Search

Anticoagulant treatment of pediatric cancer–associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.2%) with VTE who participated in the recent EINSTEIN-Jr randomized study had cancer (hematologic malignancy, 64.3%, solid malignant tumor, 35.7%). Children were allocated to either therapeutic-dose bodyweight-adjusted oral rivaroxaban (n=40) or standard anticoagulation with heparins, with or without vitamin K antagonists (n=16) and received a median of 30 concomitant medications. Based on sparse blood sampling at steady-state, pharmacokinetic (PK) parameters of rivaroxaban were derived using population PK modeling. During the 3 months of treatment, no recurrent VTE or major bleeding occurred (95% confidence interval, 0.0%-6.4%), and 3-month repeat imaging showed complete or partial vein recanalization in 20 and 24 of 52 evaluable children (38.5% and 46.2%, respectively). Anticoagulant treatment was interrupted 70 times in 26 (46.4%) children because of thrombocytopenia, invasive procedures, or adverse events, for a mean individual period of 5.8 days. Anticoagulant therapy was resumed in therapeutic doses and was not associated with thrombotic or bleeding complications. Rivaroxaban exposures were within the adult exposure range and similar to those observed in children with VTE who did not have cancer-associated VTE. Rivaroxaban and standard anticoagulants appeared safe and efficacious and were associated with reduced clot burden in most children with cancer-associated VTE, including those who had anticoagulant treatment interruptions. Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. This trial was registered at www.clinicaltrials.gov as #NCT02234843.

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], 22.6% 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, 26.7% 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. © 2020 by The American Society of Hematology This study was supported by Bayer AG and Janssen Research and Development.

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 ( P 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; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( P 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 ( P 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.

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 ...

Contains fulltext : 235339.pdf (Publisher’s version ) (Open Access) 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.

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.

Anticoagulant treatment of pediatric central venous catheter–related venous thromboembolism (CVC-VTE) has not been specifically evaluated. In EINSTEIN-Jr, 500 children with any VTE received rivaroxaban or standard anticoagulants. A predefined analysis of the CVC-VTE cohort was performed. Children with CVC-VTE (age, birth to 17 years) were administered rivaroxaban or standard anticoagulants during the 1-month (children

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) 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 /=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. 01 januari 2020

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.

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 6 months, 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 6 months (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. (C) 2016 Elsevier Ltd. All rights reserved.

