Risk Assessment Models for Venous Thromboembolism in Medical Inpatients.

Importance: Thromboprophylaxis is recommended for medical inpatients at risk of venous thromboembolism (VTE). Risk assessment models (RAMs) have been developed to stratify VTE risk, but a prospective head-to-head comparison of validated RAMs is lacking. Objectives: To prospectively validate an easy-to-use RAM, the simplified Geneva score, and compare its prognostic performance with previously validated RAMs. Design, Setting, and Participants: This prospective cohort study was conducted from June 18, 2020, to January 4, 2022, with a 90-day follow-up. A total of 4205 consecutive adults admitted to the general internal medicine departments of 3 Swiss university hospitals for hospitalization for more than 24 hours due to acute illness were screened for eligibility; 1352 without therapeutic anticoagulation were included. Exposures: At admission, items of 4 RAMs (ie, the simplified and original Geneva score, the Padua score, and the IMPROVE [International Medical Prevention Registry on Venous Thromboembolism] score) were collected. Patients were stratified into high and low VTE risk groups according to each RAM. Main Outcomes and Measures: Symptomatic VTE within 90 days. Results: Of 1352 medical inpatients (median age, 67 years [IQR, 54-77 years]; 762 men [55.4%]), 28 (2.1%) experienced VTE. Based on the simplified Geneva score, 854 patients (63.2%) were classified as high risk, with a 90-day VTE risk of 2.6% (n = 22; 95% CI, 1.7%-3.9%), and 498 patients (36.8%) were classified as low risk, with a 90-day VTE risk of 1.2% (n = 6; 95% CI, 0.6%-2.6%). Sensitivity of the simplified Geneva score was 78.6% (95% CI, 60.5%-89.8%) and specificity was 37.2% (95% CI, 34.6%-39.8%); the positive likelihood ratio of the simplified Geneva score was 1.25 (95% CI, 1.03-1.52) and the negative likelihood ratio was 0.58 (95% CI, 0.28-1.18). In head-to-head comparisons, sensitivity was highest for the original Geneva score (82.1%; 95% CI, 64.4%-92.1%), while specificity was highest for the IMPROVE score (70.4%; 95% CI, 67.9%-72.8%). After adjusting the VTE risk for thromboprophylaxis use and site, there was no significant difference between the high-risk and low-risk groups based on the simplified Geneva score (subhazard ratio, 2.04 [95% CI, 0.83-5.05]; P = .12) and other RAMs. Discriminative performance was poor for all RAMs, with an area under the receiver operating characteristic curve ranging from 53.8% (95% CI, 51.1%-56.5%) for the original Geneva score to 58.1% (95% CI, 55.4%-60.7%) for the simplified Geneva score. Conclusions and Relevance: This head-to-head comparison of validated RAMs found suboptimal accuracy and prognostic performance of the simplified Geneva score and other RAMs to predict hospital-acquired VTE in medical inpatients. Clinical usefulness of existing RAMs is questionable, highlighting the need for more accurate VTE prediction strategies.

Overuse and underuse of thromboprophylaxis in medical inpatients.

Background: Thromboprophylaxis (TPX) prescription is recommended in medical inpatients categorized as high risk of venous thromboembolism (VTE) by validated risk assessment models (RAMs), but how various RAMs differ in categorizing patients in risk groups, and whether the choice of RAM influences estimates of appropriate TPX use is unknown. Objectives: To determine the proportion of medical inpatients categorized as high or low risk according to validated RAMs, and to investigate the appropriateness of TPX prescription. Methods: This is a prospective cohort study of acutely ill medical inpatients from 3 Swiss university hospitals. Participants were categorized as high or low risk of VTE by validated RAMs (ie, the Padua, the International Medical Prevention Registry on Venous Thromboembolism, simplified, and original Geneva scores). We assessed prescription of any TPX at baseline. We considered TPX prescription in high-risk and no TPX prescription in low-risk patients as appropriate. Results: Among 1352 medical inpatients, the proportion categorized as high risk ranged from 29.8% with the International Medical Prevention Registry on Venous Thromboembolism score to 66.1% with the original Geneva score. Overall, 24.6% were consistently categorized as high risk, and 26.3% as low risk by all 4 RAMs. Depending on the RAM used, TPX prescription was appropriate in 58.7% to 63.3% of high-risk (ie, 36.7%-41.3% underuse) and 52.4% to 62.8% of low-risk patients (ie, 37.2%-47.6% overuse). Conclusion: The proportion of medical inpatients considered as high or low VTE risk varied widely according to different RAMs. Only half of patients were consistently categorized in the same risk group by all RAMs. While TPX remains underused in high-risk patients, overuse in low-risk patients is even more pronounced.

BMI1-Inhibitor PTC596 in Combination with MCL1 Inhibitor S63845 or MEK Inhibitor Trametinib in the Treatment of Acute Leukemia.

PURPOSE: Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in TP53 mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients. EXPERIMENTAL DESIGN: The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and FLT3 wild type, NPM1 mutant and wild type, as well as TP53 mutant and wild type AML cell lines and a variety of patient derived AML cells. RESULTS: AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or TP53 activator APR-246, independent of TP53 mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. BMI1 and MN1 gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments. CONCLUSIONS: The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated MN1 gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated BMI1 gene expression and MEK protein levels.