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ImportanceThe comparative effectiveness of rivaroxaban and apixaban, the most frequently prescribed oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation, is uncertain.ObjectiveTo compare major ischemic and hemorrhagic outcomes in patients with atrial fibrillation treated with rivaroxaban or apixaban.Design, Setting, and ParticipantsRetrospective cohort study using computerized enrollment and claims files for US Medicare beneficiaries 65 years or older. Between January 1, 2013, and November 30, 2018, a total of 581 451 patients with atrial fibrillation began rivaroxaban or apixaban treatment and were followed up for 4 years, through November 30, 2018.ExposuresRivaroxaban (n = 227 572) and apixaban (n = 353 879), either standard or reduced dose.Main Outcomes and MeasuresThe primary outcome was a composite of major ischemic (stroke/systemic embolism) and hemorrhagic (intracerebral hemorrhage/other intracranial bleeding/fatal extracranial bleeding) events. Secondary outcomes were nonfatal extracranial bleeding and total mortality (fatal ischemic/hemorrhagic event or other death during follow-up). Rates, hazard ratios (HRs), and rate differences (RDs) were adjusted for baseline differences in comorbidity with inverse probability of treatment weighting.ResultsStudy patients (mean age, 77.0 years; 291 966 [50.2%] women; 134 393 [23.1%] receiving reduced dose) had 474 605 person-years of follow-up (median [IQR] of 174 [62-397] days). The adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years vs 13.4 per 1000 person-years for apixaban (RD, 2.7 [95% CI, 1.9-3.5]; HR, 1.18 [95% CI, 1.12-1.24]). The rivaroxaban group had increased risk for both major ischemic events (8.6 vs 7.6 per 1000 person-years; RD, 1.1 [95% CI, 0.5-1.7]; HR, 1.12 [95% CI, 1.04-1.20]) and hemorrhagic events (7.5 vs 5.9 per 1000 person-years; RD, 1.6 [95% CI, 1.1-2.1]; HR, 1.26 [95% CI, 1.16-1.36]), including fatal extracranial bleeding (1.4 vs 1.0 per 1000 person-years; RD, 0.4 [95% CI, 0.2-0.7]; HR, 1.41 [95% CI, 1.18-1.70]). Patients receiving rivaroxaban had increased risk of nonfatal extracranial bleeding (39.7 vs 18.5 per 1000 person-years; RD, 21.1 [95% CI, 20.0-22.3]; HR, 2.07 [95% CI, 1.99-2.15]), fatal ischemic/hemorrhagic events (4.5 vs 3.3 per 1000 person-years; RD, 1.2 [95% CI, 0.8-1.6]; HR, 1.34 [95% CI, 1.21-1.48]), and total mortality (44.2 vs 41.0 per 1000 person-years; RD, 3.1 [95% CI, 1.8-4.5]; HR, 1.06 [95% CI, 1.02-1.09]). The risk of the primary outcome was increased for rivaroxaban in both those receiving the reduced dose (27.4 vs 21.0 per 1000 person-years; RD, 6.4 [95% CI, 4.1-8.7]; HR, 1.28 [95% CI, 1.16-1.40]) and the standard dose (13.2 vs 11.4 per 1000 person-years; RD, 1.8 [95% CI, 1.0-2.6]; HR, 1.13 [95% CI, 1.06-1.21]) groups.Conclusions and RelevanceAmong Medicare beneficiaries 65 years or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.

Background Benzodiazepine hypnotics and the related nonbenzodiazepine hypnotics (z-drugs) are among the most frequently prescribed medications for older adults. Both can depress respiration, which could have fatal cardiorespiratory effects, particularly among patients with concurrent opioid use. Trazodone, frequently prescribed in low doses for insomnia, has minimal respiratory effects, and, consequently, may be a safer hypnotic for older patients. Thus, for patients beginning treatment with benzodiazepine hypnotics or z-drugs, we compared deaths during periods of current hypnotic use, without or with concurrent opioids, to those for comparable patients receiving trazodone in doses up to 100 mg. Methods and findings The retrospective cohort study in the United States included 400,924 Medicare beneficiaries 65 years of age or older without severe illness or evidence of substance use disorder initiating study hypnotic therapy from January 2014 through September 2015. Study endpoints were out-of-hospital (primary) and total mortality. Hazard ratios (HRs) were adjusted for demographic characteristics, psychiatric and neurologic disorders, cardiovascular and renal conditions, respiratory diseases, pain-related diagnoses and medications, measures of frailty, and medical care utilization in a time-dependent propensity score–stratified analysis. Patients without concurrent opioids had 32,388 person-years of current use, 260 (8.0/1,000 person-years) out-of-hospital and 418 (12.9/1,000) total deaths for benzodiazepines; 26,497 person-years,150 (5.7/1,000) out-of-hospital and 227 (8.6/1,000) total deaths for z-drugs; and 16,177 person-years,156 (9.6/1,000) out-of-hospital and 256 (15.8/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (respective HRs: 0.99 [95% confidence interval, 0.81 to 1.22, p = 0.954] and 0.95 [0.82 to 1.14, p = 0.513] and z-drugs (HRs: 0.96 [0.76 to 1.23], p = 0.767 and 0.87 [0.72 to 1.05], p = 0.153) did not differ significantly from that for trazodone. Patients with concurrent opioids had 4,278 person-years of current use, 90 (21.0/1,000) out-of-hospital and 127 (29.7/1,000) total deaths for benzodiazepines; 3,541 person-years, 40 (11.3/1,000) out-of-hospital and 64 (18.1/1,000) total deaths for z-drugs; and 2,347 person-years, 19 (8.1/1,000) out-of-hospital and 36 (15.3/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (HRs: 3.02 [1.83 to 4.97], p < 0.001 and 2.21 [1.52 to 3.20], p < 0.001) and z-drugs (HRs: 1.98 [1.14 to 3.44], p = 0.015 and 1.65 [1.09 to 2.49], p = 0.018) were significantly increased relative to trazodone; findings were similar with exclusion of overdose deaths or restriction to those with cardiovascular causes. Limitations included composition of the study cohort and potential confounding by unmeasured variables. Conclusions In US Medicare beneficiaries 65 years of age or older without concurrent opioids who initiated treatment with benzodiazepine hypnotics, z-drugs, or low-dose trazodone, study hypnotics were not associated with mortality. With concurrent opioids, benzodiazepines and z-drugs were associated with increased out-of-hospital and total mortality. These findings indicate that the dangers of benzodiazepine–opioid coadministration go beyond the documented association with overdose death and suggest that in combination with opioids, the z-drugs may be more hazardous than previously thought., In a retrospective cohort study, Dr. Wayne Ray and colleagues investigate concurrent opioid and hypnotic use and mortality in older adults in US., Author summary Why was this study done? Benzodiazepines and the related z-drugs are sleep medications commonly prescribed for persons 65 years of age or older. Both can interfere with breathing, which, in turn, may cause irregular heartbeat and deaths. Opioid painkillers, often used with sleep medications, also interfere with breathing and thus could increase the likelihood of deaths with benzodiazepines or z-drugs. Trazodone, an antidepressant that in low doses often is prescribed for insomnia, has not been found to affect breathing and thus may be safer for older patients, particularly for those also taking opioids. What did the researchers do and find? We identified 400,924 persons in the US Medicare program 65 or older who began treatment with benzodiazepine, z-drug, or trazodone sleep medications. For patients without and with opioid use, we compared the rate of out-of-hospital deaths—often related to heart problems—and total mortality during treatment with benzodiazepines and z-drugs to that for trazodone. For patients with opioid exposure, benzodiazepines were associated with respective 302% and 221% increases in out-of-hospital and total mortality, and z-drugs were associated with respective 98% and 65% increases in out-of-hospital and total mortality. What do these findings mean? In older populations, the risks of concurrent benzodiazepine–opioid exposure go beyond the known increased likelihood of overdose, suggesting that greater efforts are needed to prevent use of this medication combination. Patients and clinicians should be aware that in combination with opioids, the z-drugs, thought to be relatively safe, may increase the risk of death.

