Drug-drug interactions with oral anticoagulants: information consistency assessment of three commonly used online drug interactions databases in Switzerland.

Background: Toxicity or treatment failure related to drug-drug interactions (DDIs) are known to significantly affect morbidity and hospitalization rates. Despite the availability of numerous databases for DDIs identification and management, their information often differs. Oral anticoagulants are deemed at risk of DDIs and a leading cause of adverse drug events, most of which being preventable. Although many databases include DDIs involving anticoagulants, none are specialized in them. Aim and method: This study aims to compare the DDIs information content of four direct oral anticoagulants and two vitamin K antagonists in three major DDI databases used in Switzerland: Lexi-Interact, Pharmavista, and MediQ. It evaluates the consistency of DDIs information in terms of differences in severity rating systems, mechanism of interaction, extraction and documentation processes and transparency. Results: This study revealed 2'496 DDIs for the six anticoagulants, with discrepant risk classifications. Only 13.2% of DDIs were common to all three databases. Overall concordance in risk classification (high, moderate, and low risk) was slight (Fleiss' kappa = 0.131), while high-risk DDIs demonstrated a fair agreement (Fleiss' kappa = 0.398). The nature and the mechanism of the DDIs were more consistent across databases. Qualitative assessments highlighted differences in the documentation process and transparency, and similarities for availability of risk classification and references. Discussion: This study highlights the discrepancies between three commonly used DDI databases and the inconsistency in how terminology is standardised and incorporated when classifying these DDIs. It also highlights the need for the creation of specialised tools for anticoagulant-related interactions.

Predicting delirium in older non-intensive care unit inpatients: development and validation of the DELIrium risK Tool (DELIKT).

BACKGROUND: Effective delirium prevention could benefit from automatic risk stratification of older inpatients using routinely collected clinical data. AIM: Primary aim was to develop and validate a delirium prediction model (DELIKT) suitable for implementation in hospitals. Secondary aim was to select an anticholinergic burden scale as a predictor. METHOD: We used one cohort for model development and another for validation with electronically available data collected within the first 24 h of admission. Included were patients aged ≥ 65, hospitalised ≥ 48 h with no stay > 24 h in an intensive care unit. Predictors, such as administrative and laboratory variables or an anticholinergic burden scale, were selected using a combination of feature selection filter method and forward/backward selection. The final model was based on logistic regression and the DELIKT was derived from the ß-coefficients. We report the following performance measures: area under the curve, sensitivity, specificity and odds ratio. RESULTS: Both cohorts were similar and included over 10,000 patients each (mean age 77.6 ± 7.6 years) with 11% experiencing delirium. The model included nine variables: age, medical department, dementia, hemi-/paraplegia, catheterisation, potassium, creatinine, polypharmacy and the anticholinergic burden measured with the Clinician-rated Anticholinergic Scale (CrAS). The external validation yielded an AUC of 0.795. With a cut-off at 20 points in the DELIKT, we received a sensitivity of 79.7%, specificity of 62.3% and an odds ratio of 5.9 (95% CI 5.2, 6.7). CONCLUSION: The DELIKT is a potentially automatic tool with predictors from standard care including the CrAS to identify patients at high risk for delirium.

Evaluation of the association of anticholinergic burden and delirium in older hospitalised patients - A cohort study comparing 19 anticholinergic burden scales.

AIMS: A recent review identified 19 anticholinergic burden scales (ABSs) but no study has yet compared the impact of all 19 ABSs on delirium. We evaluated whether a high anticholinergic burden as classified by each ABS is associated with incident delirium. METHOD: We performed a retrospective cohort study in a Swiss tertiary teaching hospital using data from 2015-2018. Included were patients aged ≥65, hospitalised ≥48 hours with no stay >24 hours in intensive care. Delirium was defined twofold: (i) ICD-10 or CAM and (ii) ICD-10 or CAM or DOSS. Patients' cumulative anticholinergic burden score, calculated within 24 hours after admission, was classified using a binary (<3: low, ≥3: high burden) and a categorical approach (0: no, 0.5-3: low, ≥3: high burden). Association was analysed using multivariable logistic regression. RESULTS: Over 25 000 patients (mean age 77.9 ± 7.6 years) were included. Of these, (i) 864 (3.3%) and (ii) 2770 (11.0%) developed delirium. Depending on the evaluated ABS, 4-63% of the patients were exposed to at least one anticholinergic drug. Out of 19 ABSs, (i) 14 and (ii) 16 showed a significant association with the outcomes. A patient with a high anticholinergic burden score had odds ratios (ORs) of 1.21 (95% confidence interval [CI]: 1.03-1.42) to 2.63 (95% CI: 2.28-3.03) for incident delirium compared to those with low or no burden. CONCLUSION: A high anticholinergic burden within 24 hours after admission was significantly associated with incident delirium. Although prospective studies need to confirm these results, discontinuing or substituting drugs with a score of ≥3 at admission might be a targeted intervention to reduce incident delirium.

High anticholinergic burden at admission associated with in-hospital mortality in older patients: A comparison of 19 different anticholinergic burden scales.

