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.

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.

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.

A combination study design to examine mycophenolate mofetil (MMF) and PTLD in renal transplant patients.

Renal transplant recipients who are chronically immunosuppressed by drugs are at a higher risk of developing malignancies. Commonly observed malignancies are several forms of posttransplant lymphoproliferative disorders (PTLD), skin, lip and gynaecological cancers. The risk is associated with many risk factors including the extent of immunosuppression. Mycophenolate mofetil (MMF) is an immunosuppressant, indicated for the prophylaxis of organ rejection in patients receiving allogenic renal and heart transplants. During the European approval of MMF for renal transplantation, the question was raised as to whether the use of MMF was associated with an increased risk of PTLD in comparison with alternate immunosuppressive regimens. In response, F. Hoffman-La Roche Ltd set up a prospective observational cohort study with a companion case-control study. This paper describes the objectives and the methods of these studies along with the rationale of the methodology.

Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs.

OBJECTIVE: To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting. METHODS: Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group-model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person-year. RESULTS: The average individual cost rate of arthritis-related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898). CONCLUSION: RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.

5-Aminosalicylates, sulfasalazine, steroid use, and complications in patients with ulcerative colitis.

OBJECTIVES: The choice between sulfasalazine and 5-aminosalicylate (5-ASA) drugs in the management of patients with ulcerative colitis often depends on idiosyncrasies of drug tolerance and control of the disease in individual patients. We sought to evaluate whether there were population differences in the effect of 5-ASA and sulfasalazine on the occurrence of clinically recognized adverse events. We also attempted to determine whether there were differences in the use of concomitant steroids and in the rates of hospitalization. METHODS: We reviewed a large computerized database drawn from general practices in the United Kingdom. There we found records of 2894 patients in whom general practitioners had diagnosed ulcerative colitis, and who were receiving ongoing medical therapy specific to ulcerative colitis. The period of data availability ran from the beginning of 1990 to the latter part of 1993. The average duration of observation was 2.1 yr per patient. Patient histories were categorized into distinct periods according to the dose of 5-ASAs and sulfasalazine, steroids, and immunosuppressants, and were further separated according to the activity of ulcerative colitis. Within these categories, we examined the initiation and discontinuation of steroids, incidence of new hospitalizations for ulcerative colitis, and clinical mention of adverse events. RESULTS: New clinical mentions of hepatic, pancreatic, renal, and hematological events other than anemia were similar among the 5-ASAs and were very infrequent overall. Hospitalizations for ulcerative colitis occurred with similar frequency (about 15 hospitalizations per 100 patients per year) among users of those drugs. Patients receiving sulfasalazine had lower rates of initiation of prednisolone than did patients receiving 5-ASA, but sulfasalazine was used proportionately less often in patients who had been recently hospitalized, and it may be that sulfasalazine patients were somewhat less sick, overall, than were 5-ASA-using patients. The choice of drug did not affect discontinuation rates for prednisolone among established users. CONCLUSIONS: In the United Kingdom, during the period of this study, serious adverse reactions to drugs were not an important aspect of the management of patients with ulcerative colitis. Renal and pancreatic complications of sulfasalazine and 5-ASA therapy were extremely rare. Sulfasalazine and 5-ASA drugs have similar steroid-sparing properties. Disease-specific hospitalizations are approximately 100 times more common in ulcerative colitis patients than are serious adverse drug effects. Considerations of drug efficacy should therefore dominate the choice between therapeutic agents.

Incidence of pelvic inflammatory disease among women treated for gonorrhea or chlamydia.

BACKGROUND: No estimate exists of the incidence of pelvic inflammatory disease (PID) after the occurrence of a recent bout of sexually transmitted disease (STD). METHODS: We used a computerized data file of prescriptions and medical encounters from the Fallon Community Health Plan to estimate the incidence rate of pelvic inflammatory disease (PID) among women with a recently treated episode of gonorrhea or chlamydia (STD). First we identified women with presumed gonorrhea or chlamydia on the basis of a combination of diagnostic codes for cervicitis, vulvovaginitis or Bartholin's abscess, and a computer record of a prescription for doxycycline. We then followed these women to estimate the incidence rate of PID after their treatment for gonorrhea or chlamydia. We estimated the number of cases of pelvic inflammatory disease in this cohort by selecting all women with an International Classification of Diseases (ICD) code of 614.9 entered for either an outpatient or inpatient diagnosis. RESULTS: We estimated the overall risk of PID to be about 9% during the 1-year period following treatment for gonorrhea or chlamydia, with a steep rise in risk coming within the first 45 days. CONCLUSION: The risk of PID in the year after an episode of treated STD is high, but the highest period of risk is in the first few weeks. The shape of the risk curve indicates that some PID cases may result from treatment-resistant infections, or possibly from untreated reinfections.

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.

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.

Overall mortality of cellular telephone customers.

Unlike mobile cellular telephones, in which the antenna is not part of the handset, a portable cellular telephone exposes the user's head to radio frequency energy transmitted from the antenna. This exposure has prompted concerns about potential biological effects, including brain cancer. As a first step in a record-based mortality surveillance of cellular telephone customers, we report on overall mortality of a cohort of more than 250,000 portable and mobile telephone customers during 1994. We found age-specific rates to be similar for users of the two types of telephones. For customers with accounts at least 3 years old, the ratio of mortality rates in 1994 for portable telephone users, compared with mobile telephone users, was 0.86 (90% confidence interval = 0.47-1.53).

Utility of telephone company records for epidemiologic studies of cellular telephones.

We conducted a survey of over 5,000 telephone users who were customers of one large cellular telephone company covering four major geographical areas. Our primary goal was to assess the utility of ascertaining information on telephone use and type from telephone company records. We compared information from 3,949 respondents with corresponding data from company billing records. We found that 48% of the account holders were sole users, and 69% were the primary user, meaning that they accounted for at least 75% of the use. Respondent reports of amount of telephone use were highly correlated with data on the billing record (r = 0.74). Respondent reports of telephone type were similarly correlated with data from the manufacturer (r = 0.92). We also inquired about telephone holding patterns, since these have implications for exposure. Most users reported favoring one side of the head when using the telephone, but the side of the head used was not strongly associated with handedness.

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.

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.

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.

Mortality among synthetic fiber workers exposed to glycerol polyglycidyl ether.

We studied mortality among 8,878 employees who worked at any time from 1965 to 1988 at a synthetic fibers plant in North Carolina that used a finishing agent containing glycerol polyglycidyl ether. Some glycidyl ethers are mutagenic and tumorigenic in laboratory animals. The main route of exposure to workers was inhalation of the spray mist, although there was also skin contact. We identified 553 deaths in the cohort and the standardized mortality ratio (SMR) from all causes of death combined was 0.80. For most causes of death, mortality rates in the cohort were similar to mortality rates in the U.S. population. Among categories with at least five observed deaths, the largest effect estimate was for cancer of the central nervous system (SMR = 1.77), and the SMR for lung cancer was 0.94. The cancer categories of central nervous system (brain) and "other" lymphopoietic cancers (lymphoma and myeloma) showed weak associations with duration of employment. In case-control analyses in which we utilized work history data to compute effect estimates by duration of exposure, we found no increased risk of lung cancer or brain cancer among employees with more than 5 years of exposure. Effect estimates for lymphoma and myeloma tended to increase with duration of exposure, although there were only seven deaths in this category and the effect estimates were very imprecise. To date, this study has identified no clear carcinogenic effect of glycerol polyglycidyl ether, but plausible induction periods have not yet elapsed. The cohort should continue to be monitored to obtain more precise estimates after moderate or long induction times.