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BackgroundCOVID-19 is associated with hypercoagulability and an increased incidence of thrombosis. We evaluated the clinical outcomes of adults hospitalized with COVID-19 who either continued therapeutic anticoagulants previously prescribed or who were newly started on anticoagulants during hospitalization.MethodsWe performed an observational study of adult inpatients’ with COVID-19 at 10 hospitals affiliated with Northwestern Medicine in the Chicagoland area from March 9 to June 26, 2020. We evaluated clinical outcomes of subjects with COVID-19 who were continued on their outpatient therapeutic anticoagulation during hospitalization and those who were newly started on these medications compared to those who were on prophylactic doses of these medications based on the World Health Organization (WHO) Ordinal Scale for Clinical Improvement. The primary outcome was overall death while secondary outcomes were critical illness (WHO score ≥5), need for mechanical ventilation, and death among those subjects who first had critical illness adjusted for age, sex, race, body mass index (BMI), Charlson score, glucose on admission, and use of antiplatelet agents.Results1,716 subjects with COVID-19 were included in the analysis. 171 subjects (10.0%) were continued on their outpatient therapeutic anticoagulation and 201(11.7%) were started on new therapeutic anticoagulation during hospitalization. In subjects continued on home therapeutic anticoagulation, there were no differences in overall death, critical illness, mechanical ventilation, or death among subjects with critical illness compared to subjects on prophylactic anticoagulation. Subjects receiving new therapeutic anticoagulation for COVID-19 were more likely to die (OR 5.93; 95% CI 3.71-9.47), have critical illness (OR 14.51; 95% CI 7.43-28.31), need mechanical ventilation (OR 11.22; 95% CI 6.67-18.86), and die after first having critical illness. (OR 5.51; 95% CI 2.80 −10.87).ConclusionsContinuation of outpatient prescribed anticoagulant was not associated with improved clinical outcomes. Therapeutic anticoagulation for COVID-19 in absence of other indications was associated with worse clinical outcomes.

A medical prescription is a set of health care instructions that govern the plan of care for an individual patient, which may include orders for drug therapy, diet, clinical assessment, and laboratory testing. Clinicians have long used algorithmic thinking to describe and implement prescriptions but without the benefit of a formal programming language. Instead, medical algorithms are expressed using a natural language patois, flowcharts, or as structured data in an electronic medical record system. The lack of a prescription programming language inhibits expressiveness; results in prescriptions that are difficult to understand, hard to debug, and awkward to reuse; and increases the risk of fatal medical error. This article reports on the design and evaluation of Patient-Oriented Prescription Programming Language (POP-PL), a domain-specific programming language designed for expressing prescriptions. The language is based around the idea that programs and humans have complementary strengths that, when combined properly, can make for safer, more accurate performance of prescriptions. Use of POP-PL facilitates automation of certain low-level vigilance tasks, freeing up human cognition for abstract thinking, compassion, and human communication. We implemented this language and evaluated its design attempting to write prescriptions in the new language and evaluated its usability by assessing whether clinicians can understand and modify prescriptions written in the language. We found that some medical prescriptions can be expressed in a formal domain-specific programming language, and we determined that medical professionals can understand and correctly modify programs written in POP-PL. We also discuss opportunities for refining and further developing POP-PL.

Background/Objectives Epidermal necrolysis (Stevens–Johnson syndrome and toxic epidermal necrolysis) includes immune-mediated, life-threatening inflammatory blistering disorders that can affect children. The Score of Toxic Epidermal Necrosis (SCORTEN) tool has accurately predicted the outcome of these disorders in adults but has not been tested in children. Methods We performed a retrospective chart review to compare the accuracy of the adult SCORTEN tool with that of two modifications tailored to children in predicting disease outcome. Results The longer the patient's median length of hospital stay was, the higher the adult and two proposed pediatric SCORTENs were. In addition, all patients who died had SCORTENs greater than 4. Conclusion The pediatric-modified tools were not superior to the adult SCORTEN, which accurately predicted outcome.

Objectives To evaluate the risk of all cause mortality associated with initiating compared with not initiating benzodiazepines in adults, and to address potential treatment barriers and confounding related to the use of a non-active comparator group. Design Retrospective cohort study. Setting Large de-identified US commercial healthcare database (Optum Clinformatics Datamart). Participants 1:1 high dimensional propensity score matched cohort of benzodiazepine initiators, and randomly selected benzodiazepine non-initiators with a medical visit within 14 days of the start of benzodiazepine treatment (n=1 252 988), between July 2004 and December 2013. To address treatment barriers and confounding, patients were required to have filled one or more prescriptions for any medication in the 90 days and 91-180 days before the index date (ie, the date of starting benzodiazepine treatment for initiators and the date of the selected medical visit for benzodiazepine non-initiators) and the high dimensional propensity score was estimated on the basis of more than 300 covariates. Main outcome measure All cause mortality, determined by linkage with the Social Security Administration Death Master File. Results Over a six month follow-up period, 5061 and 4691 deaths occurred among high dimensional propensity score matched benzodiazepine initiators versus non-initiators (9.3 v 9.4 events per 1000 person years; hazard ratio 1.00, 95% confidence interval 0.96 to 1.04). A 4% (95% confidence interval 1% to 8%) to 9% (2% to 7%) increase in mortality risk was observed associated with the start of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and patients initiating short acting agents. In secondary analyses comparing 1:1 high dimensional propensity score matched patients initiating benzodiazepines with an active comparator, ie, patients starting treatment with selective serotonin reuptake inhibitor antidepressants, benzodiazepine use was associated with a 9% (95% confidence interval 3% to 16%) increased risk. Conclusions This large population based cohort study suggests either no increase or at most a minor increase in risk of all cause mortality associated with benzodiazepine initiation. If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of the small increase in mortality risk observed in selected analyses.

