Venous thromboembolic disease John C. Stevenson Editor: Martin Birkhäuser

Coagulation and fibrinolysis Endothelial cells Activated platelets XII TFPI tPA PAI-1 IX Protein C Protein S VIII VII X TF Plasminogen V AT Prothrombin F1+2 Plasmin Thrombin FPA Fibrinogen Fibrin D-dimer

Venous thromboembolism Risk of VTE in postmenopausal women: 1 per 10,000 patient-years 2–3 non-fatal VTE per year for every 10,000 women given HRT Deaths from VTE: 1 per 1,000,000 patient-years

Increased VTE risk Age Obesity Malignancy Immobilization History/family history Oral estrogen Specific SERMs

Venous thromboembolism HRT affects vascular endothelium Oral HRT affects hepatic production and clearance of hemostatic factors

Oral HRT and VTE Observational studies Case-control studies (n = 7) RR 2.1 (CI 1.4–3.0) Prospective cohort studies (n = 1) RR 2.1 (CI 1.2–3.8) Oger and Scarabin. Drugs Aging 1999;14:55–61

Oral HRT and VTE Randomized clinical trials HERS RR 2.9 (CI 1.5–5.6) WHI (E alone) RR 1.3 (CI 1.0–1.8) WHI (E + P) RR 2.1 (CI 1.6–2.7) E + P (age 70–79 years) RR 7.5 vs. placebo (age 50–59 years) E + P (age 50–59 years) RR 0.7 vs. placebo (age 70–79 years) Hulley et al. J Am Med Assoc 1998;280:605–13 Cushman et al. J Am Med Assoc 2004;292:1573–80 Women’s Health Initiative Steering Committee. J Am Med Assoc 2004;291:1701–12

ERT/HRT and thromboembolic risk: absolute risk A per oral HRT increases moderately the thromboembolic risk, in particular in presence of hereditary or acquired thrombophilia, and during the first year after initiation of ERT/HRT (Age 50–59: 2 additional cases/year per 10,000 women) Low-dose transdermal HRT seems not to increase the thromboembolic risk WHI, Cushman M, et al. J Am Med Assoc 2004;292:1573–80

Oral HRT and VTE Duration and dose of HRT Risk of VTE higher in first year of treatment Risk of VTE dose-dependent Effect of HRT less than OC in women with other increased VTE risk <1 year Duration >1 year High Dose Low 2 4 6 8 Odds ratio Oger and Scarabin. Drugs Aging 1999;14:55–61 Waselenko et al. Semin Thromb Hemost 1998;24(Suppl):33–9

HRT route and VTE No HRT Transdermal HRT Oral HRT 2 4 6 8 Odds ratio 2 4 6 8 Odds ratio Scarabin, et al. Lancet 2003;362:428–32

Risk of VTE: HRT route of administration and progestogens (ESTHER study) Route/progestagen OR 95% CI Oral 4.2 1.5–11.6 Transdermal 0.9 0.4–2.1 Micronized progesterone 0.7 0.3–1.9 Pregnanes 0.9 0.4–2.3 Norpregnanes 3.9 1.5–10.0 Canonico M, et al. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Circulation 2007;115:820–2

SERMS and VTE Randomized clinical trials Tamoxifen (n = 5408) RR 1.63 (CI 1.02–2.63) Raloxifene (n = 10,101) RR 1.44 (CI 1.06–1.85) Decensi, et al. Circulation 2005;111:650–56 Barrett-Connor, et al. N Engl J Med 2006;355:125–37

Thrombophilia Established inherited Antithrombin deficiency Protein C deficiency Protein S deficiency Activated protein C resistance (factor V Leiden) Homocystinuria Dysfibrinogenemia Prothrombin gene mutation Further Homocystinuria Factor VIII elevation Low tissue factor pathway inhibitor (TFPI)

Protein C anticoagulant pathway PC PS Va T PC APC VIIIa T PS Va VIIIa APC Thrombomodulin APC receptor VIIIa inactive Va inactive Dahlback B. Thromb Res 1995;77:1–43

HRT route and ETP-APC resistance 152 hysterectomized, postmenopausal women Aged 45–65 years Randomized to placebo, transdermal estradiol 50 μg, oral estradiol 1 mg, oral estradiol 1 mg + gestodene 25 μg for 13 cycles Normalized ETP-APC sensitivity ratios measured * * *p < 0.001 vs. placebo Post, et al. Arterioscler Thromb Vasc Biol 2003;23:1116–21

HRT and prothrombotic mutations 235 postmenopausal women with VTE 22% oral E 26% transdermal E 554 postmenopausal controls 7% oral E 31% transdermal E 4.9% prevalence of factor V Leiden 2.5% prevalence of prothrombin G20210A mutation Straczek, et al. Circulation 2005;112:3495–500

Acquired ETP-APC resistance Antiphospholipid syndrome Oral contraception Pregnancy Oral estrogen (CEE and E2) replacement

Thrombophilia screening Patients with personal history of VTE Patients with first- or second-degree relative with VTE

VTE management Full anti-coagulation Low-dose warfarin (1 mg/day) lifelong Low-dose aspirin lifelong Avoidance of oral HRT (CEE, E2, tamoxifen, raloxifene)

HRT and thromboembolism IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY HRT and thromboembolism The HRT-related risk for serious venous thromboembolic events increases with age (although minimal until age 60) and is also positively associated with obesity and thrombophilia By avoiding first-pass hepatic metabolism, transdermal estrogen may avert the risk associated with oral HRT The impact on the risk of a thromboembolic event may also be affected by progestogen, depending on the type Climacteric 2007;10:181–96

HRT and thromboembolism: Misperceptions The risk of both venous and arterial thromboembolism is increased during HRT Stroke risk is substantially increased in women receiving HRT IMS Global Summit 2008. Climacteric 2008;11:267–72

HRT and thromboembolism: Evidence The risk of venous thrombosis is approximately two-fold higher with standard doses of oral HRT, but is a rare event in that the background prevalence is extremely low in a healthy woman under 60 years of age. It is also associated with obesity and with thrombophilia The risk of venous thrombosis is possibly less with transdermal, compared with oral, estrogen therapy IMS Global Summit 2008. Climacteric 2008;11:267–72