Peptic ulcer and gastrointestinal hemorrhage associated with nonsteroidal anti-inflammatory drug use in patients younger than 65 years. A large health maintenance organization cohort study.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an elevated risk of peptic ulcer and upper gastrointestinal hemorrhage, but published reports have lacked information on rates of outpatient disease, have concentrated on the elderly, and have not provided comparisons of rates for specific types of NSAIDs. METHODS: We compared incidence rates of peptic ulcer and upper gastrointestinal hemorrhage in 68 028 people younger than 65 years who used diclofenac sodium, naproxen, piroxicam, or sulindac, and who were members of a network of health maintenance organizations. We reviewed automated insurance claims data and medical records to ascertain cases and included conditions treated on an outpatient basis. RESULTS: Medical claims data were adequate for crude identification of potential cases, but review of medical records led to rejection of 63% of these, representing either no abnormality or diseases other than peptic ulcer or upper gastrointestinal hemorrhage. Of the total 112 cases, 64 (57%) were treated as outpatients. The crude incidence rate per 1000 person-years in users of any current, recent, or past NSAID was 2.2 and in distant-past users of NSAIDs was 0.75. For diclofenac, naproxen, piroxicam, and sulindac, we found a consistent pattern of decreasing NSAID effects from current to recent to past exposure. The risk of peptic ulcer or upper gastrointestinal hemorrhage was 1.6 cases per 1000 people using NSAIDs. CONCLUSIONS: Combining use of automated claims records with review of medical records promotes efficiency while maintaining specificity of case ascertainment. This study, with 57% of cases treated as outpatients, had results consistent with other published reports that were based on hospitalized patients. Within the limits of statistical error, the incidence rates of peptic ulcer and upper gastrointestinal hemorrhage appeared to be similar for the various NSAIDs studied.

The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada.

PURPOSE: Serious, although rare, ventricular arrhythmias and deaths have been reported in patients taking cisapride monohydrate. Without quantification of the risk involved, it is impossible to develop rational therapeutic guidelines. SUBJECTS AND METHODS: Arrhythmic events (sudden deaths and other events compatible with serious ventricular arrhythmias) were sought among 36,743 patients prescribed cisapride in the United Kingdom and Saskatchewan, Canada. Prescriptions and cases were identified from computerized medical claims data and physicians' office records. We compared rates of events between periods of recent cisapride use and nonrecent use, using cohort analysis. Potential confounding factors, including concomitant treatment with agents that inhibit CYP3A4 metabolism or that prolong the QT interval, were assessed in a nested case-control study. RESULTS: In the cohort analysis, the incidence of the arrhythmic events was 1.6 times greater (95% confidence interval [CI]: 0.9 to 2.9) in periods of recent use. With adjustment for clinical history, use of CYP3A4 inhibitors, and use of drugs that prolong the QT interval, the odds ratio for cisapride and cardiac outcomes was 1.0 (95% CI: 0.3 to 3.7). There was no identifiable increase in risk when cisapride was dispensed at about the same time as QT-prolonging drugs or CYP3A4 inhibitors. QT-prolonging agents were associated with a 2.5-fold increase in the risk of arrhythmic events (95% CI: 1.1 to 5.8). CONCLUSIONS: Serious rhythm disorders were not associated with cisapride use, although the upper confidence bounds do not rule out an increase in risk.

Kidney cancer and hydrocarbon exposures among petroleum refinery workers.

