1,2). It is more common in the elderly, obese, those with cancer, those undergoing surgery and with prior VTE (1,2). Strategy to reduce its occurrence has important public health

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implications. Pleotropic effects of statins may have beneficial effects on a number of potential targets associated with VTE (3-5). Statins have excellent safety profile and seem to be associated with beneficial effects in VTE in case control studies, large observational studies, meta-analyses and one randomized trial (6-18). The purpose of this paper is to review the pathophysiology of VTE, discuss potential targets of statin action in VTE risk reduction, critically review the clinical data supporting statin use in the prevention of VTE and attempt to present clinical recommendations for its use to reduce VTE occurrence. Epidemiology and public health importance of VTE VTE is common with an annual incidence of 1-5 per 1000 with about 450,000 new cases a year in the United States (1,2). It is the third most common disorder in the western population after myocardial infarction and stroke (1). About 20% of VTE are associated with cancer and another 20% are triggered by surgery or trauma (1,2). The risk of VTE in critically ill patients is about 8%, leading to an increase in hospital morbidity and mortality. It is estimated that 10-30% of individuals will die within one month of being diagnosed with a VTE; furthermore, roughly one-third of patients will have a secondary VTE within ten years of the primary event (1,2). Occurrence of VTE doubles the length of hospitalization. Preventing VTE in high-risk individuals may help reduce overall morbidity, mortality and overall health care costs. We examined the evidence that adjuvant therapy with statins in such individuals may help reduce VTE disease burden. Coagulation and Pathophysiology of VTE Regulation of coagulation is an extremely complex process and any of the multiple abnormalities that occur in this process can result in intravascular thrombosis (19-26). Initiation of thrombosis can propagate by either intrinsic pathway or the extrinsic pathway. The first step in

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the thrombus formation is platelet adhesion, aggregation, and activation. When endothelium is damaged, collagen from the vessel wall is exposed to the blood. Platelets adhere to the exposed collagen through platelet receptors, Ia/IIa. Von Willebrand factor (vWF) from the endothelium strengthens this link. Platelets get activated resulting in the release of adenosine diphosphate, serotonin, platelet-activating factor, vWF, platelet factor 4, and Thromboxane A2, which in turn, activate additional platelets resulting in platelet aggregation and platelet plug formation. This is called primary hemostasis. The process of secondary hemostasis, consists of both intrinsic and extrinsic pathways. Intrinsic pathway is the slower, surface contact pathway and extrinsic pathway is the faster, tissue contact pathway. Both result in activation of the coagulation cascade which consists of 13 coagulation factors. These factors are present in inactive form in the circulation and activation is necessary for the initiation of the coagulation process. Combination of tissue factor (TF) and Factor VII initiate the extrinsic pathway and activation of Factor XII by surface contact initiates the intrinsic pathway. The final common pathway of coagulation consists of activation of Factor X to Xa which in turn converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin which is stabilized by Factor XIII to form a mature thrombus (19-26). Vitamin K is essential for the synthesis in the liver of serine proteases such as Factors II, VII, IX, and X and Proteins C and S. There are also numerous regulators of platelet function and the coagulation process. Protein C and S inhibit coagulation. Endothelial prostacyclin-I2 inhibits platelet aggregation. Plasmin, which is generated from plasminogen by the action of endothelial t-PA, degrades fibrin and acts as an intrinsic thrombolytic system. t-PA itself is regulated by an inhibitory system. There is also an intrinsic inhibitor for TF. In other words, coagulation system is extremely complex with a complicated regulatory system with fine lines of checks and

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balances. A disturbance in any of these elements can result in either excessive thrombosis or bleeding (19-26). Prevention of intravascular thrombosis depends upon health of endothelial lining of the vessels, anticoagulant properties of the vessel wall, prevention of activation of coagulation factors, prevention of platelet adhesion, aggregation, and activation and preventing tissue and platelet phospholipids from activating coagulation cascade. There is also an intrinsic thrombolytic system. An abnormality in any of these systems may initiate inappropriate coagulation and thrombosis. Some of the factors associated with excessive thrombotic risk include not only genetically determined or acquired abnormalities within the coagulation system, but risk factors such as increased age, obesity, increased systemic inflammation, race (Blacks and Caucasians more than Asians and Hispanics), smoking, cancer, trauma, surgery, immobility, metabolic syndrome, oral contraceptives or hormone replacement, cardiovascular disease, hypercholesterolemia, winter months, and prior VTE. Statins have multiple pleiotropic effects which have potential beneficial effects in the prevention of thrombosis by acting on many of the targets mentioned above (19-26).

