Azadeh Shoaibi

Comparative Risk for Angioedema Associated With the Use of Drugs That Target the Renin-Angiotensin-Aldosterone System

BACKGROUND Although certain drugs that target the renin- angiotensin-aldosterone system are linked to an increased risk for angioedema, data on their absolute and comparative risks are limited. We assessed the risk for angioedema associated with the use of angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and the direct renin inhibitor aliskiren. METHODS We conducted a retrospective, observational, inception cohort study of patients 18 years or older from 17 health plans participating in the Mini-Sentinel program who had initiated the use of an ACEI (n = 1 845 138), an ARB (n = 467 313), aliskiren (n = 4867), or a β-blocker (n = 1 592 278) between January 1, 2001, and December 31, 2010. We calculated the cumulative incidence and incidence rate of angioedema during a maximal 365-day follow-up period. Using β-blockers as a reference and a propensity score approach, we estimated the hazard ratios of angioedema separately for ACEIs, ARBs, and aliskiren, adjusting for age, sex, history of allergic reactions, diabetes mellitus, heart failure, or ischemic heart disease, and the use of prescription nonsteroidal anti-inflammatory drugs. RESULTS A total of 4511 angioedema events (3301 for ACEIs, 288 for ARBs, 7 for aliskiren, and 915 for β-blockers) were observed during the follow-up period. The cumulative incidences per 1000 persons were 1.79 (95% CI, 1.73-1.85) cases for ACEIs, 0.62 (95% CI, 0.55-0.69) cases for ARBs, 1.44 (95% CI, 0.58-2.96) cases for aliskiren, and 0.58 (95% CI, 0.54-0.61) cases for β-blockers. The incidence rates per 1000 person-years were 4.38 (95% CI, 4.24-4.54) cases for ACEIs, 1.66 (95% CI, 1.47-1.86) cases for ARBs, 4.67 (95% CI, 1.88-9.63) cases for aliskiren, and 1.67 (95% CI, 1.56-1.78) cases for β-blockers. Compared with the use of β-blockers, the adjusted hazard ratios were 3.04 (95% CI, 2.81-3.27) for ACEIs, 1.16 (95% CI, 1.00-1.34) for ARBs, and 2.85 (95% CI, 1.34-6.04) for aliskiren. CONCLUSIONS Compared with β-blockers, ACEIs or aliskiren was associated with an approximately 3-fold higher risk for angioedema, although the number of exposed events for aliskiren was small. The risk for angioedema was lower with ARBs than with ACEIs or aliskiren.

When should case-only designs be used for safety monitoring of medical products?

To assess case‐only designs for surveillance with administrative databases.

Validity of diagnostic codes to identify cases of severe acute liver injury in the U.S. Food and Drug Administration's Mini-Sentinel Distributed Database

The validity of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) codes to identify diagnoses of severe acute liver injury (SALI) is not well known. We examined the positive predictive values (PPVs) of hospital ICD‐9‐CM diagnoses in identifying SALI among health plan members in the Mini‐Sentinel Distributed Database (MSDD) for patients without liver/biliary disease and for those with chronic liver disease (CLD).

A critical review of methods to evaluate the impact of FDA regulatory actions

To conduct a synthesis of the literature on methods to evaluate the impacts of FDA regulatory actions and identify best practices for future evaluations.

Mini‐Sentinel methods: framework for assessment of positive results from signal refinement

Marshfield Epidemiology Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA University of Colorado Skaggs School of Pharmacy and Pharmaceutical Science, Aurora, CO, USA Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA Department of Pathology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA

Prospective surveillance pilot of rivaroxaban safety within the US Food and Drug Administration Sentinel System

The US Food and Drug Administrations Sentinel system developed tools for sequential surveillance.

Missing laboratory results data in electronic health databases: implications for monitoring diabetes risk

AIM Laboratory test (lab) results may be useful to detect incident diabetes in electronic health record and claims-based studies. RESEARCH DESIGN & METHODS Using the Mini-Sentinel distributed database, we assessed the value of lab results added to diagnosis codes and dispensing claims to identify incident diabetes. RESULTS Inclusion of lab results increased the number of diabetes outcomes identified by 21%. In settings where capture of lab results was relatively complete, the absence of lab results was associated with implausibly low rates of the outcome. CONCLUSION Lab results can increase sensitivity of algorithms for detecting diabetes, and missing lab results are associated with much lower rates of diabetes ascertainment regardless of algorithm. Patterns of missing lab results may identify ascertainment bias.

