Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants.

Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person-time exposed to both an SMR and one of the three most dispensed opioids-hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids-synchronically triggered, opioid-triggered, and SMR-triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone-SMR-triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23-2.82) for carisoprodol and 1.73 (1.09-2.73) for tizanidine. In the tramadol-synchronically triggered cohort, the adjusted HRs were 0.69 (0.49-0.97) for metaxalone and 0.62 (0.42-0.90) for tizanidine. In the tramadol-SMR-triggered cohort, the adjusted HRs were 1.51 (1.01-2.26) for baclofen and 1.48 (1.03-2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.

Comparative safety of antimuscarinics versus mirabegron for overactive bladder in Parkinson disease.

BACKGROUND: Overactive bladder (OAB) is a common non-motor symptom of Parkinson disease (PD), often treated with antimuscarinics or beta-3 agonists. There is lack of evidence to guide OAB management in PD. OBJECTIVES: To assess the comparative safety of antimuscarinics versus beta-3 agonists for OAB treatment in PD. METHODS: We employed a new-user, active-comparator cohort study design. We included Medicare beneficiaries age ≥65 years with PD who were new users of either antimuscarinic or beta-3 agonist. The primary outcome was any acute care encounter (i.e., non-elective hospitalization or emergency department visit) within 90 days of OAB drug initiation. The main secondary outcome was a composite measure of acute care encounters for anticholinergic related adverse events (AEs). Matching on high-dimensional propensity score (hdPS) was used to address potential confounding. We used Cox proportional hazards models to examine the association between OAB drug category and outcomes. We repeated analyses for 30- and 180-day follow-up periods. RESULTS: We identified 27,091 individuals meeting inclusion criteria (mean age: 77.8 years). After hdPS matching, antimuscarinic users had increased risks for any acute care encounter (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.12-1.37) and encounters for anticholinergic related AEs (HR 1.18, 95% CI 1.04-1.34) compared to beta-3 agonist users. Similar associations were observed for sensitivity analyses. CONCLUSIONS: Among persons with PD, anticholinergic initiation was associated with a higher risk of acute care encounters compared with beta-3 agonist initiation. The long-term safety of anticholinergic vs. beta-3 agonist therapy in the PD population should be evaluated in a prospective study.

Potentially inappropriate medications in older adults with Parkinson disease before and after hospitalization for injury.

BACKGROUND: Parkinson disease (PD) patients are at increased risk of serious injury, such as fall-related fractures. Prescription medications are a modifiable factor for injury risk. OBJECTIVES: To determine the extent to which a serious injury requiring hospitalization affects prescribing of potentially inappropriate medications (PIMs) among older adults with PD. METHODS: We conducted a quasi-experimental difference-in-difference (DID) study using 2013-2017 Medicare data. The cohort consisted of beneficiaries with PD hospitalized for injury versus for other reasons. PIMs were classified into PD and injury-relevant categories (CNS-active PIMs, PD motor symptom PIMs, PD non-motor symptom PIMs, PIMs that reduce bone mineral density). We estimated mean standardized daily doses (SDDs) of medications within each PIM category before and at 3, 6, and 12 months after hospitalization. We used generalized linear regression models to compare changes in mean SDDs for each PIM category between the injury and non-injury group at each timepoint, adjusting for biological, clinical and social determinants of health variables. RESULTS: Both groups discontinued PIMs and/or reduced PIM doses after hospitalization. There were no between-group differences in mean SDD changes, after covariate adjustment, for any PIM category, except for the CNS-active PIMs category at 3 months (DID p-value = 0.00) and for the category of PIMs that reduce bone mineral density at all timepoints (DID p-values = 0.02, 0.04, 0.02 at 3, 6, and 12 months). CONCLUSIONS: Similar patterns of PIM among persons with PD after hospitalization for serious injury versus for other reasons may represent a missed opportunity to deprescribe high-risk medications during care transitions.