Medical professionals have long used algorithmic thinking to describe and implement health care processes without the benefit of the conceptual framework provided by a programming language. Instead, medical algorithms are expressed using English, flowcharts, or data tables. This results in prescriptions that are difficult to understand, hard to debug, and awkward to reuse. This paper reports on the design and evaluation of a domain-specific programming language, POP-PL for expressing medical algorithms. The design draws on the experience of researchers in two disciplines, programming languages and medicine. The language is based around the idea that programs and humans have complementary strengths, that when combined can make for safer, more accurate performance of prescriptions. We implemented a prototype of our language and evaluated its design by writing prescriptions in the new language and administering a usability survey to medical professionals. This formative evaluation suggests that medical prescriptions can be conveyed by a programming language's mode of expression and provides useful information for refining the language. Analysis of the survey results suggests that medical professionals can understand and correctly modify programs in POP-PL.

ImportanceCase reports describe persistent erectile dysfunction (PED) associated with exposure to 5α-reductase inhibitors (5α-RIs). Clinical trial reports and the manufacturers’ full prescribing information (FPI) for finasteride and dutasteride state that risk of sexual adverse effects is not increased by longer duration of 5α-RI exposure and that sexual adverse effects of 5α-RIs resolve in men who discontinue exposure.ObjectiveOur chief objective was to assess whether longer duration of 5α-RI exposure increases risk of PED, independent of age and other known risk factors. Men with shorter 5α-RI exposure served as a comparison control group for those with longer exposure.DesignWe used a single-group study design and classification tree analysis (CTA) to model PED (lasting ≥90 days after stopping 5α-RI). Covariates included subject attributes, diseases, and drug exposures associated with sexual dysfunction.SettingOur data source was the electronic medical record data repository for Northwestern Medicine.SubjectsThe analysis cohorts comprised all men exposed to finasteride or dutasteride or combination products containing one of these drugs, and the subgroup of men 16–42 years old and exposed to finasteride ≤1.25 mg/day.Main outcome and measuresOur main outcome measure was diagnosis of PED beginning after first 5α-RI exposure, continuing for at least 90 days after stopping 5α-RI, and with contemporaneous treatment with a phosphodiesterase-5 inhibitor (PDE5I). Other outcome measures were erectile dysfunction (ED) and low libido. PED was determined by manual review of medical narratives for all subjects with ED. Risk of an adverse effect was expressed as number needed to harm (NNH).ResultsAmong men with 5α-RI exposure, 167 of 11,909 (1.4%) developed PED (persistence median 1,348 days after stopping 5α-RI, interquartile range (IQR) 631.5–2320.5 days); the multivariable model predicting PED had four variables: prostate disease, duration of 5α-RI exposure, age, and nonsteroidal anti-inflammatory drug (NSAID) use. Of 530 men with new ED, 167 (31.5%) had new PED. Men without prostate disease who combined NSAID use with >208.5 days of 5α-RI exposure had 4.8-fold higher risk of PED than men with shorter exposure (NNH 59.8, allp< 0.002). Among men 16–42 years old and exposed to finasteride ≤1.25 mg/day, 34 of 4,284 (0.8%) developed PED (persistence median 1,534 days, IQR 651–2,351 days); the multivariable model predicting PED had one variable: duration of 5α-RI exposure. Of 103 young men with new ED, 34 (33%) had new PED. Young men with >205 days of finasteride exposure had 4.9-fold higher risk of PED (NNH 108.2,p< 0.004) than men with shorter exposure.Conclusion and relevanceRisk of PED was higher in men with longer exposure to 5α-RIs. Among young men, longer exposure to finasteride posed a greater risk of PED than all other assessed risk factors.

Source Citation Arfe A, Scotti L, Varas-Lorenzo C, et al; Safety of Non-steroidal Anti-inflammatory Drugs (SOS) Project Consortium. Non-steroidal anti-inflammatory drugs and risk of heart failure i...

Global introspection is considered an unreliable method for attribution of causality of serious adverse events (SAEs), yet remains widely used for cancer drug clinical trials. Here, we compare structured case abstraction (SCA) to the routine method for detecting, evaluating, and reporting ADEs during cancer drug clinical trials to an Institutional Review Board (IRB). We obtained all SAE reports (2001-2008) received by one IRB for six clinical trials involving bevacizumab or oxaliplatin for treatment of gastrointestinal cancers. We compared the routine IRB SAE method to SCA for adverse event detection and causality attribution. Of 205 adverse events, 182 events (75%) were not reported; of these, 6 (20%) of 30 SAEs requiring an IRB report were unreported. For the 10 item Naranjo score, the amount of information useful for causality attribution was higher with SCA than the routine method (6.0 vs. 2.4 items, P

Nephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-based contrast agents in people with severely compromised renal function.The purpose of this study was to determine the reported number of cases of nephrogenic systemic fibrosis in children using three distinct publicly available data sources.We conducted systematic searches of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) registry and published literature from January 1997 through September 2012. We contacted authors of individual published cases to obtain follow-up data. Data sets were cross-referenced to eliminate duplicate reporting.We identified 23 children with nephrogenic systemic fibrosis. Seventeen had documented exposure to gadolinium-based contrast agents. Six children had been reported in both the FAERS and the literature, four in the FAERS and the ICNSFR registry and five in all three data sources.Nephrogenic systemic fibrosis has been rarely reported in children. Although rules related to confidentiality limit the ability to reconcile reports, active pharmaco-vigilance using RADAR (Research on Adverse Drug events And Reports) methodology helped in establishing the number of individual pediatric cases within the three major data sources.