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.

Objective Studies demonstrating that higher doses of citalopram (> 40 mg) and escitalopram (> 20 mg) prolong the corrected QT interval prompted regulatory agency warnings, which are controversial, given the absence of confirmatory clinical outcome studies. We compared the risk of potential arrhythmia-related deaths for high doses of these selective serotonin reuptake inhibitors (SSRIs) to that for equivalent doses of fluoxetine, paroxetine, and sertraline. Methods The Tennessee Medicaid retrospective cohort study included 54,220 persons 30-74 years of age without cancer or other life-threatening illness who were prescribed high-dose SSRIs from 1998 through 2011. The mean age was 47 years, and 76% were female. Demographic characteristics and comorbidity for individual SSRIs were comparable. Because arrhythmia-related deaths are typically sudden and occur outside the hospital, we analyzed out-of-hospital sudden unexpected death as well as sudden cardiac deaths, a more specific indicator of proarrhythmic effects. Results The adjusted risk of sudden unexpected death for citalopram did not differ significantly from that for the other SSRIs. The respective hazard ratios (HRs) for citalopram versus escitalopram, fluoxetine, paroxetine, and sertraline were 0.84 (95% CI, 0.40-1.75), 1.24 (95% CI, 0.75-2.05), 0.75 (95% CI, 0.45-1.24), and 1.53 (95% CI, 0.91-2.55). There were no significant differences for sudden cardiac death or all study deaths, nor were there significant differences among high-risk patients (≥ 60 years of age, upper quartile baseline cardiovascular risk). Escitalopram users had no significantly increased risk for any study end point. Conclusions We found no evidence that risk of sudden unexpected death, sudden cardiac death, or total mortality for high-dose citalopram and escitalopram differed significantly from that for comparable doses of fluoxetine, paroxetine, and sertraline.

BACKGROUND AND OBJECTIVES: Little is known about opioid prescribing for children without severe conditions. We studied the prevalence of and indications for outpatient opioid prescriptions and the incidence of opioid-related adverse events in this population. METHODS: This retrospective cohort study between 1999 and 2014 included Tennessee Medicaid children and adolescents aged 2 to 17 without major chronic diseases, prolonged hospitalization, institutional residence, or evidence of a substance use disorder. We estimated the annual prevalence of outpatient opioid prescriptions and incidence of opioid-related adverse events, defined as an emergency department visit, hospitalization, or death related to an opioid adverse effect. RESULTS: There were 1 362 503 outpatient opioid prescriptions; the annual mean prevalence of opioid prescriptions was 15.0%. The most common opioid indications were dental procedures (31.1% prescriptions), outpatient procedure and/or surgery (25.1%), trauma (18.1%), and infections (16.5%). There were 437 cases of opioid-related adverse events confirmed by medical record review; 88.6% were related to the child’s prescription and 71.2% had no recorded evidence of deviation from the prescribed regimen. The cumulative incidence of opioid-related adverse events was 38.3 of 100 000 prescriptions. Adverse events increased with age (incidence rate ratio = 2.22; 95% confidence interval, 1.67–2.96; 12–17 vs 2–5 years of age) and higher opioid doses (incidence rate ratio = 1.86 [1.45–2.39]; upper versus lower dose tertiles). CONCLUSIONS: Children without severe conditions enrolled in Tennessee Medicaid frequently filled outpatient opioid prescriptions for acute, self-limited conditions. One of every 2611 study opioid prescriptions was followed by an opioid-related adverse event (71.2% of which were related to therapeutic use of the prescribed opioid).

