i3 Drug Safety

Ann Arbor, MI, United States

i3 Drug Safety

Ann Arbor, MI, United States
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Amend K.L.,i3 Drug Safety | Turnbull B.,i3 Drug Safety | Napalkov P.,Genentech | Kurth T.,French Institute of Health and Medical Research | And 5 more authors.
Neurology | Year: 2010

Objective:: To estimate the incidence rate (IR) of progressive multifocal leukoencephalopathy (PML) in patients without Hiv. Methods:: Within a large US health insurer database between January 2000 and June 2008, we conducted a retrospective observational study. We identified people with autoimmune diseases, chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), or history of bone marrow or solid organ transplantation, and a general population cohort. We developed a PML case-finding algorithm and validated PML diagnoses in medical charts. Results:: There were 138,469 patients with autoimmune diseases, 25,706 with NHL or CLL, and 8,778 with transplants. Among 699 people who met screening criteria for potential PML, 89 had a claim diagnosis of PML (International Classification of Diseases-9 046.3). Medical records were sought for 24 patients without HIV, and 6 had confirmed PML upon review of medical records. The PML IR was 2.4 (95% confidence interval [CI] 0.06-13.18) in the systemic lupus erythematosus cohort and 10.8 (95% CI 0.27-60.39) in the autoimmune vasculitis cohort per 100,000 person-years. In the NHL and CLL cohorts, the IR was 8.3 (95% CI 1.71-24.24) and 11.1 (0.28-61.74) per 100,000 person-years. The IR among patients with bone marrow transplantation was 35.4 per 100,000 person-years (95% CI 0.90-197.29). There were no cases of PML among patients with rheumatoid arthritis (95% CI 0.0-2.24), multiple sclerosis (95% CI 0.0-5.24), Sjögren disease (95% CI 0.0-21.84), or solid organ transplantation (95% Ci 0.0-26.81). Conclusions:: In this large population-based investigation of PML with thorough case finding and a known source population, the IR of medical record-confirmed PML was rare in non-HIV patient cohorts. Copyright © 2010 by AAN Enterprises, Inc.


Roberts M.R.,State University of New York at Buffalo | Roberts M.R.,Roswell Park Cancer Institute | Shields P.G.,Georgetown University | Ambrosone C.B.,Roswell Park Cancer Institute | And 11 more authors.
Carcinogenesis | Year: 2011

Base excision repair (BER) and nucleotide excision repair (NER) pathways repair damaged DNA, and polymorphisms in these genes might affect breast cancer susceptibility. We evaluated associations between seven single-nucleotide polymorphisms in four DNA repair genes (ERCC4 rs1799801, XPC rs2227998, rs2228001, rs2228000, OGG1 rs1052133 and XRCC1 rs25487 and rs25486) and breast cancer risk, examining modification by smoking and alcohol consumption, using data from the Western New York Exposures and Breast Cancer Study. Women aged 35-79 years with incident breast cancer (n = 1170) and age- and race-matched controls (n = 2115) were enrolled. Genotyping was performed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). No significant associations were observed in premenopausal women. Among postmenopausal women, rs25487 and rs25486 (OR = 1.24; 95% CI 1.01-1.51 and OR = 1.23; 95% CI 1.01-1.49, respectively, for combined heterozygous and homozygous variant compared with reference) were associated with increased risk of breast cancer. Postmenopausal women carrying the variant allele of the synonymous XPC polymorphism (rs2227998) were also at borderline significantly increased risk (OR = 1.24; 95% CI 1.01-1.52, heterozygous variant compared with reference; OR = 1.22; 95% CI 1.01-1.48, for combined heterozygous and homozygous variant compared with reference). There was no evidence of genotype-smoking and genotype-alcohol consumption interactions for pre- and postmenopausal women. These results indicate that some of the variants in BER and NER genes may influence risk of postmenopausal breast cancer. © The Author 2011. Published by Oxford University Press. All rights reserved.


