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Blood Feb 2024The direct oral anticoagulants (DOACs) rivaroxaban and dabigatran are newly licensed for the treatment and prevention of venous thromboembolism (VTE) in children and...
The direct oral anticoagulants (DOACs) rivaroxaban and dabigatran are newly licensed for the treatment and prevention of venous thromboembolism (VTE) in children and mark a renaissance in pediatric anticoagulation management. They provide a convenient option over standard-of-care anticoagulants (heparins, fondaparinux, and vitamin K antagonists) because of their oral route of administration, child-friendly formulations, and significant reduction in monitoring. However, limitations related to therapeutic monitoring when needed and the lack of approved reversal agents for DOACs in children raise some safety concerns. There is accumulating experience of safety and efficacy of DOACs in adults for a broad scope of indications; however, the cumulative experience of using DOACs in pediatrics, specifically for those with coexisting chronic illnesses, is sparse. Consequently, clinicians must often rely on their experience for treating VTE and extrapolate from data in adults while using DOACs in children. In this article, the authors share their experience of managing 4 scenarios that hematologists are likely to encounter in their day-to-day practice. Topics addressed include (1) appropriateness of indication; (2) use for special populations of children; (3) considerations for laboratory monitoring; (4) transition between anticoagulants; (5) major drug interactions; (6) perioperative management; and (7) anticoagulation reversal.
Topics: Humans; Child; Venous Thromboembolism; Anticoagulants; Dabigatran; Rivaroxaban; Blood Coagulation; Administration, Oral
PubMed: 37390311
DOI: 10.1182/blood.2022018966 -
Lancet (London, England) Jan 2022Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown. (Randomized Controlled Trial)
Randomized Controlled Trial
Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial.
BACKGROUND
Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown.
METHODS
In this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2-3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684.
FINDINGS
From Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2-3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12-0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group.
INTERPRETATION
In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis.
FUNDING
Bayer.
Topics: Adult; Aftercare; Aged; Blood Coagulation; COVID-19; Factor Xa Inhibitors; Female; Heparin; Hospitalization; Humans; Male; Middle Aged; Patient Discharge; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; COVID-19 Drug Treatment
PubMed: 34921756
DOI: 10.1016/S0140-6736(21)02392-8 -
Lancet (London, England) Jun 2021COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised... (Randomized Controlled Trial)
Randomized Controlled Trial
Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.
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.
Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Brazil; COVID-19; Endpoint Determination; Enoxaparin; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Heparin; Hospitalization; Humans; Male; Middle Aged; Patient Discharge; Rivaroxaban; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34097856
DOI: 10.1016/S0140-6736(21)01203-4 -
The Lancet. Respiratory Medicine Dec 2022COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19.
METHODS
The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1·2 mg followed by 0·6 mg 2 h later and then 0·6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2·5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www.
CLINICALTRIALS
gov, NCT04324463 and is ongoing.
FINDINGS
Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28·2%) of 1304 patients allocated to colchicine and 356 (27·2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1·04, 95% CI 0·90-1·21, p=0·58); and 281 (26·4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28·4%) of 1056 allocated to control had a primary outcome (HR 0·92, 95% CI 0·78-1·09, p=0·32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6·7%] of 1304 vs 90 [6·9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8·0%] vs 91 [8·6%]). Among patients assigned to colchicine, 8 (0·61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1·6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0·66%) of those allocated to control (p=0·042); the number of serious bleeding events was two (0·19%) versus six (0·57%), respectively (p=0·18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug.
INTERPRETATION
Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death.
FUNDING
Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation.
TRANSLATIONS
For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.
Topics: Humans; Adolescent; Adult; Rivaroxaban; Aspirin; Colchicine; Canada; Disease Progression; Oxygen; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 36228641
DOI: 10.1016/S2213-2600(22)00298-3 -
Blood Aug 2022
Topics: Colorectal Neoplasms; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Laparoscopy; Rivaroxaban; Venous Thromboembolism
PubMed: 36006673
DOI: 10.1182/blood.2022016866 -
British Journal of Haematology Feb 2016Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban,... (Review)
Review
Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot® and ecarin-based assays can be used to quantify dabigatran level and calibrated chromogenic anti-FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available.
Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Chromatography, High Pressure Liquid; Dabigatran; Drug Monitoring; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles
PubMed: 26492202
DOI: 10.1111/bjh.13810 -
Hamostaseologie Apr 2022Thrombotic events are an increasing challenge in pediatrics. Standard-of-care anticoagulants for pediatric thrombosis have several disadvantages which could be overcome... (Review)
Review
Thrombotic events are an increasing challenge in pediatrics. Standard-of-care anticoagulants for pediatric thrombosis have several disadvantages which could be overcome by using direct oral anticoagulants (DOACs). Until recently, there was not enough evidence from clinical trials to recommend for or against the use of any of the four DOACs in children with thrombosis. In this literature review, we looked at the latest clinical trials in this field. On clinicaltrials.gov, we found 13 current studies with published results. For two of the four DOACs, namely dabigatran and rivaroxaban, we found successful phase III studies which led to the approval for the use in children. The results of these pivotal phase III studies allow to finally recommend rivaroxaban and dabigatran for the prophylaxis and treatment of thrombotic events in children.