Purpose Despite significant growth of opioid prescriptions, only limited data are available regarding the comparative safety of long-acting opioids for chronic non-cancer pain. Recent data suggest that transdermal fentanyl and oxycodone CR may have greater toxicity than morphine SR in patients with non-cancer pain. Thus, we compared the risk of out-of-hospital deaths in patients with non-cancer pain filling prescriptions for transdermal fentanyl or oxycodone CR with that for morphine SR. Methods We conducted a retrospective cohort study in 50 658 patients enrolled in Tennessee Medicaid who filled prescriptions for transdermal fentanyl (n = 8717), oxycodone CR (n = 14 118), or morphine SR (n = 27 823) between 1999 and 2011. We excluded individuals with cancer or other life-threatening diagnoses and used propensity scores to adjust for multiple potential confounders. The primary outcome was out-of-hospital mortality. Results During 44 385 person-years of follow-up, 689 patients died. The out-of-hospital mortality rate among all study subjects was 155/10 000 patient-years. Contrary to earlier data suggesting greater risk, mortality was not significantly different in patients filling prescriptions for transdermal fentanyl compared with morphine SR (adjusted HR = 0.96, 95% C.I.: 0.77-1.21); moreover, patients filling prescriptions for oxycodone CR had lower mortality risk compared with those filling prescriptions for morphine SR (adjusted HR = 0.79, 95% C.I. 0.66-0.95). Conclusion In the study population, long-acting opioids for non-cancer pain were associated with high out-of-hospital mortality rates. We found comparable out-of-hospital mortality risks associated with transdermal fentanyl and morphine SR. The risk of out-of-hospital death for oxycodone CR was lower than that for morphine SR.

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.

Objective To assess the risk of adverse fetal outcomes following exposure to individual immunosuppressive drugs in pregnant women with chronic immune-mediated diseases. Methods Health plan data were obtained from the Tennessee Medicaid and Kaiser Permanente Northern California and Southern California claims databases, with linkage to both vital records and medical records. Women with inflammatory arthropathies, those with systemic lupus erythematosus, and those with inflammatory bowel disease who filled prescriptions for immunosuppressive treatments during pregnancy were included. Major congenital malformations, fetal deaths, and life-threatening neonatal complications were identified from the electronic data and validated with medical record review. Results The cohort included 608 infants, including 437 with exposure to immunosuppressive drugs during the mother's pregnancy (402 during the first trimester, and 35 during the second and third trimester only) and 171 whose mothers filled prescriptions for immunosuppressive treatments before, but not during, pregnancy. There were 25 pregnancies (4.1% of the cohort) with confirmed major congenital malformations, and 10 fetal deaths (1.6% of the cohort). Among 113 preterm infants with exposures during pregnancy, 23 (20.4%) had life-threatening neonatal complications, and among 485 term infants, 10 (2.1%) had life-threatening complications. Compared to the reference group (treatment before, but not during, pregnancy), the risk ratios (RRs) for adverse fetal outcomes associated with immunosuppressive treatments (by exposure category) during pregnancy included the following: methotrexate (RR 1.39, 95% confidence interval [95% CI] 0.43–4.53), tumor necrosis factor inhibitors (RR 0.98, 95% CI 0.38–2.55), hydroxychloroquine (RR 1.33, 95% CI 0.69–2.55), and other immunosuppressive medications (RR 0.98, 95% CI 0.48–1.98). Conclusion In this study, there was no evidence of a large increase in risk of adverse fetal outcomes from first-trimester exposure to immunosuppressive medications, although the confidence intervals for the risk ratios were wide. Further studies will be needed as use of these medications increases over time.

IMPORTANCE: Children and youths who are prescribed antipsychotic medications have multiple, potentially fatal, dose-related cardiovascular, metabolic, and other adverse events, but whether or not these medications are associated with an increased risk of death is unknown. OBJECTIVE: To compare the risk of unexpected death among children and youths who are beginning treatment with antipsychotic or control medications. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted from 1999 through 2014 and included Medicaid enrollees aged 5 to 24 years in Tennessee who had no diagnosis of severe somatic illness, schizophrenia or related psychoses, or Tourette syndrome or chronic tic disorder. Data analysis was performed from January 1, 2017, to August 15, 2018. EXPOSURES: Current, new antipsychotic medication use at doses higher than 50 mg (higher-dose group) or 50 mg or lower chlorpromazine equivalents (lower-dose group) as well as control medications (ie, attention-deficit/hyperactivity disorder medications, antidepressants, or mood stabilizers) (control group). MAIN OUTCOMES AND MEASURES: Deaths during study follow-up while out of hospital or within 7 days after hospital admission, classified as either deaths due to injury or suicide or unexpected deaths. Secondary outcomes were unexpected deaths not due to overdose and death due to cardiovascular or metabolic causes. RESULTS: This study included 189 361 children and youths in the control group (mean [SD] age, 12.0 [5.1] years; 43.4% female), 28 377 in the lower-dose group (mean [SD] age, 11.7 [4.4] years; 32.3% female), and 30 120 in the higher-dose group (mean [SD] age, 14.5 [4.8] years; 39.2% female). The unadjusted incidence of death in the higher-dose group was 146.2 per 100 000 person-years (40 deaths per 27 354 person-years), which was significantly greater than that in the control group (54.5 per 100 000 population; 67 deaths per 123 005 person-years) (P

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.

Background Little is known about adherence to guidelines recommending yearly screening with transcranial Doppler (TCD) ultrasonography to detect stroke risk for children with severe sickle cell disease. The objective was to determine the proportion of children with hemoglobin SS (HbSS) or sickle-β0-thalassemia (HbSβ0) aged 2–16 years who received recommended TCD screening from 1997 to 2008, and to identify factors associated with adherence. Procedure A retrospective cohort study included patients enrolled in Tennessee Medicaid with HbSS or HbSβ0 who received care at the two largest sickle cell centers in Tennessee. The outcome of interest was adherence with guidelines for annual screening TCD's, identified from computer claims and validated through medical record review. The cumulative rate of children who received a TCD per year was calculated using the Kaplan–Meier method. Cox proportional hazards regression was used to examine the association of child, family, and health care use characteristics with receiving a TCD. Results Among 338 TCD eligible at-risk children, 232 (68.6%) had at least one TCD during the study period. The yearly cumulative incidence of annual TCD's increased from 2.5% in 1997 to 68.3% in 2008. In multivariate models, calendar year, maternal education, and increased number of sickle cell related outpatient visits were associated with an increased rate of receiving a TCD. Conclusions Publicly insured children with HbSS or HbSβ0 had increasing adherence with TCD screening guidelines between 1997 and 2008, though 31% had no TCD at all during follow-up. Increasing number of sickle cell related outpatient visits was associated with increasing adherence to screening guidelines. Pediatr Blood Cancer 2013;60:270–274. © 2012 Wiley Periodicals, Inc.

