Publications by authors named "Akos F Pap"

23 Publications

  • Page 1 of 1

Sex-specific differences in clot resolution 3 weeks after acute pulmonary embolism managed with anticoagulants-A substudy of the EINSTEIN-PE study.

J Thromb Haemost 2021 07 12;19(7):1759-1763. Epub 2021 May 12.

Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.

Background: It is unknown whether differences in clot structure and resolution contribute to the reported risk differences of recurrent venous thromboembolism (VTE) between men and women.

Patients/methods: We used data from the EINSTEIN-PE study, a randomized, multicenter, non-inferiority study in which patients 18 years and older with acute symptomatic pulmonary embolism (PE) were randomized to rivaroxaban or enoxaparin followed by a vitamin K antagonist. PE was diagnosed by computed tomography pulmonary angiography scan or high-probability ventilation/perfusion scintigraphy. Three weeks after randomization a follow-up scan was performed. An independent adjudication committee assessed the degree of vascular obstruction.

Results And Conclusions: A total of 371 participants including 174 (46.9%) women and 197 (53.0%) men were included in the present analysis. At 3 weeks, there was no difference between men and women in complete clot resolution: 39.6% and 40.2%, respectively. The absolute reduction in pulmonary vascular obstruction at week 3 was also similar: 12.9% (95% confidence interval [CI]: 11.6-14.2) in men and 12.1% (95% CI: 10.4-13.7) in women, corresponding to a resolution ratio of 0.29 (95% CI: 0.24-0.33) and 0.35 (95% CI: 0.28-0.42), respectively. No differences in clot resolution were observed between men and women diagnosed with acute PE at 3 weeks after start of anticoagulant therapy. These findings suggest that the reported higher rate of VTE recurrence in men cannot be explained by decreased clot resolution.
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http://dx.doi.org/10.1111/jth.15326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360045PMC
July 2021

Heavy menstrual bleeding in women on anticoagulant treatment for venous thromboembolism: Comparison of high- and low-dose rivaroxaban with aspirin.

Res Pract Thromb Haemost 2021 Feb 17;5(2):308-313. Epub 2021 Feb 17.

Department of Medicine McMaster University Hamilton ON Canada.

Background: Rivaroxaban may induce heavy menstrual bleeding. It is unknown if this effect is dose related or if rivaroxaban is associated with more menstrual bleeding than aspirin.

Objectives: To demonstrate and compare menstrual patterns and actions taken among women receiving aspirin and two doses of rivaroxaban.

Methods: The EINSTEIN-CHOICE trial compared once-daily rivaroxaban 20 mg, rivaroxaban 10 mg, and aspirin 100 mg for extended treatment of venous thromboembolism in patients who had completed 6 to 12 months of anticoagulant therapy. In 362 women with menstrual cycles, menstrual flow duration and intensity assessed at days 30, 90, 180, and 360 were compared with those before starting anticoagulant therapy.

Results: Menstrual flow duration increased in 12%-18% of the 134 women given 20-mg rivaroxaban, in 6% to 12% of 120 women given 10-mg rivaroxaban, and in 9% to 12% of 108 women given aspirin. Corresponding increases in flow intensity were 19% to 24%, 14% to 21%, and 13% to 20%. The odds ratios (ORs) for increased menstrual flow duration were 1.36 (95% confidence interval [CI], 0.62-2.96) for rivaroxaban 20 mg versus aspirin, 0.77 (95% CI, 0.33-1.81) for rivaroxaban 10 mg versus aspirin, and 0.57 (95% CI, 0.26-1.25) for rivaroxaban 10 mg versus 20 mg. The ORs for increased menstrual flow intensity were 1.41 (95% CI, 0.67-2.99), 1.07 (95% CI, 0.49-2.34), and 0.76 (95% CI, 0.37- 1.57), respectively.

Conclusions: There were no statistically significant differences in menstrual hemorrhage patterns between women treated with 10 or 20 mg of rivaroxaban and aspirin. Compared with 10-mg rivaroxaban or aspirin, 20-mg rivaroxaban showed numerically more often increased menstrual flow duration and intensity.
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http://dx.doi.org/10.1002/rth2.12474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938616PMC
February 2021

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Blood Adv 2020 12;4(24):6250-6258

Bayer AG, Wuppertal, Germany.

