2015 Volume 79 Issue 5 Pages 1107-1114
Background: The incidence of venous thromboembolism (VTE) in Asians is lower than in Caucasians, but the risk of VTE associated with hormone therapy (HT) in Taiwanese postmenopausal women has not been determined.
Methods and Results: From Taiwan’s National Health Insurance Research Database, we established matched cohorts (HT users and nonusers) of postmenopausal women aged ≥50 years between 1 January 1998 and 31 December 2008. We calculated the 2-year incidence of VTE in HT users and nonusers. HT users and nonusers were matched 1:1 based on propensity-score matching. Cox regression hazard model was used to identify risk factors of VTE. We initially identified 499,594 HT users and 424,963 nonusers. There were higher percentages of cancer and cardiovascular events among the HT nonusers. After matching, the VTE incidence was 4.4 vs. 2.6 per 10,000 patient-years (adjusted hazard ratio 1.796, 95% confidence interval 1.272–2.537) in HT users and nonusers, respectively. The Cox regression hazard model showed that HT use, older age, malignancy, heart failure, and recent major surgery were independent risk factors for VTE.
Conclusions: Although the incidence of VTE was very low among this cohort of Taiwanese postmenopausal women, oral HT was still associated with an increased risk of VTE. Therefore, physicians should be aware of other potential VTE risk factors when prescribing oral HT to postmenopausal women. (Circ J 2015; 79: 1107–1114)
Hormone therapy (HT) can improve quality of life for women with hypo-estrogenic symptoms1 and is also effective for preventing osteoporotic fractures among current users.2,3 In contrast, harmful effects of HT include breast cancer and venous thromboembolism (VTE).4 Furthermore, randomized controlled trials showed that HT might increase the risk of coronary artery disease and stroke.2,5 Many women are still prescribed estrogen therapy to ameliorate postmenopausal symptoms despite recent data showing that overall health risks may exceed the benefits of long-term HT.2
Despite evidence showing that oral estrogen activates blood coagulation in postmenopausal women,6 HT had, until 1996, long been believed to have little effect on the risk of VTE.7 Recent observational studies, however, have shown consistent associations between current use of HT and an increased risk of VTE in postmenopausal women. These findings have been confirmed in randomized controlled trials.2,5 Since the publication of the Women’s Health Initiative (WHI) results,2 the medical practice of HT has been dramatically altered.8 Although a striking decrease in HT use has been noted, many women remain eligible for this treatment to correct postmenopausal climacteric symptoms and to prevent osteoporosis. Cardiovascular disease, including VTE, is an important determinant of the benefit-to-risk profile of HT.9 Both observational studies10–13 and clinical trials2,14 have shown a significant increase in VTE risk among postmenopausal women using HT. However, most of these studies have been conducted in Caucasian women, so the results are not essentially generalizable to other races. According to Japan’s guidelines for management and prevention of VTE, estrogen therapy is a weak risk factor of VTE, and there is no recommendation for HT in postmenopausal women.15 Nakamura et al reported that estrogen or/and HT did not contribute to a higher risk of VTE recurrence, but their sample size was too small to make a definitive conclusion.16 In our previous studies, the overall crude incidence of VTE was 14.4 events per 100,000 person-years in men and 17.4 events per 100,000 person-years in women, which was much lower (71–117 cases per 100,000 persons) than in Western countries.17,18 For women, the overall VTE recurrence rate was 10.1% vs. 11.4% (P=0.41) among HT users and nonusers, respectively. Meanwhile, there was no significant difference in the prevalence of HT use (including estrogen and/or progesterone) between VTE recurrent cases and VTE non-recurrent controls. Therefore, the VTE risk of HT in postmenopausal women in Taiwan needs to be determined.
We retrospectively performed a nationwide population-based matched cohort study to evaluate HT and the risk of VTE during a 2-year follow-up of Taiwanese postmenopausal women. The study was approved by the Institutional Review Board of National Cheng Kung University Hospital, Tainan, Taiwan.