Propensity scores are widely used in cohort studies to improve performance of regression models when considering large numbers of covariates. Another type of summary score, the disease risk score (DRS), which estimates disease probability conditional on nonexposure, has also been suggested. However, little is known about how it compares with propensity scores. Monte Carlo simulations were conducted comparing regression models using the DRS and the propensity score with models that directly adjust for all of the individual covariates. The DRS was calculated in 2 ways: from the unexposed population and from the full cohort. Compared with traditional multivariable outcome regression models, all 3 summary scores had comparable performance for moderate correlation between exposure and covariates and, for strong correlation, the full-cohort DRS and propensity score had comparable performance. When traditional methods had model misspecification, propensity scores and the full-cohort DRS had superior performance. All 4 models were affected by the number of events per covariate, with propensity scores and traditional multivariable outcome regression least affected. These data suggest that, for cohort studies for which covariates are not highly correlated with exposure, the DRS, particularly that calculated from the full cohort, is a useful tool.

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.

The authors suggest that placebo-controlled trials in osteoporosis are nearly always unethical, since several drugs that materially decrease the risk of fractures in such patients are currently available.

Automated databases are increasingly used in pharmacoepidemiologic studies. These databases include records of prescribed medications and encounters with medical care providers from which one can construct very detailed surrogate measures for both drug exposure and covariates that are potential confounders. Often it is possible to track day-by-day changes in these variables. However, while this information is often critical for study success, its volume can pose challenges for statistical analysis. One common approach is the use of propensity scores. An alternative approach is to construct a disease risk score. This is analogous to the propensity score in that it calculates a summary measure from the covariates. However, the disease risk score estimates the probability or rate of disease occurrence conditional on being unexposed. The association between exposure and disease is then estimated adjusting for the disease risk score in place of the individual covariates. This review describes the use of disease risk scores in pharmacoepidemiologic studies, and includes a brief discussion of their history, a more detailed description of their construction and use, a summary of simulation studies comparing their performance vis-á-vis traditional models, a comparison of their utility with that of propensity scores, and some further topics for future research.

To test the hypothesis that children enrolled in Medicaid managed care health plans that provide asthma-specific communication to providers would be more likely to have adequate asthma medication filling.We conducted a historical cohort study of 4498 children (2-17 years old) with moderate-severe asthma in Washington State and Tennessee Medicaid managed care programs from 2000 to 2002. Interviews with health plans were conducted to identify communication strategies health plans used to improve asthma care by providers in the plan. The main outcome measure was guideline-recommended filling of asthma preventer medications.Children in plans that provided specific feedback to providers about asthma quality and notified providers when children had an asthma-related event had the highest mean days plus or minus SE of filling in the 365-day follow-up period (164.6 +/- 13 days) compared with children in plans with neither (135.3 +/- 10.8 days; P.05). In children with the greatest asthma severity, enrollment in a plan with both features was associated with 27.1 additional days of filling (95% CI, 0.7-53.4 days) during the follow-up period.Health plan communication to providers was associated with increased preventer filling in children with moderate-severe asthma in 2 state Medicaid programs.

Methadone, a µ-opioid agonist long used as evidence-based treatment for opioid dependence,1 has been increasingly prescribed for chronic pain. In 2009, 4.4 million methadone prescriptions in the U.S. were for treatment of pain, accounting for 9% of prescribed opioid analgesics on a dose-adjusted basis.1 Methadone's primary advantages as an analgesic are a long elimination half-life,2 and low cost;1 however, its efficacy is comparable to that of other long-acting opioids.3 There are major concerns regarding methadone's relative safety. The risk for accidental overdose and lethal respiratory depression may be greater than that for other long-acting opioids. Because the duration of methadone's respiratory depressant effects is longer than that for its analgesic effects,4;5 inadvertent intoxication can occur as dose is increased to provide greater pain relief. This risk may be exacerbated by methadone's highly variable pharmacokinetics.4;5 In 2006, the FDA issued an advisory and the label was modified to warn of the potential for unintentional overdose.5–7 This concern was reinforced by autopsy series of opioid overdose deaths with over-representation of methadone-related cases8;9 and a U.S. study demonstrating a disproportionate number of prescription-opioid-related overdose deaths with methadone involvement.1 Methadone also has adverse cardiac effects. It prolongs the QT interval10 and has been implicated in numerous case reports of life-threatening ventricular arrhythmias.10–13 Cases of sudden cardiac death, the majority of which are due to ventricular arrhythmias,14;15 have been reported in methadone patients.16 These data have led to questions regarding the appropriateness of the widespread use of methadone for the treatment of chronic pain, particularly given other equally effective alternatives.1;3;17 However, the one cohort study comparing methadone to sustained-release (SR) morphine unexpectedly found that adjusted overall mortality was 44% lower for the methadone users.18 Given this controversy, we conducted a cohort study of patients receiving either methadone or morphine SR for non-cancer pain. Given the multiple mechanisms by which an opioid could increase mortality, the primary endpoint was total mortality during study followup.

Although angiotensin-converting enzyme (ACE) inhibitors are avoided in the second and third trimesters of pregnancy because of an increased risk of fetal pathology, adverse fetal outcomes have not been related to first-trimester exposure. For the most part, however, evidence that exposure early in pregnancy is safe comes from a limited number of animal studies and case report analyses. This cohort study included 29,507 infants enrolled in Medicaid in Tennessee who were born in the years 1985 to 2000 and for whom there was no evidence of maternal diabetes. A total of 411 infants had been exposed to some kind of antihypertensive medication only in the first trimester: 209 infants had been exposed to ACE inhibitors and 202 were exposed to other antihypertensive drugs. Among the 202 infants exposed to other antihypertensive agents in the first trimester, the risk of any major congenital malformation was not increased. Of the 209 infants exposed to ACE inhibitors in the first trimester, 18 had major congenital malformations (8.6%); the adjusted proportion was 7.1%. Seven of these 18 infants had multiple malformations, but 5 of the 7 had been exposed in the second trimester as well and 3 had been exposed in all 3 trimesters. The risk ratio (RR) for first-trimester exposure, compared with children not exposed to any type of antihypertensive drug, was 2.71 (95% confidence interval [CI], 1.72–4.27). This RR was the result of an increased number of cardiovascular malformations (n = 8; RR, 3.72; 95% CI, 1.89–7.30) and central nervous system malformations (n = 3; RR, 4.39; 95% CI, 1.37–14.02). Other malformations included renal dysplasia (n = 2), hypospadius, intestinal and choanal atresia, Hirschsprung disease, and diaphragmatic hernia (n = 1 each). A post hoc analysis revealed a significantly increased risk of renal malformations (RR, 9.32; 95% CI, 1.79–48.5), but the risk of the other malformations was not significantly increased. Women of childbearing age, like other individuals, are increasingly being given ACE inhibitors as the indications for these drugs continue to expand. The present findings strongly suggest that these drugs should not be given to pregnant women during the first trimester.

The authors argue that extensive reform of the system of drug regulation in the United States is needed to improve drug safety. In order to develop a more comprehensive system that is not so narrowly focused on testing of drugs before marketing, the authors propose a new federal authority for drug regulation, to be made up of three independent centers: a Center for New Drug Approval, a Center for Post-marketing Studies, and a Center for Drug Information.

Aim: To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. Materials & methods: Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. Results: CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). Conclusion: The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.

Summary Background Controversy has surrounded the question about whether high-dose rofecoxib increases or naproxen decreases the risk of serious coronary heart disease. We sought to establish if risk was enhanced with rofecoxib at either high or standard doses compared with remote non-steroidal anti-inflammatory drug (NSAID) use or celecoxib use, because celecoxib was the most common alternative to rofecoxib. Methods We used data from Kaiser Permanente in California to assemble a cohort of all patients age 18–84 years treated with a NSAID between Jan 1, 1999, and Dec 31, 2001, within which we did a nested case-control study. Cases of serious coronary heart disease (acute myocardial infarction and sudden cardiac death) were risk-set matched with four controls for age, sex, and health plan region. Current exposure to cyclo-oxygenase 2 selective and non-selective NSAIDs was compared with remote exposure to any NSAID, and rofecoxib was compared with celecoxib. Findings During 2 302 029 person-years of follow-up, 8143 cases of serious coronary heart disease occurred, of which 2210 (27·1%) were fatal. Multivariate adjusted odds ratios versus celecoxib were: for rofecoxib (all doses), 1·59 (95% CI 1·10–2·32, p=0·015); for rofecoxib 25 mg/day or less, 1·47 (0·99–2·17, p=0·054); and for rofecoxib greater than 25 mg/day, 3·58 (1·27–10·11, p=0·016). For naproxen versus remote NSAID use the adjusted odds ratio was 1·14 (1·00–1·30, p=0·05). Interpretation Rofecoxib use increases the risk of serious coronary heart disease compared with celecoxib use. Naproxen use does not protect against serious coronary heart disease.

Objectives We investigated whether inhibition of endogenous angiotensin II signaling reduces the recurrence rate of atrial fibrillation (AF) in patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Background Structural and electrical remodeling contribute to AF. Previous experimental studies have implicated the angiotensin II signaling pathway in this process, and recent clinical evidence supports a beneficial effect of inhibiting angiotensin II activity. Methods Using the AFFIRM database, we retrospectively identified a cohort of patients randomized to the rhythm-control arm who were in sinus rhythm. Exposure to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (ANGI) was determined, and the time to first recurrence of AF was compared between ANGI users and nonusers. Results The study cohort included 732 patients not taking ANGI through the initial 2-month follow-up and 421 patients taking ANGI during this time. Patients in the ANGI group more likely had hypertension, diabetes, coronary artery disease, and congestive heart failure compared to patients not taking ANGI. Risk of AF recurrence in the ANGI treatment group did not differ from the risk observed in patients not taking the drugs (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.77–1.09). However, in patients with congestive heart failure or impaired left ventricular function, ANGI use was associated with a lower risk of AF recurrence. Conclusions This analysis provides evidence that ANGI use may be beneficial in some patient subgroups with AF and underscores the need for randomized clinical trials defining more fully the role of angiotensin II inhibition in treating AF.

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.

Filling of prescriptions for medications labelled as category X by the United States Food and Drug Administration (considered to be contraindicated for use in pregnancy) was identified among 95 284 women enrolled in TennCare, Tennessee's programme for Medicaid enrollees and individuals without health insurance. Using administrative claims data, 391 women (4.10/1000) were identified as having filled category X prescriptions during pregnancy. This included 118 women (1.24/1000) who filled prescriptions for non-contraceptive oestrogens, 81 (0.85/1000) for sedatives, and 71 (0.75/1000) for statins. While many women had physician visits with a diagnosis consistent with a possible indication for an individual drug outside of pregnancy, none of these indications is included for use during pregnancy. Older women and disabled women were more likely than younger women (P < 0.0001) and women enrolled for other reasons (P < 0.0001) to fill category X prescriptions. Nearly two-thirds of the 391 women filled prescriptions after clinical signs or pregnancy tests would indicate pregnancy; nearly 40% filled a category X prescription after a pregnancy-related physician visit. Although the absolute rate of category X medication use in pregnancy is low, substantial numbers of women and their fetuses are exposed during pregnancy. Women above the age of 35 years and women enrolled in TennCare because of disabilities were more likely to fill prescriptions for category X medications during pregnancy than others, implying that risk communication to practitioners and women should focus on identification of these women to reduce their risk of exposure.

Background Tricyclic and other related cyclic antidepressants (TCAs), used frequently for the treatment of depression and several other indications, have cardiovascular effects that may increase the risk of sudden cardiac death. We thus sought to quantify the risk of sudden cardiac death among TCA users, according to dose, as well as among users of selective serotonin reuptake inhibitors (SSRIs). Methods We conducted a retrospective cohort study in Tennessee Medicaid, from Jan 1, 1988, through Dec 31, 1993, which included large numbers of antidepressant users and computer files describing medication use and comorbidity. The cohort included 1,282,091 person-years of follow-up for persons aged 15 to 84 years who were not in a nursing home and were free of life-threatening noncardiac illness. This included 58,956 person-years for current use of TCAs alone, 6291 person-years for SSRIs only, and 96,220 person-years for former use. Results The cohort included 1487 confirmed sudden cardiac deaths occurring in the community. When compared with nonusers of antidepressants, current users of TCAs had a dose-related increase in the risk of sudden cardiac death. Rate ratios increased from 0.97 (95% confidence interval [CI], 0.72–1.29) for doses lower than 100 mg (amitriptyline or its equivalent) to 2.53 (95% CI, 1.04–6.12) for doses of 300 mg or more (P = .03, test for dose-response). The rate ratio for SSRIs was 0.95 (95% CI, 0.42–2.15). There was no evidence that TCA doses lower than 100 mg increased the risk of sudden cardiac death in subgroups defined by pre-existing cardiovascular disease, female sex, age 65 years or older, or use of amitriptyline. Conclusions Our data suggest that SSRI antidepressants and TCAs in doses of less than 100 mg (amitriptyline equivalents) did not increase the risk of sudden cardiac death. However, higher doses of TCAs were associated with increased relative risk, which suggests that such doses should be used cautiously, particularly in patients with an elevated baseline risk of sudden death. Clinical Pharmacology & Therapeutics (2004) 75, 234–241; doi: 10.1016/j.clpt.2003.09.019

On July 1, 1996, as a cost-containment strategy, Tennessee's expanded Medicaid program, TennCare, rapidly shifted the provision of mental health services to a fully capitated, specialty "carve-out" program, TennCare Partners. We studied the effect of this transition on the continuity of antipsychotic therapy among patients with severe mental illness who had previously adhered to treatment.Study patients were 21 to 64 years of age, were enrolled throughout the study period, and had adhered to antipsychotic therapy during a 6-month base-line period that preceded the 12 months of study follow-up. The study population included 4507 patients whose follow-up began on the day the change was implemented (the post-transition cohort) and 3644 patients whose follow-up began one year earlier (the pretransition cohort). We compared the two cohorts in terms of the loss of continuity of antipsychotic therapy (missed treatment for more than 60 days during follow-up) and the mean number of days of antipsychotic therapy during follow-up.As compared with the pretransition cohort, the post-transition cohort had increased odds of loss of continuity (a multivariate odds ratio of 1.18 [95 percent confidence interval, 1.07 to 1.30], P=0.001) and a shorter mean duration of antipsychotic therapy (a mean reduction of 4.2 days [95 percent confidence interval, 1.7 to 6.7], P=0.001) during follow-up. This difference was most pronounced among high-risk patients (those requiring the administration of extended-release [depot] injections of antipsychotic medications or who had been hospitalized for psychosis) at base line, for whom continuity was most important (odds ratio for loss of continuity, 1.79 [95 percent confidence interval, 1.45 to 2.22]; P0.001; mean reduction in the number of days of antipsychotic therapy, 14.4 days [95 percent confidence interval, 9.4 to 19.4]; P0.001). These patients had decreased use of antipsychotic drugs immediately after the transition; the lower level persisted throughout the 12 months of follow-up.These findings underscore the need to ensure that shifts to widely used carve-out programs, which are designed primarily to contain costs, do not adversely affect clinical outcomes.

Context: Three recent nested case-control studies conducted in automated databases suggest that users of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have a risk of hip and other osteoporotic fractures half that of non-users of any lipid-lowering drug. However, this comparison may be biased by unmeasured factors associated with treated hyperlipidemias. Objective: To compare the risk of hip fracture among users of statins and other lipid-lowering agents, which is less susceptible to bias than the comparisons performed in the previous studies. Design and setting: Retrospective cohort study conducted in the Tennessee Medicaid program between 1 January 1989 through 31 December 1998. Subjects: New users of all lipid-lowering drugs and randomly selected non-user controls who at baseline were at least 50 years of age and did not have life threatening illness, nursing home residence, or diagnosed dementia or osteoporosis. There were 12 506 persons with new use of statins, 4798 with new use of other lipid lowering drugs, and 17 280 non-user controls. Main outcome measure: Fracture of the proximal femur (hip), excluding pathological fractures or those resulting from severe trauma. Results: During 66 690 person years of follow up, there were 186 hip fractures (2.8 per 1000). Relative to non-users, the adjusted incidence rate ratios (95% confidence interval) were 0.62 (0.45 to 0.85) for statin users and 0.44 (0.26 to 0.95) for other lipid-lowering drugs. When compared directly with the other drugs, the adjusted incidence rate ratio for statins was 1.42 (0.83–2.43). Conclusion: These data provide evidence that the previously observed protective effect of statins may be explained by unmeasured confounding factors.

Background.—Lack of information about medication effects and use in children is a long-standing and troublesome policy issue. Documenting patterns of use for medications with potential for suboptimal use and adverse effects, such as oral corticosteroids, would be useful. Objective.—To describe the use of oral corticosteroids among children enrolled in TennCare, Tennessee's managed care program for Medicaid enrollees and uninsured individuals. Design.—A retrospective cohort study. Drug Exposure.—Children enrolled in TennCare who had prescriptions filled in their name for oral corticosteroids during 1998 were identified. Descriptive information included age, race, sex, and county of residence. We identified possible indications for corticosteroid use for new users by searching encounter files for encounters temporally related to the index prescription. Subsequent use of corticosteroids was measured in the 365 days after the index prescription. Results.—Of 400 724 children continuously enrolled in TennCare during the study period, 29 362 (7327 per 100 000) children had a prescription filled for an oral corticosteroid. Steroid prescription filling was more common among young children and male children and less common among black children. Children in rural counties had oral corticosteroid prescriptions filled at a higher rate than children residing in urban counties. Nearly 75% of corticosteroid users filled only 1 prescription during the study period; 1319 children filled 4 or more prescriptions. Asthma was the most common indication for oral corticosteroid use (16%), whereas 1 in 5 users (22%) had an unknown indication for oral corticosteroid use. Conclusions.—A large number of children enrolled in TennCare had a prescription for oral corticosteroids filled in 1998. Further population-based studies describing the development of adverse effects in users of corticosteroids would be important.