Core concepts in pharmacoepidemiology: Key biases arising in pharmacoepidemiologic studies.

Pharmacoepidemiology has an increasingly important role in informing and improving clinical practice, drug regulation, and health policy. Therefore, unrecognized biases in pharmacoepidemiologic studies can have major implications when study findings are translated to the real world. We propose a simple taxonomy for researchers to use as a starting point when thinking through some of the most pervasive biases in pharmacoepidemiology. We organize this discussion according to biases best assessed with respect to the study population (including confounding by indication, channeling bias, healthy user bias, and protopathic bias), the study design (including prevalent user bias and immortal time bias), and the data source (including misclassification bias and missing data/loss to follow up). This tutorial defines, provides a curated list of recommended references, and illustrates through relevant case examples these key biases to consider when planning, conducting, or evaluating pharmacoepidemiologic studies.

Skeletal muscle relaxant drug-drug-drug interactions and unintentional traumatic injury: Screening to detect three-way drug interaction signals.

AIM: The aim of this study was to identify skeletal muscle relaxant (SMR) drug-drug-drug interaction (3DI) signals associated with increased rates of unintentional traumatic injury. METHODS: We conducted automated high-throughput pharmacoepidemiologic screening of 2000-2019 healthcare data for members of United States commercial and Medicare Advantage health plans. We performed a self-controlled case series study for each drug triad consisting of an SMR base-pair (i.e., concomitant use of an SMR with another medication), and a co-dispensed medication (i.e., candidate interacting precipitant) taken during ongoing use of the base-pair. We included patients aged ≥16 years with an injury occurring during base-pair-exposed observation time. We used conditional Poisson regression to calculate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) for injury with each SMR base-pair + candidate interacting precipitant (i.e., triad) versus the SMR-containing base-pair alone. RESULTS: Among 58 478 triads, 29 were significantly positively associated with injury; confounder-adjusted RRs ranged from 1.39 (95% CI = 1.01-1.91) for tizanidine + omeprazole with gabapentin to 2.23 (95% CI = 1.02-4.87) for tizanidine + diclofenac with alprazolam. Most identified 3DI signals are new and have not been formally investigated. CONCLUSION: We identified 29 SMR 3DI signals associated with increased rates of injury. Future aetiologic studies should confirm or refute these SMR 3DI signals.

Risk of Serious Infection With Low-dose Glucocorticoids in Patients With Rheumatoid Arthritis: An Instrumental Variable Analysis.

BACKGROUND: Low-dose glucocorticoids are commonly used in the treatment of rheumatoid arthritis (RA). Observational studies have found an increased risk of serious infection associated with low-dose glucocorticoids, but concerns about residual confounding remain. METHODS: We identified adults with RA on stable immunomodulatory therapy for >6 months receiving no glucocorticoids or ≤5 mg/day using Medicare data from 2006 to 2015. We used provider preference for glucocorticoids as an instrumental variable (IV) to assess associations between low-dose glucocorticoid use and the risk of infection requiring hospitalization using a cause-specific proportional hazards model. RESULTS: We identified 163,603 qualifying treatment episodes among 120,656 patients. Glucocorticoids ≤5 mg/day were used by 25,373/81,802 (31.0%) of patients seen by a rheumatologist with low provider preference for glucocorticoids and by 36,087/81,801 (44.1%) of patients seen by a rheumatologist with high provider preference for glucocorticoids (adjusted odds ratio 1.81, 95% confidence interval 1.77, 1.84 for association between provider preference and glucocorticoids). Chronic obstructive pulmonary disease, opioids, antibiotics, previous emergency department visits, hospitalizations, and infections requiring hospitalization infections were unbalanced with regard to exposure but not to the IV. The incidence of infection requiring hospitalization was 8.0/100 person-years among patients unexposed to glucocorticoids versus 11.7/100 person-years among those exposed. The association between glucocorticoids and infection requiring hospitalization from IV analysis (hazard ratio 1.26 [1.02-1.56]) was similar to results from a standard multivariable model (hazard ratio 1.24 [1.21-1.28]). CONCLUSIONS: Among patients with RA on stable immunomodulatory therapy, IV analysis based on provider preference demonstrated an increased risk of infection requiring hospitalization associated with low-dose glucocorticoids, similar to a traditional analysis.

