Publications

2018
Krumme AA, Pawar A, Schneeweiss S, Glynn RJ, Choudhry NK, Kulldorff M, Ortiz AS, Avorn J, Gagne JJ. Study protocol for the dabigatran, apixaban, rivaroxaban, edoxaban, warfarin comparative effectiveness research study. J Comp Eff Res. 2018;7 (1) :57-66.Abstract
Since 2010, four oral anticoagulants have been approved for marketing in addition to warfarin for treatment of thromboembolic disease. Limited head-to-head data exist comparing these treatments, leaving patients and clinicians with little guidance for selecting a strategy that balances recurrence reduction with bleeding risk. In the dabigatran, apixaban, rivaroxban, edoxaban and warfarin comparative effectiveness research study, we compare all five currently available oral anticoagulant agents for the extended treatment of deep venous thrombosis and pulmonary embolism, as well as no extended treatment, and evaluate whether results differ in specific sub-populations. As our population includes Medicare novel anticoagulant users and large numbers of commercially insured and Medicaid patients, our results will likely be transportable to the majority of US patients experiencing a DVT or pulmonary embolism. CLINICAL TRIALS REGISTRATION: NCT03271450.
Donneyong MM, Kulik A, Gagne JJ. Trends and Patterns of Corticosteroid Use During Coronary Artery Bypass Grafting Surgery in the United States. J Cardiovasc Pharmacol Ther. 2018;23 (3) :226-236.Abstract
BACKGROUND: Several clinical trials have documented clinical benefits associated with prophylactic corticosteroid administration at the time of coronary artery bypass graft (CABG) surgery, including a reduction in the risk of atrial fibrillation and hospital length of stay. Despite the published data, the extent to which providers have adopted the perioperative use of corticosteroids remains unknown. OBJECTIVES: To assess temporal trends, between-hospital variation, and determinants of perioperative intravenous corticosteroid use during CABG surgery. METHODS: We identified all patients admitted for CABG surgery in the Premier Healthcare Database (2003-2014), a large US-based inpatient database. We determined the proportion of patients administered prophylactic corticosteroids on the day of CABG surgery. Linear time-series models were used to estimate the rate and trend of corticosteroid use over time. Separate multivariable generalized estimating equation models were used to quantify the variation in and determinants of perioperative corticosteroid use. RESULTS: Of 401 788 eligible patients who underwent a CABG surgery between 2003 and 2014, 20% (n = 80 681) were administered intravenous prophylactic perioperative corticosteroids (methylprednisolone, dexamethasone, or hydrocortisone). Corticosteroid use increased from 17.5% in 2003 to 22.6% in 2014 (annual rate = 0.42%; P < .001). Individual hospitals accounted for >50% of variation in corticosteroid use. High between-hospital variation was also observed, and the probability of utilization was ≥32.4% in the upper versus ≤3.4% in the bottom quartiles of hospitals. CONCLUSION: Prophylactic corticosteroid administration during CABG has increased gradually since 2003. To further evaluate the risk-benefit trade-off associated with their use, we believe a large-scale outcomes study is warranted to assess this highly variable practice.
