Combining Super Learner with high-dimensional propensity score to improve confounding adjustment: A real-world application in chronic lymphocytic leukemia.

PURPOSE: High-dimensional propensity score (hdPS) is a semiautomated method that leverages a vast number of covariates available in healthcare databases to improve confounding adjustment. A novel combined Super Learner (SL)-hdPS approach was proposed to assist with selecting the number of covariates for propensity score inclusion, and was found in plasmode simulation studies to improve bias reduction and precision compared to hdPS alone. However, the approach has not been examined in the applied setting. METHODS: We compared SL-hdPS's performance with that of several hdPS models, each with prespecified covariates and a different number of empirically-identified covariates, using a cohort study comparing real-world bleeding rates between ibrutinib- and bendamustine-rituximab (BR)-treated individuals with chronic lymphocytic leukemia in Optum's de-identified Clinformatics® Data Mart commercial claims database (2013-2020). We used inverse probability of treatment weighting for confounding adjustment and Cox proportional hazards regression to estimate hazard ratios (HRs) for bleeding outcomes. Parameters of interest included prespecified and empirically-identified covariate balance (absolute standardized difference [ASD] thresholds of <0.10 and <0.05) and outcome HR precision (95% confidence intervals). RESULTS: We identified 2423 ibrutinib- and 1102 BR-treated individuals. Including >200 empirically-identified covariates in the hdPS model compromised covariate balance at both ASD thresholds. SL-hdPS balanced more covariates than all individual hdPS models at both ASD thresholds. The bleeding HR 95% confidence intervals were generally narrower with SL-hdPS than with individual hdPS models. CONCLUSION: In a real-world application, hdPS was sensitive to the number of covariates included, while use of SL for covariate selection resulted in improved covariate balance and possibly improved precision.

Thromboembolic Events in Users of Warfarin Treated with Different Skeletal Muscle Relaxants.

Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999−2012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13−0.77) for metaxalone to 3.44 (95% confidence interval: 1.53−7.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential >3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.

Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors and Sudden Cardiac Arrest and Ventricular Arrhythmia: Population-Based Cohort Studies.

In vivo studies suggest that arrhythmia risk may be greater with less selective dipeptidyl peptidase-4 inhibitors, but evidence from population-based studies is missing. We aimed to compare saxagliptin, sitagliptin, and linagliptin with regard to risk of sudden cardiac arrest (SCA)/ventricular arrhythmia (VA). We conducted high-dimensional propensity score (hdPS) matched, new-user cohort studies. We analyzed Medicaid and Optum Clinformatics separately. We identified new users of saxagliptin, sitagliptin (both databases), and linagliptin (Optum only). We defined SCA/VA outcomes using emergency department and inpatient diagnoses. We identified and then controlled for confounders via a data-adaptive, hdPS approach. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar year. We identified the following matched comparisons: saxagliptin vs. sitagliptin (23,895 vs. 96,972) in Medicaid, saxagliptin vs. sitagliptin (48,388 vs. 117,383) in Optum, and linagliptin vs. sitagliptin (36,820 vs. 78,701) in Optum. In Medicaid, use of saxagliptin (vs. sitagliptin) was associated with an increased rate of SCA/VA (adjusted HR (aHR), 2.01, 95% confidence interval (CI) 1.24-3.25). However, in Optum data, this finding was not present (aHR, 0.79, 95% CI 0.41-1.51). Further, we found no association between linagliptin (vs. sitagliptin) and SCA/VA (aHR, 0.65, 95% CI 0.36-1.17). We found discordant results regarding the association between SCA/VA with saxagliptin compared with sitagliptin in two independent datasets. It remains unclear whether these findings are due to heterogeneity of treatment effect in the different populations, chance, or unmeasured confounding.

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.

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.

A Retrospective Study of Comorbidities and Complications in Elderly Acute Myeloid Leukemia Patients in the United States.

