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ORIGINAL RESEARCH |
From the Pharmacoepidemiology and Pharmacoeconomic Research Unit Research Centre, Centre Hospitalier de l’Université de Montréal-Hotel-Dieu, Montreal, Quebec, Canada.
Address reprint requests to: Jacques LeLorier, MD, PhD Centre Hospitalier de l’Universite de Montreal Hotel-Dieu, Research Centre Pharmacoepidemiology and Pharmacoeconomic Research Unit 3850, St-Urbain Street Montreal, Quebec H2W 1T8 Canada E-mail: jacques.le.lorier{at}umontreal.ca
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Abstract |
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Methods: From the Quebec health insurance database we chose a cohort of 4527 women 35 years and older who received social assistance and were new users of estrogen between January 1989 and December 1997. Incident use was defined by the absence of any dispensed prescription of estrogen in the 3 years before the index date (date of first dispensed prescription). We estimated the cumulative persistence rate of treatment by Kaplan–Meier failure time analysis and identified its determinants with the Cox proportional hazards model.
Results: From the initial cohort, 3395 women (75%) renewed their first dispensed prescription and 905 (20%) continued treatment after 4 years. The determinants measured at the index date and significantly associated with a better persistence rate (relative risk [RR]) were younger than 60 years (RR 1.15, 95% confidence interval [CI] 1.01, 1.30), low dosage (RR 1.49, 95% CI 1.32, 1.70), continuous progestin combination (RR 1.40, 95% CI 1.27, 1.54), and a gynecologist as the first prescribing physician (RR 1.15, 95% CI 1.03, 1.21). Also, coronary heart disease or at least one risk factor for it in the year before the index date was associated with a better persistence rate for estrogen replacement therapy (RR 1.15, 95% CI 1.05, 1.22).
Conclusions: The persistence rate for estrogen therapy is poor, implying that few women take it long enough to benefit from it.
Previous studies have not evaluated duration of estrogen replacement therapy (ERT) beyond 1 year, considering the need for long-term treatment (at least 4 years) to obtain benefits from ERT in terms of the prevention of coronary heart disease and osteoporosis, and taking into account the potentially serious adverse events resulting from ERT, we evaluated the duration of ERT (persistence rate) over 5 years and identified its major determinants.
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Methods |
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A random sample of 25% of all women who received social assistance and at least one dispensed prescription of estrogens between January 1989 and December 1997 was selected from the pharmaceutical file of the Régie de l’Assurance Maladie du Québec. Women receiving social assistance constitute almost 5% of the total population of women in the province of Quebec, and in 1998, 10% of the general population of this province was receiving social assistance (statistical data from the Régie de l’Assurance Maladie du Québec).
Demographic, medical, and pharmaceutical data on those women were obtained from January 1988 to December 1998. The dates of their first dispensed prescriptions of estrogens were termed the index dates. Women who were 35 years or older at their index dates and who were incidental users of estrogens were included in the study. Incidental users were defined as women without any dispensed prescriptions of estrogens at least 3 years before their index dates. Women were observed for at least 1 year after their index dates. Maximum follow-up duration was 5 years.
We defined exposure to ERT as at least one dispensed prescription of oral or transdermal estrogens. The following estrogens listed in the Régie de l’Assurance Maladie du Québec formulary were included: conjugated estrogens, esterified estrogens, estropipate, estrone, and estradiol-17ß. All estrogens were converted into equivalent dosages of conjugated estrogens, according to manufacturers’ instructions.
We interpreted outcome as failure to persist with ERT, which was defined as nonrenewal of estrogen prescriptions after a permitted exposure duration. We considered exposure to estrogens the duration of a dispensed prescription plus 15 days to allow for delays in renewal. If a woman did not renew after this duration, she was considered not persistent with ERT.
From the database we ascertained the presence of possible determinants of persistence with treatment, which we defined a priori. We measured covariates such as age, treatment combination with progestin, and prescribing physician (gynecologist or general practitioner) at the index date. Drug dosage was assessed at each dispensed prescription. A chronic disease score, which weights medications according to their indication and considered a marker of general health status,2 was calculated in the year before the index date. We also recorded heart disease or its risk factors and osteoporotic fractures (hip or wrist) in the year before the index date. Vertebral fracture was not included as a covariate because its diagnosis in this database is presumed unreliable (results from radiographs were not available). Heart disease was defined as any condition that required use of a nitrate on a regular or as-needed basis in the year preceding the index date. Coronary heart disease risk factors were defined by the use of one or more medications, in the year before the index date, that included antihypertensive, lipid-lowering, and oral hypoglycemic drugs. Osteoporotic fractures were defined by a specific surgical procedure for each type of fracture or diagnosis of the fracture by ICD-9 codes in the 3 years before the index date. Information on family history, smoking, alcohol consumption, and dietary habits was not available in this database.
To obtain a better estimate of treatment persistence rate, we censored some observations based on known absolute and relative contraindications to ERT. We censored observations of women who had venous thrombosis (diagnosed by ICD-9 codes) combined with dispensed prescriptions of an oral anticoagulant during the study. We also censored observations of women who had cerebral arterial thrombosis (ICD-9 codes and a dispensed prescription of aspirin or ticlopidine), women with breast or endometrial cancer (ICD-9 codes), and women hospitalized for at least 30 days because their medication was not recorded in the Régie de l’Assurance Maladie du Québec database during hospitalization.