Dong Y-H, Jin Y, Tsacogianis TN, He M, Hsieh P-H, Gagne JJ. Use of olmesartan and enteropathy outcomes: a multi-database study. Aliment Pharmacol Ther. 2018;47 (6) :792-800.Abstract
BACKGROUND: Multiple case reports suggest that olmesartan may be linked to sprue-like enteropathy; however, few epidemiological studies have examined this association and results have been mixed. AIM: To assess whether olmesartan is associated with a higher rate of enteropathy vs other angiotensin II receptor blockers (ARBs). METHODS: We conducted a cohort study among ARB initiators in 5 US claims databases representing different health insurance programmes. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for enteropathy-related outcomes, including coeliac disease, malabsorption, concomitant diagnoses of diarrhoea and weight loss, and non-infectious enteropathy, comparing olmesartan initiators to initiators of other ARBs after propensity score (PS) matching. RESULTS: We identified 1 928 469 eligible patients. The unadjusted incidence rates were 0.82, 1.41, 1.66 and 29.20 per 1000 person-years for coeliac disease, malabsorption, concomitant diagnoses of diarrhoea and weight loss, and non-infectious enteropathy respectively. HRs after PS matching comparing olmesartan to other ARBs were 1.21 (95% CI, 1.05-1.40), 1.00 (95% CI, 0.88-1.13), 1.22 (95% CI, 1.10-1.36) and 1.04 (95% CI, 1.01-1.07) for each outcome. HRs were larger for patients aged 65 years and older (eg for coeliac disease, 1.57 [95% CI, 1.20-2.05]), for patients receiving treatment for more than 1 year (1.62 [95% CI, 1.24-2.12]), and for patients receiving higher cumulative olmesartan doses (1.78 [95% CI, 1.33-2.37]). CONCLUSIONS: This large-scale, multi-database study found a higher rate of enteropathy in olmesartan initiators as compared to initiators of other ARBs, although the absolute incidence rate was low in both groups.
Wohlfahrt A, Campos A, Iversen MD, Gagne JJ, Massarotti E, Solomon DH, Feldman CH. Use of rheumatology-specific patient navigators to understand and reduce barriers to medication adherence: Analysis of qualitative findings. PLoS One. 2018;13 (7) :e0200886.Abstract
OBJECTIVE: Adherence to medications among patients with rheumatic diseases is often suboptimal. Patient navigators, individuals trained in care coordination, motivational interviewing and basic rheumatology and pharmacology, have not been employed to explore and address this issue. We piloted a single-site, single arm intervention to determine the feasibility and acceptability of using rheumatology-specific navigators to understand and reduce barriers to adherence to oral disease modifying anti-rheumatic drugs (DMARDs). We analyzed our qualitative findings from navigator-patient interactions as well as patient satisfaction with the intervention. METHODS: We recruited patients ≥18 years with a systemic rheumatic disease who initiated an oral DMARD within the prior 6 months. Navigators conducted baseline needs assessments and 2-4 week follow-up calls to understand and address issues related to medication adherence. We analyzed patient-navigator encounters qualitatively using content analysis to identify key themes related to barriers to adherence and navigator actions performed in response to the barriers described. We also categorized intentional and unintentional nonadherent behavior and assessed satisfaction with the navigator experience (range 0-5, 5 = most satisfied). RESULTS: 107 rheumatology patients were followed for up to 6 months. Mean patient age was 55 years (+17) and 93% were female; 36% described one or more episode of intentional or unintentional nonadherence. The three most common themes identified as barriers to adherence were fear of adverse events (raised by 54%), concerns about medication effectiveness (43%), and challenges with medication acquisition (32%). 86% of participants described at least one adherence-related barrier. Frequent navigator actions included facilitation of patient-doctor communication (38%), medication and diagnosis education (27%), and development of individualized strategies to improve adherence (16%). Patients were satisfied with the navigator experience (mean 4.4 + 0.9). CONCLUSION: Navigators uncovered and addressed a number of medication adherence-related concerns and patients were satisfied with the services provided.
Kumamaru H, Lee MP, Choudhry NK, Dong Y-H, Krumme AA, Khan N, Brill G, Kohsaka S, Miyata H, Schneeweiss S, et al. Using Previous Medication Adherence to Predict Future Adherence. J Manag Care Spec Pharm. 2018;24 (11) :1146-1155.Abstract
BACKGROUND: Medication nonadherence is a major public health problem. Identification of patients who are likely to be and not be adherent can guide targeted interventions and improve the design of comparative-effectiveness studies. OBJECTIVE: To evaluate multiple measures of patient previous medication adherence in light of predicting future statin adherence in a large U.S. administrative claims database. METHODS: We identified a cohort of patients newly initiating statins and measured their previous adherence to other chronic preventive medications during a 365-day baseline period, using metrics such as proportion of days covered (PDC), lack of second fills, and number of dispensations. We measured adherence to statins during the year after initiation, defining high adherence as PDC ≥ 80%. We built logistic regression models from different combinations of baseline variables and previous adherence measures to predict high adherence in a random 50% sample and tested their discrimination using concordance statistics (c-statistics) in the other 50%. We also assessed the association between previous adherence and subsequent statin high adherence by fitting a modified Poisson model from all relevant covariates plus previous mean PDC categorized as < 25%, 25%-79%, and ≥ 80%. RESULTS: Among 89,490 statin initiators identified, a prediction model including only demographic variables had a c-statistic of 0.578 (95% CI = 0.573-0.584). A model combining information on patient comorbidities, health care services utilization, and medication use resulted in a c-statistic of 0.665 (95% CI = 0.659-0.670). Models with each of the previous medication adherence measures as the only explanatory variable yielded c-statistics ranging between 0.533 (95% CI = 0.529-0.537) for lack of second fill and 0.666 (95% CI = 0.661-0.671) for maximum PDC. Adding mean PDC to the combined model yielded a c-statistic of 0.695 (95% CI = 0.690-0.700). Given a sensitivity of 75%, the predictor improved the specificity from 47.7% to 53.6%. Patients with previous mean PDC < 25% were half as likely to show high adherence to statins compared with those with previous mean PDC ≥ 80% (risk ratio = 0.49, 95% CI = 0.46-0.50). CONCLUSIONS: Including measures of previous medication adherence yields better prediction of future statin adherence than usual baseline clinical measures that are typically used in claims-based studies. DISCLOSURES: This study was funded by the Patient-Centered Outcomes Research Institute (ME-1309-06274). Kumamaru, Kohsaka, and Miyata are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo, which is a social collaboration department supported by National Clinical Database. The department was formerly supported by endowments from Johnson & Johnson K.K., Nipro, Teijin Pharma, Kaketsuken K.K., St. Jude Medical Japan, Novartis Pharma K.K., Taiho Pharmaceutical, W. L. Gore & Associates, Olympus Corporation, and Chugai Pharmaceutical. Gagne has received grants from Novartis Pharmaceuticals and Eli Lilly and Company to the Brigham and Women's Hospital for unrelated work. He is a consultant to Aetion, a software company, and to Optum. Choudhry has received grants from the National Heart, Lung, and Blood Institute, PhRMA Foundation, Merck, Sanofi, AstraZeneca, CVS, and MediSafe. Schneeweiss is consultant to WHISCON and Aetion, a software manufacturer of which he also owns equity. He is principal investigator of investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Genentech, and Boehringer Ingelheim unrelated to the topic of this study. He does not receive personal fees from biopharmaceutical companies. No potential conflict of interest was reported by the other authors.
Sun JW, Rogers JR, Her Q, Welch EC, Panozzo CA, Toh S, Gagne JJ. Validation of the Combined Comorbidity Index of Charlson and Elixhauser to Predict 30-Day Mortality Across ICD-9 and ICD-10. Med Care. 2018;56 (9) :812.
Frosch ZAK, Gagne JJ, Gray SW, Abel GA. What Does a Cancer Diagnosis Mean? Public Expectations in a Shifting Therapeutic Environment. J Oncol Pract. 2018;14 (3) :139-140.
