Abstract
Context
Little is known about the comparative cardiovascular safety of oral hormone therapy (HT) products, which impedes women from making informed safety decisions about HT treatment of menopausal symptoms.
Objective
To compare the relative clinical cardiovascular safety of 2 commonly used oral estrogen drugs, conjugated equine estrogens (CEE) and estradiol (E2).
Design
Population-based, case-control study from 2003 to 2009 comparing cardiovascular event risk associated with current CEE and E2 use.
Setting
Large health maintenance organization where the preferred formulary estrogen changed from CEE to E2 during the course of data collection.
Participants
384 postmenopausal women 30-79 years of age using oral HT.
Intervention
None.
Outcomes
Incident venous thrombosis (VT) was the primary clinical outcome and incident myocardial infarction (MI) and ischemic stroke were secondary outcomes. As validation, an intermediate clotting phenotype, endogenous thrombin potential-based normalized activated protein C sensitivity ratio (nAPCsr), was measured in plasma of controls.
Results
We studied 68 VT, 67 MI, and 48 stroke cases, and 201 matched controls; all were current users of oral CEE or E2. In adjusted analyses, compared with current oral E2 use, current oral CEE use was associated with an increased VT risk (OR: 2.08; 95% CI: 1.02-4.27; p-value 0.045), an increased MI risk that did not reach statistical significance (OR: 1.87; 95% CI: 0.91-3.84; p=0.086), and was not associated with stroke risk (OR: 1.13; 95% CI: 0.55-2.31; p=0.736). Among controls (n=140), compared with E2 users, CEE users had higher nAPCsrs (p=0.0002), indicating a stronger clotting propensity.
Conclusions
In an observational study of oral HT users, CEE use was associated with a higher risk of incident VT and possibly MI than E2 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.
The therapeutic effectiveness of oral estrogens to treat menopausal symptoms is well established and is similar for the most commonly used estrogen products of conjugated equine estrogens (CEE) and estradiol (E2).1, 2 Little is known, however, about the relative safety of these oral hormone therapy (HT) products on cardiovascular events.
In a population-based, case-control study among postmenopausal women using oral HT, we tested the hypothesis that oral CEE is more prothrombotic than oral E2. Extrapolating findings from previous research on CEE risk, we hypothesized that current use of oral CEE would be associated with a greater risk of a first VT than current E2 use.3, 4 Further, we evaluated risk for a first myocardial infarction (MI) and first ischemic stroke and hypothesized associations in the same direction as VT. To provide biologic validity to our hypotheses, we measured differences in biologic thrombotic propensity among controls using CEE or E2.5, 6
Methods
Setting
The setting is the Heart and Vascular Health (HVH) Study, a case-control study of incident cardiovascular events (CV) and frequency-matched controls in men and women 30-79 years of age who are members of Group Health Cooperative (GHC), a large health-maintenance organization in Washington State.3, 7-10 Cases include MI, stroke, VT, and atrial fibrillation events and an index date was the date of their incident event or the date of death for out-of-hospital fatal events. Case identification began in January 1989 and complete data through December 2009 were available for this analysis. The control group was frequency matched 3:1 to the largest case group (MI) by sex, age within decade, treated hypertension status, and calendar-year of identification. Their index date was a randomly chosen date within the calendar year from which they were selected as a control.
Subjects
For this comparative safety study of estrogen type, we restricted participants to postmenopausal women using oral HT from January 2003 forward since HT use changed dramatically in the GHC population after the June 2002 publication of the first Women's Health Initiative (WHI) trial results.11, 12
Cases
Case subjects experienced an incident VT (deep vein thrombosis [DVT] or pulmonary embolism), MI, or ischemic stroke event and had no history of a prior VT, MI, or stroke events. All were using oral CEE or E2 at the time of their event and were not using anti-coagulants. Venous thrombosis, MI, and ischemic stroke events were identified using hospital discharge diagnosis International Classification of Diseases, Ninth Revision (ICD-9) codes from GHC and non-GHC facilities. In addition, VT events were identified using ICD-9 codes assigned at urgent care clinic visits, and GHC pharmacy records were reviewed to identify women who were dispensed a prescription for a low molecular-weight heparin for outpatient DVT treatment.