Angiotensin-Converting Enzyme Inhibitors Used Concomitantly with Insulin Secretagogues and the Risk of Serious Hypoglycemia.

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.

Use of prescription drug samples in the US and implications for pharmacoepidemiologic research: a systematic search of the literature.

INTRODUCTION: Free drug samples are not captured in the pharmacy claims databases used in many pharmacoepidemiologic studies, which could lead to misclassification of drug exposure status and thus bias study results. AREAS COVERED: We systematically searched the literature in PubMed/MEDLINE, Embase, and Scopus from database inception to August 2020 for studies assessing the magnitude of exposure misclassification in pharmacy claims data associated with uncaptured drug sample utilization. Our review identified five US-based studies with substantially different characteristics, contexts, methods, and results. Taken together, these studies suggest that the risk of sample-related bias may be higher for (1) studies of newly approved, patented brand-only drugs in specific classes and contexts; (2) studies of populations where sample use is common and the unexposed cohort is small; and (3) studies where the outcomes of interest are expected to be early-onset or acute, with non-constant hazards. EXPERT OPINION: In light of declining overall trends in sample use, future research on sample-related exposure misclassification should focus on delineating bias across those modern contexts where sample use remains high and optimizing bias quantification methods to create a more standardized approach. Additionally, further assessment is warranted for other sources of misclassified exposure status in claims-based pharmacoepidemiology research.

Annual Prevalence of Use of Potentially Inappropriate Medications for Treatment of Affective Disorders in Parkinson's Disease.

OBJECTIVE: To examine the national prevalence of pharmacological treatment of affective disorders in older adults with Parkinson's disease (PD), and determine the prevalence and risk factors for receipt of an American Geriatrics Society Beers Criteria® defined potentially inappropriate medication (PIM) for affective disorder treatment. DESIGN: Cross-sectional analysis of 2014 Medicare data. SETTING: Research Identifiable File data from the Centers for Medicare and Medicaid Services. PARTICIPANTS: Individuals ≥65 years of age with PD whose inpatient, outpatient, and prescription care is administered through the U.S. Medicare Program. MEASUREMENTS: The 2014 prevalence of affective (i.e., depressive and anxiety) disorders was calculated. We assessed prescription fills for affective disorder treatment and classified prescriptions according to PIM status. Patient and clinician factors associated with PIM prescriptions were determined. RESULTS: Of 84,323 beneficiaries with PD, 15.1% had prevalent depression only, 7.5% had anxiety only, and 8.5% had comorbid depression and anxiety. Among those with depression only, 80.7% were treated in 2014 (12.8% of treated received at least one PIM). The annual treatment prevalence was 62.9% (75.9% PIM) and 93.1% (63.9% PIM) in the anxiety only and comorbid group, respectively. In most groups, PIM use was less likely among men and those with dementia; geriatricians were less likely to prescribe PIMs. CONCLUSION: Treatment of affective disorders in persons diagnosed with PD is high. PIM use is also common, particularly in persons with anxiety. Future research will quantify the potential effects of these PIMs on clinical and patient outcomes.

Impact of Hospitalization and Medication Switching on Post-discharge Adherence to Oral Anticoagulants in Patients With Atrial Fibrillation.

