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Keywords:

  • epidemiology;
  • hormone therapy;
  • menopause;
  • risk factors;
  • venous thrombosis

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussions
  6. Acknowledgements
  7. References
  8. Supporting Information

Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1·6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR = 1·60, 95% confidence interval [CI], 1·06–2·36; Population attributable fraction = 6·7%, 95%CI, 1·0–10·3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the association was stronger (RR = 2·02, 95%CI, 1·31–3·12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR = 2·40, 95%CI, 1·40–4·12) than those with secondary VTE (RR = 1·08, 95%CI, 0·63–1·85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous oestrogen exposure were not associated with VTE.

Previous prospective studies and clinical trials have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE). For example, in the Nurses’ Health Study cohort, use of oral contraceptives and postmenopausal hormone therapy were associated with increased risk of pulmonary embolism (Grodstein et al, 1996). Further, in clinical trials, such as the Heart and Estrogen/progestin Replacement Study (HERS) (Grady et al, 2000) and the Women’s Health Initiative (WHI) (Cushman et al, 2004a), hormone replacement therapy increased the risk of VTE 2·1- to 2·7-fold.

A recent hospital-based case-control study indicated that reproductive markers of lifetime endogenous oestrogen exposure also might affect VTE risk in women (Simon et al, 2006). Specifically, VTE risk was associated positively with age at menopause and number of children. Compared with normal age at menopause (46–54 years), the multivariate-adjusted odds ratio (OR) of VTE for late menopause (≥55 years) was 2·53 (95% confidence interval [CI], 1·28, 4·99) (Simon et al, 2006). The adjusted OR for VTE was 1·6-fold higher for women with more than two children when compared with those with two children or fewer (Simon et al, 2006). Other studies have reported similar results that women with late menopause and a history of more than three pregnancies had increased risk of VTE (Grady et al, 2000; Samama, 2000). Given that the subjects of previous studies were predominantly whites and from hospital-based studies, these findings need confirmation in the general population. Rates of VTE are higher in African Americans than whites (Tsai et al, 2002a; White et al, 2005), so confirmation among this population is especially relevant.

To examine the association of reproductive history measures of endogenous oestrogen exposure, hormone replacement, and incident VTE among American Africans and whites, we used data from women in two population-based prospective studies.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussions
  6. Acknowledgements
  7. References
  8. Supporting Information

Study population

The Longitudinal Investigation of Thromboembolism Etiology (LITE) study is a prospective study of VTE occurrence in two pooled, multi-centre, longitudinal population-based cohort studies: the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). The LITE study design, methods, and VTE incidence rates have been described in detail elsewhere (Tsai et al, 2002a; Cushman et al, 2004b; Ohira et al, 2007; Yamagishi et al, 2009). In brief, 15 792 men and women aged 45–64 years enrolled in the ARIC study in 1987–89 and 5201 men and women aged ≥65 years enrolled in the CHS in 1989–90 underwent assessments of cardiovascular risk factors. An additional 687 African Americans were recruited to CHS using similar methods in 1992–93. The basic characteristics of the combined LITE sample, and the justification for pooling ARIC and CHS, have been published (Tsai et al, 2002a). Informed consent was obtained from participants, with approval of methods from the institutional review committees at each study center.

We first excluded participants who were not white or black or were scarcely represented in some field centres (n = 103), men (n = 9572), and pre or peri-menopausal women at baseline (n = 2436). We then excluded participants who at baseline had a history of VTE (n = 395) or cancer (n = 908), were missing menopausal data (n = 25) or were taking warfarin (n = 57). The remaining 8236 post-menopausal women were included in the analyzes. Up to three follow-up examinations were performed every 3 years in ARIC and up to nine follow-up examinations were performed annually in CHS. Reexamination rates were 78, 66, and 51 percent for ARIC, and 81, 80, 76, 87, 85, 85, 77, 76, and 70 percent for CHS, respectively. Subjects were followed to determine the incidence of VTE until December 31, 2002 for ARIC and December 31, 2001 for CHS, after a median follow up of 13·1 years in ARIC and 11·7 years in CHS.