To evaluate the hypothesis of increased kidney cancer risk after exposure to hydrocarbons, especially those present in gasoline, we conducted a case-control study in a cohort of approximately 100,000 male refinery workers from five petroleum companies. A review of 18,323 death certificates identified 102 kidney cancer cases, to each of whom four controls were matched by refinery location and decade of birth. Work histories, containing an average of 15.7 job assignments per subject, were found for 98% of the cases and 94% of the controls. To each job, industrial hygienists assigned semiquantitative ratings for the intensity and frequency of exposures to three hydrocarbon categories: nonaromatic liquid gasoline distillates, aromatic hydrocarbons, and the more volatile hydrocarbons. Ratings of "present" or "absent" were assigned for seven additional exposures: higher boiling hydrocarbons, polynuclear aromatic hydrocarbons, asbestos, chlorinated solvents, ionizing radiation, and lead. Each exposure had either no association or a weak association with kidney cancer. For the hydrocarbon category of principal a priori interest, the nonaromatic liquid gasoline distillates, the estimated relative risk (RR) for any exposure above refinery background was 1.0 (95% confidence interval [CI] 0.5-1.9). Analyses of cumulative exposures and of exposures in varying time periods before kidney cancer occurrence also produced null or near-null results. In an analysis of the longest job held by each subject (average duration 9.2 years or 40% of the refinery work history), three groups appeared to be at increased risk: laborers (RR = 1.9, 95% CI 1.0-3.9); workers in receipt, storage, and movements (RR = 2.5, 95% CI 0.9-6.6); and unit cleaners (RR = 2.3, 95% CI 0.5-9.9).

A cost density analysis of benign prostatic hyperplasia.

We assessed the frequency and cost of care for benign prostatic hyperplasia (BPH) among approximately 165,000 subscribers to Fallon Community Health Plan (FCHP), a group model health maintenance organization located in central Massachusetts. We computed rates of episodes of medical services for BPH using automated utilization files, and we estimated costs using Medicare reimbursement schedules and medication average wholesale prices. We identified 3919 men who visited a physician for BPH from January 1, 1991, until December 31, 1994, during which time they contributed 8336 person-years to the analysis. This population comprises approximately 12% of men at least 40 years old at FCHP. From 1991 to 1994, 696 (18%) men received terazosin, 219 (6%) men underwent a prostatectomy, and 41 (1%) men received finasteride. Men averaged 1.66 office visits per year to a physician for BPH. Most office visits (61%) were to a primary care physician, with 39% of the visits to a urologist. Among patients who received terazosin, the frequency of office visits increased slightly after receiving terazosin, from 2.14 to 2.62 visits per year. Among surgery patients, the frequency of visits declined after prostatectomy, from 6.31 visits per year to 1.67 visits. The individual annual cost rate for BPH care ranged from $25.00 to $25,352.00, with an average of $364.00 per person and a median cost of $126.00. The major components of the overall costs were hospital admissions (35%), terazosin dispensings (29%), and physician office visits (19%), with outpatient hospital care and ambulatory procedures accounting for the remaining 17%. Among men receiving terazosin, the average cost was $1190.00 per person-year, and among patients undergoing prostatectomy, the cost was $2630.00 per person-year. The prostatectomy rate declined by nearly 80% during the study period, while the dispensing rate for terazosin doubled, resulting in an overall decline in the total cost of care for BPH from 1991 to 1994.

Lymphatic and haematopoietic cancer mortality in a population attending school adjacent to styrene-butadiene facilities, 1963-1993.

STUDY OBJECTIVE: To evaluate the risk of mortality from lymphatic and haematopoietic cancers and other causes among students. DESIGN: The study used school records, yearbooks, and Texas Department of Health records for the school years 1963-64 to 1992-93 to construct a cohort of 15,403 students. Three mortality databases were searched to identify deaths, and mortality rates in the cohort were compared with mortality rates from the United States and Texas. Computed standardised mortality ratios and 95% confidence intervals were used. SETTING: Eastern Texas high school adjacent to facilities that have been producing synthetic styrene-butadiene since 1943. MAIN RESULTS: 338 deaths were identified. The all causes standardised mortality ratio was 0.84 (95% confidence intervals 0.74, 0.95) for men and 0.89 (0.73, 1.09) for women. The standardised mortality ratio for all lymphatic and haematopoietic cancers was 1.64 (95% confidence intervals 0.85, 2.87) for men and 0.47 (0.06, 1.70) for women. The slight male excess in lymphatic and haematopoietic cancers was stronger among men who attended school for two years or less. CONCLUSIONS: The overall mortality from lymphatic and haematopoietic cancer among the students was little different from that of the United States as a whole. A moderate excess for men, predominantly among the shorter-term students, was offset by a deficit among women. These variations are compatible with random fluctuations; the overall pattern is not indicative of an effect of environmental exposure sustained while attending the high school.

