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1.
Am Heart J ; 242: 115-122, 2021 12.
Article in English | MEDLINE | ID: covidwho-1392113

ABSTRACT

BACKGROUND: The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended thromboprophylaxis. DESIGN: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg once daily for 35 ± 4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization. The composite efficacy endpoint is a combination of symptomatic VTE, VTE-related death, VTE detected by bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35 ± 4 posthospital discharge and symptomatic arterial thromboembolism (myocardial infarction, nonhemorrhagic stroke, major adverse limb events, and cardiovascular death) up to day 35 ± 4 posthospital discharge. The key safety outcome is the incidence of major bleeding according to ISTH criteria. SUMMARY: The MICHELLE trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.1.


Subject(s)
COVID-19/complications , Factor Xa Inhibitors/administration & dosage , Rivaroxaban/administration & dosage , Thrombosis/prevention & control , Adult , Brazil , Drug Administration Schedule , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Humans , Male , Prospective Studies , Pulmonary Embolism/etiology , Pulmonary Embolism/prevention & control , Rivaroxaban/adverse effects , Thromboembolism/etiology , Thromboembolism/prevention & control , Thrombosis/etiology , Venous Thrombosis/etiology , Venous Thrombosis/prevention & control
3.
Am Heart J ; 238: 1-11, 2021 08.
Article in English | MEDLINE | ID: covidwho-1309127

ABSTRACT

BACKGROUND: Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation. DESIGN: ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria. SUMMARY: The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Enoxaparin/therapeutic use , Rivaroxaban/therapeutic use , Thrombosis/prevention & control , Administration, Oral , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Brazil , COVID-19/blood , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/administration & dosage , Enoxaparin/adverse effects , Fibrin Fibrinogen Degradation Products/analysis , Hemorrhage/chemically induced , Hospitalization , Humans , Oxygen Inhalation Therapy , Rivaroxaban/administration & dosage , Rivaroxaban/adverse effects , Thrombosis/etiology , Time Factors
4.
Lancet ; 397(10291): 2253-2263, 2021 06 12.
Article in English | MEDLINE | ID: covidwho-1253771

ABSTRACT

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/blood , COVID-19/drug therapy , Enoxaparin/therapeutic use , Heparin/therapeutic use , Rivaroxaban/adverse effects , Rivaroxaban/therapeutic use , Adult , Aged , Blood Coagulation/drug effects , Brazil/epidemiology , Endpoint Determination , Female , Fibrin Fibrinogen Degradation Products , Hemorrhage/chemically induced , Hospitalization , Humans , Male , Middle Aged , Patient Discharge , SARS-CoV-2 , Treatment Outcome
5.
An Sist Sanit Navar ; 43(2): 251-254, 2020 Aug 31.
Article in Spanish | MEDLINE | ID: covidwho-1080494

ABSTRACT

Infection caused by SARS-CoV-2 (COVID-19) is associated with an increased risk of thromboembolic disease. So-me authors recommend anticoagulation at therapeutic doses for, at least, the most severely ill patients; this practice is not free of risks, which is why only thromboembolic prophylaxis is recommended by other consensuses. In the case of previously anticoagulated patients, changing the oral anticoagulant for a low molecular weight heparin (LMWH) is generally recommended. We present the cases of two patients admitted due to COVID-19, without serious clinical data, in whom anticoagulation (acenocoumarol and rivaroxaban, respectively) was replaced by LMWH at therapeutic doses, both presenting abdominal bleeding. This type of bleeding is an infrequent complication in anticoagulated patients, but the concurrence of two cases in a short period of time in the context of the COVID-19 pandemic leads us to consider that there is not yet any clear evidence on therapeutic anticoagulation in SARS-CoV-2 infection.


Subject(s)
Anticoagulants/adverse effects , Betacoronavirus , Coronavirus Infections/complications , Hematoma/chemically induced , Pneumonia, Viral/complications , Venous Thromboembolism/prevention & control , Venous Thromboembolism/virology , Abdomen , Acenocoumarol/adverse effects , Acenocoumarol/therapeutic use , Aged, 80 and over , Anticoagulants/therapeutic use , COVID-19 , Female , Hematoma/diagnosis , Heparin, Low-Molecular-Weight/adverse effects , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Pandemics , Rivaroxaban/adverse effects , Rivaroxaban/therapeutic use , SARS-CoV-2 , Venous Thromboembolism/drug therapy
6.
Am Heart J ; 235: 12-23, 2021 05.
Article in English | MEDLINE | ID: covidwho-1070993

ABSTRACT

BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.


Subject(s)
COVID-19/complications , Factor Xa Inhibitors/therapeutic use , Hospitalization , Outpatients , Rivaroxaban/therapeutic use , Thrombosis/prevention & control , Adult , COVID-19/mortality , Cause of Death , Double-Blind Method , Extremities/blood supply , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Hemorrhage/mortality , Hospital Mortality , Humans , Ischemia/etiology , Ischemic Stroke/etiology , Male , Middle Aged , Myocardial Infarction/etiology , Placebos/therapeutic use , Rivaroxaban/adverse effects , Thrombosis/mortality , Venous Thromboembolism/mortality , Venous Thromboembolism/prevention & control
7.
Neuroradiol J ; 34(2): 147-150, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-975845

ABSTRACT

We present a case of a fatal cerebral haemorrhage in an 82-year-old male patient with coronavirus disease 2019 (COVID-19), who was taking prophylactic oral anticoagulation because of atrial fibrillation (rivaroxaban 20 mg q.d. for two years). On admission, the patient was deeply comatose, mechanically ventilated, with tachycardia up to 150 bpm, high blood pressure >210/120 mmHg and a body temperature >39°C. A computed tomography scan of the head showed a large intracerebral haemorrhage located in the deep structures of the right hemisphere, with a mass effect and bleeding to the ventricles. Rivaroxaban was discontinued at admission. The patient tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but he did not have typical symptoms of pneumonia. In the following days, the patient's neurological condition did not improve, and a fever of up to 40°C and abnormal coagulation parameters remained resistant to pharmacotherapy. The patient developed multi-system organ failure and died on day 8. Here, we review the recent literature and discuss the possible association of SARS-CoV-2-mediated endothelial injury and cardiovascular disorders with cerebrovascular complications. We postulate that anti-inflammatory treatment in COVID-19 and the stabilisation of endothelium functions can be particularly important in patients with pre-existing cardiovascular conditions.


Subject(s)
Atrial Fibrillation/drug therapy , COVID-19/complications , Cerebral Hemorrhage/etiology , Factor Xa Inhibitors/adverse effects , Hypertension/complications , Rivaroxaban/adverse effects , Stroke/prevention & control , Aged, 80 and over , Atrial Fibrillation/complications , COVID-19/diagnosis , COVID-19/physiopathology , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/therapy , Fatal Outcome , Humans , Hypotension/etiology , Male , Multiple Organ Failure/etiology , Respiratory Insufficiency/etiology , SARS-CoV-2 , Stroke/etiology , Tachycardia/etiology
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