Publications by authors named "Charles E Leonard"

112 Publications

Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data.

Ann Intern Med 2022 Jan 7;175(1):20-28. Epub 2021 Dec 7.

University of Pennsylvania, Philadelphia, Pennsylvania (G.K.D., C.E.L., J.D.L., A.C.).

Background: Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited.

Objective: To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE.

Design: Retrospective new-user cohort study.

Setting: U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020.

Participants: Adults with VTE who were newly prescribed apixaban or rivaroxaban.

Measurements: The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding.

Results: Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation.

Limitation: Short follow-up.

Conclusion: In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M21-0717DOI Listing
January 2022

Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

J Thromb Thrombolysis 2021 Nov 24. Epub 2021 Nov 24.

Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.
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http://dx.doi.org/10.1007/s11239-021-02610-4DOI Listing
November 2021

Knowledge of biosimilars and perceptions of the naming conventions for biosimilar products in clinical practice in the United States.

Drugs Ther Perspect 2021 Jun;37:338-346

Division of Rheumatology, Perelman School of Medicine, University of Pennsylvania, 5th Floor White Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.

Background: Biosimilar therapies and their naming conventions are both relatively new to the drug development market and in clinical practice. We studied the use of the four-letter naming convention in practice and the knowledge, perceptions, and preferences of US health care providers.

Methods: A survey was distributed among health care professionals with a history of utilizing biosimilars in clinical practice to measure key knowledge and the presence of discernable naming trends. Differences in responses across pre-hypothesized subgroups were tested for statistical significance.

Results: Of the 506 surveys emailed, 83 (16%) people responded. Overall, there was poor knowledge about the key concepts surrounding biosimilars. For example, only 52% of respondents correctly identified that biosimilars were not the same as the generic drug; however, frequent use correlated with superior knowledge across all groups. In reference to naming preferences, 67% of all respondents indicated that they commonly use the brand name to distinguish biosimilars in clinical practice and a majority of them (85%) indicated that the brand name was easier to remember than the nonproprietary name with the four-letter suffix. An unexpected number of neutral responses was documented. Notably, more than half of respondents (68%) indicated a neutral response when asked if the four-letter suffix promoted medical errors.

Conclusions: There remains a knowledge gap with regard to biosimilars, and lack of consensus on how the naming convention is and should be utilized in clinical practice. The data also suggest that effective biosimilar education could aid in promoting familiarity with the naming convention among health care providers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547319PMC
June 2021

Association Between Serious Hypoglycemia and Calcium-Channel Blockers Used Concomitantly With Insulin Secretagogues.

JAMA Netw Open 2021 09 1;4(9):e2124443. Epub 2021 Sep 1.

Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.24443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414188PMC
September 2021

A prospective Phase III trial evaluating patient self-reported pain and cosmesis in accelerated partial breast irradiation utilizing 3-D versus intensity-modulated radiotherapy.

Cancer Med 2021 10 1;10(20):7089-7100. Epub 2021 Sep 1.

Rocky Mountain Cancer Centers, Littleton, Colorado, USA.

Purpose/objective: The primary objective is to examine patient self-assessment of breast pain and cosmesis between three-dimensional (3D-CRT) versus intensity-modulated radiotherapy (IMRT). The secondary objective is to evaluate any relationship of treatment planning conformality of both cohorts to patient-assessed pain. Assessments were performed at interim 12, 24, 36, and 48 months with a final 5-year assessment.

Materials/methods: In total, 656 patients (3D-CRT n = 328; IMRT n = 328) were randomly assigned to either IMRT or 3D-CRT accelerated partial breast radiotherapy to 38.5 Gy in 10 BID 3.85 Gy fractions.

Results: Median follow-up was 3 years. Multivariate analysis showed that pain severity significantly decreased from baseline to the 12-month follow-up visit (<0.001 for both 3D-CRT and IMRT) in each cohort. There was significantly less pain at 2 (p = 0.002) and 3 years (0.045) in the IMRT arm versus the 3D-CRT arm when compared to the baseline pain level. There was no difference in patient-assessed cosmesis at any follow-up point; however, although MD-assessed cosmesis showed no difference from years 1 to 4, there was significantly better cosmesis for 3D-CRT versus IMRT (p = 0.047) at 5 years. There was a significant correlation between a maximum pain score and an increase in the CI (indicating less conformity) in the IMRT cohort (p < 0.01) and in the IMRT subgroup when the CI was ≤0.37 cohort arm (p = 0.01).

Conclusion: In the analysis of our primary objective we found that at 2 years, IMRT resulted in more interval improvement in breast pain after baseline when compared to patients treated with 3D-CRT planning. As seen in our secondary analysis, this may be due to the ability of IMRT to achieve higher conformality (as evidenced by lower CI values) resulting in less fibrosis. There were no differences in patient-assessed cosmesis or MD-assessed cosmesis for years 1-4; however, physician-assessed 5-year cosmesis was better with 3D-CRT.
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http://dx.doi.org/10.1002/cam4.4242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525102PMC
October 2021

Cardiovascular and major bleeding outcomes with antiplatelet and direct oral anticoagulants in patients with acute coronary syndrome and atrial fibrillation: A population-based analysis.