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 (

Background: Treatment of venous thromboembolism (VTE) in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. Methods: In a parallel-group open-label randomised study, 500 children aged birth to 17 years with documented acute VTE who had started heparinisation were assigned, in a 2:1 ratio, to receive bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants. The main treatment period was 3 months (1 month in children under 2 years with catheter-related VTE). Symptomatic recurrent VTE and bleeding were centrally assessed unaware of treatment assignment. Repeat imaging was obtained at the end of the treatment period. Findings: Recurrent VTE was the primary efficacy outcome and occurred in 4 of the 335 (1.2%) children allocated to rivaroxaban and in 5 of the 165 (3.0%) children allocated to standard anticoagulants (64.2% of whom received subcutaneous heparins only), for a hazard ratio of 0.40 (95% confidence interval, 0.11 to 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 was the principal safety outcome and occurred in 10 children (3.0%; all non-major) with rivaroxaban and in 3 children (1.9%; two major and 1 non-major) with standard anticoagulants. Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were comparable those obtained in rivaroxaban studies in adults. Interpretation: In children with acute VTE, treatment with rivaroxaban resulted in a low recurrence risk and a reduced thrombotic burden without increased bleeding, as compared to standard anticoagulants. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT02234843. Funding Statement: Bayer AG and Janssen Research & Development, LLC. Declaration of Interests: CM reports receiving personal fees and fees, paid to his institution, from Bayer, Bristol-Myers-Squibb, Pfizer and fees, paid to his institution, from BoehringerIngelheim; AWAL being employed by Bayer; RK receiving personal fees from Bayer, CSL Behring, and Kedrion; DB receiving personal fees and grant support from Actelion Pharmaceuticals, Bayer, Eli Lilly, BMS, and Novartis and grant support from AbbVie; PC receiving personal fees from Onyx Health Limited; AKC receiving personal fees from Bayer and fees, paid to his institution, from Bayer, Pfizer, Daiichi Sankyo, and Bristol-Myers-Squibb; GK receiving personal fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo and fees, paid to her institution from Pfizer; SH receiving personal fees from P and fees, paid to her institution, from Bayer, Pfizer, and Daiichi Sankyo; AS receiving personal fees from Bayer, Pfizer, Daiichi Sankyo and Boehringer Ingelheim; PA receiving personal fees and fees, paid to his institution, from Abbvie and Bayer, and fees paid to his institution from Actelion, Novartis, and Daiichi Sankyo; EC receiving personal fees from Boehringer Ingelheim and Bristol-Myers-Squibb, and fees, paid to her institution from Bayer, Pfizer, and Daiichi Sankyo; DLY receiving fees, paid to his institution, from Bayer, Pfizer, and Bristol-Myers Squibb; OL receiving personal fees from Bayer, Pfizer, Boehringer Ingelheim, and Novartis, and fees, paid to her institution, from Bayer; JB-W receiving personal fees and fees, paid to his institution, from Bayer, Daiichi Sankyo, DOASENSE and Portola and fees, paid to his institution, from Pfizer; TTB receiving fees from Boehringer Ingelheim and Bayer, and grant support from Leo Pharma; IM receiving fees from Sanofi and Bayer; MP receiving grant support from Pfizer and Sobi; MPM receiving personal fees from Bayer; GY receiving receiving personal fees from GlaxoSmithKline and Portola and personal fees and fees paid to his institution from Bayer and Daiichi Sankyo; AFP, MM, WTS, SDB, KT, DK being employed by Bayer; JH was employed by Bayer; MC receiving grant support from and serving on a data and safety monitoring board for Bayer, receiving advisory board fees from Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Asahi Kasei, receiving educational funding from Alexion Pharmaceuticals, Pfizer, CSL Behring, and Diagnostica Stago, receiving grant support, paid to his institution, from Leo Pharma, serving on a data and safety monitoring board for Daiichi Sankyo, owning stock in Alnylam Pharmaceuticals, and receiving educational funding and advisory board fees from Servier Canada; MHP receiving personal fees from Bayer; no other potential conflict of interest relevant to this article was reported. Ethics Approval Statement: The protocol was approved by the institutional review board at each participating center. Written permission from a parent or guardian and, when appropriate, child assent, were obtained.

SummaryPost-thrombotic syndrome (PTS) is a common complication of deepvein 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.Supplementary Material to this article is available online at www.thrombosis-online.com.

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.

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.

Summary 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 [ 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.

SummaryLittle is known about the onset of action after intravenous or oral administration of acetylsalicylic acid (ASA) in patients with acute coronary syndromes (ACS). The aim of the study was to compare intravenous 250 or 500 mg acetylsalicylic acid (ASA) with oral 300 mg in ASA naïve patients with ACS concerning the onset of antiplatelet effects measured by time dependent thromboxane inhibition. A total of 270 patients with ACS < 24 hours were randomised into one of three treatment arms comprising administration of a single dose of ASA as soon as possible after admission. The primary endpoint was platelet inhibition assessed by measurement of arachidonic acid (AA)-induced platelet thromboxane release (TXB2) 5 minutes (min) after study drug administration. Both 250 mg and 500 mg ASA i. v. inhibited TXB2 formation nearly completely (geometric means: from 581.7 and 573.9 ng/ml at baseline to 3.9 and 3.1 ng/ml at 5 min, respectively) compared to 300 mg oral ASA (geometric means: from 652.0 to 223.7 ng/ml) (p-value, ANCOVA: < 0.0001). Similar results were obtained for inhibition of AA-induced platelet aggregation (Multiplate ASPItest; from means 86.41 and 85.72 U to 23.04 and 20.57 U at 5 min, respectively) compared to 300 mg oral ASA from mean 87.18 to 75.56 U (p-value, ANCOVA: Supplementary Material including a list of institutions where work was performed is available online at www.thrombosis-online.com.

SummaryThe 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.Supplementary Material to this article is available online at www.thrombosis-online.com.

