Comparing Patient-Reported Outcomes Among Anti-TNF Experienced Patients With Ulcerative Colitis Initiating Vedolizumab Versus Tofacitinib.

Background: Primary and secondary nonresponse to anti-tumor necrosis factor (TNF) therapy is common in patients with ulcerative colitis (UC), yet limited research has compared the effectiveness of subsequent biological therapy. Objective: We sought to compare the effectiveness of vedolizumab and tofacitinib in anti-TNF experienced patients with UC, focusing on patient-prioritized patient-reported outcomes (PROs). Methods: We conducted a prospective cohort study nested within the Crohn's & Colitis Foundation's IBD Partners and SPARC IBD initiatives. We identified anti-TNF experienced patients with UC initiating vedolizumab or tofacitinib and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included PRO2, treatment persistence, and need for colectomy. Results: We compared 72 vedolizumab initiators and 33 tofacitinib initiators. At follow-up, Pain Interference (P = .04), but not Fatigue (P = .53) was lower among tofacitinib initiators. A trend toward higher Social Role Satisfaction was not significant. The remainder of secondary outcomes (PRO2, treatment persistence, colectomy) did not differ between treatment groups. Conclusions: Among anti-TNF experienced patients with UC, Pain Interference 4-10 months after treatment initiation was lower among tofacitinib users as compared with vedolizumab users. Many, but not all, secondary endpoints and subanalyses also favored tofacitinib. Future studies with larger sample sizes are needed to further evaluate these findings.

Assessing the impact of privacy-preserving record linkage on record overlap and patient demographic and clinical characteristics in PCORnet®, the National Patient-Centered Clinical Research Network.

OBJECTIVE: This article describes the implementation of a privacy-preserving record linkage (PPRL) solution across PCORnet®, the National Patient-Centered Clinical Research Network. MATERIAL AND METHODS: Using a PPRL solution from Datavant, we quantified the degree of patient overlap across the network and report a de-duplicated analysis of the demographic and clinical characteristics of the PCORnet population. RESULTS: There were ∼170M patient records across the responding Network Partners, with ∼138M (81%) of those corresponding to a unique patient. 82.1% of patients were found in a single partner and 14.7% were in 2. The percentage overlap between Partners ranged between 0% and 80% with a median of 0%. Linking patients' electronic health records with claims increased disease prevalence in every clinical characteristic, ranging between 63% and 173%. DISCUSSION: The overlap between Partners was variable and depended on timeframe. However, patient data linkage changed the prevalence profile of the PCORnet patient population. CONCLUSIONS: This project was one of the largest linkage efforts of its kind and demonstrates the potential value of record linkage. Linkage between Partners may be most useful in cases where there is geographic proximity between Partners, an expectation that potential linkage Partners will be able to fill gaps in data, or a longer study timeframe.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

INTRODUCTION: Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. METHODS: We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. RESULTS: Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). DISCUSSION: This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Establishing a framework for privacy-preserving record linkage among electronic health record and administrative claims databases within PCORnet®, the National Patient-Centered Clinical Research Network.

OBJECTIVE: The aim of this study was to determine whether a secure, privacy-preserving record linkage (PPRL) methodology can be implemented in a scalable manner for use in a large national clinical research network. RESULTS: We established the governance and technical capacity to support the use of PPRL across the National Patient-Centered Clinical Research Network (PCORnet®). As a pilot, four sites used the Datavant software to transform patient personally identifiable information (PII) into de-identified tokens. We queried the sites for patients with a clinical encounter in 2018 or 2019 and matched their tokens to determine whether overlap existed. We described patient overlap among the sites and generated a "deduplicated" table of patient demographic characteristics. Overlapping patients were found in 3 of the 6 site-pairs. Following deduplication, the total patient count was 3,108,515 (0.11% reduction), with the largest reduction in count for patients with an "Other/Missing" value for Sex; from 198 to 163 (17.6% reduction). The PPRL solution successfully links patients across data sources using distributed queries without directly accessing patient PII. The overlap queries and analysis performed in this pilot is being replicated across the full network to provide additional insight into patient linkages among a distributed research network.

