Background: There is ambiguity whether frail patients with atrial fibrillation (AF) managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC).Methods... Show moreBackground: There is ambiguity whether frail patients with atrial fibrillation (AF) managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC).Methods: We conducted a pragmatic, multicenter, open-label, randomized controlled superiority trial. Older AF patients living with frailty (age >= 75 years plus a Groningen Frailty Indicator (GFI) score >= 3) were randomized to switch from INR-guided VKA treatment to a NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mLmin(-1)1.73 m(-2) or with valvular AF were excluded. Follow-up was 12 months. The cause-specific hazard ratio (HR) was calculated for occurrence of the primary outcome which was a major or clinically relevant non-major bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events.Results: Between January 2018 and June 2022, a total of 2,621 patients were screened for eligibility and 1,330 patients were randomized (mean age 83 years, median GFI 4). After randomization 6 patients in the switch to NOAC arm and 1 patient in the continue with VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to a NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The HR for our primary outcome was 1.69 (95% CI 1.23-2.32). The HR for thromboembolic events was 1.26 (95% CI 0.60 to 2.61).Conclusions: Switching INR-guided VKA treatment to a NOAC in frail older patients with AF was associated with more bleeding complications compared to continuing VKA treatment, without an associated reduction in thromboembolic complications. Show less
BackgroundThe recently published 4-level Pulmonary Embolism Clinical Probability Score (4PEPS) integrates different aspects from currently available diagnostic strategies to further reduce imaging... Show moreBackgroundThe recently published 4-level Pulmonary Embolism Clinical Probability Score (4PEPS) integrates different aspects from currently available diagnostic strategies to further reduce imaging testing in patients with clinically suspected pulmonary embolism (PE).AimTo externally validate the performance of 4PEPS in an independent cohort.MethodsIn this post-hoc analysis of the prospective diagnostic management YEARS study, the primary outcome measures were discrimination, calibration, efficiency (proportion of imaging tests potentially avoided), and failure rate (venous thromboembolism (VTE) diagnosis at baseline or follow-up in patients with a negative 4PEPS algorithm). Multiple imputation was used for missing 4PEPS items. Based on 4PEPS, PE was considered ruled out in patients with a very low clinical pre-test probability (CPTP) without D-dimer testing, in patients with a low CPTP and D-dimer <1000 μg/L, and in patients with a moderate CPP and D-dimer below the age-adjusted threshold.ResultsOf the 3465 patients, 474 (14 %) were diagnosed with VTE at baseline or during 3-month follow-up. Discriminatory performance of the 4PEPS items was good (area under ROC-curve, 0.82; 95%CI, 0.80–0.84) as was calibration. Based on 4PEPS, PE could be considered ruled out without imaging in 58 % (95%CI 57–60) of patients (efficiency), for an overall failure rate of 1.3 % (95%CI 0.86–1.9).ConclusionIn this retrospective external validation, 4PEPS appeared to safely rule out PE with a high efficiency. Nevertheless, although not exceeding the failure rate margin by ISTH standards, the observed failure rate in our analysis appeared to be higher than in the original 4PEPS derivation and validation study. This highlights the importance of a prospective outcome study. Show less
Hendriks, S.V.; Hout, W.B. van den; Bemmel, T. van; Bistervels, I.M.; Eijsvogel, M.; Faber, L.M.; ... ; YEARS Investigators 2023
Background Venous thromboembolism constitutes substantial health care costs amounting to approximately 60 million euros per year in the Netherlands. Compared with initial hospitalization, home... Show moreBackground Venous thromboembolism constitutes substantial health care costs amounting to approximately 60 million euros per year in the Netherlands. Compared with initial hospitalization, home treatment of pulmonary embolism (PE) is associated with a cost reduction. An accurate estimation of cost savings per patient treated at home is currently lacking.Aim The aim of this study was to compare health care utilization and costs during the first 3 months after a PE diagnosis in patients who are treated at home