Characterisation of asthma management in the Fallon Community Health Plan from 1988 to 1991.

In order to characterise asthma management in a managed care setting, we identified 10,301 patients who were diagnosed with asthma between 1 January 1988 and 31 December 1991 at a group model health maintenance organisation in central Massachusetts, US. We obtained for these patients automated utilisation files containing data on medications, hospitalisations, emergency room visits, office visits, and estimated costs of these services. The medication dispensed to the greatest proportion of patients was beta 2 agonists either by inhalation (56%) or orally (21%). Theophylline was dispensed to 23% of the patients. Maintenance therapy was inhaled anti-inflammatory medication was uncommon, as inhaled corticosteroids (17%) and sodium cromoglycate (cromolyn sodium) [8%] were dispensed to fewer patients than other asthma medications. Among patients who had been hospitalised in the previous year, 36% were presently receiving inhaled corticosteroids, and among patients who used at least one beta 2 agonist metered-dose inhaler per month, 49% were presently receiving inhaled corticosteroids. Economic analyses showed that only 8% of the patients had either a hospital admission or an emergency room visit, but hospital costs among these patients accounted for 25% of the total costs of asthma care. In addition, the top 10% most expensive patients accounted for 42% of the total cost of asthma care. We conclude that a substantial proportion of patients at increased risk of a severe attack, by virtue of having a recent hospitalisation, do not receive maintenance anti-inflammatory therapy, and that hospitalisations among a relatively small proportion of asthma patients contribute significantly to the cost of asthma care.

Blood coagulation and idiopathic thromboembolism among fertile women.

A case-control study of fibrinolytic activity and antithrombin-III (AT-III) was conducted comparing 16 women within the childbearing ages who had a recent history of idiopathic thromboembolism to 29 age- and race-matched female controls without a history of thromboembolism. All subjects had stopped using oral contraceptives at least 12 months prior to study. No difference in AT-III was evident between cases and controls. The mean fibrinolytic response to venous occlusion in cases was significantly lower; however, baseline fibrinolysis was essentially identical. These data demonstrated a bimodal distribution of fibrinolytic response among controls. By dichotomizing fibrinolytic response between the two modes in the controls, we estimated that the rate of low fibrinolytic response was 6 times as frequent in cases as controls. Thus, low fibrinolytic response may signal a natural predisposition to thromboembolism which could be triggered by use of synthetic estrogens.

PIP: A case control study of fibrinolytic activity and (AT-3) antithrombin-3 was conducted comparing 16 women of childbearing age who had a recent history of idiopathic thromboembolism to 29 age- and race-matched female controls without such a history. All subjects had stopped using oral contraceptives at least 12 months prior to the study. No difference in AT-3 was evident between cases and controls. The mean fibrinolytic response to venous occlusion in cases was significantly lower; however, baseline fibrinolysis was essentially identical. These data demonstrated a bimodal distribution of fibrinolytic response among controls. By dichotomizing fibrinolytic response between the 2 modes in the controls, we estimated that the rate of low fibrinolytic response was 6 times as frequent as in the controls. Thus, low fibrinolytic response may signal a natural predisposition to thromboembolism which could be triggered by use of synthetic estrogens.

Fibrinolytic response and oral contraceptive associated thromboembolism.

A case-control study of fibrinolytic activity was conducted comparing 12 women with a recent history of thromboembolism while taking oral contraceptives and 28 matched female controls without a history of thromboembolism. All subjects had stopped using oral contraceptives at least 12 months prior to study. A new assay, recently developed in this laboratory, was used to evaluate the mean fibrinolytic response to venous occlusion in both cases and controls. The fibrinolytic response of all subjects was stratified into quartiles as previously described. While the controls segregated as expected, all 12 cases occurred in subjects whose fibrinolytic response fell in the first two quartiles with 8 of the 12 subjects having first quartile responses. The mean fibrinolytic response for all controls was 12.3 units while cases showed a mean response of only 3.9 units. The above data supports and extends our recent suggestion that low fibrinolytic response may signal a natural predisposition to venous thromboembolism which could be triggered by use of synthetic estrogens. However, these data do not support the use of this assay as a screening test for oral contraceptive related risk to thromboembolism since at least 50% of the control population also segregate in the first two quarters.