The Pleiotropic Effects of Statins With Antithrombotic Effects Statins have several vascular protective effects unrelated to changes in lipid profile. These include beneficial effects on the vessel wall, inflammation and thrombotic factors and are summarized in a recent review article by Violi, et al (19). Fluvastatin and simvastatin have been shown to reduce TF activity resulting in reduced conversion of Factor X to Xa and this effect was dose dependent. Atorvastatin and simvastatin reduce thrombotic activity through downregulation of Factor Va and Protein C mediated Va

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inactivation (20). Rosuvastatin increases international normalized ratio by about 10% (5). These effects are independent of lipid reduction and can occur after just 3 doses of the drug (21). Statins upregulate thrombomodulin at transcriptional level, protein C production and Krüppellike Factor 2 (KLF2) levels (22). KLF2 upregulation stimulates thrombomodulin and endothelial nitric oxide (NO) production to reduce TF and PAI-1 levels. Statins increase production of endothelial NO synthase which results in the increased production of NO. The increased generation of NO leads to vasodilation and smooth muscle relaxation. Statins also reduce inflammation and C-reactive protein. Inflammation is pro-thrombogenic and increased Creactive protein levels increases the incidence of myocardial infarction and stroke (23). Results of Cholesterol and Recurrent Events, CARE, trial showed that pravastatin decreased C-reactive protein levels unrelated to the amount of lipid lowering (24). In addition, statins inhibit Factor V and VIII activation. Statins also reduce low density lipoprotein (LDL) oxidation; oxidized LDL is taken up by macrophages resulting in TF expression (25). They also increase tPA production by vascular smooth muscle and endothelial cells increasing thrombolysis. Hypercholesterolemia increases thrombotic risk, possibly through the production of thromboxane A2 within activated platelets (4). This promotes activation of additional platelets as well as platelet aggregation. Notarbartolol, et al. showed that simvastatin significantly decreased not only blood lipid levels but also the amount of urinary 11-dehydro-TXB2 excretion, indicating the reduction of Thromboxane A2 in the body that leads to decreased platelet activation and platelet aggregation (26). Statins reduce platelet adhesion to diseased arterial walls and this effect is apparent as early as 3 days after starting statins. Macrophages play an important role in thrombosis. The recruitment of macrophages to sites of endothelial lesions causes further degradation to the vessel integrity. The macrophages

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overexpress metalloproteinases such as matrix metalloproteinase-1 (MMP-1, collagenase-1), MMP-3, MMP-9, and TF. TF is a strong propagator of the coagulation cascade. Study by Aikawa, et al suggests that lipid-lowering agents such as cerivastatin inhibit these metalloproteinases and expression of TF, reducing the thrombotic risk (25). Clinical data in support of statins in the prevention of VTE We searched MEDLINE (January 1966 to December 2018), EMBASE (January 1985 to 2018), the Cochrane review and clinicaltrials.gov for articles or trials with a subject term “deep venous thrombosis”, “pulmonary embolism”, “venous thromboembolism”, ‘‘hydroxymethylglutaryl-coenzyme A reductase inhibitor’’ or ‘‘statin’’. We also examined their cross references and selected multiple case control studies, observational studies, meta-analyses and the lone randomized trial. The findings of these studies are summarized below and listed in table 1. JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) Trial This is the only randomized trial that tested the hypothesis that treatment with 20 mg rosuvastatin reduces the risk of VTE in apparently healthy subjects with serum LDL level <130 mg/dl and high-sensitivity C-reactive protein (hsCRP) of >2mg/L. Patients with coronary artery disease and diabetes mellitus were excluded (18). A total of 17,802 subjects were enrolled. The incidence of VTE was 3.2/1000 patients years in the control group and 1.8/1000 patients years in the rosuvastatin arm (hazard ratio, HR 0.57, p=0.007) indicating that statin therapy may reduce risk of thromboembolism as primary prevention in subjects with increased hsCRP. The strengths of this trial include randomization, blinded therapy, adjudicated VTE outcomes and large sample size. However, the study was underpowered because of low event rates and the overall strength

