Journal of Thrombosis and Haemostasis, 12: 1204–1206
DOI: 10.1111/jth.12614
COMMENTARY
Is it time to try or to trial statins to prevent recurrent venous thromboembolism? M. RODGER*† *Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa; and †Clinical Epidemiology Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
To cite this article: Rodger M. Is it time to try or to trial statins to prevent recurrent venous thromboembolism?. J Thromb Haemost 2014; 12: 1204–6. E, Sørensen HT. Statin use and venous thromboembolism See also Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horvath-Puho recurrence: a combined nationwide cohort and nested case–control study. This issue, pp 1207–15.
Patients who experience venous thromboembolism (VTE) are at important risk for recurrent VTE [1]. When it occurs, recurrent VTE may have serious consequences. Recurrent VTE is fatal in more than one in 10 patients if experienced in the first 3 months of therapy, and, after the initial 3 months of therapy, one in 20 episodes of recurrent VTE are fatal [2]. Recurrent VTE leads to significant early morbidity (leg pain, leg swelling, chest pain, and shortness of breath), and increases the risk of longterm disabling post-thrombotic syndrome [3–5] and chronic thromboembolic pulmonary hypertension [6]. The statins (HMG-CoA reductase inhibitors) are hypolipidemic drugs that lower cholesterol levels and reduce mortality in people with arteriosclerotic cardiovascular disease (ASCVD) or at risk of ASCVD. However, the effects of statins extend beyond their lipid-lowering activity. There is now a large body of evidence to indicate that statins can improve endothelial function, modulate inflammation, maintain plaque stability, and inhibit thrombus formation [7–11]. Serious adverse drug reactions with statins are very uncommon. In fact, statins are available without a prescription in some jurisdictions. Many inexpensive generic statins are now widely available. So if a cheap and accessible drug with almost no side effects might prevent recurrent VTE, why not try it?
Correspondence: Marc Rodger, Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa Blood Disease Center, 501 Smyth Road, 1812-E Box 201, Ottawa, ON K1H 8L6, Canada. Tel.: +1 613 737 8899 ext. 74641; fax: +1 613 739 6102. E-mail: [email protected] Received 28 April 2014 Manuscript handled by: M. Cushman Final decision: F. R. Rosendaal, 12 May 2014
Schmidt et al. reported on an administrative database analysis exploring a potential association between statin use and the risk of recurrent VTE [12]. Through data linkage, they were able to identify 27 862 patients with a VTE, of whom 3327 were current statin users at the time of VTE diagnosis. They were then able to follow these patients for inpatient admissions for recurrent VTE, and identified 1378 recurrent events. Current use was associated with a 28% lower risk of recurrent VTE (and a higher relative reduction for more potent statins). Should clinicians break out the prescription pad to prescribe statins for VTE patients? Not yet . . . The authors acknowledge the key limitations of their work, which include potential misclassification of first VTE and recurrent VTE. In small validation substudies, they showed that their classification of first VTE was good (positive predictive value of 90%), and their classification of recurrent VTE was fair (positive predictive value of 78%). It is also possible that a healthy statin user effect is responsible for the apparent protective effect (i.e. confounding by indication). More importantly, administrative database research is, at best, hypothesis-generating. We need randomized controlled trials (RCTs) to change practice. The hypothesis that statins reduce the risk of VTE is not novel. In the early 2000s, retrospective cohort studies and case–control studies investigating the possible benefit of statins for preventing VTE appeared in the literature [13–16]. In 2002, the first trial showing the potential VTE prevention benefit of statins, the ‘Heart and Estrogen/ progestin Replacement Study’, with an estrogen/progestin primary intervention, showed a 50% reduction in VTE risk in statin users vs. non-users in a post hoc subgroup analysis [17]. Rahimi et al. conducted a meta-analysis of 22 RCTs with > 100 000 patients, comparing statin users with controls. None of the trials included VTE as a primary outcome, and only two included VTE as a secondary outcome. However, VTE outcomes were obtained
© 2014 International Society on Thrombosis and Haemostasis
Statins to prevent recurrent venous thrombosis 1205