Feldman CH, Wohlfahrt A, Campos A, Gagne JJ, Iversen MD, Massarotti E, Solomon DH, Kawachi I. Can Patient Navigators Improve Adherence to Disease-Modifying Antirheumatic Drugs? Quantitative Findings From a Six-Month Single-Arm Pilot Intervention. Arthritis Care Res (Hoboken). 2018;70 (9) :1400-1405.Abstract
OBJECTIVE: Nonadherence to disease-modifying antirheumatic drugs (DMARDs) is common, worsens during the treatment course, and results in adverse outcomes. We studied whether patient navigators (laypersons trained in care coordination, motivational interviewing, basic pharmacology, and disease management) improved oral DMARD adherence. METHODS: We enrolled 107 patients ages ≥18 years with systemic rheumatic diseases who initiated an oral DMARD within 6 months. Navigators interacted with patients up to 2-4 times per week for 6 months. Patients completed validated surveys (Morisky Medication Adherence Scale [MMAS-8], Mental Health Inventory [MHI-5], Beliefs about Medicines Questionnaire, and Brief Illness Perception Questionnaire) at baseline and at 6 months. We used paired t-tests to compare baseline and 6-month outcomes. We examined the association of age, race/ethnicity, insurance, and MHI-5 with change in MMAS-8 score using multivariable linear regression. RESULTS: Among 107 patients enrolled, 69 (64%) completed baseline and 6-month MMAS-8 surveys. Mean ± SD age was 55 ± 16 years and 93% were female. The mean ± SD baseline MMAS-8 score was 6.7 ± 1.3 (indicating borderline adherence), and the mean ± SD MHI-5 score was 60.8 ± 9.1 (<68 suggests any depressive symptoms). After 6 months, there were no significant changes in MMAS-8 (P = 0.09) or MHI-5 (P = 0.83). Patients described fewer medication concerns (P = 0.03), but a more threatening perception of illness (P = 0.01). Our multivariable model demonstrated a small change in MMAS-8 for each 5-year increase in age (β = 0.14, P = 0.02). CONCLUSION: Our intervention resulted in no significant change in adherence from baseline. A multicenter, randomized controlled trial is needed to determine whether patient navigators are effective in maintaining adherence to DMARDs over time.
2017
Sun JW, Rogers JR, Her Q, Welch EC, Panozzo CA, Toh S, Gagne JJ. Adaptation and Validation of the Combined Comorbidity Score for ICD-10-CM. Med Care. 2017;55 (12) :1046-1051.Abstract
BACKGROUND: The combined comorbidity score, which merges the Charlson and Elixhauser comorbidity indices, uses the ninth revision of the International Classification of Diseases, Clinical Modification (ICD-9-CM). In October 2015, the United States adopted the 10th revision (ICD-10-CM). OBJECTIVE: The objective of this study is to examine different coding algorithms for the ICD-10-CM combined comorbidity score and compare their performance to the original ICD-9-CM score. METHODS: Four ICD-10-CM coding algorithms were defined: 2 using General Equivalence Mappings (GEMs), one based on ICD-10-CA (Canadian modification) codes for Charlson and Elixhauser measures, and one including codes from all 3 algorithms. We used claims data from the Clinfomatics Data Mart to identify 2 cohorts. The ICD-10-CM cohort comprised patients who had a hospitalization between January 1, 2016 and March 1, 2016. The ICD-9-CM cohort comprised patients who had a hospitalization between January 1, 2015 and March 1, 2015. We used logistic regression models to predict 30-day hospital readmission for the original score in the ICD-9-CM cohort and for each ICD-10-CM algorithm in the ICD-10-CM cohort. RESULTS: Distributions of each version of the score were similar. The algorithm based on ICD-10-CA codes [c-statistic, 0.646; 95% confidence interval (CI), 0.640-0.653] had the most similar discrimination for readmission to the ICD-9-CM version (c, 0.646; 95% CI, 0.639-0.653), but combining all identified ICD-10-CM codes had the highest c-statistic (c, 0.651; 95% CI, 0.644-0.657). CONCLUSIONS: We propose an ICD-10-CM version of the combined comorbidity score that includes codes identified by ICD-10-CA and GEMs. Compared with the original score, it has similar performance in predicting readmission in a population of United States commercially insured individuals.