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of recommendation for statins for primary prevention can be considered moderate as this is the only randomized trial to test this question. The risk of VTE in the controls were higher in males (37/1000 patients-years), in those above the age of 70 years (41/1000 patients-years), obese (40/1000 patients-years), those with waist circumference >100 cm (41/1000 patients-years) and hsCRP >5 mg/L (39/1000 patients-years). Meta-analyses The most recent meta-analysis including the largest number of patients was published by Rahimi, et al in 2012 (14). They evaluated 112 randomized trials using a statin. After exclusions, they included 22 trials testing a statin versus placebo including 146,353 subjects and 613,800 person-years. They concluded that statin is not associated with a reduction in VTE, HR 0.89 with statin, p=0.08, though there was a trend towards benefit. But it has to be noted that in none of the studies, VTE was a pre-specified endpoint for outcomes and in only 3 studies, they were monitored as potential side effects of statins. In most of the studies, VTE was not an adjudicated event and in some, the VTE data were unpublished. It is possible that including unpublished data on statin use in the primary prevention of VTE might have changed the effect size and measurement noise might have widened the confidence interval. The results of some of the earlier meta-analyses are at odds with this meta-analysis (15-17). Meta-analysis by Pai, et al of 4 case control and 4 observational studies, showed a benefit of statin in VTE prevention, but this analysis did not include any randomized trials (15). Agarwal, et al included 10 studies (including JUPITER, cohort and other randomized trials) in their meta-analysis (16). Statin use was associated with a statistically significant reduction in the odds of developing VTE (adjusted odds ratio, AOR, 0.68, 95% confidence interval, CI, 0.540.86), DVT (AOR 0.59, 95% CI 0.43-0.82) and PE (AOR 0.70, 95% CI 0.53-0.94). Squizzato, et

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al included 3 randomized controlled trials, 3 cohort studies, and 8 case-control studies in their systematic review, for a total of 863,805 patients (17). Statins use significantly reduced VTE risk [odds ratio, OR, 0.81; 95% CI, 0.66-0.99]. The use of fibrates was associated with a significant increase in the risk of VTE (OR, 1.58; 95% CI, 1.23-2.02). Cohort studies Yang, et al used a database in United Kingdom consisting of 84,093 patients of whom 22,993 were on a statin. Incident of VTE was diagnosed in 72 patients (11). Statin use was associated with an incidence rate ratio of 0.8 for VTE, but this was not statistically significant. Huerta, et al also examined these data over a longer time period evaluating over 6,550 cases, and reported a 15% lower risk of VTE with the use of statins, although this was not statistically significant (12). Biere-Rafi, et al used pharmacy and hospital administrative databases in Netherlands to identify patients discharged with a diagnosis of PE (13). Of the 3,830 patients, 737 were on a statin in addition to warfarin and statin use was associated with a reduced risk of recurrent PE by about 50% (HR 0.50, 95% CI 0.36 to 0.70). Greater benefit was observed with higher potency statins. Case control studies Case-control studies also showed reductions in the risk of VTE, ranging from 26% to 58%, associated with the use of statins (6-10). In a study by Ramcharan 2,009 of 4,538 patients who had previously experienced a single episode of DVT or PE and 5,914 control patients, 3.3% of participants using statins experienced a VTE as compared with 5.7% of controls, which yielded a 59% lower risk of VTE with statins use (9). This association was not observed with other lipid-lowering medications, which were not associated with a lower, or higher, risk of VTE. Doggen, et al performed a case control study in HMO patients; 465 patients with proven

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VTE (4.5% on statins) were compared to 1,962 concurrent controls (5.6% on statins) (6). Simvastatin use was associated with a reduced risk of VTE (OR 0.51, 95% CI 0.29 to 0.91), but not pravastatin or other non-statin lipid lowering agents. Sorenson, et al in their study of 5,824 cases and 58,240 controls reported a benefit with statin therapy (OR 0.74, 95% CI 0.63 to 0.85) but not aspirin (10). Clinical situations where statin therapy may have large therapeutic benefit VTE Prophylaxis in Orthopedic Surgery It is possible that in addition to mechanical and anticoagulant therapies to prevent VTE, statin therapy may provide additional benefits to patients undergoing orthopedic surgery (27-29). A randomized controlled trial testing possible incremental benefit of rosuvastatin to anticoagulation is ongoing. Until the results of this trial become available, it may be reasonable to start a statin at least 3 days before the surgery and continue for 3-6 months until the patient is fully mobile. Statin may have additional benefit of reducing risk of perioperative myocardial infarctions in these older patients as well (27-29).