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.
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http://dx.doi.org/10.1182/bloodadvances.2020003244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756994PMC
December 2020

Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.

Circulation 2020 12 3;142(23):2219-2230. Epub 2020 Nov 3.

Department of Vascular Medicine, Klinikum Darmstadt GmbH, Germany (R.B.).

Background: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described.

Methods: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization.

Results: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity ( for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel ( for trend=0.06).

Conclusions: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050465DOI Listing
December 2020

Rivaroxaban in Peripheral Artery Disease after Revascularization.

N Engl J Med 2020 05 28;382(21):1994-2004. Epub 2020 Mar 28.

From Colorado Prevention Center (CPC) Clinical Research (M.P.B., M.R.N., W.H.C., L.D., N.J., C.N.H., W.R.H.), the Department of Medicine, Division of Cardiovascular Medicine (M.P.B., C.N.H., W.R.H.), the Department of Surgery, Division of Vascular Surgery (M.R.N.), and the Department of Medicine, Division of Endocrinology (W.H.C.), University of Colorado Anschutz Medical Campus, and the Department of Biostatistics and Informatics, Colorado School of Public Health (J.M.K.) - all in Aurora; the Department of Vascular Medicine, Klinikum Darmstadt, Darmstadt, and Center for Thrombosis and Hemostasis, University of Mainz, Mainz (R.M.B.), the Department of Vascular Medicine, Vascular Surgery-Angiology-Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg (E.S.D.), and Bayer, Wuppertal (A.F.P., E.M.) - all in Germany; the Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada (S.S.A.); Duke Clinical Research Institute, Division of Cardiology, Duke University, Durham, NC (M.R.P.); the Vascular and Interventional Radiology Department, Careggi University Hospital, University of Florence, Florence, Italy (F.F.); Ivano-Frankivsk National Medical University, Ivano-Frankivsk, Ukraine (I.G.); B-A-Z County University Teaching Hospital, Miskolc, Hungary (L.M.); University of Latvia, Pauls Stradins University Hospital, Riga (D.K.K.); ECLA (Estudios Clínicos Latino América), ICR (Instituto Cardiovascular de Rosario), Rosario, Argentina (R.D.); the Division of Angiology, Medical University Graz, Graz, Austria (M.B.); and Janssen Research and Development, Raritan (L.P.H.), and Thrombosis Group Head, Clinical Development, Bayer U.S., Whippany (S.D.B.) - both in New Jersey.

Background: Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain.

Methods: In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome.

Results: A total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P = 0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P = 0.007).

Conclusions: In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. (Funded by Bayer and Janssen Pharmaceuticals; VOYAGER PAD ClinicalTrials.gov number, NCT02504216.).
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http://dx.doi.org/10.1056/NEJMoa2000052DOI Listing
May 2020

Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

Lancet Haematol 2020 Jan 5;7(1):e18-e27. Epub 2019 Nov 5.

Bayer AG, Wuppertal, Germany.

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.
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http://dx.doi.org/10.1016/S2352-3026(19)30219-4DOI Listing
January 2020

Safety and efficacy of the partial adenosine A1 receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced ejection fraction: a phase IIb, randomized, double-blind, placebo-controlled trial.

Eur J Heart Fail 2019 11 16;21(11):1426-1433. Epub 2019 Sep 16.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.

Aims: Neladenoson bialanate is a partial adenosine A1 receptor agonist with demonstrated beneficial effects on cardiac function in animal models. We aimed to assess the dose-response effect of neladenoson bialanate on cardiac structure and function, clinical outcome, and safety in patients with heart failure (HF) with reduced ejection fraction (HFrEF).

Methods And Results: PANTHEON was a dose-finding, phase IIb, randomized, double-blind, placebo-controlled trial conducted in 92 centres in 11 countries including 462 patients with chronic HFrEF, randomized to once daily oral dose of neladenoson bialanate (5, 10, 20, 30, and 40 mg) or placebo. The primary endpoints were change from baseline to 20 weeks in left ventricular ejection fraction (LVEF) (echocardiography) and in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Mean age of the patients was 67 years, 17% were female, mean LVEF was 28%, mean NT-proBNP was 2085 ng/L. After 20 weeks of treatment, there was no dose-effect of neladenoson bialanate on changes in NT-proBNP or LVEF (primary endpoints). No effect of neladenoson bialanate was found on left ventricular volumes, high-sensitivity troponin T, or cardiovascular mortality, HF hospitalization, and urgent visits for HF (secondary endpoints). There was a dose-dependent increase in creatinine and cystatin C, and a dose-dependent decrease in estimated glomerular filtration rate and heart rate.