versus those who are initially hospitalized.Methods Patient-level data of the YEARS cohort study, including 383 normotensive patients diagnosed with PE, were used to estimate the proportion of patients treated at home, mean hospitalization duration in those who were hospitalized, and rates of PE-related readmissions and complications. To correct for baseline differences within the two groups, regression analyses was performed. The primary outcome was the average total health care costs during a 3-month follow-up period for patients initially treated at home or in hospital.Results Mean hospitalization duration for the initial treatment was 0.69 days for those treated initially at home (n = 181) and 4.3 days for those initially treated in hospital (n = 202). Total average costs per hospitalized patient were €3,209 and €1,512 per patient treated at home. The adjusted mean difference was €1,483 (95% confidence interval: €1,181–1,784).Conclusion Home treatment of hemodynamically stable patients with acute PE was associated with an estimated net cost reduction of €1,483 per patient. This difference underlines the advantage of triage-based home treatment of these patients. Show less
Bavalia, R.; Stals, M.A.M.; Mulder, F.I.; Bistervels, I.M.; Coppens, M.; Faber, L.M.; ... ; Holleman, F. 2022
BackgroundThe Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are validated scores for mortality prediction in patients with pulmonary embolism (PE). National Early Warning... Show moreBackgroundThe Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are validated scores for mortality prediction in patients with pulmonary embolism (PE). National Early Warning Score (NEWS) is a general prognostic risk score for multiple clinical settings. We investigated whether the NEWS had a comparable performance with the PESI and sPESI, for predicting intensive care unit (ICU) admission and death in patients with acute PE. MethodsIn haemodynamically stable patients with confirmed PE from the YEARS Study (2013-2015), we evaluated the performance of the NEWS, PESI and sPESI for predicting 7-day ICU admission and 30-day mortality. Receiver operating characteristic curves were plotted and the area under the curve (AUC) was calculated. ResultsOf 352 patients, 12 (3.4%) were admitted to the ICU and 5 (1.4%) died. The AUC of the NEWS for ICU admission was 0.80 (95% CI 0.66 to 0.94) and 0.92 (95% CI 0.82 to 1.00) for 30-day mortality. At a threshold of 3 points, NEWS yielded a sensitivity and specificity of 92% and 53% for ICU admission and 100% and 52% for 30-day mortality. The AUC of the PESI was 0.64 (95% CI 0.48 to 0.79) for ICU admission and 0.94 (95% CI 0.87 to 1.00) for mortality. At a threshold of 66 points, PESI yielded a sensitivity of 75% and a specificity of 38% for ICU admission. For mortality, these were 100% and 37%, respectively. The performance of the sPESI was similar to that of PESI. ConclusionIn comparison with PESI and sPESI, NEWS adequately predicted 7-day ICU admission as well as 30-day mortality, supporting its potential relevance for clinical practice. Show less
Bavalia, R.; Stals, M.A.M.; Mulder, F.I.; Bistervels, I.M.; Coppens, M.; Faber, L.M.; ... ; Holleman, F. 2022
BackgroundThe Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are validated scores for mortality prediction in patients with pulmonary embolism (PE). National Early Warning... Show moreBackgroundThe Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are validated scores for mortality prediction in patients with pulmonary embolism (PE). National Early Warning Score (NEWS) is a general prognostic risk score for multiple clinical settings. We investigated whether the NEWS had a comparable performance with the PESI and sPESI, for predicting intensive care unit (ICU) admission and death in patients with acute PE. MethodsIn haemodynamically stable patients with confirmed PE from the YEARS Study (2013-2015), we evaluated the performance of the NEWS, PESI and sPESI for predicting 7-day ICU admission and 30-day mortality. Receiver operating characteristic curves were plotted and the area under the curve (AUC) was calculated. ResultsOf 352 patients, 12 (3.4%) were admitted to the ICU and 5 (1.4%) died. The AUC of the NEWS for ICU admission was 0.80 (95% CI 0.66 to 0.94) and 0.92 (95% CI 0.82 to 1.00) for 30-day mortality. At a threshold of 3 points, NEWS yielded a sensitivity and specificity of 92% and 53% for ICU admission and 100% and 52% for 30-day mortality. The AUC of the PESI was 0.64 (95% CI 0.48 to 0.79) for ICU admission and 0.94 (95% CI 0.87 to 1.00) for mortality. At a threshold of 66 points, PESI yielded a sensitivity of 75% and a specificity of 38% for ICU admission. For mortality, these were 100% and 37%, respectively. The performance of the sPESI was similar to that of PESI. ConclusionIn comparison with PESI and sPESI, NEWS adequately predicted 7-day ICU admission as well as 30-day mortality, supporting its potential relevance for clinical practice. Show less