from adverse event data; this permitted an exploration of the effects of statins on VTE reduction. Whereas the primary analysis suggested, at best, a modest overall treatment effect with any statin (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.78–1.01), subgroup analysis by statin suggested that rosuvastatin may be the most effective statin (OR 0.60, 95% CI 0.39–0.92) [18] in primary prevention. These hypothesis-generating studies supported the need for RCTs of statins to reduce VTE risk. In the landmark JUPITER trial, Ridker et al. [19] conducted an RCT of 17 802 apparently healthy men and women at low risk of cardiovascular disease, with an LDL cholesterol level of < 3.4 mmol L 1 (i.e. normal) but a high C-reactive protein level of > 2.0 mg L 1, comparing rosuvastatin 20 mg daily and placebo. In a prespecified secondary analysis, during a mean follow-up of 1.9 years, VTE frequency was significantly reduced in the rosuvastatin group (0.18 VTEs per 100 person-years) as compared with the placebo group (0.32 VTEs per 100 person-years) (hazard ratio [HR] 0.57, 95% CI 0.37–0.86; P = 0.007; number needed to treat [NNT] per year, 714) [20]. Furthermore, the treatment was safe, with no significant differences in the rates of bleeding between the treatment groups. As VTE was not the primary outcome, and the absolute risk benefit in primary prevention was modest (NNT of 714 per year), statins are not currently widely used for the prevention of a first VTE. Considering secondary VTE prevention with statins, where reasonable NNTs may be plausible because of higher event rates, seems a justifiable next step. Like Schmidt’s study, two recent observational studies used administrative data to compare VTE recurrence rates in patients taking statins with others. In a Danish cohort of 44 330 patients with VTE, statin use was associated with a significantly lower risk of recurrent VTE than no statin use (adjusted HR 0.74, 95% CI 0.68–0.80; NNT per year, 41) [21]. In a Dutch cohort of patients with pulmonary embolism (PE), the risk of recurrent PE was evaluated in patients receiving a statin in addition to anticoagulants [22]. For 737 patients taking any statin, the risk of recurrent PE was significantly reduced by 50% (adjusted HR 0.50, 95% CI 0.36–0.70), both during and after stopping treatment with vitamin K antagonists. This study also suggested that a statin potency vs. treatment effect relationship existed, with the largest reductions in recurrent PE being observed with very potent statins (e.g. rosuvastatin 20 mg; HR 0.29, 95% CI 0.07–1.16; NNT per year, ~ 58), and smaller reductions being observed with statins of moderate potency (e.g. atorvastatin 20 mg; HR 0.44, 95% CI 0.30–0.65) and low potency (e.g. pravastatin 10 mg; HR 0.88, 95% CI 0.50–1.54). Nonetheless, these observational studies are, at best, hypothesis-generating, and do not provide high-quality evidence that should lead to practice change (i.e. statin prescriptions for VTE patients).
© 2014 International Society on Thrombosis and Haemostasis
The time is ripe for a secondary prevention RCT comparing statins with no statins in patients with VTE. It is biologically plausible, and preliminary evidence suggests that statins, and in particular potent statins, reduce the risk of recurrent VTE. Statins may have additive, and potentially even synergistic, effects in reducing the risk of recurrent VTEk in patients managed with anticoagulantbased strategies. Furthermore, it is plausible that statins may reduce the risk of recurrent VTE in those not on anticoagulants, and may therefore offer an alternative in patients with contraindications to anticoagulants (e.g. after major intracranial bleeding), who refuse to take anticoagulants (e.g. because of lifestyle modifications or fear of bleeding), or who cannot afford anticoagulants. Finally, statins may also provide protection from recurrent VTE in patients who are poorly/partially compliant with anticoagulant therapy. Statins are simple to use, inexpensive, and very safe. Hence, an RCT of statins to prevent recurrent VTE is needed, and has a high potential to change practice with little additional burden to the healthcare system (if they work!). Disclosure of Conflict of Interests The author reports receiving grants from BioMerieux during the conduct of this study. References 1 Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179: 417–26. 2 Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152: 578–89. 3 Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins M. The longterm clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1–7. 4 Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E, Tormene D, Mosena L, Pagnan A, Girolami A. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: 249–56. 5 Kahn SR, Shrier I, Julian JA, Ducruet T, Arsenault L, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, Solymoss S, Desjardins L, Lamping DL, Johri M, Ginsberg JS. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149: 698–707. 6 Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257–64. 7 Kaba NK, Francis CW, Moss AJ, Zareba W, Oakes D, Knox KL, Fernandez ID, Rainwater DL. Effects of lipids and lipid-
