key: cord-0920093-hcwiwz5k authors: Delrue, Maxime; Stépanian, Alain; Voicu, Sebastian; Nassarmadji, Kladoum; Sène, Damien; Bonnin, Philippe; Kevorkian, Jean-Philippe; Sellier, Pierre-Olivier; Molina, Jean-Michel; Neuwirth, Marie; Vodovar, Dominique; Mouly, Stéphane; Mebazaa, Alexandre; Mégarbane, Bruno; Siguret, Virginie title: No venous thromboembolic (VTE) recurrence after one-year follow-up of hospitalized COVID-19 patients diagnosed with VTE event: a prospective study date: 2022-04-07 journal: Chest DOI: 10.1016/j.chest.2022.03.043 sha: cb29b6fdb24c585856fba6d687e9813e60bd0338 doc_id: 920093 cord_uid: hcwiwz5k nan Since the beginning of the pandemics, a high prevalence of venous thromboembolic events (VTE) has been observed in hospitalized patients with severe coronavirus disease-2019 . 1 Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection induces major endothelial cell dysfunction with systemic inflammatory response, both resulting in micro-and macrovascular thrombotic events including pulmonary thrombosis/embolism. 1, 2 While multiple studies evaluated the efficacy and safety of anticoagulant therapy in COVID-19 patients with diagnosed VTE during hospital stay, limited data are available regarding outcomes after hospital discharge. [3] [4] [5] [6] [7] Notwithstanding the particular pathogenesis of thrombosis in COVID-19 patients, whether SARS-CoV-2 infection is an effective transient VTE risk factor requiring 3-6 month anticoagulant therapy 8 is still debated. We aimed to investigate the outcome of COVID-19 patients with diagnosed VTE during hospital stay, while on anticoagulant therapy and after its discontinuation over one-year follow-up. We conducted a prospective observational cohort study in our university hospital intensive care unit (ICU) and medical wards. We included all consecutive COVID-19 patients with VTE diagnosed during hospitalization from 03-25-2020 to 04-30-2021, further referred after hospital discharge to our outpatient thrombosis unit for follow-up. SARS-CoV-2 infection was diagnosed using standard RT-PCR (Cobas-SARS-CoV-2 kits ® -Roche, France). COVID-19-related symptomatic VTE, namely pulmonary embolism (PE) and/or deep vein thrombosis (DVT), were diagnosed using computed tomography pulmonary angiography (CTPA) and/or duplex ultrasound examination of the lower limb veins by certified ultrasound operators, respectively. Laboratory thrombophilia screening was performed within 24h of DVT/PE diagnosis (Table1). VTE prophylaxis and management followed local guidelines in agreement with the international guidelines regarding ICU/non-ICU COVID-19 patients 8 . In DVT/PE patients, we recommended initial anticoagulant therapy with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) if contraindicated, switched on discharge to direct oral anticoagulant (DOAC; creatinine clearance≥30mL/min). For most patients, in the absence of evidence, a 3-6-month J o u r n a l P r e -p r o o f duration of anticoagulant treatment was proposed, as recommended elsewhere. 8 Outcome criteria included symptomatic VTE recurrence (primary outcome) and bleeding event onset (secondary outcome). Visits were planned at 1, 3, 6, and 12 months after VTE diagnosis, and beyond if needed. Periodic evaluation included physical examination to assess both outcomes and when required, duplex ultrasound examination, CTPA, and laboratory reassessment of abnormal thrombophilia parameters if needed away from the acute phase. Bleeding events were adjudicated according to the ISTH criteria. 9 This study was part of the French COVID-19 cohort registry, approved by our institutional ethics committee (IDRCB-2020-A00256-33; CPP-11-20-20.02.04.68737). All participating patients gave their written informed consent. Reporting of the study conforms to broad EQUATOR guidelines. Quantitative variables were expressed as medians [25 th -75 th percentiles] and categorical variables as percentages (MedCalc ® -version11.0.1.0, Belgium). Over the 13-month study period, of the 59 discharged patients who developed COVID-19 related VTE during hospital stay, 48 patients (age, 62 years [52-67], 38M/10F) were followed in our outpatient thrombosis unit and included in the study (11 patients declined the follow-up). Median follow-up duration was 12 months [12] [13] [14] , of which 6 months [5.5-6.6] after anticoagulant discontinuation. One patient was lost to follow-up after the first visit. Hospitalization baseline clinical and laboratory characteristics are reported in Table1. During hospitalization, 40 patients (83%) presented PE (of which 8 with associated DVT); 8 patients (17%) had isolated DVT. Antiphospholipid antibodies initially present in 26 patients (54%) persisted in only four patients (8%) after 12 