Frequency and type of drug-related side effects necessitating treatment discontinuation in the Swiss Inflammatory Bowel Disease Cohort.

Eur J Gastroenterol Hepatol. 2018 Jan 30;:

Authors: Godat S, Fournier N, Safroneeva E, Juillerat P, Nydegger A, Straumann A, Vavricka S, Biedermann L, Greuter T, Fraga M, Abdelrahman K, Hahnloser D, Sauter B, Rogler G, Michetti P, Schoepfer AM, on behalf of the Swiss IBD Cohort Study Group

Abstract
BACKGROUND AND AIM: Systematic analyses of inflammatory bowel disease (IBD) drug-related side effects necessitating treatment cessation in large cohorts of patients with IBD are scarce. We aimed to assess the frequency and type of drug-related side effects requiring drug cessation in patients included in the Swiss IBD Cohort.
PATIENTS AND METHODS: A retrospective review was performed of data from the Swiss IBD Cohort physician questionnaires documenting a treatment cessation for the following drug categories: aminosalicylates, topical and systemic steroids, thiopurines, methotrexate, tumor necrosis factor-antagonists, and calcineurin inhibitors (tacrolimus, cyclosporine).
RESULTS: A total of 3192 patients were analyzed, of whom 1792 (56.1%) had Crohn's disease, 1322 (41.4%) had ulcerative colitis, and 78 (2.5%) had IBD unclassified. Of 3138 patients treated with IBD drugs, 2129 (67.8%) presented with one or several drug-related side effects necessitating drug cessation. We found a significant positive correlation between the number of concomitantly administered IBD drugs and the occurrence of side effects requiring drug cessation (P<0.001). Logistic regression modeling identified Crohn's disease diagnosis [odds ratio (OR)=1.361, P=0.017], presence of extraintestinal manifestations (OR=2.262, P<0.001), IBD-related surgery (OR=1.419, P=0.006), and the increasing number of concomitantly used IBD drugs [OR=2.007 (P<0.001) for two concomitantly used IBD drugs; OR=3.225 (P<0.001) for at least three concomitantly used IBD drugs] to be associated significantly with the occurrence of IBD drug-related adverse events that necessitated treatment cessation.
CONCLUSION: Physicians should keep in mind that the number of concomitantly administered IBD drugs is the main risk factor for drug-related adverse events necessitating treatment cessation.

PMID: 29384798 [PubMed - as supplied by publisher]

A Case of Drug-Induced Severe Endocrinopathies: What Providers in the Emergency Department Need to Know.

Adv Emerg Nurs J. 2018 Jan/Mar;40(1):16-20

Authors: Villarreal J, Townes D, Vrablik M, Ro K

Abstract
The purpose of this article is to present a discussion of immune checkpoint inhibitors (ICIs) that are relatively new, yet growing, form of cancer therapy. Immune checkpoint inhibitors increase host immune response against neoplastic cells. Strengthened immunological response increases the potential for adverse events such as life-threatening endocrinopathies. The case of a 66-year-old man with metastatic melanoma treated with nivolumab and ipilimumab presented to the emergency department with marked hyperglycemia and elevated anion gap 19 days after receiving both agents is discussed. The patient received a diagnosis of immune-mediated diabetes requiring ongoing insulin even after discontinuation of ICIs. As treatment with this class of agents expands, emergency department providers will need to become familiar with the identification of their adverse reactions to provide the proper management of care.

PMID: 29384770 [PubMed - in process]

Prevalence of Nausea and Vomiting in Adults Using Ropinirole: A Systematic Review and Meta-Analysis.

