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The Lancet. Haematology Jan 2020Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.
METHODS
In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed.
FINDINGS
From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths.
INTERPRETATION
In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants.
FUNDING
Bayer AG and Janssen Research & Development.
Topics: Adolescent; Anticoagulants; Child; Child, Preschool; Female; Humans; Infant; Male; Risk Factors; Rivaroxaban; Venous Thromboembolism
PubMed: 31699660
DOI: 10.1016/S2352-3026(19)30219-4 -
Blood Sep 2018Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.
Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Factor Xa Inhibitors; Female; Humans; Italy; Male; Middle Aged; Prospective Studies; Rivaroxaban; Thromboembolism; Treatment Outcome; Warfarin
PubMed: 30002145
DOI: 10.1182/blood-2018-04-848333 -
PloS One 2015Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.
BACKGROUND
Anticoagulation with low molecular weight heparin and vitamin K antagonists is the current standard of care (SOC) for venous thromboembolism (VTE) treatment and prevention. Although novel oral anti-coagulants (NOACs) have been compared with SOC in this indication, no head-to-head randomised controlled trials (RCTs) have directly compared NOACs. A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of NOACs for the initial and long-term treatment of VTE.
METHODS
Electronic databases (accessed July 2014) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus SOC. Eligible patients included adults with an objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as relative risks (RR) and 95% credible intervals (Crl).
RESULTS
Six Phase III RCTs met criteria for inclusion: apixaban (one RCT; n = 5,395); rivaroxaban (two RCTs; n = 3,423/4,832); dabigatran (two RCTs; n = 2,539/2,568); edoxaban (one RCT; n = 8,240). There were no statistically significant differences between the NOACs with regard to the risk of 'VTE and VTE-related death. Apixaban treatment was associated with the most favourable safety profile of the NOACs, showing a statistically significantly reduced risk of 'major or clinically relevant non-major (CRNM) bleed' compared with rivaroxaban (0.47 [0.36, 0.61]), dabigatran (0.69 [0.51, 0.94]), and edoxaban (0.54 [0.41, 0.69]). Dabigatran was also associated with a significantly lower risk of 'major or CRNM bleed' compared with rivaroxaban (0.68 [0.53, 0.87]) and edoxaban (0.77 [0.60, 0.99]).
CONCLUSIONS
Indirect comparisons showed statistically similar reductions in the risk of 'VTE or VTE-related death for all NOACs. In contrast, reductions in 'major or CRNM bleed' for initial/long-term treatment were significantly better with apixaban compared with all other NOACs, and with dabigatran compared with rivaroxaban and edoxaban. Results from the current analysis indicate that the NOACs offer clinical benefit over conventional therapy while highlighting relative differences in their bleeding profile.
Topics: Administration, Oral; Anticoagulants; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Venous Thromboembolism
PubMed: 26716830
DOI: 10.1371/journal.pone.0144856 -
Hamostaseologie Feb 2022Special aspects of anticoagulation in children include the different epidemiology of thrombosis, developmental changes in the coagulation system, age-dependent...
Special aspects of anticoagulation in children include the different epidemiology of thrombosis, developmental changes in the coagulation system, age-dependent pharmacokinetics of anticoagulants, risk of bleeding, and practical hurdles to anticoagulation. The classical anticoagulants so far used in children have several limitations, resulting in the need for regular monitoring. The pharmacological properties of direct oral anticoagulants (DOACs) and the special challenges of anticoagulation in children make the DOACs particularly attractive for children. All DOACs have pediatric development programs, targeting various indications for prevention and treatment of thrombosis. Child-appropriate formulations have been developed, age-specific dosing information generated, and safety and efficacy evaluated in ongoing phase 3 trials. Rivaroxaban and dabigatran have already been authorized for children for treatment of acute venous thrombosis and for extended secondary prevention. Their safety and efficacy have been demonstrated comparable to that of standard-of-care anticoagulants, without need for monitoring. Further studies are ongoing, which are expected to lead to pediatric authorizations of DOACs for primary venous thromboembolic event prevention in some high-risk settings. More real-life data will be necessary from postmarketing studies and registries to complement the evidence base for DOAC use in children, particularly in the youngest age groups and special disease populations.
Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Child; Dabigatran; Humans; Rivaroxaban; Venous Thromboembolism
PubMed: 35042258
DOI: 10.1055/a-1703-0821 -
Journal of Feline Medicine and Surgery Apr 2022Feline arterial thromboembolism (ATE), an often devastating outcome, was recently shown to affect 11.3% of cats with hypertrophic cardiomyopathy over 10 years. Current...
OBJECTIVES
Feline arterial thromboembolism (ATE), an often devastating outcome, was recently shown to affect 11.3% of cats with hypertrophic cardiomyopathy over 10 years. Current American College of Veterinary Internal Medicine guidelines recommend the use of clopidogrel in cats at risk for ATE, with addition of a factor Xa inhibitor in very high risk or post-ATE cases. To date, no studies have examined the safety or efficacy of this combined antithrombotic therapy. This retrospective case series aimed to assess the frequency and type of adverse events that occurred in cats prescribed dual clopidogrel and rivaroxaban therapy. Secondary aims were to evaluate indications for dual therapy and clinical outcome.
METHODS
The study included 32 cats prescribed clopidogrel (18.75 mg PO q24h) and rivaroxaban (2.5 mg PO q24h) on an outpatient basis over a 5-year period.
RESULTS
Cats were prescribed dual therapy for at least one of the following: ATE event (n = 18), presence of an intracardiac thrombi (n = 17) or presence of spontaneous echocardiographic contrast (SEC) (n = 16). Five cats experienced adverse effects that could be attributed to medications, a median of 13 days from initiation (epistaxis, hematemesis, hematochezia or hematuria). No cat required hospitalization as a result of these events. Median survival time from onset of therapy was 257 days (interquartile range [IQR] = 38-497) for all cats, 502 days (IQR = 171-663) for ATE cats, 725 days (IQR = 133-856) for cats with an ATE to two or more limbs and 301 days (IQR = 221-431) for cats with only one limb affected. Recurrence rate of ATE while on dual therapy was 16.7%; no cat newly developed an ATE while on dual therapy.
CONCLUSIONS AND RELEVANCE
Dual antithrombotic therapy with clopidogrel and rivaroxaban resulted in a low reported incidence of adverse events. Cats placed on dual therapy for an ATE event experienced a low rate of recurrence and effective thromboprophylaxis was achieved in cats with intracardiac thrombi or SEC.
Topics: Animals; Anticoagulants; Cat Diseases; Cats; Clopidogrel; Humans; Retrospective Studies; Rivaroxaban; Venous Thromboembolism
PubMed: 33966532
DOI: 10.1177/1098612X211013736 -
Blood Advances Dec 2020Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and... (Randomized Controlled Trial)
Randomized Controlled Trial
Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.
Topics: Anticoagulants; Child; Hemorrhage; Humans; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis
PubMed: 33351120
DOI: 10.1182/bloodadvances.2020003244 -
Journal of Thrombosis and Haemostasis :... Jul 2020Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous...
BACKGROUND
Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling.
METHODS
Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. Previously, these regimens were confirmed for children weighing ≥20 kg but only predicted in those <20 kg. Based on sparse blood sampling, the daily area under the plasma concentration-time curve [AUC ] and trough [C ] and maximum [C ] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients.
RESULTS
Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable.
DISCUSSION
Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.
Topics: Adolescent; Adult; Anticoagulants; Blood Coagulation; Child; Child, Preschool; Hemorrhage; Humans; Infant; Infant, Newborn; Rivaroxaban; Venous Thromboembolism
PubMed: 32246743
DOI: 10.1111/jth.14813 -
The New England Journal of Medicine Feb 2018Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) after total hip or total knee arthroplasty, but comparisons with direct oral anticoagulants are lacking for prophylaxis beyond hospital discharge.
METHODS
We performed a multicenter, double-blind, randomized, controlled trial involving patients who were undergoing total hip or knee arthroplasty. All the patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and then were randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism (the primary effectiveness outcome) and bleeding complications, including major or clinically relevant nonmajor bleeding (the primary safety outcome).