A Synthesis of Current Surveillance Planning Methods for the Sequential Monitoring of Drug and Vaccine Adverse Effects Using Electronic Health Care Data

Introduction: The large-scale assembly of electronic health care data combined with the use of sequential monitoring has made proactive postmarket drug- and vaccine-safety surveillance possible. Although sequential designs have been used extensively in randomized trials, less attention has been given to methods for applying them in observational electronic health care database settings. Existing Methods: We review current sequential-surveillance planning methods from randomized trials, and the Vaccine Safety Datalink (VSD) and Mini-Sentinel Pilot projects—two national observational electronic health care database safety monitoring programs. Future Surveillance Planning: Based on this examination, we suggest three steps for future surveillance planning in health care databases: (1) prespecify the sequential design and analysis plan, using available feasibility data to reduce assumptions and minimize later changes to initial plans; (2) assess existing drug or vaccine uptake, to determine if there is adequate information to proceed with surveillance, before conducting more resource-intensive planning; and (3) statistically evaluate and clearly communicate the sequential design with all those designing and interpreting the safety-surveillance results prior to implementation. Plans should also be flexible enough to accommodate dynamic and often unpredictable changes to the database information made by the health plans for administrative purposes. Conclusions: This paper is intended to encourage dialogue about establishing a more systematic, scalable, and transparent sequential design-planning process for medical-product safety-surveillance systems utilizing observational electronic health care databases. Creating such a framework could yield improvements over existing practices, such as designs with increased power to assess serious adverse events.

Methods for using clinical laboratory test results as baseline confounders in multi‐site observational database studies when missing data are expected

Our purpose was to quantify missing baseline laboratory results, assess predictors of missingness, and examine performance of missing data methods.

Bleeding Events Following Concurrent Use of Warfarin and Oseltamivir by Medicare Beneficiaries

Background: During the 2009 H1N1 influenza pandemic, the UK Medicines and Healthcare Products Regulatory Agency received case reports suggesting a potentiation of warfarin anticoagulation by the antiviral drug oseltamivir. We evaluated this putative interaction using Medicare data. Objective: To determine the frequency of bleeding following addition of oseltamivir or comparator drugs among Medicare beneficiaries taking warfarin. Methods: This was a retrospective cohort evaluation using Medicare nationwide data. Cohort members were Medicare Parts A, B, and D beneficiaries from June 30, 2006 to October 31, 2010 receiving warfarin for at least 1 month prior to a concomitant drug of interest (oseltamivir, ampicillin, trimethoprim–sulfamethoxazole (TMP-SMX), and angiotensin-converting enzyme (ACE) inhibitors). Bleeding within 14 days of new prescriptions for oseltamivir or comparators was identified using inpatient or emergency department ICD-9 (International Classification of Diseases, ninth revision) discharge diagnosis codes for gastrointestinal hemorrhage, epistaxis, hematuria, and intracranial bleeding. Patients with bleeding within 30 days preceding the prescription concomitant to warfarin were excluded. Results: With concomitant ACE inhibitors as reference, adjusted odds ratios (ORs) for any bleeding events within 14 days were 1.47 (95% confidence interval [CI] = 1.08-1.88), 1.24 (95% CI = 0.97-1.57), and 2.74 (95% CI = 2.53-3.03), for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. In a sensitivity analysis, adjusted ORs over a 7-day period were 1.89 (95% CI = 1.29-2.59), 1.47 (95% CI = 1.06-2.02), and 3.07 (95% CI = 2.76-3.49) for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. Conclusions: Bleeding with oseltamivir plus warfarin was not significantly increased over a 14-day observation period; a sensitivity analysis showed a statistically significant increase over a 7-day period; in contrast, the data consistently showed the known tendency of TMP-SMX to potentiate the effects of warfarin. The results should be interpreted with the limitations of this approach in mind, including the inability to control for unmeasured confounders.