The U.S. COVID-19 County Policy Database: a novel resource to support pandemic-related research.

BACKGROUND: It is increasingly recognized that policies have played a role in both alleviating and exacerbating the health and economic consequences of the COVID-19 pandemic. There has been limited systematic evaluation of variation in U.S. local COVID-19-related policies. This study introduces the U.S. COVID-19 County Policy (UCCP) Database, whose objective is to systematically gather, characterize, and assess variation in U.S. county-level COVID-19-related policies. METHODS: In January-March 2021, we collected an initial wave of cross-sectional data from government and media websites for 171 counties in 7 states on 22 county-level COVID-19-related policies within 3 policy domains that are likely to affect health: (1) containment/closure, (2) economic support, and (3) public health. We characterized the presence and comprehensiveness of policies using univariate analyses. We also examined the correlation of policies with one another using bivariate Spearman's correlations. Finally, we examined geographical variation in policies across and within states. RESULTS: There was substantial variation in the presence and comprehensiveness of county policies during January-March 2021. For containment and closure policies, the percent of counties with no restrictions ranged from 0% (for public events) to more than half for public transportation (67.8%), hair salons (52.6%), and religious gatherings (52.0%). For economic policies, 76.6% of counties had housing support, while 64.9% had utility relief. For public health policies, most were comprehensive, with 70.8% of counties having coordinated public information campaigns, and 66.7% requiring masks outside the home at all times. Correlations between containment and closure policies tended to be positive and moderate (i.e., coefficients 0.4-0.59). There was variation within and across states in the number and comprehensiveness of policies. CONCLUSIONS: This study introduces the UCCP Database, presenting granular data on local governments' responses to the COVID-19 pandemic. We documented substantial variation within and across states on a wide range of policies at a single point in time. By making these data publicly available, this study supports future research that can leverage this database to examine how policies contributed to and continue to influence pandemic-related health and socioeconomic outcomes and disparities. The UCCP database is available online and will include additional time points for 2020-2021 and additional counties nationwide.

Patient characteristics, pain treatment patterns, and incidence of total joint replacement in a US population with osteoarthritis.

BACKGROUND: Currently available medications for chronic osteoarthritis pain are only moderately effective, and their use is limited in many patients because of serious adverse effects and contraindications. The primary surgical option for osteoarthritis is total joint replacement (TJR). The objectives of this study were to describe the treatment history of patients with osteoarthritis receiving prescription pain medications and/or intra-articular corticosteroid injections, and to estimate the incidence of TJR in these patients. METHODS: This retrospective, multicenter, cohort study utilized health plan administrative claims data (January 1, 2013, through December 31, 2019) of adult patients with osteoarthritis in the Innovation in Medical Evidence Development and Surveillance Distributed Database, a subset of the US FDA Sentinel Distributed Database. Patients were analyzed in two cohorts: those with prevalent use of "any pain medication" (prescription non-steroidal anti-inflammatory drugs [NSAIDs], opioids, and/or intra-articular corticosteroid injections) using only the first qualifying dispensing (index date); and those with prevalent use of "each specific pain medication class" with all qualifying treatment episodes identified. RESULTS: Among 1 992 670 prevalent users of "any pain medication", pain medications prescribed on the index date were NSAIDs (596 624 [29.9%] patients), opioids (1 161 806 [58.3%]), and intra-articular corticosteroids (323 459 [16.2%]). Further, 92 026 patients received multiple pain medications on the index date, including 71 632 (3.6%) receiving both NSAIDs and opioids. Altogether, 20.6% of patients used an NSAID at any time following an opioid index dispensing and 17.2% used an opioid following an NSAID index dispensing. The TJR incidence rates per 100 person-years (95% confidence interval [CI]) were 3.21 (95% CI: 3.20-3.23) in the "any pain medication" user cohort, and among those receiving "each specific pain medication class" were NSAIDs, 4.63 (95% CI: 4.58-4.67); opioids, 7.45 (95% CI: 7.40-7.49); and intra-articular corticosteroids, 8.05 (95% CI: 7.97-8.13). CONCLUSIONS: In patients treated with prescription medications for osteoarthritis pain, opioids were more commonly prescribed at index than NSAIDs and intra-articular corticosteroid injections. Of the pain medication classes examined, the incidence of TJR was highest in patients receiving intra-articular corticosteroids and lowest in patients receiving NSAIDs.