Am Heart J 2021 12 24;242:71-81. Epub 2021 Aug 24.

Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA; Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Direct oral anticoagulants (DOACs) are replacing warfarin for stroke prevention in patients with atrial fibrillation (AF).

Objective: To assess the effectiveness and safety of concomitant treatment with antiplatelet-DOAC compared to antiplatelet-warfarin in patients with acute coronary syndrome (ACS) and AF.

Design: Retrospective propensity score-matched cohort study using United States-based commercial healthcare database from January 2016 to June 2019.

Participants: New-users of antiplatelet-DOAC and antiplatelet-warfarin who initiated the combined therapy within 30 days following incident ACS diagnosis.

Measurements: Primary study outcomes were recurrent cardiovascular diseases (CVD) (ie, a composite of stroke and myocardial infarction) and major bleeding events identified via discharge diagnoses. We controlled for potential confounders via propensity score matching (PSM). We generated marginal hazard ratios (HRs) via Cox proportional hazards regression using a robust variance estimator while adjusting for calendar time.

Results: After PSM, a total of 2,472 persons were included (1,236 users of antiplatelet-DOAC and 1,236 users of antiplatelet-warfarin). The use of antiplatelet-DOAC (vs. antiplatelet-warfarin) was associated with a reduced rate of recurrent CVD (adjusted HR 0.72, 95% confidence interval [CI], 0.56-0.92) and major bleeding events (adjusted HR, 0.49, 95% CI 0.33-0.72).

Limitations: Residual confounding.

Conclusions: In real-world data of AF patients with concurrent ACS, the use of antiplatelet-DOAC following ACS diagnosis was associated with a lower rate of recurrent CVD and major bleeding events compared with antiplatelet-warfarin. These findings highlight a potential promising role for DOACs in patients with ACS and AF requiring combined antiplatelet therapy.
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http://dx.doi.org/10.1016/j.ahj.2021.08.014DOI Listing
December 2021

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

Clin Pharmacol Ther 2022 Jan 17;111(1):227-242. Epub 2021 Aug 17.

Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1002/cpt.2381DOI Listing
January 2022

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

Clin Pharmacol Ther 2022 Jan 23;111(1):218-226. Epub 2021 Aug 23.

Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, and Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1002/cpt.2377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678147PMC
January 2022

Compared to commercially insured patients, Medicare advantage patients adopt newer diabetes drugs more slowly and adhere to them less.

Endocrinol Diabetes Metab 2021 Jul 2;4(3):e00245. Epub 2021 Apr 2.

Department of Biostatistics, Epidemiology, and Informatics Center for Pharmacoepidemiology Research and Training Perelman School of Medicine University of Pennsylvania Philadelphia PA USA.

Aims: To compare rates of use and adherence for newer versus older second-line diabetes drug classes in commercially insured, Medicare Advantage and dual-eligible (covered by both Medicare and Medicaid) patients.

Materials And Methods: Longitudinal cohort study using insurance claims data from 1/1/2012 to 12/31/2016 to identify patients with a first prescription, after metformin, of a second-line diabetes drug (eg sulphonylurea, DPP-4 inhibitor, thiazolidinedione, SGLT-2 inhibitor or GLP-1 receptor agonist) and to estimate their adherence to that drug class. Univariate analysis and multivariable logistic regression were used to examine the association between insurance type and use of each drug class, and between insurance type and adherence to each drug class.

Results: The study population included 96,663 patients. Trends in drug use differed by insurance type. For example, sulphonylurea use declined among the commercially insured (from 46% to 39%,  < .001) but not among Medicare Advantage or dual-eligible patients. Patterns of adherence also differed between insurance groups. For example, compared to commercial insurance, Medicare Advantage was associated with higher adherence to sulphonylurea (odds ratio [OR] 1.32, 95% CI 1.21-1.43)) but lower adherence to SGLT-2 inhibitors (OR 0.43 (95% CI 0.33-0.56)).

Conclusions: This study finds differences in utilization and adherence for diabetes drugs across insurance types. Older medications such as sulphonylureas appear to be more used and better adhered to among Medicare Advantage recipients, while the opposite is true for newer medication classes. These findings suggest a need to personalize selection of diabetes drugs according to insurance status, particularly when adherence needs optimization.
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http://dx.doi.org/10.1002/edm2.245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279610PMC
July 2021

Association of the 12-Gene Breast DCIS Score Assay With Local Recurrence in Patients With Ductal Carcinoma Treated on Accelerated Partial Breast Radiotherapy Protocols.

Front Oncol 2021 17;11:671047. Epub 2021 Jun 17.

Radiation Oncology, Rocky Mountain Cancer Centers, Aurora, CO, United States.

Background: The following analysis explores clinicopathologic factors and the 12-gene Breast DCIS Score test result in order to better define an appropriate DCIS (ductal carcinoma ) population eligible for APBI (accelerated partial breast radiotherapy).

