Publications by Year: 2017

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."
Freedman RA, Revette AC, Hershman DL, Silva K, Sporn NJ, Gagne JJ, Kouri EM, Keating NL. Understanding Breast Cancer Knowledge and Barriers to Treatment Adherence: A Qualitative Study Among Breast Cancer Survivors. Biores Open Access. 2017;6 (1) :159-168.Abstract
Disparities in breast cancer treatment receipt are common and multifactorial. Data are limited on how knowledge about one's breast cancer and understanding treatment rationales may impact treatment completion. In this qualitative analysis, we explored barriers to care with a focus on knowledge. We conducted 18 in-depth interviews with women from diverse socioeconomic backgrounds who were treated at Dana-Farber Cancer Institute ( = 12; Boston, MA) and Columbia University Medical Center ( = 6; New York, NY) and had undergone neo/adjuvant breast cancer treatment within the prior 3 years. Interviews focused on treatments received, adherence, barriers experienced, and questions related to breast cancer knowledge and treatment rationales. We analyzed transcribed interview recordings in N'Vivo using a two-stage coding process that allowed for both preconfigured and emergent themes. Answers for breast cancer knowledge were confirmed using medical records. In our analysis, over one-third of women reported incomplete therapy, including never initiating treatment, stopping treatment prematurely, or missing/delaying treatments due to logistical reasons (childcare, transportation) or patient preferences. Others reported treatment modifications because of provider recommendations. Nearly all women were able to accurately describe the rationale for recommended treatments. Among 17 women for whom medical records were available, women correctly reported 18-71% of their tumor characteristics; incorrect reporting was not consistently associated with treatment incompletion. In conclusion, logistical issues and patient preferences were the main reasons for incomplete therapy in our study. Understanding of treatment rationale was high, but breast cancer knowledge was variable. Further assessment of how knowledge may impact cancer care is warranted.
Sarpatwari A, Gagne JJ, Levidow NL, Kesselheim AS. Active Surveillance of Follow-on Biologics: A Prescription for Uptake. Drug Saf. 2017;40 (2) :105-108.Abstract
As lower-cost versions of original biologic drugs made by different manufacturers, follow-on biologics offer the promise of meaningful savings for the US health care system and improved patient health outcomes through greater medication adherence. Fulfillment of this promise, however, is predicated on the prescribing of such products. Under state drug product selection laws, pharmacists may substitute prescriptions for brand name, small-molecule drugs with their generic equivalents, but will be indefinitely prohibited from substituting prescriptions for original biologics with their follow-on biologic counterparts given a lack of product-specific guidance on demonstrating interchangeability. Even when interchangeable follow-on biologics become available, they will face heightened barriers to substitution following the enactment of so-called carve-outs in several states. Data collected to date suggest that a substantial proportion of US physicians remain skeptical of follow-on biologics despite their long record of safe and effective use in Europe. Active surveillance of follow-on biologics within the US market using insurance claims databases can help address this skepticism and help answer key questions concerning the safety of switching between original and follow-on products or between different follow-on products, and of extrapolating to broader indications. Funding is needed to support such surveillance activities and to disseminate the findings to key stakeholders.
Dong Y-H, Bykov K, Choudhry NK, Donneyong MM, Huybrechts KF, Levin R, Schneeweiss S, Gagne JJ. Clinical Outcomes of Concomitant Use of Warfarin and Selective Serotonin Reuptake Inhibitors: A Multidatabase Observational Cohort Study. J Clin Psychopharmacol. 2017;37 (2) :200-209.Abstract
BACKGROUND: Patients treated with warfarin are often coprescribed selective serotonin reuptake inhibitors (SSRIs) for coexisting depression. Some SSRIs are potent CYP2C9 inhibitors that may increase warfarin plasma concentrations and the risk of bleeding. We aimed to examine the effect of the putative CYP2C9-mediated warfarin-SSRI interaction on clinical outcomes. METHODS: We conducted an observational cohort study among warfarin initiators who had a subsequent SSRI prescription in 5 US claims databases. Patients were followed for up to 180 days as long as they were exposed to both warfarin and their index SSRI groups. Cox regression models were used to estimate hazard ratios and 95% confidence intervals for bleeding events, ischemic or thromboembolic events, and mortality comparing patients treated with SSRIs that are potent CYP2C9 inhibitors (fluoxetine, fluvoxamine) with those treated with other SSRIs after propensity score matching. FINDINGS: The eligible cohort comprised 52,129 patients. Hazard ratios were 1.14 (95% confidence interval [CI], 0.94-1.38) for bleeding events, 1.03 (95% CI, 0.87-1.21) for ischemic or thromboembolic events, and 0.90 (95% CI, 0.72-1.14) for mortality. Results were consistent across individual component outcomes, different warfarin stabilization periods, and subgroup analyses. CONCLUSIONS: Patients concomitantly treated with warfarin and SSRIs that are potent CYP2C9 inhibitors had comparable rates of bleeding events, ischemic or thromboembolic events, and mortality as did patients cotreated with warfarin and other SSRIs, although small but potentially meaningful effects on bleeding cannot be completely excluded. SSRI inhibition of CYP2C9 does not appear to affect major safety or effectiveness outcomes of warfarin treatment in clinical practice, where patients may be closely monitored.
Luo J, Gagne JJ, Landon J, Avorn J, Kesselheim AS. Comparative effectiveness and safety of thalidomide and lenalidomide in patients with multiple myeloma in the United States of America: A population-based cohort study. Eur J Cancer. 2017;70 :22-33.Abstract
BACKGROUND: The comparative effectiveness of thalidomide and lenalidomide in the treatment of multiple myeloma has not been established. We conducted an observational cohort study of multiple myeloma patients receiving either thalidomide or lenalidomide in routine care in the United States of America to assess their comparative survival and rates of peripheral neuropathy. METHODS: Myeloma patients were identified and followed using administrative claims data from a large national health insurance provider (UnitedHealth). Patients were eligible if they initiated treatment with either lenalidomide or thalidomide between 2004 and 2013. Propensity score stratified Cox proportional hazards regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for death and new-onset peripheral neuropathy (defined by International Classification of Disease, Ninth Revision codes or a new prescription intended to treat neuropathic pain). FINDINGS: Our cohort included 1264 myeloma patients who initiated either thalidomide or lenalidomide. Among 406 new users of thalidomide, 142 (35%) developed peripheral neuropathy during a mean 499 person-days of follow-up. Among 858 new users of lenalidomide, 244 (29%) developed neuropathy during 587 person-days. Compared with thalidomide initiators, lenalidomide initiators had a reduced risk of peripheral neuropathy (HR 0.71, 95% CI: 0.56-0.92). We found no difference in rates of death (HR 1.00, 95% CI: 0.71-1.41). INTERPRETATION: Our results agree with the findings of recently published trials suggesting that thalidomide and lenalidomide are equivalent with respect to survival outcomes but different with respect to neurotoxicity in clinical practice settings.
Bykov K, Yoshida K, Weisskopf MG, Gagne JJ. Confounding of the association between statins and Parkinson disease: systematic review and meta-analysis. Pharmacoepidemiol Drug Saf. 2017;26 (3) :294-300.Abstract
PURPOSE: Both statins and higher serum cholesterol have been reported to reduce to risk of Parkinson Disease (PD). Given the importance of adjusting for cholesterol levels when evaluating the effect of statins, we assessed whether the protective effect of statins would remain when adjustment for cholesterol is performed. METHODS: We conducted a systematic review of epidemiologic studies that reported quantitative estimates of the association between statins and incident PD and were published through February 2016. Random-effects meta-analysis was used to assess the effect of statins on PD separately among the studies that adjusted for either cholesterol or hyperlipidemia and studies that did not. RESULTS: Ten eligible studies that evaluated the use of statins and incident PD were identified. Among the six studies that did not adjust for cholesterol, a protective effect of statins was observed (relative risk 0.75; 95% confidence intervals (CI) 0.60 to 0.92). Excluding studies with possible bias because of reverse causation or stratifying on study design did not affect the results. No protective effect was observed among the four studies that adjusted for either cholesterol of hyperlipidemia (relative risk 0.91; 95%CI 0.68 to 1.22). The effect estimate for studies that adjusted for cholesterol was 1.04 (95%CI 0.68 to 1.59) when a study with immortal time bias was excluded. CONCLUSIONS: The apparent protective effect of statins on risk of PD is at least partially explained by confounding by statin indication. Immortal time bias and healthy user effects also could have contributed to biased results. Copyright © 2016 John Wiley & Sons, Ltd.