Measurements

Baseline cardiovascular risk factors and additional haemostatic factors included in this study were measured comparably in ARIC and CHS, as described elsewhere (Cushman et al, 1995; Folsom et al, 1997, 2002; Tsai et al, 2002a). Blood was drawn from participants in the morning in both studies, promptly centrifuged for 30 000 g-min, and stored in −70°C freezers. Factor VIII coagulant activity (FVIII) was measured as previously reported (Tsai et al, 2002b). Body mass index (BMI) was calculated as weight (kg)/height (m)2. Diabetes mellitus was defined at baseline as a fasting glucose of ≥7 mmol/l, nonfasting glucose ≥11 mmol/l, a history of physician-diagnosed diabetes, or current use of diabetes medication.

Menopause was defined on the basis of baseline interview data. A woman was considered premenopausal if she had menstruated in the last 2 years. Women <55 years of age with a hysterectomy and at least one intact ovary could not be categorized on ovarian status. The remaining women were considered postmenopausal. Postmenopausal women were further classified as having undergone a surgical menopause if they had had a bilateral oophorectomy. Natural menopause included (i) non-menstruating women with an intact uterus and at least one intact ovary and (ii) women who had had a hysterectomy, had at least one intact ovary but were 55 years of age or older (Szklo et al, 1996). Participants were also interviewed about parity and use and duration of hormone replacement therapy. Hormone replacement therapy included the use of oestrogen or oestrogen and progestin preparations. In the present study, ‘current hormone use’ was defined as use of oral oestrogen or oestrogen and progestin preparations, and thus did not include transdermal administration because it does not increase risk of VTE (Canonico et al, 2008). ‘Never hormone use’ was defined as never having used oral oestrogen or oestrogen and progestin preparations, and ‘former hormone use’ was defined as previously using oral contraceptives or an oestrogen, progestin, or androgen therapy by oral or transdermal administration.

Endpoint determination

All participants were contacted annually by phone and asked about all hospitalizations in the previous year. Hospital records were obtained and VTE events validated by two physicians, as previously reported (Cushman et al, 2004b). Diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) required positive imaging tests. Cases were classified as idiopathic (no obvious cause) or secondary (associated with cancer, major trauma, surgery, marked immobility). From the ARIC study, 110 post-menopausal women with VTE were identified (51 idiopathic, and 59 secondary). In CHS, there were 80 post-menopausal women with VTE events; 33 were idiopathic, and 47 secondary. Of the 190 events, 153 had DVT only and 37 had PE.

Statistical analysis

Age- and race-adjusted mean values or prevalences of baseline variables of interest were compared between participants with VTE and without VTE, using analysis of covariance (ancova) or logistic regression models (Wilcosky & Chambless, 1985). Data were analyzed by classifying participants into three groups according to age at menopause, defined as early (≤45 years), normal (46–54 years) and late menopause (≥55 years); according to hormone therapy as current users of oestrogen (alone or in combination with progestin), former users, and never users; and according to parity as nulliparous, one or two children, and more than two children (Simon et al, 2006). Differences among these categories in age- and race-adjusted mean values or prevalences of potential confounding factors at baseline were also calculated using ancova or logistic regression models. Rate ratios (RR) and 95% CIs of VTE were calculated with adjustment for age and other potential confounding factors using the Cox proportional hazards model. Adjustment was made for factors previously associated with VTE in this study, including age (continuous), race, BMI (continuous), diabetes status (yes, no), and FVIII (continuous). Because hormone use often changed during follow-up, we also used time-dependent Cox models (updating information on hormone use at follow-up examinations). For participants with missing information on hormone use for a given follow-up examination visit, the hormone use status from the prior examination was carried forward. In order to evaluate the effect of duration of hormone therapy on the incidence of VTE, the incidence data excluding women with 1-year or more duration of hormone therapy at baseline were also analyzed.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussions
  6. Acknowledgements
  7. References
  8. Supporting Information

The sample consisted of postmenopausal women 45 years and older who were followed for an average of 11·8 years for VTE occurrence. Table I shows means or prevalences of risk characteristics at baseline for incident cases of VTE and for those who remained free of VTE. Mean values of age, BMI, and FVIII and the prevalence of diabetes were significantly higher among women with VTE than those without VTE, and African Americans were more likely than whites to suffer VTE. There were no significant differences in age at menopause, parity number, or type of menopause between women with VTE and those without VTE in either whites and Africans Americans (Tables SI and SII).

Table I.   Baseline characteristics among post-menopausal women who did or did not develop incident venous thromboembolism, LITE.
Baseline characteristics*Venous thromboembolism (n = 190)No venous thromboemolism (n = 8046)P value
  1. Sample sizes vary somewhat among characteristics because some women had indefinable menopause status.

