Six Years of the US Food and Drug Administration's Postmarket Active Risk Identification and Analysis System in the Sentinel Initiative: Implications for Real World Evidence Generation.

Congress mandated the creation of a postmarket Active Risk Identification and Analysis (ARIA) system containing data on 100 million individuals for monitoring risks associated with drug and biologic products using data from disparate sources to complement the US Food and Drug Administration's (FDA's) existing postmarket capabilities. We report on the first 6 years of ARIA utilization in the Sentinel System (2016-2021). The FDA has used the ARIA system to evaluate 133 safety concerns; 54 of these evaluations have closed with regulatory determinations, whereas the rest remain in progress.

Comparative Risk of Angioedema With Sacubitril-Valsartan vs Renin-Angiotensin-Aldosterone Inhibitors.

Background: Data on angioedema risk among sacubitril-valsartan (SV) users in real-world settings are limited.

Objectives: We sought to evaluate the risk of angioedema among SV new users compared with angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor-blocker (ARB) new users separately.

Methods: We conducted a propensity score-matched cohort study, comparing SV new users (no use of SV, ACE inhibitor, ARB 6 months before) and SV new users with prior use (within 183 or 14 days) of ACE inhibitor or ARB (ACE inhibitor-SV and ARB-SV users; recent ACE inhibitor-SV and recent ARB-SV users, respectively) vs ACE inhibitor and ARB new users separately.

Using the IMEDS distributed database for epidemiological studies in type 2 diabetes mellitus.

Introduction: This study aimed to assess data relevancy and data quality of the Innovation in Medical Evidence Development and Surveillance System Distributed Database (IMEDS-DD) for diabetes research and to evaluate comparability of its type 2 diabetes cohort to the general type 2 diabetes population.

Research Design And Methods: A retrospective study was conducted using the IMEDS-DD. Eligible members were adults with a medical encounter between April 1, 2018 and March 31, 2019 (index period).

A new analytic tool for assessing the impact of the US Food and Drug Administration regulatory actions.

Purpose: Develop and test a flexible, scalable tool using interrupted time series (ITS) analysis to assess the impact of Food and Drug Administration (FDA) regulatory actions on drug use.

Methods: We applied the tool in the Sentinel Distributed Database to assess the impact of FDA's 2010 drug safety communications (DSC) concerning the safety of long-acting beta2-agonists (LABA) in adult asthma patients. We evaluated changes in LABA use by measuring the initiation of LABA alone and concomitant use of LABA and asthma controller medications (ACM) after the DSCs.

Risk of Severe Abnormal Uterine Bleeding Associated with Rivaroxaban Compared with Apixaban, Dabigatran and Warfarin.

Introduction: There have been reports of clinically relevant uterine bleeding events among women of reproductive age exposed to rivaroxaban.

Objective: The aim of this study was to compare the risk of severe abnormal uterine bleeding (SAUB) resulting in transfusion or surgical intervention among women on rivaroxaban versus apixaban, dabigatran and warfarin.

Methods: We conducted a retrospective cohort study in the FDA's Sentinel System (10/2010-09/2015) among females aged 18+ years with venous thromboembolism (VTE), or atrial flutter/fibrillation (AF) who newly initiated a direct oral anticoagulant (DOAC; rivaroxaban, apixaban, dabigatran) or warfarin.

Poly(U)-specific endoribonuclease ENDOU promotes translation of human CHOP mRNA by releasing uORF element-mediated inhibition.

Upstream open reading frames (uORFs) are known to negatively affect translation of the downstream ORF. The regulatory proteins involved in relieving this inhibition are however poorly characterized. In response to cellular stress, eIF2α phosphorylation leads to an inhibition of global protein synthesis, while translation of specific factors such as CHOP is induced.

Risk of Stroke and Bleeding in Atrial Fibrillation Treated with Apixaban Compared with Warfarin.

Background: A previous FDA study reported a favorable benefit risk for apixaban compared with warfarin for stroke prevention in older non-valvular atrial fibrillation (NVAF) patients (≥ 65 years). However, it remains unclear whether this favorable benefit risk persists in other populations including younger users. We examined if a similar benefit risk was observed in the Sentinel System and if it varied by age group.

