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Importance: Studies suggest pioglitazone use may increase risk of cancers., Objective: To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers., Design, Setting, and Participants: Cohort and nested case-control analyses among persons with diabetes. A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders. A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012. Cohorts were from Kaiser Permanente Northern California., Exposures: Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent., Main Outcomes and Measures: Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma., Results: Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26). Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose., Conclusions and Relevance: Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.

Context: Hospital computerized physician order entry (CPOE) systems are widely regarded as the technical solution to medication ordering errors, the largest identified source of preventable hospital medical error. Published studies report that CPOE reduces medication errors up to 81%. Few researchers, however, have focused on the existence or types of medication errors facilitated by CPOE., Objective: To identify and quantify the role of CPOE in facilitating prescription error risks., Design, Setting, and Participants: We performed a qualitative and quantitative study of house staff interaction with a CPOE system at a tertiary-care teaching hospital (2002-2004). We surveyed house staff (N = 261; 88% of CPOE users); conducted 5 focus groups and 32 intensive one-on-one interviews with house staff, information technology leaders, pharmacy leaders, attending physicians, and nurses; shadowed house staff and nurses; and observed them using CPOE. Participants included house staff, nurses, and hospital leaders., Main Outcome Measure: Examples of medication errors caused or exacerbated by the CPOE system., Results: We found that a widely used CPOE system facilitated 22 types of medication error risks. Examples include fragmented CPOE displays that prevent a coherent view of patients' medications, pharmacy inventory displays mistaken for dosage guidelines, ignored antibiotic renewal notices placed on paper charts rather than in the CPOE system, separation of functions that facilitate double dosing and incompatible orders, and inflexible ordering formats generating wrong orders. Three quarters of the house staff reported observing each of these error risks, indicating that they occur weekly or more often. Use of multiple qualitative and survey methods identified and quantified error risks not previously considered, offering many opportunities for error reduction., Conclusions: In this study, we found that a leading CPOE system often facilitated medication error risks, with many reported to occur frequently. As CPOE systems are implemented, clinicians and hospitals must attend to errors that these systems cause in addition to errors that they prevent.

Context: Retrospective drug utilization review is required of all state Medicaid programs and is performed by most private-sector prescription programs. However, it has not been shown to improve clinical outcomes or reduce the rate of potential prescribing errors, known as "exceptions.", Objective: To look for an effect of retrospective drug utilization review on the rate of exceptions and of clinical outcomes in patients with an exception., Design, Setting, and Participants: Longitudinal ecologic study of the rate of exceptions, controlling for preintervention trends and calendar time; and a cohort study of all-cause and cause-specific hospitalizations in patients with an exception, controlling for potential individual-level confounders in 6 Medicaid programs using the same software in the mid-1990s., Main Outcome Measures: The rate of exceptions was examined as a function of retrospective drug utilization review implementation. In addition, before-after comparisons were made of the incidence of all-cause and cause-specific hospitalization in patients with exceptions., Results: We found no reduction in the rate of exceptions coincident with retrospective drug utilization review implementation (rate increase, 0.064 exceptions per 1000 prescriptions per month; 95% confidence interval [CI], -0.006 to 0.133). We also found no effect of retrospective drug utilization review on the incidence of all-cause hospitalization (odds ratio, 0.99; 95% CI, 0.98-1.00) or cause-specific hospitalization. These results persisted in multiple subgroup analyses. Study states intervened using physician alerts in between 1% and 25% of exceptions., Conclusions: We were unable to identify an effect of retrospective drug utilization review on the rate of exceptions or on clinical outcomes. Given the lack of evidence for effectiveness, and suggestions from previous research of possible harm, policymakers should consider withdrawing the legislative mandate for retrospective drug utilization review.

Context: A large body of evidence documents the role of phytoestrogens in influencing hormone-dependent states. Infants fed soy formula receive high levels of phytoestrogens, in the form of soy isoflavones, during a stage of development at which permanent effects are theoretically possible. However, a paucity of data exists on the long-term effects of infant soy formulas., Objective: To examine the association between infant exposure to soy formula and health in young adulthood, with an emphasis on reproductive health., Design, Setting, and Participants: Retrospective cohort study conducted from March to August 1999 among adults aged 20 to 34 years who, as infants, participated during 1965-1978 in controlled feeding studies conducted at the University of Iowa, Iowa City (248 were fed soy formula and 563 were fed cow milk formula during infancy)., Main Outcome Measures: Self-reported pubertal maturation, menstrual and reproductive history, height and usual weight, and current health, compared based on type of formula exposure during infancy., Results: No statistically significant differences were observed between groups in either women or men for more than 30 outcomes. However, women who had been fed soy formula reported slightly longer duration of menstrual bleeding (adjusted mean difference, 0.37 days; 95% confidence interval [CI], 0.06-0.68), with no difference in severity of menstrual flow. They also reported greater discomfort with menstruation (unadjusted relative risk for extreme discomfort vs no or mild pain, 1.77; 95% CI, 1.04-3.00)., Conclusions: Exposure to soy formula does not appear to lead to different general health or reproductive outcomes than exposure to cow milk formula. Although the few positive findings should be explored in future studies, our findings are reassuring about the safety of infant soy formula.

