Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis.

BACKGROUND Menopausal hormone therapy is widely used to alleviate climacteric symptoms but may increase the risk of venous and arterial vascular events. OBJECTIVE The objective was to synthesize the evidence about the risk of vascular events in postmenopausal women who use oral estrogen therapy (ET) and transdermal ET. METHODS We searched bibliographical databases through August 2013 for longitudinal comparative studies that enrolled postmenopausal women using either oral or transdermal ET and reported the outcomes of interest: venous thromboembolism (VTE), pulmonary embolism, deep venous thrombosis (DVT), myocardial infarction (MI), and stroke. Two reviewers independently selected and appraised studies. Outcomes were pooled using random effects meta-analysis and were reported as risk ratio (RR) and 95% confidence interval (CI). RESULTS We included 15 observational studies at moderate risk of bias with follow-up of 3 to 20.25 years. When compared to transdermal ET, oral ET was associated with increased risk of a first episode of VTE (RR, 1.63; 95% CI, 1.40-1.90; I(2) = 53%), DVT (RR, 2.09; 95% CI, 1.35-3.23; I(2) = 0 %), and possibly stroke (RR, 1.24; 95% CI, 1.03-1.48; a single case-controlled study), but not MI (RR, 1.17; 95% CI, 0.80-1.71; I(2) = 74%). CONCLUSION Observational evidence warranting low confidence suggests that compared to transdermal ET, oral ET may be associated with increased risk of VTE and DVT, but not MI.

[1]  J. Simon.  What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? , 2014, Menopause.

[2]  Lewis H Kuller,et al.  Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. , 2013, JAMA.

[3]  R. Lobo.  Where are we 10 years after the Women's Health Initiative? , 2013, The Journal of clinical endocrinology and metabolism.

[4]  F. Rosendaal,et al.  The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy , 2013, Journal of thrombosis and haemostasis : JTH.

[5]  V. Beral,et al.  Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study , 2012, Journal of thrombosis and haemostasis : JTH.

[6]  M. Duh,et al.  Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy , 2011, Menopause.

[7]  M. Horellou,et al.  Hormone therapy and recurrence of venous thromboembolism among postmenopausal women , 2011, Menopause.

[8]  P. Scarabin,et al.  Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women , 2010, Current opinion in hematology.

[9]  S. Suissa,et al.  Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study , 2010, BMJ : British Medical Journal.

[10]  S. Suissa,et al.  Hormone replacement therapy and the risk of venous thromboembolism: a population‐based study , 2010, Journal of thrombosis and haemostasis : JTH.

[11]  F. Clavel-Chapelon,et al.  Postmenopausal Hormone Therapy and Risk of Idiopathic Venous Thromboembolism: Results From the E3N Cohort Study , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[12]  R. Jacobsen,et al.  Hormone therapy and risk of myocardial infarction: a national register study. , 2008, European heart journal.

[13]  P. Bath,et al.  Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis , 2008, European heart journal.

[14]  M. L'hermite,et al.  Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. , 2008, Maturitas.

[15]  G. Guyatt,et al.  A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. , 2008, The Journal of clinical endocrinology and metabolism.

[16]  E. Oger,et al.  Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study , 2007, Circulation.

[17]  J. Manson,et al.  Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. , 2006, Journal of women's health.

[18]  R. Farmer,et al.  Myocardial infarction risk and hormone replacement: differences between products. , 2006, Maturitas.

[19]  W. Utian.  Health and Quality of Life Outcomes , 2005 .

[20]  J. Douketis,et al.  Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case–control study , 2005, Journal of thrombosis and haemostasis : JTH.

[21]  C. Chilvers,et al.  Post menopausal hormone replacement therapy and risk of acute myocardial infarction--a case control study of women in the East Midlands, UK. , 2003, European heart journal.

[22]  E. Oger,et al.  Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk , 2003, The Lancet.

[23]  J. Hippisley-Cox,et al.  A case-control study on the effect of hormone replacement therapy on ischaemic heart disease. , 2003, The British journal of general practice : the journal of the Royal College of General Practitioners.

[24]  E. Høibraaten.  [Postmenopausal hormone replacement therapy and cardiovascular disease]. , 2002, Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke.

[25]  G. Watt,et al.  Different Effects of Oral and Transdermal Hormone Replacement Therapies on Factor IX, APC Resistance, t-PA, PAI and C-reactive Protein , 2001, Thrombosis and Haemostasis.

[26]  J. Carson,et al.  Risk of venous thromboembolism in users of hormone replacement therapy , 1996, The Lancet.

[27]  J. Manson,et al.  Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. , 1996, The New England journal of medicine.

[28]  P. Tugwell,et al.  The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses , 2014 .

[29]  P. Scarabin.  Hormone therapy and venous thromboembolism among postmenopausal women. , 2014, Frontiers of hormone research.

[30]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.