Methods: This exploratory analysis aimed to retrospectively measure the association between the 12-gene Oncotype DX Breast DCIS Score assay (Redwood City, CA) and relevant clinicopathologic factors with locoregional recurrence in a pooled cohort of women treated with local excision and APBI on prospective phase II (NCT01185145) and phase III (NCT01185132) clinical trials. Univariable Cox proportional hazards regression was used to determine whether there was an association between local recurrence and DCIS Score result risk group (≥ 39 < 39) and clinicopathologic factors.

Results: This analysis included 104 evaluable patients (n = 18 from NCT01185145 and n = 86 from NCT01185132). The median age was 60 years (range: 40-79). Seventy-nine percent of patients were postmenopausal. The median span of DCIS was 10 mm (range 2-45 mm). Two-thirds of the cohort presented with necrosis (71%). The distribution of DCIS Score results ranged from 0 to 82, with 69% of patients having a DCIS Score result < 39. The median follow-up time was 8.2 years in NCT01185145 versus 3.0 years in NCT01185132. There were 6 local ipsilateral breast recurrences. DCIS Score result was significantly associated with local recurrence in univariable modeling, hazard ratio = 10.3 (95% CI 1.7, 198.4); p = 0.010. None of the clinicopathologic characteristics resulted in any significant association with locoregional recurrence.

Conclusion: The Breast DCIS Score assay demonstrated risk stratification in this cohort of patients treated with local excision and APBI pooled from two clinical trials. These results are consistent with those recently published utilizing whole breast radiotherapy. Due to the small number of local recurrence events and limited follow-up time, further investigations are needed to confirm findings.
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http://dx.doi.org/10.3389/fonc.2021.671047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247917PMC
June 2021

Spotlight commentary: A role for real-world evidence to inform the clinical care of patients with diabetes mellitus.

Br J Clin Pharmacol 2021 Dec 4;87(12):4549-4551. Epub 2021 May 4.

School of Pharmacy, University College London, London, UK.

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http://dx.doi.org/10.1111/bcp.14882DOI Listing
December 2021

A Comparison of Predicted Ipsilateral Tumor Recurrence Risks in Patients With Ductal Carcinoma in Situ of the Breast After Breast-Conserving Surgery by Breast Radiation Oncologists, the Van Nuys Prognostic Index, the Memorial Sloan Kettering Cancer Center DCIS Nomogram, and the 12-Gene DCIS Score Assay.

Adv Radiat Oncol 2021 Mar-Apr;6(2):100607. Epub 2020 Nov 1.

Rocky Mountain Cancer Centers, Littleton, Colorado.

Purpose: To compare ipsilateral breast event (IBE) risks in patients with ductal carcinoma in situ of the breast (DCIS) post-lumpectomy, as estimated by breast radiation oncologists, the Van Nuys Prognostic Index, the Memorial Sloan Kettering Cancer Center (MSKCC) DCIS nomogram, and the 12-gene Oncotype DX DCIS score assay.

Methods And Materials: Consecutive DCIS cases treated with lumpectomy from November 2011 to August 2014 with available DCIS score results were identified. Three radiation oncologists independently estimated the 10-year IBE risk. The Van Nuys Prognostic Index and MSKCC nomogram 10-year IBE risk estimates were generated. Differences and correlations between the IBE estimates and clinicopathologic factors were evaluated.

Results: Ninety-one patients were identified for inclusion. Forty-eight percent would have been ineligible for the E5194 study. The mean risk of IBE from the DCIS score assay was 12.4%, compared with a range of 18.9% to 26.8% from other sources. The mean IBE risk from the DCIS score assay was lower regardless of E5194 eligibility. The MSKCC nomogram and DCIS score assay risk estimates were weakly correlated with each other ( = .23) and were each moderately correlated with the other risk estimates ( = .41-.56). When applying the radiation oncologists' treatment recommendations based on their proposed risk cutoffs, evaluating risk according to the DCIS score assay led to the highest proportion of patients recommended excision alone.

Conclusions: IBE risk estimates for this general community cohort of DCIS cases vary significantly among commonly available clinical predictive tools and individual radiation oncologist estimates. Surgical margins and tumor size continue to factor prominently in radiation oncologist decision algorithms. The differences found between the IBE risk estimate methods suggests that they are not interchangeable and the methods that rely on clinicopathologic features may tend to overestimate risk.
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http://dx.doi.org/10.1016/j.adro.2020.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071725PMC
November 2020

Validity of ICD-10-CM diagnoses to identify hospitalizations for serious infections among patients treated with biologic therapies.

Pharmacoepidemiol Drug Saf 2021 07 3;30(7):899-909. Epub 2021 May 3.

United States Food and Drug Administration, Silver Spring, Maryland, USA.

Purpose: Identifying hospitalizations for serious infections among patients dispensed biologic therapies within healthcare databases is important for post-marketing surveillance of these drugs. We determined the positive predictive value (PPV) of an ICD-10-CM-based diagnostic coding algorithm to identify hospitalization for serious infection among patients dispensed biologic therapy within the FDA's Sentinel Distributed Database.

