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Purpose Hydrocodone, codeine, oxycodone, and tramadol are frequently prescribed to adolescents for moderate pain related to minor trauma or dental, surgical, or medical procedures. Pharmacokinetic and pharmacodynamic differences between these opioids could affect their relative safety. We aimed to compare occurrence of opioid-related adverse events in adolescents without cancer or other severe conditions taking hydrocodone, codeine, oxycodone, and tramadol. Methods Retrospective cohort study of 201 940 Tennessee Medicaid enrollees 12 to 17 years of age without cancer, other severe conditions, or evidence of substance abuse with 529 731 filled prescriptions for study opioids. Adverse events were defined as an emergency department visit, hospital admission, or death related to opioid use, confirmed by medical record review. Serious events had opioid-related escalation of care, hospitalization, or death. Propensity-score adjusted hazard ratios (HRs) were calculated with hydrocodone as the reference category. Results The incidence of opioid-related adverse events per 10 000 person-years of opioid exposure was 97.5 for hydrocodone (127 events/13 026 person-years), 91.2 for codeine (58/6,359), 229.7 for oxycodone (43/1,872), and 317.7 for tramadol (47/1479). The HRs for tramadol in comparison with hydrocodone for all and serious events were 2.98 (2.03-4.39) and 2.94 (1.81-4.75), respectively. Increased risk for tramadol was consistently present when the adverse events were restricted to those with neurologic-respiratory depression/other symptoms of possible overdose. Conclusion In adolescents without cancer or other severe conditions prescribed short-acting opioids, the incidence of both all opioid-related adverse events and more serious events with opioid-related escalation of care, hospitalization, or death was consistently greater for tramadol than for hydrocodone.

Purpose Pharmacoepidemiologic studies of acute effects of episodic exposures often must control for many time-dependent confounders. Marginal structural models permit this and provide unbiased estimates when confounders are on the causal pathway. However, if causal pathway confounding is minimal, analyses with time-dependent propensity scores, calculated for time periods defined by individual drug prescriptions, may have better efficiency. We justify time-dependent propensity scores and compare the performance of these methods in a case study from a previous investigation of the risk of medication toxicity death in current users of propoxyphene and hydrocodone, with both substantial time-dependent confounding and a large number of covariates. Methods The cohort included Tennessee Medicaid enrollees who filled a qualifying study opioid prescription between 1992 and 2007. We identified 22 time-dependent covariates that accounted for most of the confounding in the original study. We compared analyses with all covariates in the regression model with those based on time-dependent propensity scores and those from marginal structural models. Results We identified 489,008 persons with 1,771,295 propoxyphene and 4,088,754 hydrocodone prescriptions. The unadjusted hazard ratio (propoxyphene : hydrocodone) was 0.70 (95%CI, 0.46–1.07). Estimates from inclusion of all covariates in the model, time-dependent propensity score analysis with inverse probability of treatment weighting, and marginal structural models were 1.63 (1.04–2.57), 1.65 (1.01–2.72), and 1.64 (0.83–3.27), respectively. Findings varied little with use of alternative propensity score methods, time origin, or techniques for marginal structural model estimation. Conclusions Time-dependent propensity scores may be useful for pharmacoepidemiologic studies with time-varying exposures when causal pathway confounding is limited. Copyright © 2014 John Wiley & Sons, Ltd.

PURPOSE: To assess the safety of psychotropic medication use in children and adolescents, it is critical to be able to identify suicidal behaviors from medical claims data and distinguish them from other injuries. The purpose of this study was to develop an algorithm using administrative claims data to identify medically treated suicidal behavior in a cohort of children and adolescents. METHODS: The cohort included 80 183 youth (6-18 years) enrolled in Tennessee's Medicaid program from 1995-2006 who were prescribed antidepressants. Potential episodes of suicidal behavior were identified using external cause-of-injury codes (E-codes) and ICD-9-CM codes corresponding to the potential mechanisms of or injuries resulting from suicidal behavior. For each identified episode, medical records were reviewed to determine if the injury was self-inflicted and if intent to die was explicitly stated or could be inferred. RESULTS: Medical records were reviewed for 2676 episodes of potential self-harm identified through claims data. Among 1162 episodes that were classified as suicidal behavior, 1117 (96%) had a claim for suicide and self-inflicted injury, poisoning by drugs, or both. The positive predictive value of code groups to predict suicidal behavior ranged from 0-88% and improved when there was a concomitant hospitalization but with the limitation of excluding some episodes of confirmed suicidal behavior. CONCLUSIONS: Nearly all episodes of confirmed suicidal behavior in this cohort of youth included an ICD-9-CM code for suicide or poisoning by drugs. An algorithm combining these ICD-9-CM codes and hospital stay greatly improved the positive predictive value for identifying medically treated suicidal behavior. Copyright © 2013 John Wiley & Sons, Ltd. Language: en