BACKGROUND: Comorbidities in acute myeloid leukemia (AML) patients have been shown to increase with age. However, few studies have described the disease burden in elderly AML patients, a population generally underrepresented in clinical trials. We aimed to characterize the comorbidities and complications in elderly AML patients. PATIENTS AND METHODS: Patients aged ≥ 65 years with a primary diagnosis of AML were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (2000-2013) and were followed until the end of 2014. AML patients were matched 1:1 to noncancer patients by age, sex, geographic region, and race. A subset of patients with relapsed and/or refractory (R/R) AML was identified by modifying a previously validated algorithm. Baseline comorbidities and complications (eg, infectious, hematologic, cardiovascular) during follow-up were assessed using ICD-9 codes. Cox proportional hazards models were used to determine associations between AML and developing select complications. RESULTS: Compared to matched noncancer controls, AML patients (n = 3911) had higher baseline National Cancer Institute comorbidity index scores (1.81 vs. 1.63, P < .01), higher incidence rates (per 100 person-years) for all events of interest, and a higher risk of developing cardiovascular disease (hazard ratio = 4.61; 95% confidence interval, 4.07-5.21), type 2 diabetes mellitus (hazard ratio = 3.85; 95% confidence interval, 3.35-4.42), and stroke (hazard ratio = 2.60; 95% confidence interval, 2.32-2.92). R/R AML patients were younger, had lower National Cancer Institute comorbidity scores, lower incidence rates of events of interest, and a longer follow-up time compared to non-R/R AML patients. CONCLUSION: Elderly AML patients had more comorbidities and higher rates of complications compared to noncancer controls. Considering comorbidities and complications in elderly AML patients may improve clinical decision making.

Drug-Induced Anaphylaxis Documented in Electronic Health Records.

BACKGROUND: Although drugs represent a common cause of anaphylaxis, few large studies of drug-induced anaphylaxis have been performed. OBJECTIVE: To describe the epidemiology and validity of reported drug-induced anaphylaxis in the electronic health records (EHRs) of a large United States health care system. METHODS: Using EHR drug allergy data from 1995 to 2013, we determined the population prevalence of anaphylaxis including anaphylaxis prevalence over time, and the most commonly implicated drugs/drug classes reported to cause anaphylaxis. Patient risk factors for drug-induced anaphylaxis were assessed using a logistic regression model. Serum tryptase and allergist visits were used to assess the validity and follow-up of EHR-reported anaphylaxis. RESULTS: Among 1,756,481 patients, 19,836 (1.1%) reported drug-induced anaphylaxis; penicillins (45.9 per 10,000), sulfonamide antibiotics (15.1 per 10,000), and nonsteroidal anti-inflammatory drugs (NSAIDs) (13.0 per 10,000) were most commonly implicated. Patients with white race (odds ratio [OR] 2.38, 95% CI 2.27-2.49), female sex (OR 2.20, 95% CI 2.13-2.28), systemic mastocytosis (OR 4.60, 95% CI 2.66-7.94), Sjögren's syndrome (OR 1.94, 95% CI 1.47-2.56), and asthma (OR 1.50, 95% CI 1.43-1.59) had an increased odds of drug-induced anaphylaxis. Serum tryptase was performed in 135 (<1%) anaphylaxis cases and 1,587 patients (8.0%) saw an allergist for follow-up. CONCLUSIONS: EHR-reported anaphylaxis occurred in approximately 1% of patients, most commonly from penicillins, sulfonamide antibiotics, and NSAIDs. Females, whites, and patients with mastocytosis, Sjögren's syndrome, and asthma had increased odds of reporting drug-induced anaphylaxis. The low observed frequency of tryptase testing and specialist evaluation emphasize the importance of educating providers on anaphylaxis management.

Mobile health apps preferences and practice among ambulatory cardiovascular patients.

AIM: To determine if patients in cardiology practices would be interested in or willing to use mobile health technologies. METHODS: Patients seen at an ambulatory cardiology clinic for any indication were included. A paper survey was administered during pre-intake that assessed frequency of use, familiarity with and interest in mobile health applications. Data were analyzed using an exploratory logistic regression analysis to determine demographic predictors for technology utilization. RESULTS: A total of 306 patients were included (a plurality, 39.3%, in age group 50-69; 62.7% male). Those from median household incomes between US$30,000 and US$74,999 and those 18-29 years old were more likely to have used a health app (0.53 and 1.21, respectively). Those between 18 and 29 years were less interested in virtual visits with their healthcare provider (-0.92) and those over age 70 were less comfortable using their phone apps (-0.80). CONCLUSION: Age and income are important predictors of mobile health app adoption.