In 1998, a multidisciplinary team of investigators initiated the Research on Adverse Drug events And Reports (RADAR) project, a post-marketing surveillance effort that systematically investigates and disseminates information describing serious and previously unrecognized serious adverse drug and device reactions (sADRs).Herein, we describe the findings, dissemination efforts, and lessons learned from the first decade of the RADAR project.After identifying serious and unexpected clinical events suitable for further investigation, RADAR collaborators derived case information from physician queries, published and unpublished clinical trials, case reports, US FDA databases and manufacturer sales figures.All major RADAR publications from 1998 to the present are included in this analysis.For each RADAR publication, data were abstracted on data source, correlative basic science findings, dissemination and resultant safety information.RADAR investigators reported 43 serious ADRs. Data sources included case reports (17 sADRs), registries (5 sADRs), referral centers (8 sADRs) and clinical trial reports (13 sADRs). Correlative basic science findings were reported for ten sADRs. Thirty-seven sADRS were described as published case reports (5 sADRs) or published case-series (32 sADRs). Related safety information was disseminated as warnings or boxed warnings in the package insert (17 sADRs) and/or 'Dear Healthcare Professional' letters (14 sADRs).An independent National Institutes of Health-funded post-marketing surveillance programme can supplement existing regulatory and pharmaceutical manufacturer-supported drug safety initiatives.

Purpose: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration’s Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. Methods: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were “renal problems” and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. Results: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 10 years. Multiple myeloma (n 220, 46%), breast cancer (n 98, 20%), and prostate cancer (n 24, 5%) were identified. Agents included ZOL (n 411, 87.5%), pamidronate (n 8, 17%), and alendronate (n 36, 2%). Outcomes included hospitalization (n 304, 63.3%) and death (n 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. Conclusion: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS.

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways.

Although amiodarone is the most commonly prescribed anti-arrhythmic drug, its use is limited by serious toxicities, including optic neuropathy. Current reports of amiodarone-associated optic neuropathy identified from the Food and Drug Administration's Adverse Event Reporting System and published case reports were reviewed. A total of 296 reports were identified: 214 from the Adverse Event Reporting System, 59 from published case reports, and 23 from adverse events reports for patients enrolled in clinical trials. Mean duration of amiodarone therapy before vision loss was 9 months (range 1-84 months). Insidious onset of amiodarone-associated optic neuropathy (44%) was the most common presentation, and nearly one third were asymptomatic. Optic disk edema was present in 85% of cases. Following drug cessation, 58% had improved visual acuity, 21% were unchanged, and 21% had further decreased visual acuity. Legal blindness (

Background: Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined. Methods: We completed a comprehensive literature search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed. Results: One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0–12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R [proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9–34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4–31.1]. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01–16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ2 = 2.12, P = 0.5473). Conclusions: The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.

The validity of information regarding drug toxicity in humans depends on the quality of the methods and instruments used to assess adverse drug events (ADEs). This study evaluates the quality of instruments used to assess and report ADEs to institutional review boards (IRBs) at US cancer centers. Forms from all 49 National Cancer Institute (NCI)-designated centers were assessed for utility in abstracting event type, severity, and causality; patient demographics; safety monitoring; and consequent changes in the conduct of the relevant study. Of the 55 items considered essential for ADE reporting, one item (event description) was present on all the forms. Seventy-eight percent of the instruments prompted for global introspection of the investigator, a method known to be unreliable. Of the 34 items that our panel of experts considered essential for event description, the median number of items present was four (domain = 1-11). The use of a validated tool to describe and assess event type, severity, and causality may lead to more timely, accurate identification of safety signals in cancer treatment.

Importance Two meta-analyses conclude that finasteride treatment of androgenic alopecia (AGA) is safe but do not assess quality of safety reporting. Objective To assess safety reporting for clinical trial reports of finasteride for AGA. Data Sources MEDLINE, ClinicalTrials.gov, and a clinical data repository for an academic medical center. Study Selection Published clinical trial reports for finasteride treatment of AGA. Data Extraction and Synthesis For each trial, we assessed quality of adverse event reporting, extracted the number and type of adverse events in treatment and placebo groups, and assessed duration of safety evaluation and adequacy of blinding. Two observers independently extracted the data; differences were resolved by consensus. We assessed generalizability in a large cohort of men prescribed finasteride, 1.25 mg/d or less, by assessing for eligibility in the finasteride-AGA pivotal trials. Main Outcomes and Measures Quality was assessed as adequate, partially adequate, inadequate, or no events reported. We used funnel plots of the hazard ratio to assess bias. Results Of 34 clinical trials, none had adequate safety reporting, 19 were partially adequate, 12 were inadequate, and 3 reported no adverse events. Funnel plots were asymmetric with a bias toward lower odds ratio for sexual adverse effects, suggesting systematic underdetection. No reports assessed adequacy of blinding, 18 (53%) disclosed conflicts of interest, and 19 (56%) received funding from the manufacturer. Duration of drug safety evaluation was 1 year or less for 26 of 34 trials (76%). Of 5704 men in the clinical data repository who were treated for AGA with finasteride, 1.25 mg/d or less, for AGA, only 31% met inclusion criteria for the pivotal trials referenced in the manufacturer’s full prescribing information and 33% took finasteride for more than 1 year. Conclusions and Relevance Available toxicity information from clinical trials of finasteride in men with AGA is very limited, is of poor quality, and seems to be systematically biased. In a cohort of men prescribed finasteride for routine treatment of AGA, most would have been excluded from the pivotal studies that supported US Food and Drug Administration approval for AGA. Published reports of clinical trials provide insufficient information to establish the safety profile for finasteride in the treatment of AGA.