Kesselheim AS, Gagne JJ, Franklin JM, Eddings W, Fulchino LA, Campbell EG. Do patients trust the FDA?: a survey assessing how patients view the generic drug approval process. Pharmacoepidemiol Drug Saf. 2017;26 (6) :694-701.Abstract
PURPOSE: Skepticism about the safety and effectiveness of certain generic drugs remains, particularly related to generic drugs that are approved by the Food and Drug Administration (FDA) using product-specific bioequivalence studies that differ from the standard testing pathway. The current study was designed to assess patient knowledge and perceptions of the generic drug approval process. METHODS: We conducted a survey of patients with 10 different chronic diseases. We recruited survey participants from the CVS Advisor Panel, a proprietary database of 124 621 CVS customers pre-consented to participate in online research activities. We created a survey to collect data on patients' perceptions of the FDA's generic drug approval process, as well as their experiences with generic drugs approved using modified bioequivalence approaches used to treat their chronic medical conditions. RESULTS: Our survey of 753 patients with chronic diseases (65% response rate) showed that most (74%) expressed little familiarity with FDA's approval process for generic drugs, but nearly all (89%) believed that FDA approval ensures the safety and effectiveness of generic drugs. About one-fifth of respondents reported hearing concerns about their generic drugs, most commonly from physicians (35-36%) and the Internet (32-38%), but there were no differences in patients' reports of concerns about generic versions of the six study drugs approved using product-specific pathways versus comparator drugs. CONCLUSIONS: Patients have little knowledge about the generic drug approval system, but positive belief in the safety and effectiveness of generic drugs. Patients do not appear to have greater concern about generic drugs approved via product-specific pathways. Copyright © 2017 John Wiley & Sons, Ltd.
Wyss R, Hansen BB, Ellis AR, Gagne JJ, Desai RJ, Glynn RJ, Stürmer T. The "Dry-Run" Analysis: A Method for Evaluating Risk Scores for Confounding Control. Am J Epidemiol. 2017;185 (9) :842-852.Abstract
A propensity score (PS) model's ability to control confounding can be assessed by evaluating covariate balance across exposure groups after PS adjustment. The optimal strategy for evaluating a disease risk score (DRS) model's ability to control confounding is less clear. DRS models cannot be evaluated through balance checks within the full population, and they are usually assessed through prediction diagnostics and goodness-of-fit tests. A proposed alternative is the "dry-run" analysis, which divides the unexposed population into "pseudo-exposed" and "pseudo-unexposed" groups so that differences on observed covariates resemble differences between the actual exposed and unexposed populations. With no exposure effect separating the pseudo-exposed and pseudo-unexposed groups, a DRS model is evaluated by its ability to retrieve an unconfounded null estimate after adjustment in this pseudo-population. We used simulations and an empirical example to compare traditional DRS performance metrics with the dry-run validation. In simulations, the dry run often improved assessment of confounding control, compared with the C statistic and goodness-of-fit tests. In the empirical example, PS and DRS matching gave similar results and showed good performance in terms of covariate balance (PS matching) and controlling confounding in the dry-run analysis (DRS matching). The dry-run analysis may prove useful in evaluating confounding control through DRS models.
Dong Y-H, Alcusky M, Maio V, Liu J, Liu M, Wu L-C, Chang C-H, Lai M-S, Gagne JJ. Evidence of potential bias in a comparison of β blockers and calcium channel blockers in patients with chronic obstructive pulmonary disease and acute coronary syndrome: results of a multinational study. BMJ Open. 2017;7 (3) :e012997.Abstract
OBJECTIVES: A number of observational studies have reported that, in patients with chronic obstructive pulmonary disease (COPD), β blockers (BBs) decrease risk of mortality and COPD exacerbations. To address important methodological concerns of these studies, we compared the effectiveness and safety of cardioselective BBs versus non-dihydropyridine calcium channel blockers (non-DHP CCBs) in patients with COPD and acute coronary syndromes (ACS) using a propensity score (PS)-matched, active comparator, new user design. We also assessed for potential unmeasured confounding by examining a short-term COPD hospitalisation outcome. SETTING AND PARTICIPANTS: We identified 22 985 patients with COPD and ACS starting cardioselective BBs or non-DHP CCBs across 5 claims databases from the USA, Italy and Taiwan. PRIMARY AND SECONDARY OUTCOME MEASURES: Stratified Cox regression models were used to estimate HRs for mortality, cardiovascular (CV) hospitalisations and COPD hospitalisations in each database after variable-ratio PS matching. Results were combined with random-effects meta-analyses. RESULTS: Cardioselective BBs were not associated with reduced risk of mortality (HR, 0.90; 95% CI 0.78 to 1.02) or CV hospitalisations (HR, 1.06; 95% CI 0.91 to 1.23), although statistical heterogeneity was observed across databases. In contrast, a consistent, inverse association for COPD hospitalisations was identified across databases (HR, 0.54; 95% CI 0.47 to 0.61), which persisted even within the first 30 days of follow-up (HR, 0.55; 95% CI 0.37 to 0.82). Results were similar across a variety of sensitivity analyses, including PS trimming, high dimensional-PS matching and restricting to high-risk patients. CONCLUSIONS: This multinational study found a large inverse association between cardioselective BBs and short-term COPD hospitalisations. The persistence of this bias despite state-of-the-art pharmacoepidemiologic methods calls into question the ability of claims data to address confounding in studies of BBs in patients with COPD.

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