  2. BMI, body mass index.

  3. *Age- and race-adjusted.

  4. †Race-adjusted.

  5. ‡Age-adjusted.

  6. §Current user only.

Age (years)†64·061·0<0·001
Race (% African American)‡37·029·10·02
Mean age at menopause (years)44·845·20·51
Age at menopause (%)
 Early menopause (≤45 years)44·443·40·44
 Normal menopause (46–54 years)48·351·2
 Late menopause (≥55 years)7·35·4
Parity (%)
 Nulliparous12·611·20·83
 One to two children38·138·4
 Greater than two children49·350·4
Hormone therapy use (%)
 Never used63·463·30·93
 Former use of oestrogen or progesterone18·219·2
 Current use of oestrogen and/or progesterone18·217·5
 Duration of hormone therapy use (years)§5·15·40·77
Type of menopause (%)
 Natural81·483·40·47
 Surgical18·616·6 
BMI (kg/m2)29·327·6<0·001
Diabetes mellitus (%)14·29·60·03
Factor VIII (%)151132<0·001

Table II presents age- and race-adjusted mean values or prevalences of VTE risk factors at baseline according to the categories of age at menopause, parity, hormone therapy, and type of menopause. Women with late menopause (≥55 years) had a higher mean BMI compared with women with early or normal menopause. The prevalence of diabetes and mean BMI were lower among women with parity of one to two than among women who were nulliparous or had parity of more than two. Current users of oestrogen and/or progesterone had a lower mean BMI and factor VIII, and lower prevalence of diabetes compared with never and former users.

Table II.   Age- and race-adjusted baseline characteristics according to age at menopause, parity, hormone therapy use, and cause of menopause, LITE.
Baseline characteristicsNo. at riskRace (% African American)*PBMI (kg/m2)PDiabetes mellitus (%)PFactor VIII (%)P
  1. Sample sizes vary somewhat among characteristics because some women had indefinable menopause status.

  2. BMI, body mass index.

  3. *Age-adjusted.

Age at menopause (%)
 Early menopause (≤45 years)357764·0<0·00127·50·0019·80·881320·02
 Normal menopause (46–54 years)346476·727·79·8135
 Late menopause (≥55 years)45269·628·510·5134
Parity (%)
 Nulliparous92667·2<0·00127·1<0·00110·30·011320·23
 One to two children309577·227·08·4132
 Greater than two children415067·328·210·5134
Hormone therapy use (%)
 Never used502568·0<0·00128·0<0·00110·8<0·001135<0·001
 Former use of oestrogen or progesterone157975·227·69·0130
 Current use of oestrogen and/or progesterone143979·326·25·9128
Type of menopause (%)
 Natural623873·0<0·00127·60·539·40·011330·76
 Surgical124859·327·711·8133

Compared with normal menopause, the multivariate-adjusted RRs of VTE for early menopause was 1·16 (95% CI, 0·83, 1·63) and for late menopause was 1·49 (95% CI, 0·89, 2·58), neither being statistically significant (Table III). Further, when modelled as continuous variables, there were no associations of age at menopause or parity number with the risk of VTE (P = 0·23 and P = 0·62, respectively). There were no significant associations of parity or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1·6-fold higher multivariate-adjusted RR of VTE compared with those not taking hormones in the time-dependent model (RR = 1·60, 95% CI, 1·06, 2·36). When we excluded women with 1-year or more duration of hormone therapy at baseline, the associations of current hormone use with the incidence of VTE was stronger; the multivariate-adjusted RR for current hormone use was 2·02 (95%CI, 1·31, 3·12). When we analyzed the associations of oestrogen alone or oestrogen in combination with progestin, separately, the association of current hormone use with the incidence of VTE was similar between oestrogen/progestin and oestrogen alone; the RRs were 1·60 (95%CI, 0·97–2·62) for oestrogen/progestin and 1·59 (95%CI, 1·06–2·37) for oestrogen alone. Furthermore, we calculated population attributable risk, the percentage of VTE occurrence in the population associated with current hormone use, using the formula p(RR-1)/[1-p(RR-1)], where p is the prevalence of current hormone use among participants. The population attributable risk was 6·7% (95%CI, 1·0–10·3). The associations of hormone replacement with the incidence of VTE did not differ among the categories of menopause age, parity, or type of menopause (P for interactions >0·30).