Effect of Mailing Educational Material to Patients With Atrial Fibrillation and Their Clinicians on Use of Oral Anticoagulants: A Randomized Clinical Trial.

Importance: Only about half of patients with atrial fibrillation (AF) who are at increased risk for stroke are treated with an oral anticoagulant (OAC), despite guideline recommendations for their use. Educating patients with AF about prevention of stroke with OACs may enable them as agents of change to initiate OAC treatment. Objective: To determine whether an educational intervention directed to patients and their clinicians stimulates the use of OACs in patients with AF who are not receiving OACs. Design, Setting, and Participants: The Implementation of a Randomized Controlled Trial to Improve Treatment With Oral Anticoagulants in Patients With Atrial Fibrillation (IMPACT-AFib) trial was a prospective, multicenter, open-label, pragmatic randomized clinical trial conducted from September 25, 2017, to May 1, 2019, embedded in health plans that participate in the US Food and Drug Administration's Sentinel System. It used the distributed database comprising health plan members to identify eligible patients, their clinicians, and outcomes. IMPACT-AFib enrolled patients with AF, a CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) score of 2 or more, no evidence of OAC prescription dispensing in the preceding 12 months, and no hospitalization-related bleeding event within the prior 6 months. Interventions: Randomization to a single mailing of patient and/or clinician educational materials vs control. Main Outcomes and Measures: Analysis was performed on a modified intention-to-treat basis. The primary end point was the proportion of patients with at least 1 OAC prescription dispensed or at least 4 international normalized ratio test results within 1 year of the intervention. Results: Among 47 333 patients, there were 24 909 men (52.6%), the mean (SD) age was 77.9 (9.7) years, mean (SD) CHA2DS2-VASc score was 4.5 (1.7), 22 404 patients (47.3%) had an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more, and 8890 patients (18.8%) had a history of hospitalization for bleeding. There were 2328 of 23 546 patients (9.9%) in the intervention group with initiation of OAC at 1 year compared with 2330 of 23 787 patients (9.8%) in the control group (adjusted OR, 1.01 [95% CI, 0.95-1.07]; P = .79). Conclusions and Relevance: Among a large population with AF with a guideline indication for OACs for stroke prevention who were randomized to a mailed educational intervention or to usual care, there was no clinically meaningful, numerical, or statistically significant difference in rates of OAC initiation. More-intensive interventions are needed to try and address the public health issue of underuse of anticoagulation for stroke prevention among patients with AF. Trial Registration: ClinicalTrials.gov Identifier: NCT03259373.

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

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.

Identifying prescribing cascades in Alzheimer's disease and related dementias: The calcium channel blocker-diuretic prescribing cascade.

PURPOSE: Prescribing cascades occur when a physician prescribes a new drug to address the side-effect of another drug. Persons with Alzheimer's disease and related dementias (ADRD) are at increased risk for prescribing cascades. Our objective was to develop an approach to estimating the proportion of calcium channel blocker-diuretic (CCB-diuretic) prescribing cascades among persons with ADRD in two U.S. health plans. METHODS: We identified patients aged ≥50 on January 1, 2017, dispensed a drug to treat ADRD in the 365-days prior to/on cohort entry date. Patients had medical/pharmacy coverage for 1 year before and through cohort entry. We excluded individuals with an institutional stay encounter in the 45 days prior to cohort entry and censored patients based on: disenrollment from coverage, death, or end of data. We identified incident and prevalent CCB use in the 183-days following cohort entry, and identified subsequent incident diuretic use among incident and prevalent CCB-users within 365-days from cohort entry. RESULTS: There were 121 538 eligible patients. Approximately 62% were female, with a mean age of 79.5 (SD ±8.6). Overall 2.1% of the cohort experienced a prevalent CCB-diuretic prescribing cascade with 1586 incident diuretic-users among 36 462 prevalent CCB-users (4.3%, 95% CI 4.1-4.6%]); and there were161 incident diuretic-users among 3304 incident CCB-users (4.9%, 95% CI 4.2-5.7%) (incident CCB-diuretic cascade). CONCLUSIONS: We describe an approach to identify prescribing cascades in persons with ADRD, which can be used to assess the proportion of prescribing cascades in large cohorts. We determined the proportion of CCB-diuretic prescribing cascades was low.

