William D. Finkle

Increased Risk of Endometrial Carcinoma among Users of Conjugated Estrogens

The possibility that the use of conjugated estrogens increases the risk of endometrial carcinoma was investigated in patients and a twofold age-matched control series from the same population. Conjugated estrogens (principally sodium estrone sulfate) use was recorded for 57 per cent of 94 patients with endometrial carcinoma, and for 15 per cent of controls. The corresponding point estimate of the (instantaneous) risk ratio was 7.6 with a one-sided 95 per cent lower confidence limit of 4.7. The risk-ratio estimate increased with duration of exposure: from 5.6 for 1 to 4.9 years exposure to 13.9 for seven or more years. The estimated proportion of cases related to conjugated estrogens, the etiologic fraction, was 50 per cent with a one-sided 95 per cent lower confidence limit of 41 per cent. These data suggest that conjugated estrogens have an etiologic role in endometrial carcinoma.

Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men

Background An association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly. Methods We conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation. Results In all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged ≥75 years (ptrend = 0.03), while no trend was seen for PDE5I (ptrend = 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11). Discussion In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.

Estrogen and endometrial carcinoma. An independent pathology review supporting original risk estimate.

Initial evidence suggested that estrogen therapy increases the risk of endometrial carcinoma. It was then suggested that some studies may have exaggerated the hazard of estrogen therapy by including patients with atypical endometrial hyperplasia among those having endometrial carcinoma. Three internationally recognized pathologists reviewed the histology slides available from the Ziel and Finkle study, which originally reported a risk ratio of 7.6 for estrogen users. At least one of the pathologists concurred with the original diagnosis in all but one case. Furthermore, all pathologists aggreed that 74 per cent (66/89) were correctly diagnosed. In the 66 patients with unanimous diagnosis, 61 per cent (40/66) had used conjugated estrogens, versus 57 per cent (54/94) in the original study. On the basis of 66 patients and 132 matched controls, the revised risk-ratio estimate is 8.1 (with a one-sided 95 per cent lower confidence limit of 4.5), validating the original estimate.

Risk of Fractures Requiring Hospitalization After an Initial Prescription for Zolpidem, Alprazolam, Lorazepam, or Diazepam in Older Adults

To determine whether zolpidem is a safer alternative to benzodiazepines.

Increased Risk of Serious Injury Following an Initial Prescription for Diphenhydramine

BACKGROUND Diphenhydramine may be associated with excess risk of injury relative to nonsedating H1-receptor antagonists. OBJECTIVE This study sought to compare the risk of injury in patients exposed to diphenhydramine with the risk of injury in patients exposed to loratadine. METHODS A retrospective cohort study of injury was carried out in 12,106 patients whose initial antihistamine prescription was for diphenhydramine and in 24,968 patients whose initial antihistamine prescription was for loratadine. Data were taken from a health care claims database that included employees, dependents, and retirees who filed claims from January 1991 through December 1998. Rates of six serious injuries in the diphenhydramine cohort after and before the first prescription were compared with rates in the loratadine cohort after and before the first prescription. RESULTS In the 30 days after the first antihistamine prescription, the rate of all injuries was 308 per 1,000 person-years in the diphenhydramine cohort versus 137 per 1,000 person-years in the loratadine cohort. The rate ratio estimate adjusted for age and gender using Poisson regression was 2.27 (95% confidence limits [CL] 1.93, 2.66). In the corresponding 30 days of the preceding year, the injury rates in the diphenhydramine and loratadine cohorts were 128 and 125 per 1,000 person-years, and the adjusted rate ratio was 1.02 (CL 0.83, 1.26). Thus, the cohorts appeared to have similar preprescription injury rates. The differences between the cohorts declined with time from prescription: For all injuries, the estimated percentage decline in the rate ratio was 4.1% per day (CL 3.3, 4.9), and the estimated time from the initial prescription until the diphenhydramine cohort returned to baseline risk was 32.3 days (CL 26.9, 37.6). CONCLUSIONS If these associations are causal, the percentage of the injuries attributable to diphenhydramine was 55% (CL 41, 65), implying a substantial number of excess injuries and costs incurred as the result of diphenhydramine use. The high use rates of this drug and the high incidence of injury suggest that further study of the association between injury and type of antihistamine is needed.