Conclusions: In patients with chronic HFrEF, treatment with neladenoson bialanate was not associated with dose-dependent favourable effects on cardiac structure and function, cardiac risk markers, or clinical outcome but was associated with a dose-dependent decrease in renal function.

Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02992288.
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http://dx.doi.org/10.1002/ejhf.1591DOI Listing
November 2019

Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.

Lancet Haematol 2019 Oct 13;6(10):e500-e509. Epub 2019 Aug 13.

Bayer AG, Wuppertal, Germany.

Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents.

Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843.

Findings: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events.

Interpretation: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism.

Funding: Bayer AG, Janssen Research and Development.
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http://dx.doi.org/10.1016/S2352-3026(19)30161-9DOI Listing
October 2019

Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study.

Thromb J 2018 21;16:34. Epub 2018 Dec 21.

Royal Children's Hospital, University of Melbourne, Murdoch Childrens Research Institute, Melbourne, Australia.

Background: Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily.

Methods: EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0-18 years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months.

Conclusions: EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.

Trial Registration: Clinicaltrials.gov NCT02234843, registered on 9 September 2014.
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http://dx.doi.org/10.1186/s12959-018-0188-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302520PMC
December 2018

Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin.

Thromb Res 2018 08 10;168:121-129. Epub 2018 Jul 10.

Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Background: Full- or lower-dose anticoagulant therapy or aspirin can be used for extended therapy in patients with venous thromboembolism (VTE), but information on their relative benefit-risk profiles is limited.

Methods: Data from the EINSTEIN-CHOICE trial were used to compare the benefit-risk profiles of extended treatment with rivaroxaban (20 or 10 mg once daily) and aspirin (100 mg once daily) in VTE patients who had completed 6 to 12 months of anticoagulation therapy. One-year cumulative incidences of recurrent VTE and major bleeding were estimated and benefits and risks were calculated by determining the between group differences in a hypothetical population of 10,000 VTE patients treated for 1 year.

Findings: A total of 1107 patients were treated with 20 mg of rivaroxaban, 1127 with 10 mg of rivaroxaban, and 1131 with aspirin. The cumulative incidences of recurrent VTE in the rivaroxaban 20-mg, rivaroxaban 10-mg and aspirin groups were 1.9%, 1.6%, and 5.0%, respectively, whereas the cumulative incidences of major bleeding were 0.7%, 0.4% and 0.5%, respectively. The incidences of the combined outcome of recurrent VTE and major bleeding were 2.8% and 3.4% lower in the rivaroxaban 20-mg and 10-mg groups than in the aspirin group. For 10,000 patients treated for 1 year, there would be 284 (95% confidence interval [CI] 106 to 462) and 339 (95% CI 165 to 512) fewer events with rivaroxaban 20 mg or 10 mg than with aspirin.

Interpretation: Compared with aspirin, extended anticoagulation with once daily rivaroxaban reduces recurrent VTE with a favourable benefit-risk profile.

Funding: Bayer AG.
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http://dx.doi.org/10.1016/j.thromres.2018.06.009DOI Listing
August 2018

Risk of recurrent venous thromboembolism according to baseline risk factor profiles.

Blood Adv 2018 04;2(7):788-796

Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON, Canada.

The optimal duration of anticoagulation for venous thromboembolism (VTE) is uncertain. In this prespecified analysis, we used data from 2 randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with aspirin (100 mg) or placebo for extended VTE treatment to estimate the risk of recurrence according to baseline risk factor profiles. Index VTE events were centrally classified as unprovoked, or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at 1 year were calculated. A total of 2832 patients received rivaroxaban; 1131 received aspirin, and 590 received placebo. With unprovoked VTE, rates of recurrence in the 1173 patients given rivaroxaban, the 468 given aspirin, and the 243 given placebo were 2.0%, 5.9%, and 10.0%, respectively. There were no recurrences in patients with VTE provoked by major transient risk factors. With VTE provoked by minor persistent risk factors, recurrence rates in the 1184 patients given rivaroxaban, the 466 given aspirin, and the 248 given placebo were 2.4%, 4.5%, and 10.7%, respectively. For patients with minor transient risk factors, recurrence rates were 0.4% in the 268 patients given rivaroxaban, 4.2% in the 121 given aspirin, and 7.1% in the 56 given placebo. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.56-1.16; and HR, 0.68; 95% CI, 0.32-1.30, respectively). Therefore, such patients may also benefit from extended anticoagulation therapy.
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http://dx.doi.org/10.1182/bloodadvances.2018017160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894264PMC
April 2018

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism.