Antidopaminergic-Antiparkinsonian Medication Prescribing Cascade in Persons with Alzheimer's Disease.

OBJECTIVES: Persons living with Alzheimer's disease (AD) may be at increased risk for prescribing cascades due to greater multimorbidity, polypharmacy, and the need for more complex care. Our objective was to assess the proportion of the antidopaminergic-antiparkinsonian medication prescribing cascades among persons living with Alzheimer's disease. SETTING: Two large administrative claims databases in the United States. PARTICIPANTS: We identified patients aged ≥50 on January 1, 2017, who were dispensed a drug used to treat Alzheimer's disease for at least 1 day in the 365 days prior to or on cohort entry date and who had medical and pharmacy coverage in the 365 days prior to the cohort entry date. We excluded individuals with a recent institutional stay. We identified incident antidopaminergic (antipsychotic/metoclopramide) use in the 183 days following cohort entry and identified subsequent incident antiparkinsonian drug use within 8 to 365 days. RESULTS: There were 121,538 patients with Alzheimer's disease eligible for inclusion. Approximately 62% were women with a mean age of 79.5 (SD ± 8.6). The mean number of drugs dispensed was 9.2 (SD ± 4.9). There were 36 incident antiparkinsonian users among 4,534 incident antipsychotic/metoclopramide users (0.8%). CONCLUSION: We determined that the proportion of antidopaminergic-antiparkinsonian medication prescribing cascades, widely considered as high-priority, was low. Our approach can be used to assess the proportion of prescribing cascades in populations considered to be at high risk and to prioritize system-level interventional efforts to improve medication safety in these patients.

PCORnet® 2020: current state, accomplishments, and future directions.

OBJECTIVE: To describe PCORnet, a clinical research network developed for patient-centered outcomes research on a national scale. STUDY DESIGN AND SETTING: Descriptive study of the current state and future directions for PCORnet. We conducted cross-sectional analyses of the health systems and patient populations of the 9 Clinical Research Networks and 2 Health Plan Research Networks that are part of PCORnet. RESULTS: Within the Clinical Research Networks, electronic health data are currently collected from 337 hospitals, 169,695 physicians, 3,564 primary care practices, 338 emergency departments, and 1,024 community clinics. Patients can be recruited for prospective studies from any of these clinical sites. The Clinical Research Networks have accumulated data from 80 million patients with at least one visit from 2009 to 2018. The PCORnet Health Plan Research Network population of individuals with a valid enrollment segment from 2009 to 2019 exceeds 60 million individuals, who on average have 2.63 years of follow-up. CONCLUSION: PCORnet's infrastructure comprises clinical data from a diverse cohort of patients and has the capacity to rapidly access these patient populations for pragmatic clinical trials, epidemiological research, and patient-centered research on rare diseases.

Prescribing cascades in persons with Alzheimer's disease: engaging patients, caregivers, and providers in a qualitative evaluation of print educational materials.