Trained abstractors reviewed the medical records of all potential cases to verify the diagnosis of VT, MI, or ischemic stroke and to determine how the diagnosis was made. Events criteria were adapted from the Leiden Thrombophilia Study (LETS) for VT and from the Cardiovascular Health Study (CHS) for MI and stroke.13-15 Venous thrombosis events were classified as study eligible if they were diagnosed by an imaging modality, if the event was a fatal PE based on ICD-9/10 diagnostic information, or if diagnosed by a physician based on the presence of symptoms in the absence of imaging. Ninety-three percent of eligible VT cases had positive diagnostic imaging test results. For MI, verification was based on symptoms, electrocardiogram findings, cardiac enzyme levels, and physician diagnosis and treatment. For ischemic stroke, verification required the rapid onset of a neurologic deficit that persisted at least 24 hours or evidence of infarction on brain imaging studies, which was present in 98% of the cases.7, 9
Controls
Control subjects included in this analysis were postmenopausal and had no prior history of VT, MI, or stroke; all were using oral CEE or E2 at the time of their index date and were not using anti-coagulants.
Measures
Hormone Therapy Use
Use of HT was ascertained from GHC computerized pharmacy database. More than 95% of GHC members in the age range of our subjects fill all or almost all (90-100%) of their prescriptions through GHC pharmacies.16 The detailed pharmacy data include GHC member identification number, drug name, date the prescription was filled, medication strength, quantity of medication prescribed, and dosing instructions or the number of days the supply of medication was intended to last.
The GHC formulary contains preferred agents within each drug class. From January 2003 through January 2005, the preferred estrogen was oral CEE. In February 2005, to save on drug costs, GHC changed the preferred agent to oral E2; it has remained the preferred agent. Switching estrogens was encouraged by GHC but women were allowed to remain on the more expensive, non-preferred drug if they chose but would require an additional co-payment. In this study, 87% of women were using the preferred estrogen at their index date. Other oral estrogens, such as esterified estrogen and transdermal estrogens, were rarely used during 2003-2009 and women using them were excluded from the analysis.
A woman was considered a current user of oral HT if she received enough medication with her last prescription before the index date to last until her index date given at least 80% compliance with treatment. Daily oral estrogen dose was calculated from computerized pharmacy data using pill strength and dosing instructions or days’ supply. Recency of HT initiation was defined as the number of days between the index date and the date of the first prescription fill for oral HT. Concomitant use of a progestogen was calculated similarly using an 80% compliance adjustment. Among progestogen users, 96% were using MPA.
Covariates
Demographic and health status information was obtained by review of the entire GHC ambulatory medical record up to the index date. The number of GHC visits in the year before the index date was recorded as well as birth date, height, weight, and race. Menopausal status at the index date was based on information collected from the GHC medical record for cases and controls. A woman was considered postmenopausal if she had experienced the onset of menopausal symptoms or a cessation of ovarian function that occurred naturally or through a bilateral oophorectomy. If not explicitly stated in the record, postmenopausal status was assigned to women at the age of 55 years and older. We collected information on risk factors for venous and arterial thrombotic events including information on smoking, general health, hypertension, diabetes, cholesterol, history of cardiovascular conditions and procedures, cancer (all cancers except non-melanoma skin cancers), and hospitalizations or inpatient surgeries in the last 30 days. Additional data were collected from surviving subjects who were invited to participate in a telephone interview. Missing data were uncommon, and no more than 5% of the data for any variable was imputed using multiple imputation.
Phlebotomy
Subjects who participated in the interview were invited to donate a venous blood sample. The first 4.5 mL of blood was collected into a tube of 3.2% sodium citrate. Samples were centrifuged at 4°C for 10 min at 1300·g and stored at −70°C.
