David D. Dore

Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide.

ABSTRACT Objective: To estimate risk and relative risk (RR) of acute pancreatitis among patients using incretin-based diabetes therapies (exenatide or sitagliptin) compared to patients treated with agents with established safety profiles (metformin or glyburide). Research design and methods: The study population was derived from a large US commercial health insurance transaction database using an active drug safety surveillance system (i3 Aperio*). This analysis is based on data from June 2005 through June 2008. Cohorts of exenatide and sitagliptin initiators were each matched to an equal number of metformin or glyburide (met/gly) initiators using propensity scores to reduce confounding in the comparison of outcomes during follow-up. Patients with claims suggesting pancreatic disease in the 6 months prior to cohort entry were excluded. * i3 Drug Safety, Waltham, MA 02451, USA, www.i3aperio.com Main outcome measure: Claims for hospitalizations associated with a primary diagnosis of acute pancreatitis (ICD-9 577.0). Results: There were 27 996 exenatide initiators and 16 276 sitagliptin initiators and approximately equal numbers of matched comparators. During follow-up of up to 1 year, acute pancreatitis occurred among 0.13% of patients treated with exenatide and 0.12% of patients treated with sitagliptin. The risk of acute pancreatitis was comparable for initiators of exenatide (RR 1.0; 95% confidence interval (CI) 0.6–1.7) and sitagliptin (RR 1.0; 95% CI 0.5–2.0) relative to the comparison cohorts. Conclusions: These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.

A cohort study of acute pancreatitis in relation to exenatide use

Aim: Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs.

Nonbenzodiazepine sleep medication use and hip fractures in nursing home residents

IMPORTANCE It is important to understand the relationship between sleep medication use and injurious falls in nursing home residents. OBJECTIVE To conduct a case-crossover study to estimate the association between nonbenzodiazepine hypnotic drug use (zolpidem tartrate, eszopiclone, or zaleplon) and the risk for hip fracture among a nationwide sample of long-stay nursing home residents, overall and stratified by individual and facility-level characteristics. DESIGN AND SETTING Case-crossover study performed in an academic research setting. PARTICIPANTS The study participants included 15,528 long-stay US nursing home residents 50 years or older with a hip fracture documented in Medicare Part A and Part D fee-for-service claims between July 1, 2007, and December 31, 2008. MAIN OUTCOME MEASURES Odds ratios (ORs) of hip fracture were estimated using conditional logistic regression models by comparing the exposure to nonbenzodiazepine hypnotic drugs during the 0 to 29 days before the hip fracture (hazard period) with the exposure during the 60 to 89 and 120 to 149 days before the hip fracture (control periods). Analyses were stratified by individual and facility-level characteristics. RESULTS Among the study participants, 1715 (11.0%) were dispensed a nonbenzodiazepine hypnotic drug before the hip fracture, with 927 exposure-discordant pairs included in the analyses. The mean (SD) age of participants was 81.0 (9.7) years, and 77.6% were female. The risk for hip fracture was elevated among users of a nonbenzodiazepine hypnotic drug (OR, 1.66; 95% CI, 1.45-1.90). The association between nonbenzodiazepine hypnotic drug use and hip fracture was somes greater in new users (OR, 2.20; 95% CI, 1.76-2.74) and in residents with mild vs moderate to severe impairment in cognition (OR, 1.86 vs 1.43; P = .06), with moderate vs total or severe functional impairment (OR, 1.71 vs 1.16; P = .11), with limited vs full assistance required with transfers (OR, 2.02 vs 1.43; P = .02), or in a facility with fewer Medicaid beds (OR, 1.90 vs 1.46; P = .05). CONCLUSIONS AND RELEVANCE The risk for hip fracture is elevated among nursing home residents using a nonbenzodiazepine hypnotic drug. New users and residents having mild to moderate cognitive impairment or requiring limited assistance with transfers may be most vulnerable to the use of these drugs. Caution should be exercised when prescribing sleep medications to nursing home residents.

Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users

BACKGROUND We extended an earlier study that found a twofold higher risk of venous thromboembolism (VTE) associated with the transdermal contraceptive system relative to norgestimate-containing oral contraceptives (NGM-OC). STUDY DESIGN This case-control study identified potential cases of VTE, acute myocardial infarction (AMI) and stroke from 24 months of additional health care claims, with adjudication via medical records. Randomly selected controls were matched to cases on age (15-44 years) and characteristics of contraception use. Conditional logistic regression models provided odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS The transdermal contraceptive system was associated with a twofold higher risk of VTE (OR 2.0; 95% CI 1.2-3.3) compared with users of NGM-OC. The OR for stroke was 0.6 (95% CI 0.1-3.2) and for AMI 1.2 (95% CI 0.3-4.7). CONCLUSION This extension was consistent with the earlier study, showing a twofold increased risk of VTE associated with use of the transdermal contraceptive system relative to NGM-OC.

Effect of discontinuing cholinesterase inhibitor therapy on behavioral and mood symptoms in nursing home patients with dementia

BACKGROUND Cholinesterase inhibitors (CHEIs) ameliorate some types of behavioral symptoms in patients with Alzheimers disease. However, there has been little previous study of the outcomes associated with discontinuing these medications. OBJECTIVE The primary aim of this study was to evaluate the extent to which discontinuing CHEI therapy affected behavioral and mood symptoms in a cohort of nursing home residents with a diagnosis of dementia compared with residents receiving longer-term CHEI therapy. METHODS This was a retrospective cohort study using Rhode Island Medicaid prescription claims and the Minimum Data Set (MDS). Participants were Rhode Island nursing home residents aged > or =60 years with a diagnosis of Alzheimers disease or non-Alzheimers dementia, treated with CHEI monotherapy, and enrolled in the Medicaid program between January 1, 2004, and December 31, 2005. The discontinuation cohort (CHEI-DC) was selected by identifying residents who received 3 to 9 months of uninterrupted CHEI therapy. The continuation cohort (CHEI-CONT) was prescribed continuous CHEI therapy for >9 months. Changes in scores on the Aggressive Behavior Scale (ABS) and the Depression Rating Scale (DRS) for CHEI-DC residents were compared with changes in scores for CHEI-CONT residents. Secondary outcomes included change over time for individual behavioral symptoms and indicators of cognitive and functional status coded on the MDS. RESULTS The final matched sample (N = 178) included 62 CHEI-DC cases and 116 CHEI-CONT controls. More than half of the cohort was aged > or =85 years, and the sample was predominantly female. A diagnosis of Alzheimers disease was documented in 40.3% of the CHEI-DC patients and in 46.5% of the CHEI-CONT patients. Behavioral worsening, indicated by an increase in the estimated mean monthly point change in ABS score, occurred in the CHEI-DC group (0.08; 95% CI, 0.01 to 0.16) but not in the CHEI-CONT group (-0.01; 95% CI, -0.06 to 0.04), and the between-group difference was significant (0.09; 95% CI, 0.01 to 0.18). There were no significant between-group differences in the mean monthly point change in mood symptoms on the DRS (0.04; 95% CI, -0.03 to 0.12). For the secondary outcomes, the mean monthly MDS point change for frequency of repetitive verbal behaviors indicated that CHEI-DC patients exhibited significantly more episodes of repetitive questioning (0.17; 95% CI, 0.05 to 0.29) and repetitive health complaints (0.16; 95% CI, 0.04 to 0.27) compared with CHEI-CONT residents. Continued use of CHEIs was associated with more time spent in leisure-related activities over the study period (-0.26; 95% CI, -0.50 to -0.02), with the CHEI-DC group spending less time in activities (0.11; 95% CI, 0 to 0.23); the between-group difference was also significant (0.37; 95% CI, 0.10 to 0.65). CONCLUSION Results of this retrospective analysis suggest that, compared with longer duration of CHEI therapy, discontinuation of CHEIs in these nursing home residents with dementia was associated with some adverse behavioral changes and decreased time spent engaging in leisure-related activities.

