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
Mulder, F.I.; Kraaijpoel, N.; Carrier, M.; Guman, N.A.; Jara-Palomares, L.; Nisio, M. di; ... ; Es, N. van 2023
BackgroundPlatelet RNA sequencing has been shown to accurately detect cancer in previous studies.ObjectivesTo compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited .Show moreBackgroundPlatelet RNA sequencing has been shown to accurately detect cancer in previous studies.ObjectivesTo compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited cancer screeningin patients with unprovoked venous thromboembolism (VTE).MethodsPatients aged ≥40 years with unprovoked VTE were recruited at 13 centers and followed for 12 months for cancer. Participants underwent standard-of-care limited cancer screening, and platelet RNA sequencing analysis was performed centrally at study end for cases and selected controls. Sensitivity and specificity were calculated, using the predefined primary positivity threshold of 0.54 for platelet RNA sequencing aiming at 86% test sensitivity, and an additional predefined threshold of 0.89 aiming at 99% test specificity.ResultsA total of 476 participants were enrolled, of whom 25 (5.3%) were diagnosed with cancer during 12-month follow-up. For each cancer patient, 3 cancer-free patients were randomly selected for the analysis. The sensitivity of limited screening was 72% (95% CI, 52-86) at a specificity of 91% (95% CI, 82-95). The area under the receiver operator characteristic for platelet RNA sequencing was 0.54 (95% CI, 0.41-0.66). At the primary positivity threshold, all patients had a positive test, for a sensitivity estimated at 100% (95% CI, 87-99) and a specificity of 8% (95% CI, 3.7-16.4). At the secondary threshold, sensitivity was 68% (95% CI, 48-83; p value compared with limited screening 0.71) at a specificity of 36% (95% CI, 26-47).ConclusionPlatelet RNA sequencing had poor diagnostic accuracy for detecting occult cancer in patients with unprovoked VTE with the current algorithm. 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
Es, J. van; Cheung, Y.W.; Es, N. van; Klok, F.A.; Dronkers, C.E.A.; Wolde, M. ten; ... ; Middeldorp, S. 2020
Background: Evidence for guideline recommendations for the treatment of venous thromboembolism (VTE) during anticoagulant therapy is scarce. We aimed to observe and to describe the management of... Show moreBackground: Evidence for guideline recommendations for the treatment of venous thromboembolism (VTE) during anticoagulant therapy is scarce. We aimed to observe and to describe the management of VTE occurring during anticoagulant therapy.Methods: This prospective multi-center, observational study included patients with objectively confirmed VTE during anticoagulant therapy (breakthrough event), with a follow-up of 3 months, after the breakthrough event.Results: We registered 121 patients with a breakthrough event, with a mean age of 56 years (range, 19 to 90); 61 were male (50%). Fifty-eight patients (48%) had an active malignancy. At the time of the breakthrough event, 57 patients (47%) were treated with a vitamin K antagonist (VKA), 53 patients (44%) with low-molecular-weight heparin (LMWH) and 11 patients (9%) with direct oral anticoagulants, unfractionated heparin, or VKA plus LMWH. A total of 21 patients (17%) were receiving a subtherapeutic dose of an anticoagulant. The main regimens to treat recurrence in patients on VKA were: switch to LMWH (33%), temporary double treatment with LMWH and VKA (23%), and VKA with a higher target INR (19%). In patients with a breakthrough on LMWH, the most frequently chosen regimen was a permanent dose increase (74%). During 3-month follow-up, 7% of patients had a second breakthrough event and 8% experienced major or clinically relevant non-major bleeding.Conclusion: There is wide variation in the management of VTE during anticoagulant treatment, reflecting a heterogeneous and complex clinical situation. Despite intensifying anticoagulation, the risk of a second breakthrough event in this population is 7%. Show less
Pol, L.M. van der; Tromeur, C.; Bistervels, I.M.; Ni Ainle, F.; Bemmel, T. van; Bertoletti, L.; ... ; Artemis Study Investigators 2019
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; Bistervels, I.M.; Mens, T.E. van; Hulle, T. van der; Beenen, L.F.M.; Exter, P.L. den; ... ; Klok, F.A. 2018
The rate of identified isolated subsegmental pulmonary embolism (ssPE) has doubled with advances in computed tomography pulmonary angiography (CTPA) technology, but its clinical relevance is... Show moreThe rate of identified isolated subsegmental pulmonary embolism (ssPE) has doubled with advances in computed tomography pulmonary angiography (CTPA) technology, but its clinical relevance is debated. The YEARS diagnostic algorithm was shown to safely reduce the number of required CTPAs in the diagnostic management of PE. We hypothesized that the higher threshold for performing CTPA in YEARS was associated with a lower prevalence of ssPE compared to the conventional diagnostic algorithm. We compared 2291 consecutive patients with suspected PE managed according to YEARS to 3306 consecutive control patients managed according to the Wells score for the prevalence of isolated ssPE. In the YEARS cohort, 52% were managed without CTPA, 12% had pulmonary embolism (PE) of which 10% were isolated ssPE, and the 3-month diagnostic failure rate was 0.35%. In the control cohort, 32% were managed without CTPA, 20% had PE of which 16% were isolated ssPE, and the 3-month failure rate was 0.73%. The isolated ssPE prevalence was significantly lower in YEARS (absolute difference 6.2% (95% confidence interval [CI] 1.4-10), Odds Ratio 0.58 (95% CI 0.37-0.90). In conclusion, YEARS is associated with a lower prevalence of isolated ssPE, due to reduction in CTPAs by the higher D-dimer threshold. This was however not associated with a higher risk of recurrent VTE during follow-up. 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