We used SAS 6.11 software (SAS Institute, Cary, NC) for statistical analysis, and we estimated the cumulative treatment persistence rate by Kaplan–Meier failure time analysis in which data were censored for women at the end of observation if they were still receiving treatment, and for those who had one of the stated conditions. We also censored data for women who were lost to follow-up because they moved out of the province or were no longer receiving social assistance. We conducted multivariable analysis with the Cox proportional hazards model and estimated the relative risk (RR) with a 95% confidence interval (CI) for each covariate.3 In that model, we analyzed dosage as a time-dependent variable because it might change in time, especially for women with dose-related side effects.
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From the initial cohort, 3395 women (75%) renewed their first dispensed prescriptions of ERT, and 1947 (43%) continued their treatment beyond 1 year. Only 905 (20%) received ERT after 4 years (Figure 1). Among women who stopped estrogen therapy, 68% had other dispensed prescriptions subsequently. The mean duration between the time they were considered not persistent with ERT and the time they resumed treatment was 6 months. After resuming therapy, those women were not more persistent than those who did not resume therapy; persistence rates for the groups were similar.
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presents the results of multivariable analysis. Age younger than 60 years at the index date was associated with better persistence rate (RR 1.15, 95% CI 1.01, 1.30). We stratified those younger women into two age groups with the following results: RR of 1.30 (95% CI 0.70, 2.50) for women between 35 and 45 years old and 1.54 (95% CI 0.80, 3.01) for those between 46 and 59 years old. A dosage level less than 0.9 mg/day (RR 1.49, 95% CI 1.32, 1.70) and a gynecologist as the first prescribing physician (RR 1.15, 95% CI 1.03, 1.21) were markers of better persistence. Combination of progestins was not associated significantly with better persistence than estrogen alone (RR 1.10, 95% CI 0.90, 1.18). However, continuous combination with progestins, at the index date, was associated with better persistence than sequential combination (RR 1.40, 95% CI 1.32, 1.70). This model also demonstrated that coronary heart disease or at least one risk factor of it in the year before the index date yielded better persistence (RR 1.15, 95% CI 1.05, 1.22). There was an insufficient number of women with hip or wrist fractures to show association with ERT persistence.
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Discussion |
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Most women in our study started estrogen therapy at a mean age of 50 years, which might correspond to the onset of menopause; we suspect those women took the drugs mainly to relieve menopausal symptoms and stopped as soon as the symptoms disappeared. Women who start older constitute a population for which the preventive use of estrogen might have a major effect on the use of health resources; however, persistence in older women was lower than in younger women.
Most adverse effects considered minor but unpleasant are dose dependent; therefore, to facilitate persistence, we recommend the lowest possible starting dosage, because low dosage has been proved adequate for increasing bone density.9–11 Nonhysterectomized women need to combine progestin with estrogen to reduce the risk of endometrial cancer. Sequential combination, as opposed to continuous combination, is associated with the return of menses, which might explain the lower persistence rate with sequential combination.
In Quebec, women can see gynecologists without referral from family physicians. We observed a significantly better persistence rate when ERT was initiated by gynecologists rather than family physicians. This could be because of a difference in characteristics of women who decide to see gynecologists or are referred to them, or to the fact that gynecologists have knowledge and tools to detect major side effects and their reassurance might translate into better information on risks and benefits.
In our study, women with coronary heart disease or at least one risk factor of it tended to be slightly more persistent with treatment, suggesting that they and their physicians are more concerned and motivated.
In addition to a large sample and information on diagnosis, allowing us to account for the major side effects of ERT, this database also contains complete characterization of exposure to ERT. However, it is limited in its ability to identify symptoms, and while obtaining information on dispensed prescriptions, we had to assume that women took all of the dispensed prescriptions. Considering those limitations, our results could have overestimated the true rate of persistence. One important limitation of this study was the impossibility of identifying women who had hysterectomies. We had information on hysterectomies done during but not before the study. Progestins combined with estrogen are highly associated with the presence of the uterus, we believe it represents a good proxy for women who have had hysterectomies.
With regard to external validity, our data on social assistance recipients, a population for which medications and medical services are free, show that persistence with ERT is not related to the amount of money needed for health care. We also conducted a similar study on a population 65 years and older, independently of socioeconomic status, which yielded comparable results in global persistence with treatment.12
We believe that our results underscore the importance of evaluating drugs known to influence risk of diseases. That is especially true when a public health system is responsible for costs related to the misuse of drugs and also for the costs of treatment of conditions that have not been prevented because of low persistence.
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Footnotes |
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The authors thank Mr. Jacques Barry for providing access to the RAMQ databases and Mr. Ovid Da Silva for editing this manuscript.
Received June 1, 2000. Received in revised form September 11, 2000. Accepted September 28, 2000.
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2. Von Korff M, Wagner EH, Saunders K. A chronic disease score from automated pharmacy data. J Clin Epidemiol 1992;45:197–203.[Medline]
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10. Lindsay R, Tohme JF. Estrogen treatment of patients with established postmenopausal osteoporosis. Obstet Gynecol 1990;76:290–4.
11. Williams CL, Stancel GM. Estrogens and progestins. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, eds. The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996;1411–40.
12. Pilon D. L’estrogénotherapie de substitution: Persistance dans le traitement et implications économiques. Actval Med 2000;3:44–6.
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