Summary 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 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. Funding Bayer HealthCare AG, Johnson & Johnson Pharmaceutical Research and Development LLC.

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 non-major 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. (C) 2015 by the Society for Academic Emergency Medicine

background The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. methods In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. results The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. conclusions Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

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.

INTRODUCTION: Earlier studies showed risperidone to be effective in the treatment of aggression and self-injurious behaviour in adults with mental retardation but also having adverse side effects. This study was conducted to evaluate the effects of zuclopenthixol withdrawal. METHODS: After open treatment with zuclopenthixol (n=49) responders were randomly assigned to continue (n=19) or discontinue (n=20) zuclopenthixol treatment during a 12-week double-blind, placebo-controlled period. Effects were measured using the Disability Assessment Schedule (DAS), improvement on the Clinical Global Impression Scale (CGI-I), and the Nurse's Observation Scale for Inpatient Evaluation (NOSIE). RESULTS: Ten patients (20%) discontinued the study due to insufficient therapeutic effect or adverse events in the open period. EFFICACY: The superiority of zuclopenthixol over placebo among all randomized patients was supported not only by primary efficacy measure but also by the comparisons of mean scores of all secondary efficacy measures tested in a step-down-procedure (DAS, p

Summary. Background: Prothrombin fragment 1 + 2 is excreted in urine (uF1 + 2) as a result of thrombin generation and, therefore, may be a useful marker of coagulation status. Objectives: To assess uF1 + 2 levels after total hip replacement (THR) in patients with venous thromboembolism (VTE) and bleeding events. Patients/methods: This study was conducted in parallel with a prospective, dose-finding study evaluating the efficacy and safety of different doses of rivaroxaban (Xarelto®, Bayer HealthCare AG, Wuppertal, Germany) for thromboprophylaxis, relative to enoxaparin. Deep vein thrombosis was diagnosed by mandatory venography performed 5–9 days after THR, or earlier if symptomatic. Symptomatic pulmonary embolism was diagnosed by objective testing. Bleeding complications were registered and stratified into major bleeding, clinically relevant, non-major bleeding, and minor bleeding, using predefined criteria. Results: Eighty-four patients had a VTE and 57 patients had a bleeding event (n = 722). Significantly higher median uF1 + 2 levels were observed in the VTE group on day 3 after THR (P = 0.03), compared with control. Median uF1 + 2 levels were lower in the bleeding group on day 3 after THR (P = 0.005) and on the day of venography (P = 0.36), compared with control. Comparisons between the VTE and bleeding groups showed significantly lower median uF1 + 2 levels in the bleeding group on day 3 after THR and on the day of venography (P