Dore D.D.,I3 Drug Safety | Dore D.D.,Brown University | Chaudhry S.,I3 Drug Safety | Hoffman C.,I3 Drug Safety | And 2 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2011

Purpose: To estimate the positive predictive value (PPV) of claims for acute pancreatitis among initiators of antihyperglycemic drugs in commercial health insurance claims data. Methods: As part of a systematic study of the occurrence of acute pancreatitis among antihyperglycemic drug initiators (N=260255) within a large US health insurer's claims database, we identified potential cases of acute pancreatitis and confirmed them through medical record review. Potential cases had an International Classification of Diseases, 9th revision diagnosis code for acute pancreatitis (577.0) associated with an inpatient or emergency department claim. We sought 860 medical records to confirm potential cases and received 585 (70%), which were reviewed by a clinical adjudication committee. We estimated the PPV and 95% confidence intervals (CI) of claims for these medical records and a subset that had the diagnosis code listed in the first position of an inpatient claim. Results: The PPV was 0.50 (95% CI 0.44-0.53) for an acute pancreatitis diagnosis code in any position and 0.60 (95% CI 0.55-0.65) if in the first position of an inpatient claim. The estimated PPV varied across strata defined by patient characteristics and was generally lower within strata where potential risk factors for acute pancreatitis were present. Conclusions: These data indicate that health insurance claims-based identification of acute pancreatitis might overestimate actual cases and introduce appreciable bias, usually toward the null. Further case confirmation or relative risk correction may be necessary to address potential bias. Copyright © 2010 John Wiley & Sons, Ltd.


Dore D.D.,I3 Drug Safety | Dore D.D.,Brown University | Bloomgren G.L.,Biogen Idec | Wenten M.,Biogen Idec | And 7 more authors.
Diabetes, Obesity and Metabolism | Year: 2011

Aim: Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs. Methods: This cohort study included patients without claims for prior pancreatic disease who initiated exenatide or other antihyperglycaemic drugs between June 2005 and December 2007. Acute pancreatitis was identified with diagnosis codes and confirmed through review of blinded medical records. Poisson regression models provided estimates of rate ratios (RRs) and 95% confidence intervals (CIs) comparing the rate of acute pancreatitis during periods of current (days supplied + 31 days), recent (current definition + 31 days) and past use (≥32 days beyond current definition) of exenatide relative to other antihyperglycaemic drugs, adjusted for propensity scores. A prespecified nested case-control analysis provided RR estimates adjusted for patient characteristics abstracted from medical records. Results: Initiators of exenatide (N = 25719) had more baseline claims for obesity and concomitant diabetes drugs than comparators (N = 234536). There were 40 confirmed cases of acute pancreatitis in the exenatide cohort and 254 among other antihyperglycaemic drug initiators. Compared to other antihyperglycaemic drugs, the propensity score-adjusted RR for exenatide was 0.5 (95% CI 0.2-0.9) for current use, 1.1 (95% CI 0.4-3.2) for recent use and 2.8 (95% CI 1.6-4.7) for past use. The case-control analysis resulted in a RR of 0.2 for current use (95% CI 0.0-1.4) and 0.1 for recent use (95% CI 0.0-1.3), but an attenuated RR in the past use association (RR 1.1; 95% CI 0.1-11.0). Conclusions: Exenatide use was not associated with an increased risk of acute pancreatitis. © 2011 Blackwell Publishing Ltd.


Dore D.D.,i3 Drug Safety | Dore D.D.,Brown University | Norman H.,i3 Drug Safety | Loughlin J.,i3 Drug Safety | And 2 more authors.
Contraception | Year: 2010

Background: We extended an earlier study that found a twofold higher risk of venous thromboembolism (VTE) associated with the transdermal contraceptive system relative to norgestimate-containing oral contraceptives (NGM-OC). Study Design: This case-control study identified potential cases of VTE, acute myocardial infarction (AMI) and stroke from 24 months of additional health care claims, with adjudication via medical records. Randomly selected controls were matched to cases on age (15-44 years) and characteristics of contraception use. Conditional logistic regression models provided odds ratios (ORs) and 95% confidence intervals (CIs). Results: The transdermal contraceptive system was associated with a twofold higher risk of VTE (OR 2.0; 95% CI 1.2-3.3) compared with users of NGM-OC. The OR for stroke was 0.6 (95% CI 0.1-3.2) and for AMI 1.2 (95% CI 0.3-4.7). Conclusion: This extension was consistent with the earlier study, showing a twofold increased risk of VTE associated with use of the transdermal contraceptive system relative to NGM-OC. © 2010 Elsevier Inc. All rights reserved.