Dig Dis Sci. 2018 Jan 30;:

Authors: Kurin M, Bielefeldt K, Levinthal DJ

Abstract
BACKGROUND: Nausea and vomiting are commonly associated with medication use. Dopaminergic agonists have been associated with these symptoms, but their impact in patients without Parkinson's disease, such as those with restless legs syndrome (RLS), is not well characterized.
AIMS: We sought to determine whether the non-ergoline dopamine agonist ropinirole is associated with nausea and vomiting in adults with RLS.
METHODS: We conducted a systematic review using PUBMED, EMBASE, and clinical trial databases to identify placebo-controlled clinical trials of ropinirole for RLS treatment. We extracted data including dosing schedule and the proportion of patients reporting nausea and/or vomiting. We also determined hazard ratios (HR) using a random effects proportional hazard model.
RESULTS: We extracted data from a pool of 13 studies. The prevalence of nausea in the ropinirole-treated RLS group (RLS-R; N = 1528) was 37.2% compared to 9.4% in the placebo-treated RLS group (RLS-P; N = 1395) (p < 0.0001). The prevalence of vomiting in the RLS-R group was 10.9% compared to 2.6% in the RLS-P group (p < 0.0001). Ropinirole use was associated with a higher risk of reporting nausea (HR 5.924 [4.410-7.959], p < 0.001) and experiencing vomiting (HR 4.628 [3.035-7.057], p < 0.0001). Nausea and vomiting represented nearly 50% of all adverse events reported.
CONCLUSIONS: Nausea and vomiting are quite common side effects in those using ropinirole for RLS. As RLS is more widely recognized and treated; the prevalence of ropinirole-induced nausea and vomiting could grow substantially. Ropinirole use should be considered as a cause of chronic nausea and vomiting.

PMID: 29383607 [PubMed - as supplied by publisher]

Severe cutaneous adverse drug reactions of Chinese inpatients: a meta-analysis.

An Bras Dermatol. 2017 May-Jun;92(3):345-349

Authors: Deng Q, Fang X, Zeng Q, Lu J, Jing C, Huang J

Abstract
BACKGROUND: The rate of severe cutaneous adverse drug reactions is low, and these reactions can result in death or disability. An evidence-based epidemiological study of severe cutaneous adverse drug reactions in China has not been reported.
OBJECTIVE: The aim of this study was to analyze epidemiology and characteristics of severe cutaneous adverse drug reactions of Chinese inpatients during the recent 15 years with meta-analysis.
METHODS: We retrospectively reviewed Chinese literature reporting severe cutaneous adverse drug reactions and collecting data from 2000 to 2015, which were in accordance with our inclusion criteria. All included data were analyzed with the Launch Open Meta-Analyst software.
RESULTS: Twenty-five articles involving 928 cases with severe cutaneous adverse drug reactions were included. Men to women ratio was 1.14:1. Twenty-one per cent of the patients had drug allergy history. Antibiotics (26.0%), sedative hypnotics and anticonvulsants (21.6%), and antipyretic analgesics (17.1%) were the most common causative drugs. The most frequent clinical subtype was Stevens-Johnson syndrome (50.1%), followed by toxic epidermal necrolysis (25.4%), exfoliative dermatitis (21.0%) and drug-induced hypersensitivity syndrome (1.6%). In addition to skin rashes, patients with severe cutaneous adverse drug reactions suffered mostly from fever (73%), and blood routine abnormality (66.7%).
STUDY LIMITATIONS: This meta-analysis is limited by its retrospective design and by its methodological variation.
CONCLUSION: The most common causative drugs were antibiotics and sedative hypnotics and anticonvulsants. Stevens-Johnson syndrome was the most frequent clinical subtype of severe cutaneous adverse drug reactions. In addition to skin rashes, patients with severe cutaneous adverse drug reactions suffered mostly from fever, mucosal lesion, and hematologic abnormalities.

PMID: 29186246 [PubMed - indexed for MEDLINE]

FDA Adds Online REMS Table.

Am J Nurs. 2017 Nov;117(11):21

Authors: Aschenbrenner DS

PMID: 29076851 [PubMed - indexed for MEDLINE]

Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia.

Science. 2017 10 06;358(6359):105-108

Authors: Tinnermann A, Geuter S, Sprenger C, Finsterbusch J, Büchel C

Abstract
Value information about a drug, such as the price tag, can strongly affect its therapeutic effect. We discovered that value information influences adverse treatment outcomes in humans even in the absence of an active substance. Labeling an inert treatment as expensive medication led to stronger nocebo hyperalgesia than labeling it as cheap medication. This effect was mediated by neural interactions between cortex, brainstem, and spinal cord. In particular, activity in the prefrontal cortex mediated the effect of value on nocebo hyperalgesia. Value furthermore modulated coupling between prefrontal areas, brainstem, and spinal cord, which might represent a flexible mechanism through which higher-cognitive representations, such as value, can modulate early pain processing.

PMID: 28983051 [PubMed - indexed for MEDLINE]

Safety and efficacy of anti-influenza drugs, intravenous peramivir against influenza virus infection in elderly patients with underlying disease.

J Microbiol Immunol Infect. 2017 Aug;50(4):541-544

Authors: Takamatsu K, Marumo S, Fukui M, Hata A

Abstract
We retrospectively analyzed data of 38 elderly patients, each with an underlying disease, to evaluate peramivir safety and efficacy. Six patients (15.8%) experienced adverse events, all tolerated. Median time from administration until the return to normal temperatures was 31.5 h (95% CI: 22.4-40.6). Results confirm intravenous peramivir's usefulness.

PMID: 28720319 [PubMed - indexed for MEDLINE]

High-risk prescribing in an Irish primary care population: trends and variation.

Br J Clin Pharmacol. 2017 Dec;83(12):2821-2830

Authors: Byrne CJ, Cahir C, Curran C, Bennett K

Abstract
AIMS: The aims of the present study were to examine the prevalence of high-risk prescribing (HRP) in community-dwelling adults in Ireland from 2011-2015 using consensus-validated indicators, factors associated with HRP, and the variation in HRP between general practitioners (GPs) and in the dispensing of high-risk prescriptions between pharmacies.
METHODS: A repeated cross-sectional national pharmacy claims database study was conducted. Prescribing indicators were based on those developed in formal consensus studies and applicable to pharmacy claims data. Multilevel logistic regression was used to examine factors associated with HRP and dispensing.
RESULTS: There were significant reductions in the rates of most indicators over time (P < 0.001). A total of 66 022 of 300 906 patients at risk in 2011 [21.9%, 95% confidence interval (CI) 21.8, 22.1%], and 42 109 of 278 469 in 2015 (15.1%, 95% CI 15.0, 15.3%), received ≥1 high-risk prescription (P < 0.001). In 2015, indicators with the highest rates of HRP were prescription of a nonsteroidal anti-inflammatory drug (NSAID) without gastroprotection in those ≥75 years (37.2% of those on NSAIDs), coprescription of warfarin and an antiplatelet agent or high-risk antibiotic (19.5% and 16.2% of those on warfarin, respectively) and prescription of digoxin ≥250 μg day-1 in those ≥65 years (14.0% of those on digoxin). Any HRP increased significantly with age and number of chronic medications (P < 0.001). a) After controlling for patient variables, the variation in the rate of HRP between GPs was significant (P < 0.05); and b) after controlling for patient variables and the prescribing GP, the variation in the rate of dispensing of high-risk prescriptions between pharmacies was significant (P < 0.05).
CONCLUSIONS: HRP in Ireland has declined over time, although some indicators persist. The variation between GPs and pharmacies suggests the potential for improvement in safe medicines use in community care, particularly in vulnerable older populations.

PMID: 28701029 [PubMed - indexed for MEDLINE]

Emerging In Vitro Liver Technologies for Drug Metabolism and Inter-Organ Interactions.

Tissue Eng Part B Rev. 2016 Oct;22(5):383-394

Authors: Bale SS, Moore L, Yarmush M, Jindal R

Abstract
In vitro liver models provide essential information for evaluating drug metabolism, metabolite formation, and hepatotoxicity. Interfacing liver models with other organ models could provide insights into the desirable as well as unintended systemic side effects of therapeutic agents and their metabolites. Such information is invaluable for drug screening processes particularly in the context of secondary organ toxicity. While interfacing of liver models with other organ models has been achieved, platforms that effectively provide human-relevant precise information are needed. In this concise review, we discuss the current state-of-the-art of liver-based multiorgan cell culture platforms primarily from a drug and metabolite perspective, and highlight the importance of media-to-cell ratio in interfacing liver models with other organ models. In addition, we briefly discuss issues related to development of optimal liver models that include recent advances in hepatic cell lines, stem cells, and challenges associated with primary hepatocyte-based liver models. Liver-based multiorgan models that achieve physiologically relevant coupling of different organ models can have a broad impact in evaluating drug efficacy and toxicity, as well as mechanistic investigation of human-relevant disease conditions.

