The relation between venous and arterial thrombosis Walter Ageno Department of Clinical Medicine University of Insubria Varese - Italy

Asymptomatic atherosclerosis and deep vein thrombosis Atherosclerosis defined by ultrasound detected carotid plaques in patients with DVT and controls Atherosclerosis Idiopathic DVT 47% Secondary DVT 27.4% Controls 32% OR: 2.4 (1.4-4.0) (idiopathic vs secondary or controls) Prandoni et al, N Engl J Med 2003

Venous thromboembolism is associated with an increased risk of subsequent atherosclerosis

The long-term clinical course of PE Cardiovascular Events 0.40 Cardiovascular Events Idiopathic PE PE with transient RF 0.30 Cumulative Hazard 0.20 P=.005 0.10 0.00 6 12 18 24 30 36 42 48 Becattini et al., Eur Heart J 2005

Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta-analysis IRR Unprovoked VTE vs Provoked VTE 1.86 (1.19-2.89) Controls 1.87 (1.32-2.65) Becattini et al JTH 2010

Atherosclerosis is not associated with an increased risk of subsequent venous thromboembolism

Cardiovascular risk factors and venous thromboembolism

Cardiovascular risk factors Obesity Hypertension Diabetes mellitus Dyslipidemia Smoking Metabolic syndrome

Obesity (BMI>30 Kg/m2) Hypertension Diabetes Triglycerides levels OR 2.33 (1.68, 3.24) Hypertension OR 1.51 (1.23, 1.85) Diabetes OR 1.41 (1.12, 1.77) Triglycerides levels WMD 17.48 (9.64, 28.33) HDL cholesterol levels WMD –2.86 (-4.34, -1.38)

Risk of VTE and Circumference of the Waist Arch. Int. Med. 1999; 159: 1886-90 50 60 70 80 90 100 54 65 75 Age (years) % of men without VTE after 26 years follow up Circumf. <100 cm Circumf. >100 cm

Anthropometric measures of obesity and risk of venous thromboembolism: the Tromso study Conclusions—Our findings indicate that WC is the preferable anthropometric measure of obesity to identify subjects at risk and to predict risk of VTE. Borch KH ATVB 2009

Metabolic Syndrome and inflammation Inflammatory adipokines: - TNF α - Leptin - Interleukin – 6 CRP Adiponectin

Metabolic Syndrome and risk of VTE: LITE study (12 years follow up) Idiopathic VTE events (n:195) Women Men (n=11,333) (n=8,863) Abdominal obesity 1.91 (1.23, 2.95) 2.42 (1.53, 3.81) High glucose 0.92 (0.57, 1.49) 1.06 (0.65, 1.72) High triglycerides 0.80 (0.49, 1.29) 0.79 (0.48, 1.32) Low HDL 0.59 (0.37-1.04) 1.57 (0.98-2.52) Elevated blood pressure 1.29 (0.85-1.98) 0.83 (0.52-1.33) Met Syn 0.76 (0.51-1.15) 1.59 (1.02-2.47) Steffen L et al JTH 2009

Risk of VTE in the Metabolic Syndrome: Tromso Study (11 years follow up) Age and gender adjusted HR (95 % CI) Metabolic syndrome 1.65 (1.22-2.23) Abdominal obesity 2.12 (1.59-2.83) Hypertriglyceridemia 1.26 (0.95-1.69) Low HDL cholesterol 1.07 (0.76-1.52) Hypertension 1.39 (0.98-1.97) Impaired glucose metabolism 1.51 (0.98-2.35) Borch K et al, JTH 2009

Common risk factors for arterial and venous thrombosis Advanced age Obesity Abdominal obesity Hormonal therapy Metabolic syndrome DIC HIT Antiphospholipid antibodies Hyperhomocysteinemia Cancer Myeloproliferative neoplasms PNH Heart failure Smoking Chronic kidney failure Nephrotic syndrome Inflammatory bowel disease

The effect of primary or secondary prevention strategies for cardiovascular disease in patients with venous thromboembolism

Fish, fruit, and vegetable intake and the risk of VTE Quintiles of daily nutrient intake Servings/d 1 2 3 4 5 p trend Fruit and vegetables Quintile ranges <2.5 2.5-3.5 3.5-4.5 4.5-5.8 >5.8 HR 1.0 0.73 0.57 0.47 0.59 0.03 95% CI n.s. .37-.90 .29-.77 .36-.99 Fish Quintile ranges <0.1 .1-.14 .15-.25 .25-.43 >0.43 HR 1.0 0.58 0.60 0.55 0.70 0.30 95% CI .37-.90 .39-.92 .35-.88 n.s. Red and processed meat Quintiles ranges <0.5 .5-.75 .75-1.0 1.0-1.5 >1.5 HR 1.0 1.24 1.21 1.09 2.01 0.02 95% CI n.s. n.s. n.s. 1.15-3.53 Steffen LM et al Circulation 2007

Alcohol consumption and the risk of VTE Alcohol consumers vs abstainers (2-4 glasses per day resulted in the largest beneficial effect) Overall OR 0.67 (0.58-0.77) Women OR 0.66 (0.53-0.84) Men OR 0.82 (0.63-1.07) PE only OR 0.56 (0.46-0.70) DVT only OR 0.74 (0.63-0.88) Fibrinogen levels were consistently decreased, FVII and vWF levels mildly decreased but not consistently Pomp ER et al Thromb Haemost 2008

Aspirin for the secondary prevention of VTE: WARFASA and ASPIRE pooled analysis Brighton T et al NEJM 2012

OR 0.81 (0.66-0.99)

Statin treatment reduces the risk of recurrent pulmonary embolism 3093 patients with a first episode of PE with a mean age of 61.3 ± 17.0 years. 737 patients (24%) had at least one prescription of statins during follow-up (median duration of statin therapy: 1557 days; 5-4055 days). During a median follow up of 1529 days (1-4155), 285 (9.2%) patients experienced a recurrent PE. Biere-Rafi S et al Eur Heart J 2012

Statin treatment reduces the risk of recurrent pulmonary embolism Treatment with statins reduced recurrent PE (HR 0.48, 95%CI 0.35-0.67) The protective effect was present both during and after stopping VKA treatment. A dose-response relationship was shown for both duration and potency Finally, statin treatment also reduced cardiovascular events and all-cause mortality. Biere-Rafi S et al Eur Heart J 2012

Conclusions Patients with (unprovoked) VTE are at increased risk of cardiovascular events Common risk factors may, at least in part, explain this association Effective treatment for the primary and secondary prevention of cardiovascular disease play a role also in the prevention of VTE