Laboratory measures
Thrombotic potential was assessed using the endogenous thrombin potential (ETP)-based normalized activated protein C (APC) sensitivity ratio (nAPCsr), which quantifies resistance to APC and has been shown to be a strong predictor of VT in the setting of estrogen treatment.5, 17 Citrated plasma collected from control subjects between were shipped on dry ice from Seattle, Washington, USA, to Leiden University Medical Center (LUMC), Leiden, The Netherlands, for analysis. Plasma, which was thawded once, was used to measure ETP-based APC resistance directly using a fluorogenic assay (Thrombinoscope TM, Synapse BV, Maastricht, the Netherlands), which measures thrombin generation. The ETP was calculated from the area under the thrombin generation curve and the nAPCsr was the normalized ratio of the amount of thrombin generated in the absence of APC and the quantity generated in the presence of APC.18 Higher values for ETP-nACPsr indicate a more prothrombotic profile.
Analysis
Association of estrogen type with clinical thrombosis
Multiple logistic regression was used to assess the association of the type of currently used estrogen and occurrence of VT, MI, and ischemic stroke, separately. Adjustment variables included design and a priori potential confounding variables. For VT analyses, we included age, treated hypertension status, race (white versus other), body mass index (BMI; weight [kg]/height [m]2), cancer history (cancer diagnosed within 5 years before and 3 months after index), number of GHC visits in the year before the index date, current statin use, treated diabetes, prevalent CV disease (history of MI, stroke, angina, cardiovascular or carotid revascularization, claudication, or peripheral vascular disease), current smoking status, current progestogen use, and estrogen daily dose (using categories of low [CEE <0.625 mg; E2 <1.0 mg] and modal/high [CEE ≥0.625 mg; E2 ≥1.0 mg]). For MI and ischemic stroke analyses, we added total cholesterol and systolic blood pressure variables and removed the cancer variable. To take advantage of the quasi experiment provided by the formulary change in the standard estrogen preparation, we included the log sampling ratio for the reference year as an offset in the logistic model rather than using regression adjustment for reference year; this provided odds ratio (OR) estimates for the marginal association between case status and estrogen formulation standardized to the reference-year distribution of cases. Results are presented throughout as estimated ORs with corresponding 95% confidence intervals (CIs), calculated using robust standard errors.
Stratified analyses fit separate models in subgroups according to progestogen use, estrogen dose (low versus modal/high), recency of HT initiation (<3 years versus ≥3 years), and age (<60 years versus ≥60 years), and tested differences in the ORs across strata using multiplicative models. Sensitivity analyses of the primary findings were conducted assuming 100% compliance with hormone therapy instead of 80% and restricting analyses to include only those using the preferred agent on the GHC formulary at their index date.
Association of CEE and E2 use with thrombotic propensity
We assessed the thrombotic potential of the 2 types of estrogen drugs. Among a subset of controls who agreed to phlebotomy (n=140), we compared levels of log-transformed nAPCsr between CEE and E2 users using multiple linear regression with robust standard errors, and adjusting for potential confounders. Current hormone type and dose was based on use at phlebotomy; adjustment variable information was obtained at the index date. The differences in hemostatic measure levels are reported as a CEE:E2 ratio of the adjusted geometric means. Secondary analyses paralleled those used with the clinical outcomes, as described above.
Results
From January 2003 through December 2009, there were 68, 67, and 48 postmenopausal women who experienced an incident VT, MI, or ischemic stroke event, respectively, and 201 controls, all of whom were current users of oral CEE or E2. The participants were mostly white, with an average age ranging from 63 to 68 years (Table 1). Case subjects were more likely than control subjects to have arterial and venous thrombosis risk factors. Among controls (Table 2), those using oral E2 had a slightly larger risk-factor burden than those using CEE, but there was no major difference in age, BMI, self-reported health status, or recency of the HT initiation.
