Risk of Venous Thromboembolism Associated With Local and Systemic Use of Hormone Therapy in Peri- and Postmenopausal Women and in Relation to Type and Route of Administration

  

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 Risk of Venous Thromboembolism Associated With Local and Systemic Use of Hormone Therapy in Peri- and Postmenopausal Women and in Relation to Type and Route of Administration

 Menopause. 2016;23(6):593-599

Objective. The aim of the study was to assess the risk of venous thromboembolism (VTE) associated with systemic hormone therapy according to type and to route of administration and the risk of VTE associated with locally administered estrogen.

• Comparisons with Previous RCTs (HT vs Placebo)

• Comparisons with Previous Studies (Estrogens Plus Progestogens vs Estrogens Only)

  (Comparisons include data from WISDOM, WHI, HERS, Million Womens Study trials)

   

Strengths and Limitations

  Our study is the first to highlight both local and systemic use, route of administration, and the importance of the progestogen component. The strengths of this study is the population-based design, the detailed and standardized data collection through interviews, and the possibilities to assess several intrinsic and extrinsic risk factors in the same population including known risk factors for VTE. It was possible to study various estrogen treatment preparations. The diagnostic classification based on presence of both a verified radiological examination of VTE and commenced anticoagulant therapy reduces the risk of misclassification.^[18] Potential limitations include the possibility of selection bias, the limited sample size, and the lack of laboratory data to define menopause status. Also recall—bias cannot be ruled out as the information on exposure was collected retrospectively, however we tried to minimize this by sending all participants a letter with a memory support catalogue and a time schedule to fill in before the interview. Our study was an observational study of VTE cases and selected controls and not a randomized study. We could therefore only estimate relative risks (or relative odds) of VTE in women with and without a particular exposure and not directly estimate disease risk. As only 5% of our study population had a previous arterial disease, excluding these women from the analyses would not have influenced the results.

Conclusions

The VTE risk is higher among users of combined estrogen– progestogen treatment than among users of estrogen only. Orally administered estrogen only generated greater risk than transdermal preparations. Transdermal estrogen treatment and estrogen for local effect seem not to be related to an increased risk of VTE. No statistically significant difference in VTE risk by type of progestogen was found.

References

1. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933-938.
2. 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.
3. Salonen Ros H, Lichtenstein P, Bellocco R, Petersson G, Cnattingius S. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001;12:456-460.
4. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-593.
5. Barnabei VM, Cochrane BB, Aragaki AK, et al. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gynecol 2005;105:1063-1073.
6. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
7. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008;336:1227-1231.
8. Olie V, Canonico M, Scarabin PY. Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol 2010;17:457-463.
9. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573-1580.
10. Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy—results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost 2000;84:961-967.
11. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-613.
12. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ 2007;335:239.
13. Canonico M, Plu-Bureau G, Scarabin PY. Progestogens and venous thromboembolism among postmenopausal women using hormone therapy. Maturitas 2011;70:354-360.
14. Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost 2013;11:124-131.
15. Sweetland S, Beral V, Balkwill A, et al. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost 2012;10:2277-2286.
16. Scarabin PY. Hormone therapy and venous thromboembolism among postmenopausal women. Front Horm Res 2014;43:21-32.
17. American College of Gynecologists. ACOG committee opinion no. 556: postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. Obstet Gynecol 2013;121:887-890.
18. Bergendal A, Bremme K, Hedenmalm K, et al. Risk factors for venous thromboembolism in pre- and postmenopausal women. Thromb Res 2012;130:596-601.
19. Berglind IA, Andersen M, Citarella A, Linder M, Sundstrom A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause 2015;22:369-376.
20. Renoux C, Dell'Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost 2010;8:979-986.
21. Scarabin PY. Hormones and venous thromboembolism among postmenopausal women. Climacteric 2014;17 (suppl 2):34-37.
22. Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev 2013;34:171-208.
23. Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010;30:340-345.
24. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840-845.
25. Canonico M, Alhenc-Gelas M, Plu-Bureau G, Olie V, Scarabin PY. Activated protein C resistance among postmenopausal women using transdermal estrogens: importance of progestogen. Menopause 2010; 17:1122-1127.
26. Lowe GD, Upton MN, Rumley A, McConnachie A, O'Reilly DS, Watt GC. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein—a cross-sectional population survey. Thromb Haemost 2001; 86:550-556.
27. Oger E, Alhenc-Gelas M, Lacut K, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol 2003;23:1671-1676.
28. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997;17:3071-3078.
29. Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001;85:619-625.
30. Benoit T, Leguevaque P, Roumiguie M, et al. Use of local estrogenotherapy in urology and pelviperineology: a systematic review. Prog Urol 2015;25:628-635.