Inge M. van Schouwenburg Population Based Cohort Study on the Risk of Arterial Thrombosis in Subjects with Venous Thrombosis Inge M. van Schouwenburg Division of Hemostasis and Thrombosis, Department of Hematology University Medical Center Groningen The Netherlands

Disclosures for I.M. van Schouwenburg In compliance with ACCME policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. No relevant conflicts of interest to declare Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Presentation includes discussion of the following off-label use of a drug or medical device: <N/A> 2

Background Previous studies have shown an increased relative risk of arterial thrombosis after venous thrombosis1,2 Absolute risks are unknown Previous studies have shown a mild relation between arterial thrombotic risk factors and venous thrombosis3 1. Sørensen et al. Lancet 2007 2. Klok et al. Blood 2009 3. Ageno et al. Circulation 2008

Aim of the study To assess the absolute risk of arterial thrombosis after venous thrombosis - Type of event - Environmental risk factors - Persistence of risk through time If an association is present, could this be explained by the presence of arterial thrombotic risk factors?

Methods – Study Population Prevention of REnal and Vascular ENd-stage Disease (PREVEND) Groningen population aged 28-75 years (n=85,421) Questionnaire regarding arterial thrombotic risk factors and morbidity + a vial to collect a first morning urine sample 40,856 responders Follow-up between 1997-2007 End follow-up: death, moving out of the city, arterial bleeding, arterial thrombosis, end of study, 31-12-2005.

Methods – Adjudication of events Anticoagulation clinics and national registry of hospital discharge diagnoses, confirmed in patients medical records ATE: Myocardial infarction, Coronary artery disease, Peripheral arterial occlusive disease, Ischemic stroke VTE: Deep vein thrombosis, Pulmonary embolism Provoked: surgery, trauma, immobilization for more than 7 days, pregnancy, puerperium, the use of oral contraceptives or hormonal replacement therapy, or malignancy

Results – Baseline Characteristics Total 40,856 Male, n 18,625 Mean age at enrollment, y 50 Arterial thrombotic risk factors Hypertension, % 29 Hyperlipidemia, % 14 Diabetes Mellitus, % 3 Current Smokers, % 42 Microalbuminuria (>20 mg/L) , % 8 Previous ATE, % 4 INTERHEART: HT: 21% (39% in cases), DM:8, rokers: 27 (45 in cases)

Results – Number of events Characteristic Value Venous thrombosis, n 537 Mean age at onset, y 62 Arterial thrombosis, n 2314 66

Results – Risk of ATE AI, per 1,000 py (95% CI) Adjusted HRa Venous thrombosis 24 (16-34) 1.8 (1.3-2.6) Previous ATE 47 (43-51) 2.2 (2.0-2.5) Hypertension 14 (13-14) 1.3 (1.3-1.5) Hyperlipidemia 19 (17-20) 1.4 (1.2-1.5) Diabetes Mellitus 27 (23-31) 1.5 (1.3-1.8) Current Smokers 9 (9-10) 1.9 (1.7-2.1) Albumin Excretion <10 mg/L 7 (7-7) Reference 10-20 mg/L 8 (8-9) 1.1 (1.0-1.3) 20-200 mg/L 17 (15-19) 1.4 (1.3-1.6) >200 mg/L 31 (23-40) 1.6 (1.2-2.1) a Adjusted for age, sex and all other arterial thrombotic risk factors (Reference group are those without the exposure)

Results – Risk of VTE Crude HR (95% CI) Adjusted HRa Hypertension 1.5 (1.2-1.7) 1.1 (0.9-1.3) Hyperlipidemia 1.1 (0.9-1.4) 0.8 (0.6-1.0) Diabetes Mellitus 1.2 (0.7-1.9) 0.7 (0.5-1.2) Current Smokers 0.9 (0.7-1.0) Albumin Excretion <10 mg/L Reference 10-20 mg/L 1.0 (0.8-1.3) 1.1 (0.8-1.3) 20-200 mg/L 1.8 (1.4-2.4) 1.5 (1.1-2.0) >200 mg/L 2.9 (1.6-5.5) 2.0 (1.1-3.8) Crude HR Ageno, HT 1.51 sig, HC 1.16 niet sig, DM: 1.42 sig, smok: 1.18, niet sig. a Adjusted for age and sex (Reference group are those without the exposure)

Risk of arterial thrombosis after venous thrombosis Results Risk of arterial thrombosis after venous thrombosis AI, per 1,000 py (95% CI) Adjusted HRa (95% CI) Venous thrombosis 24 (16-34) 1.8 (1.3-2.6) Unprovoked VTE 28 (16-45) 1.9 (1.2-3.1) Provoked VTE 15 (6-30) 1.4 (0.7-2.9) Deep vein thrombosis 26 (16-40) 2.3 (1.5-3.5) Pulmonary embolism 20 (9-37) 1.2 (0.6-2.3) a Adjusted for age, sex and all other arterial thrombotic risk factors (Reference group are those without the exposure)

Risk of arterial thrombosis after venous thrombosis Results Risk of arterial thrombosis after venous thrombosis Adjusted HRa (95% CI) 1 year After 1 year All venous thrombosis 2.6 (1.5-4.6) 1.5 (1.0-2.4) Unprovoked VTE 2.5 (1.1-5.6) 1.7 (1.0-3.1) Provoked VTE 2.4 (0.9-6.3) 0.9 (0.3-2.8) Deep vein thrombosis 3.5 (1.8-6.8) 1.8 (1.0-3.2) Pulmonary embolism 1.4 (0.5-4.4) 1.1 (0.5-2.5) a Adjusted for age, sex and all thrombotic arterial risk factors

Conclusions Patients with venous thrombosis have a high absolute risk of subsequent arterial thrombosis This risk could not be explained by the presence of arterial thrombotic risk factors The risk of arterial thrombosis was highest within the first year after venous thrombosis, especially in patients with unprovoked venous thrombosis

Authors Inge M. van Schouwenburg Bakhtawar K. Mahmoodi Ron T. Gansevoort Nic J.G.M. Veeger Margaretha M. Visser Willem M. Lijfering Jan van der Meer †