1206 M. Rodger
8 9
10
11
12
13
14
15 16
lowering therapy on hemostatic factors in patients with myocardial infarction. J Thromb Haemost 2004; 2: 718–25. Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005; 25: 287–94. Undas A, Brozek J, Musial J. Anti-inflammatory and antithrombotic effects of statins in the management of coronary artery disease. Clin Lab 2002; 48: 287–96. Undas A, Celinska-Lowenhoff M, Kaczor M, Musial J. New nonlipid effects of statins and their clinical relevance in cardiovascular disease. Thromb Haemost 2004; 91: 1065–77. Adams NB, Lutsey PL, Folsom AR, Herrington DH, Sibley CT, Zakai NA, Ades S, Burke GL, Cushman M. Statin therapy and levels of hemostatic factors in a healthy population: the MultiEthnic Study of Atherosclerosis. J Thromb Haemost 2013; 11: 1078–84. Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horvath-Puho E, Sorense HT. Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case–control study. J Thromb Haemost 2014; 12: 1207–15. 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: 1405–10. Doggen CJM, 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: 700–1. Yang C-C, Jick SS, Jick H. Statins and the risk of idiopathic venous thromboembolism. J Clin Pharmacol 2002; 53: 101–5. Lacut K, Le Gal G, Abalain JH, Mottier D, Oger E. Differential associations between lipid-lowering drugs, statins and fibrates,
17
18
19
20
21
22
and venous thromboembolism: role of drug induced homocysteinemia? Thromb Res 2007; 122: 314–19. Herrington DM, Vittinghoff E, Lin F, Fong J, Harris F, Hunninghake D, Bittner V, Schrott HG, Blumenthal RS, Levy R. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002; 105: 2962–7. 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: e1001310. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–207. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig 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: 1851–61. Nguyen CD, Andersson C, Jensen TB, Gjesing A, Schjerning Olsen AM, Malta HC, Buller H, Torp-Pedersen C, Gislason GH. Statin treatment and risk of recurrent venous thromboembolism: a nationwide cohort study. BMJ Open 2013; 3: e003135. Biere-Rafi S, Hutten BA, Squizzato A, Ageno W, Souverein PC, de Boer A, Gerdes VE, Buller HR, Kamphuisen PW. Statin treatment and the risk of recurrent pulmonary embolism. Eur Heart J 2013; 34: 1800–6.
© 2014 International Society on Thrombosis and Haemostasis
DOI: 10.1111/jth.12614
COMMENTARY
Is it time to try or to trial statins to prevent recurrent venous thromboembolism? M. RODGER*† *Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa; and †Clinical Epidemiology Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
To cite this article: Rodger M. Is it time to try or to trial statins to prevent recurrent venous thromboembolism?. J Thromb Haemost 2014; 12: 1204–6. E, Sørensen HT. Statin use and venous thromboembolism See also Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horvath-Puho recurrence: a combined nationwide cohort and nested case–control study. This issue, pp 1207–15.
Patients who experience venous thromboembolism (VTE) are at important risk for recurrent VTE [1]. When it occurs, recurrent VTE may have serious consequences. Recurrent VTE is fatal in more than one in 10 patients if experienced in the first 3 months of therapy, and, after the initial 3 months of therapy, one in 20 episodes of recurrent VTE are fatal [2]. Recurrent VTE leads to significant early morbidity (leg pain, leg swelling, chest pain, and shortness of breath), and increases the risk of longterm disabling post-thrombotic syndrome [3–5] and chronic thromboembolic pulmonary hypertension [6]. The statins (HMG-CoA reductase inhibitors) are hypolipidemic drugs that lower cholesterol levels and reduce mortality in people with arteriosclerotic cardiovascular disease (ASCVD) or at risk of ASCVD. However, the effects of statins extend beyond their lipid-lowering activity. There is now a large body of evidence to indicate that statins can improve endothelial function, modulate inflammation, maintain plaque stability, and inhibit thrombus formation [7–11]. Serious adverse drug reactions with statins are very uncommon. In fact, statins are available without a prescription in some jurisdictions. Many inexpensive generic statins are now widely available. So if a cheap and accessible drug with almost no side effects might prevent recurrent VTE, why not try it?