N Engl J Med 2017 03 18;376(13):1211-1222. Epub 2017 Mar 18.

From the Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON (J.I.W.), and the Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (P.S.W.) - both in Canada; Bayer Pharmaceuticals, Leverkusen (A.W.A.L., M.C.S.F., G.H., A.F.P., S.D.B.), Vascular Medicine, Klinikum Darmstadt, Darmstadt (R.B.), the Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz (R.B.), and the Department of Hematology, Medical Clinic I, University Hospital Carl Gustav Carus, Dresden (J.B.-W.) - all in Germany; the Department of Epidemiology and Technology Assessment, University of Maastricht, Maastricht, the Netherlands (M.H.P.); the Division of Angiology and Hemostasis and the Faculty of Medicine, University of Geneva, Geneva (H.B.); the Department of Haematology, Prince of Wales Hospital, Sydney (T.A.B.); the Department of Haematology and Oncology, King's College London (J.B.-W.), the Department of Haematological Medicine, Guy's and St. Thomas' Hospitals, King's College Hospital (A.T.C.), and Thrombosis Research Institute and University College London (A.K.K.) - all in London; the University of Washington School of Medicine, Seattle (B.L.D.); Centre d'Investigation Clinique 1408, Sainbiose U1059, Investigation Network on Venous Thromboembolism, Service de Médecine Vasculaire et Thérapeutique, Centre Hospitalo-Universitaire, Hôpital Nord, Saint Etienne, France (H.D.); Janssen Research and Development, Raritan, NJ (L.H.); Hospital Beneficência Portuguesa, São Paulo (B.B.); Vascular Medicine and Hemostasis, University of Leuven, Leuven, Belgium (P.V.); and the Department of Cardiothoracic and Vascular Sciences, Vascular Medicine Unit, University of Padua, Padua, Italy (P.P.).

Background: Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin.

Methods: In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding.

Results: A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups.

Conclusions: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).
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http://dx.doi.org/10.1056/NEJMoa1700518DOI Listing
March 2017

Choosing wisely: The impact of patient selection on efficacy and safety outcomes in the EINSTEIN-DVT/PE and AMPLIFY trials.

Thromb Res 2017 Jan 21;149:29-37. Epub 2016 Nov 21.

Thrombosis & Atherosclerosis Research Institute and McMaster University, Hamilton, Ontario, Canada.

Background: The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively).

Methods: To determine the effect of these methodological differences on outcomes, the patients enrolled in EINSTEIN-DVT/PE were divided into 2 cohorts; the 5253 patients that matched the exclusion criteria for AMPLIFY and were treated for at least 6months (cohort 1) and the 2368 patients who would have been ineligible for AMPLIFY (cohort 2).

Results: Compared with patients in cohort 2, those in cohort 1 were older and more often male and there were more with unprovoked VTE, prior VTE, cancer and known thrombophilia. In cohort 1, rivaroxaban would have significantly reduced recurrent VTE (relative risk [RR], 0.64; 95% confidence interval [CI], 0.43-0.95) and major bleeding (RR, 0.50; 95% CI, 0.30-0.82) compared with conventional therapy, whereas the two treatments would have had similar effects on recurrent VTE (RR, 1.08; 95% CI, 0.65-1.79) and major bleeding (RR, 1.03; 95% CI, 0.48-2.18) in cohort 2.

Conclusions: This analysis illustrates the influence of patient selection and treatments duration on outcome results and highlights the limitations of cross-trial comparisons.
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http://dx.doi.org/10.1016/j.thromres.2016.11.014DOI Listing
January 2017

Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis. A post-hoc analysis.

Thromb Haemost 2016 Sep 1;116(4):733-8. Epub 2016 Sep 1.

