Granata R, Isgaard J (eds): Cardiovascular Issues in Endocrinology. Front Horm Res. Basel, Karger, 2014, vol 43, pp 21–32 (DOI: 10.1159/000360554)
Hormone Therapy and Venous Thromboembolism among Postmenopausal Women Pierre-Yves Scarabin Inserm, CESP Center for Research in Epidemiology and Population Health, U1018, Hormones and Cardiovascular Diseases Team, and University of Paris Sud, UMRS 1018, Villejuif, France
Abstract
Despite recent data showing that overall health risks may exceed benefits from postmenopausal hormone therapy (HT) [1], many women are still prescribed this therapy to counteract moderate to severe menopause-related symptoms. Postmenopausal women with an intact uterus who use systemic estrogens are also prescribed progestogen to negate the increased risk of endometrial cancer.
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/2/2015 1:57:06 PM
Venous thromboembolism (VTE) is a major harmful effect of hormone therapy (HT) among postmenopausal women. A large variety of HT can be used with significant differences in adverse effects. There is evidence that the VTE risk among HT users depends on the route of estrogen administration. Oral but not transdermal estrogens dose-dependently increase the VTE risk. This difference is supported by biological data. Whereas oral estrogens increase thrombin generation and induce resistance to activated protein C, transdermal estrogens have minimal effect on hemostasis. Past users of oral estrogens have a similar VTE risk to never users. Among users of oral estrogens, the VTE risk is higher within the 1st year of treatment. The combination of oral estrogen use and either obesity or thrombogenic mutations further enhances the VTE risk, whereas transdermal estrogens may not confer additional risk in women at high VTE risk. Significant differences in the VTE risk between HT preparations are also related to the type of concomitant progestogen. The VTE risk is greater in women using medroxyprogesterone acetate than in those receiving other progestins, whereas micronized progesterone appears safe. Based on the current data, transdermal estrogen alone or combined with progesterone could be the safer HT especially in women at high risk for © 2014 S. Karger AG, Basel thrombosis.
Major harmful effects of HT include breast cancer, venous thromboembolism (VTE) and stroke [1]. VTE, encompassing deep vein thrombosis and pulmonary embolism, is a common condition among postmenopausal women with an incidence of about 1 event per 1,000 woman-years around 50 years. VTE constitutes a major health care problem because of its high morbidity and mortality. Risk factors for VTE include age, a past history of VTE, obesity and inherited thrombophilia, such as factor V Leiden or prothrombin G20210A mutation. Clinical and genetic risk factors may interact with HT to increase the incidence of VTE [2]. Acknowledge of these interactions is of major importance to identify high-risk women and to prevent VTE among women considered for HT. A large variety of HT can be used among postmenopausal women and these preparations may differ with respect to their adverse effects. There is a growing body of evidence that the VTE risk among HT users depends on the route of estrogen administration. Indeed, consistent data showed that oral but not transdermal estrogens were associated with an increased VTE risk among postmenopausal women [3]. In addition, the type of concomitant progestogen has recently emerged as a major determinant of the VTE risk in women using HT [4]. This review focuses on the characteristics of HT that are related to the VTE risk and summarizes current data by clinical and genetic background of postmenopausal women.
Observational Studies
While combined oral contraceptives are known to promote VTE for decades, HT has long been believed to have little effect on the risk of VTE. Until the mid-1990s, early studies have failed to provide evidence for an association between HT and VTE. Since October 1996, many observational studies consistently reported a 2- to 3-fold increased risk of VTE among postmenopausal women using HT. Systematic reviews and meta-analyses of observational studies have been published, and some results are well established [2, 3]. Past users of HT have a similar VTE risk as never users. Among HT users, the VTE risk is higher within the 1st year of treatment. However, few studies provided information on the VTE risk by characteristics of HT, including the type and dose of estrogens, the route of estrogen administration and the potential role of progestogens. These few studies are described later in this chapter.
All the randomized trials of HT that included VTE as a clinical outcome are summarized in table 1. Trials in which less than 5 women within each group experienced VTE are not shown.
22
Scarabin Granata R, Isgaard J (eds): Cardiovascular Issues in Endocrinology. Front Horm Res. Basel, Karger, 2014, vol 43, pp 21–32 (DOI: 10.1159/000360554)
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/2/2015 1:57:06 PM
Randomized Trials
Table 1. VTE in randomized trials of HT among postmenopausal women Trial
Clinical background, mean age (range)
Women, n follow-up
Events, n HT/placebo
Active treatment (per day)
RR (95% CI)
HERS [5]
Previous heart disease 67 years (44–79)
2,763 4.1 years
34/12
0.625 mg CEE + 2.5 mg MPA
2.89 (1.50–5.58)
EVTET [6]
Previous VTE 56 years (42–69)
140 1.3 years
8/1
2 mg E2 + 1 mg NETA
7.80 (0.99–60.5)
WHI [7] E + MPA vs. P
Women with intact uterus from the general population 63 years (50–79)
16,608 5.2 years
151/67
0.625 mg CEE + 2.5 mg MPA
2.06 (1.57–2.70)
WHI [8] E alone
Women without uterus from the general population 64 years (50–79)
10,739 7 years
77/54
0.625 mg CEE
1.33 (0.99–1.79)
WISDOM [9]
Women from the general population 63 years (50–69)
5,692 1 year
22/3
0.625 mg CEE 0.625 mg CEE + 2.5 mg MPA
7.36 (2.20–24.60)
E = Estrogen; P = placebo; NETA = norethisterone acetate. Trials including
Hormone Therapy and Venous Thromboembolism among Postmenopausal Women Pierre-Yves Scarabin Inserm, CESP Center for Research in Epidemiology and Population Health, U1018, Hormones and Cardiovascular Diseases Team, and University of Paris Sud, UMRS 1018, Villejuif, France
Abstract
Despite recent data showing that overall health risks may exceed benefits from postmenopausal hormone therapy (HT) [1], many women are still prescribed this therapy to counteract moderate to severe menopause-related symptoms. Postmenopausal women with an intact uterus who use systemic estrogens are also prescribed progestogen to negate the increased risk of endometrial cancer.