BACKGROUND: Adherence to chronic medications remains poor in practice. There is limited evidence on how hospitalization affects post-discharge adherence to oral anticoagulants (OACs) in individuals with atrial fibrillation. The aim of this study was to examine the impact of hospitalization and medication switching on post-discharge adherence to OACs in the population with atrial fibrillation. METHODS: A quasi-experimental pre-post observational study was conducted using United States commercial insurance health care claims from the 2009 to 2016 Optum database. Adults with atrial fibrillation taking OACs who had a random hospitalization occurring after the first observed OAC prescription fill and no other admission in the preceding and following 6 months were identified. OAC adherence was estimated by the proportion of days covered within 6 and 12 months before and after hospitalization. Difference-in-difference analysis was employed to compare the pre-hospitalization and post-hospitalization proportion of days covered, stratified by reasons for hospitalization (i.e., bleeding vs non-bleeding-related reasons) and adjusting for imbalanced baseline characteristics between groups. Change in adherence when the OAC was switched at discharge was also examined. RESULTS: The 22,429 individuals who met study criteria were predominantly male (52.4%), white (77.2%), and older age (median 74 years). A clinically significant hemorrhage was the reason for 1029 (4.5%) of qualifying hospitalizations. After covariate adjustment, there was a reduction in the proportion of days covered after discharge, regardless of admission diagnosis (p<0.0001). The 6-month difference-in-difference analyses revealed that adherence was incrementally reduced by 3.2% (p=0.0003) in the bleeding group compared with the nonbleeding group, whereas switching from warfarin to a direct oral anticoagulant after hospitalization was associated with a smaller reduction by 3.4% in adherence (p=0.0342) compared with other switchers, regardless of the reason for hospitalization. The 12-month difference-in-difference analyses revealed similar results. CONCLUSIONS: Hospitalization is temporally associated with a reduction in adherence to OACs, regardless of reason for hospitalization. More effective strategies are needed to improve OAC adherence, particularly during transition of care.

Incidence rates of and risk factors for opioid overdose in new users of prescription opioids among US Medicaid enrollees: A cohort study.

PURPOSE: To measure incidence rates of and risk factors for opioid overdose among new users of prescription opioids in the Medicaid population. METHODS: A cohort study using Medicaid claims from four states (1999-2012) among adults continuously enrolled in Medicaid for ≥3 years free of opioid prescriptions and opioid overdose before cohort entry. Exposure and outcome of interest were prescription opioid use and apparent incident opioid overdose identified in inpatient and outpatient claims (sensitivity ≈ 97%; positive predictive value ≈ 87%), respectively. RESULTS: Among new prescription opioid users (1 336 140 persons; 246 466 person-years), the overall opioid overdose incidence rate per 100 000 person-years was 247.1 (95% confidence interval [CI], 227.5-266.7), with 251.0 (CI, 188.6-313.5) in 2002 and 225.5 (CI, 142.0-309.0) in 2012. A lower hazard for opioid overdose was seen for age 65-80 years (adjusted hazard ratio [HR], 0.50; CI, 0.37-0.66) and 80-100 years (0.35; 0.23-0.52) vs 18-35 years; females (0.79; 0.67-0.93) vs males; and other/unknown race/ethnicity (0.71; 0.54-0.93) vs whites. A higher hazard was seen for initial opioid dose in morphine milligram equivalents (MMEs), 50-100 MME/day (1.52; 1.24-1.86) and >100 MME/day (1.98; 1.55-2.53), vs <50 MME/day; prior diagnosis of substance use disorders (2.30; 1.91-2.79) or mental health conditions (1.75; 1.47-2.08); and prior prescriptions for benzodiazepines (1.43; 1.13-1.81). CONCLUSION: In Medicaid enrollees in four study states during 2002 to 2012, opioid overdose incidence rate per 100 000 person-years among apparent new users of prescription opioids was 247.1, with 251.0 in 2002 and 225.5 in 2012. Younger ages, white race/ethnicity, higher MME opioid daily doses, prior substance use disorders, mental health conditions, and benzodiazepine prescriptions were associated with a higher risk of opioid overdose incidence.

Assessment of Beliefs and Attitudes About Statins Posted on Twitter: A Qualitative Study.