Purpose The opioid analgesic propoxyphene was withdrawn from the U.S. market in 2010, motivated by concerns regarding fatality in overdose and adverse cardiac effects, including prolongation of the QT interval. These concerns were based on case reports, summary vital statistics, and surrogate endpoint studies.

There is frequent and growing use of medications that prevent abnormal blood clotting, including anticoagulants, antifibrinolytics, and platelet inhibitors. However, their therapeutic benefits must be balanced against the risk of bleeding complications, which for some of these drugs are relatively frequent. Warfarin, the most commonly used oral anticoagulant, substantially increases the risk of major bleeding complications, including hemorrhagic stroke and gastrointestinal hemorrhage,1 to as high as 3%-8% per year.2 Similarly, serious bleeding is a frequent complication of platelet P2Y12 adenosine diphosphate receptor antagonists 3-5 such as clopidogrel. Indeed, the elevated incidence of serious bleeding for prasugrel may deter use of this newer drug in high-risk patients.5 Thus, optimal clinical use of anti-clotting agents requires accurate information on the risk of serious bleeding complications. The clinical trials that establish efficacy provide valuable information. However, trial patients often have lower risk of adverse effects than do those in actual practice. Trials often exclude the highest risk patients, include procedures that are not part of routine clinical practice to reduce the occurrence of adverse effects, and may have insufficient power to examine drug-drug or drug-disease interactions.6 Epidemiologic studies of patients in actual clinical practice thus are essential to quantify the risk of bleeding complications for commonly prescribed anti-clotting agents. Automated databases of medical care encounters for defined populations are a potentially valuable resource for epidemiologic studies of bleeding complications. These databases include records of prescriptions written by clinicians, filled by patients or administered in institutions, records that provide a reliable measure of drug exposure that would be difficult or very expensive to obtain in other ways.7 These prescription records permit classification of anti-clotting drug exposure on a day-to-day basis, which is important because increased bleeding generally is an acute effect of these drugs. Similarly, the use of other medications that may alter the risk of bleeding8 can be closely tracked. A prerequisite for the study of bleeding complications with automated databases is a reliable definition for bleeding endpoints. One could identify potential endpoints from the computerized files and review medical records to determine ultimate endpoint status.9 However, this is not always possible and, even when possible, may be expensive and time-consuming. We thus developed a case definition for serious bleeding designed for use in automated databases. We report here its validation relative to a definition based upon review of medical records, utilizing a sample from an in-progress cohort study of warfarin-related bleeding in a Tennessee Medicaid population.

Purpose To determine the prevalence of chronic use of rofecoxib 50 mg. Rofecoxib is unusual among nonsteroidal anti-inflammatory drugs (NSAIDs) in that the licensed dose for acute pain is double the maximum dose recommended for chronic use. The 50 mg dose is recommended for acute pain only, for a maximum of 5 days. In clinical trials of chronic use for arthritis, hypertension was more frequent in patients assigned 50 mg rofecoxib than in those assigned lower doses or other NSAIDs. Thus chronic use of high doses of rofecoxib has implications for patient safety. Methods Cross-sectional analysis of the prevalence of chronic use of rofecoxib 50 mg in 2001, among persons aged ≥50 years, enrolled in the Tennessee Medicaid program. Results On 1 July 2001, 14% of the study population had a current prescription for an NSAID, with a supply of pills for >5 days. Of all NSAID prescriptions, 25% were for rofecoxib, and 17% of these prescriptions were for >25 mg daily. Of those prescribed >25 mg daily, 71% filled prescriptions for at least 50 mg for 30 days. In this latter group, 60% and 69% filled another rofecoxib prescription within 1 and 2 weeks, respectively, of the end of their 30 days supply. Demographics and co-morbid conditions of high dose rofecoxib users did not differ substantially from users of other NSAIDs or the total population. Conclusion Use of rofecoxib 50 mg for >5 days is relatively common. In view of dose-related adverse effects, such use should be discouraged. Copyright © 2003 John Wiley & Sons, Ltd.