PMID: 27049038 [PubMed - indexed for MEDLINE]

High incidence and early onset of nivolumab-induced pneumonitis: four case reports and literature review.

BMC Pulm Med. 2018 Jan 30;18(1):23

Authors: Koyama N, Iwase O, Nakashima E, Kishida K, Kondo T, Watanabe Y, Takahashi H, Umebayashi Y, Ogawa Y, Miura H

Abstract
BACKGROUND: Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody used as an immune checkpoint inhibitor, is commonly employed for its anti-tumor effects against various types of malignant tumors. However, its administration is complicated by immune-related adverse events (irAEs), including pneumonitis.
CASE PRESENTATION: We present a case series of four patients with malignant melanoma, non-small cell lung cancer, and hypopharyngeal carcinoma who demonstrated pneumonitis induced by nivolumab, and further review clinicopathological characteristics of these patients in comparison with those of previously reported patients with nivolumab-induced pneumonitis. In our series, 20% of patients who were treated with nivolumab developed pneumonitis, all of which occurred approximately 2 weeks after the initiation of nivolumab treatment. Prompt recognition of the nivolumab-induced pneumonitis allowed for successful resolution. Computed tomography scan images of the patients demonstrated predominantly cryptogenic organizing pneumonia patterns. All patients were males, who had been heavily treated with antitumor drugs prior to nivolumab.
CONCLUSIONS: Our case series showed that nivolumab had a high incidence of drug-induced pneumonitis with early onset, supporting the need for renewed attention to nivolumab-induced pneumonitis, particularly in patients with a history of heavy antitumor treatments.

PMID: 29378571 [PubMed - in process]

Infusion Room-Based Transition to Practice Model for Teaching Cancer Systemic Therapy Management.

J Oncol Pract. 2017 Nov;13(11):e909-e915

Authors: Duff JM, Markham MJ, George TJ, Close JL

Abstract
PURPOSE: Oncology training requirements mandate that fellows demonstrate competence in delivery of cancer therapeutics, understand clinical indications for treatment, and manage toxicities by completion of training. An academic training environment may hinder fellows' engagement in prescribing, monitoring, and adjusting cancer therapy; thus, trainees may complete their fellowship with limited experience in developing such critical skills. To provide hands-on experience in cancer systemic therapy management, we created a novel infusion room-based rotation in the final year of training; here we report the structure, logistics, and evaluation of this innovative program.
METHODS: In 2004, The University of Florida Hematology Oncology Fellowship Program created an outpatient infusion room rotation called Transition to Practice (TTP). We surveyed 20 graduates of the program to assess the ability of the rotation to teach skills necessary for systemic therapy management and identify which fellowship rotations had an impact on their readiness to practice independently.
RESULTS: Nineteen graduates completed the survey. TTP was rated highest for promoting independence in making decisions related to therapy and adjustment to the treatment plan. It was less valuable in teaching the financial aspects of cancer therapy encounters. The Veterans Affairs Medical Center continuity clinic and the TTP rotation were highly regarded for preparing graduates to practice oncology independently.
CONCLUSION: We consider the TTP model an effective learning environment for oncology trainees to develop the essential skill set for managing cancer systemic therapy on the basis of this single-institution analysis of recent graduates. This model could be applied to training other oncology professionals, such as advanced practice providers, who are new to the field.

PMID: 28885879 [PubMed - indexed for MEDLINE]

Clinical Effects of a Pharmacist Intervention in Acute Wards - A Randomized Controlled Trial.

Basic Clin Pharmacol Toxicol. 2017 Oct;121(4):325-333

Authors: Nielsen TRH, Honoré PH, Rasmussen M, Andersen SE

Abstract
The purpose of the study was to investigate the clinical effect of a clinical pharmacist (CP) intervention upon admission to hospital on inpatient harm and to assess a potential educational bias. Over 16 months, 593 adult patients taking ≥4 medications daily were included from three Danish acute medicine wards. Patients were randomized to either the CP intervention or the usual care (prospective control). To assess a potential educational bias, a retrospective control group was formed by randomization. The CP intervention comprised medication history, medication reconciliation, medication review and entry of proposed prescriptions into the electronic prescribing system. The primary outcome of inpatient harm was identified using triggers from the Institute of Healthcare Improvement Global Trigger Tool. Harms were validated and rated for severity by two independent and blinded outcome panels. Secondary end-points were harms per patient, length of hospital stay, readmissions and 1-year mortality. Harm affected 11% of the patients in the intervention group compared to 17% in the combined control group, odds ratio (OR) 0.57 (CI 0.32-1.02, p = 0.06). The incidence of harm was similar in the intervention and prospective control groups, OR 0.80 (CI 0.40-1.59, p = 0.52) but occurred less frequently in the intervention than in the retrospective control group OR 0.46 (CI 0.25-0.85, p = 0.01). An educational bias from the intervention to the control group might have contributed to this negative outcome. In conclusion, the CP intervention at admission to hospital had no statistically significant effect on inpatient harm.

PMID: 28457021 [PubMed - indexed for MEDLINE]

Asking the right questions to get the right answers: using cognitive interviews to review the acceptability, comprehension and clinical meaningfulness of patient self-report adverse event items in oncology patients.

Acta Oncol. 2016 Sep - Oct;55(9-10):1220-1226

Authors: Holch P, Warrington L, Potrata B, Ziegler L, Hector C, Keding A, Harley C, Absolom K, Morris C, Bamforth L, Velikova G

Abstract
BACKGROUND: Standardized reporting of treatment-related adverse events (AE) is essential in clinical trials, usually achieved by using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) reported by clinicians. Patient-reported adverse events (PRAE) may add value to clinician assessments, providing patient perspective on subjective toxicity. We developed an online patient symptom report and self-management system for real-time reporting and managing AE during cancer treatment integrated with electronic patient records (eRAPID). As part of this program we developed a patient version of the CTCAE (version 4.0), rephrasing terminology into a self-report format. We explored patient understanding of these items via cognitive interviews.
MATERIAL AND METHOD: Sixty patients (33 female, 27 male) undergoing treatment were purposively sampled by age, gender and tumor group (median age 61.5, range 35-84, 12 breast, 12 gynecological, 13 colorectal, 12 lung and 11 renal). Twenty-one PRAE items were completed on a touch-screen computer. Subsequent audio-recorded cognitive interviews and thematic analysis explored patients' comprehension of items via verbal probing techniques during three interview rounds (n = 20 patients/round).
RESULTS: In total 33 item amendments were made; 29% related to question comprehension, 68% response option and 3% order effects. These amendments to phrasing and language improved patient understanding but maintained CTCAE grading and key medical information. Changes were endorsed by members of a patient advisory group (N = 11).
CONCLUSION: Item adaptations resulted in a bank of consistently interpreted self-report AE items for use in future research program. In-depth analysis of items through cognitive interviews is an important step towards developing an internationally valid system for PRAE, thus improving patient safety and experiences during cancer treatment.

PMID: 27551774 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/01/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/01/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Eliciting adverse effects data from participants in clinical trials.

Cochrane Database Syst Rev. 2018 Jan 16;1:MR000039

Authors: Allen EN, Chandler CI, Mandimika N, Leisegang C, Barnes K

Abstract
BACKGROUND: Analysis of drug safety in clinical trials involves assessing adverse events (AEs) individually or by aggregate statistical synthesis to provide evidence of likely adverse drug reactions (ADR). While some AEs may be ascertained from physical examinations or tests, there is great reliance on reports from participants to detect subjective symptoms, where he/she is often the only source of information. There is no consensus on how these reports should be elicited, although it is known that questioning methods influence the extent and nature of data detected. This leaves room for measurement error and undermines comparisons between studies and pooled analyses. This review investigated comparisons of methods used in trials to elicit participant-reported AEs. This should contribute to knowledge about the methodological challenges and possible solutions for achieving better, or more consistent, AE ascertainment in trials.
OBJECTIVES: To systematically review the research that has compared methods used within clinical drug trials (or methods that would be specific for such trials) to elicit information about AEs defined in the protocol or in the planning for the trial.
SEARCH METHODS: Databases (searched to March 2015 unless indicated otherwise) included: Embase; MEDLINE; MEDLINE in Process and Other Non-Indexed Citations; Cochrane Methodology Register (July 2012); Cochrane Central Register of Controlled Trials (February 2015); Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects (January 2015); Health Technology Assessment database (January 2015); CINAHL; CAB Abstracts; BIOSIS (July 2013); Science Citation Index; Social Science Citation Index; Conference Proceedings Citation Index - Science. The search used thesaurus headings and synonyms for the following concepts: (A): Adverse events AND measurement; (B): Participants AND elicitation (also other synonyms for extraction of information about adverse effects from people); (C): Participants AND checklists (also other synonyms as for B). Pragmatic ways were used to limit the results whilst trying to maintain sensitivity. There were no date or sample size restrictions but only reports published in English were included fully, because of resource constraints as regards translation.
SELECTION CRITERIA: Two types of studies were included: drug trials comparing two or more methods within- or between-participants to elicit participant-reported AEs, and research studies performed outside the context of a trial to compare methods which could be used in trials (evidenced by reference to such applicability). Primary outcome data included AEs elicited from participants taking part in any such clinical trial. We included any participant-reported data relevant for an assessment of drug-related harm, using the original authors' terminology (and definition, where available), with comment on whether the data were likely to be treatment-emergent AEs or not.
DATA COLLECTION AND ANALYSIS: Titles and abstracts were independently reviewed for eligibility. Full texts of potentially eligible citations were independently reviewed for final eligibility. Relevant data were extracted and subjected to a 100% check. Disagreements were resolved by discussion, involving a third author. The risk of bias was independently assessed by two authors. The Cochrane 'Risk of bias' tool was used for reports comparing outcomes between participants, while for within-participant comparisons, each study was critically evaluated in terms of potential impact of the design and conduct on findings using the framework of selection, performance, detection, attrition, reporting, and other biases. An attempt was made to contact authors to retrieve protocols or specific relevant missing information. Reports were not excluded on the basis of quality unless data for outcomes were impossible to compare (e.g. where denominators differed). A narrative synthesis was conducted because differences in study design and presentation meant that a quantitative meta-analysis was not possible.
MAIN RESULTS: The 33 eligible studies largely compared open questions with checklist-type questions or rating scales. Two included participant interviews. Despite different designs, populations and details of questioning methods, the narrative review showed that more specific questioning of participants led to more AEs detected compared to a more general enquiry. A subset of six studies suggested that more severe, bothersome, or otherwise clinically relevant AEs were reported when an initial open enquiry was used, while some less severe, bothersome, or clinically relevant AEs were only reported with a subsequent specific enquiry. However, two studies showed that quite severe or debilitating AEs were only detected by an interview, while other studies did not find a difference in the nature of AEs between elicitation methods. No conclusions could be made regarding the impact of question method on the ability to detect a statistically significant difference between study groups. There was no common statistical rubric, but we were able to represent some effect measures as a risk ratio of the proportion of participants with at least one AE. This showed a lower level of reporting for open questions (O) compared to checklists (CL), with a range for the risk ratios of 0.12 to 0.64.
AUTHORS' CONCLUSIONS: This review supports concerns that methods to elicit participant-reported AEs influence the detection of these data. There was a risk for under-detection of AEs in studies using a more general elicitation method compared to those using a comprehensive method. These AEs may be important from a clinical perspective or for patients. This under-detection could compromise ability to pool AE data. However, the impact on the nature of the AE detected by different methods is unclear. The wide variety and low quality of methods to compare elicitation strategies limited this review. Future studies would be improved by using and reporting clear definitions and terminology for AEs (and other important variables), frequency and time period over which they were ascertained, how they were graded, assessed for a relationship to the study drug, coded, and tabulated/reported. While the many potential AE endpoints in a trial may preclude the development of general AE patient-reported outcome measurement instruments, much could also be learnt from how these employ both quantitative and qualitative methods to better understand data elicited. Any chosen questioning method needs to be feasible for use by both staff and participants.

PMID: 29372930 [PubMed - as supplied by publisher]

Capecitabine/cisplatin versus 5-fluorouracil/cisplatin in Chinese patients with advanced and metastatic gastric cancer: Re-analysis of efficacy and safety data from the ML17032 phase III clinical trial.

Asia Pac J Clin Oncol. 2018 Jan 26;:

Authors: Chen J, Xiong J, Wang J, Zheng L, Gao Y, Guan Z

Abstract
AIM: To confirm non-inferiority and test potential superiority of capecitabine/cisplatin (XP) over 5-fluorouracil (5-FU)/cisplatin (FP) as first-line treatment for advanced gastric cancer (AGC) in Chinese patients.
METHODS: In open-label phase III ML17032 trial, AGC (stage IIIA-IV) patients with or without metastases were randomized 1:1 to receive cisplatin (80 mg/m2 /day intravenous [IV] day 1) with either capecitabine (1000 mg/m2 /day oral [PO] twice daily [BID], days 1-14; XP) or 5-FU (800 mg/m2 /day continuous IV days 1-5; FP) every 3 weeks. The primary objective was to confirm the non-inferiority of XP over FP for progression-free survival (PFS).
RESULTS: The intent-to-treat (ITT) population included 126 Chinese patients (XP-62, FP-64; 67.5% male, mean age 54.7 years). The primary analysis was performed on the per-protocol (PP) population (105 patients; XP-51, FP-54; 65.7% male). Median PFS in the XP and FP groups was 7.2 and 4.5 months, respectively. The adjusted hazard ratio (HR) for PFS was 0.52 (95% confidence interval [CI]: 0.32-0.83, P = 0.006). Unadjusted HR for PFS in the ITT population was 0.63 (95% CI, 0.42-0.94, P = 0.022). The most frequent drug-related grade 3/4 adverse events (AEs) were neutropenia (XP-20.7%, FP-17.7%) and gastrointestinal disorders (XP-19.0%, FP-19.4%). The overall incidence of grade 3/4 AEs (XP-43.1%, FP-46.8%), serious AEs (XP-1.7%, FP-3.2%), and AEs related to treatment discontinuation (XP-10.3%, FP-16.1%) were comparable.
CONCLUSION: XP had a similar safety profile and may demonstrate superiority for PFS compared to FP as first-line treatment of Chinese patients with AGC (NCT02563054).

PMID: 29372626 [PubMed - as supplied by publisher]

Methodological Considerations for Comparison of Brand Versus Generic Versus Authorized Generic Adverse Event Reports in the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Clin Drug Investig. 2017 Dec;37(12):1143-1152

Authors: Rahman MM, Alatawi Y, Cheng N, Qian J, Peissig PL, Berg RL, Page DC, Hansen RA

Abstract
BACKGROUND: The US Food and Drug Administration Adverse Event Reporting System (FAERS), a post-marketing safety database, can be used to differentiate brand versus generic safety signals.
OBJECTIVE: To explore the methods for identifying and analyzing brand versus generic adverse event (AE) reports.
METHODS: Public release FAERS data from January 2004 to March 2015 were analyzed using alendronate and carbamazepine as examples. Reports were classified as brand, generic, and authorized generic (AG). Disproportionality analyses compared reporting odds ratios (RORs) of selected known labeled serious adverse events stratifying by brand, generic, and AG. The homogeneity of these RORs was compared using the Breslow-Day test. The AG versus generic was the primary focus since the AG is identical to brand but marketed as a generic, therefore minimizing generic perception bias. Sensitivity analyses explored how methodological approach influenced results.
RESULTS: Based on 17,521 US event reports involving alendronate and 3733 US event reports involving carbamazepine (immediate and extended release), no consistently significant differences were observed across RORs for the AGs versus generics. Similar results were obtained when comparing reporting patterns over all time and just after generic entry. The most restrictive approach for classifying AE reports yielded smaller report counts but similar results.
CONCLUSION: Differentiation of FAERS reports as brand versus generic requires careful attention to risk of product misclassification, but the relative stability of findings across varying assumptions supports the utility of these approaches for potential signal detection.

PMID: 28933038 [PubMed - indexed for MEDLINE]

General practitioners' views on (long-term) prescription and use of problematic and potentially inappropriate medication for oldest-old patients-A qualitative interview study with GPs (CIM-TRIAD study).