INTRODUCTION: Prescribing cascades occur when the side effect of a drug is misinterpreted as a new medical condition, and a second drug is prescribed to address the side effect. Persons with Alzheimer's disease (AD) are at increased risk of prescribing cascades due to greater multimorbidity, polypharmacy, and complexity of care. The objective of this study was to evaluate educational materials about prescribing cascades in persons with AD, and elicit input on their use in a future trial. METHODS: We interviewed community-dwelling adults with either an AD diagnosis or a prescription drug used to treat AD (n = 12), caregivers of patients meeting the same criteria (n = 14), and providers (n = 15). We coded interview transcripts and organized themes according to the communication-human information processing model. We revised the materials based on the interviews, and surveyed participating caregivers and providers for their reactions to the revised materials. RESULTS: Analysis of patients', caregivers', and providers' comments suggest: (a) Providers had conflicting views about the messaging of materials; (b) Caregivers were likely to read letters addressed to patients; (c) Providers were likely to ignore letters, but were receptive to patient/caregiver-initiated conversations; (d) Patients and caregivers had difficulty understanding prescribing cascades; (e) Providers worried that mailed materials would undermine trust; (f) Participants had mixed views on how materials might affect the clinical encounter; (g) Participants felt that materials would improve patient/caregiver engagement. When surveyed, most providers found the revised materials informative and actionable, and most caregivers found them understandable and useful. CONCLUSIONS: This evaluation of educational materials about prescribing cascades in patients with AD provides strong support for engaging caregivers to communicate with providers about prescribing cascades. By giving patients and caregivers a basic description of the prescribing cascade concept, our educational materials may help them prepare for a conversation with the provider, who can then tailor the discussion of the possible cascade to the specific needs of the individual patient and caregiver. However, evidence on whether materials can stimulate such conversations awaits testing in a future trial. LAY SUMMARY: Patient, caregiver and provider thoughts on educational materials about prescribing and medication safety Prescribing cascades occur when the side effect of a medication is misinterpreted as a new medical condition, and a second medication is prescribed to treat the side effect. Persons with Alzheimer's disease (AD) are at increased risk of prescribing cascades because they often have more medical conditions, more medications, and more complex care. The goal of this study was to evaluate mailed educational materials about prescribing cascades in persons with AD, and get input on their use in a future study. We interviewed 12 adults with AD, or prescribed a medication to treat AD, 14 caregivers of persons with AD, and 15 providers. We reviewed the interview transcripts to identify important findings about our educational materials. We edited the materials based on the interviews, and sent participating caregivers and providers a questionnaire to get their reactions to the new materials. Important findings from the interviews suggest: (a) Providers had conflicting views about the recommendations given; (b) Caregivers were likely to read letters addressed to patients; (c) Providers were likely to ignore letters, but were receptive to patients/caregivers introducing the topic; (d) Patients and caregivers had difficulty understanding prescribing cascades; (e) Providers worried mailed materials would undermine trust; (f) Participants had mixed views on how materials might affect a doctor's appointment; (g) Participants felt strongly that materials would improve patient/caregiver engagement. When surveyed, almost all providers found the revised materials informative and actionable; and most caregivers found them understandable and useful. These findings provide strong support for engaging caregivers to communicate with providers about prescribing cascades. The educational materials may help patients and caregivers prepare for a conversation with the provider, who can then tailor the discussion of the possible cascade to the specific needs of the individual patient and caregiver. However, evidence on whether materials can stimulate such conversations awaits testing in a future study.

Underuse of oral anticoagulants in privately insured patients with atrial fibrillation: A population being targeted by the IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AFib).

BACKGROUND: Many studies showing underuse of oral anticoagulants (OACs) in patients with atrial fibrillation (AF) predated the advent of the non-vitamin K antagonist OACs. We retrospectively examined use of OACs in a large commercially insured population. METHODS: Administrative claims data from 4 research partners participating in FDA-Catalyst, a program of the Sentinel Initiative, were queried in September 2017. Patients were included if they were ≥30 years old with ≥365 days of medical/pharmacy coverage, and had ≥2 diagnosis codes for AF, a CHA2DS2-VASc score ≥2, absence of contraindications to OAC use, and no evidence of OAC use in the 365 days before the index AF diagnosis. The main outcome measures of the current analysis were rates of OAC use in the prior 12 months of cohort identification and factors associated with non-use. RESULTS: A total of 197,806 AF patients met the eligibility criteria prior to assessment of OAC treatment. Of these, 179,580 (91%) patients were ≥65 years old and 73,286 (37%) patients were ≥80 years old. Half of the patients (98,903) were randomized to the early intervention arm in the IMPACT-AFib trial and constitute the cohort for this analysis. Of these, 32,295 (33%) had no evidence of OAC use in the prior 12 months. Compared with patients with evidence of OAC use in the prior 12 months, patients without OAC use were more likely to be ≥80 years old, women, and have a history of anemia (51% vs 47%) and less likely to have diabetes (41% vs 44%), history of stroke or TIA (15% vs 19%), and history of heart failure (39% vs 48%). CONCLUSIONS: Despite a high risk of stroke, one-third of privately insured patients with AF and no obvious contraindications to an OAC were not treated with an OAC. There is an unmet need for evidence-based interventions that could lead to greater use of OACs in patients with AF at risk for stroke.