PIP: A case-control study of fibrinolytic activity was conducted comparing 12 women with a recent history of thromboembolism while taking (OCs) oral contraceptives and 28 matched female controls without a history of thromboembolism. All subjects had stopped using OCs at least 12 months prior to study. A new assay, recently developed in this laboratory, was used to evaluate the mean fibrinolytic response to venous occlusion in both cases and controls. The fibrinolytic response of all subjects was stratified into quartiles as previously described. While the controls segregated as expected, all 12 cases occurred in subjects whose fibrinolytic response fell in the first 2 quartiles with 8 of the 12 subjects having 1st quartile responses. The mean fibrinolytic response for all controls was 12.3 units while cases showed a mean response of only 3.9 units. The above data supports and extends our recent suggestion that low fibrinolytic response may signal a natural predispositon to venous thromboembolism which could be triggered by use of synthetic estrogens. However, these data do not support the use of this assay as a screening test for OC related risk to thromboembolism since at least 50% of the control population also segregate in the first 2 quarters.

Manufacturing characteristics associated with strut fracture in Björk-Shiley 60 degrees Convexo-Concave heart valves.

Björk-Shiley Convexo-Concave (CC) valves sometimes experience fracture of the outlet strut. Previously implicated valve characteristics that predict strut fracture include larger valve size, larger opening angle (70 degrees vs 60 degrees), remilling, weld date, and implant in the mitral position. While the associations between risk, size, and opening angle suggest that part of the elevated incidence of strut fracture might be due to the design of the Björk-Shiley valves, only a small fraction of implanted valves have experienced strut fracture. In consequence, previously unexamined variations in the manufacturing process have been suggested as possible factors affecting the failure risk of individual valves; materials, manufacturing steps, quality control, and specific workers have all been put forward as potential explanations for valve-to-valve variation in risk. We conducted a case-control study of CC60 degrees valves implanted in the USA and Canada and manufactured between January 1, 1979 and March 31, 1984. Cases included all verified strut fractures reported to the manufacturer from 1979 through January, 1992. up to 10 controls were selected for each case. Controls were matched to cases on implanting surgeon and were required to have been implanted and functioning at least as long as their respective case valves. We reviewed case and control manufacturing records. There were 150 cases and 1095 surgeon-matched controls. Large mitral valves were at greatest risk of strut fracture; 33mm mitral valves were estimated to be 23 times more likely to fracture than 21-25mm aortic valves. Valves welded in 1979 and 1980 were less likely to fracture than those welded in any other time period; however, no specific manufacturing procedures or personnel were uniquely associated with this time period. Valves with more flexible outlet struts, as determined by the hook deflection and load deflection tests during manufacture, appear to have been at higher risk than valves with more rigid outlet struts. There were three welders who had worked on a sufficient number of valves to allow separate estimation of the risk in the valves they welded. One welder's work was associated with about one-third the risk of valves worked on by the other two. Examination of receiver operating characteristic curves revealed, however, that welder identity added little to the discriminating information already available in the form of valve size and implant position. It is concluded that welder identity and strut flexibility appear to contribute to the risk of outlet strut fracture in Björk-Shiley CC60 degrees valves. Neither of these factors, however, is sufficient to account for much of the previously unexplained variation in risk. No other characteristic measurable in existing manufacturing records appears to predict risk of strut fracture in any useful way.

Mortality update of cellulose fiber production workers.

Mortality ascertainment was extended through 1990 for a cohort of 1271 workers involved in the production of cellulose triacetate fiber at a plant in Rock Hill, South Carolina. Each subject was employed for at least three months between 1 January 1954 and 1 January 1977 in jobs that entailed exposure to the highest concentrations of methylene chloride. Median exposures in 1977 ranged from 140 to 745 ppm (8-h time-weighted average). The observed numbers of deaths from specific causes were compared with the expected numbers of deaths computed from rates in York County, South Carolina. For most causes of death, there was little if any association with employment. Among causes of particular interest, no new deaths were observed from cancer of the liver and biliary tract, although the excess from the earlier study persisted (4 observed, 1.34 expected). No excess mortality was observed for cancer of the pancreas (2 observed, 2.42 expected) or for ischemic heart disease (43 observed, 47.8 expected).