Telithromycin Use and Spontaneous Reports of Hepatotoxicity

AbstractBackground and objective: Recent reports have described cases of telithromycin-related hepatotoxicity. The objective of this study is to quantify the effect of telithromycin use on the risk of hepatotoxicity. Methods: We conducted a spontaneous-report case-control study of hepatotoxicity in telithromycin recipients using reports from the US FDA Adverse Event Reporting System. Reports from between 1 January 2005 and 30 June 2005 were examined. Cases included reports of patients with abnormal liver function tests, hepatocellular damage and hepatic impairment, while patients with reported conditions with similar reporting probabilities were considered as controls. The primary outcome measure of the analysis was the reporting odds ratio (ROR) evaluating the a priori hypothesis that telithromycin use confers an elevated risk of hepatotoxicity relative to other agents. Results: A total of 2219 cases and 20 667 controls were identified. We estimated an ROR for hepatotoxicity associated with telithromycin compared with other agents of 1.82 (95% CI 1.12, 2.96) after controlling for age and gender, approximating an 82% excess risk in users of telithromycin relative to users of other agents. Conclusions: This analysis is the first to specifically quantify the effect of telithromycin on the risk of hepatotoxicity. Telithromycin use may increase the risk of hepatotoxicity by >80%. Biases inherent in spontaneous reports include under-reporting of events and differential or time-varying reporting due to enhanced clinician awareness. Future studies should employ alternative data sources because of the inherent limitations of passive surveillance systems.

Atypical antipsychotic use and risk of fracture in persons with Parkinsonism.

Our objective was to estimate the effect of atypical antipsychotics (AAs) on the rate of fractures in a parkinsonism population. We conducted an age‐ and state‐matched nested case‐control study in five states (CA, FL, NY, OH, IL) using the Medicaid analytic extract from 2001 to 2002. Eligible participants had a diagnosis of parkinsonism, excluding persons with secondary parkinsonism, bone cancer, bone infections, schizophrenia, schizoaffective disorder, and those who used conventional antipsychotics. The primary outcome was the occurrence of a fracture of the femur, ankle, fibula, tibia, humerus, radius, or ulna (N = 851). Risk‐set sampling defined controls (N = 4220). We used conditional‐logistic regression to derive adjusted odds ratios (AOR) and 95% confidence intervals of the association between fracture and use of quetiapine, risperidone, or olanzapine in the 60 days before the index date compared to nonuse. After adjustment for confounding, use of quetiapine (AOR 2.4; 95% CI 1.5–3.8), risperidone (AOR 1.2; 95% CI 0.9–1.7), or olanzapine (AOR 1.7; 95% CI 1.2–2.4) was associated with a higher rate of fracture. Use of an AA was associated with a higher rate of fracture in persons with parkinsonism. Prescribers must be cautious when using these agents in elderly persons with parkinsonism.

A pooled analysis of exenatide use and risk of acute pancreatitis

Abstract Objective: To estimate the association between exenatide BID use and acute pancreatitis across two claims-based studies. Research design and methods: We pooled two cohort studies within separate commercial health insurance databases. We included initiators of exenatide BID and all other antihyperglycemic drugs without prior pancreatitis from 2005−2008. Poisson regression models provided rate ratios (RRs) and 95% confidence intervals (CIs) of the association of exenatide BID with acute pancreatitis adjusted for quintiles of propensity scores. Main outcome measures: Primary inpatient diagnoses of acute pancreatitis with correction for misclassification via a validation sub-study. Results: There were 49,956 initiators of exenatide BID and 692,333 initiators of other antihyperglycemic drugs. Patients in the two studies were similar on many demographic and clinical characteristics. Exenatide BID initiators had a higher prevalence of diagnoses consistent with diabetes complications (e.g. peripheral neuropathy) and cardiovascular risk factors (e.g. hypertension). In both studies, current exenatide BID use was not associated with uncorrected outcomes of acute pancreatitis (pooled RR 1.0; CI 0.8–1.3). PPV correction resulted in a slightly higher point estimate for current use (pooled RR 1.3; CI 1.0–1.7) and past use (pooled RR 1.6; 95% CI 1.2−2.1). Conclusions: These data are consistent with little or no higher risk of acute pancreatitis associated with current exenatide BID use relative to nonuse. Although previous work identified non-causal mechanisms, an increased incidence of acute pancreatitis following cessation of treatment remains a possibility. Bias due to residual confounding or outcome misclassification may remain, and should be considered a potential explanation for these findings.