weeks. Forty patients (83%) received LMWH, 2 (4%) UFH and 6 (13%) DOAC (3 apixaban and 3 rivaroxaban) for initial VTE management. After discharge, 45 patients (94%) received DOAC (35 apixaban, 10 rivaroxaban) and three (6%) received LMWH. Anticoagulants were discontinued after 3 months in one DVT patient (2%) and 6 months in 38 additional patients (79%). Anticoagulants were continued in eight patients (16%) in relation to antiphospholipid syndrome (n=3), past VTE history (n=2) and underlying cancer (n=3). Outcomes during follow-up are summarized in Figure1. No symptomatic VTE recurrence was observed neither during nor after anticoagulant therapy discontinuation. One 66-year-old patient with a 6-year history of ischemic cardiomyopathy developed non-ST-elevation myocardial infarction five months after apixaban initiation and underwent coronary stenting with apixaban switch to dual antiplatelet therapy. During the anticoagulant therapy period, five patients (11%) presented bleedings including three major hemorrhages affecting the gastrointestinal tract (2 in-hospital, 1 post-discharge) and two minor episodes (both post-discharge). One major bleeding patient further developed confirmed heparin-induced thrombocytopenia, requiring heparin switch to argatroban, then danaparoïd, and finally to apixaban without bleeding recurrence. In addition, once anticoagulation was stopped, one 66-year-old man with past polycythemia vera (6-month apixaban for PE, then switched to aspirin), died 9 months later from major duodenal hemorrhage (Figure1). To the best of our knowledge, this is one of the first prospective real-life studies evaluating outcomes over 12-months following COVID-19-related VTE diagnosis in hospitalized patients. We report the absence of VTE recurrence during the follow-up on anticoagulant therapy and after discontinuation. Only few studies reported shorter follow-up (from 10 to 159 days) in cohorts of 24 to 737 COVID-19-related VTE patients, [3] [4] [5] [6] [7] showing a very low rate of VTE recurrence (0.0 to 2.4%) during anticoagulant therapy, consistently with our data. Moreover, we provided new data confirming the low VTE recurrence risk up to 6 months after anticoagulant discontinuation. This low risk in COVID-19 patients is similar to what is observed in patients with VTE provoked by a transient non-surgical factor. 10 Our data support limited anticoagulant therapy duration of 3-6 months in COVID-19 patients, in agreement with current guidelines, 8 although selected individuals (e.g., with a past VTE history) may require long-term anticoagulation. The rate of major bleedings (6.3%) on anticoagulant therapy in our cohort was comparable to those reported in previous studies (2.6 to 11.0%) 3-7 but heterogeneity of patient recruitment and anticoagulant management across studies makes comparisons difficult. Despite limitations due to its single-center design and small sample size, our study presents significant strengths such as the inclusion of critically and non-critically ill COVID-19 patients. Moreover, by contrast to other studies, we report outcomes after a relatively long-term anticoagulant therapy discontinuation. To conclude, our study with prospective one-year follow-up supports the low VTE recurrence risk in either critically or non-critically ill COVID-19 patients with VTE while on anticoagulant therapy and 6month after its discontinuation. Our data remain to be confirmed in larger cohorts. (94) 35 (73) 10 (21) 3 (6) Length of hospital stay (days) 11 [7-18] Hemoglobin (g/dL) 12.7 [11.4-13.3] Platelet count (G/L) 323 Leukocytes (G/L) 8.2 [6. 8-10.3] Serum creatinine (µM) 72.0 [59.0-84.0] Fibrinogen (g/L) 5.89 [4.8-7.8] D-dimer (ng/mL) 3,410 [1, 450 ] Lupus anticoagulant, n (%)* † † 24 (50) Anti-cardiolipin and/or anti-beta-2-GPI antibodies, n (%)** 7 (15) Persistence of anti-phospholipid antibodies ≥12 weeks, n (%) 4 (8) Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review Updated hospital associated venous thromboembolism outcomes with 90-days follow-up after hospitalisation for severe COVID-19 in two UK critical care units Long-term follow-up of patients with venous thromboembolism and COVID-19: Analysis of risk factors for death and major bleeding Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review COVID-19 patients and the radiology department -advice from the European Society of Radiology (ESR) and the ABBREVIATION LIST: COVID-19 = Coronavirus disease CTPA = computed tomography pulmonary angiography DVT = deep vein thrombosis LMWH = low-molecular-weight heparin SARS-CoV-2 = severe acute respiratory syndrome coronavirus UFH = Unfractionated heparin The authors would like to thank Clara Noizat and Charlyne Brakta for helping with data gathering.