Aims The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment... Show moreAims The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment.Methods and results Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient's opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm.Conclusions For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.[GRAPHICS]. Show less
Hendriks, S.V.; Hout, W.B. van den; Bemmel, T. van; Bistervels, I.M.; Eijsvogel, M.; Faber, L.M.; ... ; YEARS Investigators 2021
Background Venous thromboembolism constitutes substantial health care costs amounting to approximately 60 million euros per year in the Netherlands. Compared with initial hospitalization, home... Show moreBackground Venous thromboembolism constitutes substantial health care costs amounting to approximately 60 million euros per year in the Netherlands. Compared with initial hospitalization, home treatment of pulmonary embolism (PE) is associated with a cost reduction. An accurate estimation of cost savings per patient treated at home is currently lacking.Aim The aim of this study was to compare health care utilization and costs during the first 3 months after a PE diagnosis in patients who are treated at home versus those who are initially hospitalized.Methods Patient-level data of the YEARS cohort study, including 383 normotensive patients diagnosed with PE, were used to estimate the proportion of patients treated at home, mean hospitalization duration in those who were hospitalized, and rates of PE-related readmissions and complications. To correct for baseline differences within the two groups, regression analyses was performed. The primary outcome was the average total health care costs during a 3-month follow-up period for patients initially treated at home or in hospital.Results Mean hospitalization duration for the initial treatment was 0.69 days for those treated initially at home ( n =181) and 4.3 days for those initially treated in hospital ( n =202). Total average costs per hospitalized patient were Euro3,209 and Euro1,512 per patient treated at home. The adjusted mean difference was Euro1,483 (95% confidence interval: Euro1,181-1,784).Conclusion Home treatment of hemodynamically stable patients with acute PE was associated with an estimated net cost reduction of Euro1,483 per patient. This difference underlines the advantage of triage-based home treatment of these patients. Show less
Leeksma, A.C.; Derks, I.A.M.; Kasem, M.H.; Kilic, E.; Klein, A. de; Jager, M.J.; ... ; Eldering, E. 2021
Recurrent mutations in splicing factor 3B subunit 1 (SF3B1) have been identified in several malignancies and are associated with an increased expression of 3' cryptic transcripts as a result of... Show moreRecurrent mutations in splicing factor 3B subunit 1 (SF3B1) have been identified in several malignancies and are associated with an increased expression of 3' cryptic transcripts as a result of alternative branchpoint recognition. A large fraction of cryptic transcripts associated with SF3B1 mutations is expected to be sensitive for RNA degradation via nonsense-mediated mRNA decay (NMD). Several studies indicated alterations in various signaling pathways in SF3B1-mutated cells, including an impaired DNA damage response (DDR) in chronic lymphocytic leukemia (CLL). In this study, we investigated isogenic cell lines and treatment naive primary CLL samples without any TP53 and/or ATM defect, and found no significant effects of SF3B1 mutations on the ATM/p53 response, phosphorylation of H2AX and sensitivity to fludarabine. Cryptic transcripts associated with SF3B1 mutation status were observed at relatively low levels compared to the canonical transcripts and were validated as target for mRNA degradation via NMD. Expression of cryptic transcripts increased after NMD inhibition. In conclusion, our results confirm involvement of NMD in the biological effects of SF3B1 mutations. Further studies may elucidate whether SF3B1-mutant patients could benefit from NMD modulatory agents. Show less