Topics: Administration, Oral; Adolescent; Anticoagulants; Child; Dabigatran; Humans; Infant, Newborn; Rivaroxaban; Thrombosis
PubMed: 35488165
DOI: 10.1055/a-1740-7080 -
Journal of Veterinary Internal Medicine Nov 2022The potential effects of glucocorticoid administration on rivaroxaban's anticoagulant bioactivity in dogs, and an appropriate rivaroxaban dosage regimen for dogs...
BACKGROUND
The potential effects of glucocorticoid administration on rivaroxaban's anticoagulant bioactivity in dogs, and an appropriate rivaroxaban dosage regimen for dogs receiving glucocorticoid therapy are unknown.
HYPOTHESIS/OBJECTIVES
The objective was to determine whether glucocorticoid administration influences the anticoagulant effects of rivaroxaban in healthy dogs. We hypothesized that administration of rivaroxaban and prednisone would reduce the anticoagulant intensity compared with rivaroxaban alone.
ANIMALS
Nine healthy dogs.
METHODS
Randomized, cross-over study. Dogs were administered prednisone (2 mg/kg, PO, q24h), rivaroxaban (1.5 mg/kg, PO, q24h), or prednisone and rivaroxaban, and the coagulation status was evaluated using prothrombin time (PT), and rivaroxaban-calibrated anti-Xa activity (RIVA, results were log transformed for analysis), before drug administration and on days 2, 4, and 8. Linear mixed models and correlation were used to evaluate associations in variables (P < .05 was considered significant).
RESULTS
There were no differences in RIVA results for the rivaroxaban and prednisone/rivaroxaban groups on day 8 (P = .599, median 87 [range 45-156] to 167 [56-333], respectively, median difference 90 ng/mL [95% CI:87.3-161.8]) There was a strong correlation between RIVA and PT results when days 2, 4, and 8 were combined (r = .846, P < .001), and increased during drug administration, day 2 (r = .810, P < .001), day 4 (r = .863, P < .001), and day 8 (r = .885, P < .001).
CONCLUSIONS AND CLINICAL IMPORTANCE
Clotting times in the PT correlate with rivaroxaban levels and may prove useful for drug monitoring. Prednisone administration had no apparent influence on the anticoagulant effects of rivaroxaban in healthy dogs, suggesting that combined therapy will not require dosage adjustments.
Topics: Dogs; Animals; Prednisone; Rivaroxaban; Glucocorticoids; Cross-Over Studies; Anticoagulants
PubMed: 36399000
DOI: 10.1111/jvim.16572 -
Journal of Clinical Pharmacology Aug 2021Rivaroxaban is a factor Xa inhibitor oral anticoagulant first approved for use in the United States in 2011. Under the drug class commonly termed direct oral... (Review)
Review
Rivaroxaban is a factor Xa inhibitor oral anticoagulant first approved for use in the United States in 2011. Under the drug class commonly termed direct oral anticoagulants, rivaroxaban is approved for the most indications within its class, 7 indications, which are: (1) reduction of risk of stroke and systemic embolism (SE) in nonvalvular atrial fibrillation, (2) treatment of deep vein thrombosis (DVT), (3) treatment of pulmonary embolism (PE), (4) reduction in the risk of recurrence of DVT and/or PE, (5) prophylaxis of DVT following hip or knee replacement surgery, (6) prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, and (7) reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Considering the relationship between cardiovascular disease, renal impairment, and the use of oral anticoagulants, the following targeted review was created. This review reports the results of the primary pharmacology, pharmacokinetic modeling, clinical safety and efficacy, and real-world postmarketing effectiveness and safety of rivaroxaban in patients with various degrees of renal impairment. Based on these data, rivaroxaban is a viable option for when anticoagulation is needed in patients who have both cardiovascular disease and renal impairment. However, as with any therapy, the benefits and risks of intervention should be carefully assessed and balanced. Patients treated with rivaroxaban for several of its approved indications should have their kidney function assessed prior to and during continued therapy to ensure consistency with the drug label.
Topics: Anticoagulants; Area Under Curve; Humans; Myocardial Infarction; Patient Acuity; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Renal Insufficiency; Rivaroxaban; Stroke; Thrombosis
PubMed: 33599985
DOI: 10.1002/jcph.1838 -
Blood Reviews Jan 2017Direct oral anticoagulants (DOACs) offer noninferior efficacy and improved safety compared to vitamin K antagonists (VKAs) for the prevention and treatment of venous... (Review)
Review
Direct oral anticoagulants (DOACs) offer noninferior efficacy and improved safety compared to vitamin K antagonists (VKAs) for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Unlike VKAs, DOACs do not require routine laboratory monitoring of anticoagulant effect and dose adjustment. In certain situations, however, laboratory assessment of anticoagulant effect may be desirable. Here we review the utility of currently available assays for assessment of DOAC effect and recommend an optimal assessment strategy for each drug, including calibrated dilute thrombin time or ecarin-based assays for dabigatran and calibrated anti-Xa activity assays for the factor Xa inhibitors. We also discuss reversal strategies, both specific and nonspecific, for each drug, including the preferential use of idarucizumab for the reversal of dabigatran and two agents, andexanet and ciraparantag, currently under development for the reversal of rivaroxaban, apixaban, and edoxaban.
Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Dabigatran; Factor Xa Inhibitors; Humans; International Normalized Ratio; Rivaroxaban
PubMed: 27625113
DOI: 10.1016/j.blre.2016.08.006