BMC Fam Pract. 2017 Feb 17;18(1):22

Authors: Pohontsch NJ, Heser K, Löffler A, Haenisch B, Parker D, Luck T, Riedel-Heller SG, Maier W, Jessen F, Scherer M

Abstract
BACKGROUND: Potentially inappropriate medication (PIM) is defined as medication with uncertain therapeutic effects and/or potential adverse drug reactions outweighing the clinical benefits. The prescription rate of PIM for oldest-old patients is high despite the existence of lists of PIM (e.g. the PRISCUS list) and efforts to raise awareness. This study aims at identifying general practitioners' views on PIM and aspects affecting the (long-term) use of PIM.
METHODS: As part of the CIM-TRIAD study, we conducted semi-structured, qualitative interviews with 47 general practitioners, discussing 25 patients with and 22 without PIM (according to the PRISCUS list). The interview guideline included generic and patient-specific questions. Interviews were digitally recorded and transcribed verbatim. We content analyzed the interviews using deductive and inductive category development.
RESULTS: The majority of the general practitioners were not aware of the PRISCUS list. Agents deemed potentially inappropriate from the general practitioners' point of view and the PRISCUS list are not completely superimposable. General practitioners named their criteria to identify appropriate medication for elderly patients (e.g. renal function, cognitive state) and emphasized the importance of monitoring. We identified prescription- (e.g. benzodiazepines on alternative private prescription), medication- (e.g. subjective perception that PIM has no alternative), general practitioner- (e.g. general practitioner relies on specialists), patient- (e.g. "demanding high-user", positive subjective benefit-risk-ratio) and system-related aspects (e.g. specialists lacking holistic view, interface problems) related to the (long term) use of PIM.
CONCLUSIONS: While the PRISCUS list does not seem to play a decisive role in general practice, general practitioners are well aware of risks associated with PIM. Our study identifies some starting points for a safer handling of PIM, e.g. stronger dissemination of the PRISCUS list, better compensation of medication reviews, "positive lists", adequate patient information, multifaceted interventions and improved communication between general practitioners and specialists.

PMID: 28212616 [PubMed - indexed for MEDLINE]

Ezetimibe-Statin Combination Therapy.

Dtsch Arztebl Int. 2016 Jul 01;113(26):445-53

Authors: Nußbaumer B, Glechner A, Kaminski-Hartenthaler A, Mahlknecht P, Gartlehner G

Abstract
BACKGROUND: To date, most clinical comparisons of ezetimibe-statin combination therapy versus statin monotherapy have relied entirely on surrogate variables. In this systematic review, we study the efficacy and safety of ezetimibe-statin combination therapy in comparison to statin monotherapy in terms of the prevention of cardiovascular events in hyperlipidemic patients with atherosclerosis and/or diabetes mellitus.
METHODS: This review is based on a systematic literature search (1995 to July 2015) in PubMed, the Excerpta Medica Database (EMBASE), the Cochrane Library, and the ClinicalTrials.gov registry.
RESULTS: Nine randomized, controlled trials with data from a total of 19 461 patients were included. Ezetimibe-statin combination therapy was associated with a lower risk of cardiovascular events than statin monotherapy: 33% of the patients treated with ezetimibe and a statin, and 35% of those treated with a statin alone, had a cardiovascular event within seven years (number needed to treat [NNT]: 50 over 7 years). Combination therapy was also significantly more effective in preventing a composite endpoint consisting of death due to cardiovascular disease, nonfatal myocardial infarction, unstable angina pectoris, coronary revascularization, and nonfatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [0,89; 0,99]; p = 0.016). Diabetic patients benefited from combination therapy rather than monotherapy with respect to cardiovascular morbidity (HR 0.87 [0.78; 0.94]). On the other hand, the addition of ezetimibe to statin therapy did not lessen either cardiovascular or overall mortality. Serious undesired events occurred in 38% of the patients taking ezetimibe and a statin nd in 39% of the patients taking a statin alone (relative risk 1.09 [0.77; 1.55]).
CONCLUSION: In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect was similar in the two treatment groups.

PMID: 27412989 [PubMed - indexed for MEDLINE]