Translating claims-based CHA DS -VaSc and HAS-BLED to ICD-10-CM: Impacts of mapping strategies.

Purpose: The CHA DS -VaSc and HAS-BLED risk scores are commonly used in the studies of oral anticoagulants (OACs). The best ways to map these scores to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes is unclear, as is how they perform in various types of OAC users. We aimed to assess the distributions of CHA DS -VaSc and HAS-BLED scores and C-statistics for outcome prediction in the ICD-10-CM era using different mapping strategies.

Quantifying how small variations in design elements affect risk in an incident cohort study in claims.

Background: Epidemiological study reporting is improving but is not transparent enough for easy evaluation or replication. One barrier is insufficient details about design elements in published studies.

Methods: Using a previously conducted drug safety evaluation in claims as a test case, we investigated the impact of small changes in five key design elements on risk estimation.

Reproducing Protocol-Based Studies Using Parameterizable Tools-Comparison of Analytic Approaches Used by Two Medical Product Surveillance Networks.

The US Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's preprogrammed, parameterizable analytic tools, we reproduced two protocol-based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin-based drugs, compared with use of ≥ 2 oral hypoglycemic agents. Results from the replication new-user cohort analyses aligned with those from the CNODES nested case-control studies.

Antipsychotic Use and Stroke: A Retrospective Comparative Study in a Non-Elderly Population.

Objective: To evaluate stroke risk among users of typical antipsychotics compared to users of atypical antipsychotics in a non-elderly and non-demented US population.

Methods: New users of antipsychotics aged 18-64 years without dementia were identified via electronic health care data from 13 health plans participating in the Sentinel System from January 2001 to September 2015. The risk of hospitalized stroke events, identified via ICD-9-CM diagnostic criteria, was compared between typical and atypical antipsychotic users using 1:1 matching on propensity score.

Association of Risk for Venous Thromboembolism With Use of Low-Dose Extended- and Continuous-Cycle Combined Oral Contraceptives: A Safety Study Using the Sentinel Distributed Database.

Importance: Continuous/extended cyclic estrogen use (84/7 or 365/0 days cycles) in combined oral contraceptives (COCs) could potentially expose women to an increased cumulative dose of estrogen, compared with traditional cyclic regimens (21/7 days cycle), and may increase the risk for venous thromboembolism (VTE).

Objective: To determine, while holding the progestogen type constant, whether the risk for VTE is higher with use of continuous/extended COCs than with cyclic COCs among women who initiated a COC containing ethinyl estradiol and levonorgestrel.

Design, Setting, And Participants: Incident user retrospective cohort study of primarily commercially insured US population identified from the Sentinel Distributed Database.

Assessing the impact of the new ICD-10-CM coding system on pharmacoepidemiologic studies-An application to the known association between angiotensin-converting enzyme inhibitors and angioedema.

Purpose: To replicate the well-established association between angiotensin-converting enzyme inhibitors versus beta blockers and angioedema in the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) era.

Methods: We conducted a retrospective, inception cohort study in a large insurance database formatted to the Sentinel Common Data Model. We defined study periods spanning the ICD-9-CM era only, ICD-10-CM era only, and ICD-9-CM and ICD-10-CM era and conducted simple-forward mapping (SFM), simple-backward mapping (SBM), and forward-backward mapping (FBM) referencing the General Equivalence Mappings to translate the outcome (angioedema) and covariates from ICD-9-CM to ICD-10-CM.

Early impact of the ICD-10-CM transition on selected health outcomes in 13 electronic health care databases in the United States.

Purpose: To describe the consistency in the frequency of 5 health outcomes across the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification (ICD-10-CM) eras in the US.

Methods: We examined the incidence of 3 acute conditions (acute myocardial infarction [AMI], angioedema, ischemic stroke) and the prevalence of 2 chronic conditions (diabetes, hypertension) during the final 5 years of the ICD-9-CM era (January 2010-September 2015) and the first 15 months of the ICD-10-CM era (October 2015-December 2016) in 13 electronic health care databases in the Sentinel System. For each health outcome reviewed during the ICD-10-CM era, we evaluated 4 definitions, including published algorithms derived from other countries, as well as simple-forward, simple-backward, and forward-backward mapping using the General Equivalence Mappings.