Objective To determine the frequency of use of recommended gastroprotective strategies in a cohort of patients receiving recurrent treatment with nonsteroidal antiinflammatory drugs (NSAIDs). Methods A cross-sectional study was performed using administrative data from the Tennessee Medicaid (TennCare) program. The study population consisted of 76,765 recurrent recipients of NSAIDs (NSAID users), comprising 24% of the 319,402 persons ages 50 years or older enrolled in the TennCare program from January 1999 through June 2000. Frequency of use of either of 2 recommended gastroprotective strategies, involving either traditional NSAIDs combined with recommended anti-ulcer cotherapy or use of a selective cyclooxygenase 2–inhibiting drug (coxib), was measured and categorized by risk for ulcer complication. Results Among this cohort of recurrent NSAID users, 16% received 1 of the 2 recommended gastroprotective therapies: 10% received traditional NSAIDs along with antiulcer drugs at the recommended doses and 6% received coxibs. Among those patients with ≥2 risk factors for ulcer complications (age 75 years or older, peptic ulcer or gastrointestinal bleeding in the past year, or concurrent use of oral anticoagulants or corticosteroids), 30% received such gastroprotective therapy. Conclusion Use of recommended strategies to decrease ulcer complications in vulnerable populations is relatively uncommon.

Summary Background Non-aspirin, non-steroidal anti-inflammatory drugs (NANSAIDs) have complex effects that could either prevent or promote coronary heart disease. Comparison of the NANSAID rofexocib with naproxen showed a substantial difference in acute myocardial infarction risk, which has been interpreted as a protective effect of naproxen. We did an observational study to measure the effects of NANSAIDs, including naproxen, on risk of serious coronary heart disease. Methods We used data from the Tennessee Medicaid programme obtained between Jan 1, 1987, and Dec 31, 1998, to identify a cohort of new NANSAID users (n=181 441) and an equal number of non-users, matched for age, sex, and date NANSAID use began. Both groups were 50–84 years of age, were not resident in a nursing home, and did not have life-threatening illness. The study endpoint was hospital admission for acute myocardial infarction or death from coronary heart disease. Findings During 532634 person-years of follow-up, 6362 cases of serious coronary heart disease occurred, or 11·9 per 1000 person-years. Multivariate-adjusted rate ratios for current and former use of NANSAIDs were 1·05 (95% CI 0·97–1·14) and 1·02 (0·97–1·08), respectively. Rate ratios for naproxen, ibuprofen, and other NANSAIDs were 0·95 (0·82–1·09), 1·15 (1·02–1·28), and 1·03 (0·92–1·16), respectively. There was no protection among long-term NANSAID users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1·05 (0·91–1·21). When naproxen was directly compared with ibuprofen, the current-use rate ratio was 0·83 (0·69–0·98). Interpretation Absence of a protective effect of naproxen or other NANSAIDs on risk of coronary heart disease suggests that these drugs should not be used for cardioprotection.

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.

OBJECTIVES: Recent data showing possible increased risk for suicidal behavior among children and adolescents treated with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants have created significant concern among patients, families, and providers, including concerns about the risk of individual antidepressants. This study was designed to compare the risk for medically treated suicide attempts among new users of sertraline, paroxetine, citalopram, escitalopram, and venlafaxine to risk for new users of fluoxetine. METHODS: A retrospective cohort study included 36 842 children aged 6 to 18 years enrolled in Tennessee Medicaid between 1995 and 2006 who were new users of 1 of the antidepressant medications of interest (defined as filling no prescriptions for antidepressants in the preceding 365 days). Medically treated suicide attempts were identified from Medicaid files and vital records and confirmed with medical record review. RESULTS: Four hundred nineteen cohort members had a medically treated suicide attempt with explicit or inferred attempt to die confirmed through medical record review, including 4 who completed suicide. The rate of confirmed suicide attempts for the study drugs ranged from 24.0 per 1000 person-years to 29.1 per 1000 person-years. The adjusted rate of suicide attempts did not differ significantly among current users of SSRI and SNRI antidepressants compared with current users of fluoxetine. Users of multiple antidepressants concomitantly had increased risk for suicide attempt. CONCLUSIONS: In this population-based study of children recently initiating an antidepressant, there was no evidence that risk of suicide attempts differed for commonly prescribed SSRI and SNRI antidepressants.

OBJECTIVE: To determine the frequency of possible medication errors in a population of older home healthcare patients according to expert panel objective criteria. DESIGN: A cross-sectional survey. SETTING: Two of the largest urban home healthcare agencies in the United States. PARTICIPANTS: Home healthcare patients age 65 and older admitted to selected offices of these agencies between October 1996 and September 1998. MEASUREMENTS: We used two sets of consensus-based expert panel criteria to define possible medication errors. The Home Health Criteria identify patients with patterns of medication use and signs and symptoms that indicate sufficient likelihood of a medication-related problem to warrant reevaluating the patient. The Beers criteria identify medications that experts have deemed generally inappropriate for older patients. RESULTS: The 6,718 study subjects took a median of five drugs; 19% were taking nine or more medications. A possible medication error was identified for 19% of patients according to Home Health Criteria, 17% according to the Beers criteria, and 30% according to either. Possible errors increased linearly with number of medications taken. When patients taking one to three medications were compared with those taking nine or more drugs, the percentages with possible errors were, respectively, 10% and 32% for the Home Health Criteria, 8% and 32% for the Beers criteria, and 16% and 50% for both. CONCLUSION: Nearly one-third of the home healthcare patients surveyed had evidence of a potential medication problem or were taking a drug considered inappropriate for older people. More-effective methods are needed to improve medication use in this vulnerable population. J Am Geriatr Soc 49:719–724, 2001.

