Life-threatening Adverse Drug Events Research Articles

Development of in silico prediction models for drug-induced liver malignant tumors based on the activity of molecular initiating events: Biologically interpretable features.

Liver malignant tumors (LMTs) have recently been reported as severe and life-threatening adverse drug events associated with drug-induced liver injury (DILI). DILIs are the most common adverse drug event and can cause the withdrawal of medicinal products or major regulatory action. To reduce the attrition rate and cost of drug discovery, various quantitative structure-toxicity relationship models have been proposed to predict the probability of a DILI based on the chemical structure of a drug. However, there are many unresolved issues regarding the predictors of LMT-inducing drugs, and biologically interpretable prediction models for LMT have not been developed. Here, we constructed prediction models for whether a drug is LMT-inducing based on the activity of molecular initiating events (MIEs), which are biologically interpretable features and are defined as the initial interaction between a molecule and biosystem. We then constructed five machine learning models (i.e., LightGBM, XGBoost, random forest, neural network, and support vector machine) and evaluated their predictive performances. LightGBM achieved the best performance among the tested models. The MIEs making the highest contribution to the model construction for drug-induced LMT were inducement of Enhanced Level of Genome Instability Gene 1 (human ATAD5), nuclear factor-κ B, and activation of thyrotropin-releasing hormone receptor. These results support the previous literature and can be related to the mechanism onset of drug-induced LMT. Our findings may provide useful knowledge for drug development, research, and regulatory decision-making and will contribute to building more accurate and meaningful DILI prediction models by increasing understanding of biological predictors.

Detection of overdose and underdose prescriptions-An unsupervised machine learning approach.

Overdose prescription errors sometimes cause serious life-threatening adverse drug events, while underdose errors lead to diminished therapeutic effects. Therefore, it is important to detect and prevent these errors. In the present study, we used the one-class support vector machine (OCSVM), one of the most common unsupervised machine learning algorithms for anomaly detection, to identify overdose and underdose prescriptions. We extracted prescription data from electronic health records in Kyushu University Hospital between January 1, 2014 and December 31, 2019. We constructed an OCSVM model for each of the 21 candidate drugs using three features: age, weight, and dose. Clinical overdose and underdose prescriptions, which were identified and rectified by pharmacists before administration, were collected. Synthetic overdose and underdose prescriptions were created using the maximum and minimum doses, defined by drug labels or the UpToDate database. We applied these prescription data to the OCSVM model and evaluated its detection performance. We also performed comparative analysis with other unsupervised outlier detection algorithms (local outlier factor, isolation forest, and robust covariance). Twenty-seven out of 31 clinical overdose and underdose prescriptions (87.1%) were detected as abnormal by the model. The constructed OCSVM models showed high performance for detecting synthetic overdose prescriptions (precision 0.986, recall 0.964, and F-measure 0.973) and synthetic underdose prescriptions (precision 0.980, recall 0.794, and F-measure 0.839). In comparative analysis, OCSVM showed the best performance. Our models detected the majority of clinical overdose and underdose prescriptions and demonstrated high performance in synthetic data analysis. OCSVM models, constructed using features such as age, weight, and dose, are useful for detecting overdose and underdose prescriptions.

The Continuity of Chronic Medications in Multimorbid Patients during Perioperative Period: Retrospective Analysis

Background. Failure of continuity at care transitions results in 50% of all medication errors and up to 20% of adverse drug events (ADEs). In surgical patients medication errors occur more often than in medical patients due to perioperative corrections of medications and greater number of in-hospital transitions. The frequency of ADE in surgical patients varies from 2.3 to 27.7%.
 Aims to determine the prevalence and structure of unintentional discrepancies (UDs) in medications at admission to and discharge from surgery departments, report their potential clinical impact and analyse possible risk factors.
 Methods. Retrospective observational study was conducted in a general hospital in Russia. The study included patients hospitalized for elective surgery in Surgical Departments from January to June 2019. The pre-admission Best Possible Medication History (BPMH) for every patient was obtained. The BPMHs were compared with admission medication orders and hospital discharge prescriptions to identify UDs. Detected UDs were analysed for potential ADE with severity evaluation.
 Results. 206 patients were included, 55.83% were female, mean age 63.85 (9.38), median of chronic medications was 3 drugs. At least one UD was detected in 70.87% of patients at admission and in 92.72% at discharge, respectively, with averages of 1.30 and 2.81 discrepancies per patient. Cardiovascular drugs were the most frequent class involved at both admission (72.2%) and discharge (68.05%) in UDs. The most often UDs at both admission (51.68%) and discharge (94.65%) were omissions, incorrect dose (22.47% and 2.25%), and additional medications (11.6% and 1.55%). UDs had the potential to cause significant ADEs in 81.27%, serious ADEs in 18.35% of cases. Only 0.37% of UDs could contribute to life-threatening ADEs. The relative risk of discrepancies in patients of 60 years and older was 1.292-fold higher; three and more chronic medications increase risk 1.565-fold; diabetic or thyroid medications increase risk 1.932-fold.
 Conclusions. We reported on the first study of medication discrepancies conducted in Russian hospital. Estimated frequency, structure and risk factors of UDs in medications at admission to and discharge from surgery departments are similar to those from other countries. To decrease UDs in medications, implementation of medication reconciliation is needed.

