Use of statins and reduced risk of recurrence of VTE in an older population

Summary

We aimed to determine whether statin use is associated with a decreased risk of recurrent venous thromboembolism (VTE) in older patients. We used a pre-assembled cohort of patients at least 65 years of age diagnosed with incident VTE between January 1, 1994 and December 31, 2004 in the province of Québec, Canada and followed until December 31, 2005. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) of recurrent VTE associated with current and past use of statins, compared with non-use. The cohort included 25,681 patients with incident VTE. During a mean follow-up of 3.0 years, there were 2343 recurrent VTE events (rate: 3.1 per 100 personyears). Compared with non-use, current use of statins was associated with a decreased risk of VTE recurrence (rates: 1.55 vs 3.47 per 100 per year, respectively; HR: 0.74, 95 % CI: 0.61–0.89), while no association was observed with past use (HR: 0.98, 95 % CI: 0.76–1.25). In a secondary analysis, longer durations of statin use were associated with greater risk reductions (0–6 months, HR 0.82, 95 % CI: 0.67–1.01; 6–12 months, HR 0.62, 95 % CI: 0.43–0.90; ≥ 12 months, HR: 0.50, 95 % CI: 0.33–0.74; p-value for trend ≤ 0.001). The use of statin was associated with a decreased risk of recurrent VTE in older patients. This study supports the need for randomised controlled trials to assess the efficacy and safety of statins in the long-term treatment of VTE.

Keywords

Deep-vein thrombosis - elderly - pulmonary embolism - statins - venous thromboembolism

^* This work was carried out at the Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal. Presented in oral abstract form at the European Society of Cardiology Congress, Barcelona, Spain. August 2014.