Although no gold standard exists to assess a patient's anticholinergic burden, a review identified 19 anticholinergic burden scales (ABSs). No study has yet evaluated whether a high anticholinergic burden measured with all 19 ABSs is associated with in-hospital mortality and length of stay (LOS). We conducted a cohort study at a Swiss tertiary teaching hospital using patients' electronic health record data from 2015-2018. Included were patients aged ≥65 years, hospitalised ≥48 h without stays and >24 h in intensive care. Patients' cumulative anticholinergic burden score was classified using a binary (<3: low, ≥3: high) and categorical approach (0: no, 0.5-3: low, ≥3: high). In-hospital mortality and LOS were analysed using multivariable logistic and linear regression, respectively. We included 27,092 patients (mean age 78.0 ± 7.5 years, median LOS 6 days). Of them, 913 died. Depending on the evaluated ABS, 1370 to 17,035 patients were exposed to anticholinergics. Patients with a high burden measured by all 19 ABSs were associated with a 1.32- to 3.03-fold increase in in-hospital mortality compared with those with no/low burden. We obtained similar results for LOS. To conclude, discontinuing drugs with anticholinergic properties (score ≥3) at admission might be a targeted intervention to decrease in-hospital mortality and LOS.

External validation of the PAR-Risk Score to assess potentially avoidable hospital readmission risk in internal medicine patients.

BACKGROUND: Readmission prediction models have been developed and validated for targeted in-hospital preventive interventions. We aimed to externally validate the Potentially Avoidable Readmission-Risk Score (PAR-Risk Score), a 12-items prediction model for internal medicine patients with a convenient scoring system, for our local patient cohort. METHODS: A cohort study using electronic health record data from the internal medicine ward of a Swiss tertiary teaching hospital was conducted. The individual PAR-Risk Score values were calculated for each patient. Univariable logistic regression was used to predict potentially avoidable readmissions (PARs), as identified by the SQLape algorithm. For additional analyses, patients were stratified into low, medium, and high risk according to tertiles based on the PAR-Risk Score. Statistical associations between predictor variables and PAR as outcome were assessed using both univariable and multivariable logistic regression. RESULTS: The final dataset consisted of 5,985 patients. Of these, 340 patients (5.7%) experienced a PAR. The overall PAR-Risk Score showed rather poor discriminatory power (C statistic 0.605, 95%-CI 0.575-0.635). When using stratified groups (low, medium, high), patients in the high-risk group were at statistically significant higher odds (OR 2.63, 95%-CI 1.33-5.18) of being readmitted within 30 days compared to low risk patients. Multivariable logistic regression identified previous admission within six months, anaemia, heart failure, and opioids to be significantly associated with PAR in this patient cohort. CONCLUSION: This external validation showed a limited overall performance of the PAR-Risk Score, although higher scores were associated with an increased risk for PAR and patients in the high-risk group were at significantly higher odds of being readmitted within 30 days. This study highlights the importance of externally validating prediction models.

Quality of anticholinergic burden scales and their impact on clinical outcomes: a systematic review.

PURPOSE: Older people are at risk of anticholinergic side effects due to changes affecting drug elimination and higher sensitivity to drug's side effects. Anticholinergic burden scales (ABS) were developed to quantify the anticholinergic drug burden (ADB). We aim to identify all published ABS, to compare them systematically and to evaluate their associations with clinical outcomes. METHODS: We conducted a literature search in MEDLINE and EMBASE to identify all published ABS and a Web of Science citation (WoS) analysis to track validation studies implying clinical outcomes. Quality of the ABS was assessed using an adapted AGREE II tool. For the validation studies, we used the Newcastle-Ottawa Scale and the Cochrane tool Rob2.0. The validation studies were categorized into six evidence levels based on the propositions of the Oxford Center for Evidence-Based Medicine with respect to their quality. At least two researchers independently performed screening and quality assessments. RESULTS: Out of 1297 records, we identified 19 ABS and 104 validations studies. Despite differences in quality, all ABS were recommended for use. The anticholinergic cognitive burden (ACB) scale and the German anticholinergic burden scale (GABS) achieved the highest percentage in quality. Most ABS are validated, yet validation studies for newer scales are lacking. Only two studies compared eight ABS simultaneously. The four most investigated clinical outcomes delirium, cognition, mortality and falls showed contradicting results. CONCLUSION: There is need for good quality validation studies comparing multiple scales to define the best scale and to conduct a meta-analysis for the assessment of their clinical impact.

G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer.

Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-stimulating factor (G-CSF) secretion by the triple-negative breast cancer (TNBC) cell line MDA-MB-231 gave rise to immunosuppressive HLA-DRlo macrophages that promoted migration of breast cancer cells via secretion of TGF-α. In human breast cancer samples (n = 548), G-CSF was highly expressed in TNBC (p < 0.001) and associated with CD163+ macrophages (p < 0.0001), poorer overall survival (OS) (p = 0.021) and significantly increased numbers of TGF-α+ cells. While G-CSF blockade in the 4T1 mammary tumor model promoted maturation of MHCIIhi blood monocytes and TAMs and significantly reduced lung metastasis, anti-CSF-1R treatment promoted MHCIIloF4/80hiMRhi anti-inflammatory TAMs and enhanced lung metastasis in the presence of high G-CSF levels. Combined anti-G-CSF and anti-CSF-1R therapy significantly increased lymph node metastases, possibly via depletion of the so-called "gate-keeper" subcapsular sinus macrophages. These results indicate that G-CSF promotes the anti-inflammatory phenotype of tumor-induced macrophages when CSF-1R is inhibited and therefore caution against the use of M-CSF/CSF-1R targeting agents in tumors with high G-CSF expression.