Predictors of serious adverse drug events from opioids: Results from the Food and Drug Administration Adverse Events Reporting System.

Opioids pose significant increased risk for serious adverse drug events (ADEs). The purpose was to identify significant predictors and their associated magnitude of risk for serious life-threatening opioid ADEs. A post hoc design was used to examine predictors of opioid analgesics ADEs with Food and Drug Administration Adverse Events Reporting System (FAERS) data. The sample consisted of all eligible cases from the second quarter of the 2019 FAERS where an opioid analgesic was identified as the primary suspect for an ADE. Logistic regression was used to predict serious life-threatening ADEs. Final predictors included age, gender, misuse/substance use disorder, number of concurrent opioids; use of benzodiazepines, other sedatives, and antidepressants; and use of morphine, fentanyl, and oxycodone. Life-threatening ADEs, excluding suicide and suicide attempts, comprised 19.9% of the cases. Protective factors that reduced risk included female gender, use of antidepressants, and use of morphine. Harmful factors that increased risk of a serious ADE included misuse/substance use disorder, use of benzodiazepines, and use of other sedatives. Persons taking an opioid with both a benzodiazepine and another sedative increased risk of a serious ADE by 18.78 times. Results provide risk data helpful to share with people who use prescribed opioids for self-management of pain. Combination of opioids and clinically indicated antidepressants that do not both promote serotonin uptake inhibition may reduce risk for serious opioid ADEs. Practitioners should continue to avoid prescribing benzodiazepines and other sedatives when opioids are used.

European Databases on Stability and Compatibility of Injectable Medicinal Products in Europe

AbstractIn hospitals, the majority of medication therapy is administered intravenously. Especially, in intensive care units, simultaneous of various injectable drugs is a common practice Drug incompatibilities have been reported to be associated with up to 60 % of all serious and life-threatening adverse drug events. Several databases are used by hospital pharmacists to answer the questions of (in)compatibility of co-administered injectable drugs. The objective of this article is to present the European databases on compatibility and stability of injectable drugs. According to a questionnaire which was sent to the National Hospital Pharmacy Associations of the 28 countries of European Community there are three national databases available in EU countries which are in alphabetical order, Belgium, France and Germany. The Belgian database is dedicated to injectable medications, is updated and distributed annually in French language on a USB key. STABILIS® is an international database giving information with pictograms translated into 29 languages. This database contains also monographs of non-injectable drugs. The internet-based ADKA STABIL-Datenbank is focused on anticancer drug therapy, listing detailed datasets in German language on stability and compatibility including the references.

Differences in Adverse Drug Events Among Pediatric Patients With and Without Cancer: Sub-Analysis of a Retrospective Cohort Study

ObjectivesThis study investigated the differences in the incidence and severity of adverse drug events (ADEs) in pediatric patients with and without cancer.MethodsWe used data from the Japan Adverse Drug Events Study for pediatrics, a cohort study enrolling pediatric inpatients at two tertiary care teaching hospitals in Japan. ADEs were identified by on-site review of all medical charts, incident reports, and prescription queries by pharmacists. Two independent physicians reviewed all potential ADEs and classified ADEs in terms of severity and class of causative medication. We compared the incidence and characteristics of ADEs between pediatric cancer patients and non-cancer patients.ResultsWe enrolled 1189 patients during the study period, 27 with cancer and 1162 without cancer. We identified 480 ADEs in 234 patients (20%): 191 ADEs among 21 cancer patients and 289 ADEs among 213 non-cancer patients (7.1 per patient vs. 0.25 per patient, respectively; p < 0.0001). The most common medications associated with ADEs in cancer patients were antitumor agents; in contrast, medications associated with fatal or life-threatening ADEs in cancer patients were most often sedatives (25%) and blood products (25%). Medications associated with fatal or life-threatening ADEs among non-cancer patients were most often sedatives (15%). The percentages of fatal or life-threatening ADEs in cancer patients and non-cancer patients were 2.1 and 4.5%, respectively.ConclusionsPediatric patients with cancer have a higher risk for ADEs. Although the overall severity was similar between patients with and without cancer, the most common classes of causative medication and medications associated with a higher rate of severe ADEs differed. Application of this information may help minimize the impact of ADEs in pediatric patients.