Surgery for malignant disorders Hypercoagulable state produced by malignancy and surgery combined with immobility results in high VTE risk and should be considered for prophylactic statin therapy to reduce VTE risk. There is an ongoing trial addressing patients with gynecological malignancies undergoing surgery (28). Patients with malignancies with hypercoagulable states

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Cancers of prostate, stomach, and pancreas are associated with hypercoagulable state even in the absence of surgery or hospitalization and statin therapy may be helpful to reduce VTE risk. A trial addressing this question is ongoing (29). Patients with prior VTE A meta-analysis performed a systematic review of 14 studies to evaluate the effects of lipid-lowering drugs on VTE occurrence. Five of these 14 studies included patients with previous episodes of VTE. The use of statins reduced the risk of VTE in this meta-analysis (17). Heart failure patients: Heart failure patients are at high risk of VTE because of venous stasis and immobility. In addition, the risk of atrial fibrillation is in the range of 20-30% and there a possibility that statin therapy may reduce both VTE and stroke risk as well as risk of atrial fibrillation which may worsen heart failure and increase hospitalization. There is also a suggestion that statin therapy may improve myocardial performance in non-ischemic cardiomyopathy. Patients with coronary artery disease, who make up about 50% of these patients, have a clear indication for statins. Multiple VTE risk factors Our suggestion is that statins should be considered for primary thromboprophylaxis in subjects with multiple VTE risk factors, as risk of VTE may exceed 10/1000 patient-years. The risk factors to consider include: advanced age, immobility, prolonged air travel, obesity, metabolic syndrome, high hsCRP, high LDL, hormone replacement therapy, use of tamoxifen, and varicose veins. Conclusions VTE is common and is associated with morbidity, mortality and health care costs. We suggest that statin therapy for potential thromboprophylaxis may be clinically beneficial in high-risk

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patients and should be seriously considered in patients undergoing hip and knee surgeries, surgery for malignancies, high-risk hospitalized patients, those with prothrombogenic malignancies, those with heart failure and multiple VTE risk factors. Although various statins and doses have been studied, rosuvastatin, at a dose of 20 mg, appears to be one of the favorable agents. Randomized trials are needed to confirm if statin therapy is beneficial in these patients.

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3. Arslan F, Gerard Pasterkamp G, de Kleijn DP. Unraveling Pleiotropic Effects Of Statins: Bit By Bit, a Slow Case With Perspective. Circ Res 2008;103:334-336. 4. Puccettia L, Santillib F, Pasquia AL, Lattanzio S, Liani R, Ciani F, Ferrante E, Ciabattoni G, Scarpini F, Ghezzi A, Auteri A, Davi G. Effects of atorvastatin and rosuvastatin on thromboxane-dependent platelet activation and oxidative stress in hypercholesterolemia. Atherosclerosis 2010;214:122-128. 5. Yu CY, Campbell SE, Zhu B, Knadler MP, Small DS, Sponseller CA, Hunt TL, Morgan RE. Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin. Curr Med Res Opin 2012;28(2):187-194. 6. 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;2:700-701. 7. Lacut K, Oger E, Le Gal G, Couturaud F, Louis S, Leroyer C, Mottier D. Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based casecontrol study. Fundam Clin Pharmacol 2004;18:477-482. 8. Lacut K, Le Gal G, Abalain JH, Mottier D, Oger E. Differential associations between lipidlowering drugs, statins and fibrates, and venous thromboembolism: role of drug induced homocysteinemia?. Thromb Res 2008;122(3):314-319. 9. Ramcharan AS, van Stralen KJ, Snoep JD, Mantel-Teeuwisse AK, Rosendaal FR, Doggen CJM. HMG-CoA-reductase inhibitors, other lipid lowering medication, antiplatelet therapy, and the risk of venous thrombosis. J Thromb Haemost 2009;7:514-520. 10. Sørensen HT, Horvath-Puho E, Søgaard KK, Christensen S, Johnson SP, Thomsen RW, Prandoni P, Baron JA. Arterial cardiovascular events, statins, low dose aspirin and subsequent

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risk of venous thromboembolism: a population-based case-control study. J Thromb Haemost 2009;7:521-528. 11. Yang CC, Jick SS, Jick H. Statins and the risk of idiopathic venous thromboembolism. Br J Clin Pharmacol 2002;53:101-105. 12. Huerta C, Johansson S, Wallander MA, Garcia Rodriguez 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. 13. Bierre-Rafi 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 2008;67:99-109. 14. Rahimi K, Bhala N, Kamphuisen P, Emberson J, Biere-Rafi S, Krane V, Robertson M, Wikstrand J, McMurray J. 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. 15. 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. 16. 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;10:1375-1383. 17. Squizzato A, Galli M, Romualdi E, Dentali F, Kamphuisen PW, Guasti L, Venco A, Ageno W. Statins, fibrates, and venous thromboembolism: A meta-analysis. Eur Heart J 2010;31(10):1248-1256.

