Publications by authors named "Timothy Brighton"

37 Publications

A multi-laboratory assessment of congenital thrombophilia assays performed on the ACL Top 50 family for harmonisation of thrombophilia testing in a large laboratory network.

Clin Chem Lab Med 2021 Jun 14. Epub 2021 Jun 14.

Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia.

Objectives: Thrombophilia testing is commonly performed within hemostasis laboratories, and the ACL TOP 50 family of instruments represent a new 'single platform' of hemostasis instrumentation. The study objective was to evaluate these instruments and manufacturer reagents for utility of congenital thrombophilia assays.

Methods: Comparative evaluations of various congenital thrombophilia assays (protein C [PC], protein S [PS], antithrombin [AT], activated protein C resistance [APCR]) using newly installed ACL TOPs 550 and 750 as well as comparative assessments with existing, predominantly STAGO, instrumentation and reagents. Verification of manufacturer assay normal reference ranges (NRRs).

Results: HemosIL PC and free PS assays showed good comparability with existing Stago methods (R>0.9) and could be considered as verified as fit for purpose. HemosIL AT showed high relative bias with samples from patients on direct anti-Xa agents, compromising utility. Manufacturer NRRs for PC, PS and AT were verified with minor variance. Given the interference with direct anti-Xa agents, an alternate assay (Hyphen) was evaluated for AT, and the NRR also verified. The HemosIL Factor V Leiden (APC Resistance V) evidenced relatively poor performance compared to existing assays, and could not be adopted for use in our network.

Conclusions: This evaluation of HemosIL reagents on ACL TOP 50 Family instruments identified overall acceptable performance of only two (PC, free PS) of four thrombophilia assays, requiring use of third-party reagents on ACL instruments for the other two assays (AT, APCR).
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http://dx.doi.org/10.1515/cclm-2021-0499DOI Listing
June 2021

Verification of the ACL Top 50 Family (350, 550, and 750) for Harmonization of Routine Coagulation Assays in a Large Network of 60 Laboratories.

Am J Clin Pathol 2021 Apr 23. Epub 2021 Apr 23.

Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, Australia.

Objectives: To verify a single platform of hemostasis instrumentation, the ACL TOP 50 Family, comprising 350, 550, and 750 instruments, across a large network of 60 laboratories.

Methods: Comparative evaluations of instrument classes (350 vs 550 and 750) were performed using a large battery of test samples for routine coagulation tests, comprising prothrombin time/international normalized ratio, activated partial thromboplastin time (APTT), thrombin time, fibrinogen and D-dimer, and using HemosIL reagents. Comparisons were also made against existing equipment (Diagnostica Stago Satellite, Compact, and STA-R Evolution) and existing reagents to satisfy national accreditation standards. Verification of manufacturer normal reference ranges (NRRs) and generation of an APTT heparin therapeutic range were undertaken.

Results: The three instrument types were verified as a single instrument class, which will permit standardization of methods and NRRs across all instruments (n = 75) to be deployed in 60 laboratories. In particular, ACL TOP 350 test result data were similar to ACL TOP 550 and 750 and showed no to limited bias. All manufacturer NRRs were verified with occasional minor variance.

Conclusions: This ACL TOP 50 Family (350, 550, and 750) verification will enable harmonization of routine coagulation across all laboratories in the largest public pathology network in Australia.
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http://dx.doi.org/10.1093/ajcp/aqab004DOI Listing
April 2021

Effect of sample heat inactivation on test levels of HIT-IgG detected by the ACL AcuStar.

Thromb Res 2021 04 18;200:12-15. Epub 2021 Jan 18.

Prince of Wales Hospital, NSW Health Pathology, Randwick, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2021.01.004DOI Listing
April 2021

A multicenter laboratory assessment of a new automated chemiluminescent assay for ADAMTS13 activity.

J Thromb Haemost 2021 02 21;19(2):417-428. Epub 2020 Nov 21.

Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal disorder caused by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency. Prompt identification/exclusion of TTP can thus be facilitated by rapid ADAMTS13 testing. The most commonly utilized (enzyme-linked immunosorbent assay [ELISA]-based) assay takes several hours to perform and so does not generally permit rapid testing.

Objectives: To evaluate the utility of a new automated test for ADAMTS13 activity, the HemosIL AcuStar ADAMTS13 Activity assay, based on chemiluminescence and able to be performed on an ACL AcuStar instrument within 33 minutes.

Patients/methods: This multicenter (n = 8) assessment included testing of more than 700 test samples, with similar numbers of prospective (n = 348) and retrospective (n = 385) samples. The main comparator was the Technozym ADAMTS13 Activity ELISA. We also assessed comparative performance for detection of ADAMTS13 inhibitors using a Bethesda assay.