Y. W. Cheung, MD, Department of Vascular Medicine, F4-143, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands, Tel.: +31 20 5665976, Fax: +31 20 5669343, E-mail:

Post-thrombotic syndrome (PTS) is a common complication of deep-vein thrombosis (DVT). Poor quality treatment with vitamin K antagonists (VKA) is a risk factor for PTS. We hypothesised that treatment with the direct oral anticoagulant (DOAC) rivaroxaban may lower PTS incidence as compared to enoxaparin/VKA, as DOACs have a more stable pharmacologic profile than VKA. We performed a post-hoc subgroup analysis of the Einstein DVT trial (n=3449). Kaplan-Meier survival analysis was performed to compare the cumulative incidence of PTS between the rivaroxaban and enoxaparin/VKA groups. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models. We included 336 patients with a mean age of 58 ± 16 years and a median follow-up after index DVT of 57 months (interquartile range 48-64). Of these, 162 (48 %) had been treated with rivaroxaban and 174 (52 %) with enoxaparin/VKA. The cumulative PTS incidence at 60 months follow-up was 29 % in the rivaroxaban group and 40 % in the enoxaparin/VKA group. After adjusting for age, gender, body mass index, previous VTE, ipsilateral recurrent DVT, extent of DVT, idiopathic DVT, duration of anticoagulant treatment, compliance to assigned study medication, elastic compression stocking use and active malignancy, the HR of PTS development for rivaroxaban was 0.76 (95 % CI: 0.51-1.13). In conclusion, treatment of acute DVT with rivaroxaban was associated with a numerically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment. The potential effect on reducing PTS deserves evaluation in a large randomised trial.
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http://dx.doi.org/10.1160/TH16-01-0041DOI Listing
September 2016

Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists.

Thromb Haemost 2016 Jan 29;115(2):424-32. Epub 2015 Oct 29.

Marcello Di Nisio, Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" of Chieti-Pescara, via dei Vestini 31, 66013 Chieti, Italy, Tel.: +39 0328 3290020, Fax: +39 0871 357361, E-mail:

The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i.e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0%) of 4130 patients receiving rivaroxaban and in 72 (1.7%) of 4116 receiving enoxaparin/VKAs, with 44% of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti-inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation.
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http://dx.doi.org/10.1160/TH15-06-0474DOI Listing
January 2016

Treatment of pulmonary embolism with rivaroxaban: outcomes by simplified Pulmonary Embolism Severity Index score from a post hoc analysis of the EINSTEIN PE study.

Acad Emerg Med 2015 Mar 25;22(3):299-307. Epub 2015 Feb 25.

Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH.

Objectives: The objective was to assess adverse outcomes in relation to the simplified Pulmonary Embolism Severity Index (PESI) score in patients treated with rivaroxaban or standard therapy in the phase III EINSTEIN PE study and to evaluate the utility of the simplified PESI score to identify low-risk pulmonary embolism (PE) patients.

Methods: A post hoc analysis of EINSTEIN PE data was performed to assess the efficacy and safety of rivaroxaban in patients with a range of simplified PESI scores. Recurrent venous thromboembolism, fatal PE, all-cause mortality, and major bleeding were stratified by simplified PESI scores of 0, 1, or ≥2 and according to treatment period at 7, 14, 30, and 90 days and at the end of the full intended treatment period.

Results: Simplified PESI scores could be calculated in 4,831 of the 4,832 randomized patients; of those, 53.6, 36.7, and 9.7% had PESI scores of 0, 1, and ≥2, respectively. Among patients with simplified PESI scores of 0 or 1, fatal PE, all-cause mortality, and other adverse outcomes were uncommon within the first 7, 14, and 30 days. Patients with simplified PESI scores of ≥2 had more frequent adverse outcomes. Major bleeding was lower in the rivaroxaban group, particularly in those with simplified PESI scores of 1 or ≥2.

Conclusions: The findings support using risk stratification with the simplified PESI score to identify low-risk patients with PE.
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http://dx.doi.org/10.1111/acem.12615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405051PMC
March 2015

Use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic venous thromboem-bolism in the EINSTEIN DVT and EINSTEIN PE studies.

Acad Emerg Med 2015 Feb 9;22(2):142-9. Epub 2015 Feb 9.