Correspondence: Marc Rodger, Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa Blood Disease Center, 501 Smyth Road, 1812-E Box 201, Ottawa, ON K1H 8L6, Canada. Tel.: +1 613 737 8899 ext. 74641; fax: +1 613 739 6102. E-mail: [email protected] Received 28 April 2014 Manuscript handled by: M. Cushman Final decision: F. R. Rosendaal, 12 May 2014
Schmidt et al. reported on an administrative database analysis exploring a potential association between statin use and the risk of recurrent VTE [12]. Through data linkage, they were able to identify 27 862 patients with a VTE, of whom 3327 were current statin users at the time of VTE diagnosis. They were then able to follow these patients for inpatient admissions for recurrent VTE, and identified 1378 recurrent events. Current use was associated with a 28% lower risk of recurrent VTE (and a higher relative reduction for more potent statins). Should clinicians break out the prescription pad to prescribe statins for VTE patients? Not yet . . . The authors acknowledge the key limitations of their work, which include potential misclassification of first VTE and recurrent VTE. In small validation substudies, they showed that their classification of first VTE was good (positive predictive value of 90%), and their classification of recurrent VTE was fair (positive predictive value of 78%). It is also possible that a healthy statin user effect is responsible for the apparent protective effect (i.e. confounding by indication). More importantly, administrative database research is, at best, hypothesis-generating. We need randomized controlled trials (RCTs) to change practice. The hypothesis that statins reduce the risk of VTE is not novel. In the early 2000s, retrospective cohort studies and case–control studies investigating the possible benefit of statins for preventing VTE appeared in the literature [13–16]. In 2002, the first trial showing the potential VTE prevention benefit of statins, the ‘Heart and Estrogen/ progestin Replacement Study’, with an estrogen/progestin primary intervention, showed a 50% reduction in VTE risk in statin users vs. non-users in a post hoc subgroup analysis [17]. Rahimi et al. conducted a meta-analysis of 22 RCTs with > 100 000 patients, comparing statin users with controls. None of the trials included VTE as a primary outcome, and only two included VTE as a secondary outcome. However, VTE outcomes were obtained
© 2014 International Society on Thrombosis and Haemostasis
Statins to prevent recurrent venous thrombosis 1205
from adverse event data; this permitted an exploration of the effects of statins on VTE reduction. Whereas the primary analysis suggested, at best, a modest overall treatment effect with any statin (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.78–1.01), subgroup analysis by statin suggested that rosuvastatin may be the most effective statin (OR 0.60, 95% CI 0.39–0.92) [18] in primary prevention. These hypothesis-generating studies supported the need for RCTs of statins to reduce VTE risk. In the landmark JUPITER trial, Ridker et al. [19] conducted an RCT of 17 802 apparently healthy men and women at low risk of cardiovascular disease, with an LDL cholesterol level of < 3.4 mmol L 1 (i.e. normal) but a high C-reactive protein level of > 2.0 mg L 1, comparing rosuvastatin 20 mg daily and placebo. In a prespecified secondary analysis, during a mean follow-up of 1.9 years, VTE frequency was significantly reduced in the rosuvastatin group (0.18 VTEs per 100 person-years) as compared with the placebo group (0.32 VTEs per 100 person-years) (hazard ratio [HR] 0.57, 95% CI 0.37–0.86; P = 0.007; number needed to treat [NNT] per year, 714) [20]. Furthermore, the treatment was safe, with no significant differences in the rates of bleeding between the treatment groups. As VTE was not the primary outcome, and the absolute risk benefit in primary prevention was modest (NNT of 714 per year), statins are not currently widely used for the prevention of a first VTE. Considering secondary VTE prevention with statins, where reasonable NNTs may be plausible because of higher event rates, seems a justifiable next step. Like Schmidt’s study, two recent observational studies used administrative data to compare VTE recurrence rates in patients taking statins with others. In a Danish cohort of 44 330 patients with VTE, statin use was associated with a significantly lower risk of recurrent VTE than no statin use (adjusted HR 0.74, 95% CI 0.68–0.80; NNT per year, 41) [21]. In a Dutch cohort of patients with pulmonary embolism (PE), the risk of recurrent PE was evaluated in patients receiving a statin in addition to anticoagulants [22]. For 737 patients taking any statin, the risk of recurrent PE was significantly reduced by 50% (adjusted HR 0.50, 95% CI 0.36–0.70), both during and after stopping treatment with vitamin K antagonists. This study also suggested that a statin potency vs. treatment effect relationship existed, with the largest reductions in recurrent PE being observed with very potent statins (e.g. rosuvastatin 20 mg; HR 0.29, 95% CI 0.07–1.16; NNT per year, ~ 58), and smaller reductions being observed with statins of moderate potency (e.g. atorvastatin 20 mg; HR 0.44, 95% CI 0.30–0.65) and low potency (e.g. pravastatin 10 mg; HR 0.88, 95% CI 0.50–1.54). Nonetheless, these observational studies are, at best, hypothesis-generating, and do not provide high-quality evidence that should lead to practice change (i.e. statin prescriptions for VTE patients).