Source of DataThe National Health Insurance (NHI) databases used in this study included all inpatient and outpatient medical claims from January 1, 1997 to December 31, 2008. In these databases, medical information of disease diagnosis, prescription drugs, procedures, and surgery incurred during a hospitalization or at an outpatient visit are documented. For administration processing by the NHI in Taiwan, all healthcare service providers are requested to submit all diagnosis information using the International Classification of Disease-Clinical Modification, 9th revision (ICD-9-CM), together with the service claims.
Study PopulationOur 2 study cohorts consisted of randomly selected women who were between 50 and 79 years old during the study period from year 2000 through 2008 and (1) had a prescription for HT or medical service for a postmenopausal condition (ICD-9: 627.xx) or (2) had neither prescription for HT nor medical service for a postmenopausal condition. We excluded all subjects with a diagnosis of VTE prior to the enrollment, who were ever prescribed HT in the previous 3 years, or who had a history of undergoing a hysterectomy. In addition, women without any visit and medical records after age 50 or who had a follow-up duration less than 90 days were also excluded. We used a propensity-score method to match the selected cohort populations to overcome initial selection bias for HT users and nonusers (Figure 1). The selected variables in the propensity-score method included age and potential VTE confounding factors. Graphs of before and after propensity-score matching are shown in Figure S1 and S2, respectively.
Flow chart of participants’ disposition. HT, hormone therapy; VTE, venous thromboembolism.
HT users were defined as women having any HT prescriptions during the study period, and the first HT prescription date was the index date. A list of all medications containing estrogens and/or progestogens recommended for HT and available in Taiwan during the study period was extracted from the database. In Taiwan, there were no pharmaceutical products for transdermal HT, tibolone, or estradiol implant during the study years. For HT nonusers, the index date was the date of the first medical visit during 2000–2008.
Outcome Definition and Follow-upThe primary endpoints were a principal or secondary admission diagnosis of VTE, which included DVT or PE. All incident cases of VTE occurring during the study period were identified from the claims database by the ICD9-CM codes of 451.1x, 451.2, 451.83, 453.1, 453.2, 453.4, 453.8, 453.9, and 415.1x. To avoid misdiagnoses, we only selected inpatients who met the following criteria: (1) a discharge diagnosis of DVT or PE; (2) received a course of subcutaneous or intravenous anticoagulation therapy with unfractionated heparin or surgical thrombectomy during hospitalization and continued oral warfarin therapy after discharge; and (3) hospitalization of at least 3 days, unless the patient died. We also identified outpatients with VTE who met the following criteria: (1) principle diagnosis of DVT or thrombophlebitis; and (2) received a course of subcutaneous anticoagulation therapy with low-molecular-weight heparin and continued oral warfarin therapy.
We followed the cohort population until the date of the first study endpoint (VTE), death, or 2 years, whichever occurred first.
Potential Confounding VariablesWe considered other medications (systemic steroids, NSAIDs, statins, antiplatelet agents, anticoagulant drugs, selective serotonin reuptake inhibitors) and variables believed to affect the risk of VTE (age, sex, hypertension, heart failure, cancer, varicose veins, diabetes mellitus, extremity fractures, myocardial infarction, ischemic and hemorrhagic cerebrovascular events, chronic lung diseases, liver diseases, renal diseases) as potential confounders. The comorbidities predisposing patients to VTE were recorded using ICD-9-CM codes (Table S2). The medications before or within 90 days of the index date were recorded, and other variables were measured for 1 year prior to the index date.
Statistical AnalysisDemographic data are expressed as mean (± SD) or percentage. In general, differences in proportions were tested with the chi-square test or Fisher’s exact test, and differences in location parameters of continuous variables were tested with Student’s t-test. We calculated the incidence rates of VTE per 10,000 person-years for the HT users and nonusers.
Intent-to-treat analysis was used to evaluate the association between HT and risk of VTE; once a patient met the definition for exposure to HT, she was considered exposed from that point forward, even if she discontinued therapy. Time-to-event curves for each cohort were calculated by the Kaplan-Meier method and compared by means of log-rank test. The estimates of relative risk, with 95% confidence intervals (CIs), were derived from Cox proportional-hazard models, adjusted for potential confounders including medications and comorbidities.