The Department of Cardiothoracic and Vascular Sciences, University of Padua, Padua, Italy.

Objectives: In the EINSTEIN DVT and EINSTEIN PE studies, the majority of patients received heparins to bridge the period during venous thromboembolism (VTE) diagnosis confirmation and the start of the study. In contrast to vitamin K antagonists (VKAs), rivaroxaban may not require initial heparin treatment.

Methods: To evaluate the effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to enoxaparin/VKA, the 3-month incidence of recurrent VTE, and the 14-day incidence of major and nonmajor clinically relevant bleeding were compared in patients who did and did not receive prestudy heparin.

Results: Of the 8,281 patients randomized, 6,937 (83.8%) received prestudy heparin (mean ± SD duration = rivaroxaban: 1.04 [± 0.74] days; enoxaparin 1.03 [± 0.42] days), and 1,344 (16.2%) did not. In patients who did not receive prestudy heparin, the incidences of recurrent VTE were similar in rivaroxaban (15 of 649, 2.3%) and enoxaparin/VKA (13 of 695, 1.9%) patients (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 0.52 to 2.37). The incidences of recurrent VTE were also similar in rivaroxaban (54 of 3,501, 1.5%) and enoxaparin/VKA (69 of 3,436, 2.0%) patients who did receive prestudy heparin (adjusted HR = 0.74; 95% CI = 0.52 to 1.06; pinteraction  = 0.32). The incidences of major or nonmajor clinically relevant bleeding with rivaroxaban were not significantly different from those with enoxaparin/VKA, either with (105 of 3,485, 3.0% vs. 104 of 3,428, 3.0%; adjusted HR = 0.98; 95% CI = 0.75 to 1.29) or without (24 of 645, 3.7% vs. 30 of 688, 4.4%; adjusted HR = 0.81; 95% CI = 0.46 to 1.40; pinteraction  = 0.68) prestudy heparin.

Conclusions: Although the majority of patients in the EINSTEIN studies received prestudy heparin, there were no notable differences in treatment effect of rivaroxaban versus enoxaparin/VKA in those who did and did not receive it.
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http://dx.doi.org/10.1111/acem.12585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024063PMC
February 2015

Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials.

Lancet Haematol 2014 Oct 28;1(1):e37-46. Epub 2014 Sep 28.

University of Padua, Padua, Italy.

Background: Patients with venous thromboembolism and cancer have a substantial risk of recurrent venous thromboembolism and bleeding during anticoagulant therapy. Although monotherapy with low-molecular-weight heparin is recommended in these patients, in clinical practice many patients with venous thromboembolism and cancer do not receive this treatment. We aimed to assess the efficacy and safety of a single-drug regimen with oral rivaroxaban compared with enoxaparin followed by vitamin K antagonists, in the subgroup of patients with cancer enrolled in the EINSTEIN-DVT and EINSTEIN-PE randomised controlled trials.

Methods: We did a subgroup analysis of patients with active cancer (either at baseline or diagnosed during the study), a history of cancer, or no cancer who were enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Eligible patients with deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE) were randomly assigned in a 1:1 ratio to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy (enoxaparin 1·0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2·0-3·0). Randomisation with a computerised voice-response system was stratified according to country and intended treatment duration (3, 6, or 12 months). The prespecified primary efficacy and safety outcomes of both the trials and this subanalysis were symptomatic recurrent venous thromboembolism and clinically relevant bleeding, respectively. We did efficacy and mortality analyses in the intention-to-treat population, and bleeding analyses for time spent receiving treatment plus 2 days in the safety population (all patients who received at least one dose of study drug). The EINSTEIN-DVT and EINSTEIN-PE studies are registered at ClinicalTrials.gov, numbers NCT00440193 and NCT00439777.