Methods: We identified health plan members who met the following algorithm criteria: (1) hospital ICD-10-CM discharge diagnosis of serious infection between July 1, 2016 and August 31, 2018; (2) either outpatient/emergency department infection diagnosis or outpatient antimicrobial treatment within 7 days prior to hospitalization; (3) inflammatory bowel disease, psoriasis, or rheumatological diagnosis within 1 year prior to hospitalization, and (4) were dispensed outpatient biologic therapy within 90 days prior to admission. Medical records were reviewed by infectious disease clinicians to adjudicate hospitalizations for serious infection. The PPV (95% confidence interval [CI]) for confirmed events was determined after further weighting by the prevalence of the type of serious infection in the database.

Results: Among 223 selected health plan members who met the algorithm, 209 (93.7% [95% CI, 90.1%-96.9%]) were confirmed to have a hospitalization for serious infection. After weighting by the prevalence of the type of serious infection, the PPV of the ICD-10-CM algorithm identifying a hospitalization for serious infection was 80.2% (95% CI, 75.3%-84.7%).

Conclusions: The ICD-10-CM-based algorithm for hospitalization for serious infection among patients dispensed biologic therapies within the Sentinel Distributed Database had 80% PPV for confirmed events and could be considered for use within pharmacoepidemiologic studies.
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http://dx.doi.org/10.1002/pds.5253DOI Listing
July 2021

Evaluation of serious bleeding signals during concomitant use of clopidogrel and hypnotic drugs.

Biomed Pharmacother 2021 Jul 10;139:111559. Epub 2021 Apr 10.

Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for Therapeutic Effectiveness Research, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: In a previous drug-drug interaction (DDI) screening study intended to generate hypotheses, clopidogrel + either eszopiclone or zolpidem (vs. clopidogrel alone) were associated with serious bleeding.

Objectives: To confirm or refute these DDI signals and examine associations with other hypnotics in an independent population of United States Medicaid beneficiaries METHODS: We employed a bi-directional self-controlled case series design in eligible individuals concomitantly exposed to one of 12 hypnotics (precipitants, exposures of interest) plus either clopidogrel (the object drug) or pravastatin (the negative control object drug). The outcome was hospital presentation with serious bleeding. Using conditional Poisson regression, we calculated confounder-adjusted rate ratios (RRs) and 95% confidence intervals for serious bleeding during clopidogrel + precipitant use (vs. clopidogrel alone). To distinguish a DDI from a precipitant's inherent effect on bleeding, we divided effect measures by the adjusted RR for the corresponding pravastatin + precipitant pair to obtain ratios of RR (RRRs).

Results: Among 23,194 users of clopidogrel and 3824 of pravastatin who experienced serious bleeding during an active prescription for one of these agents, confounder-adjusted RRRs for serious bleeding were 6.63 (0.39-113.01) and 0.77 (0.53-1.11) with eszopiclone and zolpidem, respectively, whereas confounder-adjusted RRRs for other hypnotics ranged from 0.18 (0.04-0.85) for triazolam to 1.79 (0.16-20.44) for zaleplon. Statistical imprecision therefore precluded us from confirming or refuting these prior signals with eszopiclone and zolpidem.

Conclusions: While we could not confirm or refute previously identified DDI signals, numerically elevated RRRs for serious bleeding with several clopidogrel + hypnotic pairs warrant further examination.
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http://dx.doi.org/10.1016/j.biopha.2021.111559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187300PMC
July 2021

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study.

Ann Intern Med 2021 07 30;174(7):910-919. Epub 2021 Mar 30.

Perelman School of Medicine and Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania (G.K.D., C.E.L., J.D.L.).

Background: Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited.

Objective: To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF.

Design: New-user retrospective propensity score-matched cohort study.

Setting: U.S.-based commercial health care database from 1 January 2010 to 30 June 2019.

Participants: Adults with valvular AF who were newly prescribed DOACs or warfarin.

Measurements: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding.

Results: Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]).

Limitation: Relatively short follow-up; inability to ascertain disease severity.

Conclusion: In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M20-6194DOI Listing
July 2021

Pharmacosafety of fluoroquinolone and macrolide antibiotics in the clinical care of patients with myasthenia gravis.

Muscle Nerve 2021 08 26;64(2):156-162. Epub 2021 Mar 26.

Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Introduction/aims: Anecdotal case reports have suggested a potential association of fluoroquinolones and macrolides with myasthenia gravis (MG) exacerbation, prompting warnings against the use of these drugs in this population. However, large-scale and reliable population-based data that demonstrate this association are lacking. This study aims to examine the association between outpatient treatment with fluoroquinolones or macrolides and MG-related hospitalization.

Methods: A retrospective cohort study consisting of adult MG patients was conducted using a large de-identified healthcare claims database. Antibiotic prescription claims were identified, and MG-related hospitalizations were assessed at 15, 30, and 90 days after the date of prescription. We used mixed effects survival regression with log-logistic distribution and independent covariance matrix to estimate odds ratios (ORs) of hospitalization for each potentially exacerbating antibiotic using beta-lactam as the reference and adjusting for covariates.