Background: In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA).... Show moreBackground: In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA). Treatment with the direct oral thrombin inhibitor dabigatran appears to be associated with a reduced risk of HMB compared with VKA. These findings come from small observational studies or post hoc analyses of trials in which HMB was not a primary outcome. Use of tranexamic acid during the menstrual period may be effective in patients with HMB, but prospective data regarding efficacy and safety in patients on anticoagulant treatment are lacking.Rationale and Design: A direct comparison of a factor Xa inhibitor and a thrombin inhibitor with HMB as primary outcome, as well as an evaluation of the effects of adding tranexamic acid in women with anticoagulant-associated HMB is highly relevant for clinical practice. The MEDEA study is a randomized, open-label, pragmatic clinical trial to evaluate management strategies in premenopausal women with HMB associated with factor Xa inhibitor therapy.Outcomes: Women using factor Xa inhibitors with proven HMB, as assessed by a pictorial blood loss assessment chart (PBAC) score of >150, will be randomized to one of three study arms: (i) switch to dabigatran; (ii) continue factor Xa inhibitor with addition of tranexamic acid during the menstrual period; or (iii) continue factor Xa inhibitor without intervention. The primary outcome is the difference in PBAC score before and after randomization. Here, we present the rationale and highlight several unique features in the design of the study. Show less
Hendriks, S.V.; Bavalia, R.; Bemmel, T. van; Bistervels, I.M.; Eijsvogel, M.; Faber, L.M.; ... ; YEARS Investigators 2020
Background: Studies have shown the safety of home treatment of patients with pulmonary embolism (PE) at low risk of adverse events. Management studies focusing on home treatment have suggested that... Show moreBackground: Studies have shown the safety of home treatment of patients with pulmonary embolism (PE) at low risk of adverse events. Management studies focusing on home treatment have suggested that 30% to 55% of acute PE patients could be treated at home, based on the HESTIA criteria, but data from day-to-day clinical practice are largely unavailable.Aim: To determine current practice patterns of home treatment of acute PE in the Netherlands.Method: We performed a post-hoc analysis of the YEARS study. The main outcomes were the proportion of patients who were discharged < 24 h and reasons for admission if treated in hospital. Further, we compared the 3-month incidence of PE-related unscheduled readmissions between patients treated at home and in hospital.Results: Of the 404 outpatients with PE included in this post-hoc analysis of the YEARS study, 184 (46%) were treated at home. The median duration of admission of the hospitalized patients was 3.0 days. The rate of PE related readmissions of patients treated at home was 9.7% versus 8.6% for hospitalized patients (crude hazard ratio 1.1 (95% CI 0.57-2.1)). The 3-month incidence of any adverse event was 3.8% in those treated at home (2 recurrent VTE, 3 major bleedings and two deaths) compared to 10% in the hospitalized patients (3 recurrent VTE, 6 major bleedings and fourteen deaths).Conclusions: In the YEARS study, 46% of patients with PE were treated at home with low incidence of adverse events. PE-related readmission rates were not different between patients treated at home or in hospital. Show less
Background The Hestia criteria can be used to select pulmonary embolism (PE) patients for outpatient treatment. The subjective Hestia criterion "medical/social reason for admission" allows the... Show moreBackground The Hestia criteria can be used to select pulmonary embolism (PE) patients for outpatient treatment. The subjective Hestia criterion "medical/social reason for admission" allows the treating physician to consider any patient-specific circumstances in the final management decision. It is unknown how often and why this criterion is scored. Methods This is a patient-level post hoc analysis of the combined Hestia and Vesta studies. The main outcomes were the frequency of all scored Hestia items in hospitalized patients and the explicit reason for scoring the subjective criterion. Hemodynamic parameters and computed tomography-assessed right ventricular (RV)/left ventricular (LV) ratio of those only awarded with the subjective criterion