Association of β-Blockers With Functional Outcomes, Death, and Rehospitalization in Older Nursing Home Residents After Acute Myocardial Infarction

Importance Although &bgr;-blockers are a mainstay of treatment after acute myocardial infarction (AMI), these medications are commonly not prescribed for older nursing home residents after AMI, in part owing to concerns about potential functional harms and uncertainty of benefit. Objective To study the association of &bgr;-blockers after AMI with functional decline, mortality, and rehospitalization among long-stay nursing home residents 65 years or older. Design, Setting, and Participants This cohort study of nursing home residents with AMI from May 1, 2007, to March 31, 2010, used national data from the Minimum Data Set, version 2.0, and Medicare Parts A and D. Individuals with &bgr;-blocker use before AMI were excluded. Propensity score–based methods were used to compare outcomes in people who did vs did not initiate &bgr;-blocker therapy after AMI hospitalization. Main Outcomes and Measures Functional decline, death, and rehospitalization in the first 90 days after AMI. Functional status was measured using the Morris scale of independence in activities of daily living. Results The initial cohort of 15 720 patients (11 140 women [70.9%] and 4580 men [29.1%]; mean [SD] age, 83 [8] years) included 8953 new &bgr;-blocker users and 6767 nonusers. The propensity-matched cohort included 5496 new users of &bgr;-blockers and an equal number of nonusers for a total cohort of 10 992 participants (7788 women [70.9%]; 3204 men [29.1%]; mean [SD] age, 84 [8] years). Users of &bgr;-blockers were more likely than nonusers to experience functional decline (odds ratio [OR], 1.14; 95% CI, 1.02-1.28), with a number needed to harm of 52 (95% CI, 32-141). Conversely, &bgr;-blocker users were less likely than nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67-0.83) and had similar rates of rehospitalization (HR, 1.06; 95% CI, 0.98-1.14). Nursing home residents with moderate or severe cognitive impairment or severe functional dependency were particularly likely to experience functional decline from &bgr;-blockers (OR, 1.34; 95% CI, 1.11-1.61 and OR, 1.32; 95% CI, 1.10-1.59, respectively). In contrast, little evidence of functional decline due to &bgr;-blockers was found in participants with intact cognition or mild dementia (OR, 1.03; 95% CI, 0.89-1.20; P = .03 for effect modification) or in those in the best (OR, 0.99; 95% CI, 0.77-1.26) and intermediate (OR, 1.05; 95% CI, 0.86-1.27) tertiles of functional independence (P = .06 for effect modification). Mortality benefits of &bgr;-blockers were similar across all subgroups. Conclusions and Relevance Use of &bgr;-blockers after AMI is associated with functional decline in older nursing home residents with substantial cognitive or functional impairment, but not in those with relatively preserved mental and functional abilities. Use of &bgr;-blockers yielded a considerable mortality benefit in all groups.

Age, Antipsychotics, and the Risk of Ischemic Stroke in the Veterans Health Administration

Background and Purpose— Time-dependent effects of antipsychotics on risk of stroke and potential effect modification by age have not been fully investigated. A case–case–time–control design uses within- and between-case comparisons to evaluate short-term effects at the same time as adjusting for unmeasured time-invariant confounders and exposure-time trends. Methods— We conducted a case–case–time–control design study using data from the Veterans Health Administration. Veterans with inpatient hospitalizations for ischemic stroke between 2002 and 2007 were included. For every stroke case, the “current” exposure period was defined as 1 to 30 days before hospitalization and the “reference” period as 91 to 120 days before hospitalization. Exposure during the current period was compared with exposure during the reference period within cases. Exposure-time trend-adjusted estimates of the effect of antipsychotic exposure on risk of stroke were obtained by dividing exposure odds for antipsychotic exposure by average exposure odds for other medications over the same time period among the same cases. Results— After adjusting for exposure-time trends, odds of stroke were 1.8 (95% CI, (1.7–1.9) times higher when exposed to antipsychotics than when unexposed. Age-stratified estimates suggest a greater triggering effect of antipsychotics among older patients. Conclusions— Exposure to antipsychotics may be a proximal trigger for stroke. Elevation in risk is apparent after brief exposure to antipsychotics.