Diagnosed prevalence of Alzheimer's disease and related dementias in Medicare Advantage plans.

INTRODUCTION: One-third of Medicare beneficiaries are enrolled in Medicare Advantage (MA). Yet, little is known about MA beneficiaries diagnosed with Alzheimer's disease (AD) and AD-related dementias (AD/ADRD). METHODS: We calculated the prevalence of AD/ADRD diagnoses in 2014 and 2016 in three MA plans. We determined the demographic characteristics of beneficiaries diagnosed with AD/ADRD, and whether they disenrolled from the MA plan for any reason within 364 days from the index date. RESULTS: In 2014 and 2016, the overall prevalence of AD/ADRD diagnoses was 5.6% and 6.5%, respectively. In 2016, AD/ADRD beneficiaries were on average 82.4 (SD = 7.4) years of age, 61.8% female, and had multiple comorbidities. By 364 days post-index date, 32% of beneficiaries with AD/ADRD had disenrolled from their plan. The demographic characteristics of 2014 beneficiaries with diagnosed AD/ADRD were similar to their 2016 counterparts. DISCUSSION: The prevalence of AD/ADRD diagnosis in MA is lower than rates reported in Medicare fee-for-service.

Practical challenges in the conduct of pragmatic trials embedded in health plans: Lessons of IMPACT-AFib, an FDA-Catalyst trial.

IMPACT-AFib was an 80,000-patient randomized clinical trial implemented by five US insurance companies (health plans) aimed at increasing the use of oral anticoagulants by individuals with atrial fibrillation who were at high risk of stroke and not on treatment. The underlying thesis was that patients could be change agents to initiate prescribing discussions with their providers. We tested the effect of mailing information to both patients and their providers. We used administrative medical claims and pharmacy dispensing data to identify eligible patients, to randomize them to an early or delayed intervention, and to assess clinical outcomes. The core data were analysis-ready datasets each site had created and curated for the FDA's Sentinel System, supplemented by updated "fresh" pharmacy and enrollment data to ensure eligibility at the time of intervention. Following mutually agreed upon procedures, sites linked to additional internal source data to implement the intervention-educational information mailed to patients and their providers in the early intervention arm, and to providers of patients in the delayed intervention arm approximately 12 months later. The primary analysis compares the early intervention arm to the delayed intervention arm, prior to the delayed intervention being conducted (i.e. compares intervention to non-intervention). The endpoints of interest were evidence of initiation of anticoagulation (primary) as well as clinical endpoints, including stroke and hospitalization for bleeding. Major challenges, some unanticipated, identified during the planning phase include convening multi-stakeholder investigator teams and advisors, addressing ethical concerns about not intervening in a usual care comparison group, and identifying and avoiding interference with sites' routine programs that were similar to the intervention. Needs and challenges during the implementation phase included the fact that even limited site-specific programming greatly increased time and effort, the need to refresh research data extracts immediately before outreach to patients and providers, potential difficulty identifying low-cost medications such as warfarin that may not be reimbursed by health plans and so not discoverable in dispensing data, the need to develop workarounds when "providers" in claims data were facilities, difficulty addressing clustering of patients by provider because providers can have multiple identifiers within and between health plans, and the need to anticipate loss to follow up because of health plan disenrollment or change in benefits. As pragmatic trials begin to shape evidence generation within clinical practice, investigators should anticipate issues inherent to claims data and working with multiple large sites. In IMPACT-AFib, we found that investing in collaboration and communication among all parties throughout all phases of the study helped ensure common understanding, early identification of challenges, and streamlined actual implementation.