Table 1.
Characteristics of case and control subjects
| Case Event Type | ||||
|---|---|---|---|---|
| Characteristic | Control N=201 | MI N=67 | Stroke N=48 | VT N=68 |
| Age, y (SD) | 65.0 (8.8) | 63.4 (9.2) | 67.6 (8.5) | 63.2 (9.9) |
| White†, n (%) | 182 (90.6) | 58 (86.6) | 40 (83.3) | 63 (92.7) |
| GHC visits in previous year, n (SD) | 5.6 (4.7) | 6.7 (5.7) | 7.9 (6.7) | 12.0 (8.5) |
| Self-reported health excellent or very good†, n (%) | 73 (36.3) | 12 (17.9) | 12 (25.0) | 16 (23.5) |
| BMI, kg/m2 (SD) | 28.2 (5.3) | 29.4 (7.2) | 28.4 (5.8) | 29.8 (7.7) |
| Current smoking, n (%) | 9 (4.5) | 22 (32.8) | 6 (12.5) | 7 (10.3) |
| CVD, n (%) | 12 (6.0) | 8 (11.9) | 5 (10.4) | 5 (7.4) |
| Treated diabetes, n (%) | 4 (2.0) | 12 (17.9) | 6 (12.5) | 8 (11.8) |
| Treated hypertension, n (%) | 112 (55.7) | 42 (62.7) | 30 (62.5) | 32 (47.1) |
| Systolic blood pressure, mmHg (SD) | 132 (18.6) | 135 (20.7) | 142 (25.2) | 129 (17.1) |
| Diastolic blood pressure, mmHg (SD) | 76 (10.2) | 76 (12.2) | 79 (11.5) | 76 (11.0) |
| Total cholesterol, mg/dL (SD) | 219 (39.4) | 224 (49.9) | 231 (41.0) | 216 (40.1) |
| Current statin use, n (%) | 26 (12.9) | 14 (20.9) | 10 (20.8) | 10 (14.7) |
| Diagnosis of cancer within 5 years†, n (%) | 4 (2.0) | 0 (0) | 2 (4.2) | 16 (23.5) |
| Recent hospitalization or surgery, n (%) | 0 (0) | 0 (0) | 0 (0) | 16 (23.5) |
| Hysterectomy, n (%) | 136 (67.7) | 35 (52.2) | 34 (70.8) | 45 (66.2) |
| Oral estrogen | ||||
| Estradiol, n (%) | 114 (56.7) | 29 (43.3) | 23 (47.9) | 29 (42.7) |
| Conjugated equine, n (%) | 87 (43.3) | 38 (56.7) | 25 (52.1) | 39 (57.4) |
| Oral estrogen daily dose* | ||||
| Low, n (%) | 57 (28.4) | 18 (26.9) | 8 (16.7) | 16 (23.5) |
| Modal, n (%) | 125 (62.2) | 38 (56.7) | 31 (64.6) | 41 (60.3) |
| High, n (%) | 19 (9.5) | 11 (16.4) | 9 (18.8) | 11 (16.2) |
| Recency of starting HT | ||||
| ≤ 3 years, n (%) | 27 (13.4) | 10 (14.9) | 3 (6.3) | 15 (22.1) |
| > 3 years, n (%) | 174 (86.6) | 57 (85.1) | 45 (93.8) | 53 (77.9) |
| Current progestogen use, n (%) | 56 (27.9) | 26 (38.8) | 11 (22.9) | 21 (30.9) |
| Progestogen dose** | ||||
| Low and modal, n (%) | 37 (66.1) | 18 (69.2) | 8 (72.7) | 15 (71.4) |
| High, n (%) | 19 (33.9) | 8 (30.8) | 3 (27.3) | 6 (28.6) |
BMI = body mass index; CVD = cardiovascular disease defined as a history of angina, CABG, angioplasty, carotid endarterectomy, claudication or peripheral vascular bypass; GHC = Group Health Cooperative; HT = hormone therapy
Results missing for some individuals: Race missing for 12 individuals (3.1%); self-reported health excellent or very good missing for 108 individuals (28.1%); and diagnosis of cancer within 5 years missing for 2 individuals (0.5%).