We conducted several sensitivity analyses to test the robustness of our findings. First, we performed an “as-treated” analysis to test the HT-user effect. We followed HT nonusers for 2 years and followed HT users who only used HT for less than 90 days. Second, we conducted a nested case-control study within unmatched cohorts. Cases were defined as admission for VTE during 2000–2008, using the admission date as the index date. For each case, we randomly selected up to 20 controls among the cohort members in the risk sets defined by the case. Each control was matched with a case using age (±2 years) and the year of start in the practice (±2 years). Controls had to be alive and free of VTE on the event date of their corresponding case. The event date of the case was assigned to the matched controls and defined their index date. Individuals were considered current users if they had an HT prescription in the 1-year period and it continued until at least 1 month before the index date. Recent users were defined as having at least 1 prescription issued in the year before the index date, but the last prescription was more than 30 days and less than 91 days before the index date. Remote users were defined as having at least 1 prescription issued in the year before the index date, but the last prescription was more than 90 days before the index date. Nonusers were those who have not received any prescription for HT in the year preceding the index date. We estimated adjusted rate ratios (RR) with 95% CIs for the association between HT use and VTE using conditional logistic regression. All computations were performed using SAS software version 9.1.3 (SAS Institute Inc, Cary, NC, USA).
The study population consisted of 1,588,318 postmenopausal women who had at least 3 years of medical records before enrollment. Within this population, we excluded women with previous histories of VTE, HT use, or surgical hysterectomy before they were 50 years old. From 2000 to 2008, prescriptions for HT in postmenopausal women were significantly decreasing from 123,314 women in 2000 to 28,290 women in 2008. Initially, we identified 499,594 HT users and 424,963 HT nonusers in the cohorts (Figure 1). The baseline clinical characteristics of each cohort are presented in Table S1. The percentage of patients with menopausal-related symptoms was 90.6% among the HT users and 6.1% among the HT nonusers. We found higher percentages of comorbid diseases, including cancer, diabetes, coronary artery disease, heart failure, and old cerebrovascular events, in the non-HT cohort than in the HT cohort. The cumulative incidence rates of VTE before matching are displayed in Figure 2. The incidence rate of VTE was 6.7 per 10,000 patient-years for HT users and 6.2 per 10,000 patient-years for the nonusers [adjusted hazard ratio (HR): 0.997 (0.88–1.13)]. Therefore, we used the propensity-score method to create another set of HT (n=179,351) and non-HT (n=179,351) cohorts (Table 1). The cumulative incidence rates of VTE after matching are displayed in Figure 3. The incidence rate of VTE was 4.4 per 10,000 patient-years for HT users and 2.6 per 10,000 patient-years for nonusers [adjusted HR 95% CI: 1.796 (1.272–2.537)]. During the follow-up, the incidence rate of breast cancer was 40.9 per 10,000 patient-years for HT users and 52.0 per 10,000 patient-years for nonusers; the respective incidence rates were 12.9 and 7.2 per 10,000 patient-years for uterine cancer, and 128.6 and 107.0 per 10,000 patient-years for acute coronary syndrome.
Kaplan-Meier estimates of VTE-free survival distribution before propensity-score matching. The incidence rate of VTE was 6.7 per 10,000 patient-years for HT users and 6.2 per 10,000 patient-years for nonusers [adjusted hazard ratio: 0.997 (0.88–1.13)]. HT, hormone therapy; VTE, venous thromboembolism.