Findings: In patients with active cancer (diagnosed at baseline or during treatment), recurrent venous thromboembolism occurred in 16 (5%) of 354 patients allocated to rivaroxaban and 20 (7%) of 301 patients allocated to enoxaparin and vitamin K antagonist (hazard ratio [HR] 0·67, 95% CI 0·35 to 1·30). Clinically relevant bleeding occurred in 48 (14%) of 353 patients receiving rivaroxaban and in 49 (16%) of 298 patients receiving standard therapy (HR 0·80, 95% CI 0·54 to 1·20). Major bleeding occurred in eight (2%) of 353 patients receiving rivaroxaban and in 15 (5%) of 298 patients receiving standard therapy (HR 0·42, 95% CI 0·18 to 0·99). The overall frequency of recurrent venous thromboembolism in patients with only a history of cancer (five [2%] of 233 patients in the rivaroxaban group vs five [2%] of 236 in the standard therapy group; HR 0·98, 95% CI 0·28-3·43) was similar to that of patients without cancer (65 [2%] of 3563 vs 70 [2%] of 3594, respectively; HR 0·93, 95% CI 0·66-1·30), but the frequency was increased in patients with active cancer at baseline (six [2%] of 258 vs eight [4%] of 204, respectively; HR 0·62, 95% CI 0·21-1·79) and most markedly increased in patients whose diagnosis of cancer was made during the study (ten [10%] of 96 vs 12 [12%] of 97, respectively; HR 0·80, 95% CI 0·34-1·88). The overall frequency of major bleeding in patients with only a history of cancer (one [<1%] patient in the rivaroxaban group vs four [2%] patients in the standard therapy group; HR 0·23, 95% CI 0·03-2·06) was similar to that of patients without cancer (31 [1%] vs 53 [1%], respectively; HR 0·58, 95% CI 0·37-0·91), but was increased in patients with active cancer at baseline (five [2%] vs eight [4%], respectively; HR 0·47, 95% CI 0·15-1·45) and was highest in those with cancer diagnosed during the study (three [3%] vs seven [7%], respectively; HR 0·33, 95% CI 0·08-1·31).

Interpretation: In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin in patients with cancer is warranted.

Funding: Bayer HealthCare Pharmaceuticals and Janssen Research & Development.
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http://dx.doi.org/10.1016/S2352-3026(14)70018-3DOI Listing
October 2014

Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment.

Thromb J 2014 24;12:25. Epub 2014 Nov 24.

Department of Medicine, University of Padua, Padua, Italy.

Background: Patients with renal impairment receiving classical anticoagulation for venous thromboembolism (VTE) are at increased risk of bleeding and possibly pulmonary embolism. We examined the efficacy and safety of oral rivaroxaban in patients with VTE with and without renal impairment.

Methods: Prespecified subgroup analysis of the EINSTEIN DVT and EINSTEIN PE studies comparing fixed-dose rivaroxaban with enoxaparin/a vitamin K antagonist (VKA), performed in 8246 patients enrolled from 2007 to 2011 in 314 hospitals.

Results: Outcomes were recurrent VTE and major or clinically relevant nonmajor bleeding in patients with normal renal function (n = 5569; 67.3%) or mild (n = 2037; 24.6%), moderate (n = 636; 7.7%), or severe (n = 21; 0.3%) renal impairment. Rates of recurrent VTE were 1.8%, 2.8%, 3.3%, and 4.8% in patients with normal renal function and mild, moderate, and severe renal impairment, respectively (ptrend = 0.001). Hazard ratios for recurrent VTE were similar between treatment groups across renal function categories (pinteraction = 0.72). Major bleeding in rivaroxaban recipients occurred in 0.8%, 1.4%, 0.9%, and 0%, respectively (ptrend = 0.50). Respective rates in enoxaparin/VKA recipients were 1.0%, 3.0%, 3.9%, and 9.1% (ptrend < 0.001). Rivaroxaban-enoxaparin/VKA hazard ratios were 0.79 (95% confidence interval [CI] 0.46-1.36) for normal renal function, 0.44 (95% CI 0.24-0.84) for mild renal impairment, and 0.23 (95% CI 0.06-0.81) for moderate renal impairment (pinteraction = 0.034).

Conclusions: Patients with symptomatic VTE and renal impairment are at increased risk of recurrent VTE. Renal impairment increased the risk of major bleeding in enoxaparin/VKA-treated patients but not in rivaroxaban-treated patients.

Trial Registration: NCT00440193 and NCT00439777.
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http://dx.doi.org/10.1186/1477-9560-12-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351845PMC
March 2015

Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies.

Thromb J 2013 Dec 16;11(1):25. Epub 2013 Dec 16.

Bayer HealthCare, Aprather Weg 18a, Wuppertal D-42096, Germany.