Rasburicase, a recombinant urate oxidase, is used to rapidly metabolize uric acid in patients with hyperuricaemia. Rasburicase is an immunogenic therapeutic protein, which has been shown to elicit antibody response in 64 % of healthy volunteers within 1-6 weeks after the initial course, with persistent antibodies for over 1 year. Drug labelling indicates that anaphylaxis rarely occurs (in1 % of patients) after a single course of therapy with rasburicase, but there are no data available on the incidence of anaphylaxis in patients receiving a subsequent rasburicase course.The objective of this study was to determine the incidence of anaphylaxis after multiple treatment courses of rasburicase.A retrospective chart review was performed on 97 consecutively treated patients who received repeated courses of rasburicase for hyperuricaemia.None of the 97 patients who were reviewed experienced anaphylaxis during the first rasburicase course; however, six patients (6.2 %) experienced anaphylaxis during a subsequent rasburicase treatment course (p = 0.03).Anaphylaxis after a second course of rasburicase appears to occur more frequently than described in the US Food and Drug Administration-approved package insert for initial treatment courses. Given the serious nature of anaphylactic events, caution is advised when administering repeated courses of rasburicase.

OBJECTIVES We undertook the review of all available cases of hypersensitivity reactions after placement of a drug-eluting stent (DES) and classified potential causes. BACKGROUND Six months after the approval of the first DES, the Food and Drug Administration (FDA) reported 50 hypersensitivity reactions after stent placement but later concluded these were due to concomitantly prescribed medications such as clopidogrel. Nevertheless, the FDA continued to receive reports of hypersensitivity. METHODS Reports available from April 2003 through December 2004 for hypersensitivity-like reactions associated with the sirolimus-eluting stent (CYPHER, Cordis Corp., Miami Lakes, Florida) and paclitaxel-eluting stent (TAXUS, Boston Scientific Corp., Natick, Massachusetts) were reviewed. Sources of reports included the FDA's adverse-device-event database, the published literature, and investigators from the Research on Adverse Drug/Device events And Reports (RADAR) project. Causality was assessed using standardized World Health Organization criteria. RESULTS Of 5,783 reports identified for the DES in the FDA database, 262 unique events included hypersensitivity symptoms. Of these reports, 2 were certainly and 39 unlikely caused by clopidogrel and 1 was certainly, 9 probably, and 13 unlikely caused by the DES. From all sources, we identified 17 distinct cases that were probably or certainly caused by the stent, of which 9 had symptoms that lasted longer than four weeks. Four autopsies confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing. CONCLUSIONS The FDA reports and autopsy findings suggest that DES may be a cause of systemic and intrastent hypersensitivity reactions that, in some cases, have been associated with late thrombosis and death.

Background: Nevirapine is a nonnucleoside reverse transcriptase antiretroviral agent. Among HIV-infected individuals, rare instances (

Purpose: To describe the clinical findings, occurrence rates, causality evidence, and dissemination media for serious cancer drug–associated adverse drug reactions (ADRs) reported in the postmarketing setting. Methods: ADRs were termed serious if they resulted in death or severe organ failure. ADR information for oncology drugs from package insert (PI) revisions, so-called Dear Doctor letters, and journal articles was evaluated to identify serious ADRs reported from 2000 to 2002. Timing and content of information disseminated was assessed. Results: Twenty-five serious ADRs associated with 22 oncology drugs were identified after approval. Approximately half of these serious ADRs are associated with drugs approved before 1995. ADRs were described in articles in medical journals (17 ADRs), PI revisions (18 ADRs), and Dear Doctor letters (12 ADRs). PI revisions occurred less than 1 year after peer-reviewed publication for four ADRs. These revisions often differed for similar ADRs that occurred with drugs of the same class. Five of the seven ADRs lacking PI changes occurred with off-label use, for which PI change is not recommended by US Food and Drug Administration (FDA) policy. No cancer drug was withdrawn from the market during the observation period. Conclusion: Our findings demonstrate that serious ADRs may be discovered as long as 36 years after a drug receives FDA approval. This suggests a need for continued vigilance and efficient strategies for dissemination of information about ADRs associated with cancer drugs.

e14072 Background: Romidepsin (R) is indicated for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. Hypomagnesemia (HM) is common in these patients and is also listed in the Full Prescribing Information (FPI) for R. Moreover, since cardiac arrhythmias are associated with HM, patients exposed to R may be at higher risk. This study assessed whether HM was causally related to R exposure and to what extent magnesium (M) supplementation was undertaken in those with HM. Methods: We searched a large, U.S. patient data repository to detect all patients (aged 20-94 years) exposed to R (10/2010-01/2017). For these patients, serum M, as well as M supplementation data, was collected. Baseline M was assessed at initial R exposure, and HM was defined as either, a decline in M to < 1.8 mg/dL after R exposure or, in those with baseline M < 1.8 mg/dL, a decline in M by ≥0.1 mg/dL after R exposure. For each patient with HM after R exposure, the validated Naranjo Adverse Drug Reaction Probability Scale (NADRPS) was used to determine the probability that HM was caused by R. Results: Of 51 R-exposed CTCL (or other lymphoma) patients, 25 (49.0%) had HM. Of these 25, NADRPS scores yielded: 1 doubtful, 16 possible, 8 probable and 0 definite. Additionally, 24 of 25 patients with HM had documentation for presence or absence of M supplementation: 9 (37.5%) had supplementation with M agents considered to be bioavailable, 12 (50%) received M agents considered to have low bioavailability, and 3 (12.5%) had no M supplementation. Conclusions: In this study population, 25 of 51 (49.0%) patients had HM after R exposure, which appears to nearly double the percentage of patients described in the FPI. Moreover, 8 of 25 (32%) patients with HM had causality attributed to R exposure. In addition, 15 of 24 (63%) patients with HM received M supplementation with agents considered to have low bioavailability or received no M supplementation. These findings support the need for ongoing monitoring of R-exposed patients with low M, as well as the importance of repleting M with agents considered to be adequately bioavailable. Also, given that HM appears to be more frequent in this study population compared to pre-marketing data in the FPI, further studies are warranted.