| HT users (n=179,351) |
Non-HT users (n=179,351) |
P value | |
|---|---|---|---|
| Mean age, years±SD | 60.7±8.1 | 59.5±7.6 | <0.0001 |
| Cancer | 4,791 (2.7) | 4,613 (2.6) | 0.7638 |
| Coronary artery disease | 14,740 (8.2) | 16,350 (9.1) | <0.0001 |
| Congestive heart failure | 3,066 (1.7) | 2,999 (1.7) | 0.3856 |
| Old stroke* | 4,470 (2.5) | 4,047 (2.3) | <0.0001 |
| Varicose veins | 459 (0.3) | 533 (0.3) | 0.0186 |
| Hypertension | 41,696 (23.3) | 43,298 (24.1) | <0.0001 |
| Diabetes mellitus | 20,602 (11.5) | 21,700 (12.1) | <0.0001 |
| Chronic lung disease | 16,865 (9.4) | 18,979 (10.6) | <0.0001 |
| Renal disease | 5,625 (3.1) | 6,198 (3.5) | <0.0001 |
| Major surgery in previous 90 days | |||
| Neurologic surgery | 195 (0.1) | 183 (0.1) | 0.0001 |
| Thoracic surgery | 2,008 (1.1) | 2,148 (1.2) | 0.0289 |
| Abdominal surgery | 2,131 (1.2) | 2,389 (1.3) | 0.0001 |
| Urogenital surgery | 506 (0.3) | 677 (0.4) | <0.0001 |
| Orthopedic surgery | 244 (0.1) | 230 (0.1) | 0.5199 |
| Medication history in previous 180 days | |||
| Warfarin | 682 (0.4) | 753 (0.4) | <0.0001 |
| Antiplatelet agent | 32,680 (18.2) | 36,258 (20.2) | <0.0001 |
| Statin | 7,650 (4.3) | 8,475 (4.7) | <0.0001 |
| Systemic steroids | 34,180 (19.1) | 39,830 (22.2) | <0.0001 |
| Oral hypoglycemic agent | 15,188 (8.5) | 15,361 (8.6) | 0.3007 |
| Insulin | 1,832 (1.0) | 1,767 (1.0) | 0.2762 |
| PPI | 1,286 (0.7) | 1,558 (0.9) | <0.0001 |
| SSRI | 1,225 (0.7) | 1,421 (0.8) | 0.0001 |
| NSAID | 93,668 (52.2) | 103,589 (57.8) | <0.0001 |
Data are presented as number (percentage). *Stroke includes ischemic and hemorrhagic stroke. HT, hormone therapy; NSAID, nonsteroidal antiinflammatory drug; PPI, proton-pump inhibitor; SSRI, selective serotonin reuptake inhibitor.
Kaplan-Meier estimates of VTE-free survival distribution after propensity-score matching. The incidence rate of VTE was 4.4 per 10,000 patient-years for HT users and 2.6 per 10,000 patient-years for nonusers [adjusted hazard ratio 95% confidence interval: 1.796 (1.272–2.537)]. HT, hormone therapy; VTE, venous thromboembolism.
In the matched cohorts, Cox regression hazard model analysis demonstrated that older age, cancer, heart failure, and undergoing major abdominal surgery were independent risk factors for developing VTE (Table 2). HT use [adjusted HR 95% CI: 1.796 (1.272–2.537)] was an independent risk factor for developing VTE after propensity-score matching.
| Variable | Adjusted HR (95% CI) |
|---|---|
| HT | 1.796 (1.272–2.537) |
| Diabetes mellitus | 1.657 (0.589–4.664) |
| Age | 1.010 (1.009–1.011) |
| Cancer | 1.518 (1.285–1.794) |
| Coronary artery disease | 1.543 (0.775–3.073) |
| Old stroke | 4.020 (0.870–18.570) |
| Heart failure | 1.256 (1.120–1.407) |
| Chronic lung disease | 1.299 (0.651–2.593) |
| Hypertension | 0.573 (0.296–1.109) |
| Kidney disease | 2.623 (0.935–7.361) |
| Varicose veins | 2.779 (0.219–35.243) |
| Major surgery in previous 90 days | |
| Neurologic surgery | 1.521 (0.780–2.968) |
| Thoracic surgery | 1.007 (0.808–1.255) |
| Abdominal surgery | 1.277 (1.025–1.592) |
| Urogenital surgery | 1.132 (0.701–1.828) |
| Orthopedic surgery | 1.145 (0.606–2.162) |
CI, confidence interval; HR, hazard ratio; VTE, venous thromboembolism. Other abbreviation as in Table 1.
