Sheila Weiss Smith

Impact of an Antimicrobial Allergy Label in the Medical Record on Clinical Outcomes in Hospitalized Patients

Study Objective. To determine the impact of having an antimicrobial allergy label in the medical record on clinical outcomes in hospitalized patients.

Cancer Pharmacogenomics and Pharmacoepidemiology: Setting a Research Agenda to Accelerate Translation

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled “Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation” on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

Erythropoiesis-stimulating agents are not associated with increased risk of thrombosis in patients with myelodysplastic syndromes

Background There are limited reports of thrombosis among myelodysplastic syndrome patients exposed to erythropoiesis stimulating agents. It is not clear whether erythropoiesis stimulating agents are associated with an increased risk of thrombosis in myelodysplastic syndromes, as they are among patients with solid tumors. Design and Methods The association between use of erythropoiesis stimulating agent and transient thrombosis risk in patients with myelodysplastic syndromes was assessed in a case-crossover study nested within a cohort of incident myelodysplastic syndrome patients. Using the US Surveillance, Epidemiology, and End Results Medicare-linked database, cases with an incident diagnosis of deep vein thrombosis were identified. Using conditional logistical regression, the odds of exposure to erythropoiesis stimulating agents in the 12 weeks prior to the incident deep vein thrombosis (hazard period) was compared to the exposure odds in a prior 12-week comparison period. Results Within the cohort of eligibles with myelodysplastic syndromes (n=5,673) there were 212 incident cases of deep vein thrombosis events. Mean age was 76.2 (standard deviation=±8.6) years. Use of erythropoiesis stimulating agents was not associated with deep vein thrombosis in the crude nor the adjusted models (OR=1.21, 95% CI: 0.60, 2.43). Central venous catheter placement (OR=6.47, 95% CI: 2.37, 17.62) and red blood cell transfusion (OR=4.60, 95% CI: 2.29, 9.23) were associated with deep vein thrombosis. Conclusions Despite the link between use of erythropoiesis stimulating agents and thrombosis among patients with solid tumors, this study provides evidence that their safety profile may be different among patients with myelodysplastic syndromes.

A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: A report from the southern network on adverse reactions (SONAR)

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk-benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States.

Data Mining in Drug Safety

Data mining is used in pharmacovigilance as an adjunct to traditional pharmacovigilance practices. There remains ongoing debate as to the impact automated signal detection would have on pharmacovigilance resources. An important component of this debate is the value of each statistical alert or signal of disproportional reporting (SDR) and the resources needed to evaluate SDRs that are clinically unimportant. Using the terminology of diagnostic testing, such SDRs are called false positives as they are statistically positive but are clinically negative. Based on the clinical testing paradigm, a more stringent threshold increases the sensitivity of the test by lowering the number of false positives; however, the trade off of increased sensitivity is a reduced specificity, i.e. potentially missing clinically relevant problems.In developing the protocol to assess the clinical validity of an SDR, a literature search was conducted to determine what threshold(s) were commonly used for data mining adverse event databases. Of the more than 100 manuscripts identified, 41 published the results of data mining excursions with a clearly identified threshold for significance. The commonly used data mining algorithms were proportional reporting ratio (PRR), reporting odds ratio (ROR), multi-item gamma Poisson shrinker (MGPS) and Bayesian confidence propagation neural network (BPCNN).There was some variation in the threshold used for each algorithm. For the PRR, thresholds of 1.0, 1.5 and 2.0 were reported. Some authors required a Chi-squared test statistic of ≥4.0. Minimum drug-event pair counts were most often required for the frequentist measures of disproportionality, PRR and ROR. Among the Bayesian algorithms, MGPS and BPCNN, there was variation in the metric used and, within a metric, variation in thresholds and the use of minimum case counts. Metrics based on the MGPS algorithm that have been used to determine statistical significance include the empirical Bayes geometric mean (EBGM), the lower 95% confidence interval of the EBGM, the lower 95% confidence interval of the empirical Bayes arithmetic mean, EBlog2 and interaction signal score. Based on the published literature, there is considerable variation in defining a significant alert or SDR among practitioners of pharmacovigilance data mining. Research into the impact of such variations in practice on SDR volume and value is urgently needed.

Novel Adverse Events of Bevacizumab in the US FDA Adverse Event Reporting System Database

AbstractBackground: Bevacizumab is the first in its class, vascular endothelial growth factor (VEGF) inhibitor that was initially approved by the US FDA in 2004 for the treatment of metastatic colon cancer and other solid tumors. Preapproval clinical trials, particularly for oncology drugs, are limited in their ability to detect certain adverse effects and, therefore, the FDA and pharmaceutical sponsors collect and monitor reports of adverse events (AEs) following approval. Objective: The purpose of this study was to screen the FDA’s Adverse Event Reporting System (AERS) database for novel AEs that may be attributed to bevacizumab. Methods: The FDA AERS database was used to identify all AE reports for bevacizumab from February 2004 to September 2009. Disproportionality analysis was conducted for bevacizumab against all other drugs in the background by setting statistical significance at proportional reporting ratio (PRR) ≥2, observed case count ≥3 and chi-square ≥4. Subsequent clinical evaluation was performed to determine the clinical relevance of the findings and to group related events. Results: A total of 523 Preferred Terms (PTs) were disproportionally reported; following clinical review 63 (12%) were found to be both unlabelled and of clinical importance. These PTs were grouped into 15 clinical disorder groups. Among the clinical disorders, electrolyte abnormalities had the greatest number of reports (n = 426) followed by cardiovascular events (n = 421), gastrointestinal events (n = 345), nervous system disorders (n = 106) and pneumonitis (n = 96). On sensitivity analysis, a number of clinically important unlabelled disorders, such as necrotizing fasciitis, vessel wall disorders, arrhythmia and conduction disorder and autoimmune thrombocytopenia still met the statistical significance criteria. Conclusions: During the study period, out of 12 010 AE reports mentioning bevacizumab, it was listed as the suspect drug in 94.2% of the reports. Our disproportionality analysis identified many events that are already recognized as AEs of bevacizumab, but it also identified a number of clinically important unlabelled terms, which if confirmed in future studies would have potential implications for use of bevacizumab in clinical practice.