Background: The worldwide EINSTEIN DVT and EINSTEIN PE studies randomized 8282 patients with acute symptomatic deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) and, for the first time in trials in this setting, included patients in China. This analysis evaluates the results of these studies in this subgroup of patients.

Methods: A total of 439 Chinese patients who had acute symptomatic DVT (n=211), or PE with or without DVT (n=228), were randomized to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy of enoxaparin overlapping with and followed by an adjusted-dose vitamin K antagonist, for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or non-major clinically relevant bleeding.

Results: The primary efficacy outcome occurred in seven (3.2%) of the 220 patients in the rivaroxaban group and in seven (3.2%) of the 219 patients in the standard-therapy group (hazard ratio, 1.04; 95% confidence interval 0.36-3.0; p=0.94). The principal safety outcome occurred in 13 (5.9%) patients in the rivaroxaban group and in 20 (9.2%) patients in the standard-therapy group (hazard ratio, 0.63; 95% confidence interval 0.31-1.26; p=0.19). Major bleeding was observed in no patients in the rivaroxaban group and in five (2.3%) patients in the standard-therapy group. In fragile patients (defined as age >75 years, creatinine clearance <50 mL/min, and/or body weight ≤50 kg), the principal safety outcome occurred in four (8.9%) of the 45 patients who received rivaroxaban compared with seven (15.2%) of the 46 patients who received standard therapy.

Conclusions: In Chinese patients with acute symptomatic DVT and/or PE, rivaroxaban was as efficacious as enoxaparin followed by vitamin K antagonist therapy, with a similar safety profile. The relative efficacy and safety of rivaroxaban compared with enoxaparin/vitamin K antagonist were consistent with that found in the rest of the world.

Trial Registration Number: EINSTEIN PE, ClinicalTrials.gov NCT00439777; EINSTEIN DVT, ClinicalTrials.gov NCT00440193.
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http://dx.doi.org/10.1186/1477-9560-11-25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896794PMC
December 2013

Urinary Prothrombin Fragment 1+2 in relation to Development of Non-Symptomatic and Symptomatic Venous Thromboembolic Events following Total Knee Replacement.

Thrombosis 2011 3;2011:150750. Epub 2011 May 3.

Department of Orthopaedics, Århus University Hospital, Nørrebrogade 44, 8000 Århus C, Denmark.

Prothrombin fragment 1+2 is excreted in urine (uF1+2) as a result of in vivo thrombin generation and can be a marker of coagulation status after an operative procedure. This study compared uF1+2 levels in patients with symptomatic and non-symptomatic venous thromboembolism (VTE) after total knee replacement (TKR) and in event-free sex- and age-matched controls. Significantly higher median uF1+2 levels were seen in the VTE patients on days 1, 3, and the day of venography (mostly day 7) after TKR compared with controls. The uF1+2 levels tended to be high in some patients with symptomatic VTE; however, the discriminatory efficacy of the test could not be evaluated. In conclusion, this study showed that patients with VTE tend to have significantly higher uF1+2 levels compared with patients without events between days 1 and 7 after TKR surgery. Measurement of uF1+2 could provide a simple, non-invasive clinical test to identify patients at risk of VTE.
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http://dx.doi.org/10.1155/2011/150750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195289PMC
November 2011

Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.

Lancet 2008 Jul 24;372(9632):31-9. Epub 2008 Jun 24.

Barts and the London School of Medicine and Dentistry, London, UK.

Background: The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin.

Methods: 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020.

Findings: The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25).

Interpretation: Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty.
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http://dx.doi.org/10.1016/S0140-6736(08)60880-6DOI Listing
July 2008

Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours: discontinuation study.

Br J Psychiatry 2007 May;190:447-8

Department of Child and Adolescent Psychiatry, University of Rostock, Rostock, Germany.

We investigated the effects of zuclopenthixol on aggressive behaviour in patients with intellectual disabilities by randomly withdrawing it after a 6-week period of open treatment. Of the 49 patients responding to the treatment, 39 took part in a randomised withdrawal trial. The placebo subgroup (n=20) showed more aggressive behaviour as indicated by outcomes observed by external raters on the Modified Overt Aggression Scale than did the continuing subgroup (n=19). The results indicate that discontinuation of zuclopenthixolin this population leads to an increase in aggressive behaviour.
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http://dx.doi.org/10.1192/bjp.bp.105.016535DOI Listing
May 2007
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