Treatment analysis also presented HT use as a potential risk factor for VTE (adjusted HR 1.97; 95% CI, 1.36–2.80). Several baseline characteristics and potential risk factors for VTE were compared between the controls and cases (Table 3). The risk of VTE was increased with current use of oral HT (adjusted odds ratio (OR) 2.39; 95% CI: 1.98–2.88) relative to nonusers. Similarly, the risk increased with recent use of oral HT (OR 1.58; 95% CI: 1.21–2.04). However, there was no significant risk with remote use of oral HT (OR 1.19; 95% CI: 0.99–1.43). We showed that VTE risk was extremely increased with a history of cancer, varicose veins, heart failure, or undergoing major surgery (Table 4). Besides, the risk was increased with current use of oral progestogens (OR 4.68; 95% CI: 2.02–10.81) and oral estrogen–progestogen combination (OR 3.01; 95% CI: 2.40–3.79) (Table 5).
| Cases (n=3,833) |
Controls (n=76,660) |
P value | |
|---|---|---|---|
| Mean age, years±SD | 65.1±8.4 | 65.1±8.4 | 1.0000 |
| Cancer | 1,026 (24.8) | 14,517 (17.5) | <0.0001 |
| Old myocardial infarction | 834 (20.1) | 9,522 (11.5) | <0.0001 |
| Congestive heart failure | 1,097 (28.6) | 13,847 (18.1) | <0.0001 |
| Old stroke* | 765 (20.0) | 15,806 (20.6) | 0.32 |
| Extremity fracture | 482 (11.6) | 6,500 (7.9) | <0.0001 |
| Varicose veins | 207 (5.4) | 601 (0.8) | <0.0001 |
| Hypertension | 2,811 (73.3) | 49,529 (64.6) | <0.0001 |
| Diabetes mellitus | 1,515 (39.5) | 43,059 (56.2) | <0.0001 |
| Chronic lung disease | 1,583 (41.3) | 24,692 (32.2) | <0.0001 |
| Liver disease | 812 (19.6) | 13,011 (15.7) | <0.0001 |
| Renal disease | 942 (24.6) | 17,687 (23.1) | 0.03 |
| Hyperlipidemia | 1,212 (29.3) | 14,770 (17.8) | <0.0001 |
| Osteoarthritis of extremities | 2,095 (50.6) | 25,582 (30.9) | <0.0001 |
| Depression | 106 (2.6) | 1,425 (1.7) | <0.0001 |
| Major surgery in previous 90 days | |||
| Neurologic surgery | 98 (2.6) | 670 (0.9) | <0.0001 |
| Thoracic surgery | 618 (16.1) | 4,930 (6.4) | <0.0001 |
| Abdominal surgery | 593 (15.5) | 5,235 (6.8) | <0.0001 |
| Urogenital surgery | 128 (3.3) | 958 (1.3) | <0.0001 |
| Orthopedic surgery | 231 (6.0) | 356 (0.46) | <0.0001 |
| Medication history in previous 180 days | |||
| ACEI/ARB | 1,692 (40.9) | 21,605 (26.1) | <0.0001 |
| α-blocker | 160 (4.2) | 3,237 (4.2) | 0.88 |
| β-blocker | 1,699 (44.3) | 26,040 (34.0) | <0.0001 |
| Calcium-channel blocker | 1,657 (43.2) | 29,934 (39.1) | <0.0001 |
| Antiplatelet agent | 2,252 (58.8) | 34,660 (45.2) | <0.0001 |
| Statin | 681 (17.8) | 14,237 (18.6) | 0.21 |
| Systemic steroids | 1,853 (48.3) | 23,898 (31.2) | <0.0001 |
| Oral hypoglycemic agent | 895 (23.4) | 37,691 (49.2) | <0.0001 |
| Insulin | 343 (9.0) | 10,064 (13.1) | <0.0001 |
| PPI | 335 (8.7) | 5,233 (6.8) | <0.0001 |
| SSRI | 166 (4.3) | 2,430 (3.2) | <0.0001 |
| NSAID | 3,283 (85.7) | 51,689 (67.4) | <0.0001 |
Data are presented as number (percentage). *Stroke includes ischemic and hemorrhagic stroke. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker. Other abbreviations as in Table 1.
