Development and validation of a tool to assess the risk of QT drug-drug interactions in clinical practice

Background The exact risk of developing QTc-prolongation when using a combination of QTc-prolonging drugs is still unknown, making it difficult to interpret these QT drug-drug interactions (QT-DDIs). A tool to identify high-risk patients is needed to support healthcare providers in handling automatically generated alerts in clinical practice. The main aim of this study was to develop and validate a tool to assess the risk of QT-DDIs in clinical practice. Methods A model was developed based on risk factors associated with QTc-prolongation determined in a prospective study on QT-DDIs in a university medical center inthe Netherlands. The main outcome measure was QTc-prolongation defined as a QTc interval > 450 ms for males and > 470 ms for females. Risk points were assigned to risk factors based on their odds ratios. Additional risk factors were added based on a literature review. The ability of the model to predict QTc-prolongation was validated in an independent dataset obtained from a general teaching hospital against QTc-prolongation as measured by an ECG as the gold standard. Sensitivities, specificities, false omission rates, accuracy and Youden's index were calculated. Results The model included age, gender, cardiac comorbidities, hypertension, diabetes mellitus, renal function, potassium levels, loop diuretics, and QTc-prolonging drugs as risk factors. Application of the model to the independent dataset resulted in an area under the ROC-curve of 0.54 (95% CI 0.51-0.56) when QTc-prolongation was defined as > 450/470 ms, and 0.59 (0.54-0.63) when QTc-prolongation was defined as > 500 ms. A cut-off value of 6 led to a sensitivity of 76.6 and 83.9% and a specificity of 28.5 and 27.5% respectively. Conclusions A clinical decision support tool with fair performance characteristics was developed. Optimization of this tool may aid in assessing the risk associated with QT-DDIs.Clinical Pharmacy and Toxicolog

Inpatient prescribing of dual antiplatelet therapy according to the guidelines:a prospective intervention study

Background: In dual antiplatelet therapy (DAPT), low-dose acetylsalicylic acid is combined with a P2Y12 inhibitor. However, combining antithrombotic agents increases the risk of bleeding. Guidelines on DAPT recommend using this combination for a limited period of between three weeks and 30 months. This implies the risk of DAPT being erroneously continued after the intended stop date. Objective: The primary objective of this study is to assess the proportion of hospitalized patients treated with DAPT whose treatment deviated erroneously and unintentionally from the guidelines. We also assessed risk factors and the effect of a pharmacist intervention. Methods: All patients admitted to the Spaarne Gasthuis (Haarlem/ Hoofddorp, the Netherlands) who used DAPT between March 25th , 2019, and June 14th , 2019, were, in addition to receiving regular care, reviewed to assess whether their therapy was in line with the guidelines' recommendation and whether deviations were unintended and erroneous. In the event of an unintended deviation, the pharmacist intervened by contacting the prescriber by phone and giving advice to adjust the antithrombotic therapy in line with the guideline. Results: We included 411 patients, of whom 21 patients (5.1%) had a treatment that deviated from the guidelines. For 11 patients (2.7%), the deviation was unintended and erroneous. The major risk factor for erroneous deviation was the use of DAPT before hospital admission (OR 18.7; 95%Cl 4.79-72.7). In patients who used DAPT before admission, 18 out of 58 (31.0%) had a deviation from the guidelines of whom 8 (13.8%) were erroneous. For these eight patients, the pharmacist contacted the prescriber, and in these cases the therapy was adjusted in line with the guidelines. Conclusions: Adherence to the guidelines recommending DAPT was high within the hospital. However, patients who used DAPT before hospital admission had a higher risk of erroneous prescription of DAPT. Intervention by a pharmacist increased adherence to guidelines and may reduce the number of preventable bleeding cases

Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol

PURPOSE: Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients. METHODS: We included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group. RESULTS: In the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47-9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37-4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79-9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing. CONCLUSION: Co-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently

Comparison of two algorithms to support medication surveillance for drug-drug interactions between QTc-prolonging drugs

Background: QTc-prolongation is an independent risk factor for developing life-threatening arrhythmias. Risk management of drug-induced QTc-prolongation is complex and digital support tools could be of assistance. Bindraban et al. and Berger et al. developed two algorithms to identify patients at risk for QTc-prolongation. Objective: The main aim of this study was to compare the performances of these algorithms for managing QTcprolonging drug-drug interactions (QT-DDIs). Materials and Methods: A retrospective data analysis was performed. A dataset was created from QT-DDI alerts generated for inand outpatients at a general teaching hospital between November 2016 and March 2018. ECGs recorded within 7 days of the QT-DDI alert were collected. Main outcomes were the performance characteristics of both algorithms. QTc-intervals of > 500 ms on the first ECG after the alert were taken as outcome parameter, to which the performances were compared. Secondary outcome was the distribution of risk scores in the study cohort. Results: In total, 10,870 QT-DDI alerts of 4987 patients were included. ECGs were recorded in 26.2 % of the QT-DDI alerts. Application of the algorithms resulted in area under the ROC-curves of 0.81 (95 % CI 0.79-0.84) for Bindraban et al. and 0.73 (0.70-0.75) for Berger et al. Cut-off values of >= 3 and >= 6 led to sensitivities of 85.7 % and 89.1 %, and specificities of 60.8 % and 44.3 % respectively. Conclusions: Both algorithms showed good discriminative abilities to identify patients at risk for QTcprolongation when using >= 2 QTc-prolonging drugs. Implementation of digital algorithms in clinical decision support systems could support the risk management of QT-DDIs

Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients

Introduction: Delirium occurs frequently in critically ill patients and is associated with disease severity and infection. Although several pathways for delirium have been described, biomarkers associated with delirium in intensive care unit (ICU) patients is not well studied. We examined plasma biomarkers in delirious and nondelirious patients and the role of these biomarkers on long-term cognitive function.Methods: In an exploratory observational study, we included 100 ICU patients with or without delirium and with ("inflamed”) and without ("noninflamed”) infection/systemic inflammatory response syndrome (SIRS). Delirium was diagnosed by using the confusion-assessment method-ICU (CAM-ICU). Within 24 hours after the onset of delirium, blood was obtained for biomarker analysis. No differences in patient characteristics were found between deliriousand nondelirious patients. To determine associations between biomarkers and delirium, univariate and multivariatelogistic regression analyses were performed. Eighteen months after ICU discharge, a cognitive-failure questionnaire was distributed to the ICU survivors.Results: In total, 50 delirious and 50 nondelirious patients were included. We found that IL-8, MCP-1, procalcitonin (PCT), cortisol, and S100-b were significantly associated with delirium in inflamed patients (n = 46). In the noninflamed group of patients (n = 54), IL-8, IL-1ra, IL-10 ratio Ab1-42/40, and ratio AbN-42/40 were significantly associated with delirium. In multivariate regression analysis, IL-8 was independently associated (odds ratio, 9.0; 95% confidence interval (CI), 1.8 to 44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95% CI 1.1 to 5.9), and Ab1-42/40 (OR, 0.03; 95% CI, 0.002 to 0.50) with delirium in noninflamed patients. Furthermore, levels of several amyloid-b forms, but not human Tau or S100-b, were significantly correlated with self-reported cognitive impairment 18 months after ICU discharge, whereas inflammatory markers were not correlated to impaired longterm cognitive function.Conclusions: In inflamed patients, the proinflammatory cytokine IL-8 was associated with delirium, whereas in noninflamed patients, antiinflammatory cytokine IL-10 and Ab1-42/40 were associated with delirium. This suggests that the underlying mechanism governing the development of delirium in inflamed patients differs from that in noninflamed patients. Finally, elevated levels of amyloid-b correlated with long-term subjective cognitive-impairment delirium may represent the first sign of a (subclinical) dementia process. Future studies must confirm these results

Guidelines for mono, double and triple antithrombotic therapy

Guidelines for antithrombotic therapy are complex, especially if a patient has several indications that require antithrombotic therapy. In general, no patient should receive lifelong double or triple antithrombotic therapy. In this overview, we outline the most common indications for mono, double and triple antithrombotic therapy; the preferred antithrombotic therapy and the recommended duration of therapy. Both antiplatelet therapy and therapeutic anticoagulation therapy with vitamin K antagonists or direct oral anticoagulants were included. European guidelines were used or, if no European guidelines were available, the Dutch guidelines were used

The value of radiographic markers in the diagnostic work-up of rotator cuff tears, an arthroscopic correlated study

Objective To evaluate the value of radiographs during the diagnostic work-up of rotator cuff tears, using arthroscopy as reference standard. Materials and methods This retrospective study included 236 shoulders of 236 patients. All radiographs were evaluated for inferior cortical acromial sclerosis, lateral acromial spur, superior migration of the humeral head, greater tubercle cysts, and subacromial space calcifications. Predictive value of these radiographic signs in predicting rotator cuff tears was determined with arthroscopy as reference standard. Results According to arthroscopy, 131 shoulders were diagnosed with rotator cuff tears. Seventy-two out of 131 shoulders (55%) had inferior cortical acromial sclerosis, 37 (28%) lateral acromial spur, 21 (16%) superior migration of the humeral head, 7 (5%) greater tubercle cysts and 15 subacromial space calcifications (11%). Inferior cortical acromial sclerosis (P = 0.001), lateral spur (P = 0.001), superior migration (P = 0.002), and cysts (P = 0.03) were significantly and independently associated with rotator cuff tears, whereas subacromial calcifications (p = 0.21) was not. Inferior cortical acromial sclerosis, superior migration, lateral acromial spur, and cysts combined have a positive predictive value of 78%. Conclusions The combination of inferior cortical acromial sclerosis, lateral acromial spur, superior migration of the humeral head, and greater tubercle cysts has a high positive predictive value for the presence of full-thickness rotator cuff tears. In patients with a high suspicion for having a rotator cuff tear based on radiographic findings, MRI can be performed directly without the delay and costs caused by an additional ultrasound exam

Emerging Artificial Societies Through Learning

The NewTies project is implementing a simulation in which societies of agents are expected to de-velop autonomously as a result of individual, population and social learning. These societies are expected to be able to solve environmental challenges by acting collectively. The challenges are in-tended to be analogous to those faced by early, simple, small-scale human societies. This report on work in progress outlines the major features of the system as it is currently conceived within the project, including the design of the agents, the environment, the mechanism for the evolution of language and the peer-to-peer infrastructure on which the simulation runs.Artificial Societies, Evolution of Language, Decision Trees, Peer-To-Peer Networks, Social Learning