Table III.   Multivariate-adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of incidental venous thromboembolism, LITE, 1987–2002.
VariableNo. at riskNo. of casesPerson-years of follow upModel 1*Model 2†
RR95%CIRR95%CI
  1. Sample sizes vary somewhat among characteristics because some women had indefinable menopause status.

  2. *Adjusted for age, race, body mass index, diabetes mellitus, and factor VIII at baseline.

  3. †Further adjusted for other reproductive variables.

  4. ‡Time dependent analysis.

Age at menopause
 Early menopause (≤45 years)35778242 4331·16(0·84–1·60)1·16(0·83–1·63)
 Normal menopause (46–54 years)34647740 6951 1 
 Late menopause (≥55 years)4521649751·44(0·84–2·48)1·49(0·89–2·58)
Parity
 Nulliparous9262710 0681·14(0·71–1·83)1·15(0·72–1·84)
 One to two children30957136 1581 1 
 Greater than two children41509049 9900·89(0·64–1·25)0·90(0·64–1·26)
Hormone therapy use‡
 Never use502512058 1591 1 
 Former use of oestrogen or progesterone15793618 4350·96(0·63–1·46)1·07(0·72–1·62)
 Current use of oestrogen and/or progesterone14393017 7611·58(1·08–2·32)1·60(1·06–2·36)
Type of menopause
 Natural623814372 9181 1 
 Surgical12483115 0951·03(0·67–1·59)0·91(0·58–1·44)

As shown in Table IV, the multivariate-adjusted RRs of VTE for current users of hormone replacement tended to be higher in those with idiopathic VTE (RR = 2·40, 95%CI, 1·40, 4·12) than secondary VTE (RR = 1·08, 95%CI, 0·63, 1·85). Women with late menopause had a 1·8-fold higher multivariate-adjusted RR of idiopathic VTE compared with normal menopause, but this did not reach statistical significance (RR = 1·85, 95% CI, 0·87, 3·94).

Table IV.   Multivariate-adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of venous thromboembolism for current users of oestrogen and/or progesterone* compared with non-users , LITE, 1987–2002.
StratumNo. of casesMultivariate-adjusted†
RR95% CI
  1. ARIC, Atherosclerosis Risk in Communities (ARIC) Study; CHS, Cardiovascular Health Study.

  2. *Adjusted for age, sex, (race), body mass index, diabetes mellitus and factor VIII.

  3. †Time dependent analysis.

ARIC1061·44(0·90–2·32)
CHS 801·86(1·01–3·46)
Whites1231·63(1·07–2·49)
Non-whites 631·25(0·53–2·97)
Idiopathic 842·40(1·40–4·12)
Secondary1021·08(0·63–1·85)

Discussions

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussions
  6. Acknowledgements
  7. References
  8. Supporting Information

Although previous hospital-based studies reported that late menopause and a history of having more than two children were associated with increased risk of VTE (Grady et al, 2000; Samama, 2000; Simon et al, 2006), the present population-based prospective study found no associations of parity or late menopause with incidence of VTE. On the other hand, women currently using hormone replacement had an increased risk of VTE, consistent with previous studies (Grodstein et al, 1996; Grady et al, 2000; Cushman et al, 2004a). Therefore, effects of oestrogen exposure on incidence of VTE differ between endogenous production and exogenous administration.

The EStrogen and THromboEmbolism Risk (ESTHER) study, in which more than 95% of subjects were whites, indicated that markers of lifetime endogenous oestrogen exposure, such as age at menopause and number of children, were positively associated with the risk of VTE (Simon et al, 2006). As in previous studies (Tsai et al, 2002a; White et al, 2005), we found that compared with whites, African Americans have a higher risk of VTE, and they tend to have earlier menopause and more children. In analysis stratified by race, there were no significant associations of age at menopause or parity with the incidence of VTE in either whites or Africans Americans. Many studies have reported that oral oestrogen use can induce an acquired activated protein C resistance and activate blood coagulation (Hoibraaten et al, 2001) (Oger et al, 2003) (Cushman et al, 2001). However, to our knowledge, the associations of late menopause and the number of children with hemostatic variables have not been reported. We previously reported that endogenous oestrogen was associated with increased levels of inflammatory markers, such as C reactive protein and white cell count in ARIC (Folsom et al, 2005), but these inflammatory markers were not associated with the risk of VTE in LITE (Tsai et al, 2002b). Therefore, further study is needed to confirm whether there is any association of markers of lifetime endogenous oestrogen exposure with the incidence of VTE, especially among African Americans.