Frequency and Severity of Adverse Drug Events by Medication Classes: The JADE Study.

Adverse drug events (ADEs) are a significant concern in daily practice; however, the profile of high-risk drugs remains unclear. Our objective was to categorize high-risk medication classes according to frequency and severity of ADEs. The JADE study is a prospective cohort study of 3459 hospitalized adult patients. We investigated the ADEs and medications prescribed to the patients. The rate of ADEs for each medication class was calculated by dividing the number of ADEs by the number of patients who received each medication class on admission. Overall, 14,435 medications were ordered on admission for patients (median 4; interquartile range, 2-6). Electrolytes and fluids were most frequently prescribed (1876 patients, 54%). Sedatives, antibiotics, peptic ulcer drugs, and analgesics were also commonly prescribed. The frequency was similar in both elderly and younger patients. Among 1010 identified ADEs, antibiotics were most frequently associated with ADEs (31 ADEs per 100 prescribed patients on admission). In patients 65 years and older, corticosteroids, anticonvulsants, laxatives, nonsteroidal anti-inflammatory drugs, and antipsychotics were the 5 most frequent medication classes causing ADEs following antibiotics. In patients younger than 65 years, antibiotics were also the most frequent cause of ADEs, followed by laxatives, lipid-lowering agents, anticonvulsants, and corticosteroids. Among cardiovascular agent-associated ADEs, 46% were fatal or life threatening in elderly patients, whereas antihypertensives were most often associated with fatal or life-threatening ADEs (25%) in younger patients. The medication classes frequently associated with ADEs did not necessarily induce severe ADEs.

Adverse drug events caused by serious medication administration errors

ObjectiveTo determine how often serious or life-threatening medication administration errors with the potential to cause harm (potential adverse drug events) result in actual harm (adverse drug events (ADEs)) in the...

Identifying Medication Misadventures: Poor Agreement Among Medical Record, Physician, Nurse, and Patient Reports

To analyze and compare four different methods of detecting medication misadventures in order to determine the optimal system for reporting clinically observed medication misadventures. Prospective cohort study. Forty-eight-bed general internal medicine inpatient ward at a large academic teaching hospital with a decentralized pharmacy system. One hundred twenty-six patients (54% male, mean age 54 yrs) with 133 consecutive admissions to the ward (mean length of stay 7.8 days) over an 8-week period from December 2001-February 2002. Medication misadventures were detected by four methods: house staff (resident physicians) report during their morning conference, nursing report during shift change, patient report at the discharge interview, and standardized medical record review. All methods of reporting medication misadventures were compared with the hospital's existing electronic medication misadventure reporting system. Overall, 63 patients (47% of 133 admissions) experienced at least one medication misadventure. Thirty-seven adverse drug events (ADEs) and 69 medication errors were observed over 1035 patient bed-days. Little overlap was noted among the four intervention methods, with nearly 80% of all 106 events detected by only a single method (medical record review 51% [54 events], patient interview 11% [12], house-staff report 9% [10], nurse report 8% [9]). Of the 37 ADEs, 6 (16%) were due to medication errors and 10 (27%) were preventable. Of five life-threatening ADEs, all were preventable, and all were reported in the medical record and the electronic reporting system; however, only two were reported by a nurse, two by a resident physician, and one by a patient. Little overlap was noted among the individual medication misadventure reporting methods, suggesting the need to use multiple complementary methods to identify medication misadventures in hospitalized patients. These findings have important implications for development of surveillance systems, design of prevention initiatives, and future medication safety research.