• References

• 1 Tagalakis V, Patenaude V, Kahn SR. et al. Incidence of and mortality from venous thromboembolism in a real-world population: The Q-VTE study cohort. Am J Med 2013; 126 832 e13-21.
• 2 Silverstein RL, Bauer KA, Cushman M. et al. Venous thrombosis in the elderly: More questions than answers. Blood 2007; 110: 3097-3101.
• 3 Kahn SR, Shrier I, Julian JA. et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149: 698-707.
• 4 Douketis JD, Gu CS, Schulman S. et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med 2007; 147: 766-774.
• 5 Herrington DM, Vittinghoff E, Lin F. et al. Statin therapy, cardiovascular events, and total mortality in the heart and estrogen/progestin replacement study (HERS). Circulation 2002; 105: 2962-2967.
• 6 Spencer FA, Gurwitz JH, Schulman S. et al. Venous thromboembolism in older adults: A community-based study. Am J Med 2014; 127: 530-537.
• 7 Ramcharan AS, Van Stralen KJ, Snoep JD. et al. Hmg-coa reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis. J Thromb Haemost 2009; 07: 514-520.
• 8 Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: Implications for cardiovascular event reduction. J Am Med Assoc 1998; 279: 1643-1650.
• 9 Glynn RJ, Danielson E, Fonseca FA. et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. New Engl J Med 2009; 360: 1851-1861.
• 10 Agarwal V, Phung OJ, Tongbram V. et al. Statin use and the prevention of venous thromboembolism: A meta-analysis. Int J Clin Pract 2010; 64: 1375-1383.
• 11 Lacut K, Le Gal G, Abalain JH. et al. Differential associations between lipidlowering drugs, statins and fibrates, and venous thromboembolism: Role of drug induced homocysteinemia?. Thromb Res 2008; 122: 314-319.
• 12 Kaba NK, Francis CW, Moss AJ. Z et al. Effects of lipids and lipid-lowering therapy on hemostatic factors in patients with myocardial infarction. J Thromb Haemost 2004; 02: 718-725.
• 13 Lin TH, Huang CH, Voon WC. et al. The effect of fluvastatin on fibrinolytic factors in patients with hypercholesterolemia. Kaohsiung J Med Sci 2000; 16: 600-606.
• 14 Van De Ree MA, De Maat MP, Kluft C. et al. Decrease of hemostatic cardiovascular risk factors by aggressive vs Conventional atorvastatin treatment in patients with type 2 diabetes mellitus. J Thromb Haemost 2003; 01: 1753-1757.
• 15 Holschermann H, Hilgendorff A, Kemkes-Matthes B. et al. Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients. Transplantation 2000; 69: 1830-1836.
• 16 Potaczek DP, Undas A, Iwaniec T. et al. The angiotensin-converting enzyme gene insertion/deletion polymorphism and effects of quinapril and atorvastatin on haemostatic parameters in patients with coronary artery disease. Thromb Haemost 2005; 94: 224-225.
• 17 Ray JG, Mamdani M, Tsuyuki RT. et al. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med 2001; 161: 1405-1410.
• 18 Sorensen HT, Horvath-Puho E, Sogaard 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; 07: 521-528.
• 19 Doggen CJ, Lemaitre RN, Smith NL. et al. Hmg coa reductase inhibitors and the risk of venous thrombosis among postmenopausal women. J Thromb Haemost 2004; 02: 700-701.
• 20 Grady D, Wenger NK, Herrington D. et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The heart and estrogen/progestin replacement study. Ann Intern Med 2000; 132: 689-696.
• 21 Khemasuwan D, Divietro ML, Tangdhanakanond K. et al. Statins decrease the occurrence of venous thromboembolism in patients with cancer. Am J Med 2010; 123: 60-65.
• 22 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; 09: e1001310.
• 23 Delluc A, Tromeur C, Le Moigne E. et al. Lipid lowering drugs and the risk of recurrent venous thromboembolism. Thromb Res 2012; 130: 859-863.
• 24 Nguyen CD, Andersson C, Jensen TB. et al. Statin treatment and risk of recurrent venous thromboembolism: A nationwide cohort study. Br Med J Open 2013; 03: e003135.
• 25 Biere-Rafi S, Hutten BA, Squizzato A. et al. Statin treatment and the risk of recurrent pulmonary embolism. Eur Heart J 2013; 34: 1800-1806.
• 26 Schmidt M, Cannegieter SC, Johannesdottir SA. et al. Statin use and venous thromboembolism recurrence: A combined nationwide cohort and nested case-control study. Thromb Haemost 2014; 12: 1207-1215.
• 27 Tagalakis V, Kahn SR. Determining the test characteristics of claims-based diagnostic codes for the diagnosis of venous thromboembolism in a medical service claims database. Pharmacoepidemiol Drug Saf 2011; 20: 304-307.
• 28 Tamblyn R, Lavoie G, Petrella L. et al. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Quebec. J Clin Epidemiol 1995; 48: 999-1009.
• 29 Statistics Canada. Canadian classification of diagnostic, therapeutic, and surgical procedures (catalogue 82-562e). Ottawa: Minister of Industry, Science and Technology; 1993
• 30 Levy AR, Tamblyn RM, Fitchett D. et al. Coding accuracy of hospital discharge data for elderly survivors of myocardial infarction. Can J Cardiol 1999; 15: 1277-1282.
• 31 Mayo NE, Wood-Dauphinee S, Gayton D. et al. Nonmedical bed-days for stroke patients admitted to acute-care hospitals in Montreal, Canada. Stroke 1997; 28: 543-549.
• 32 Tagalakis V, Kondal D, Ji Y. et al. Men had a higher risk of recurrent venous thromboembolism than women: A large population study. Gend Med 2012; 09: 33-43.
• 33 White RH, Zhou H, Murin S. Death due to recurrent thromboembolism among younger healthier individuals hospitalized for idiopathic pulmonary embolism. Thromb Haemost 2008; 99: 683-690.
• 34 Fisher LD, Lin DY. Time-dependent covariates in the Cox proportional-hazards regression model. Ann Rev Public Health 1999; 20: 145-157.
• 35 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Br Med J 2003; 326: 1423-1427.
• 36 Dormuth CR, Patrick AR, Shrank WH. et al. Statin adherence and risk of accidents: A cautionary tale. Circulation 2009; 119: 2051-2057.
• 37 Brookhart MA, Patrick AR, Dormuth C. et al. Adherence to lipid-lowering therapy and the use of preventive health services: An investigation of the healthy user effect. Am J Epidemiol 2007; 166: 348-354.
• 38 Undas A, Brummel-Ziedins KE, Mann KG. Anticoagulant effects of statins and their clinical implications. Thromb Haemost 2014; 111: 392-400.
• 39 Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 2008; 167: 492-499.
• 40 Tagalakis V, Patenaude V, Kahn SR. et al. Treatment patterns of venous thromboembolism in a real-world population: the Q-VTE study cohort. Thromb Res 2014; 134: 795-802.
• 41 Merli GJ, Hollander JE, Lefebvre P. et al. Rates of hospitalisation among patients with deep vein thrombosis before and after the introduction of rivaroxaban. Hosp Pract 2015; 43: 85-93.
• 42 Sugiyama T, Tsugawa Y, Tseng CH. et al. Different time trends of caloric and fat intake between statin users and nonusers among us adults: Gluttony in the time of statins?. J Am Med Assoc Intern Med 2014; 174: 1038-1045.
• 43 Doggen CJ, Smith NL, Lemaitre RN. et al. Serum lipid levels and the risk of venous thrombosis. Arterioscler Thromb Vasc Biol 2004; 24: 1970-1975.
• 44 Eichinger S, Pecheniuk NM, Hron G. et al. High-density lipoprotein and the risk of recurrent venous thromboembolism. Circulation 2007; 115: 1609-1614.
• 45 The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 363. 2499-2510.
• 46 The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 366. 1287-1297.
• 47 Prins MH, Lensing AWA, Bauersachs R. et al. Oral rivaroxaban vs standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21.
• 48 Amarenco P, Bogousslavsky J, Callahan 3rd A. et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549-559.
• 49 Collins R, Armitage J, Parish S. et al. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363: 757-767.
• 50 McKinney JSI, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke 2012; 43: 2149-2156.