To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts.The Research on Adverse Drug events And Reports methodology was used for assessment-the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration.The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA.Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA.This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.

BackgroundThe Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) is a repository of spontaneously-reported adverse drug events (ADEs) for FDA-approved prescription drugs. FAERS reports include both structured reports and unstructured narratives. The narratives often include essential information for evaluation of the severity, causality, and description of ADEs that are not present in the structured data. The timely identification of unknown toxicities of prescription drugs is an important, unsolved problem. ObjectiveThe objective of this study was to develop an annotated corpus of FAERS narratives and biomedical named entity tagger to automatically identify ADE related information in the FAERS narratives. MethodsWe developed an annotation guideline and annotate medication information and adverse event related entities on 122 FAERS narratives comprising approximately 23,000 word tokens. A named entity tagger using supervised machine learning approaches was built for detecting medication information and adverse event entities using various categories of features. ResultsThe annotated corpus had an agreement of over .9 Cohen’s kappa for medication and adverse event entities. The best performing tagger achieves an overall performance of 0.73 F1 score for detection of medication, adverse event and other named entities. ConclusionsIn this study, we developed an annotated corpus of FAERS narratives and machine learning based models for automatically extracting medication and adverse event information from the FAERS narratives. Our study is an important step towards enriching the FAERS data for postmarketing pharmacovigilance.

Using the balanced scorecard to measure outcomes, a multidisciplinary team worked to improve antiemetic therapy and decrease postoperative nausea and vomiting. Patient satisfaction measures were nausea and pain scales (10 cm, nonnumbered, visual analog). The quality measure was number of vomiting episodes. Cost measures were length of postoperative stay and antiemetic requirement. Institutional learning was assessed by spread of prescribing changes beyond the first cohort of patients. Intervention subjects were providers of general anesthesia in two cohorts of patients (60 and 346) undergoing laparoscopic cholecystectomy. Outcome assessment revealed low nausea and vomiting scores throughout the study, and antiemetic use decreased 50%. There were no deteriorations in pain scores or length of stay. Balanced scorecard measurements suggest no adverse unintended outcomes consequent to changes in prescribing behavior. Balanced scorecard processes assisted consensus among pharmacists, nurses, and physicians that may have accelerated behavioral changes.

Responses of oxytocin and PRL to mechanical breast pumping and the influence of physiological indicators of stress were measured at 2, 4, and 6 weeks postpartum to determine potential causes of inadequate milk production in 18 women with prematurely delivered, nonnursing (,1500 g) infants. Median milk production was similar to that reported in breastfeeding mothers, but a third of mothers were producing less than half as much by week 6. Plasma oxytocin was similar to that previously reported for breastfeeding mothers. The oxytocin area under the curve (AUC) for breast-pumping sessions (70 min) was correlated at each occasion (r 5 0.37, 0.58, and 0.55, respectively) with milk yield. Unlike reports of PRL levels in breastfeeding women, PRL AUC declined between weeks 2 and 6 weeks postpartum (P 5 0.03); significant increases in plasma PRL occurred in response to pumping at 2 and 4 weeks, but not at 6 weeks. Salivary amylase, a measure of a-adrenergic activity, was highly negatively correlated on each occasion with PRL AUC (r 52 0.58, 20.68, and 20.86, respectively), but not with oxytocin. Salivary cortisol was negatively correlated to a lesser degree. We hypothesize that deficiencies in preterm lactation are mediated in part upon stress-induced suppression of PRL secretion through an adrenergic mechanism. (J Clin Endocrinol Metab 85: 3661‐3668, 2000)

Because of the critical role of neutrophils in host defenses, it was hypothesized that stimulation of neutrophil production and function with Filgrastim would improve the outcome of hospitalized patients with community-acquired pneumonia. To test this hypothesis, a randomized, placebo-controlled, multicenter trial of Filgrastim (300 micrograms/day up to 10 days) as an adjunct to antibiotics was conducted for these patients. Outcome measures included time to resolution of morbidity (TRM, a composite measure of temperature, respiratory rate, blood oxygenation, and chest radiograph), 28-day mortality, length of stay, and adverse events. Filgrastim increased blood neutrophils 3-fold, but TRM, mortality, and length of hospitalization were not affected. Treatment, however, accelerated radiologic improvement and appeared to reduce serious complications (e.g., empyema, adult respiratory distress syndrome, and disseminated intravascular coagulation). Filgrastim administration was safe and well tolerated in these patients. Additional trials are needed to establish the value of this approach to treatment of infectious diseases.

The US Code of Federal Regulation (21 CFR 207) mandates that pharmaceutical manufacturers submit their FDA-approved drug information as medication Package Insert (PI). PI should provide comprehensive, current, and accurate information about the medical use of a drug. However, PI narratives are cumbersome for healthcare providers to navigate and are therefore rarely used by them. We are developing Paracelsus, a tool for automatically extracting structured drug information from PI. Paracelsus has the potential to allow healthcare providers to benefit from the rich drug information in PI for patient care. In this study, we report the development and evaluation of Paracelsus on drug-drug interactions. We show that Paracelsus performs with a high accuracy, discovering interactions not covered by other medical compendia, and in addition automatically detecting inconsistencies in the package inserts.