Objective: To compare the efficacy and safety of oral rivaroxaban with that of enoxaparin/vitamin K antagonist (VKA) in patients with cancer among 8282 patients with acute venous thromboembolism (VTE) enrolled in the EINSTEIN programme. Rationale: Patients with cancer and VTE constitute a medical challenge for physicians because anticoagulant treatment is indicated to prevent recurrent VTE but is associated with a high risk of major bleeding. Methods: EINSTEIN DVT and EINSTEIN PE were randomized, event-driven, non-inferiority, open-label phase III studies. Patients were treated for 3, 6 or 12 months with rivaroxaban (15 mg twice daily for 21 days followed by 20 mg once daily) or enoxaparin/VKA (international normalized ratio 2.0–3.0) and followed for suspected recurrent VTE, bleeding and mortality. Cancer patients were classified as: active cancer at baseline (diagnosis or treatment within 6 months before enrolment or recurrent/metastatic cancer) or diagnosed during the study (n = 655); or a history of cancer (n = 469). Results: Recurrent VTE occurred with a similar incidence in the rivaroxaban and enoxaparin/VKA groups in patients with active cancer (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.35–1.30) and patients with a history of cancer (HR 0.98; 95% CI 0.28–3.43). In patients with active cancer, the risk of major bleeding was significantly reduced in the rivaroxaban group (HR 0.42; 95% CI 0.18–0.99), whereas it was similar between treatments in patients with a history of cancer (HR 0.23; 95% CI 0.03–2.06). Mortality occurred with a similar incidence between treatments in patients with active cancer (HR 0.93; 95% CI 0.64–1.35) and patients with a history of cancer (HR 1.12; 95% CI 0.30–4.22). Rivaroxaban Enoxaparin/VKA HR (95% CI) Recurrent VTE, n (%) Active cancer 16/354 (4.5) 20/301 (6.6) 0.67 (0.35–1.30) History of cancer 5/233 (2.1) 5/236 (2.1) 0.98 (0.28–3.43) Major bleeding, n (%) Active cancer 8/353 (2.3) 15/298 (5.0) 0.42 (0.18–0.99) History of cancer 1/231 (0.4) 4/236 (1.7) 0.23 (0.03–2.06) Mortality, n (%) Active cancer 58/354 (16.4) 53/301 (17.6) 0.93 (0.64–1.35) History of cancer 5/233 (2.1) 4/236 (1.7) 1.12 (0.30–4.22) Conclusions: Rivaroxaban had similar efficacy to enoxaparin/VKA in patients with VTE and active cancer or a history of cancer, but was associated with a significant reduction in major bleeding in patients with active cancer. Disclosure: M.H. Prins: is a consultant advisor for Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Pfizer, Sanofi, Boehringer Ingelheim, GlaxoSmithKline (GSK), LEO, and ThromboGenics; T. Lensing, F. Misselwitz, A.F. Pap, M. Trajanovic and S.D. Berkowitz: is an employee of Bayer HealthCare Pharmaceuticals; P. Prandoni: has received consultant fees from Bayer Pharma, Daiichi Sankyo, Pfizer, Boehringer-Ingelheim and Sanofi-Aventis; A.T. Cohen: has received consultancy and clinical trial funding from Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Daiichi, GSK, Johnson & Johnson, Mitsubishi Pharma, Pfizer, Portola, Sanofi-aventis, Schering-Plough & Takeda; B.L. Davidson: has received travel support from Bayer Healthcare, and is a steering committee member for Bayer HealthCare and Daiichi Sankyo;P. Wells: has received research support from Bristol-Myers Squibb, Pfizer; has participated on scientific advisory boards for Bayer Schering Pharma, Pfizer & Boehringer Ingelheim; and has received honoraria from Bayer Schering Pharma, Pfizer & Biomerieux.

Summary Background The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study. Methods After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m 2 fluorouracil intravenously on days 1–3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m 2 and folinic acid 20 mg/m 2 daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat. Findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0–62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15·5 months in 175 patients with chemoradiotherapy vs 16·1 months in 178 patients without; hazard ratio 1·18 [95% Cl 0·90–1·55], p=0·24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19·7 months in 238 patients with chemotherapy vs 14·0 months in 235 patients without; hazard ratio 0·66 [0·52–0·83], p=0·0005). Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

SummaryWe 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 zuclopenthixol in this population leads to an increase in aggressive behaviour.

Background The Pulmonary Embolism Severity Index (PESI) has been validated in the setting of standard treatment of pulmonary embolism with initial low molecular weight heparin followed by vitamin K antagonists. We evaluated the proposed simplified PESI in a large, phase III randomized trial involving patients with symptomatic pulmonary embolism with or without deep vein thrombosis, who were treated with rivaroxaban or standard therapy. Methods The EINSTEIN PE study was an open-label, randomized, phase III study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin overlapping with and followed by a vitamin K antagonist (warfarin or acenocoumarol, target international normalized ratio 2.0–3.0) for 3, 6, or 12 months in patients with acute, symptomatic pulmonary embolism. At baseline, the simplified PESI score was assessed, with 1 point each assigned for age >80 years, history of cancer, chronic cardiopulmonary disease, heart beat ≥110 beats per minute, systolic blood pressure Results It was possible to calculate the simplified PESI score in 4831 of the 4832 included patients, of whom 2589 (53.6%) had a PESI score of 0; 1775 (36.7%) had a score of 1; and 467 (9.7%) had a score of 2 or 3. No patient had a simplified PESI score greater than 3. Incidences of outcomes in relation to time period, simplified PESI score and treatment are presented in the following table. Conclusions Among patients with a simplified PESI score of 0 or 1, major clinical outcome events were rare during the first 30 days of treatment and were similar in patients treated with rivaroxaban or standard therapy. Patients with a simplified PESI score of 2 or more in both treatment groups had more frequent adverse outcomes both initially and in the long term. Disclosures: Fermann: Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Radiometer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cubist: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cardiorentis: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Prins:Bayer HealthCare: Consultancy; Sanofi-aventis: Consultancy; Boehringer Ingelheim: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Consultancy; Leo Pharma: Consultancy; Thrombogenics: Consultancy; Pfizer: Consultancy. Wells:BMS/Pfizer: Research Funding; Pfizer: Honoraria; Bayer Schering Pharma: Honoraria; Boehringer Ingelheim: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria; Biomerieux: Honoraria. Pap:Bayer Pharma AG: Employment. Lensing:Bayer Pharma AG: Employment.