Desai RJ, Gagne JJ, Lii J, Liu J, Friedman S, Kim SC. Comparative risk of incident venous thromboembolism in patients with inflammatory bowel disease initiating tumour necrosis factor-α inhibitors or nonbiologic agents: a cohort study. CMAJ. 2017;189 (47) :E1438-E1447.Abstract
BACKGROUND: Inflammatory bowel disease (IBD) increases the risk of venous thromboembolism (VTE) by 2 to 3 times. We compared the reduction in risk of incident VTE associated with use of tumour necrosis factor-α (TNF-α) inhibitors versus nonbiologic immunomodulatory agents in patients with IBD. METHODS: This observational cohort study used data from public (Medicaid, 2000-2010; Medicare, 2007-2013) and private (Optum Clinformatics, 2004-2013) health insurance programs in the United States. We included a total of 21 671 patients who had IBD without a prior diagnosis of cancer or VTE. The exposure of interest was treatment initiation with TNF-α inhibitor or nonbiologic (azathioprine, mercaptopurine, methotrexate, cyclosporine). The outcome of interest was admission to hospital with VTE as the principal diagnosis. We used Cox proportional hazard regression models to estimate hazard ratios (HRs) separately for each database after risk adjustment for more than 50 covariables using propensity score fine stratification. We used inverse variance meta-analytic methods to pool the adjusted HRs across the 3 databases. RESULTS: We included a total of 5173 patients who started TNF-α inhibitor therapy (1439 in the Medicaid database, 1480 in Medicare and 2254 in Optum Clinformatics) and 16 498 who initiated a nonbiologic agent (5041 in Medicaid, 5166 in Medicare, 6291 in Optum Clinformatics). The adjusted pooled HR for VTE risk with TNF-α inhibitor versus a nonbiologic agent was 0.78 (95% confidence interval [CI] 0.60 to 1.02). The HR was lower in patients with Crohn disease (pooled HR 0.62, 95% CI 0.44 to 0.86) and younger patients (18-44 yr; pooled HR 0.55, 95% CI 0.34 to 0.87). INTERPRETATION: We did not find a statistically significant association between risk of VTE and use of TNF-α inhibitors, relative to nonbiologics, in patients with IBD overall. However, an association was evident for patients younger than 45 years and those with Crohn disease.
Desai RJ, Spoendlin J, Mogun H, Gagne JJ. Contemporary Time Trends in Use of Antiplatelet Agents Among Patients with Acute Coronary Syndrome and Comorbid Diabetes Mellitus or Chronic Kidney Disease. Pharmacotherapy. 2017;37 (10) :1322-1327.Abstract
STUDY OBJECTIVE: To describe contemporary trends of P2Y12 inhibitor use in patients with acute coronary syndrome (ACS) and comorbid diabetes mellitus (DM) and/or chronic kidney disease (CKD) who have a higher risk of recurring ACS and may benefit from treatment with higher efficacy third-generation agents (prasugrel and ticagrelor). DESIGN: Observational cohort study. SETTING: A large U.S. commercial insurance program (2009-2015). PATIENTS: P2Y12 inhibitor initiated within 2 weeks after an ACS event. MEASUREMENTS AND MAIN RESULTS: We identified 98,649 P2Y12 inhibitor initiators, of whom 24.5% had comorbid DM (no CKD), 10.5% had CKD (no DM), and 12.6% had DM and CKD. Overall, 85.2% of patients initiated clopidogrel, followed by prasugrel (11.6%) and ticagrelor (3.2%). Prasugrel use decreased over time irrespective of preexisting DM and/or CKD; ticagrelor use increased. In logistic regression models accounting for patient demographics and clinical covariates, preexisting DM alone was not associated with prasugrel or ticagrelor versus clopidogrel treatment initiation; however, having CKD with or without DM significantly reduced the likelihood of receiving prasugrel versus clopidogrel (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.74-0.88 for CKD alone; OR 0.91, 95% CI 0.83-0.98 for DM and CKD). Comorbid DM and CKD reduced the odds of initiating ticagrelor versus clopidogrel (OR 0.80, 95% CI 0.70-0.92). PRINCIPAL CONCLUSIONS: We observed lower or similar use of prasugrel and ticagrelor compared with clopidogrel in patients with ACS and comorbid DM and/or CKD. Given the potential for worse clinical outcomes with clopidogrel in these patients, our findings highlight the need to investigate the implications of these trends on recurrent ACS and bleeding events.