| HT exposure | Adjusted OR (95% CI) |
|---|---|
| No use | 1.000 (reference) |
| HT use | |
| Current (≤30 days) | 2.39 (1.98–2.88) |
| Recent (31–90 days) | 1.58 (1.21–2.04) |
| Remote (>90 days) | 1.19 (0.99–1.43) |
| Ischemic heart disease | 1.210 (1.103–1.328) |
| Old stroke | 0.950 (0.841–1.073) |
| Varicose veins | 5.661 (4.663–6.872) |
| Heart failure | 1.276 (1.159–1.405) |
| Hypertension | 1.027 (0.922–1.145) |
| Diabetes mellitus | 0.955 (0.860–1.061) |
| Chronic lung diseases | 1.002 (0.926–1.084) |
| Cancer | |
| CNS | 1.064 (0.745–1.520) |
| Respiratory tract | 1.073 (0.902–1.277) |
| Gastrointestinal tract | 1.534 (1.316–1.789) |
| Genitourinary tract | 1.325 (1.136–1.545) |
| Lymphoma & leukemia | 0.981 (0.738–1.303) |
| Major surgery in previous 90 days | |
| Neurologic surgery | 1.532 (1.174–1.999) |
| Thoracic surgery | 2.278 (2.031–2.554) |
| Abdominal surgery | 2.096 (1.869–2.351) |
| Urogenital surgery | 1.493 (1.194–1.867) |
| Orthopedic surgery | 9.481 (7.729–11.631) |
Together with the matching of age and enrollment year, potential confounders included in the analyses are: history of varicose veins, diagnosed cancer in the year before the index date, hypertension, chronic lung disease, renal insufficiency, cardiovascular and cerebrovascular diseases, and major surgery in the 3 months prior to the index date. CNS, central nervous system; OR, odds ratios. Other abbreviations as in Tables 1,2.
| Cases | Controls | Crude OR (95% CI) |
Adjusted OR (95% CI) |
|
|---|---|---|---|---|
| HT nonusers | 3,322 | 69,988 | Reference | Reference |
| Current HT users | 217 | 1,998 | 3.04 (2.58–3.58) | 2.39 (1.98–2.88) |
| Estrogen only | 33 | 551 | 1.45 (0.98–2.15) | 1.29 (0.84–1.98) |
| Progestogen only | 13 | 76 | 5.38 (2.71–10.69) | 4.68 (2.02–10.81) |
| Combination | 171 | 1,371 | 3.72 (3.06–4.53) | 3.01 (2.40–3.79) |
Abbreviations as in Tables 1,2,4.