Background: The impact of non-accrued clinical research (NACR) represents an important economic burden that is under consideration as the U.S. Department of Health and Human Services looks into reforming the regulations governing IRB review. NACR refers to clinical research projects that fail to enroll subjects. A delineation of the issues surrounding NACR is expected to enhance subject accrual and to minimize occurrence of NACR. The authors assessed demographics, characteristics, and reasons for NACR at an academic medical center, including time trends, funding source, research team (principal investigator, department), IRB resource utilization (IRB level of review, number of required IRB reviews, initial IRB turn-around time, and duration of NACR). Methods: The authors analyzed data from 848 clinical research study closures during 2010 and 2011 to determine proportion, incidence, and characteristics of NACR. S tudies with subject enrollment during the same time period were used as a comparative measure. Results: Data from 704 (83.0%) study closures reported enrollment of 1 or more subjects while 144 (17.0 %) reported NACR (zero enrollment). PI-reported reasons for NACR included: 32 (22.2%) contract or funding issues; 43 (30.0%) insufficient study-dedicated resources; 41 (28.4%) recruitment issues; 17 (11.8%) sponsor-initiated study closure and 11 (7.6%) were “other/reason unreported”. Conclusions : NACR is not uncommon, affecting about one in six clinical research projects in the study population and reported to be more common in some other institutions. The complex and fluid nature of research conduct, non-realistic enrollment goals, and delays in both the approval and/or accrual processes contribute to NACR. Results suggest some simple strategies that investigators and institutions may use to reduce NACR, including careful feasibility assessment, reduction of institutional delays, and prompt initiation of subject accrual for multi-center studies using competitive enrollment. Institutional action to support investigators in the conduct clinical research is also encouraged to reduce likelihood of NACR. doi: http://dx.doi.org/10.4021/jocmr1320w

The Food and Drug Administration recommends renal function estimation using laboratory testing for patients at risk for chronically reduced kidney function before the administration of gadolinium-based contrast agents (GBCAs). Point-of-care (POC) estimated glomerular filtration rate (eGFR) testing was added to the pre-magnetic resonance (MR) questionnaire at our institution in June 2008 for all patients undergoing a contrast-enhanced MR exam. This study was done to evaluate the effectiveness of a pre-MR screening questionnaire about kidney disease and to assess POC eGFR detection of additional patients at risk for nephrogenic systemic fibrosis.This retrospective study was approved by our institutional review board and determined to be Health Insurance Portability and Accountability Act compliant. Medical records, laboratory data, and pre-MR questionnaires of all patients who presented for contrast-enhanced MR scans during October 2008 were reviewed. The National Kidney Disease Education Program isotope-dilution mass spectrometry-traceable Modification of Diet in Renal Disease equation was used to calculate eGFRs using the POC creatinine laboratory value, age, race, and gender. Sensitivity and specificity were calculated using 2 × 2 tables, and 95% confidence intervals were calculated with exact binomial confidence intervals.A total of 1167 individuals presented for contrast-enhanced MR scans. Of 13 individuals on dialysis, 2 did not report renal disease. Of 1154 individuals not on dialysis, 25 had an eGFR30 mL/min/1.73 m(2) (95% CI 1.41%-3.18%). Of these 25, 13 did and 12 did not report renal disease. The sensitivity of the questionnaire for identifying patients with an eGFR30 mL/min/1.73 m(2) was 63.2%. POC eGFR estimations identified a prevalence of 2.17% (95% CI: 1.41%-3.18%) of the total individuals not on dialysis, with an eGFR30 mL/min/1.73 m(2). Patients who denied kidney dysfunction had a 1.08% (95% CI: 0.56%-1.88%) posttest probability of having an eGFR30 mL/min/1.73 m(2).POC eGFR testing identified a significant number of individuals with renal dysfunction not found by the pre-MR imaging questionnaire alone.

Purpose: Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB. Experimental Design: sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed. Results: Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P < 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P < 0.05). Some key clinical information was discrepant between the two sources. Conclusions: The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients.

Background: Limiting the effects of a large-scale bioterrorist anthrax attack will require rapid and accurate detection of the earliest victims. We undertook this study to improve physicians' ability to rapidly detect inhalational anthrax victims. Methods: We conducted a case-control study to compare chest radiograph findings from 47 patients from historical inhalational anthrax cases and 188 community-acquired pneumonia control subjects. We then used classification tree analyses to derive an algorithm of chest radiograph findings and clinical characteristics that accurately and explicitly discriminated between inhalational anthrax and community-acquired pneumonia. Results: Twenty-two of the 47 patients from historical inhalational anthrax cases (46.8%) had reported chest radiograph findings. All 22 case patients (100%) had mediastinal widening, pleural effusion, or both. However, 16 case patients (72.7%) also had infiltrates. In comparison, all 188 community-acquired control subjects had reported chest radiographs. Of these, 127 control subjects (67.6%) had infiltrates, 43 control subjects (22.9%) had pleural effusions, and 15 control subjects (8.0%) had mediastinal widening. A derived algorithm with three predictor variables (chest radiograph finding of mediastinal widening, altered mental status, and elevated hematocrit) is 100% sensitive (95% confidence interval [CI], 73.5 to 100) and 98.3% specific (95% CI, 95.1 to 99.6). The derivation process used 12 patients with inhalational anthrax and 177 control subjects with community-acquired pneumonia who had information available for all three variables. Conclusions: There are significant chest radiograph differences between inhalational anthrax and community-acquired pneumonia, but none of the chest radiograph findings are both highly sensitive and highly specific. The derived clinical algorithm can improve physicians' ability to discriminate inhalational anthrax from community-acquired pneumonia, but its utility is limited to previously healthy individuals and its accuracy may be limited by missing values.

