[Translation into French and republication of: "Anticoagulant treatment of cancer-associated thromboembolism"]. / Traduction et republication de : « Traitement anticoagulant de la maladie veineuse thromboembolique associée au cancer ¼.

Venous thromboembolism (VTE) is a frequent and potentially fatal complication in patients with cancer. During the initial period after the thromboembolic event, a patient receiving anticoagulant treatment is exposed both to a risk of VTE recurrence and also to an elevated bleeding risk conferred by the treatment. For this reason, the choice of anticoagulant is critical. The choice should take into account patient-related factors (such as functional status, age, body mass index, platelet count and renal function), VTE-related factors (such as severity or site), cancer-related factors (such as activity and progression) and treatment related factors (such as drug-drug interactions), which all potentially influence bleeding risk, and patient preference. These should be evaluated carefully for each patient during a multidisciplinary team meeting. For most patients, apixaban or a low molecular-weight heparin is the most appropriate initial choice for anticoagulant treatment. Such treatment should be offered to all patients with active cancer for at least 6months. The patient and treatment should be re-evaluated regularly, and anticoagulant treatment changed when necessary. Continued anticoagulant treatment beyond 6months is justified if the cancer remains active or if the patient experienced recurrence of VTE in the first 6months. In other cases, the interest of continued anticoagulant treatment may be considered on an individual patient basis in collaboration with oncologists.

Adult breast, lung, pancreatic, upper and lower gastrointestinal cancer patients with hospitalized venous thromboembolism in the national French hospital discharge database.

BACKGROUND: Venous thromboembolism (VTE) and cancer are strongly associated. In France, evidence on patients with pancreatic, upper GI [gastrointestinal], lower GI, lung, or breast cancer-associated VTE and their hospital management is limited. The aims of this study were to provide data on the number of hospitalized VTE events among cancer patients, the patients' characteristics, and their hospital management to estimate the burden of disease and the hospital burden of cancer-related VTE and to provide guidance on research. METHODS: This longitudinal, observational, and retrospective study was based on the comprehensive hospital discharge database (PMSI). Adult patients (≥ 18 years old) hospitalized with a cancer of interest in 2016 and hospitalized (within 2 years with VTE (captured a as a principal, related, or significant associated diagnosis) were included in the study. RESULTS: We identified 340,946 cancer patients, of which 7.2% (24,433 patients) were hospitalized with VTE. The proportions of hospitalized VTE were 14.6% (3,237) for patients with pancreatic cancer, 11.2% (8,339) for lung cancer, 9.9% (2,232) for upper GI cancer, 6.7% (7,011) for lower GI cancer, and 3.1% (3,614) for breast cancer. Around two thirds of cancer patients with a hospitalized VTE had active cancer (with metastases and/or receiving chemotherapy during the six months prior to the index date): from 62% of patients with pancreatic cancer to 72% with breast cancer. Around a third of patients were admitted to the hospital through the emergency room, up to 3% of patients stayed in an intensive care unit. The average length of stay ranged from 10 (breast cancer) to 15 days (upper GI cancer). Nine (lower GI cancer) to 18% (pancreatic cancer) of patients died during the VTE hospital stay. CONCLUSIONS: The burden of cancer-associated VTE is substantial, both in terms of the number of patients affected and in the hospital use. These findings offer guidance on future research on VTE prophylaxis in a very high-risk population, particularly in patients with active cancer.

Towards optimal use of antithrombotic therapy of people with cancer at the end of life: A research protocol for the development and implementation of the SERENITY shared decision support tool.

BACKGROUND: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs. METHODS: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe. RESULTS: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life. CONCLUSIONS: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers.

Incidence and impact of anticoagulation-associated abnormal menstrual bleeding in women after venous thromboembolism.

Preliminary data and clinical experience have suggested an increased risk of abnormal uterine bleeding (AUB) in women of reproductive age treated with anticoagulants, but solid data are lacking. The TEAM-VTE study was an international multicenter prospective cohort study in women aged 18 to 50 years diagnosed with acute venous thromboembolism (VTE). Menstrual blood loss was measured by pictorial blood loss assessment charts at baseline for the last menstrual cycle before VTE diagnosis and prospectively for each cycle during 3 to 6 months of follow-up. AUB was defined as an increased score on the pictorial blood loss assessment chart (>100 or >150) or self-reported AUB. AUB-related quality of life (QoL) was assessed at baseline and the end of follow-up using the Menstrual Bleeding Questionnaire. The study was terminated early because of slow recruitment attributable to the COVID-19 pandemic. Of the 98 women, 65 (66%) met at least one of the 3 definitions of AUB during follow-up (95% confidence interval [CI], 57%-75%). AUB occurred in 60% of women (36 of 60) without AUB before VTE diagnosis (new-onset AUB; 95% CI, 47%-71%). Overall, QoL decreased over time, with a mean Menstrual Bleeding Questionnaire score increase of 5.1 points (95% CI, 2.2-7.9), but this decrease in QoL was observed only among women with new-onset AUB. To conclude, 2 of every 3 women who start anticoagulation for acute VTE experience AUB, with a considerable negative impact on QoL. These findings should be a call to action to increase awareness and provide evidence-based strategies to prevent and treat AUB in this setting. This was an academic study registered at www.clinicaltrials.gov as #NCT04748393; no funding was received.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Direct oral anticoagulants in the treatment of acute venous thromboembolism in patients with obesity: A systematic review with meta-analysis.

BACKGROUND: Direct oral anticoagulants' (DOAC) pharmacokinetics are affected by obesity. Their efficacy and safety in obesity (BMI≥30 kg/m2) and morbid obesity (BMI≥40 kg/m2) are still unclear in the treatment of venous thromboembolism (VTE). OBJECTIVES: To compare the efficacy/safety of DOAC versus vitamin K antagonist (VKA)/low molecular weight heparin (LMWH) for the treatment of VTE in patients with obesity and morbid obesity. The primary efficacy/safety outcomes were VTE recurrence and major bleeding (MB). Clinically relevant non-MB and mortality were also evaluated. METHODS: A systematic literature search (MEDLINE, EMBASE, CENTRAL, Web of Science) identified studies evaluating DOAC in the treatment of VTE in patients with obesity and reporting one of the outcomes. Relative risks (RR) and 95 % confidence intervals (CI) were estimated using the Mantel-Haenszel method. RESULTS: We included 21 studies (50,360pts) of which 16,150 patients had a BMI≥30 kg/m2 and 6443 patients had a BMI≥40 kg/m2. VTE recurrence was similar with DOAC compared to VKA/LMWH in patients with obesity (RR 1.03;95 %CI 0.93-1.15;p = 0.55) and morbid obesity (RR 1.06;95 %CI 0.94-1.19;p = 0.35). DOAC were also associated with a reduction in MB (RR 0.57;95 %CI 0.34-0.94;p = 0.03 and RR 0.71;95 %CI 0.50-1.00;p = 0.05 in patients with obesity and morbid obesity, respectively). Subgroup analyses comparing randomized controlled trials to observational studies showed consistent results. No difference was observed in regards of clinically relevant non-MB and mortality. CONCLUSION: There is no signal for differences in VTE recurrence in patients with obesity and morbid obesity treated with DOAC compared to VKA/LMWH, while DOAC likely reduce the risk of MB compared to VKA/LMWH.

Follow-up of guidelines and impact on the management of suspected deep vein thrombosis in emergency departments.

AIMS: To evaluate the implementation of the European Society of Cardiology (ESC) guidelines concerning the diagnostic management of deep vein thrombosis (DVT) in emergency departments (ED); and to estimate the additional financial cost and the increase in the time spent in the ED if the guidelines are not followed. PATIENTS AND METHODS: Retrospective, bi-centric study including all patients directly admitted or referred to the ED for a suspected isolated DVT, between April 1, 2019, and July 30, 2019. The diagnostic management was compared to the 2017 ESC's guidelines. RESULTS: 107 patients were included, 13 had DVT (12%) and three had superficial venous thrombosis (3%). A total of 26 patients (24%) had a diagnostic management according to guidelines. In 72 patients (67%), no assessment of clinical probability score was found. Among the 35 patients in whom a clinical probability score was calculated, 5 patients had an unnecessary D-dimer assay and 2 patients had unjustified imaging. The median time spent in the ED was 185minutes when the recommendations were followed, and 250minutes when they were not (P=0.317). The total estimated additional cost was €232.20. CONCLUSION: The rate of adherence to the guidelines is low, mainly due to the absence of calculation of a clinical probability. This leads, in addition to the risk of diagnostic error, to an increase in the time spent in the EDs and inappropriate use of the technical platform, resulting in additional costs of care.