Importance: Statins are prescribed to help lower cholesterol levels but have poor adherence rates. Attitudes or beliefs toward medications are important to ascertain because they may be associated with patient behavior. Objective: To identify health-related discussion in Twitter posts mentioning a statin and analyze the content within these posts. Design, Setting, and Participants: This qualitative study included 11 852 posts related to 1 of 8 statins (7 licensed for use in the United States and 5 licensed in the United Kingdom) collected from May 10, 2013, to August 28, 2018. Twitter posts were identified as health related or not, and if health related, whether they were posted by a statin user, someone who knows a statin user, a health care professional, or undetermined. The health-related tweets were classified by the type of information posted, such as a belief about the medication, an adverse event, a question, or a reference to the cost of the medication. Data were analyzed from January 22 to November 19, 2019. Main Outcomes and Measures: The number of posts by each user type identified and the categories identified by analyzing the content. Results: Of the 11 852 Twitter posts about statins, 5201 (43.9%) were health related. The most frequent posts provided resource information, such as a link to a journal article (1824 of 5201 [35.1%]). The second most frequent type of health-related posts included personal beliefs or attitudes toward statins (1097 of 5201 [21.1%]). Personal experiences of adverse events (353 of 5201 [6.8%]), discussions about dosage (320 of 5201 [6.2%]), and questions about statins (191 of 5201 [3.7%]) followed. Posts indicated polarized beliefs and attitudes to statins from saving lives to causing death. Some beliefs, such as the direct confirmation that the use of statins mitigates the effects of an unhealthy diet, have not been extensively highlighted as common practice in the literature. Conclusion and Relevance: This qualitative content analysis of Twitter posts about statins provides insights into beliefs about statins. Patient perspectives gathered from social media may help to inform research and improve public health messages and communication between health care professionals and patients.

Assessment of Physician Prescribing of Muscle Relaxants in the United States, 2005-2016.

Importance: Little is known to date about national trends in the prescribing of skeletal muscle relaxants (SMRs), the use of which is associated with important safety concerns, especially in older adults and in those who use concomitant opioids. Objective: To measure national trends in SMR prescribing over a 12-year period. Design, Setting, and Participants: This cross-sectional study used data from the National Ambulatory Medical Care Survey from January 2005 to December 2016. Data were analyzed from August 21, 2018, to July 18, 2019. The study included patients with ambulatory care visits who had encounters with non-federally funded, office-based physicians in the United States. Exposures: SMR use, categorized as newly prescribed or continued therapy at the office visit. Main Outcomes and Measures: Ambulatory care visits-overall and stratified by calendar year, geographic region, and patient age, sex, and race-in which an SMR was newly prescribed or continued were quantified. Among office visits in which an SMR was newly prescribed, diagnoses were assessed. Concomitant medications were quantified for all office visits, stratified by new or continued therapy. Survey visit weights were used to estimate nationally representative measures, and age-standardized rates were generated by geographic region using US Census data. Results: This study included a total of 314 970 308 office visits (mean [SD] age, 53.5 [15.2] years; 194 621 102 [61.8%] men and 120 349 206 [38.2%] women). In 2016, there were 30 730 262 (95% CI, 30 626 464-30 834 060) US ambulatory care visits in which an SMR was either newly prescribed or continued as ongoing therapy. Patients in these visits were most frequently female (58.2% [95% CI, 57.9%-58.6%]), white (53.7% [95% CI, 53.4%-54.0%]), and aged 45 to 64 years (48.5% [95% CI, 48.2%-48.9%]). During the study period, office visits with a prescribed SMR nearly doubled from 15.5 million (95% CI, 15.4-15.6 million) in 2005 to 30.7 million (95% CI, 30.6-30.8 million) in 2016. Although visits for new SMR prescriptions remained stable, office visits with continued SMR drug therapy tripled from 8.5 million (95% CI, 8.4-8.5 million) visits in 2005 to 24.7 million (95% CI, 24.6-24.8 million) visits in 2016. Older adults accounted for 22.2% (95% CI, 21.8%-22.6%) of visits with an SMR prescription. Concomitant use of an opioid was recorded in 67.2% (95% CI, 62.0%-72.5%) of all visits with a continuing SMR prescription. Conclusions and Relevance: This study found that SMR use increased rapidly between 2005 and 2016, which is a concern given the prominent adverse effects and limited long-term efficacy data associated with their use. These findings suggest that approaches are needed to limit the long-term use of SMRs, especially in older adults, similar to approaches to limit long-term use of opioids and benzodiazepines.