Results: Overall, the chemiluminescent assay yielded similar results to the comparator ELISA, albeit with slight negative bias. ADAMTS13 inhibitor detection was also comparable, albeit with slight positive bias with the AcuStar assay. Assay precision was similar with both assays, and we also verified assay normal reference ranges.

Conclusions: The HemosIL AcuStar ADAMTS13 Activity assay provided results rapidly, which were largely comparable with the Technozym ADAMTS13 Activity ELISA assay, albeit lower on average. Conversely, inhibitor levels tended to be identified at a higher level on average. Thus, the HemosIL AcuStar ADAMTS13 Activity assay provides a fast and accurate means to quantitate plasma levels of ADAMTS13 for TTP/ADAMTS13 identification/exclusion, and potentially also for other applications.
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http://dx.doi.org/10.1111/jth.15157DOI Listing
February 2021

A multicentre assessment of contemporary laboratory assays for heparin induced thrombocytopenia.

Pathology 2021 Feb 5;53(2):247-256. Epub 2020 Oct 5.

NSW Health Pathology, NSW, Australia; Prince of Wales Hospital, Randwick, NSW, Australia.

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy. In some patients, HIT causes platelet activation and thrombosis (sometimes abbreviated HITT), which leads to adverse clinical sequalae ('pathological HIT'). The likelihood of HIT is initially assessed clinically, typically using a scoring system, of which the 4T score is that most utilised. Subsequent laboratory testing to confirm or exclude HIT facilitates exclusion or diagnosis and management. The current investigation comprises a multicentre (n=9) assessment of contemporary laboratory testing for HIT, as performed over the past 1-3 years in each site and comprising testing of over 1200 samples. The primary laboratory test used by study participants (n=8) comprised a chemiluminescence procedure (HIT-IgG) performed on an AcuStar instrument. Additional immunological testing performed by study sites included lateral flow (STiC, Stago), enzyme linked immunosorbent assay (ELISA), Asserachrom (HPIA IgG), PaGIA (BioRad), plus functional assays, primarily serotonin release assay (SRA) or platelet aggregation methods. The chemiluminescence procedure yielded a highly sensitive screening method for identifying functional HIT, given high area under the curve (AUC, generally ≥0.9) in a receiver operator characteristic (ROC) analysis against SRA as gold standard. ELISA testing resulted in lower ROC AUC scores (<0.8) and higher levels of false positives. Although there is clear association with the likelihood of HIT, the 4T score had less utility than literature suggests, and was comparable to a previous study reported by some of the authors.
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http://dx.doi.org/10.1016/j.pathol.2020.07.012DOI Listing
February 2021

Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration.

J Thromb Haemost 2020 11 1;18(11):2958-2967. Epub 2020 Oct 1.

Feinstein Institutes for Medical Research and The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY, USA.

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed.

Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate.

Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials.

Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.
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http://dx.doi.org/10.1111/jth.15094DOI Listing
November 2020

Incidental intravascular large B-cell lymphoma in a renal cell carcinoma.

Pathology 2020 Oct 27;52(6):731-734. Epub 2020 Aug 27.

Histopathology, Douglass Hanly Moir Pathology, Macquarie Park, Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.pathol.2020.06.012DOI Listing
October 2020

An integrated approach to inherited platelet disorders: results from a research collaborative, the Sydney Platelet Group.

Pathology 2020 Feb 10;52(2):243-255. Epub 2020 Jan 10.

Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia; Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia.

Inherited disorders of platelet function (IPFD) and/or number (IPND) are heterogeneous conditions that result in variable mucocutaneous bleeding symptoms as a result of deranged primary haemostasis caused by platelet dysfunction or thrombocytopenia. Diagnosis is important to guide post-operative bleeding prophylactic strategies, to avoid treatment with inappropriate medications, and inform prognosis. Achieving an accurate diagnosis has traditionally been hampered by the requirement of multiple, often complex, laboratory tests that are not always available at single centres. To improve the diagnosis of these disorders a research collaborative was established, the Sydney Platelet Group, that explored an integrated approach combining traditional and contemporary platelet phenotypic and genetic diagnostic platforms available at four Sydney tertiary hospitals. Herein we report the outcomes of the first 50 patients evaluated using this approach. The cohort included 22 individuals with suspected IPFD and 28 with thrombocytopenia. Bleeding scores were higher in individuals with IPFD (mean 5.75; SD 4.83) than those with IPNDs (mean 2.14; SD 2.45). In cases with suspected IPFD, diagnosis to the level of the defective pathway was achieved in 71% and four individuals were found not to have a definitive platelet function defect. Dense granule secretion disorders were the most common platelet pathway abnormality detected (n=5). Mean bleeding scores in these individuals were not significantly different to individuals with defects in other commonly detected platelet pathways (dense granules, signal transduction and 'undetermined'). A molecular diagnosis was achieved in 52% of individuals with IPNDs and 5% with IPFD. Likely pathogenic and pathogenic variants detected included variants associated with extra-haematological complications (DIAPH1, MYH9) and potential for malignancy (ANKRD26 and RUNX1). The level of platelet investigation undertaken by this initiative is currently not available elsewhere in Australia and initial results confirm the utility of this integrated phenotypic-genetic approach.
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http://dx.doi.org/10.1016/j.pathol.2019.10.005DOI Listing
February 2020

Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis.