The association of antidepressant treatment with COPD maintenance medication use and adherence in a comorbid Medicare population: A longitudinal cohort study.

Unlabelled: The effect of treating comorbid depression to achieve optimal management of chronic obstructive pulmonary disease (COPD) has not yet empirically tested. We examined the association between antidepressant treatment and use of and adherence to COPD maintenance medications among patients with new-onset COPD and comorbid depression.

Methods: Using 2006-2012 Medicare data, this retrospective cohort study identified patients with newly diagnosed COPD and new-onset major depression.

Adherence and healthcare utilization among older adults with COPD and depression.

Background And Objective: Adherence to chronic obstructive pulmonary disease (COPD) maintenance medications and antidepressants may reduce healthcare utilization among multimorbid individuals with COPD and depression. We quantified the independent effects of adherence to antidepressants and COPD maintenance medications on healthcare utilization among individuals co-diagnosed with COPD and depression.

Procedures: We conducted a retrospective cohort study using a 2006-2012 5% random sample of Medicare beneficiaries co-diagnosed with COPD and depression who had two or more prescription fills of both COPD maintenance medications and antidepressants.

Concomitant use of calcium channel blockers with dual antiplatelet therapy and re-hospitalization for acute coronary syndrome.

Background: Existing studies suggested that concomitant use of calcium channel blockers (CCBs) may interfere with the antiplatelet effect of clopidogrel. The objective of this study was to examine the effect of concomitant use of CCBs and clopidogrel on risks of acute coronary syndrome (ACS) re-hospitalization in patients receiving percutaneous coronary intervention.

Methods: Using the Taiwan National Health Insurance Research Database, we identified 51 925 patients who were admitted for newly diagnosed ACS, received percutaneous coronary intervention, and used clopidogrel within 1 year after discharge.

Adherence to Maintenance Medications among Older Adults with Chronic Obstructive Pulmonary Disease. The Role of Depression.

Rationale: Among individuals with chronic obstructive pulmonary disease (COPD), depression is one of the most common yet underrecognized and undertreated comorbidities. Although depression has been associated with reduced adherence to maintenance medications used in other conditions, such as diabetes, little research has assessed the role of depression in COPD medication use and adherence.

Objectives: The objective of this study was to assess the impact of depression on COPD maintenance medication adherence among a nationally representative sample of Medicare beneficiaries newly diagnosed with COPD.

Mortality Risk of Antipsychotic Dose and Duration in Nursing Home Residents with Chronic or Acute Indications.

Objectives: To examine disease-specific associations between antipsychotic dose and duration and all-cause mortality.

Design: Retrospective cohort study.

Setting: A 5% random sample of Medicare beneficiaries who had a Minimum Data Set 2.

Exploratory and Confirmatory Factor Analyses of Delirium Symptoms in a Sample of Nursing Home Residents.

Objective: This study examined the latent constructs of delirium symptoms among nursing home (NH) residents in the United States.

Method: Cross-sectional NH assessment data (Minimum Data Set 2.0) from the 2009 Medicare Current Beneficiary Survey were used.

Treated Behavioral Symptoms and Mortality in Medicare Beneficiaries in Nursing Homes with Alzheimer's Disease and Related Dementias.

Objectives: To assess changes in behavioral symptoms associated with Alzheimer's disease and related dementias (ADRDs) after antipsychotic (AP) or antidepressant (AD) treatment and to estimate the effect of treatment response on mortality risk.

Design: Retrospective cohort study using 2006-2009 Medicare administrative and prescription drug claims data linked to Minimum Data Set 2.0.

New episodes of depression among Medicare beneficiaries with chronic obstructive pulmonary disease.

Objectives: Depression is a common comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with increased exacerbations, healthcare utilization, and mortality. Among Medicare beneficiaries newly diagnosed with COPD, the objectives of this study were to (1) estimate the rate of new episodes of depression and (2) identify factors associated with depression.

Methods: We identified beneficiaries with a first diagnosis of COPD during 2006-2012 using a 5% random sample of Medicare administrative claims data by searching for ICD-9-CM codes 490, 491.