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/2/2015 1:57:06 PM
Venous thromboembolism (VTE) is a major harmful effect of hormone therapy (HT) among postmenopausal women. A large variety of HT can be used with significant differences in adverse effects. There is evidence that the VTE risk among HT users depends on the route of estrogen administration. Oral but not transdermal estrogens dose-dependently increase the VTE risk. This difference is supported by biological data. Whereas oral estrogens increase thrombin generation and induce resistance to activated protein C, transdermal estrogens have minimal effect on hemostasis. Past users of oral estrogens have a similar VTE risk to never users. Among users of oral estrogens, the VTE risk is higher within the 1st year of treatment. The combination of oral estrogen use and either obesity or thrombogenic mutations further enhances the VTE risk, whereas transdermal estrogens may not confer additional risk in women at high VTE risk. Significant differences in the VTE risk between HT preparations are also related to the type of concomitant progestogen. The VTE risk is greater in women using medroxyprogesterone acetate than in those receiving other progestins, whereas micronized progesterone appears safe. Based on the current data, transdermal estrogen alone or combined with progesterone could be the safer HT especially in women at high risk for © 2014 S. Karger AG, Basel thrombosis.
Major harmful effects of HT include breast cancer, venous thromboembolism (VTE) and stroke [1]. VTE, encompassing deep vein thrombosis and pulmonary embolism, is a common condition among postmenopausal women with an incidence of about 1 event per 1,000 woman-years around 50 years. VTE constitutes a major health care problem because of its high morbidity and mortality. Risk factors for VTE include age, a past history of VTE, obesity and inherited thrombophilia, such as factor V Leiden or prothrombin G20210A mutation. Clinical and genetic risk factors may interact with HT to increase the incidence of VTE [2]. Acknowledge of these interactions is of major importance to identify high-risk women and to prevent VTE among women considered for HT. A large variety of HT can be used among postmenopausal women and these preparations may differ with respect to their adverse effects. There is a growing body of evidence that the VTE risk among HT users depends on the route of estrogen administration. Indeed, consistent data showed that oral but not transdermal estrogens were associated with an increased VTE risk among postmenopausal women [3]. In addition, the type of concomitant progestogen has recently emerged as a major determinant of the VTE risk in women using HT [4]. This review focuses on the characteristics of HT that are related to the VTE risk and summarizes current data by clinical and genetic background of postmenopausal women.
Observational Studies
While combined oral contraceptives are known to promote VTE for decades, HT has long been believed to have little effect on the risk of VTE. Until the mid-1990s, early studies have failed to provide evidence for an association between HT and VTE. Since October 1996, many observational studies consistently reported a 2- to 3-fold increased risk of VTE among postmenopausal women using HT. Systematic reviews and meta-analyses of observational studies have been published, and some results are well established [2, 3]. Past users of HT have a similar VTE risk as never users. Among HT users, the VTE risk is higher within the 1st year of treatment. However, few studies provided information on the VTE risk by characteristics of HT, including the type and dose of estrogens, the route of estrogen administration and the potential role of progestogens. These few studies are described later in this chapter.
All the randomized trials of HT that included VTE as a clinical outcome are summarized in table 1. Trials in which less than 5 women within each group experienced VTE are not shown.
22
Scarabin Granata R, Isgaard J (eds): Cardiovascular Issues in Endocrinology. Front Horm Res. Basel, Karger, 2014, vol 43, pp 21–32 (DOI: 10.1159/000360554)
Downloaded by: Univ. of California San Diego 132.239.1.230 - 6/2/2015 1:57:06 PM
Randomized Trials
Table 1. VTE in randomized trials of HT among postmenopausal women Trial
Clinical background, mean age (range)
Women, n follow-up
Events, n HT/placebo
Active treatment (per day)
RR (95% CI)
HERS [5]
Previous heart disease 67 years (44–79)
2,763 4.1 years
34/12
0.625 mg CEE + 2.5 mg MPA
2.89 (1.50–5.58)
EVTET [6]
Previous VTE 56 years (42–69)
140 1.3 years
8/1
2 mg E2 + 1 mg NETA
7.80 (0.99–60.5)
WHI [7] E + MPA vs. P
Women with intact uterus from the general population 63 years (50–79)
16,608 5.2 years
151/67
0.625 mg CEE + 2.5 mg MPA
2.06 (1.57–2.70)
WHI [8] E alone
Women without uterus from the general population 64 years (50–79)
10,739 7 years
77/54
0.625 mg CEE
1.33 (0.99–1.79)
WISDOM [9]
Women from the general population 63 years (50–69)
5,692 1 year
22/3
0.625 mg CEE 0.625 mg CEE + 2.5 mg MPA
7.36 (2.20–24.60)
E = Estrogen; P = placebo; NETA = norethisterone acetate. Trials including
