Summary
The association between use of hormone replacement therapy (HRT) and the risk of venous thromboembolism (VTE) has been assessed in relatively few epidemiological studies. Evidence from the earliest studies did not support an increased risk of VTE among HRT users. However, methodological limitations in most studies, including small sample size and inadequate control of confounding, did not allow firm conclusions to be made.
Most of these limitations have been overcome in 5 recent studies which consistently show that the risk of VTE among women currently using HRT is 2 to 3 times higher than among women not using HRT. The overall relative risk of VTE for women currently using HRT obtained from these studies was 2.6 (95% confidence interval 1.6 to 4.2). This association is unlikely to be explained by confounding or other potential biases affecting observational studies. The risk appears to be more prominent during the first year of HRT use, and in 2 studies the risk disappeared after the first year of therapy. A dose-response relationship, with a doubling of risk among users of high doses of estrogens, was shown in 2 of these studies. No major differences were observed with the different types of therapy, but users of unopposed estrogen therapy and transdermal therapy might be at lower risk than users of opposed regimens and oral preparations.
Evidence from these new studies indicates that, among healthy post-menopausal women, between 1 and 2 additional cases of VTE per 10 000 women can be annually attributed to current use of HRT. The Committee on Safety of Medicines in the UK evaluated this risk as small and considered that it does not change the overall benefit-risk profile of HRT for most women.
Similar content being viewed by others
References
A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Surgically confirmed gallbladder, venous thromboembolism, and breast tumors in relation to postmenopausal estrogen therapy. N Engl J Med 1974; 290: 15–9
Pettiti DB, Wingerd J, Pellegrin F, et al. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242: 1150–4
Devor M, Barrett-Connor E, Renvall M, et al. Estrogen replacement therapy and the risk of venous thrombosis. Am J Med 1992; 92: 275–84
Quinn DA, Thompson BT, Terrin ML, et al. A prospective investigation of pulmonary embolism in women and men. JAMA 1992; 268: 1689–96
Hammond CB, Jelovsek FR, Lee KL, et al. Effects of long-term estrogen replacement therapy: I. Metabolic effects. Am J Obstet Gynecol 1979; 133: 525–36
Nachtigall LE, Nachtigall RH, Nachtigall RD, et al. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979; 54: 74–9
Daly E, Vessey MP, Hawkins MM, et al. Case-control study of venous thromboembolism disease and use of hormone replacement therapy. Lancet 1996; 348: 977–80
Jick H, Derby L. The risk of hospitalization for idiopathic venous thromboembolism among users of postmenopausal estrogens. Lancet 1996; 348: 981–3
Pérez-Gutthann S, García Rodríguez LA, Castellsague J, et al. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997; 314: 796–800
Varas C, García Rodríguez LA, Cattaruzzi C, et al. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in Southern-Europe. Am J Epidemiol. In press
Grodstein F, Stampfer MJ, Goldhaber SZ, et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996; 348: 983–7
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–88
The Writing Group for the Estradiol Clotting Factors Study. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. Thromb Haemost 1996; 75: 476–80
Vandenbroucke JP, Koster T, Briët E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1454–7
Rosing J, Tans G, Nicolaes GAF, et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97: 233–8
Vandenbroucke JP, Rosendaal FR. End of the line for ‘thirdgeneration-pill’ controversy? [commentary]. Lancet 1997; 349: 1113–4
Committee on Safety of Medicines, Medicines Control Agency. Risk of venous thromboembolism with hormone replacement therapy. Curr Probl Pharmacovigilance 1996; 22: 9–10
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Castellsague, J., Gutthann, S.P. & Rodríguez, L.A.G. Recent Epidemiological Studies of the Association Between Hormone Replacement Therapy and Venous Thromboembolism. Drug-Safety 18, 117–123 (1998). https://doi.org/10.2165/00002018-199818020-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-199818020-00003