Patient and physician characteristics associated with erythropoiesis-stimulating agent use in patients with myelodysplastic syndromes

Patient and physician characteristics associated with use of erythropoiesis-stimulating agents in myelodysplastic syndrome patients have not yet been described. Myelodysplastic syndrome patients diagnosed from 2001 to 2005 were identified from the Surveillance Epidemiology and End Results-Medicare database. Multivariate regressions examined the association between patient and physician characteristics and the probability of receiving any erythropoiesis-stimulating agents, and of receiving therapeutic-length (≥8 week) treatment episodes. Among the 6,588 myelodysplastic syndrome patients studied, 65% received erythropoiesis-stimulating agents. Use of erythropoiesis-stimulating agents was lower for blacks compared to whites (OR 0.78; 95% CI:0.61–0.99), single persons compared to married (OR 0.77; 95% CI:0.62–0.97), Medicaid recipients (OR 0.66; 95% CI:0.55–0.79), and those living in census tracts with lower educational attainment. Patients who did not consult a hematology-oncology specialist were less likely to receive erythropoiesis-stimulating agents. Specialist access, financial resources and mobility are key determinants of receipt of erythropoiesis-stimulating agents among myelodysplastic syndrome patients.

Gastroenterologists' prescribing of infliximab for Crohn's disease: A national survey

Background: Practice guidelines suggest that immunomodulators (IMs) be given prior to infliximab (IFX) in patients with Crohns disease (CD). The package insert for IFX recommends that maintenance therapy be prescribed for patients who respond to induction therapy. Our aim was to determine the extent to which gastroenterologists (GIs) are utilizing IM prior to IFX and prescribing maintenance IFX when treating patients with CD. Methods: An 18‐item questionnaire was developed and validated. The survey was sent to 4515 GIs who are members of the American Gastroenterology Association. Bivariate and multivariate analyses were performed. Results: In all, 305 GIs responded; 70% use an IM prior to IFX, 86% prescribe maintenance IFX, and 62% reported both use of IM prior to IFX and use of maintenance IFX. Academic GIs, Midwest GIs, and GIs prescribing IFX a few times per year were more likely to report both use of an IM prior to IFX and use of maintenance IFX (odds ratio [OR] = 4.56, 2.18, and 2.25, respectively). GIs demonstrated awareness of the risk of reactivation of tuberculosis when initiating IFX and appropriately manage infusion reactions. GIs were unable to rank serious adverse reactions associated with IFX. Conclusions: A total of 38% of GIs did not report the use of IM prior to IFX and/or did not use maintenance IFX. GIs practicing outside the Midwest and those in nonacademic settings may need additional training regarding prescribing IFX.

Radiopharmaceuticals drug interactions: a critical review

Radiopharmaceuticals play a critical role in modern medicine primarily for diagnostic purposes, but also for monitoring disease progression and response to treatment. As the use of image has been increased, so has the use of prescription medications. These trends increase the risk of interactions between medications and radiopharmaceuticals. These interactions which have an impact on image by competing with the radiopharmaceutical for binding sites for example can lead to false negative results. Drugs that accelerate the metabolism of the radiopharmaceutical can have a positive impact (i.e. speeding its clearance) or, if repeating image is needed, a negative impact. In some cases, for example in cardiac image among patients taking doxirubacin, these interactions may have a therapeutic benefit. The incidence of drug-radiopharmaceuticals adverse reactions is unknown, since they may not be reported or even recognized. Here,we compiled the medical literature, using the criteria of a systematic review established by the Cochrane Collaboration, on pharmaceutical-drug interactions to provide a summary of documented interactions by organ system and radiopharmaceuticals. The purpose is to provide a reference on drug interactions that could inform the nuclear medicine staff in their daily routine. Efforts to increase adverse event reporting, and ideally consolidate reports worldwide, can provide a critically needed resource for prevention of drug-radiopharmaceuticals interactions.

Improving medication error reporting in hospice care.

The aims of this study are to determine the incidence of medication errors, characterize the type/severity of errors, and estimate the impact of an educational intervention on medication error processes in a hospice population. Medication errors from 2 hospice organizations were collected and coded for type of error/ outcome severity. The educational intervention included a 2-hour in-service and twice weekly reminders. A survey to assess participants’ change in knowledge and attitudes regarding medication error reporting through the study period and was administered at 3 different time points. Data analysis revealed that medication error reporting increased in one hospice program, that participants’ ability to correctly identify medication errors increased (P < .001), and awareness of medication errors in hospice care increased (P < .01) after the intervention.