Enger C.,I3 Drug Safety | Bennett D.,Glaxosmithkline | Dawson K.L.,Glaxosmithkline | Aivado M.A.,Glaxosmithkline | And 2 more authors.
Annals of Hepatology | Year: 2011

Therapies for immune thrombocytopenia (ITP) may be associated with abnormal hepatobiliary laboratory (HBL) values, but the epidemiology of these abnormalities is unknown in the ITP population. The study aim was to provide prevalence and incidence rates, as well as risk factors for abnormal HBL values among a cohort of patients with chronic or persistent primary ITP. Health insurance claims data from 3,244 patients with chronic or persistent ITP was examined to estimate the prevalence of abnormal HBL values: elevated levels of Alanine Aminotransferase (ALT), A separate Aminotransferase (AST), total bilirubin, and Alkaline Phosphatase (ALP). Incidence of abnormal HBL values was estimated in a sub cohort of 2557 (79%) patients without evidence of comorbidities related to secondary thrombocytopenia, liver disease, or abnormal HBL values during the 12-month baseline period. The baseline prevalence of ALT and AST > 3x the upper limit of normal (ULN) was 4.6 and 3.7%, respectively. The baseline prevalence of total bilirubin and ALP >1.5x ULN was 4.2 and 3.2%, respectively. The incidence rate of new HBL abnormalities (HBLA) was 1.24/1,000 person-years (95% CI: 0.52-2.56) for ALT>3x ULN and 0.41/1,000 person-years (95% CI: 0.08-1.32) for AST>3x ULN. HBLAs were significantly associated with male gender, liver disease, diabetes, congestive heart failure, lupus, hematological cancers, and HIV infection. In conclusion, the prevalence of HBLA, specifically ALT>3x ULN, among the ITP population is relatively high compared with a trial fibrillation, though within the confidence interval for that estimate. HBLAs were significantly associated with male gender, liver disease, and several other comorbidities, thus, distinguishing drug-induced liver injury in this population is clinically challenging.


Iannaccone C.K.,Brigham and Women's Hospital | Lee Y.C.,Brigham and Women's Hospital | Cui J.,Brigham and Women's Hospital | Frits M.L.,Brigham and Women's Hospital | And 5 more authors.
Rheumatology | Year: 2011

The objective of this review is to report on the progress of the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry data collection and summarize previous research in understanding therapeutic response to DMARDs using clinical and genetic data. The BRASS Registry, established in 2003, is a large, single-centre, prospective and observational cohort of 1100 RA patients. Patients with either new-onset or established RA disease are recruited from the practices of rheumatologists. Annual visits collect information on demographics, 28-joint DAS-CRP3 (DAS-28-CRP3), medication use, comorbidities and functional status (Modified Health Assessment Questionnaire, Short Form Health Survey 12). Two published studies have utilized BRASS to examine genetic predictors of treatment response. In a cross-sectional study, examining the association between candidate single nucleotide polymorphisms (SNPs) and disease activity in a subset of 120 RA patients on MTX monotherapy, the minor allele of ATIC rs4673993 was associated with low disease activity (P = 0.01, DAS-28-CRP3 43.2). In an international collaboration, 55 BRASS patients receiving anti-TNF therapy were genotyped for 31 SNPs associated with the risk of RA. With our collaborators, we discovered an SNP at the protein tyrosine phosphatase, receptor type, C (PTPRC) gene locus that was associated with EULAR 'good response'. With accurate data collection and the capacity to run genome-wide association studies and SNP analyses, the BRASS Registry has the ability to determine the contribution of genetic variants to disease onset and to assess their usefulness as biomarkers for treatment response and drug toxicity. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.


Wang F.T.,i3 Drug Safety | Mast T.C.,Merck And Co. | Glass R.J.,i3 Drug Safety | Loughlin J.,i3 Drug Safety | And 2 more authors.
Pediatrics | Year: 2010