For CEE daily dose, low is <0.625 mg, modal is 0.625 mg, and high is >0.625 mg; for E2, <1.0 mg, 1.0 mg, and >1.0 mg
For progestogen users only. Low and modal doses for medroxyprogesterone were ≤2.5 mg; for micronized progestin were <50 ug; and for norethindrone were <0.25 mg.
Table 2.
Characteristics of controls by type of estrogen used
| Estrogen Type | ||
|---|---|---|
| Characteristic | Estradiol N=114 | Conjugated Equine N=87 |
| Age, y (SD) | 65.0 (9.1) | 65.1 (8.5) |
| White, n (%) | 101 (88.6) | 81 (93.1) |
| GHC visits in previous year, n (SD) | 5.9 (4.8) | 5.1 (4.5) |
| Self-reported health excellent/very good†, n(%) | 40 (35.1) | 33 (37.9) |
| BMI, kg/m2 (SD) | 28.1 (5.6) | 28.4 (5.0) |
| Current smoking, n (%) | 5 (4.4) | 4 (4.6) |
| CVD, n (%) | 10 (8.8) | 2 (2.3) |
| Treated diabetes, n (%) | 3 (2.6) | 1 (1.2) |
| Treated hypertension, n (%) | 71 (62.3) | 41 (47.1) |
| Systolic blood pressure, mmHg (SD) | 131 (18.9) | 133 (18.3) |
| Diastolic blood pressure, mmHg (SD) | 75 (10.6) | 77 (9.6) |
| Total cholesterol, mg/dL (SD) | 217 (42.0) | 220 (36.0) |
| Current statin use, n (%) | 18 (15.8) | 8 (9.2) |
| Cancer within 5 years†, n (%) | 3 (2.6) | 1 (1.2) |
| Recent hospitalization or surgery, n (%) | 0 (0) | 0 (0) |
| Hysterectomized, n (%) | 74 (64.9) | 62 (71.3) |
| Oral estrogen dose* | ||
| Low, n (%) | 36 (31.6) | 21 (24.1) |
| Modal, n (%) | 68 (59.7) | 57 (65.5) |
| High, n (%) | 10 (8.8) | 9 (10.3) |
| Recency of starting HT | ||
| ≤ 3 years, n (%) | 19 (16.7) | 8 (9.2) |
| > 3 years, n (%) | 95 (83.3) | 79 (90.8) |
| Current progestogen use, n (%) | 33 (29.0) | 23 (26.4) |
| Progestogen dose** | ||
| Low and modal, n (%) | 22 (66.7) | 15 (65.2) |
| High, n (%) | 11 (33.3) | 8 (34.8) |
BMI = body mass index; CVD = cardiovascular disease defined as a history of angina, CABG, angioplasty, carotid endarterectomy, claudication or peripheral vascular bypass; GHC = Group Health Cooperative; HT = hormone therapy
Results missing for some individuals: self-reported health excellent or very good missing for 40 individuals (19.9%); and diagnosis of cancer within 5 years missing for 1 individual (0.5%).
For CEE, <0.625 mg, 0.625, and >0.625 mg; for E2, <1.0 mg, 1.0 mg, >1.0 mg
For progestogen users only. Low and modal doses for medroxyprogesterone were ≤2.5 mg; for micronized progestin were <50 ug; and for norethindrone were <0.25 mg.
In analyses adjusting for design and potential confounding variables (Table 3), we observed a greater risk of VT associated with current oral CEE use than with current oral E2 use: OR: 2.08; 95% CI: 1.02-4.27; p-value 0.045. For the outcome of MI, current oral CEE use was also associated with an increase in MI risk, although less clearly: OR: 1.87; 95% CI: 0.91-3.84; p=0.086. No increased risk was observed for ischemic stroke: OR: 1.13; 95% CI: 0.55-2.31; p=0.736.