Purpose Measurement of drug exposure is a major methodologic challenge for pharmacoepidemiologic studies of acute effects of medications taken intermittently. If the effect is plausible only during periods of active drug use, daily (or even more frequent) exposure measurement is optimal. Benzodiazepines, episodically used hypnotics and anxiolytics, impair psychomotor function and some epidemiologic studies have reported users have increased risk of unintentional injuries. However, several prospective cohort studies of this question defined benzodiazepine exposure status from a single baseline measurement, and these have not consistently reported increased risk. We used data from an historical cohort study to demonstrate the extent of misclassification potentially induced by this practice. Methods The cohort consisted of 2510 Tennessee nursing home residents 65 years of age or older identified in a prior study of antidepressants and falls. Both baseline users (any in 7 days preceding start of follow-up) and current use (use on a given day of follow-up) of benzodiazepines were determined from facility medication administration records, which record information on drugs given to the resident each day. Falls were ascertained from nursing home incident reports and medical records. The effect of benzodiazepine exposure for each ascertaiment method was estimated from incidence rate ratios adjusted for multiple fall risk factors by Poisson regression. Results The 666 baseline benzodiazepine users had current use on 44.6% (95%CI, 40.2–49.2%) of follow-up person-days; baseline non-users had current use for 3.7% of days (2.8–4.7%). Misclassification increased with length of follow-up and with quintile of fall risk. The adjusted fall incidence rate ratios for the baseline user and current use definitions were 1.02 (95%CI, 0.95–1.10) and 1.44 (1.33–1.56), respectively. Conclusion These findings strongly suggest that to avoid potentially serious misclassification, studies of the acute effects of benzodiazepines and other drugs taken intermittently need to track exposure on a day-by-day basis. Copyright © 2002 John Wiley & Sons, Ltd.

We compared the incidence of angioedema during exposure to angiotensin converting enzyme inhibitors (ACEIs) in blacks with that in whites in a retrospective cohort study of Medicaid recipients from Michigan, Ohio and Tennessee during 1986- 1992. Medicaid administrative files were used to identify filled prescriptions for ACEIs and calcium channel blockers (CCBs), and to identify first episodes of angioedema that occurred during exposure to an ACEI or CCB. There were 48,776 black and 106,482 white patients with 43,989 and 114,448 person-years of exposure to an ACEI, respectively. For comparison, there were 49,004 black and 110,129 white patients with 43,064 and 117,684 person-years of exposure to a CCB, respectively. The incidence of angioedema in blacks ranged from 3.3 to 4.6 per 1000 person-years of ACEI exposure--three to four times higher than that for whites in each state. Controlling for a slightly greater incidence of angioedema in blacks and other covariates, black users of ACEIs had a 3.1-fold greater incidence than white users. First exposure to ACEIs was associated with a higher risk of angioedema than chronic exposure in blacks, but not whites. Among blacks, the rate of angioedema during the first 30 days of exposure was 11.4 times greater (95% confidence interval [CI], 3.5 to 37.0) among ACEI users than CCB users; for those with at least 1 year of exposure, the rate was 4.5 times higher (95% CI, 2.6 to 8.0). Among whites, the increased risk of angioedema was more modest (rate ratio 1.7, 95% CI, 1.3 to 2.4 compared to CCB users) and did not differ by duration of ACEI use. In an analysis of angioedema cases and randomly selected controls in a subset of the full cohort, the greater risk of ACEI-associated angioedema in blacks was not explained by concurrent exposure to diuretics or antibiotics. Blacks may be at greater risk of angioedema when taking ACEIs than whites. Further study is necessary to confirm these findings, to examine effects of underlying disease on angioedema incidence, and to describe any racial differences in the severity of angioedema occurring with ACEIs.