Connolly JG, Wang SV, Fuller CC, Toh S, Panozzo CA, Cocoros N, Zhou M, Gagne JJ, Maro JC. Development and application of two semi-automated tools for targeted medical product surveillance in a distributed data network. Curr Epidemiol Rep. 2017;4 (4) :298-306.Abstract
Purpose of Review: An important component of the Food and Drug Administration's Sentinel Initiative is the active post-market risk identification and analysis (ARIA) system, which utilizes semi-automated, parameterized computer programs to implement propensity-score adjusted and self-controlled risk interval designs to conduct targeted surveillance of medical products in the Sentinel Distributed Database. In this manuscript, we review literature relevant to the development of these programs and describe their application within the Sentinel Initiative. Recent Findings: These quality-checked and publicly available tools have been successfully used to conduct rapid, replicable, and targeted safety analyses of several medical products. In addition to speed and reproducibility, use of semi-automated tools allows investigators to focus on decisions regarding key methodological parameters. We also identified challenges associated with the use of these methods in distributed and prospective datasets like the Sentinel Distributed Database, namely uncertainty regarding the optimal approach to estimating propensity scores in dynamic data among data partners of heterogeneous size. Summary: Future research should focus on the methodological challenges raised by these applications as well as developing new modular programs for targeted surveillance of medical products.
Braun IM, Meyer FL, Gagne JJ, Nabati L, Yuppa DP, Carmona MA, Burstein HJ, Suzuki J, Nayak MM, Martins Y. Experts' perspectives on the role of medical marijuana in oncology: A semistructured interview study. Psychooncology. 2017;26 (8) :1087-1092.Abstract
BACKGROUND: Expansion of medical marijuana (MM) laws in the United States may offer oncology new therapeutic options. However, the scientific evidence for MM remains in infancy. This study qualitatively explored professional opinion around the role of MM in cancer care. METHODS: Semistructured interviews were administered to a sample of individuals with expertise at the interface of MM and oncology nationally. Key informant criteria included an oncologic clinical or research background and any of the following: publications, research, or lectures on cannabinoids or cancer symptoms; involvement in the development of MM dispensaries or legislation; and early adoption of state MM certification procedures. A gold standard, grounded, inductive approach was used to identify underlying themes. RESULTS: Participants (N = 15) were predominantly male, in their sixth decade, working in academic settings. Themes ranged from strong beliefs in marijuana's medical utility to reservations about this notion, with calls for expansion of the scientific evidence base and more stringent MM production standards. All participants cited nausea as an appropriate indication, and 13 of 15 pain. Over one-third believed MM to have a more attractive risk profile than opioids and benzodiazepines. CONCLUSIONS: Expert opinion was divided between convictions in marijuana's medicinal potential and guardedness in this assertion, with no participant refuting MM's utility outright. Emergent themes included that MM ameliorates cancer-related pain and nausea and is safer than certain conventional medications. Participants called for enhanced purity and production standards, and further research on MM's utility.
Go AS, Singer DE, Toh S, Cheetham CT, Reichman ME, Graham DJ, Southworth MR, Zhang R, Izem R, Goulding MR, et al. Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study. Ann Intern Med. 2017;167 (12) :845-854.Abstract
Background: Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. Objective: To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice. Design: Retrospective cohort. Setting: National U.S. Food and Drug Administration Sentinel network. Patients: Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014. Measurements: Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score-matched patients starting treatment with dabigatran or warfarin. Results: Among 25 289 patients starting dabigatran therapy and 25 289 propensity score-matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran. Limitation: Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values). Conclusion: In matched adults with atrial fibrillation treated in practice, the incidences of stroke and bleeding with dabigatran versus warfarin were consistent with those seen in trials. The possible relationship between dabigatran and myocardial infarction warrants further investigation. Primary Funding Source: U.S. Food and Drug Administration.
Wang SV, Schneeweiss S, Berger ML, Brown J, de Vries F, Douglas I, Gagne JJ, Gini R, Klungel O, Mullins DC, et al. Reporting to Improve Reproducibility and Facilitate Validity Assessment for Healthcare Database Studies V1.0. Value Health. 2017;20 (8) :1009-1022.Abstract
PURPOSE: Defining a study population and creating an analytic dataset from longitudinal healthcare databases involves many decisions. Our objective was to catalogue scientific decisions underpinning study execution that should be reported to facilitate replication and enable assessment of validity of studies conducted in large healthcare databases. METHODS: We reviewed key investigator decisions required to operate a sample of macros and software tools designed to create and analyze analytic cohorts from longitudinal streams of healthcare data. A panel of academic, regulatory, and industry experts in healthcare database analytics discussed and added to this list. CONCLUSION: Evidence generated from large healthcare encounter and reimbursement databases is increasingly being sought by decision-makers. Varied terminology is used around the world for the same concepts. Agreeing on terminology and which parameters from a large catalogue are the most essential to report for replicable research would improve transparency and facilitate assessment of validity. At a minimum, reporting for a database study should provide clarity regarding operational definitions for key temporal anchors and their relation to each other when creating the analytic dataset, accompanied by an attrition table and a design diagram. A substantial improvement in reproducibility, rigor and confidence in real world evidence generated from healthcare databases could be achieved with greater transparency about operational study parameters used to create analytic datasets from longitudinal healthcare databases.
Wang SV, Schneeweiss S, Berger ML, Brown J, de Vries F, Douglas I, Gagne JJ, Gini R, Klungel O, Mullins DC, et al. Reporting to Improve Reproducibility and Facilitate Validity Assessment for Healthcare Database Studies V1.0. Pharmacoepidemiol Drug Saf. 2017;26 (9) :1018-1032.Abstract
PURPOSE: Defining a study population and creating an analytic dataset from longitudinal healthcare databases involves many decisions. Our objective was to catalogue scientific decisions underpinning study execution that should be reported to facilitate replication and enable assessment of validity of studies conducted in large healthcare databases. METHODS: We reviewed key investigator decisions required to operate a sample of macros and software tools designed to create and analyze analytic cohorts from longitudinal streams of healthcare data. A panel of academic, regulatory, and industry experts in healthcare database analytics discussed and added to this list. CONCLUSION: Evidence generated from large healthcare encounter and reimbursement databases is increasingly being sought by decision-makers. Varied terminology is used around the world for the same concepts. Agreeing on terminology and which parameters from a large catalogue are the most essential to report for replicable research would improve transparency and facilitate assessment of validity. At a minimum, reporting for a database study should provide clarity regarding operational definitions for key temporal anchors and their relation to each other when creating the analytic dataset, accompanied by an attrition table and a design diagram. A substantial improvement in reproducibility, rigor and confidence in real world evidence generated from healthcare databases could be achieved with greater transparency about operational study parameters used to create analytic datasets from longitudinal healthcare databases.
Wang SV, He M, Jin Y, Wyss R, Shin HJ, Ma Y, Keeton S, Fireman B, Karami S, Major JM, et al. A review of the performance of different methods for propensity score matched subgroup analyses and a summary of their application in peer-reviewed research studies. Pharmacoepidemiol Drug Saf. 2017;26 (12) :1507-1512.Abstract
PURPOSE: When evaluating safety signals, there is often interest in understanding safety in all patients for whom compared treatments are reasonable alternatives, as well as in specific subgroups of interest. There are numerous ways that propensity score (PS) matching can be implemented for subgroup analyses. METHODS: We conducted a systematic literature review of methods papers that compared the performance of alternative methods to implement PS matched subgroup analyses and examined how frequently different PS matching methods have been used for subgroup analyses in applied studies. RESULTS: We identified 5 methods papers reporting small improvements in covariate balance and bias with use of a subgroup-specific PS instead of a mis-specified overall PS within subgroups. Applied research papers frequently used PS for subgroups in ways not evaluated in methods papers. Thirty three percent used PS to match in the overall cohort and broke the matched sets for subgroup analysis without further adjustment. CONCLUSIONS: While the performance of several alternative ways to use PS matching in subgroup analyses has been evaluated in methods literature, these evaluations do not include the most commonly used methods to implement PS matched subgroup analyses in applied studies. There is a need to better understand the relative performance of commonly used methods for PS matching in subgroup analyses, particularly within settings encountered during active surveillance, where there may be low exposure, infrequent outcomes, and multiple subgroups of interest.