Context: Recent epidemiologic studies have raised the concern that calcium channel blocker use may increase the risk of cancer overall and of several specific cancers., Objective: To assess whether calcium channel blocker use increases the risk of cancer overall and of specific cancers., Design: Case-control drug surveillance study based on data collected from 1983 to 1996., Setting: Hospitals in Baltimore, Md, New York, NY, and Philadelphia, Pa., Patients: A total of 9513 patients aged 40 to 69 years with incident cancer of various sites and 6492 controls aged 40 to 69 years admitted for nonmalignant conditions., Main Outcome Measures: Incident cancer overall and 23 specific cancers., Results: Calcium channel blocker use was unrelated to the risk of cancer overall (relative risk [RR], 1.1; 95% confidence interval [CI], 0.9-1.3). Use was not significantly associated with increased risks of individual cancers, including those previously implicated, except cancer of the kidney (RR, 1.8; 95% CI, 1.1 -2.7). Recent use, use for 5 or more years, and use of individual calcium channel blocker drugs were also not associated with cancer incidence. Use of beta-blockers and angiotensin-converting enzyme inhibitors was generally unrelated to cancer overall or individual cancers, but both were associated with kidney cancer (RR, 1.8; 95% CI, 1.3-2.5; and RR, 1.9; 95% CI, 1.2-3.0, respectively)., Conclusions: The present study suggests that the use of calcium channel blockers is unrelated to an increase in the overall risk of cancer or of individual cancers, except kidney cancer, which has been associated with hypertension or drugs to treat hypertension in previous studies.

Context: The risks of blood transfusion have been studied extensively but the benefits and the hemoglobin concentration at which patients should receive a transfusion have not., Objective: To determine the effect of perioperative transfusion on 30- and 90-day postoperative mortality., Design: Retrospective cohort study., Setting: A total of 20 US hospitals between 1983 and 1993., Participants: A total of 8787 consecutive hip fracture patients, aged 60 years or older, who underwent surgical repair., Main Outcome Measures: Primary outcome was 30-day postoperative mortality; secondary outcome was 90-day postoperative mortality. The "trigger" hemoglobin level was defined as the lowest hemoglobin level prior to the first transfusion during the time period or, for patients in the nontranfused group, as the lowest hemoglobin level during the time period., Results: Overall 30-day mortality was 4.6% (n=402; 95% confidence interval [CI], 4.1%-5.0%); overall 90-day mortality was 9.0% (n=788; 95% CI, 8.4%-9.6%). A total of 42% of patients (n=3699) received a postoperative transfusion. Among patients with trigger hemoglobin levels between 80 and 100 g/L (8.0 and 10.0 g/dL), 55.6% received a transfusion, while 90.5% of patients with hemoglobin levels less than 80 g/L (8.0 g/dL) received postoperative transfusions. Postoperative transfusion did not influence 30- or 90-day mortality after adjusting for trigger hemoglobin level, cardiovascular disease, and other risk factors for death: for 30-day mortality, the adjusted odds ratio (OR) was 0.96 (95% CI, 0.74-1.26); for 90-day mortality, the adjusted hazard ratio was 1.08 (95% CI, 0.90-1.29). Similarly, 30-day mortality after surgery did not differ between those who received a preoperative transfusion and those who did not (adjusted OR, 1.23; 95% CI, 0.81-1.89)., Conclusions: Perioperative transfusion in patients with hemoglobin levels 80 g/L (8.0 g/dL) or higher did not appear to influence the risk of 30- or 90-day mortality in this elderly population. At hemoglobin concentrations of less than 80 g/L (8.0 g/dL), 90.5% of patients received a transfusion, precluding further analysis of the association of transfusion and mortality.

Objective: To evaluate the risk of gastrointestinal and operative site bleeding associated with the use of parenteral ketorolac tromethamine., Design: Postmarketing surveillance inception cohort study., Setting: A total of 35 hospitals throughout the Philadelphia, Pa, region, 1991 to 1993., Patients: Patients administered 10,272 courses of parenteral ketorolac therapy were compared with patients administered 10,247 courses of a parenteral opiate who were matched to the ketorolac patients by hospital, admitting service, and date of initiation of study drug., Main Outcome Measures: Medical records were reviewed for demographics, medical history, doses and duration of study drug, various aspects of the hospital course including surgery and concomitant medications, and adverse events., Results: The multivariate adjusted odds ratio (OR) comparing ketorolac with opiates for gastrointestinal bleeding was 1.30 (95% confidence interval [CI], 1.11 to 1.52); for operative site bleeding, the OR was 1.02 (95% CI, 0.95 to 1.10). The OR was elevated further in subjects 75 years of age or older for both gastrointestinal bleeding (OR = 1.66; 95% CI, 1.23 to 2.25) and operative site bleeding (OR = 1.12; 95% CI, 0.94 to 1.35). A dose-response relationship was evident between average daily ketorolac dose and both gastrointestinal bleeding and operative site bleeding (trend test P < .001 for both). When analgesic therapy lasted 5 or fewer days, ketorolac was associated with only a small increased risk of gastrointestinal bleeding (OR = 1.17; 95% CI, 0.99 to 1.30); when therapy was prolonged beyond 5 days, the OR was 2.20 (95% CI, 1.36 to 3.57). The association of ketorolac with operative site bleeding was not affected by duration of therapy., Conclusions: The overall associations between ketorolac use and both gastrointestinal bleeding and operative site bleeding are small. However, the risk associated with the drug is larger and clinically important when ketorolac is used in higher doses, in older subjects, and for more than 5 days. Improving physicians' prescribing practices by limiting the dose and duration of ketorolac use, especially in the elderly, should enhance its overall risk-benefit balance.

Postmarketing drug surveillance (PMS) assesses the epidemiology of drug use and monitors beneficial or harmful effects of drugs following marketing. If used systematically, PMS can substantially improve drug therapy in the United States. This can be accomplished by generating information on drug use and effects otherwise unavailable, by enabling a more efficient drug approval process, and by educating drug prescribers. However, to be successful, any PMS system will need a good deal of input from such prescribers.