Source Citation Ott BR, Daiello LA, Dahabreh IJ, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med. 2015;30:348-58. 25575908

BACKGROUND Gemcitabine is a commonly used chemotherapeutic agent structurally and pharmacologically similar to cytarabine. Recently, instances of severe gemcitabine-associated lung injury have been reported. Herein, investigators affiliated with the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program evaluated clinical characteristics of gemcitabine-associated severe acute lung injury from clinical trial reports, medical literature case reports, and spontaneous reports to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). METHODS Clinical data were obtained by reviewing adverse event case reports for gemcitabine-associated lung injury as reported in the medical literature and in the FDA AERS database. Upper limit estimates of ADE rate were derived from review of published clinical trials reporting gemcitabine-associated lung injury rates of 10% or higher. RESULTS A total of 178 reports of gencitabine-associated lung injury were identified; in AERS, there were 55 cases from clinical trials and 92 spontaneous reports. A comprehensive search revealed 31 medical literature reports. Clinical features of gemcitabine-associated lung injury included dyspnea, fever, pulmonary infiltrate, and cough with recognition of toxicity occurring after a median duration of 48 (range, 1-529) days after initiation of gemcitabine. The taxanes, docetaxel and paclitaxel, were frequently reported as coadministered therapies. Eleven Phase II or Phase III clinical trials with 317 patients identified gemcitabine-associated lung injury rates of greater than 10%, with the highest rates (22% and 42%) being observed in Phase III clinical trials where Hodgkin disease patients were treated with a regimen that included gemcitabine and bleomycin. CONCLUSIONS High rates of gemcitabine-associated severe lung injury were observed when gemcitabine was combined with other therapies known to also cause lung injury. Physicians should have a high index of suspicion for this toxicity and report the relevant clinical findings to the FDA's AERS. Cancer 2006. © 2006 American Cancer Society.

ContextIn 1998, a multidisciplinary team of investigators initiated RADAR (Research on Adverse Drug events And Reports), a clinically based postmarketing surveillance program that systematically investigates and disseminates information describing serious and previously unrecognized adverse drug and device reactions (ADRs).ObjectiveTo describe the structure, operations, and preliminary findings from the RADAR project and related dissemination efforts by pharmaceutical suppliers and the US Food and Drug Administration (FDA).DesignAfter identifying a serious and unexpected clinical event suitable for further investigation, RADAR collaborators postulated clinical hypotheses and derived case series and incidence estimates from physician queries, published and unpublished clinical trials, published case reports, FDA databases, and manufacturer sales figures.ResultsRADAR investigators identified 16 types of serious ADRs among 1699 patients, of whom 169 (10%) died as a result of the reaction. Initial cases were identified by 7 RADAR investigators, 4 collaborating physicians, 2 attorneys, and by reviewing 3 published reports. Additional sources included queries of occupational health programs and medical directors of interventional cardiology laboratories (3 types of ADRs), published manuscripts and clinical trials (11 types of ADRs), review of medical records at a RADAR site (2 types of ADRs), unpublished clinical trial reports (3 types of ADRs), and reports from attorneys, family members, or patients (4 types of ADRs). Incidence estimates, ranging from 0.4% to 33%, were derived from 5 clinical trial reports, 2 physician queries, and 2 observational databases. Laboratory support for hypotheses included identification of 3 neutralizing antibodies and 3 histopathological findings. ADR reports were disseminated as 8 revised package inserts, 7 “dear doctor” letters, and 9 peer-reviewed articles.ConclusionA new, clinically based, hypothesis-driven approach to postmarketing surveillance may supplement existing regulatory surveillance systems and improve patient safety.

We undertook the review of all available cases of hypersensitivity reactions after placement of a drug-eluting stent (DES) and classified potential causes.Six months after the approval of the first DES, the Food and Drug Administration (FDA) reported 50 hypersensitivity reactions after stent placement but later concluded these were due to concomitantly prescribed medications such as clopidogrel. Nevertheless, the FDA continued to receive reports of hypersensitivity.Reports available from April 2003 through December 2004 for hypersensitivity-like reactions associated with the sirolimus-eluting stent (CYPHER, Cordis Corp., Miami Lakes, Florida) and paclitaxel-eluting stent (TAXUS, Boston Scientific Corp., Natick, Massachusetts) were reviewed. Sources of reports included the FDA's adverse-device-event database, the published literature, and investigators from the Research on Adverse Drug/Device events And Reports (RADAR) project. Causality was assessed using standardized World Health Organization criteria.Of 5,783 reports identified for the DES in the FDA database, 262 unique events included hypersensitivity symptoms. Of these reports, 2 were certainly and 39 unlikely caused by clopidogrel and 1 was certainly, 9 probably, and 13 unlikely caused by the DES. From all sources, we identified 17 distinct cases that were probably or certainly caused by the stent, of which 9 had symptoms that lasted longer than four weeks. Four autopsies confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing.The FDA reports and autopsy findings suggest that DES may be a cause of systemic and intrastent hypersensitivity reactions that, in some cases, have been associated with late thrombosis and death.