Results: Among 1556 MG patients receiving 894 fluoroquinolone prescriptions, 729 macrolide prescriptions, and 1608 beta-lactam prescriptions during the study period, there was no difference in 15, 30, or 90-day odds of MG-related hospitalization between fluoroquinolone or macrolide users compared to prescribed beta-lactams. However, estimates were higher for fluoroquinolones than macrolides, even after covariate adjustment (adjusted OR [aOR] 4.60, 95% confidence interval [CI] 0.55-38.57 for fluoroquinolones and OR 0.56, 95% CI 0.32-0.97 for macrolides, respectively, at 15 days).

Discussion: Fluoroquinolone and macrolide antibiotics are prescribed frequently to patients with MG. While statistical imprecision precludes a definitive conclusion, elevated ORs for fluoroquinolones raise the possibility of an underpowered association that merits further investigation.
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http://dx.doi.org/10.1002/mus.27230DOI Listing
August 2021

Population-Based Signals of Antidepressant Drug Interactions Associated With Unintentional Traumatic Injury.

Clin Pharmacol Ther 2021 08 14;110(2):409-423. Epub 2021 Mar 14.

Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Antidepressants are very widely used and associated with traumatic injury, yet little is known about their potential for harmful drug interactions. We aimed to identify potential drug interaction signals by assessing concomitant medications (precipitant drugs) taken with individual antidepressants (object drugs) that were associated with unintentional traumatic injury. We conducted pharmacoepidemiologic screening of 2000-2015 Optum Clinformatics data, identifying drug interaction signals by performing self-controlled case series studies for antidepressant + precipitant pairs and injury. We included persons aged 16-90 years codispensed an antidepressant and ≥ 1 precipitant drug(s), with an injury during antidepressant therapy. We classified antidepressant person-days as either precipitant-exposed or precipitant-unexposed. The outcome was an emergency department or inpatient discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to calculate confounder adjusted rate ratios (RRs) and accounted for multiple estimation via semi-Bayes shrinkage. We identified 330,884 new users of antidepressants who experienced an injury. Among such persons, we studied concomitant use of 7,953 antidepressant + precipitant pairs. Two hundred fifty-six (3.2%) pairs were positively associated with injury and deemed potential drug interaction signals; 22 of these signals had adjusted RRs > 2.00. Adjusted RRs ranged from 1.06 (95% confidence interval: 1.00-1.12, P = 0.04) for citalopram + gabapentin to 3.06 (1.42-6.60) for nefazodone + levonorgestrel. Sixty-five (25.4%) signals are currently reported in a seminal drug interaction knowledgebase. We identified numerous new population-based signals of antidepressant drug interactions associated with unintentional traumatic injury. Future studies, intended to test hypotheses, should confirm or refute these potential interactions.
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http://dx.doi.org/10.1002/cpt.2195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316258PMC
August 2021

National outpatient medication utilization for opioid and alcohol use disorders from 2014 to 2016.

J Subst Abuse Treat 2020 12 22;119:108141. Epub 2020 Sep 22.

The University of Texas at Austin College of Pharmacy, 2409 University Ave, Austin, TX 78712, USA. Electronic address:

Background And Aims: Research has recommended a combination of pharmacotherapy and behavioral therapy to treat opioid use disorder (OUD) or alcohol use disorder (AUD). The objective of this study was to estimate the prevalence of U.S. outpatient visits in which patients had a documented OUD or AUD and in what proportion of these visits the patient was receiving medication for OUD (MOUD) or AUD (MAUD), alone or in combination with behavioral therapy.

Design: Cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) from 2014 to 2016.

Setting: NAMCS provides national estimates based on the latest census data, for all U.S. outpatient medical visits.

Participants/cases: All visits involving patients aged ≥18 years with an OUD or AUD diagnosis.

Measurement: Medications for OUD included buprenorphine, buprenorphine/naloxone, or naltrexone; medications for AUD included acamprosate, disulfiram, or naltrexone. We defined behavioral therapy as provision of psychosocial therapy, mental health counseling, or stress management. We also compared annualized data between 2014 and 2016 using the Chi-square test.

Findings: From 2014 to 2016, NAMCS recorded nearly 2.3 billion adult outpatient visits, including 17.1 million and 21.7 million visits involving patients with an OUD or AUD diagnosis, respectively. From 2014 to 2016, a decreased prevalence of annual visits involved AUD (11.7 vs. 9.9/1000, P < 0.0001), while those for OUD increased (9.3 vs. 13.3/1000, P < 0.0001). Among office visits with an OUD diagnosis, a MOUD was documented in 14.2 million (83.1%) visits and behavioral therapy was provided in 4.4 million (25.6%). Among office visits with an AUD diagnosis, an MAUD was documented in approximately 800,000 (3.6%) and behavioral therapy in 5.4 million (24.8%).

Conclusion: These data highlight an opportunity to increase the use of MAUD and offer behavioral therapy to those with OUD and/or AUD.
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http://dx.doi.org/10.1016/j.jsat.2020.108141DOI Listing
December 2020

Developing a Standardized and Reusable Method to Link Distributed Health Plan Databases to the National Death Index: Methods Development Study Protocol.

JMIR Res Protoc 2020 Nov 2;9(11):e21811. Epub 2020 Nov 2.

Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, United States.