The Patient-Centered Outcomes Research Network Antibiotics and Childhood Growth Study: Implementing Patient Data Linkage.

PCORnet, the Patient-Centered Outcomes Research Network, is comprised of health systems and health plans that transform electronic health records (EHRs) and claims data to a common data model (CDM) to facilitate real-world clinical research. Because patients receive health care in multiple care delivery settings, linking health records across systems and health plan claims would provide a more comprehensive and accurate picture of health care for patients. The current study expanded on a PCORnet Antibiotics and Childhood Growth (ABX) study to (1) identify and implement a privacy-preserving patient linkage solution among a clinical data research network and a health plan network within the ABX Study, and (2) assess overlap in prescribed and dispensed antibiotics and additional data gained from claims among the linked patients. This manuscript describes the linkage process and resulting overlap analysis. The authors identified 549 patients from the EHR record study cohort who had claims records with the health plan. Sixty percent (n = 329) of patients had consistent antibiotic exposure data across the 2 sources, indicating antibiotic exposure (44.3%) or nonexposure (15.7%). Among total antibiotic prescribing records, 43.1% had a matched claims record for dispensing within 60 days. Among antibiotic dispense records 26.5% were not associated with a prescribing record in the linked health systems. These findings showcase the feasibility of linking health plan claims data to PCORnet CDM in a privacy-preserving manner while also demonstrating continued gaps in data that may occur. The study highlights the importance of combining multiple health data sources for comprehensive clinical research.

Bystander Ethics and Good Samaritanism: A Paradox for Learning Health Organizations.

In 2012, a U.S. Institute of Medicine report called for a different approach to health care: "Left unchanged, health care will continue to underperform; cause unnecessary harm; and strain national, state, and family budgets." The answer, they suggested, would be a "continuously learning" health system. Ethicists and researchers urged the creation of "learning health organizations" that would integrate knowledge from patient-care data to continuously improve the quality of care. Our experience with an ongoing research study on atrial fibrillation-a trial known as IMPACT-AFib-gave us some insight into one of the challenges that will have to be dealt with in creating these organizations. Although the proposed educational intervention study placed no restrictions on what providers and health plans could do, the oversight team argued that the ethical principle of beneficence did not allow the researchers to be "bystanders" in relation to a control group receiving suboptimal care. In response, the researchers designed a "workaround" that allowed the project to go forward. We believe the experience suggests that what we call "bystander ethics" will create challenges for the kinds of quality improvement research that LHOs are designed to do.

Cross-Network Directory Service: Infrastructure to enable collaborations across distributed research networks.

INTRODUCTION: Existing large-scale distributed health data networks are disconnected even as they address related questions of healthcare research and public policy. This paper describes the design and implementation of a fully functional prototype open-source tool, the Cross-Network Directory Service (CNDS), which addresses much of what keeps distributed networks disconnected from each other. METHODS: The set of services needed to implement a Cross-Directory Service was identified through engagement with stakeholders and workgroup members. CNDS was implemented using PCORnet and Sentinel network instances and tested by participating data partners. RESULTS: Web services that enable the four major functional features of the service (registration, discovery, communication, and governance) were developed and placed into an open-source repository. The services include a robust metadata model that is extensible to accommodate a virtually unlimited inventory of metadata fields, without requiring any further software development. The user interfaces are programmatically generated based on the contents of the metadata model. CONCLUSION: The CNDS pilot project gathered functional requirements from stakeholders and collaborating partners to build a software application to enable cross-network data and resource sharing. The two partners-one from Sentinel and one from PCORnet-tested the software. They successfully entered metadata about their organizations and data sources and then used the Discovery and Communication functionality to find data sources of interest and send a cross-network query. The CNDS software can help integrate disparate health data networks by providing a mechanism for data partners to participate in multiple networks, share resources, and seamlessly send queries across those networks.

FDA-Catalyst-Using FDA's Sentinel Initiative for large-scale pragmatic randomized trials: Approach and lessons learned during the planning phase of the first trial.