Implementation of a systematic comprehensive geriatric assessment for elderly patients suspected of pulmonary hypertension.

BACKGROUND: The phenotype of patients seen for a suspicion of pulmonary hypertension has changed, with an increasing age and frequency of comorbidities. Selection of elderly patients, in whom a classical work-up is mandatory, is challenging. Comprehensive geriatric assessment (CGA) has modified the management of elderly patients with cancer. Pulmonary hypertension (PH) shares with cancer a functional impact and may evolve rapidly, depending on the group of PH. We assessed the impact of a systematic CGA in patients over 70 years old referred for a suspicion of PH. METHODS: A standardised CGA was performed on every patient older than 70 years old, referred for a PH suspicion, before considering invasive tests for diagnosis and treatment, between July 2014 and May 2019. Our primary aim was to describe the impact of CGA on the decision to stop or pursue the recommended diagnostic work-up for PH. RESULTS: Among the thirty-one patients evaluated [mean age 81,5 (72-91) years], a negative CGA leads to stop the diagnostic work-up in eleven patients. Among the nineteen remaining patients, sixteen had confirmed PH, with half being chronic thromboembolic pulmonary hypertension. CONCLUSIONS: Our study indicates that comprehensive geriatric assessment could be an excellent first screen for elderly patients referred for a PH suspicion. Involving a geriatric physician stopped the investigations in one third of patients. In patients with a favourable CGA, PH was confirmed in most of the cases, with chronic thromboembolic pulmonary hypertension being the first cause of PH.

DLNO/DLCO ratio evolution under targeted therapy in patients with pulmonary hypertension.

The ratio of the diffusing capacity of the lung for carbon monoxide (DLCO) and for nitric oxide (DLNO) measured simultaneously is modified in patients with precapillary pulmonary hypertension (PH). The potential impact of targeted therapy on the DLCO/DLNO ratio is unknown. Simultaneous measurements of DLNO and DLCO were performed at baseline, 3-4 month follow-up (first evaluation) and 12-month follow-up (second evaluation) after initiation of targeted PH therapies in incident cases of precapillary PH. The main outcome was the change in DLNO/DLCO ratio under treatment between baseline and the first evaluation. Twenty-nine patients were included (mean age: 66.8 years, 62.1% female). No significant change in the DLNO/DLCO ratio was found between baseline and the first evaluation. Similarly, no significant differences were noted with regard to changes in Dm or Vc, the DLNO/DLCO ratio in different patient subgroups, or in the 20 patients evaluated at the second follow-up. Within the limitations of this study, the DLNO/DLCO ratio is not useful in monitoring the response to treatment in PH.

Measuring functional limitations after venous thromboembolism: Optimization of the Post-VTE Functional Status (PVFS) Scale.

INTRODUCTION: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE functional status (PVFS) scale is still needed. METHODS: Guided by the input of VTE experts and patients, we refined the PVFS scale and its accompanying manual, and attempted to acquire broad consensus on its use. RESULTS: A Delphi analysis was performed involving 53 international VTE experts with diverse scientific and clinical backgrounds. In this process, the number of scale grades of the originally proposed PVFS scale was reduced and descriptions of the grades were improved. After these changes, a consensus was reached on the number/definitions of the grades, and method/timing of the scale assessment. The relevance and potential impact of the scale was confirmed in three focus groups totaling 18 VTE patients, who suggested additional changes to the manual, but not to the scale itself. Using the improved manual, the κ-statistics between PVFS scale self-reporting and its assessment via the structured interview was 0.75 (95%CI 0.58-1.0), and 1.0 (95%CI 0.83-1.0) between independent raters of the recorded interview of 16 focus groups members. CONCLUSION: We improved the PVFS scale and demonstrated broad consensus on its relevance, optimal grades, and methods of assessing among international VTE experts and patients. The interobserver agreement of scale grade assignment was shown to be good-to-excellent. The PVFS scale may become an important outcome measure of functional impairment for quality of patient care and in future VTE trials.

DOAC compared to LMWH in the treatment of cancer related-venous thromboembolism: a systematic review and meta-analysis.