Background: Certain medications may increase the risk of death or death from specific causes (eg, sudden cardiac death), but these risks may not be identified in premarket randomized trials. Having the capacity to examine death in postmarket safety surveillance activities is important to the US Food and Drug Administration's (FDA) mission to protect public health. Distributed networks of electronic health plan databases used by the FDA to conduct multicenter research or medical product safety surveillance studies often do not systematically include death or cause-of-death information.

Objective: This study aims to develop reusable, generalizable methods for linking multiple health plan databases with the Centers for Disease Control and Prevention's National Death Index Plus (NDI+) data.

Methods: We will develop efficient administrative workflows to facilitate multicenter institutional review board (IRB) review and approval within a distributed network of 6 health plans. The study will create a distributed NDI+ linkage process that avoids sharing of identifiable patient information between health plans or with a central coordinating center. We will develop standardized criteria for selecting and retaining NDI+ matches and methods for harmonizing linked information across multiple health plans. We will test our processes within a use case comprising users and nonusers of antiarrhythmic medications.

Results: We will use the linked health plan and NDI+ data sets to estimate the incidences and incidence rates of mortality and specific causes of death within the study use case and compare the results with reported estimates. These comparisons provide an opportunity to assess the performance of the developed NDI+ linkage approach and lessons for future studies requiring NDI+ linkage in distributed database settings. This study is approved by the IRB at Harvard Pilgrim Health Care in Boston, MA. Results will be presented to the FDA at academic conferences and published in peer-reviewed journals.

Conclusions: This study will develop and test a reusable distributed NDI+ linkage approach with the goal of providing tested NDI+ linkage methods for use in future studies within distributed data networks. Having standardized and reusable methods for systematically obtaining death and cause-of-death information from NDI+ would enhance the FDA's ability to assess mortality-related safety questions in the postmarket, real-world setting.

International Registered Report Identifier (irrid): DERR1-10.2196/21811.
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http://dx.doi.org/10.2196/21811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669437PMC
November 2020

Investigation of Concomitant Use of Alzheimer's Disease Drugs with Sulfonylureas and Serious Hypoglycemia.

Epidemiology 2021 01;32(1):e3-e5

Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,

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http://dx.doi.org/10.1097/EDE.0000000000001263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708459PMC
January 2021

Does hospitalization for thromboembolism improve oral anticoagulant adherence in patients with atrial fibrillation?

J Am Pharm Assoc (2003) 2020 Nov - Dec;60(6):986-992.e2. Epub 2020 Sep 1.

Background: It is not known how medication adherence changes after hospitalization for a sentinel thromboembolic event.

Objective: The purpose of this study was to examine the impact of hospitalization for ischemic stroke or thromboembolism on postdischarge adherence to oral anticoagulants in patients with atrial fibrillation.

Methods: We conducted a quasi-experimental pre-post observational study using a large U.S. commercial insurance health care claims database. Adult patients with atrial fibrillation taking oral anticoagulants with a random hospitalization for a nonbleeding-related reason occurring after the first observed oral anticoagulant prescription fill, with no other admissions within the preceding and following 6 months, were identified in Optum Clinformatics (Eden Prairie, MN) from 2009 to 2016. Adherence was estimated by the proportion of days covered within 6 and 12 months before and after hospitalization. Difference-in-difference analysis using a generalized linear model was employed to compare pre- and post-hospitalization proportions of days covered (PDCs) by reasons for hospitalization (i.e., ischemic stroke or thromboembolism vs. other nonbleeding-related reasons), adjusting for imbalanced baseline characteristics.

Results: Of the 21,400 individuals meeting inclusion criteria, 5.4% were hospitalized for ischemic stroke or thromboembolism and 94.6% for other nonbleeding-related reasons. Baseline characteristics were quite similar between groups, except for a few covariables such as age or CHADS-VASc score. Minority race or ethnicity individuals had 0.7% lower overall PDC than whites (P = 0.006). After covariate adjustment, 6-month adherence declined by 1.1% less in individuals hospitalized for ischemic stroke or thromboembolism, compared with other nonbleeding reasons, although the difference was not statistically significant (P = 0.17). Similar results were observed for the 12-month window.

Conclusion: This real-world study suggests that more effective strategies are needed to improve adherence to oral anticoagulant, particularly after a thromboembolic event.
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http://dx.doi.org/10.1016/j.japh.2020.08.004DOI Listing
June 2021

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

Pharmacotherapy 2020 10 21;40(10):1022-1035. Epub 2020 Sep 21.

Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1002/phar.2457DOI Listing
October 2020

Screening to identify signals of opioid drug interactions leading to unintentional traumatic injury.

Biomed Pharmacother 2020 Oct 30;130:110531. Epub 2020 Jul 30.

Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Center for Therapeutic Effectiveness Research, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Background: Efforts to minimize harms from opioid drug interactions may be hampered by limited evidence on which drugs, when taken concomitantly with opioids, result in adverse clinical outcomes.