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18. Glynn RJ, Danielson E, Fonseca FAH, Genest J, Gott AM, Kastelein JJP, Koening W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Ridker PM. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851-1861. 19. Violi F, Calvieri C, Ferro D, Pignatelli P. Statin as antithrombotic drugs. Circulation 2013; 127:251-257. 20. Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997;17:265-272. 21. Sanguigni V, Pignatelli P, Lenti L, Ferro D, Bellia A, Carnevale R, Tesauro M, Sorge R, Lauro R, Violi F. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation 2005;111:412-419. 22. Hanson SR, Griffin JH, Harker LA, Kelly AB, Esmon CT, Gruber A. Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J Clin Invest 1993;92:20032012. 23. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and risks of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979. 24. Ridker PM, Rifai Nader, Pfeffer MA, Sacks Frank, Braunwald Eugene. Long-Term Effects of Pravastatin on Plasma Concentration of C-reactive Protein. Circulation 1999;100:230-235. 25. Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y, Shiomi M, Schoen FJ, Libby P. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001;103:276-283.

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26. Notarbartolo A, Davì G, Averna M, Barbagallo CM, Ganci A, Giammarresi C, La Placa FP, Patrono C. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995;15:247-251. 27. NCT01021488 {published data only} Hallym University Medical Center. Rosuvastatin for Preventing Deep Vein Thrombosis (STOP-DVT). http://clinicaltrials.gov/ct2/show/results/NCT01021488 (accessed 1/27/2018). 28. NCT00259662 {published data only}Yale University. High-Dose Periop Statins for Prevention of DVT. http://clinicaltrials.gov/show/NCT00259662 (accessed 1/27/2018). 29. NCT01524653 {published data only} University of Vermont. Detecting the impact of statin therapy on lowering risk of venous thrombo-embolic events (DISOLVE). http://clinicaltrials.gov/ct2/show/NCT01524653 (accessed 1/27/2018).

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Table 1: Published studies reporting the frequency of venous thromboembolism (VTE) in statin users Study

Study Type

No. of subjects

Statin used

Outcome with statin

JUPITER trial

RCT

17802

Rosuvastatin 20 mg daily

HR 0.57 (95% CI 0.37-0.86)

Rahimi 2012

Metaanalysis

105,759

Any statin

OR 0.89 (95% CI 0.78-1.01)

Agarwal 2010

Metaanalysis

971,307

Any statin

AOR 0.68 (95% CI 0.54-0.86)

Pai 2011

Metaanalysis

Any statin

HR 0.67 (95% CI 0.53-0.84)

Squizzato 2010

Metaanalysis

836,805

Any statin

AOR 0.81 (95% CI 0.66-0.99)

Yang 2002

Cohort study

22,993/61,100

Any statin

IRR 0.8 (95% CI 0.3-2.7)

Ramcharan 2009

Case-control

4538/5914

Any statin

OR 0.55 (95% CI 0.46-0.67)

Sørensen 2009

Case-control

5824/58240

Any statin

OR 0.74 (95% CI 0.63-0.85)

Lacut 2004

Case-control

377/377

Any statin

OR 0.42 (95% CI 0.23-0.76)

Lacut 2008

Case-control

677/677

Any statin

OR 0.53 (95% CI 0.37-0.78)

Huerta 2007

Case-control

6,550/10,000

Any statin

OR 0.70 (95% CI 0.50-0.97)

Doggen 2004

Case-control

465/1962

Lipid lowering agent

Simvastatin OR 0.51 (95%CI 0.29-0.91) Pravastatin OR 1.85 (95%CI 0.65–5.26) Nonstatin lipid lowering 1.43 (0.62–3.25)

RCT: randomized clinical trial VTE: venous thromboembolism HR: hazard ratio OR: odds ratio AOR: adjusted odds ratio JUPITER: Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

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