BMJ 1997;314:796 (15 March)

General practice

Hormone replacement therapy and risk of venous thromboembolism: population based case-control study

Susanne Pérez Gutthann, head,a Luis A Garcia Rodriguez, director,b Jordi Castellsague, research associate,a Alberto Duque Oliart, research associate a

a Global Pharmaco-epidemiology Novartis Pharmaceuticals Medical Department Gran Via Corts Catalanes 764 08013 Barcelona Spain, b Centro Español de Investigación Farmaco-epidemiológica Universidad Complutense 28003 Madrid Spain

Correspondence to: Dr Pérez Gutthann

Objective: To evaluate the association between use of hormone replacement therapy and the risk of idiopathic venous thromboembolism.
Design: Population based case-control study.
Setting: Population enrolled in the General Practice Research Database, United Kingdom.
Subjects: A cohort of 347 253 women aged 50 to 79 without major risk factors for venous thromboembolism was identified. Cases were 292 women admitted to hospital for a first episode of pulmonary embolism or deep venous thrombosis; 10 000 controls were randomly selected from the source cohort.
Main outcome measures: Adjusted relative risks estimated from unconditional logistic regression.
Results: The adjusted odds ratio of venous thromboembolism for current use of hormone replacement therapy compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This increased risk was restricted to first year users, with odds ratios of 4.6 (2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months after starting treatment. No major risk differences were observed between users of low and high doses of oestrogens, unopposed and opposed treatment, and oral and transdermal preparations. The risk of idiopathic venous thromboembolism among non-users of replacement therapy was estimated to be 1.3 per 10 000 women per year. Among current users, idiopathic venous thromboembolism occurs at two to three times the rate in non-users, resulting in one to two additional cases per 10 000 women per year.
Conclusions: Current use of hormone replacement therapy was associated with a higher risk of venous thromboembolism, although the risk seemed to be restricted to the first year of use.

Key messages

  • Recent epidemiological studies have shown a twofold to fourfold increased risk of venous thromboembolism among postmenopausal women using hormone replacement therapy

  • This population based case-control study further examined the risk of idiopathic venous thromboembolism associated with the use of hormone replacement therapy, in the population of the General Practice Research Database

  • Overall, there was a twofold relative risk of venous thromboembolism associated with current use of hormone replacement therapy

  • The risk seemed to be restricted to users in their first year of treatment; after this period the risk was similar to that of non-users

  • This study indicates that between one and two cases of idiopathic venous thromboembolism per 10 000 women per year could be attributable to current use of hormone replacement therapy


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?

This article has been cited by other articles:

  • Rathbun, S. (2008). Venous thromboembolism in women. Vasc Med 13: 255-266 [Abstract]  
  • Wierman, M. E., Kohrt, W. M. (2007). Review Article: Vascular and Metabolic Effects of Sex Steroids: New Insights Into Clinical Trials. Reproductive Sciences 14: 300-314 [Abstract]  
  • Skouby, S. O., Sidelmann, J. J., Nilas, L., Jespersen, J. (2007). A comparative study of the effect of continuous combined conjugated equine estrogen plus medroxyprogesterone acetate and tibolone on blood coagulability. Hum Reprod 22: 1186-1191 [Abstract] [Full text]  
  • Rexrode, K. M., Manson, J. E. (2007). Are Some Types of Hormone Therapy Safer Than Others?: Lessons From the Estrogen and Thromboembolism Risk Study. Circulation 115: 820-822 [Full text]  
  • Canonico, M., Oger, E., Plu-Bureau, G., Conard, J., Meyer, G., Levesque, H., Trillot, N., Barrellier, M.-T., Wahl, D., Emmerich, J., Scarabin, P.-Y., for the Estrogen and Thromboembolism Risk (ESTHER), (2007). Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study. Circulation 115: 840-845 [Abstract] [Full text]  
  • Warren, M. P. (2007). Historical Perspectives in Postmenopausal Hormone Therapy: Defining the Right Dose and Duration. Mayo Clin Proc. 82: 219-226 [Abstract] [Full text]  
  • Zerr-Fouineau, M., Chataigneau, M., Blot, C., Schini-Kerth, V. B. (2007). Progestins overcome inhibition of platelet aggregation by endothelial cells by down-regulating endothelial NO synthase via glucocorticoid receptors. FASEB J. 21: 265-273 [Abstract] [Full text]  
  • The ESHRE Capri Workshop Group, (2006). Hormones and cardiovascular health in women. Hum Reprod Update 12: 483-497 [Abstract] [Full text]  
  • Hemelaar, M., Rosing, J., Kenemans, P., Thomassen, M. C. L.G.D., Braat, D. D.M., van der Mooren, M. J. (2006). Less Effect of Intranasal Than Oral Hormone Therapy on Factors Associated With Venous Thrombosis Risk in Healthy Postmenopausal Women. Arterioscler. Thromb. Vasc. Bio. 26: 1660-1666 [Abstract] [Full text]  
  • Curb, J. D., Prentice, R. L., Bray, P. F., Langer, R. D., Van Horn, L., Barnabei, V. M., Bloch, M. J., Cyr, M. G., Gass, M., Lepine, L., Rodabough, R. J., Sidney, S., Uwaifo, G. I., Rosendaal, F. R. (2006). Venous thrombosis and conjugated equine estrogen in women without a uterus.. Arch Intern Med 166: 772-780 [Abstract] [Full text]  
  • Cushman, M., Prentice, R., Psaty, B. M., Rosendaal, F. R., for the WHI Investigators, (2005). Estrogen Plus Progestin and Risk of Venous Thrombosis--Reply. JAMA 293: 1322-1323 [Full text]  
  • Rosendaal, F. R. (2005). Venous Thrombosis: The Role of Genes, Environment, and Behavior. ASH Education Book 2005: 1-12 [Abstract] [Full text]  
  • Gomes, M. P. V., Deitcher, S. R. (2004). Risk of Venous Thromboembolic Disease Associated With Hormonal Contraceptives and Hormone Replacement Therapy: A Clinical Review. Arch Intern Med 164: 1965-1976 [Abstract] [Full text]  
  • Cushman, M., Kuller, L. H., Prentice, R., Rodabough, R. J., Psaty, B. M., Stafford, R. S., Sidney, S., Rosendaal, F. R., for the Women's Health Initiative Investigators, (2004). Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA 292: 1573-1580 [Abstract] [Full text]  
  • Hippisley-Cox, J., Hammersley, V., Pringle, M., Coupland, C., Crown, N., Wright, L. (2004). Methodology for Assessing the Usefulness of General Practice Data for Research in One Research Network. Health Informatics Journal 10: 91-109 [Abstract]  
  • Petitti, D. B. (2003). New hope for hormone replacement and the heart?. J Am Coll Cardiol 42: 1246-1248 [Full text]  
  • Chatrath, R., Ronningen, K. L., LaBreche, P., Severson, S. R., Jayachandran, M., Bracamonte, M. P., Miller, V. M. (2003). Effect of puberty on coronary arteries from female pigs. J. Appl. Physiol. 95: 1672-1680 [Abstract] [Full text]  
  • Duggan, C., Marriott, K., Edwards, R., Cuzick, J. (2003). Inherited and Acquired Risk Factors for Venous Thromboembolic Disease Among Women Taking Tamoxifen to Prevent Breast Cancer. JCO 21: 3588-3593 [Abstract] [Full text]  
  • Oger, E., Alhenc-Gelas, M., Lacut, K., Blouch, M.-T., Roudaut, N., Kerlan, V., Collet, M., Abgrall, J.-F., Aiach, M., Scarabin, P.-Y., Mottier, D. (2003). Differential Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Sensitivity to Activated Protein C Among Postmenopausal Women: A Randomized Trial. Arterioscler. Thromb. Vasc. Bio. 23: 1671-1676 [Abstract] [Full text]  
  • Post, M. S., Christella, M., Thomassen, L.G.D., van der Mooren, M. J., van Baal, W. M., Rosing, J., Kenemans, P., Stehouwer, C. D.A. (2003). Effect of Oral and Transdermal Estrogen Replacement Therapy on Hemostatic Variables Associated With Venous Thrombosis: A Randomized, Placebo-Controlled Study in Postmenopausal Women. Arterioscler. Thromb. Vasc. Bio. 23: 1116-1121 [Abstract] [Full text]  
  • Humphries, K. H., Gill, S. (2003). Risks and benefits of hormone replacement therapy: The evidence speaks. CMAJ 168: 1001-1010 [Abstract] [Full text]  
  • Lewin, K., Sinclair, H., Bond, C. (2003). Women's knowledge of and attitudes towards hormone replacement therapy. Fam Pract 20: 112-119 [Abstract] [Full text]  