Risk of sudden cardiac arrest and ventricular arrhythmia with sulfonylureas: An experience with conceptual replication in two independent populations.

Sulfonylureas are commonly used to treat type 2 diabetes mellitus. Despite awareness of their effects on cardiac physiology, a knowledge gap exists regarding their effects on cardiovascular events in real-world populations. Prior studies reported sulfonylurea-associated cardiovascular death but not serious arrhythmogenic endpoints like sudden cardiac arrest (SCA) or ventricular arrhythmia (VA). We assessed the comparative real-world risk of SCA/VA among users of second-generation sulfonylureas: glimepiride, glyburide, and glipizide. We conducted two incident user cohort studies using five-state Medicaid claims (1999-2012) and Optum Clinformatics commercial claims (2000-2016). Outcomes were SCA/VA events precipitating hospital presentation. We used Cox proportional hazards models, adjusted for high-dimensional propensity scores, to generate adjusted hazard ratios (aHR). We identified 624,406 and 491,940 sulfonylurea users, and 714 and 385 SCA/VA events, in Medicaid and Optum, respectively. Dataset-specific associations with SCA/VA for both glimepiride and glyburide (vs. glipizide) were on opposite sides of and could not exclude the null (glimepiride: aHRMedicaid 1.17, 95% CI 0.96-1.42; aHROptum 0.84, 0.65-1.08; glyburide: aHRMedicaid 0.87, 0.74-1.03; aHROptum 1.11, 0.86-1.42). Database differences in data availability, populations, and documentation completeness may have contributed to the incongruous results. Emphasis should be placed on assessing potential causes of discrepancies between conflicting studies evaluating the same research question.

Sulfonylureas and Metformin Were Not Associated With an Increased Rate of Serious Bleeding in Warfarin Users: A Self-Controlled Case Series Study.

Drug interactions between warfarin and sulfonylureas are suggested by pharmacokinetic information and prior studies. However, clinical evidence on the association of such interactions and the risk of bleeding is lacking. Using healthcare claims data from 5 US Medicaid programs from 1999-2011 and a self-controlled case series design with warfarin as an object drug, we calculated confounder-adjusted rate ratios (RRs) for concomitant use of sulfonylureas and metformin for 3 outcomes separately: (i) serious bleeding as a composite outcome of gastrointestinal bleeding (GIB) and nontraumatic intracranial hemorrhage (ICH); (ii) GIB; and (iii) ICH. In 6,463 warfarin users experiencing serious bleeding, an increased rate of serious bleeding was not associated with concomitant use of glimepiride (RR: 0.93; 95% confidence interval (CI) 0.75-1.15), glipizide (RR: 0.97; 95% CI 0.84-1.13), glyburide (RR: 0.89; 95% CI 0.76-1.06), or metformin (RR: 0.85; 95% CI 0.76-0.96), nor was the occurrence of the component outcomes of GIB or ICH. These results suggest that use of sulfonylureas or metformin was not associated with an increased rate of serious bleeding in warfarin users.

Frequency of and risk factors for potentially inappropriate medication use in Parkinson's disease.