Table 3.
Risk of venous thrombosis, myocardial infarction, and ischemic stroke associated with current oral CEE use compared with current oral E2 use
| Event type | E2 use Case/Control | CEE use Case/Control | Reference (E2 use) | Adjusted Odds Ratio for CEE use (95% CI), p-value |
|---|---|---|---|---|
| Venous thrombosis | 29/114 | 39/87 | 1.00 | 2.08* (1.02-4.27), p=0.045 |
| Myocardial infarction | 29/114 | 38/87 | 1.00 | 1.87** (0.91-3.84), p=0.086 |
| Ischemic stroke | 23/114 | 25/87 | 1.00 | 1.13** (0.55-2.31), p=0.736 |
Adjusted for age, treated hypertension status, race, body mass index, cancer history, number of GHC visits in the year before the index date, current statin use, treated diabetes, prevalent cardiovascular disease, current smoking status, current progestogen use, and estrogen daily dose.
Adjusted for age, treated hypertension status, race, body mass index, number of GHC visits in the year before the index date, current statin use, treated diabetes, prevalent cardiovascular disease, systolic blood pressure, total cholesterol, current smoking status, current progestogen use, and estrogen daily dose.
Secondary and sensitivity analyses
When the population was stratified by concomitant progestogen use, estrogen dose, recency of initiation, and age, we found no statistical evidence of interaction (all p-values for interaction >0.09; see Supplemental Figures S1, S2, and S3). In subset sensitivity analyses that assumed 100% compliance with HT use and that restricted use to those using the preferred estrogen, relative risk estimates were reduced with wide confidence intervals.
Relative APC Resistance
The median ETP-based nAPCsr level was 1.96 (interquartile range [IQR] 1.40-2.78) among control women using oral E2 (n=94) and was 2.68 (IQR 2.17-7.18) among control women using oral CEE (n=46). The geometric mean nAPCsr level among CEE users was 68% greater than that of E2 users: CEE:E2 ratio = 1.68 (95% CI: 1.24-2.28; p=0.0002) after adjusting for age, race, BMI, cancer, treated diabetes, current smoking, self-reported health, factor V Leiden variant, smoking, current stain use, estrogen dose, and progestogen use. In stratified analyses, there was not strong statistical evidence of differences by subgroup (see Supplemental Figure S4).
Discussion
In this contemporary observational study of women using HT, we found that current oral CEE use was associated with a greater risk of an incident VT than current oral E2 use. We also found that among controls, women using oral CEE had a greater resistance to APC than women using oral E2, providing biologic support for the increased risk seen in the case-control analysis. For arterial endpoints, MI relative-risk estimates were similar to estimates for VT but did not reach statistical significance. For ischemic stroke, however, our data did not suggest relative-risk differences by estrogen type. Although no statistical differences were observed in subgroups, the relative-risks of VT and MI were only slightly elevated for low-dose CEE compared with low-dose E2 users. For VT, there was also a suggestion that relative risks were elevated for those using progestogen and recent starters compared with non-progestogen users and longer-term users, respectively, findings that parallel those of WHI, which compared CEE with placebo.11, 19
Comparative Safety of Hormone Therapies and Cardiovascular Risk
Cardiovascular risk associated with HT has been widely discussed, especially as it concerns timing of HT initiation relative to menopause, but far less attention has been directed toward the comparative safety of these products in women who initiate therapy to treat the vasomotor symptoms of menopause.20 To our knowledge, no trial is under way that includes clinical cardiovascular endpoints. Among the published observational studies of HT that include clinical cardiovascular endpoints, data are limited and have focused primarily on the route of HT delivery, comparing oral with transdermal formulations.21-27 We previously described the comparative safety of oral esterified estrogen compared with oral CEE and found that compared with oral esterified estrogen, oral CEE was associated with an increased risk of VT and possibly MI and ischemic stroke; findings were validated in controls, where oral CEE users had greater resistance to APC than oral esterified estrogen users.3, 4, 28 Further, recent publications suggest that estrogen and progestogen drug type may be differentially associated with cardiovascular event risk although primary analyses compared HT use with non-use.26, 27
In this study, we provided information on the relative cardiovascular safety of 2 commonly used oral estrogens but do not provide information on absolute risks or risks relative to women not using HT. Women who seek HT for menopausal symptom treatment are different from those who do not, and accounting for these differences in observational studies has been problematic.29
Limitations and Strengths
In this observational comparative-safety study, the type of estrogen a woman received was not determined by randomization but rather by when the woman received estrogen. This quasi-experimental design, where differences in treatment approaches are largely system-wide and not related to patient-specific factors, overcomes some biases associated with non-random treatment allocation. That our study compares only HT users—a requirement for a comparative safety study of HT approaches—provides additional strengths since we avoid issues of confounding by indication since all women were using HT.