Mostaghim SR, Gagne JJ, Kesselheim AS. Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study. BMJ. 2017;358 :j3837.Abstract
 To determine if drugs approved through the Food and Drug Administration's expedited development and review pathways have different rates of safety related label changes after approval compared with drugs approved through standard non-expedited pathways. Retrospective cohort study. FDA public records, January 1997 to April 2016. 382 FDA approved drugs. The number of times a particular safety section of a label (boxed warning, contraindication, warning, precaution, or adverse reaction) was changed during a drug's time on the market. The relative rate of safety related label changes per year for expedited pathway and non-expedited pathway drugs was compared by forming matched pairs of drugs in the same therapeutic class that were approved within three years of each other. Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients. Expedited development and regulatory review pathways can accelerate the availability of new drugs, but drugs approved through these pathways are associated with increased safety related label changes after approval, particularly for the types of changes representing the highest risk warnings. To inform appropriate policy interventions, additional research should explore the causal factors contributing to these different rates.
Zhou M, Wang SV, Leonard CE, Gagne JJ, Fuller C, Hampp C, Archdeacon P, Toh S, Iyer A, Woodworth TS, et al. Sentinel Modular Program for Propensity Score-Matched Cohort Analyses: Application to Glyburide, Glipizide, and Serious Hypoglycemia. Epidemiology. 2017;28 (6) :838-846.Abstract
Sentinel is a program sponsored by the US Food and Drug Administration to monitor the safety of medical products. We conducted a cohort assessment to evaluate the ability of the Sentinel Propensity Score Matching Tool to reproduce in an expedited fashion the known association between glyburide (vs. glipizide) and serious hypoglycemia. Thirteen data partners who contribute to the Sentinel Distributed Database participated in this analysis. A pretested and customizable analytic program was run at each individual site. De-identified summary results from each data partner were returned and aggregated at the Sentinel Operations Center. We identified a total of 198,550 and 379,507 new users of glyburide and glipizide, respectively. The incidence of emergency department visits and hospital admissions for serious hypoglycemia was 19 per 1000 person-years (95% confidence interval = 17.9, 19.7) for glyburide users and 22 (21.6, 22.7) for glipizide users. In cohorts matched by propensity score based on predefined variables, the hazard ratio (HR) for glyburide was 1.36 (1.24, 1.49) versus glipizide. In cohorts matched on a high-dimensional propensity score based on empirically selected variables, for which the program ran to completion in five data partners, the HR was 1.49 (1.31, 1.70). In cohorts matched on propensity scores based on both predefined and empirically selected variables via the high-dimensional propensity score algorithm (the same five data partners), the HR was 1.51 (1.32, 1.71). These findings are consistent with the literature, and demonstrate the ability of the Sentinel Propensity Score Matching Tool to reproduce this known association in an expedited fashion.See video abstract at, http://links.lww.com/EDE/B275.
Najafzadeh M, Gagne JJ, Schneeweiss S. Synergies From Integrating Randomized Controlled Trials and Real-World Data Analyses. Clin Pharmacol Ther. 2017;102 (6) :914-916.Abstract
Analyses using administrative claims databases or national registries provide estimates of benefits and harms of medications in real-world settings for large and diverse patient populations. Whereas claims-based nonrandomized studies and randomized-controlled trials (RCTs) have distinct limitations, their strengths are complementary. Integrating RCT and claims data offers substantial synergies. We propose obtaining routinely collected longitudinal claims data from RCT participants and discuss the added value of the novel evidence that can be derived from this "information overlap."

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