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Esterified Estrogens and Conjugated Equine Estrogens and the Risk of Venous Thrombosis

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Esterified Estrogens and Conjugated Equine Estrogens and the Risk of Venous Thrombosis ORIGINAL CONTRIBUTION Esterified Estrogens and Conjugated Equine Estrogens and the Risk of Venous Thrombosis Nicholas L. Smith, PhD Context Clinical trial evidence indicates that estrogen therapy with or without pro- Susan R. Heckbert, MD, PhD gestins increases venous thrombotic risk. The findings from these trials, which used Rozenn N. Lemaitre, PhD oral conjugated equine estrogens, may not be generalizable to other estrogen com- pounds. Alex P. Reiner, MD, MPH Objective To compare risk of venous thrombosis among esterified estrogen users, Thomas Lumley, PhD conjugated equine estrogen users, and nonusers. Noel S. Weiss, MD, DrPH Design, Setting, and Participants This population-based, case-control study was Eric B. Larson, MD, MPH conducted at a large health maintenance organization in Washington State. Cases were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a Frits R. Rosendaal, MD first venous thrombosis between January 1995 and December 2001 and controls were Bruce M. Psaty, MD, PhD matched on age, hypertension status, and calendar year. LINICAL TRIAL EVIDENCE FROM Main Outcome Measure Risk of first venous thrombosis in relation to current use the Heart and Estrogen/ of esterified or conjugated equine estrogens, with or without concomitant progestin. Current use was defined as use at thrombotic event for cases and a comparable ref- progestin Replacement Study erence date for controls. (HERS) and the Women’s CHealth Initiative (WHI) indicates that es- Results Five hundred eighty-six incident venous thrombosis cases and 2268 con- trols were identified. Compared with women not currently using hormones, current trogen therapy, with or without pro- users of esterified estrogen had no increase in venous thrombotic risk (odds ratio [OR], gestins, is associated with an increased 0.92; 95% confidence interval [CI], 0.69-1.22). In contrast, women currently taking risk of venous thrombosis (VT) in post- conjugated equine estrogen had an elevated risk (OR, 1.65; 95% CI, 1.24-2.19). When menopausal women.1-3 The HERS in- analyses were restricted to estrogen users, current users of conjugated equine estro- vestigators observed a relative risk of 2.7 gen had a higher risk than current users of esterified estrogen (OR, 1.78; 95% CI, (95% confidence interval [CI], 1.4- 1.11-2.84). Among conjugated equine estrogen users, increasing daily dose was as- 5.0) for estrogen plus progestin therapy, sociated with increased risk (trend P value = .02). Among all estrogen users, concomi- and the WHI investigators observed a tant progestin use was associated with increased risk compared with use of estrogen relative risk of 2.1 (95% CI, 1.6-2.8) and alone (OR, 1.60; 95% CI, 1.13-2.26). 1.3 (95% CI, 1.0-1.8) for estrogen with Conclusion Our finding that conjugated equine estrogen but not esterified estro- and without concomitant progestin use, gen was associated with venous thrombotic risk needs to be replicated and may have respectively. Each of these trials evalu- implications for the choice of hormones in perimenopausal and postmenopausal women. ated oral conjugated equine estrogens JAMA. 2004;292:1581-1587 www.jama.com (CEEs) and medroxyprogesterone acetate. nal bleeding.6-8 Nearly all compari- pausal estrogen therapy from EE to CEE Various estrogen compounds and sons have evaluated the most com- for current and new users of hormone their modes of administration are monly used estrogens, CEE and therapy. Formulary switches such as known to differ in estrogen constitu- micronized estradiol. Esterified estro- ents, metabolism, and their affinity for gens (EEs) have received less atten- estrogen receptors.4,5 Clinical compari- Author Affiliations: Departments of Epidemiology (Drs tion. All these products, nonetheless, Smith, Heckbert, Reiner, Weiss, and Psaty), Medi- son studies of these compounds have continue to be used to treat menopause- cine (Drs Lemaitre and Psaty), Biostatistics (Dr Lum- focused mainly on mode of delivery, ley), and Health Services (Dr Psaty), University of Wash- related vasomotor symptoms in peri- and outcomes have generally been re- ington, Seattle; Center for Health Studies, Group Health menopausal and postmenopausal Cooperative, Seattle, Wash (Drs Heckbert, Larson, and stricted to the relief of menopausal Psaty); and Leiden University Medical Center, Leiden, women. symptoms and the occurrence of vagi- the Netherlands (Dr Rosendaal). In October 1999, the Group Health Corresponding Author: Nicholas L. Smith, PhD, Car- Cooperative (GHC) pharmacies diovascular Health Research Unit, 1730 Minor Ave, See also p 1573. Suite 1360, Seattle, WA 98101 ([email protected] switched the standard postmeno- .edu). ©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, October 6, 2004—Vol 292, No. 13 1581 Downloaded from www.jama.com at Penn State Milton S Hershey Med Ctr, on November 8, 2005 ESTROGENS AND