In the present study, women currently using hormone replacement had a 1·6-fold higher risk of VTE. This RR is somewhat lower than reported by other observational studies. A recent meta-analysis of hormone replacement therapy and risk of VTE (Canonico et al, 2008), assessing seven case-control studies and one cohort study, showed that the pooled OR of current oral oestrogen use for VTE was 2·5 (95%CI, 1·9, 3·4) compared with non-users. Our confidence interval overlapped that of the meta-analysis. Differences of the duration of treatment may contribute to inter-study differences of effect (Hernán et al, 2008). In the meta-analysis, the risk of VTE was significantly higher for treatment within the first year (pooled OR, 4·0, 95%CI, 2·9, 5·7) than for treatment later (pooled OR, 2·1, 95%CI, 1·3, 3·8) (Canonico et al, 2008). In the present study, the mean duration of hormone therapy use was about 5 years at baseline, and this could attenuate an effect of hormone therapy on the risk of VTE, even though we updated information on hormone use at follow-up examinations. Further, when we excluded women with one or more years duration of hormone therapy at baseline, the associations of current hormone use with the VTE grew stronger, which also supports the above hypothesis (Hernán et al, 2008).

A strength of the present study is that the cohorts studied were typical of general US adult populations, including both African Americans and whites. Potential limitations of this study warrant consideration. First, as in most clinical studies, we ascertained only clinically recognized VTE. This depended on participants’ accurate reporting of hospitalizations and on their physicians’ diagnostic work-up of suspected VTE events. During this study period, few VTEs were probably diagnosed and treated as outpatient events, but they would not be detected. However, misclassification of the VTE outcome was probably too rare to significantly alter our findings. Second, in the present study, because of limited numbers, we did not fully investigate the impact of unopposed and opposed oestrogen therapy on VTE separately. However, as well as our findings, others suggested that there is little difference in the risk of VTE between users of oestrogen alone and oestrogen plus progestin (Canonico et al, 2008). Third, we did not analyze the association between transdermal hormone use and VTE, but transdermal hormone use does not seem to increase risk of VTE. In the meta-analysis, the risk of VTE was clearly elevated for treatment by oral oestrogen (pooled OR, 2·5, 95%CI, 1·9, 3·4) but not for treatment by transdermal oestrogen (pooled OR, 1·2, 95%CI, 0·9, 1·7) (Canonico et al, 2008). Fourth, the number of VTE events in the present study was relatively small. We therefore may have missed a modest association of late menopause with incidence of VTE (RR, 1·49, CI, 0·89, 2·58) due to low power. A larger study would be needed to verify whether such a modest association exists. Fifth, among the post-menopausal women in this study, younger women may have been more likely to have had non-natural menopause compared with older women, which may have affected the associations. However, when we excluded women aged 54 years and less from the analyzes, the associations of reproductive history and hormone replacement with the incidence of VTE were unchanged; the multivariate-adjusted RR were 1·44 (95%CI, 0·83, 2·51) for late menopause and 1·67 (95%CI, 1·08, 2·57) for current hormone use. Finally, although we analyzed the associations of hormone use with the incidence of VTE using information on hormone use updated at follow-up examinations, some participants who were not re-examined missed updating. This could have led to an underestimate of the association of current hormone use with the risk of VTE.

In conclusion, women currently using hormone replacement had a 1·6-fold higher risk of VTE than those without a history of hormone therapy use during 12 years of follow-up in this general population study. However, there were no associations of reproductive markers, such as greater parity and late menopause, with incidence of VTE.

Acknowledgements

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussions
  6. Acknowledgements
  7. References
  8. Supporting Information

This study was supported by grant R01 HL59367 (LITE), contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 (ARIC), and contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant U01 HL080295 (CHS) from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. The authors thank the staff and participants of ARIC and CHS projects for their important contributions over many years.

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  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussions
  6. Acknowledgements
  7. References
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussions
  6. Acknowledgements
  7. References
  8. Supporting Information

Table SI. Baseline characteristics among post-menopausal women who did or did not develop incident venous thromboembolism, Whites, LITE.

Table SII. Baseline characteristics among post-menopausal women who did or did not develop incident venous thromboembolism, African Americans, LITE.

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