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

Study Objective: Adverse drug events (ADEs) have been studied in hospitalized patients. Less is known about this common type of injury in emergency department patients. This study seeks to measure the risks, incidence, severity, and costs of ADEs in an ED population. Methods: ED charts of visits to a university-affiliated tertiary-care ED occurring between March 1 and May 31, 1997, were retrospectively reviewed. The main outcome measures were ADE incidence, severity, and total cost. Visits identified by investigators as containing a suspected ADE were further assessed by using the Naranjo Adverse Drug Reaction (ADR) probability scale. Events judged as probable ADEs (Naranjo ADR probability scale score of >4) were compared with ED control visits best matched by age for disposition, survival, severity, payer, sex, race, age, number of drugs, and total cost. Results: Of 13,602 visits, 13,004 records were available. Three hundred twenty-one had suspected and 217 had probable ADEs (1.7% of evaluable encounters); these were compared with visits by 217 age-matched control patients. Insulin and warfarin were the most commonly responsible drugs. Patients with ADEs were older (mean age 45.1 versus 36.8 years; mean difference 8.3; 95% confidence interval [CI] 3.7 to 12.9), were more often women (odds ratio [OR] 1.48; 95% CI 1.01 to 2.16), took more drugs (mean number of drugs 4.1 versus 1.9; mean difference 2.2; 95% CI 1.7 to 2.8), and were hospitalized more frequently (OR 2.29; 95% CI 1.33 to 3.94) than control patients. Conclusion: ADEs encompassed an important segment of ED encounters and annual health care costs. ED screening may provide useful information about the epidemiology of outpatient ADEs. [Hafner JW Jr, Belknap SM, Squillante MD, Bucheit KA. Adverse drug events in emergency department patients. Ann Emerg Med. March 2002;39:258-267.]

Source Citation Weich S, Pearce HL, Croft P, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ. 2014;348:g1996. 24647164

This ‘Patient Safety Alert’ is the second in a series of periodic features in the Journal providing important information regarding the occurrence, management and prevention of sentinel events. A ‘sentinel event’ is an unexpected occurrence involving death or serious physical or psychological injury, or the risk of such injury. This risk includes any variation in a care provision process, where recurrence of the variation would carry significant likelihood of a serious adverse outcome. Such events are called ‘sentinel’ because they signal the need for immediate investigation and response. These articles are reprinted here with permission of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and are based on articles published by JCAHO in the publication ‘Sentinel Event Alert’ which appears on the JCAHO website at www.jcaho.org. In 1996 JCAHO established a Sentinel Event Policy designed to encourage health care organizations to self-report health care errors. In the ensuing years JCAHO has developed and implemented a procedure for recording, assembling and analyzing the data provided in these reports. Application of this carefully formulated process – termed a ‘root cause analysis’ – for identifying the underlying causes of the performance variation or adverse event provides a means for structured investigation of the occurrence and for improvement of systems to prevent reoccurrence. Data reported to the JCAHO under the Sentinel Event Policy by JCAHO-accredited health care organizations and by outside experts and organizations provide the basis for this series of Alerts. Since the Joint Commission for Accreditation of Healthcare Organizations (JCAHO) began tracking sentinel events in 1995, JCAHO’s Board of Commissioners’ Accreditation Committee has reviewed 89 cases related to medication errors, one of the most common causes of avoidable harm to patients in health care organizations. ‘Medication errors have caused serious problems In an address to this same topic, during the years 1995 and 1996 the Institute for Safe in health care organizations. It makes sense to be aware of risk reduction information and react to it Medication Practices (ISMP) in Huntingdon Valley, PA, USA, conducted a study to before something serious takes place.’ determine the drugs and situations most likely to cause harm to patients. Approximately 161 health care organizations submitted data on serious errors that had taken place during this period. The results of the study showed that a majority of the medication errors resulting in death or serious injury involved a small number of specific medications. The ISMP has termed these medications that have the highest risk of causing injury when misused ‘high-alert medications’ [1]. The top five high-alert medications identified by the ISMP are (i) insulin, (ii) opiates and narcotics, (iii) injectable potassium chloride (or phosphate) concentrate [2], (iv) intravenous anticoagulants (heparin) and (v) sodium chloride solutions above 0.9%. Listed below are some common risk factors associated with the storage and use of these high-alert medications and suggested strategies for increasing patient safety and avoiding harm.

Source Citation Olsen AM, Fosbol EL, Lindhardsen J, et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: ...

Abstract 1351 Purpose Rasburicase (recombinant urate oxidase) is used to rapidly metabolize uric acid in patients with hyperuricemia. Rasburicase is considered immunogenic given that it is produced by a genetically modified Saccharomyces cerevisiae. Rasburicase labeling indicates that anaphylaxis rarely occurs ( Methods Electronic medical records were used to identify patients with hematological malignancies who were treated with rasburicase for separate episodes of hyperuricemia. All evaluable patients received subsequent identical low doses of rasburicase (3mg or 6mg) for separate hyperuricemia episodes with at least 21 day intervals. Anaphylaxis included diagnostic coding and documentation in the record of angioedema and airway compromise. Results Ninety-seven patients met criteria for inclusion in the study. No patients experienced anaphylaxis during the first treatment course of rasburicase, however six patients (6.2%) experienced anaphylaxis after a subsequent course (p=0.03), three of which required intubation, and two resulted in cardiac arrest with one death (see Table 1). The subsequent course of rasburicase associated with anaphylaxis was administered an average of 8.5 months after the first course and anaphylaxis occurred, on average, 93 minutes after rasburicase was administered. Notably, two of the six patients met laboratory criteria for tumor lysis syndrome at the time of the anaphylactic reaction. There was no evidence of hemolysis in the six patients, and they were not tested for G6PD deficiency or methemoglobinemia. The calculated number needed to harm after administration of a subsequent course of rasburicase is 17 (95% CI 9.1 – 71.9). Conclusion This study indicates that, in our population, the incidence of anaphylaxis after the administration of subsequent treatment courses of rasburicase for hyperuricemic episodes may be greater than that described in the FDA-approved package insert for initial treatment courses. Caution is advised given the serious nature of the events (i.e. anaphylaxis, cardiac arrest, death) when administering repeated courses of rasburicase, and as with other agents that may predispose to immediate hypersensitivity reactions, premedication with antihistamines and corticosteroids should be considered. Disclosures: Off Label Use: Rasburicase is not approved for the administration of repeated courses of therapy.