Abstract 207 Background: The extent of deep vein thrombosis (DVT) is, for many physicians, an important variable that is considered in decisions on the type and duration of anticoagulant treatment. Although it has been consistently demonstrated that localization of the initial DVT is a powerful and independent predictor of recurrent venous thromboembolism (VTE) after discontinuation of anticoagulation (Baglin T et al. J Thromb Haemost 2010;8:2436–2442), it remains unknown to what extent localization of the initial DVT affects the occurrence of recurrent VTE while patients are on anticoagulation. Data from the EINSTEIN DVT study, which randomized 3,449 patients with proximal DVT, offers an opportunity to investigate this question. Aim: To investigate whether localization of the initial DVT was predictive of the rate of recurrent venous thromboembolic events in the whole cohort of patients in the EINSTEIN DVT study, in those who received rivaroxaban, or in those who received conventional anticoagulation with enoxaparin plus vitamin K antagonists (VKA) followed by VKA alone. Methods: Patients were randomized to rivaroxaban or enoxaparin plus VKA followed by VKA only for intended treatment durations of 3, 6, or 12 months. Patients were grouped into four categories according to the extent of the proximal vein thrombosis that was recorded at baseline: 1) popliteal vein alone; 2) popliteal and superficial femoral vein; 3) popliteal, superficial femoral, and common femoral vein; and 4) all combinations of DVT without popliteal vein involvement. Patients were followed for recurrent events. All baseline and recurrent events were assessed by a central independent adjudication committee that was unaware of treatment allocation. The effect of thrombus location on the incidence of recurrent VTE was assessed using a Cox proportional hazard model. Results: Recurrent VTE occurred in 21/1,040 (2.0%) patients with popliteal vein thrombosis only; in 28/1,002 (2.8%) patients with thrombosis located in the popliteal and superficial femoral vein; in 26/935 (2.8%) patients with thrombosis in the popliteal, superficial femoral, and common femoral vein (± iliac vein); and in 11/370 (3.0%) patients without popliteal vein involvement. None of these differences was statistically significant (p=0.87). The relative effect of rivaroxaban versus enoxaparin/VKA was similar in these subgroups (Table). Conclusions: At baseline, most patients in the EINSTEIN DVT study had thrombosis that involved more than one proximal vein. While patients were on treatment, the extent of the DVT at baseline was not predictive for recurrent VTE irrespective of type of treatment. Patients with extensive thrombosis (i.e. popliteal, superficial femoral, and common femoral vein involvement) had a recurrence rate below 3%, which was similar to the rate of recurrence in patients with thrombosis in only one vein at baseline. In summary, this analysis suggests that the localization and extent of the initial DVT was not predictive of the rate of recurrent venous thromboembolic events in the EINSTEIN DVT patient population while patients were on anticoagulation. Character count: 2670/3800 (spaces excluded) (2983 including table) Disclosures: Prins: Bayer HealthCare: Consultancy, Honoraria. Prandoni:GSK: Membership on an entity's Board of Directors or advisory committees. Lensing:Bayer HealthCare AG: Employment. van Bellen:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pap:Bayer HealthCare AG: Employment. Raskob:Bayer: Consultancy, Honoraria; Johnson & Johnson: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Boehringer-Ingelhiem: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi-Aventis: Consultancy, Honoraria. Büller:Sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.