Content. The risk for serious gastrointestinal complications due to nonsteroidal anti-inflammatory drugs (NSAIDs) is high in the elderly. Acetaminophen-based regimens are safer and may be as effective as NSAIDs for the treatment of osteoarthritis in many patients. Objective. To determine the effects of an educational program on NSAID use and clinical outcomes in nursing homes. Design and Setting. Randomized controlled study. Ten pairs of Tennessee nursing homes with ≥8% of residents receiving NSAIDs were randomized to intervention or control. Subjects. Nursing home residents (intervention n = 76 and control n = 71) aged 65 years and older taking NSAIDs regularly. Interventions. An educational program for physicians and nursing home staff that included the risks and benefits of NSAIDs in the elderly and an algorithm that substituted acetaminophen, topical agents, and nonpharmacologic measures for the treatment of noninflammatory musculoskeletal pain. Intervention and control subjects were assessed at baseline and 3 months later. Main Outcome Measures. Differences in NSAID and acetaminophen use, and pain, function, and disability scores in intervention and control nursing home subjects. Results. The intervention was effective resulting in markedly decreased NSAID use and increased acetaminophen use. Mean number of days of NSAID use in the 7 day periods before the baseline and 3 month assessments decreased from 7.0 to 1.9 days in intervention home subjects compared with a decrease from 7.0 to 6.2 days in control homes (P = 0.0001). Acetaminophen use in the 7 days immediately before the 3 month assessment increased by 3.1 days in intervention home subjects compared with 0.31 days in control homes (P = 0.0001). A similar proportion of subjects in control (32.5%) and intervention (35.4%) groups had worsening of their arthritis pain score (P = 0.81). Conclusions. An educational intervention effectively reduced NSAID use in nursing homes without worsening of arthritis pain.

Background & Aims Proton pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. Methods This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow-up. The study end points were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. Results Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63−0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94−1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84−1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39−0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70−1.06). Findings were similar in both study populations. Conclusions In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper gastrointestinal bleeding; the greatest reduction occurred in patients also taking antiplatelet drugs or NSAIDs.

Renal prostaglandin inhibition by nonsteroidal antiinflammatory drugs (NSAIDs) may decrease renal function, especially under conditions of low effective circulating volume. To evaluate the risk of important deterioration of renal function due to this effect, the authors performed a nested case-control study using Tennessee Medicaid enrollees agedor =65 years in 1987-1991. Cases were patients who had been hospitalized with community-acquired acute renal failure; they were selected on the basis of medical record review of Medicaid enrollees with selected discharge diagnoses. Information on the timing, duration, and dose of prescription NSAIDs used, demographic factors, and comorbidity was gathered from computerized Medicaid-Medicare data files. Of the 1,799 patients with acute renal failure (4.51 hospitalizations per 1,000 person-years), 18.1% were current users of prescription NSAIDs as compared with 11.3% of 9,899 randomly selected population controls. After control for demographic factors and comorbidity, use of NSAIDs increased the risk of acute renal failure 58% (adjusted odds ratio = 1.58; 95% confidence interval (CI): 1.34, 1.86). For ibuprofen, which accounted for 35% of NSAID use, odds ratios associated with dosages ofor =1,200 mg/day,1,200-2,400 mg/day, andor =2,400 mg/day were 0.94 (95% CI: 0.58, 1.51), 1.89 (95% CI: 1.34, 2.67), and 2.32 (95% CI: 1.45, 3.71), respectively (test for linear trend: p = 0.009). Prescription NSAID use resulted in an estimated 25 excess hospitalizations associated with renal failure per 10,000 years of use. Thus, NSAIDs represent a relatively uncommon but avoidable cause of acute renal failure in frail elderly persons.

Objective. To compare perinatal outcomes among the managed care organizations (MCOs) providing care to beneficiaries enrolled in TennCare, Tennessee's capitated Medicaid managed care program. Design. Retrospective cohort analysis. Subjects. Infants born in Tennessee during 1995 to women enrolled in TennCare. Primary Outcome Measures. Prenatal care use, birth weight (BW), death in the first 60 days of life, and delivery of extremely low BW ( Results. During 1995, 34 402 infants were born to mothers enrolled in TennCare. The MCOs differed widely in the demographic characteristics of their enrollees. In addition, there were small differences in prenatal care utilization, but no differences in BW outcomes among the MCOs. In multivariate analysis, however, infants born to women enrolled in 1 MCO were 2.8 times more likely to die in the first 60 days of life than were infants born to women enrolled in the largest MCO (OR: 2.81; 95% CI: 1.31–6.03). Women enrolled in this same MCO seemed to have a higher proportion of extremely low BW ( Conclusion. The differences among MCOs in early infant death and in the delivery of high-risk infants in hospitals lacking appropriate neonatal facilities suggest that monitoring of care delivery to vulnerable children should include assessment of appropriate use of specialized services.

Objectives.To identify sociodemographic predictors of infant injury mortality and to compare trends in injury mortality rates for high- and low-risk US infants from 1985 to 1991.Design.Historical cohort.Setting/Study Participants.The National Center for Health Statistics linked US infants (Main Outcome Measures.Multivariate regression was used to identify sociodemographic factors associated with injury mortality. The adjusted relative risks (RRs) of maternal age, education, marital status, number of other children, and infant birth weight were used to categorize infants into risk groups. We compared trends in injury rates for the highest and lowest risk groups.Results.There were 5963 injury deaths and 18.6 million infant years or 32.1 injury deaths per 100 000 infant years. Highest risk infants were born to mothers who were younger than 20 years compared with older than 30 years (RR, 3.25; 95% CI, 2.92–3.63), had less than a high school education compared with a college education (RR, 2.22; 95% CI, 1.95–2.53), had more than 2 other children compared with no other children (RR, 3.15; 95% CI, 2.88–3.45), were unmarried (RR, 1.67; 95% CI, 1.57–1.78), or had birth weights ≤1500 g compared with >2500 g (RR, 3.36; 95% CI, 2.94–3.84). Infants in the highest risk group (21.0% of the population) had a >10-fold increased risk of injury mortality compared with the lowest risk group (18.1% of the population) and there was no evidence that this disparity was narrowing.Conclusions.Sociodemographic predictors of infant injury mortality include maternal age, education, number of other children, marital status, and infant birth weight. Based on these factors, 1 in 5 infants in the United States can be identified at birth as having a >10-fold increased risk of injury mortality compared with infants in lowest risk group. Programs to reduce injuries in these high-risk groups are urgently needed.

The aprotinin story began in 1987, when investigators reported that the use of the drug in patients undergoing repeat open-heart surgery decreased the need for blood transfusion by a factor of 8.1 In 1993, the Food and Drug Administration (FDA) approved the use of aprotinin to reduce blood loss during coronary-artery bypass grafting, and the drug became widely used in cardiac surgery. In 2006, the use of aprotinin became controversial when the drug was associated with an increased risk of renal failure, myocardial infarction, stroke, and death in a large observational study.2,3 Two subsequent cohort studies also linked aprotinin . . .