RISK OF VENOUS THROMBOSIS these occur in health maintenance or- inclusion criteria as VT cases and tains records of all prescriptions filled ganization (HMO) settings when medi- had no history of DVT or PE. For con- through GHC since 1977. More than cations are thought to be therapeuti- trols, the index date was a randomly 95% of GHC members in this age group cally interchangeable.9-11 The formulary chosen date within the calendar year fill almost all prescriptions through change occurred during data collec- from which they were selected as a GHC pharmacies.14 Pharmacy data con- tion for a case-control study of cardio- control. tain detailed information that in- vascular outcomes that included VT, Women with VT were identified from cludes GHC member identification which presented us with the opportu- inpatient and outpatient care settings. number, drug name, date the prescrip- nity to examine the association of oral In the inpatient setting, International tion was filled, medication strength, EE and CEE with VT risk in perimeno- Classification of Diseases, Ninth Revi- quantity of medication prescribed, and pausal and postmenopausal women. sion codes were abstracted from GHC dosing instructions or the number of hospitalization records, which in- days the supply of medication would METHODS cluded hospital stays at GHC and non- last. Setting and Design GHC facilities. In the outpatient set- Oral estrogen was classified into 3 The setting for this observational study ting, GHC pharmacy records were used subgroups: (1) CEE, such as Premarin; was GHC, a large HMO in western to identify women who were dis- (2) EE, such as Estratab and Menest; and Washington State. Health care deliv- pensed a prescription for a low- (3) other estrogens, primarily micron- ery and medication prescribing at GHC molecular-weight heparin for nonhos- ized estradiol, which accounted for less are based primarily on GHC treat- pitalized DVT treatment. Additionally, than 1% of all estrogen prescriptions dur- ment guidelines. This case-control women were identified from 3 GHC ing the 7 years of the study.The proges- study of VT was part of a larger, ongo- clinics where a pharmacy-based out- tin prescribed was almost exclusively ing, population-based, case-control patient treatment protocol for DVT was medroxyprogesterone acetate and was study of VT, myocardial infarction, and implemented in 1997. dispensed as a separate pill from estro- stroke and shares with it a single con- Trained medical record abstractors gen for virtually all subjects. trol group.12,13 The study was ap- reviewed the medical records of all po- A woman was considered a current proved by the GHC Human Subjects tential cases to verify the diagnosis of user of a hormone if she received Review Committee, and informed con- VT and to determine how the diagno- enough medication with her last pre- sent was obtained from individuals who sis was made. Events were classified as scription to last until her index date ac- could be contacted and waived by the study eligible if they were diagnosed by cording to an assumption of 80% com- committee for those who could not be an imaging modality (Doppler or du- pliance. An 80% compliance adjustment contacted. plex ultrasound, computed tomogra- was made by increasing the number of phy, pulmonary angiography, or ven- days that a prescription would last by Study Population tilation-perfusion scan) or by physician 25%. We excluded women for whom Study participants were perimeno- judgment in the presence of symp- there was no record of a GHC phar- pausal and postmenopausal female toms or according to treatment strate- macy prescription being filled in the 5 GHC members aged 30 to 89 years. gies. Ninety-two percent of the eli- years before the index date (n=39), Cases were all GHC members who ex- gible cases had positive diagnostic women using progestin without estro- perienced a first deep VT (DVT) or pul- imaging test results. gen at the index date (n=38), and monary embolism (PE) diagnosed be- Menopausal status at the index date women who were current users of tween January 1, 1995, and December was defined by the cessation of ovarian creams or patches and not using estro- 31, 2001, the most recent year of com- function that occurred naturally or gen pills (n=54). plete and cleaned data in this ongoing through a bilateral oophorectomy for Daily oral estrogen dose was calcu- study. The date of the VT served as an cases and controls and was based on in- lated from computerized pharmacy data index date before which information on formation collected from the GHC medi- by using pill strength and dosing in- hormone use and other exposures was cal record. A woman was considered structions or number of supply days. ascertained. Controls were a random perimenopausal at the onset of meno- For estrogens other than CEE and EE, sample of GHC members who com- pausal symptoms. If menopausal sta- estrogen dose was based on CEE prised a pool of individuals shared by tus was not explicitly stated in the rec- equivalents.15 Recency of therapy ini- several case-control studies.
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