A Retrospective Cohort Study of Implanted Medical Devices and Selected Chronic Diseases in Medicare Claims Data

PURPOSE Several case-control studies have observed associations of implanted medical devices and certain connective-tissue and neurologic diseases. We reexamined these and other associations using cohort comparisons. METHODS We compared the incidence of 52 diseases in several retrospective cohorts constructed from Medicare claims data. Six cohorts were defined by implantation of medical devices (silicone, metal bone or joint implants, breast implants, penile implants, pacemakers, artificial heart valves), and four comparison cohorts were defined by surgeries not involving implants. RESULTS We observed associations that were generally consistent with previous reports, including associations of bone and joint implants with connective-tissue diseases, and an association of penile implants with idiopathic progressive neuropathy. We also observed associations of breast implants and pacemakers with connective-tissue diseases. CONCLUSIONS For the most part, our study confirms our previous case-control results. Although confounding by presurgical conditions (such as diabetes) remains a plausible explanation of the findings, several associations are worthy of more detailed research.

A case-control study of prosthetic implants and selected chronic diseases

We examined the association between prosthetic nonbreast implants and selected malignant neoplasms, connective tissue disorders, and neurologic diseases. We conducted a case-control study from an insurance claims database. We selected controls who had diseases for which no association with implants have been claimed or reported. Data were analyzed using both tabular and polytomous regression analysis methods, including methods to account for the large number of comparisons. All analyses exhibited positive associations between implants (both silicone and metal) and neurologic conditions, especially idiopathic progressive neuropathy and Meniere syndrome, as well as the expected associations with arthritic conditions. There also was an unexpected negative association between metal implants and brain tumors. In conclusion, further studies of prosthetic implants and neurologic diseases appear warranted. These studies should obtain medical histories to control for possible confounding effects of drug treatments associated with implant surgery.

Endometrial cancer risk after discontinuing use of unopposed conjugated estrogens (California, United States).

To examine the decline in risk of endometrial cancer after discontinuation of use of conjugated estrogens, we conducted a case-control study in a prepaid health plan. We identified 318 patients who had endometrial cancer but had no history of bilateral oophorectomy and had been in the Southern California (United States) Kaiser Foundation Health Plan for more than 10 years. For each patient, one or two control members were selected, 599 in all, matched for age and duration of membership at the time of cancer detection and who had had neither hysterectomy nor bilateral oophorectomy. A history of prescriptions for conjugated estrogens and of potential confounders was obtained for each subject by reviewing outpatient medical records. Rate ratios (RR) contrasting users with nonusers were estimated by time of latest prescription. We found that estrogen-induced risk of endometrial cancer decreases rapidly as the estrogen-free interval increases. The RR estimates, adjusted for duration of use and potential confounding factors, declined from 5.0 for those receiving their latest prescription within 24 months (95 percent confidence limits [CL]=2.6–9.8), to 1.8 for those receiving their latest prescription within 24 to 48 months (CL=0.9–3.7), to values near one for each latest prescription interval earlier than 48 months ago (P for trend = 0.0004). For those who used conjugated estrogens extensively (five or more prescriptions, five to 10 years ago), the RR estimate declined from 5.1 for those whose latest prescription was within two years to 0.6 yr for those whose latest prescription was four to five years previously (P for trend = 0.05).

A Case-Control Study of Prosthetic Implants and Selected Chronic Diseases in Medicare Claims Data

PURPOSE In an exploratory case-control study of a private insurance-claims database, Greenland and Finkle (Ann Epidemiol. 1996;6:530-540) observed associations of certain prosthetic nonbreast implants with certain connective-tissue and neurologic conditions. We wished to test these associations using the same design with new data. METHODS We examined these associations in a case-control analysis of Medicare claims data. To control for possible confounding effects of surgery, our analysis examined nonimplant surgeries of severity similar to implant surgeries. RESULTS We again found associations of silicone and metal implants with connective-tissue and neurologic conditions, but we also found similar associations of carpal-tunnel surgery with those conditions. CONCLUSIONS Possible explanations for these findings include confounding by presurgical conditions. Therefore, we recommend further studies be done in which such conditions can be measured and controlled.