were compared with patients treated at home. Results From the 1,166 patients screened, data were available for all 600 who were hospitalized. Most were hospitalized to receive oxygen therapy (45%); 227 (38%) were only awarded with the subjective criterion, of whom 51 because of "intermediate to intermediate-high risk PE." Compared with patients with intermediate risk PE (RV/LV ratio > 1.0) treated at home (179/566, 32%), hospitalized patients with only the subjective criterion had a higher mean RV/LV ratio (mean difference +0.30, 95% confidence interval [CI] 0.19-0.41) and a higher heart rate (+18/min, 95% CI 10-25). No relevant differences were observed for other hemodynamic parameters. Conclusion The most frequent reason for hospital admission was oxygen therapy. In the decision to award the subjective criterion as sole argument for admission, the severity of the RV overload and resulting hemodynamic response of the patient was taken into account rather than just abnormal RV/LV ratio. Show less
Background Pulmonary embolism is one of the leading causes of maternal death in the Western world. Because of the low specificity and sensitivity of the d-dimer test, all pregnant women with... Show moreBackground Pulmonary embolism is one of the leading causes of maternal death in the Western world. Because of the low specificity and sensitivity of the d-dimer test, all pregnant women with suspected pulmonary embolism undergo computed tomographic (CT) pulmonary angiography or ventilation-perfusion scanning, both of which involve radiation exposure to the mother and fetus. Whether a pregnancy-adapted algorithm could be used to safely avoid diagnostic imaging in pregnant women with suspected pulmonary embolism is unknown. Methods In a prospective study involving pregnant women with suspected pulmonary embolism, we assessed three criteria from the YEARS algorithm (clinical signs of deep-vein thrombosis, hemoptysis, and pulmonary embolism as the most likely diagnosis) and measured the d-dimer level. Pulmonary embolism was ruled out if none of the three criteria were met and the d-dimer level was less than 1000 ng per milliliter or if one or more of the three criteria were met and the d-dimer level was less than 500 ng per milliliter. Adaptation of the YEARS algorithm for pregnant women involved compression ultrasonography for women with symptoms of deep-vein thrombosis; if the results were positive (i.e., a clot was present), CT pulmonary angiography was not performed. All patients in whom pulmonary embolism had not been ruled out underwent CT pulmonary angiography. The primary outcome was the incidence of venous thromboembolism at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to safely rule out pulmonary embolism. Results A total of 510 women were screened, of whom 12 (2.4%) were excluded. Pulmonary embolism was diagnosed in 20 patients (4.0%) at baseline. During follow-up, popliteal deep-vein thrombosis was diagnosed in 1 patient (0.21%; 95% confidence interval [CI], 0.04 to 1.2); no patient had pulmonary embolism. CT pulmonary angiography was not indicated, and thus was avoided, in 195 patients (39%; 95% CI, 35 to 44). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester; CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester. Conclusions Pulmonary embolism was safely ruled out by the pregnancy-adapted YEARS diagnostic algorithm across all trimesters of pregnancy. CT pulmonary angiography was avoided in 32 to 65% of patients. Show less
Pol, L.M. van der; Tromeur, C.; Bistervels, I.; Bemmel, T. van; Couturaud, F.; Faber, L.M.; ... ; Huisman, M.V. 2018
The efficacy of autologous (αβ) T-cell–based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent... Show moreThe efficacy of autologous (αβ) T-cell–based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex–independent mechanism. We studied whether Vγ9Vδ2-T cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2-T cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2-T–cell function in CLL patients. Dysfunction of Vγ9Vδ2-T cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2-T cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2-T cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2-T cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2-T cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-T-cell–based therapy with ibrutinib. Show less
Pol, L.M. van der; Hulle, T. van der; Cheung, Y.W.; Mairuhu, A.T.A.; Schaar, C.G.; Faber, L.M.; ... ; Klok, F.A. 2017