Mortality of cellulose fiber production workers.

Mortality was studied among 1271 employees of a cellulose fiber production plant in Rock Hill, South Carolina, in the United States. Each subject was employed for at least three months between 1 January 1954 and 1 January 1977 in jobs that entailed exposure to the highest concentrations of methylene chloride. In the cohort 122 deaths were identified through 1 September 1986, and mortality rates for the cohort were compared with mortality rates for York County, South Carolina. Deficit mortality was observed for cancers of the respiratory system, breast, and pancreas and from ischemic heart disease. Excess mortality was observed for cancers of the buccal cavity and pharynx and the liver and biliary tract, and for melanoma as well. The largest relative excess was for liver and biliary tract cancers. There were only four deaths in this category; however, three of the four deaths were cancer of the biliary tract (3 observed, 0.15 expected, standardized mortality ratio 20).

Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors: challenges in comparative effectiveness using Medicare data.

An evidence gap exists in comparing the effectiveness of angiotensin receptor II blockers (ARBs) for hypertension with that of angiotensin-converting enzyme inhibitors (ACEIs). We identified elderly hypertensive patients in whom ACEI/ARB therapy had been initiated after hospitalization for coronary artery disease (CAD), heart failure (HF), or stroke and who were eligible for Medicare and state pharmacy assistance programs. Of 18,801 initiators of ACEIs and 2,641 initiators of ARBs, 2,535 died during the follow-up. We observed substantial differences in characteristics between ARB and ACEI initiators, suggesting that ARB users were more health seeking. The incidence of death and sudden cardiac death (SCD) in ACEI initiators was 77 and 22 per 1,000 person-years, respectively. The relative risk for SCD comparing ARB initiators to ACEI initiators was 0.69 (95% confidence interval (CI) 0.50-0.96); when the analysis was restricted to patients with low ejection fraction (EF), the relative risk was 1.1. The reduced risk of SCD can be explained, at least partly, by (i) residual confounding because ARB users were healthier on unobserved domains and (ii) lack of data on EF.

Accessing third-party data for research: trust me? Trust me not?

Epidemiologists are often asked to evaluate product safety or provide information about the history of disease and use of health services. Most of this research is conducted through sponsorship from a governmental or other non-profit agency, or with direct support from a for-profit company with an economic interest in the outcome. Vast amounts of information that are routinely collected for administrative and billing purposes may also be used for research. These data can reveal information about the etiology of disease, utilization patterns of prescription drugs, and trends in disease occurrence. Using third-party data requires a trusting partnership between researchers and data custodians. Although such data offer public health benefits, their use can also lead to embarrassment and legal action. Five guiding principles will help outside contractors facilitate access to third-party data and avoid pitfalls. (1) Understand the sponsor's objectives by understanding the purpose of the research. (2) Identify and approach data resources that have appropriate information. (3) Consider special issues relating to accessing confidential information. (4) Establish terms of the research engagement with the sponsor. (5) Establish ground rules with the data provider.

Leukemia among nuclear workers with protracted exposure to low-dose ionizing radiation.

We conducted an analysis of leukemia mortality and protracted exposure to low-dose ionizing radiation. We used data from seven published epidemiologic studies of nuclear workers that reported individual monitoring information for radiation exposure. We found 83 leukemia deaths among white males from a combined total of more than 1.4 million person-years. We calculated an overall relative risk for leukemia of 1.5, after adjustment for age and calendar time, for workers with cumulative occupational doses of 10 mSv (1 rem) or greater, compared with those with cumulative doses of less than 10 mSv. An adjusted relative risk of 1.8 was observed when individuals with 10-50 mSv (1-5 rem) were compared with those who had cumulative occupational doses of less than 10 mSv. The adjusted relative risk for those with doses greater than 50 mSv relative to those with doses less than 10 mSv was 1.2, although the data were especially sparse in this dose range. These combined data indicate a small elevated risk of leukemia for doses of ionizing radiation under 50 mSv.