© 2014 International Society on Thrombosis and Haemostasis
The time is ripe for a secondary prevention RCT comparing statins with no statins in patients with VTE. It is biologically plausible, and preliminary evidence suggests that statins, and in particular potent statins, reduce the risk of recurrent VTE. Statins may have additive, and potentially even synergistic, effects in reducing the risk of recurrent VTEk in patients managed with anticoagulantbased strategies. Furthermore, it is plausible that statins may reduce the risk of recurrent VTE in those not on anticoagulants, and may therefore offer an alternative in patients with contraindications to anticoagulants (e.g. after major intracranial bleeding), who refuse to take anticoagulants (e.g. because of lifestyle modifications or fear of bleeding), or who cannot afford anticoagulants. Finally, statins may also provide protection from recurrent VTE in patients who are poorly/partially compliant with anticoagulant therapy. Statins are simple to use, inexpensive, and very safe. Hence, an RCT of statins to prevent recurrent VTE is needed, and has a high potential to change practice with little additional burden to the healthcare system (if they work!). Disclosure of Conflict of Interests The author reports receiving grants from BioMerieux during the conduct of this study. References 1 Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179: 417–26. 2 Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152: 578–89. 3 Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins M. The longterm clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1–7. 4 Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E, Tormene D, Mosena L, Pagnan A, Girolami A. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141: 249–56. 5 Kahn SR, Shrier I, Julian JA, Ducruet T, Arsenault L, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, Solymoss S, Desjardins L, Lamping DL, Johri M, Ginsberg JS. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149: 698–707. 6 Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257–64. 7 Kaba NK, Francis CW, Moss AJ, Zareba W, Oakes D, Knox KL, Fernandez ID, Rainwater DL. Effects of lipids and lipid-
1206 M. Rodger
8 9
10
11
12
13
14
15 16
lowering therapy on hemostatic factors in patients with myocardial infarction. J Thromb Haemost 2004; 2: 718–25. Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005; 25: 287–94. Undas A, Brozek J, Musial J. Anti-inflammatory and antithrombotic effects of statins in the management of coronary artery disease. Clin Lab 2002; 48: 287–96. Undas A, Celinska-Lowenhoff M, Kaczor M, Musial J. New nonlipid effects of statins and their clinical relevance in cardiovascular disease. Thromb Haemost 2004; 91: 1065–77. Adams NB, Lutsey PL, Folsom AR, Herrington DH, Sibley CT, Zakai NA, Ades S, Burke GL, Cushman M. Statin therapy and levels of hemostatic factors in a healthy population: the MultiEthnic Study of Atherosclerosis. J Thromb Haemost 2013; 11: 1078–84. Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horvath-Puho E, Sorense HT. Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case–control study. J Thromb Haemost 2014; 12: 1207–15. 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: 1405–10. Doggen CJM, 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: 700–1. Yang C-C, Jick SS, Jick H. Statins and the risk of idiopathic venous thromboembolism. J Clin Pharmacol 2002; 53: 101–5. Lacut K, Le Gal G, Abalain JH, Mottier D, Oger E. Differential associations between lipid-lowering drugs, statins and fibrates,
17
18
19
20
21
22
and venous thromboembolism: role of drug induced homocysteinemia? Thromb Res 2007; 122: 314–19. Herrington DM, Vittinghoff E, Lin F, Fong J, Harris F, Hunninghake D, Bittner V, Schrott HG, Blumenthal RS, Levy R. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002; 105: 2962–7. 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: e1001310. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–207. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig 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: 1851–61. Nguyen CD, Andersson C, Jensen TB, Gjesing A, Schjerning Olsen AM, Malta HC, Buller H, Torp-Pedersen C, Gislason GH. Statin treatment and risk of recurrent venous thromboembolism: a nationwide cohort study. BMJ Open 2013; 3: e003135. Biere-Rafi S, Hutten BA, Squizzato A, Ageno W, Souverein PC, de Boer A, Gerdes VE, Buller HR, Kamphuisen PW. Statin treatment and the risk of recurrent pulmonary embolism. Eur Heart J 2013; 34: 1800–6.
© 2014 International Society on Thrombosis and Haemostasis