  • Bracamonte, M. P., Jayachandran, M., Rud, K. S., Miller, V. M. (2002). Acute effects of 17beta -estradiol on femoral veins from adult gonadally intact and ovariectomized female pigs. Am. J. Physiol. Heart Circ. Physiol. 283: H2389-H2396 [Abstract] [Full text]  
  • Douketis, J. (2002). Review: postmenopausal oestrogen replacement therapy increases the risk for venous thromboembolism. Evid. Based Med. 7: 138-138 [Full text]  
  • Nelson, H. D., Humphrey, L. L., Nygren, P., Teutsch, S. M., Allan, J. D. (2002). Postmenopausal Hormone Replacement Therapy: Scientific Review. JAMA 288: 872-881 [Abstract] [Full text]  
  • Hulley, S., Furberg, C., Barrett-Connor, E., Cauley, J., Grady, D., Haskell, W., Knopp, R., Lowery, M., Satterfield, S., Schrott, H., Vittinghoff, E., Hunninghake, D., for the HERS Research Group, (2002). Noncardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA 288: 58-64 [Abstract] [Full text]  
  • Miller, J., Chan, B. K.S., Nelson, H. D. (2002). Postmenopausal Estrogen Replacement and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis for the U.S. Preventive Services Task Force. ANN INTERN MED 136: 680-690 [Abstract] [Full text]  
  • Rosendaal, F.R., Helmerhorst, F.M., Vandenbroucke, J.P. (2002). Female Hormones and Thrombosis. Arterioscler. Thromb. Vasc. Bio. 22: 201-210 [Abstract] [Full text]  
  • Brighouse, D. (2001). Hormone replacement therapy (HRT) and anaesthesia. Br J Anaesth 86: 709-716 [Abstract] [Full text]  
  • Donker, G. A, Spreeuwenberg, P., Bartelds, A. I., van der Velden, K., Foets, M. (2000). Hormone replacement therapy: changes in frequency and type of prescription by Dutch GPs during the last decade of the millennium. Fam Pract 17: 508-513 [Abstract] [Full text]  
  • Compston, J. E. (2000). Pharmacological interventions for post-menopausal osteoporosis: an evidence-based approach. Rheumatology (Oxford) 39: 1309-1312 [Full text]  
  • Atkins, D., Miller, J. (2000). Hormone replacement therapy was associated with increased venous thromboembolism and deep venous thrombosis. Evid. Based Med. 5: 175-175 [Full text]  
  • Mosca, L. (2000). The Role of Hormone Replacement Therapy in the Prevention of Postmenopausal Heart Disease. Arch Intern Med 160: 2263-2272 [Abstract] [Full text]  
  • Varas-Lorenzo, C., Garcia-Rodriguez, L. A., Perez-Gutthann, S., Duque-Oliart, A. (2000). Hormone Replacement Therapy and Incidence of Acute Myocardial Infarction : A Population-Based Nested Case-Control Study. Circulation 101: 2572-2578 [Abstract] [Full text]  
  • Grady, D., Wenger, N. K., Herrington, D., Khan, S., Furberg, C., Hunninghake, D., Vittinghoff, E., Hulley, S., for the Heart and Estrogen/progestin Replacement S, (2000). Postmenopausal Hormone Therapy Increases Risk for Venous Thromboembolic Disease: The Heart and Estrogen/progestin Replacement Study. ANN INTERN MED 132: 689-696 [Abstract] [Full text]  
  • Hemminki, E. (2000). Hormone replacement therapy: discrepancies between evidence and recommendations. Scand J Public Health 28: 81-83 [Abstract]  
  • Heit, J. A., Silverstein, M. D., Mohr, D. N., Petterson, T. M., O'Fallon, W. M., Melton III, L. J. (2000). Risk Factors for Deep Vein Thrombosis and Pulmonary Embolism: A Population-Based Case-Control Study. Arch Intern Med 160: 809-815 [Abstract] [Full text]  
  • Fioretti, F., Tavani, A., Gallus, S., Franceschi, S., La Vecchia, C. (2000). Menopause and risk of non-fatal acute myocardial infarction: an Italian case-control study and a review of the literature. Hum Reprod 15: 599-603 [Abstract] [Full text]  
  • (1999). Drugs in the peri-operative period: 3 - Hormonal contraceptives and hormone replacement therapy. DTB 37: 78-80 [Abstract] [Full text]  
  • Ettinger, B., Black, D. M., Mitlak, B. H., Knickerbocker, R. K., Nickelsen, T., Genant, H. K., Christiansen, C., Delmas, P. D., Zanchetta, J. R., Stakkestad, J., Gluer, C. C., Krueger, K., Cohen, F. J., Eckert, S., Ensrud, K. E., Avioli, L. V., Lips, P., Cummings, S. R., for the Multiple Outcomes of Raloxifene Evaluation, (1999). Reduction of Vertebral Fracture Risk in Postmenopausal Women With Osteoporosis Treated With Raloxifene: Results From a 3-Year Randomized Clinical Trial. JAMA 282: 637-645 [Abstract] [Full text]  
  • Hart, R. G., Pearce, L. A., McBride, R., Rothbart, R. M., Asinger, R. W. (1999). Factors Associated With Ischemic Stroke During Aspirin Therapy in Atrial Fibrillation : Analysis of 2012 Participants in the SPAF I–III Clinical Trials. Stroke 30: 1223-1229 [Abstract] [Full text]  
  • Hulley, S., Grady, D., Bush, T., Furberg, C., Herrington, D., Riggs, B., Vittinghoff, E., for the Heart and Estrogen/progestin Replacement S, (1998). Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women. JAMA 280: 605-613 [Abstract] [Full text]  
  • Petitti, D. B. (1998). Hormone Replacement Therapy and Heart Disease Prevention: Experimentation Trumps Observation. JAMA 280: 650-652 [Full text]  
  • Yaffe, K., Sawaya, G., Lieberburg, I., Grady, D. (1998). Estrogen Therapy in Postmenopausal Women: Effects on Cognitive Function and Dementia. JAMA 279: 688-695 [Abstract] [Full text]  
  • Grady, D., Hulley, S. B., Furberg, C. (1997). Venous Thromboembolic Events Associated With Hormone Replacement Therapy. JAMA 278: 477-477 [Abstract]  



Doc2Doc Vacancy
Access jobs at BMJ Careers
Whats new online at Student 

BMJ