BACKGROUND: impairments in neurotransmitter pathways put Parkinson's disease (PD) patients at risk for drug-disease interactions and adverse medication events. OBJECTIVE: to determine the prevalence and risk factors for potentially inappropriate medication (PIM) prescriptions, as defined by the 2015 Beers List, in PD. METHODS: cross-sectional analysis was conducted on 2014 Medicare beneficiaries with PD who had parts A, B and D coverage. The prevalence of PIM prescriptions for older adults was determined overall, and specifically for medications that can exacerbate motor symptoms or cognitive impairment in PD. Logistic regression models were constructed to determine the association between age, sex, race, geography and poverty with PIM prescriptions. RESULTS: the final sample included 458,086 beneficiaries. In 2014, 35.8% of beneficiaries with PD filled a prescription for at least one PIM for older adults. In total, 8.7% of beneficiaries received a PIM that could exacerbate motor symptoms and 29.0% received a PIM that could worsen cognitive impairment. After adjustment, in all models, beneficiaries who were younger, female, white, urban-dwelling and eligible for Medicaid benefits were more likely to receive a PIM. CONCLUSION: PIM prescriptions are not uncommon in PD, particularly for medications that can exacerbate cognitive impairment. Future research will examine underlying drivers of sex and other disparities in PIM prescribing. Additional studies are needed to understand the impact of PIMs on disease symptoms, healthcare utilisation and patient outcomes.

The risk of sudden cardiac arrest and ventricular arrhythmia with rosiglitazone versus pioglitazone: real-world evidence on thiazolidinedione safety.

BACKGROUND: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). METHODS: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset. RESULTS: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01). CONCLUSIONS: Rosiglitazone and pioglitazone appear to be associated with similar risks of SCA/VA.

Drug Enforcement Agency 2014 Hydrocodone Rescheduling Rule and Opioid Dispensing after Surgery.

BACKGROUND: In 2014, the U.S. Drug Enforcement Agency reclassified hydrocodone from Schedule III to Schedule II of the Controlled Substances Act, resulting in new restrictions on refills. The authors hypothesized that hydrocodone rescheduling led to decreases in total opioid dispensing within 30 days of surgery and reduced new long-term opioid dispensing among surgical patients. METHODS: The authors studied privately insured, opioid-naïve adults undergoing 10 general or orthopedic surgeries between 2011 and 2015. The authors conducted a differences-in-differences analysis that compared overall opioid dispensing before versus after the rescheduling rule for patients treated by surgeons who frequently prescribed hydrocodone before rescheduling (i.e., patients who were functionally exposed to rescheduling's impact) while adjusting for secular trends via a comparison group of patients treated by surgeons who rarely prescribed hydrocodone (i.e., unexposed patients). The primary outcome was any filled opioid prescription between 90 and 180 days after surgery; secondary outcomes included the 30-day refill rate and the amount of opioids dispensed initially and at 30 days postoperatively. RESULTS: The sample included 65,136 patients. The percentage of patients filling a prescription beyond 90 days was similar after versus before rescheduling (absolute risk difference, -1.1%; 95% CI, -2.3% to 0.1%; P = 0.084). The authors estimated the rescheduling rule to be associated with a 45.4-mg oral morphine equivalent increase (difference-in-differences estimate; 95% CI, 34.2-56.7 mg; P < 0.001) in initial opioid dispensing, a 4.1% absolute decrease (95% CI, -5.5% to -2.7%; P < 0.001) in refills within 30 days, and a 37.7-mg oral morphine equivalent increase (95% CI, 20.6-54.8 mg; P = 0.008) in opioids dispensed within 30 days. CONCLUSIONS: Among patients treated by surgeons who frequently prescribed hydrocodone before the Drug Enforcement Agency 2014 hydrocodone rescheduling rule, rescheduling did not impact long-term opioid receipt, although it was associated with an increase in opioid dispensing within 30 days of surgery.

Publisher Correction: Effect of statins on the association between high temperature and all-cause mortality in a socioeconomically disadvantaged population: a cohort study.

 A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.