Iron Deficiency Anemia: Safety and Cost-Effectiveness of Treatment with Various Intravenous Iron Preparations

Introduction: Iron deficiency anemia is one of the most commonly encountered hematologic medical conditions in general practice. Oral replacement of iron can be a slow and suboptimal process, limited by low absorption rates and disease-enhanced malabsorption. When clinicians are faced with patients with large iron deficits, intravenous (IV) iron is the best option. Currently there are four IV preparations available; iron sucrose, iron gluconate, low-molecular weight iron dextran and high-molecular weight iron dextran. Upon informal questioning, we found reluctancy by many physicians to use iron dextran due to fear of allergic reactions. We examine these four preparations for clinical utility, adverse drug events (ADEs), and cost-effectiveness.Methods: We performed a systematic review and retrospective meta-analysis of studies investigating various forms of intravenous iron preparations for toxicity, ADEs, and costs. Also, we obtained actual costs of infusing intravenous iron at four hospitals in metro Louisville, KY.Results: Fourteen studies met the criteria and were reviewed. One study compared all four iron preparations, two compared three preparations and the rest compared two. Eight had a small sample size. The number of ADEs were quite small. Data from FDAderived ADE reporting of the four IV iron preparations from 2001–2003 showed a total of 1141 per 30,063,800 doses administered, yielding an ADE rate of approximately 38 per million. Absolute rate of all ADEs for iron sucrose, iron gluconate, low molecular weight iron dextran and high molecular weight iron dextran were 19.2, 18.5, 36.9, and 117.8 per million, respectively. Absolute rates of life-threatening ADEs were significantly lower at 0.6, 0.9, 3.3, and 11.3 per million respectively for iron sucrose, iron gluconate, low molecular weight iron dextran, and high molecular weight iron dextran. Based on cost differences between iron sucrose and dextran preparations, the cost to prevent one lifethreatening ADE related to the use of lower molecular weigh iron dextran was estimated to be $5.0–7.8 million. Also the cost to prevent one low-molecular weight iron dextran related death was estimated to be $33 million. These calculations are based on cost of preparations only. Estimates based on hospital-related costs incurred due to multiple infusions vs total dose infusion (TDI) puts the estimate of cost to prevent one lower molecular weight related death over $150 million.Conclusions: The perceived rate of ADEs related to infusion of IV iron preparations in medical practice has been overstated. Smaller studies with lower patient and total infusion numbers, and anecdotal evidence, tended to overestimate the frequency of life-threatening reactions. The incidence of ADEs and serious life-threatening ADEs, is exceedingly low for all IV iron preparations. In light of costs associated with the use of iron sucrose and iron gluconate vs iron dextran, we recommend that all clinicians re-assess the clinical utility of low molecular weight iron dextran for iron deficiency anemia necessitating parenteral iron replacement. Moreover, large doses of iron dextran can be safely given, thereby reducing costs associated with multiple small infusions of iron sucrose.

Update on adverse drug events associated with parenteral iron

We previously compared the safety profile of three formulations of intravenous iron used during 1998-2000 and found higher rates of adverse drug events (ADEs) associated with the use of higher molecular weight iron dextran and sodium ferric gluconate complex compared with lower molecular weight iron dextran. Since that time, iron sucrose has become widely available and clinicians have gained additional experience with sodium ferric gluconate complex. We obtained data from the United States Food and Drug Administration (FDA) on ADEs attributed to the provision of four formulations of intravenous iron during 2001-2003, including higher and lower molecular weight iron dextran, sodium ferric gluconate complex and iron sucrose. We estimated the odds of intravenous iron-related ADEs using 2 x 2 tables and the chi(2) test. The total number of reported parenteral iron-related ADEs was 1141 among approximately 30,063,800 doses administered, yielding a rate of 3.8 x 10(-5), or roughly 38 per million. Eleven individuals died in association with the ADE. Relative to lower molecular weight iron dextran, total and life-threatening ADEs were significantly more frequent among recipients of higher molecular weight iron dextran and significantly less frequent among recipients of sodium ferric gluconate complex and iron sucrose. The absolute rates of life-threatening ADEs were 0.6, 0.9, 3.3 and 11.3 per million for iron sucrose, sodium ferric gluconate complex, lower molecular weight iron dextran and higher molecular weight iron dextran, respectively. Based on differences in the average wholesale price of iron sucrose and lower molecular weight iron dextran in the US, the cost to prevent one life-threatening ADE related to the use of lower molecular weight iron dextran was estimated to be 5.0-7.8 million dollars. The cost to prevent one lower molecular weight iron dextran-related death was estimated to be 33 million dollars. The frequency of intravenous iron-related ADEs reported to the FDA has decreased, and overall, the rates are extremely low. This is the fourth report suggesting increased risks associated with the provision of higher molecular weight iron dextran. Life-threatening and other ADEs appear to be lower with the use of non-dextran iron formulations, although the cost per ADE prevented is extremely high.