Rising drug allergy alert overrides in electronic health records: an observational retrospective study of a decade of experience.

OBJECTIVE: There have been growing concerns about the impact of drug allergy alerts on patient safety and provider alert fatigue. The authors aimed to explore the common drug allergy alerts over the last 10 years and the reasons why providers tend to override these alerts. DESIGN: Retrospective observational cross-sectional study (2004-2013). MATERIALS AND METHODS: Drug allergy alert data (n = 611,192) were collected from two large academic hospitals in Boston, MA (USA). RESULTS: Overall, the authors found an increase in the rate of drug allergy alert overrides, from 83.3% in 2004 to 87.6% in 2013 (P < .001). Alarmingly, alerts for immune mediated and life threatening reactions with definite allergen and prescribed medication matches were overridden 72.8% and 74.1% of the time, respectively. However, providers were less likely to override these alerts compared to possible (cross-sensitivity) or probable (allergen group) matches (P < .001). The most common drug allergy alerts were triggered by allergies to narcotics (48%) and other analgesics (6%), antibiotics (10%), and statins (2%). Only slightly more than one-third of the reactions (34.2%) were potentially immune mediated. Finally, more than half of the overrides reasons pointed to irrelevant alerts (i.e., patient has tolerated the medication before, 50.9%) and providers were significantly more likely to override repeated alerts (89.7%) rather than first time alerts (77.4%, P < .001). DISCUSSION AND CONCLUSIONS: These findings underline the urgent need for more efforts to provide more accurate and relevant drug allergy alerts to help reduce alert override rates and improve alert fatigue.

Clinicians' Reports in Electronic Health Records Versus Patients' Concerns in Social Media: A Pilot Study of Adverse Drug Reactions of Aspirin and Atorvastatin.

INTRODUCTION: Large databases of clinician reported (e.g., allergy repositories) and patient reported (e.g., social media) adverse drug reactions (ADRs) exist; however, whether patients and clinicians report the same concerns is not clear. OBJECTIVES: Our objective was to compare electronic health record data and social media data to better understand differences and similarities between clinician-reported ADRs and patients' concerns regarding aspirin and atorvastatin. METHODS: This pilot study explored a large repository of electronic health record data and social media data for clinician-reported ADRs and patients concerns for two common medications: aspirin (n = 31,817 ADRs accessible in clinical data; n = 19,186 potential ADRs accessible in social media data) and atorvastatin (n = 15,047 ADRs accessible in clinical data; n = 23,408 potential ADRs accessible in social media data). RESULTS: We found that the most frequently reported ADRs matched the most frequent patients' concerns. However, several less frequently reported reactions were more prevalent on social media (i.e., aspirin-induced hypoglycemia was discussed only on social media). Overall, we found a relatively strong positive and statistically significant correlation between the frequency ranking of reactions and patients' concerns for atorvastatin (Pearson's r = 0.61, p < 0.001) but not for aspirin (Pearson's r = 0.1, p = 0.69). CONCLUSION: Future studies should develop further natural language methods for a more detailed data analysis (i.e., identifying causality and temporal aspects in the social media data).

High Override Rate for Opioid Drug-allergy Interaction Alerts: Current Trends and Recommendations for Future.

This study examined trends in drug-allergy interaction (DAI) alert overrides for opioid medications - the most commonly triggered alerts in the computerized provider order entry (CPOE). We conducted an observational analysis of the DAI opioid alerts triggered over the last decade (2004-2013, n=342,338) in two large academic hospitals in Boston (United States). We found an increasing rate of DAI alert overrides culminating in 89.7% in 2013. Allergic reactions included a high proportion (38.2%) of non-immune mediated opioid reactions (e.g. gastrointestinal upset). The DAI alert override rate was high for immune mediated (88.6%) and life threatening reactions (87.8%). Exact allergy-medication matches were overridden less frequently (about 70%) compared to non-exact matches within allergy groups (over 90%). About one-third of the alert override reasons pointed to irrelevant alerts (i.e."Patient has tolerated the medication before") and 44.9% were unknown. Those findings warrant further investigation into providers' reasons for high override rate. User interfaces should evolve to enable less interruptive and more accurate alerts to decrease alert fatigue.