RESULTS
A total of 3424 patients (1804 undergoing total hip arthroplasty and 1620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1707 patients (0.64%) in the aspirin group and in 12 of 1717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], -0.55 to 0.66; P<0.001 for noninferiority and P=0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, -0.65 to 0.29; P=0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, -1.07 to 0.47; P=0.43).
CONCLUSIONS
Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT01720108 .).
Topics: Aged; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Aspirin; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Risk Factors; Rivaroxaban; Venous Thromboembolism
PubMed: 29466159
DOI: 10.1056/NEJMoa1712746 -
JAMA Network Open Feb 2023Parenteral enoxaparin is a preferred anticoagulant used in the acute phase for patients with acute coronary syndrome (ACS). The safety and efficacy of short-term... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Rivaroxaban vs Enoxaparin on Major Cardiac Adverse Events and Bleeding Risk in the Acute Phase of Acute Coronary Syndrome: The H-REPLACE Randomized Equivalence and Noninferiority Trial.
IMPORTANCE
Parenteral enoxaparin is a preferred anticoagulant used in the acute phase for patients with acute coronary syndrome (ACS). The safety and efficacy of short-term low-dose rivaroxaban in this clinical setting remain unknown.
OBJECTIVE
To compare the safety and efficacy of rivaroxaban vs enoxaparin in the acute phase of ACS.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, prospective, open-label, active-controlled, equivalence and noninferiority trial was conducted from January 2017 through May 2021 with a 6-month follow-up at 21 hospitals in China. Participants included patients with ACS missing the primary reperfusion window or before selective revascularization. Data were analyzed from November 2021 to November 2022.
INTERVENTIONS
Participants were randomized 1:1:1 to oral rivaroxaban 2.5 mg or 5 mg or 1 mg/kg subcutaneous enoxaparin twice daily in addition to dual antiplatelet therapy (DAPT; aspirin 100 mg and clopidogrel 75 mg once daily) for a mean of 3.7 days.
MAIN OUTCOMES AND MEASURES
The primary safety end point was bleeding events, as defined by the International Society on Thrombosis and Haemostasis, and the primary efficacy end point was major adverse cardiovascular events (MACEs), including cardiac death, myocardial infarction, rerevascularization, or stroke during the 6-month follow-up.
RESULTS
Of 2055 enrolled patients, 2046 (99.6%) completed the trial (mean [SD] age 65.8 [8.2] years, 1443 [70.5%] male) and were randomized to enoxaparin (680 patients), rivaroxaban 2.5 mg (683 patients), or rivaroxaban 5 mg (683 patients). Bleeding rates were 46 patients (6.8%) in the enoxaparin group, 32 patients (4.7%) in the rivaroxaban 2.5 mg group, and 36 patients (5.3%)in the rivaroxaban 5 mg group (rivaroxaban 2.5 mg vs enoxaparin: noninferiority hazard ratio [HR], 0.68; 95% CI, 0.43 to 1.07; P = .005; rivaroxaban 5 mg vs enoxaparin: noninferiority HR, 0.88; 95% CI, 0.70 to 1.09; P = .001). The incidence of MACEs was similar among groups, and noninferiority was reached in the rivaroxaban 5 mg group (HR, 0.60; 95% CI, 0.31 to 1.16, P = .02) but not in the rivaroxaban 2.5 mg group (HR, 0.68; 95% CI, 0.36 to 1.30; P = .05) compared with the enoxaparin group.
CONCLUSIONS AND RELEVANCE
In this equivalence and noninferiority trial, oral rivaroxaban 5 mg showed noninferiority to subcutaneous enoxaparin (1 mg/kg) for patients with ACS treated with DAPT during the acute phase. Results of this feasibility study provide useful information for designing future randomized clinical trials with sufficient sample sizes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03363035.
Topics: Humans; Male; Aged; Female; Rivaroxaban; Enoxaparin; Platelet Aggregation Inhibitors; Acute Coronary Syndrome; Aspirin; Prospective Studies; Hemorrhage
PubMed: 36763358
DOI: 10.1001/jamanetworkopen.2022.55709 -
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