OBJECTIVE: In clinical trials, the pentavalent rotavirus vaccine (RV5) was efficacious in preventing severe rotavirus gastroenteritis (RGE) and related health care encounters. We assessed the vaccine effectiveness (VE) of RV5 among US infants during the first 2 rotavirus seasons after vaccine licensure. METHODS: Using a large, national, health insurance claim database, we monitored 2 cohorts of infants (infants who received 3 doses of RV5 and a concurrent group of infants who received 3 doses of diphtheriatetanus-acellular pertussis vaccine but did not receive RV5) through the 2007 and 2008 rotavirus seasons (January 1 to May 31), to identify cases of RGE and all-cause acute gastroenteritis (AGE) resulting in medical care encounters. We estimated the VE in reducing hospitalizations, emergency department (ED) and physician office visits, and health care resource utilization, as measured by days and costs of hospitalizations and ED visits. RESULTS: A total of 33 140 RV5-vaccinated infants and 26 167 infants in the concurrent diphtheria-tetanus-acellular pertussis vaccine cohort were included in the analysis. The VE against RGE (hospitalization and ED) was 100% (95% confidence interval [CI]: 87%-100%), whereas the VE against AGE was 59% (95% CI: 47%-68%). In the outpatient setting, the VE against RGE and AGE was 96% (95% CI: 76%-100%) and 28% (95% CI: 22%-33%), respectively. There was a complete (100%) reduction in RGE hospitalization and ED visit days and a 100% reduction in costs. RV5 was associated with a 66% decrease in AGE-related hospitalization and ED visit days and a 74% reduction in costs. CONCLUSIONS: In this first nationwide study evaluating VE under conditions of routine use, RV5 was highly effective in preventing RGE and AGE and in reducing health care resource utilization. Further research is needed to assess VE with an incomplete rotavirus vaccination regimen. Copyright © 2010 by the American Academy of Pediatrics.


PubMed | i3 Drug Safety
Type: Journal Article | Journal: Pharmacoepidemiology and drug safety | Year: 2011

To estimate the positive predictive value (PPV) of claims for acute pancreatitis among initiators of antihyperglycemic drugs in commercial health insurance claims data.As part of a systematic study of the occurrence of acute pancreatitis among antihyperglycemic drug initiators (N=260,255) within a large US health insurers claims database, we identified potential cases of acute pancreatitis and confirmed them through medical record review. Potential cases had an International Classification of Diseases, 9th revision diagnosis code for acute pancreatitis (577.0) associated with an inpatient or emergency department claim. We sought 860 medical records to confirm potential cases and received 585 (70%), which were reviewed by a clinical adjudication committee. We estimated the PPV and 95% confidence intervals (CI) of claims for these medical records and a subset that had the diagnosis code listed in the first position of an inpatient claim.The PPV was 0.50 (95% CI 0.44-0.53) for an acute pancreatitis diagnosis code in any position and 0.60 (95% CI 0.55-0.65) if in the first position of an inpatient claim. The estimated PPV varied across strata defined by patient characteristics and was generally lower within strata where potential risk factors for acute pancreatitis were present.These data indicate that health insurance claims-based identification of acute pancreatitis might overestimate actual cases and introduce appreciable bias, usually toward the null. Further case confirmation or relative risk correction may be necessary to address potential bias.


PubMed | i3 Drug Safety
Type: Journal Article | Journal: Diabetes, obesity & metabolism | Year: 2011

Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs.This cohort study included patients without claims for prior pancreatic disease who initiated exenatide or other antihyperglycaemic drugs between June 2005 and December 2007. Acute pancreatitis was identified with diagnosis codes and confirmed through review of blinded medical records. Poisson regression models provided estimates of rate ratios (RRs) and 95% confidence intervals (CIs) comparing the rate of acute pancreatitis during periods of current (days supplied + 31 days), recent (current definition + 31 days) and past use (32 days beyond current definition) of exenatide relative to other antihyperglycaemic drugs, adjusted for propensity scores. A prespecified nested case-control analysis provided RR estimates adjusted for patient characteristics abstracted from medical records.Initiators of exenatide (N = 25719) had more baseline claims for obesity and concomitant diabetes drugs than comparators (N = 234536). There were 40 confirmed cases of acute pancreatitis in the exenatide cohort and 254 among other antihyperglycaemic drug initiators. Compared to other antihyperglycaemic drugs, the propensity score-adjusted RR for exenatide was 0.5 (95% CI 0.2-0.9) for current use, 1.1 (95% CI 0.4-3.2) for recent use and 2.8 (95% CI 1.6-4.7) for past use. The case-control analysis resulted in a RR of 0.2 for current use (95% CI 0.0-1.4) and 0.1 for recent use (95% CI 0.0-1.3), but an attenuated RR in the past use association (RR 1.1; 95% CI 0.1-11.0).Exenatide use was not associated with an increased risk of acute pancreatitis.

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