Objective: To identify signals of opioid drug interactions by identifying concomitant medications (precipitant drugs) taken with individual opioids (object drugs) that are associated with unintentional traumatic injury DESIGN: We conducted pharmacoepidemiologic screening of Optum Clinformatics Data Mart, identifying drug interaction signals by performing confounder-adjusted self-controlled case series studies for opioid + precipitant pairs and injury.

Setting: Beneficiaries of a major United States-based commercial health insurer during 2000-2015 PATIENTS: Persons aged 16-90 years co-dispensed an opioid and ≥1 precipitant drug(s), with an unintentional traumatic injury event during opioid therapy, as dictated by the case-only design EXPOSURE: Precipitant-exposed (vs. precipitant-unexposed) person-days during opioid therapy.

Outcome: Emergency department or inpatient International Classification of Diseases discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to generate confounder adjusted rate ratios. We accounted for multiple estimation via semi-Bayes shrinkage.

Results: We identified 25,019, 12,650, and 10,826 new users of hydrocodone, tramadol, and oxycodone who experienced an unintentional traumatic injury. Among 464, 376, and 389 hydrocodone-, tramadol-, and oxycodone-precipitant pairs examined, 20, 17, and 16 (i.e., 53 pairs, 34 unique precipitants) were positively associated with unintentional traumatic injury and deemed potential drug interaction signals. Adjusted rate ratios ranged from 1.23 (95 % confidence interval: 1.05-1.44) for hydrocodone + amoxicillin-clavulanate to 4.21 (1.88-9.42) for oxycodone + telmisartan. Twenty (37.7 %) of 53 signals are currently reported in a major drug interaction knowledgebase.

Limitations: Potential for reverse causation, confounding by indication, and chance CONCLUSIONS: We identified previously undescribed and/or unappreciated signals of opioid drug interactions associated with unintentional traumatic injury. Subsequent etiologic studies should confirm (or refute) and elucidate these potential drug interactions.
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http://dx.doi.org/10.1016/j.biopha.2020.110531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606771PMC
October 2020

Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids.

J Bone Joint Surg Am 2020 Jul;102(14):1230-1238

Division of Rheumatology (M.D.G. and J.F.B.), Department of Biostatistics, Epidemiology, and Informatics (M.D.G., J.F.B., C.E.L., T.A.M., and S.H.), and the Department of Orthopedic Surgery (S.M.), University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Cyclooxygenase-2 (COX-2) has been found to be important for fracture-healing in animal models, raising concerns about use of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors after fractures. We evaluated associations of NSAIDs, COX-2 inhibitors, and opioids with nonunion after long-bone fracture.

Methods: Using private health insurance claims data from Optum's de-identified Clinformatics Data Mart database from January 1, 2000, to September 30, 2015, we identified adults with a single long-bone fracture or commonly paired long-bone fractures who had 1 year of available follow-up data. Using multivariable logistic regression models, we examined associations between NSAID, COX-2-inhibitor, or opioid prescription fills after the fracture and the risk of nonunion within 1 year, defined as a nonunion diagnosis with a procedure to treat the nonunion.

Results: A nonunion diagnosis with a procedure to treat the nonunion was identified after 2,996 (0.9%) of the 339,864 fracture episodes, with rates varying by fracture site. The risk of that outcome was greater in patients who had filled COX-2-inhibitor prescriptions (adjusted odds ratio = 1.84 [95% confidence interval = 1.38 to 2.46]) or opioid prescriptions (1.69 [1.53 to 1.86]), but not in patients who had filled nonselective-NSAID prescriptions (1.07 [0.93 to 1.23]) after the fracture. Results were similar when the outcome definition was changed to just a nonunion diagnosis.

Conclusions: COX-2 inhibitors, but not nonselective NSAIDs, were associated with a greater risk of nonunion after fracture. Opioids were also associated with nonunion risk, although patients filling prescriptions for opioids may have had more severe fractures.

Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.19.01415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508275PMC
July 2020

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

JAMA Netw Open 2020 06 1;3(6):e207664. Epub 2020 Jun 1.

Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.7664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315288PMC
June 2020

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

Sci Rep 2020 06 22;10(1):10070. Epub 2020 Jun 22.

Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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: aHR 1.17, 95% CI 0.96-1.42; aHR 0.84, 0.65-1.08; glyburide: aHR 0.87, 0.74-1.03; aHR 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.
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http://dx.doi.org/10.1038/s41598-020-66668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308403PMC
June 2020

Receipt of Substance Use Counseling Among Ambulatory Patients Prescribed Opioids in the United States.

Subst Abuse 2020 22;14:1178221819894588. Epub 2020 May 22.

The University of Texas at Austin College of Pharmacy, San Antonio, TX, USA.

Background: As opioid-related overdose deaths climb in the U.S., risk reduction measures are increasingly important. One such measure recommended involves provision of proactive substance use counseling regarding the risks of opioid analgesics. This is particularly important in patients at increased risk of overdose, such as those with substance use disorders (SUD) or those receiving concomitant medications that further increase the overdose risk (eg, benzodiazepines, gabapentinoids, or Z-hypnotics). However, previous research regarding the likelihood that such counseling is provided during outpatient prescriber visits is lacking.