Low molecular weight heparins (LMWH) are the standard of care for the treatment of cancer-associated venous thromboembolism (CA-VTE). We performed a systematic review and meta-analysis to compare the effects of direct oral anticoagulants (DOAC) versus LMWH for the treatment of CA-VTE. The primary efficacy and safety outcomes were VTE recurrence and major bleeding (MB). The secondary outcomes were clinically relevant non-MB (CRNMB), all-cause mortality and the net clinical benefit. We searched MEDLINE, EMBASE, CENTRAL and Web of Science (inception-December 2019) and abstracts of relevant conferences (2000-2019) to identify randomized controlled trials comparing DOAC and LMWH for the treatment of CA-VTE. Relative risks (RR) and 95% confidence intervals were estimated (Mantel-Haenszel method, random-effects models). A non-inferiority analysis with a margin of 1.3 for the upper boundary of the RR was conducted for the primary outcomes. From 637 references, we included four publications which encompass three trials (1756 patients). Compared to LMWH, DOAC were associated with a trend for decreased VTE recurrence (RR 0.51; 95%CI 0.25-1.03; p = 0.06; I2 = 51%), whereas MB (RR 1.64; 95%CI 1.00-2.69; p = 0.05; I2 = 0%) and CRNMB (RR 1.83; 95%CI 1.04-3.20; p = 0.03; I2 = 50%) were significantly more frequent with DOAC. Conversely, all-cause mortality (RR 1.06; 95%CI 0.83-1.35; p = 0.64; I2 = 36%) and net clinical benefit (RR 0.74; 95%CI 0.38-1.42; p = 0.36; I2 = 65%) were comparable. DOAC were non-inferior to LMWH in preventing CA-VTE recurrence, but were associated with an increased risk of MB and CRNMB. Further studies are required to confirm these results and inform on the risk/benefit ratio for specific populations.

What's next after the clot? Residual pulmonary vascular obstruction after pulmonary embolism: From imaging finding to clinical consequences.

Surviving an embolism exposes patients to potential long-term complications, such as altered quality of life, persistent dyspnea, impaired exercise capacity or pulmonary hypertension. The common objective factor in most of these situations is the presence of residual pulmonary vascular obstruction (RPVO). Planar ventilation/perfusion scintigraphy (V/Q lung scan) is the gold standard for assessing RPVO, which occurs in 46 to 66% of patients at 3 months and persists in 25 to 29% of patients a year after acute PE. Assessed early (i.e. before discharge), RPVO could predict acute PE development with a high negative predictive value. Evaluated after anticoagulation therapy, RPVO could help to manage anticoagulation treatment and predict the risk of PE recurrence and patients identified at risk of developing chronic thromboembolic pulmonary hypertension. In this comprehensive review, we provide an overview of the current knowledge of RPVO after PE from imaging diagnosis to clinical consequences. In the first part, we mainly focus on the imaging modalities capable of detecting and quantifying RPVO. We then focus on the symptoms and syndromes linked with this residual obstruction after PE. Although the occurrence of RPVO and long-term complications varies greatly from one patient to another, we finally aim to identify the patients and diseases at risk of developing residual obstruction.

Chronic thromboembolic pulmonary hypertension suspicion after pulmonary embolism in cancer patients.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe condition which should be screened in patient with persistent dyspnea after pulmonary embolism (PE). After PE, CTEPH incidence was estimated between 0.1 and 9.1% in overall patients. Although cancer is associated with an increased risk of CTEPH, CTEPH incidence is still unknown in cancer patients with PE. We aimed to estimate the frequency CTEPH-likely patients after PE, in cancer patients. MATERIALS: We individualized cancer patients of a monocentric prospective registry including consecutive patients with symptomatic PE. The primary outcome was the frequency of "CTEPH-likely" patients defined by the European Respiratory Society (ERS) guidelines (an accelerated tricuspid regurgitation more than 2.8m/s and at least 1-2 segmental or larger-sized defects, after more than 3 months of therapeutic anticoagulation). RESULTS: We included 129 cancer patients with PE. Colorectal cancer (19%), breast cancer (17%) and prostate cancer (15%) were the most frequent cancers. PE occurred after surgery or medical immobilization in 17% of patients, while 26% of patients had history of venous thromboembolism. During the follow-up, 2 patients (1.5%) had a clinical suspicion of CTEPH and only 1 patient with ovarian cancer (0.75% 95%CI [0.0%-2.2%]) was classified as "CTEPH-likely", 6 months after PE. CONCLUSION: The frequency of screening for CTEPH seems negligible in PE patients with cancer. Concomitant cancer may affect the clinical suspicion of CTEPH.