BACKGROUND: The US Food and Drug Administration's Sentinel Initiative is well positioned to support pragmatic clinical trials. FDA-Catalyst combines direct contact with health plan members and/or providers with data in the Sentinel infrastructure. Here, we describe the rationale, feasibility analyses, and lessons learned from the planning phase of the first large pragmatic trial conducted using the Sentinel Initiative's delivery system capabilities-IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (the IMPACT-AFib trial). METHODS: During the planning phase, we convened representatives from five commercial health plans, FDA, study coordinating centers, and a patient representative for protocol development, institutional review board preparation, and other activities. Administrative claims data from the plans were included in a retrospective cohort analysis to assess sample size for the trial. Members ≥30 years old with ≥365 days of medical/pharmacy coverage, ≥2 diagnosis codes for atrial fibrillation, a guideline-based indication for oral anticoagulant use for stroke prevention, and no evidence of oral anticoagulant use in the 365 days prior to the index atrial fibrillation diagnosis in 2013 were included. Exclusions for the analysis included other conditions requiring anticoagulation, history of intracranial hemorrhage, and gastrointestinal bleed. We calculated rates of oral anticoagulant use, transient ischemic attack or stroke, and bleeding in the 365 days following the index atrial fibrillation diagnosis. RESULTS: A total of 44,786 members with atrial fibrillation with no evidence of recent oral anticoagulant use were identified. In total, 87% (n = 38,759) were classified as having a guideline-based indication for oral anticoagulants. Of those, 33% (n = 12,867) had a new oral anticoagulant dispensed during the following year, 15% (n = 5917) were hospitalized for stroke or transient ischemic attack, and 9% (n = 3469) for bleeding events. This information was used to develop the trial protocol including sample size, power calculations, and level of randomization. CONCLUSION: Sentinel infrastructure generated preliminary data that supported planning and implementation of a large pragmatic trial embedded in health plans. This planning identified unanticipated challenges that must be addressed in similar trials.

Diagnostic Algorithms for Cardiovascular Death in Administrative Claims Databases: A Systematic Review.

INTRODUCTION: Valid algorithms for identification of cardiovascular (CV) deaths allow researchers to reliably assess the CV safety of medications, which is of importance to regulatory science, patient safety, and public health. OBJECTIVE: The aim was to conduct a systematic review of algorithms to identify CV death in administrative health plan claims databases. METHODS: We searched MEDLINE, EMBASE, and Cochrane Library for English-language studies published between January 1, 2012 and October 17, 2017. We examined references in systematic reviews to identify earlier studies. Selection included any observational study using electronic health care data to evaluate the sensitivity, specificity, positive predictive value (PPV), or negative predictive value (NPV) of algorithms for CV death (sudden cardiac death [SCD], myocardial infarction [MI]-related death, or stroke-related death) among adults aged ≥ 18 years in the United States. Data were extracted by two independent reviewers, with disagreements resolved through further discussion and consensus. The Quality Assessment of Diagnostic Accuracy Studies-2 instrument was used to assess the risk of bias. RESULTS: Five studies (n = 4 on SCD, n = 1 on MI- and stroke-related death) were included after a review of 2053 citations. All studies reported algorithm PPVs, with incomplete reporting on other accuracy parameters. One study was at low risk of bias, three studies were at moderate risk of bias, and one study was at unclear risk of bias. Two studies identified community-occurring SCD: one identified events using International Classification of Disease, Ninth Revision (ICD-9) codes on death certificates and other criteria from medical claims (PPV = 86.8%) and the other identified events resulting in hospital presentation using first-listed ICD-9 codes on emergency department or inpatient medical claims (PPV = 92.3%). Two studies used death certificates alone to identify SCD (PPV = 27% and 32%, respectively). One study used medical claims to identify CV death (PPV = 36.4%), coronary heart disease mortality (PPV = 28.3%), and stroke mortality (PPV = 34.5%). CONCLUSION: Two existing algorithms based on medical claims diagnoses with or without death certificates can accurately identify SCD to support pharmacoepidemiologic studies. Developing valid algorithms identifying MI- and stroke-related death should be a research priority. PROSPERO 2017 CRD42017078745.