Objectives: To determine the percentage of U.S. ambulatory care visits in which patients taking prescription opioids received substance use counseling, and whether counseling was more common in patients with concomitant GABAergic medication(s) (benzodiazepine, gabapentinoid or Z-hypnotic) or substance use disorder (SUD) diagnosis.

Methods: A cross-sectional analysis was conducted of all patients aged ⩾18 years identified as having a prescription opioid on their medication list within the 2014-2015 National Ambulatory Medical Care Survey data.

Results: Among 162.7 million visits in which patients were taking opioid medication(s), substance use counseling was provided in 2.4%. During visits for patients receiving opioid(s) plus GABAergic(s), substance use counseling was marginally more common (3.1% versus 2.0%, < .0001). Substance use counseling was also more common among visits for patients taking opioid(s) with SUD (18.9% versus 1.5%, < .0001). Among visits in which a patient was diagnosed with SUD and taking opioid(s) plus GABAergic(s), counseling was more common (23.1% versus 1.4%, < .0001) compared to patients taking opioid(s) plus GABAergic(s) without SUD.

Conclusions: Among national ambulatory care visits in the United States, substance use counseling is provided infrequently for patients taking opioids, even when significant risk factors are present. Increasing patient education may help reduce opioid-related overdose mortality.
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http://dx.doi.org/10.1177/1178221819894588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249603PMC
May 2020

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

Clin Pharmacol Ther 2020 11 31;108(5):1010-1017. Epub 2020 May 31.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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.
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http://dx.doi.org/10.1002/cpt.1885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788336PMC
November 2020

Pharmacoepidemiologic Screening of Potential Oral Anticoagulant Drug Interactions Leading to Thromboembolic Events.

Clin Pharmacol Ther 2020 08 16;108(2):377-386. Epub 2020 May 16.

Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Drug-drug interactions (DDIs) with oral anticoagulants may lead to under-anticoagulation and increased risk of thromboembolism. Although warfarin is susceptible to numerous DDIs, few studies have examined DDIs resulting in thromboembolism or those involving direct-acting oral anticoagulants (DOACs). We aimed to identify medications that increase the rate of hospitalization for thromboembolic events when taken concomitantly with oral anticoagulants. We conducted a high-throughput pharmacoepidemiologic screening study using Optum Clinformatics Data Mart, 2000-2016. We performed self-controlled case series studies among adult users of oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban) with at least one hospitalization for a thromboembolic event. Among eligible patients, we identified all oral medications frequently co-prescribed with oral anticoagulants as potential interacting precipitants. Conditional Poisson regression was used to estimate rate ratios comparing precipitant exposed vs. unexposed time for each anticoagulant-precipitant pair. To minimize within-person confounding by indication for the precipitant, we used pravastatin as a negative control object drug. Multiple estimation was adjusted using semi-Bayes shrinkage. We screened 1,622 oral anticoagulant-precipitant drug pairs and identified 226 (14%) drug pairs associated with statistically significantly elevated risk of thromboembolism. Using pravastatin as the negative control object drug, this list was reduced to 69 potential DDI signals for thromboembolism, 33 (48%) of which were not documented in the DDI knowledge databases Lexicomp and/or Micromedex. There were more DDI signals associated with warfarin than DOACs. This study reproduced several previously documented oral anticoagulant DDIs and identified potential DDI signals that deserve to be examined in future etiologic studies.
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http://dx.doi.org/10.1002/cpt.1845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765337PMC
August 2020

Biosimilar Uptake in Academic and Veterans Health Administration Settings: Influence of Institutional Incentives.

Arthritis Rheumatol 2020 07 5;72(7):1067-1071. Epub 2020 May 5.

University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester.

Objective: To compare uptake in the ordering of biosimilars at a Veterans Affairs Medical Center (VAMC) to that at an academic medical center, where institutional incentives for infused medications differ.

Methods: We performed a cross-sectional study of medical record data and estimated institutional financial incentives at 2 medical centers in Philadelphia: 1) the University of Pennsylvania Health System (UPHS), and 2) the local VAMC. All ordering events for filgrastim or infliximab products were quantified over time and stratified according to product (biosimilar versus reference product) and center. Financial incentives to the institutions over time were determined based on actual drug costs for the VAMC and average sales prices (ASPs) and Medicare Part B reimbursement rates for UPHS.

Results: There were 15,761 infusions of infliximab at UPHS, of which 99% were for the reference product. There was a sharper decline in the use of reference products at the VAMC; 62% of the 446 infliximab infusions ordered at the VAMC were for the reference product. ASPs were consistently lower for biosimilar infliximab products, but the estimated institutional financial incentives remained similar over time for biosimilar and reference infliximab at UPHS. At the VAMC, the costs for 100-mg vials of reference infliximab and infliximab-abda were $623.48 and $115.58, respectively: a $507.90 (81%) savings per vial.

Conclusion: The uptake of infliximab biosimilars has been slow at an academic medical center compared to a nearby VAMC, where financial savings are realized by the institution from its use. Slow adoption of biosimilar medications may impact the rates of decline in costs.
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http://dx.doi.org/10.1002/art.41277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329608PMC
July 2020
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