The VTE incidence among healthy postmenopausal women is 16–22 cases per 10,000 women per year.2,19 Data from epidemiologic and randomized controlled studies consistently demonstrates an increased risk of VTE events in postmenopausal women who use oral HT.2,7,14,19 In the HERS trial, VTE was not confined to the first year of oral HT use, but the increased risk declined from approximately 4-fold in the first year to less than 2-fold after the third year of use.20 The WHI studies confirmed the magnitude and timing of the VTE risk estimates from previous studies.2,19 In the WHI study, there were 34 and 16 VTE events per 10,000 woman-years in the oral HT and placebo groups, respectively. However, only rarely have Asian studies reported on the risk of VTE in postmenopausal women who use oral HT. One questionnaire study regarding the incidence of VTE during oral HT in Japanese women estimated that the crude incidence of VTE was 1.7–3.4 per 10,000 woman-years.21 Our nationwide study showed that the incidence of VTE among postmenopausal women was 4.4 per 10,000 patient-years for HT users and 2.6 per 10,000 patient-years for nonusers, which is much lower than in Caucasian populations. We considered that the low incidence of VTE in this specific population could be explained by the low incidence of VTE in the general population in Taiwan and other Asian countries.17,22–24
In 2012, the Cochrane Collaboration reported a comprehensive review of long-term HT for postmenopausal women.25 Even in relatively healthy postmenopausal women, combined continuous HT carried a significant risk of coronary event, VTE, stroke, breast cancer, gall bladder disease, or death from lung cancer, whereas estrogen-only HT significantly increased the risk of VTE. However, we found in our study that both progestogen-only and estrogen-progestogen combination HT contributed to a higher risk of VTE in postmenopausal women. Our cohort study showed that the use of oral HT increased the risk of VTE 1.796-fold. When we calculated the risk of VTE by nested case-control analysis, the greatest increased risk of VTE was observed in current users of oral HT, but declined for recent and remote users. During the 2.4 years of follow-up after discontinuation of oral estrogen-progestogen combination HT in the WHI trial, the increased risk of VTE disappeared (HR 0.95, 95% CI: 0.63–1.44).26 A further decline in the risk of VT was found in the follow-up of the estrogen-only HT cohort in the WHI trial (HR 0.63, 95% CI: 0.41–0.98).27 Because the available evidence for postmenopausal HT does not support a cardiovascular benefit, HT should not be prescribed for the prevention of cardiovascular disease, and short-term prescription for relieving menopausal symptoms should be the main indication.
Recent statements from the International Menopause Society and the British Menopause Society also recommend that lower doses should be used, preferably with a transdermal route of administration, if HT is to be prescribed for women over 60 years of age with postmenopausal syndrome.28,29 VTE risk is further increased in those with a personal or family history of VTE, advanced age, obesity, and other risk factors such as surgery or hospitalization.28,29 In our study, the independent risk factors for VTE in postmenopausal women included use of oral HT and coexisting cardiovascular diseases such as old myocardial infarction, old stroke, heart failure, and varicose veins. Older age and undergoing major surgery also contributed to a higher risk of VTE, which was consistent with previous studies.
Our findings have several clinical implications for Asian populations. Although our previous studies showed that the overall incidence of VTE in Taiwan is lower than that in Western countries, the use of oral HT in postmenopausal women increases the risk of VTE. Therefore, physicians should be cautious when prescribing oral HT to postmenopausal women with other potential VTE risk factors. We also observed that the risk of VTE in current users seemed to be higher than that in recent and remote users, which suggests that women should take oral HT for the shortest time possible.
Study LimitationsFirst, the healthcare claims data did not contain the body mass index or smoking status. Previous studies disclosed that obesity possibly contributes to VTE risk among postmenopausal women. Because information on body mass index for all patients was unavailable, we could not adjust the analysis in this respect; however, we assumed that an obesity differential bias would be absent in the population-level comparison in this study. Second, because transdermal HT was not available in Taiwan, we could not evaluate whether the effect of transdermal HT on VTE would be different from that of oral HT. Third, we did not take into account that some women might seek traditional or alternative medical treatment for menopausal-related symptoms because information on over-the-counter herbal products or nutritional supplements for menopausal symptoms was unavailable.
Although the incidence of VTE is low in the general Taiwanese population, including postmenopausal women, oral HT is significantly associated with an increased risk of VTE in postmenopausal women. Therefore, Taiwanese postmenopausal women should take oral HT for as short a time as possible if indicated and physicians should be cautious when prescribing oral HT to women with other potential VTE risk factors.
Grants: This study was funded by the Ministry of Science and Technology, Taiwan (NSC-100-2629-B-006-001) and National Cheng Kung University Hospital, Taiwan (NCKUH-10001005). The funding organizations did not have a role in the design, conduct, or analysis of this study.
Supplementary File 1
Table S1. Overall clinical characteristics of the Taiwanese postmenopausal women from 2000 to 2008 before propensity-score matching
Table S2. World Health Organization ICD-9-CM used in current analysis
Figure S1. Propensity-score distribution of hormone therapy users and nonusers before matching.
Figure S2. Propensity-score distribution of hormone therapy users and nonusers after matching.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-14-1227
