Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens | Cardiology | JAMA Internal Medicine | JAMA Network
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MacLennan  A, Lester  S, Moore  V.  Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review.  Climacteric. 2001;4(1):58-74.PubMedGoogle ScholarCrossref
Nelson  HD.  Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review.  JAMA. 2004;291(13):1610-1620.PubMedGoogle ScholarCrossref
Smith  NL, Heckbert  SR, Lemaitre  RN,  et al.  Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis.  JAMA. 2004;292(13):1581-1587.PubMedGoogle ScholarCrossref
Smith  NL, Heckbert  SR, Doggen  CJ,  et al.  The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women.  J Thromb Haemost. 2006;4(8):1701-1706.PubMedGoogle ScholarCrossref
Rosing  J, Tans  G, Nicolaes  GA,  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(1):233-238.PubMedGoogle ScholarCrossref
Nicolaes  GA, Thomassen  MC, Tans  G, Rosing  J, Hemker  HC.  Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals.  Blood Coagul Fibrinolysis. 1997;8(1):28-38.PubMedGoogle ScholarCrossref
Psaty  BM, Heckbert  SR, Atkins  D,  et al.  The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women.  Arch Intern Med. 1994;154(12):1333-1339.PubMedGoogle ScholarCrossref
Psaty  BM, Heckbert  SR, Koepsell  TD,  et al.  The risk of myocardial infarction associated with antihypertensive drug therapies.  JAMA. 1995;274(8):620-625.PubMedGoogle ScholarCrossref
Lemaitre  RN, Heckbert  SR, Psaty  BM, Smith  NL, Kaplan  RC, Longstreth  WT  Jr.  Hormone replacement therapy and associated risk of stroke in postmenopausal women.  Arch Intern Med. 2002;162(17):1954-1960.PubMedGoogle ScholarCrossref
Heckbert  SR, Wiggins  KL, Glazer  NL,  et al.  Antihypertensive treatment with ACE inhibitors or β-blockers and risk of incident atrial fibrillation in a general hypertensive population.  Am J Hypertens. 2009;22(5):538-544.PubMedGoogle ScholarCrossref
Rossouw  JE, Anderson  GL, Prentice  RL,  et al; Writing Group for the Women’s Health Initiative Investigators.  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(3):321-333.PubMedGoogle ScholarCrossref
Buist  DS, Newton  KM, Miglioretti  DL,  et al.  Hormone therapy prescribing patterns in the United States.  Obstet Gynecol. 2004;104(5, pt 1):1042-1050.PubMedGoogle ScholarCrossref
Koster  T, Rosendaal  FR, de Ronde  H, Briët  E, Vandenbroucke  JP, Bertina  RM.  Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.  Lancet. 1993;342(8886-8887):1503-1506.PubMedGoogle ScholarCrossref
Psaty  BM, Kuller  LH, Bild  D,  et al.  Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study.  Ann Epidemiol. 1995;5(4):270-277.PubMedGoogle ScholarCrossref
Price  TR, Psaty  B, O’Leary  D, Burke  G, Gardin  J.  Assessment of cerebrovascular disease in the Cardiovascular Health Study.  Ann Epidemiol. 1993;3(5):504-507.PubMedGoogle ScholarCrossref
Heckbert  SR, Weiss  NS, Koepsell  TD,  et al.  Duration of estrogen replacement therapy in relation to the risk of incident myocardial infarction in postmenopausal women.  Arch Intern Med. 1997;157(12):1330-1336.PubMedGoogle ScholarCrossref
Tans  G, van Hylckama Vlieg  A, Thomassen  MC,  et al.  Activated protein C resistance determined with a thrombin generation–based test predicts for venous thrombosis in men and women.  Br J Haematol. 2003;122(3):465-470.PubMedGoogle ScholarCrossref
Rosing  J, Middeldorp  S, Curvers  J,  et al.  Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study.  Lancet. 1999;354(9195):2036-2040.PubMedGoogle ScholarCrossref
Anderson  GL, Limacher  M, Assaf  AR,  et al; Women’s Health Initiative Steering Committee.  Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.  JAMA. 2004;291(14):1701-1712.PubMedGoogle ScholarCrossref
Guallar  E, Manson  JE, Laine  C, Mulrow  C.  Postmenopausal hormone therapy: the heart of the matter.  Ann Intern Med. 2013;158(1):69-70.PubMedGoogle ScholarCrossref
Scarabin  PY, Oger  E, Plu-Bureau  G; Estrogen and Thromboembolism Risk Study Group.  Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.  Lancet. 2003;362(9382):428-432.PubMedGoogle ScholarCrossref
Canonico  M, Oger  E, Plu-Bureau  G,  et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group.  Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.  Circulation. 2007;115(7):840-845.PubMedGoogle ScholarCrossref
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(2):340-345.PubMedGoogle ScholarCrossref
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(5):979-986.PubMedGoogle Scholar
Renoux  C, Dell’aniello  S, Garbe  E, Suissa  S.  Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study.  BMJ. 2010;340:c2519. www.bmj.com/content/340/bmj.c2519?view=long&pmid=20525678. Accessed August 14, 2013.PubMedGoogle ScholarCrossref
Sweetland  S, Beral  V, Balkwill  A,  et al; The Million Women Study Collaborators.  Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study [published online September 10, 2012].  J Thromb Haemost. 2012. doi:10.1111/j.1538-7836.2012.04919.x.PubMedGoogle Scholar
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(1):124-131.PubMedGoogle ScholarCrossref
Lemaitre  RN, Weiss  NS, Smith  NL,  et al.  Esterified estrogen and conjugated equine estrogen and the risk of incident myocardial infarction and stroke.  Arch Intern Med. 2006;166(4):399-404.PubMedGoogle ScholarCrossref
Prentice  RL, Langer  R, Stefanick  ML,  et al; Women’s Health Initiative Investigators.  Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women’s Health Initiative clinical trial.  Am J Epidemiol. 2005;162(5):404-414.PubMedGoogle ScholarCrossref
Ansbacher  R.  The pharmacokinetics and efficacy of different estrogens are not equivalent.  Am J Obstet Gynecol. 2001;184(3):255-263.PubMedGoogle ScholarCrossref
Bhavnani  BR.  Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism.  Proc Soc Exp Biol Med. 1998;217(1):6-16.PubMedGoogle ScholarCrossref
O’Connell  MB.  Pharmacokinetic and pharmacologic variation between different estrogen products.  J Clin Pharmacol. 1995;35(9)(suppl):18S-24S.PubMedGoogle ScholarCrossref
Original Investigation
January 2014

Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens

Author Affiliations
  • 1Department of Epidemiology, University of Washington, Seattle
  • 2Group Health Research Institute, Group Health Cooperative, Seattle, Washington
  • 3Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington
  • 4Department of Medicine, University Hospitals of Geneva, Geneva, Switzerland
  • 5Department of Medicine, University of Washington, Seattle
  • 6Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
  • 7Department of Biostatistics, University of Washington, Seattle
  • 8Department of Statistics, University of Auckland, Auckland, New Zealand
  • 9Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
  • 10Department of Health Services, University of Washington, Seattle
JAMA Intern Med. 2014;174(1):25-34. doi:10.1001/jamainternmed.2013.11074

Importance  Little is known about the comparative cardiovascular safety of oral hormone therapy products, which impedes women from making informed safety decisions about hormone therapy to treat menopausal symptoms.

Objective  To compare the relative clinical cardiovascular safety of 2 commonly used oral estrogen drugs—conjugated equine estrogens (CEEs) and estradiol.

Design, Setting, and Participants  Population-based, case-control study from January 1, 2003, to December 31, 2009, comparing cardiovascular event risk associated with current CEEs and estradiol use in a large health maintenance organization in which the preferred formulary estrogen changed from CEEs to estradiol during the course of data collection. Participants were 384 postmenopausal women aged 30 to 79 years using oral hormone therapy.

Main Outcomes and Measures  Incident venous thrombosis was the primary clinical outcome, and incident myocardial infarction and ischemic stroke were secondary outcomes. As validation, an intermediate clotting phenotype, the endogenous thrombin potential–based normalized activated protein C sensitivity ratio, was measured in plasma of controls.

Results  We studied 68 venous thrombosis, 67 myocardial infarction, and 48 ischemic stroke cases, with 201 matched controls; all participants were current users of oral CEEs or estradiol. In adjusted analyses, current oral CEEs use compared with current oral estradiol use was associated with an increased venous thrombosis risk (odds ratio, 2.08; 95% CI, 1.02-4.27; P = .045) and an increased myocardial infarction risk that did not reach statistical significance (odds ratio, 1.87; 95% CI, 0.91-3.84; P = .09) and was not associated with ischemic stroke risk (odds ratio, 1.13; 95% CI, 0.55-2.31; P = .74). Among 140 controls, CEEs users compared with estradiol users had higher endogenous thrombin potential–based normalized activated protein C sensitivity ratios (P < .001), indicating a stronger clotting propensity.

Conclusions and Relevance  In an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk.