Burden Of Adverse Drug Events Research Articles

Graph neural network-based subgraph analysis for predicting adverse drug events

PurposeAdverse drug events (ADEs) are a significant global public health concern, and they have resulted in high rates of hospital admissions, morbidity, and mortality. Prior to the use of machine learning and deep learning methods, ADEs may not become well recognized until long after a drug has been approved and is widely used, which poses a significant challenge for ensuring patient safety. Consequently, there is a need to develop computational approaches for earlier identification of ADEs not detected during pre-registration clinical trials. MethodsThis paper presents a state-of-the-art network-based approach that models patients as subgraphs composed of nodes of International Classification of Diseases (ICD) codes and directed edges illustrating disease progression. Four Graph Neural Network (GNN) variants were employed to make sub-graph level predictions that answer three Research Questions (RQ): 1) whether ADE(s) would occur given a patient's prior diagnoses history, 2) when an ADE would occur, and 3) which ADE would occur. The first and second RQs were addressed using a binary classification approach. The third RQ was addressed using a multi-label classification model. ResultsThe proposed network-based approach demonstrated superior performance in predicting ADEs, with the GraphSage model exhibiting the highest accuracy for both RQ 1 (0.8863) and RQ 3 (0.9367), while the Graph Attention Networks (GAT) model was found to perform best for RQ 2 (0.8769). Furthermore, an analysis segmented by ADE classification revealed that while RQs 1 and 3 exhibited minimal variance across different ADE categories, a distinct advantage was observed for categories B, C, and E in the context of RQ 2 when applying this sub-graph method. ConclusionThe network-based approach demonstrates the potential of GNNs in supporting the early detection and prevention of ADEs. Accurately predicting ADEs could enable healthcare professionals to make informed clinical decisions, take preventive measures and adjust medication regimens before serious adverse events occur. The proposed prediction method could also lead to optimized usage of healthcare resources by preventing hospital admissions and reducing the overall burden of adverse drug events on the healthcare systems.

Assessment of Potentially Inappropriate Prescribed Medications in Older Patients Using STOPP/START Criteria at Soba University Hospital: A Descriptive Retrospective Study

Background: Potentially inappropriate prescriptions (PIPs) have significant clinical, humanistic, and economic impacts. Identifying PIPs may reduce their burden of adverse drug events. “Screening Tool of Older Person's potentially inappropriate Prescriptions (STOPP) and Screening Tool of Alert doctors to the Right Treatment (START) criteria” are promising tools that formulated to identify potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) in geriatrics. To determine the PIMs and PPOs using STOPP/START criteria and to determine the most frequent PIPs.
 Methods: The study was a descriptive cross-sectional hospital-based retrospective study. Medical files of elderly (≥65 years) patients admitted to the internal medicine unit at Soba university hospital from January to July 2020 were used. Data were collected using a checklist of STOPP/START criteria (version 2) to determine PIPs. Statistical package for social sciences was used for data analysis.
 Results: A total of 100 patients were included, around 59% were aged between 65-70 years, and 58% were males. The mean number of medications was 5.3 ± 1.9 drugs/patient. The results showed that the prevalence of PIPs was 68%. The STOPP criteria detected 209 PIMs in 42 patients, whereas the START criteria detected 155 PPOs in 45 patients. Furthermore, the drugs that used beyond the indication period was the most common PIMs, whereas the most detected PPOs were observed in the cardiovascular system medications.
 Conclusion: The study revealed a high prevalence of PIPs among elderly patients. This necessitates a further evaluation of its impact on clinical outcomes and implements interventions to improve prescribing practice.

The pattern of adverse drug events to antiepileptic drugs: A cross-sectional study at a tertiary care teaching hospital

Background: The goal of antiepileptic therapy is to achieve complete seizure control with minimum adverse effects impacting negatively on the quality of life. The drugs available in the market for the treatment of epilepsy have their own new and unique adverse drug reaction profile. Aims and Objective: To study the pattern of adverse drug events (ADEs) to antiepileptic drugs (AEDs) in a tertiary care teaching rural hospital in India. Materials and Methods: Data of all the patients visited the Outpatient Department of Neuromedicine, Neurosurgery, and Paediatric Department of the Shree Krishna Hospital in the study duration and who received AEDs as treatment, irrespective of diagnosis, age or sex were collected after obtaining written informed consent from the patients. All the adverse events reported spontaneously as well as founded by researcher during the interview at each visit were recorded in the case record form with all necessary information. Results: Total 112 ADEs were reported from 58 (36.25%) patients in 6-month follow-up. Central nervous system was most frequently affected with 68 (60.71%) ADEs followed by the gastrointestinal system (68, 60.71%). Phenytoin was most commonly suspected AEDs (with 39 cases) followed by carbamazepine (in 23 cases). Causality assessment by the WHO-UMC criteria most common association was possible in 75 (66.96%) cases, probable 21 (18.75%), certain 6 (5.36%), and conditional/unclassified 10 (8.93%). Similar result was obtained by Naranjo’s criteria as possible 84 (75.00%), probable 22 (19.64%), and definite 6 (5.36%). 91 (80.36%) ADEs were not preventable by modified Schumock and Thornton scale. Severity assessment by Hartwig’s criteria showed 79 (70.53%) ADEs as mild. Number of AEDs given per patient had a statistical correlation with ADEs. Conclusions: There are higher chances of development of ADEs in patients taking AEDs. However, at individualized regimens, the burden of ADEs is likely to be related more to individual responsiveness, type of AEDs/AED combinations chosen, and physician treatment skills, intensive therapeutic surveillance, education about epilepsy and the importance of drug compliance, and psychosocial interventions.

The burden of adverse drug events

Drug safety should be considered as part of the balance between benefit and risk, and represents a burden to the patient, the healthcare professional, the regulator and industry. Each of these has a different view on adverse drug reactions and these are discussed in this article.

Reducing inappropriate polypharmacy: the process of deprescribing.

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.

Prevalence, nature and potential preventability of adverse drug events - a population-based medical record study of 4970 adults.

AimsTo estimate the 3 month prevalence of adverse drug events (ADEs), categories of ADEs and preventable ADEs, and the preventability of ADEs among adults in Sweden. Further, to identify drug classes and organ systems associated with ADEs and estimate their seriousness.MethodsA random sample of 5025 adults in a Swedish county council in 2008 was drawn from the Total Population Register. All their medical records in 29 inpatient care departments in three hospitals, 110 specialized outpatient clinics and 51 primary care units were reviewed retrospectively in a stepwise manner, and complemented with register data on dispensed drugs. ADEs, including adverse drug reactions (ADRs), sub-therapeutic effects of drug therapy (STEs), drug dependence and abuse, drug intoxications from overdose, and morbidities due to drug-related untreated indication, were detected during a 3 month study period, and assessed for preventability.ResultsAmong 4970 included individuals, the prevalence of ADEs was 12.0% (95% confidence interval (CI) 11.1, 12.9%), and preventable ADEs 5.6% (95% CI 5.0, 6.2%). ADRs (6.9%; 95% CI 6.2, 7.6%) and STEs (6.4%; 95% CI 5.8, 7.1%) were more prevalent than the other ADEs. Of the ADEs, 38.8% (95% CI 35.8–41.9%) was preventable, varying by ADE category and seriousness. ADEs were frequently associated with nervous system and cardiovascular drugs, but the associated drugs and affected organs varied by ADE category.ConclusionsThe considerable burden of ADEs and preventable ADEs from commonly used drugs across care settings warrants large-scale efforts to redesign safer, higher quality healthcare systems. The heterogeneous nature of the ADE categories should be considered in research and clinical practice for preventing, detecting and mitigating ADEs.

Application of the STOPP/START criteria: a systematic review of the prevalence of potentially inappropriate prescribing in older adults, and evidence of clinical, humanistic and economic impact

Potentially inappropriate prescribing (PIP) has significant clinical, humanistic and economic impacts. Identifying PIP in older adults may reduce their burden of adverse drug events. Tools with explicit criteria are being developed to screen for PIP in this population. These tools vary in their ability to identify PIP in specific care settings and jurisdictions due to such factors as local prescribing practices and formularies. One promising set of screening tools are the STOPP (Screening Tool of Older Person's potentially inappropriate Prescriptions) and START (Screening Tool of Alert doctors to the Right Treatment) criteria. We conducted a systematic review of research studies that describe the application of the STOPP/START criteria and examined the evidence of the impact of STOPP/START on clinical, humanistic and economic outcomes in older adults. We performed a systematic review of studies from relevant biomedical databases and grey literature sources published from January 2007 to January 2012. We searched citation and reference lists and contacted content experts to identify additional studies. Two authors independently selected studies using a predefined protocol. We did not restrict selection to particular study designs; however, non-English studies were excluded during the selection process. Independent extraction of articles by two authors used predefined data fields. For randomized controlled trials and observational studies comparing STOPP/START to other explicit criteria, we assessed risk of bias using an adapted tool. We included 13 studies: a single randomized controlled trial and 12 observational studies. We performed a descriptive analysis as heterogeneity of study populations, interventions and study design precluded meta-analysis. All observational studies reported the prevalence of PIP; however, the application of the criteria was not consistent across all studies. Seven of the observational studies compared STOPP/START with other explicit criteria. The STOPP/START criteria were reported to be more sensitive than the more-frequently-cited Beers criteria in six studies, but less sensitive than a set of criteria developed in Australia. The STOPP criteria identified more medications associated with adverse drug events than the 2002 version of the Beers criteria. Patients with PIP, as identified by STOPP, had an 85% increased risk of adverse drug events in one study (OR = 1·85, 95% CI: 1·51-2·26; P < 0·001). There was limited evidence that the application of STOPP/START criteria optimized prescribing. Research involving the application of STOPP/START on the impact on the quality of life was not found. The direct costs of PIP were documented in three studies from Ireland, but more extensive analyses on the economic impact or studies from other jurisdictions were not found. The STOPP/START criteria have been used to review the medication profiles of community-dwelling, acute care and long-term care older patients in Europe, Asia and North America. Observational studies have reported the prevalence and predictors of PIP. The STOPP/START criteria appear to be more sensitive than the 2002 version of the Beers criteria. Limited evidence was found related to the clinical and economic impact of the STOPP/START criteria.

Genome-wide Studies in Pharmacogenomics: Harnessing the Power of Extreme Phenotypes

Baldwin et al. on paclitaxel-induced sensory peripheral neuropathy [5], and Brown et al. on temozolomideassociated cytotoxicity [6] have advanced our understanding of DNA sequence variations and drug response, and several pharmaco genomic tests are on their way to clinical practice [7]. The studies on toxic drug reactions in particular have extra power compared with typical GWAS. For example, the study by Daly et al. on flucloxacillin-induced liver injury, an extreme and rare drug response phenotype, included only 51 affected individuals and 282 controls, yet it reported the unprecedented odds risk ratio of 80.6 (p = 8.7 × 10 for carriers of HLA-B*5701) [4], while typical GWAS odds risk ratios are below 2. We propose that the extreme phenotypes approach should be prioritized for genomewide pharmacogenomic studies, including those exploring genomic biomarkers for treatment efficacy as an alternative to enrolling very large random patient cohorts. This is based on both the likelihood of an enrichment for genomic signal due to the ‘Mendelian’ nature of the pheno type, the favorable study costs and reduced ‘noise’ arising from inaccurate pheno typing. Taken together, it seems far more effective to compare genome-wide data between ‘excellent drug responders’ versus nonresponders, compared with analyzing such data from huge patient cohorts representing a large spectrum of intermediate responders. The superior power of the extreme phenotype approach is exemplified by the recent study of Edmond et al., who identified DCTN4 as a modifier of chronic infection in cystic fibrosis among 91 individuals whose exomes were sequenced [8]. As a further example, expression levels of CHL1 were recently reported as Four years ago this journal featured a theme issue on genome-wide association studies (GWAS) in pharmacogenomics. In our accompanying editorial we noted that “relatively few GWAS on drug response were so far published compared with the large numbers of disease risk GWAS” and called upon the pharmacogenomics research community to apply this powerful, hypothesis-free research approach for improving knowledge on drug safety and efficacy [1]. Our call seems to have been timely, as the past few years have witnessed an increase in pharmacogenomics-oriented genome-wide studies. Among PubMed-listed pharmacogenomics-related manuscripts, the fraction of those mentioning both ‘pharmacogenomics’ and ‘genome-wide’ as keywords have risen fourfold over the past few years, from 2.1% in 2006 to nearly 9% of total manuscripts published between 2009 and 2012 (Table 1). However, as in past years, only a tiny fraction (under 2%) of published genome-wide studies (in all areas) are concerned with pharmacogenomics (Table 1), a disappointingly low figure considering the huge societal burden of adverse drug events and ineffective therapeutics [2].

Pharmacoeconomics and Aging

The aging of the general population in industrialized countries has brought to public attention the increasing incidence of age-related clinical conditions, because the long-term impact of diseases on functional status and on costs are greater in older people than in any other age group. With the aging of the population, it is becoming increasingly important to quantify the burden of illness in the elderly; this will be vital not only in planning for the necessary health services that will be required in coming years, but also in order to measure the benefit to be expected from interventions to prevent disability in older people. The management of multiple and chronic disorders has become a more important issue for healthcare authorities because of increasing requests for medical assistance and healthcare interventions. Among these, pharmacological treatments and drug utilization in older people are pressing issues for healthcare managers and politicians; indeed, a relatively small proportion of the population accounts for a substantial part of public drug costs. Two key sources of pressure are well known: the growing number of elderly persons, who are the highest per-capita users of medicines, and the introduction of new, often more expensive, medicines. On the other hand, the development of strategies for controlling costs, while providing the elderly with equitable access to needed pharmaceuticals, should be based on an evaluation of the economic impact of pharmacological care in older people, taking into account the burden of illness, drug utilization data, drug technology assessment evidence and results. Furthermore, there are major factors affecting pharmacological care in older people: for example inappropriate prescribing, lack of adherence and compliance, and the burden of adverse drug events. The assessment of these factors should be considered a priority in pharmacoeconomic evaluations in the aging population, and the most relevant evidence will be reviewed in this paper with examples referring to particular settings or conditions and diseases, such as the presence of cardiovascular risk factors, diabetes and chronic pain.