Our case-control design captured users of oral HT at time of sampling, regardless of their duration of HT use, and does not address the potential for selection bias due to differential initiation or discontinuation of therapy. Our risk estimates are therefore in relation to active use of oral HT and do not directly address the relative risk of initiating HT. Our subgroup analyses, however, suggest that we were able to capture to some extent VT risk differences by time since HT initiation. Given that our study design was more likely to capture initiators of E2 than CEE, CEE initiators were under-represented in our study and a potential bias may have been to underestimate CEE risk relative to E2. Further, residual confounding could be present if factors associated with changes in HT use and CV diagnosis throughout the study period were not fully adjusted for. A new-user study design among women initiating HT who are followed for future thrombotic events would provide such information.
Other strengths of the study include the population-based design, the use of GHC pharmacy data to capture detailed HT exposure prior to index date, the verification of thrombotic outcome events, and the use of both biologic and clinical phenotypes to assess thrombotic risk associations.
Biologic Rationale
Pharmaceutical estrogens are molecularly distinct. Conjugated equine estrogens are manufactured from the urine of pregnant mares and contains 10 known biologically active estrogen compounds as well as others that have yet to be described.30, 31 Its primary compounds are estrone and equilin sulfate.31, 32 Estradiol is a “natural” or “bioequivalent” estrogen, containing only synthetic 17 β-estradiol. How estrogenic compounds modulate thrombotic risk remains poorly understood and our data suggest that risk potential may vary by the type or amount of estrogen-derived molecules within various marketed estrogens.3, 4, 28, 32
Clinical Significance
The findings of this comparative-safety investigation need replication. If confirmed, the results would provide valuable information to women and their healthcare professionals when making safety decisions regarding available HT options for menopausal symptom management. The number of avoidable venous and possibly cardiac thrombotic events may be lowered by selecting lower-risk medications.
Summary
In an observational study of HT use, we found that women using oral CEE were at an increased risk of incident VT compared with women using oral E2. This finding was supported by biologic data on APC resistance. Our data also suggested an increase in the risk of MI but not ischemic stroke for CEE compared with E2 use. These findings need replication but suggest that oral estrogen drugs have different levels of cardiovascular risk.
Supplementary Material
Acknowledgements and Funding Sources
The lead author (NLS) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. For all authors, there are no potential conflicts of interest including relevant financial interests, activities, and relationships. Dr. Psaty serves on a data safety and monitoring board for a clinical trial of a device funded by Zoll LifeCor and on a steering committee for the Yale Open Data Access Project funded by Meditronic, Inc.
The Heart and Vascular Health study is supported by the National Health Lung and Blood Institute grants HL43201, HL60739, HL68986, HL73410, HL74745, HL85251, and HL95080. The funding organization had no role in the present study or analysis. Marc Blondon is a recipient of a fellowship for prospective researcher from the Swiss National Science Foundation.
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