Identifying the health risks from very low-dose sparsely ionizing radiation.

The health risks from low-dose sparsely ionizing (low-LET) radiation have been the subject of continued debate. At present, quantitative estimates of risk are extremely uncertain due to the controversy surrounding both the dosimetry for A-bomb survivor data and the choice of mathematical models for extrapolating risk from high to low doses. Nevertheless, much can be learned about the nature of the health risks by reviewing the epidemiologic literature. We present a summary of diseases which have been associated with low-LET radiation (less than 1000 rad) in at least two independent studies, according to the mean cumulative organ dose at which the disease was observed. At organ doses of less than or equal to 50 rad, the only diseases that have been reported consistently are thyroid cancer, salivary gland tumors, and leukemia. The first two diseases were observed in association with x-ray epilation of the scalp for tinea capitis, a therapy which is no longer employed. On the other hand, leukemia has been observed repeatedly to occur at cumulative doses of greater than or equal to 30 rad low-LET radiation.

Bromocriptine and puerperal seizures.

Case reports have prompted concern that the use of bromocriptine mesylate to prevent lactation in the puerperium increases the risk of postpartum seizure. We conducted a record-based case-control study of postpartum seizures in three data bases to evaluate this relation. We identified 43 women who had a postpartum seizure, and we matched 319 controls individually by hospital of delivery, quinquenium of age, and time of delivery. Overall, women taking bromocriptine had a 22% lower risk for seizures, that is, the relative risk estimate was 0.78, with a 90% confidence interval of 0.29 to 1.87. A reduction in seizure risk is consistent with reports of antiseizure activity for bromocriptine in various species, including humans. We found a small positive association between bromocriptine use and seizures occurring more than 72 hours after delivery, with a relative risk estimate of 1.6 after controlling for seizure history. This association was offset by a strong negative association between bromocriptine use and early-occurring seizures. The pattern of an initial reduced risk followed by an increase to normal or above-normal levels of risk could result from an antiseizure activity of bromocriptine, with a rebound in risk when bromocriptine is withdrawn.

Patient factors associated with strut fracture in Björk-Shiley 60 degrees convexo-concave heart valves.

BACKGROUND: Previously established predictors of outlet strut fracture in Björk-Shiley convexo-concave (CC) valves include larger valve size, larger opening angle (70 degrees versus 60 degrees), younger age at implant, and date of manufacture. We sought to identify patient characteristics that might be predictive of strut fracture and to refine the estimates associated with previously identified predictors. METHODS AND RESULTS: We conducted a case-control study of CC60 degrees valves implanted in the United States and Canada and manufactured between January 1, 1979, and March 31, 1984. Cases included all valves with verified outlet strut fractures reported to the manufacturer from January 1979 through January 1992. Up to 10 controls were selected for each case. Control valves were matched according to implanting surgeon and were required to have been functioning at least as long as their matched case valves. Case and control medical records were reviewed for information on patient medical history before the valve implant. There were 96 case and 634 control valves for which clinical data were available. Patient age and valve size and implant position were confirmed as important determinants of fracture. There was a strong inverse gradient of risk with age. The risk of fracture was 42% lower for each 10-year increment of patient age at time of implant. Large mitral valves were at greatest risk of strut fracture, with the largest mitral valves (33 mm) estimated to be 33 times more likely to fracture than the smallest (21 to 25 mm) aortic valves. Date of manufacture was also associated with risk; valves welded from mid-1981 through March 1984 were more likely to fracture than those manufactured in 1979 and 1980. Body surface area < 1.5 m2 was associated with 1/16 the risk of body surface area > or = 2.0 m2. No other patient factor was strongly associated with the risk of strut fracture. CONCLUSIONS: Few patient features identifiable in the implant record are predictive of strut fracture. Our analysis supports previous work in identifying valve size, patient age, and date of manufacture as predictors of fracture and adds body surface area. A number of these associations suggest that conditions associated with higher cardiac output may also place patients at increased risk.