Bleeding complications are a serious adverse effect of medications that prevent abnormal blood clotting. To facilitate epidemiologic investigations of bleeding complications, we developed and validated an automated database case definition for bleeding-related hospitalizations.The case definition utilized information from an in-progress retrospective cohort study of warfarin-related bleeding in Tennessee Medicaid enrollees 30 years of age or older. It identified inpatient stays during the study period of January 1990 to December 2005 with diagnoses and/or procedures that indicated a current episode of bleeding. The definition was validated by medical record review for a sample of 236 hospitalizations.We reviewed 186 hospitalizations that had medical records with sufficient information for adjudication. Of these, 165 (89%, 95%CI: 83-92%) were clinically confirmed bleeding-related hospitalizations. An additional 19 hospitalizations (10%, 7-15%) were adjudicated as possibly bleeding-related. Of the 165 clinically confirmed bleeding-related hospitalizations, the automated database and clinical definitions had concordant anatomical sites (gastrointestinal, cerebral, genitourinary, other) for 163 (99%, 96-100%). For those hospitalizations with sufficient information to distinguish between upper/lower gastrointestinal bleeding, the concordance was 89% (76-96%) for upper gastrointestinal sites and 91% (77-97%) for lower gastrointestinal sites.A case definition for bleeding-related hospitalizations suitable for automated databases had a positive predictive value of between 89% and 99% and could distinguish specific bleeding sites.

Purpose To facilitate studies of medications and sudden cardiac death, we developed and validated a computer case definition for these deaths. The study of community dwelling Tennessee Medicaid enrollees 30–74 years of age utilized a linked database with Medicaid inpatient/outpatient files, state death certificate files, and a state ‘all-payers’ hospital discharge file. Methods The computerized case definition was developed from a retrospective cohort study of sudden cardiac deaths occurring between 1990 and 1993. Medical records for 926 potential cases had been adjudicated for this study to determine if they met the clinical definition for sudden cardiac death occurring in the community and were likely to be due to ventricular tachyarrhythmias. The computerized case definition included deaths with (1) no evidence of a terminal hospital admission/nursing home stay in any of the data sources; (2) an underlying cause of death code consistent with sudden cardiac death; and (3) no terminal procedures inconsistent with unresuscitated cardiac arrest. This definition was validated in an independent sample of 174 adjudicated deaths occurring between 1994 and 2005. Results The positive predictive value of the computer case definition was 86.0% in the development sample and 86.8% in the validation sample. The positive predictive value did not vary materially for deaths coded according to the ICO-9 (1994–1998, positive predictive value = 85.1%) or ICD-10 (1999–2005, 87.4%) systems. Conclusion A computerized Medicaid database, linked with death certificate files and a state hospital discharge database, can be used for a computer case definition of sudden cardiac death. Copyright © 2009 John Wiley & Sons, Ltd.

Purpose To assess the positive predictive value of computerized records in a linked database of vital records and infant claims, with medical record confirmation to detect congenital malformations in a Medicaid population. Methods Study subjects were selected from cases identified for three studies of congenital malformations in the Tennessee Medicaid (TennCare) population including 173 827 (studies 1 and 2) and 519 465 (study 3) mother/infant pairs. Possible malformations were identified from computerized databases of birth certificates linked with maternal and infant claims. Medical records were reviewed for all possible congenital malformations and positive predictive values were calculated for each data source and for each malformation. Results Among 1430 potential congenital malformations identified from either birth certificates or inpatient claims, 67.7% were confirmed by medical record review. The positive predictive value varied considerably depending on the data source and the organ system. For example, cardiac defects had a very low positive predictive value when identified from birth certificates, and somewhat higher positive predictive value when identified from inpatient claims. Orofacial defects had 90.9% positive predictive value from birth certificates and inpatient claims. Requiring evidence of a diagnostic or therapeutic procedure increased the positive predictive value to >90% for specific defects, but substantially reduced the number of included cases. Conclusions Depending on the defect, computerized claims data linked to vital records offer opportunities for identifying birth defects in populations of vulnerable persons. However, for many defects, medical record confirmation is likely to be required to provide valid identification of malformation occurrence. Copyright © 2007 John Wiley & Sons, Ltd.

Assigning a cause to an individual event is a natural impulse. This impulse sometimes finds its way into epidemiologic research, if researchers assign a specific cause to some cases of a disease under study. In epidemiologic studies of drug effects, assigning a cause to specific cases is often used as a reason to exclude these cases from cohort or case-control studies, because the disease in these cases is thought to be the result of a 'known cause'. These exclusions are invalid. It is always valid, however, to exclude all subjects with 'known' causes from a study, cases from the numerator and the people or person-time at risk from the denominator (or from the control series in a case-control study). If the exclusions from the denominator would be negligibly small or the relative number of excluded cases with 'known' causes is small, then the exclusion of just the cases with 'known' causes will introduce little bias.