BMJ 2019 07 24;366:l4363. Epub 2019 Jul 24.

School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada

Objectives: To determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence for recurrent VTE up to 10 years.

Design: Systematic review and meta-analysis.

Data Sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019).

Study Selection: Randomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment.

Data Extraction And Synthesis: Two investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of initial VTE were investigated as potential sources of between study heterogeneity.

Results: 18 studies involving 7515 patients were included in the analysis. The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3-5, and 3.1 events/year (1.7 to 4.9) in years 6-10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%).

Conclusions: In patients with a first episode of unprovoked VTE who completed at least three months of anticoagulant treatment, the risk of recurrent VTE was 10% in the first year after treatment, 16% at two years, 25% at five years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death. These estimates should inform clinical practice guidelines, enhance confidence in counselling patients of their prognosis, and help guide decision making about long term management of unprovoked VTE.

Systematic Review Registration: PROSPERO CRD42017056309.
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http://dx.doi.org/10.1136/bmj.l4363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651066PMC
July 2019

Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab in High-Risk Smoldering Multiple Myeloma.

Clin Cancer Res 2019 07 19;25(13):3772-3775. Epub 2019 Mar 19.

University Hospital, Internal Medicine V and National Center for Tumor Diseases Heidelberg, Heidelberg, Germany.

Purpose: IL6 is important for the growth and survival of myeloma cells. This study evaluated blocking IL6 with siltuximab to delay the transition from high-risk smoldering multiple myeloma (SMM) to multiple myeloma.

Patients And Methods: In a randomized, double-blind, placebo-controlled, multicenter study, 85 patients with high-risk SMM were randomized to 15 mg/kg siltuximab (43 patients) or placebo (42 patients). The primary endpoint was 1-year progression-free survival (PFS) rate, based on IMWG CRAB criteria. Secondary endpoints included progressive disease indicator rate, PFS, and safety.

Results: Median age was 62 years (range: 21-84); 57% were male and 87% had a baseline Eastern Cooperative Oncology Group score of 0. The 1-year PFS rate was 84.5% (siltuximab) and 74.4% (placebo). After a median follow-up of 29.2 months, 32.6% of PFS events occurred with siltuximab and 42.9% with placebo. Median PFS was not reached with siltuximab but was 23.5 months with placebo [HR 0.50 (95% confidence interval, 0.24-1.04); = 0.0597]. The safety profile of siltuximab was comparable with placebo. Most adverse events in the siltuximab group were grade 2/3; the most common serious adverse events were infections/infestations, and renal/urinary disorders. Mortality was low in both groups (3 deaths in the siltuximab group and 4 in the placebo group).

Conclusions: Although this study did not meet the prespecified protocol hypothesis criteria, data suggest that siltuximab may delay the progression of high-risk SMM.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3470DOI Listing
July 2019

HIT or miss? A comprehensive contemporary investigation of laboratory tests for heparin induced thrombocytopenia.

Pathology 2018 Jun 17;50(4):426-436. Epub 2018 Apr 17.

Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, NSW, Australia; NSW Health Pathology, NSW, Australia; Sydney Centres for Thrombosis and Haemostasis, Westmead, NSW, Australia.

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy, which in a proportion of patients causes platelet activation and thrombosis. Initial clinical assessment of the likelihood of HIT is facilitated by laboratory testing to confirm or exclude HIT. This prospective investigation was performed over an 18-month period, and has involved testing of over 300 test samples from over 100 consecutive patients. Clinical assessment by 4T score was supplemented by laboratory tests that comprised both immunological [lateral flow ('STiC'), chemiluminescence (AcuStar; HIT-IgG), ELISA (Asserachrom HPIA IgG)] and functional assays [SRA, platelet aggregation using whole blood ('Multiplate') and platelet rich plasma ('LTA')]. We observed both false positive and false negative test findings with most assays. Overall, the whole blood aggregation method provided a reasonable alternative to SRA for identifying functional HIT. STiC, AcuStar and ELISA procedures were fairly comparable in terms of screening for HIT, although STiC and AcuStar both yielded false negatives, albeit also resulting in fewer false positives than ELISA. The 4T score had less utility in our patient cohort than we were expecting, although there was an association with the likelihood of HIT. Nevertheless, we accept that our observations are based on limited test numbers. In conclusion, no single approach (clinical or laboratory) was associated with optimal sensitivity or specificity of HIT exclusion or identification, and thus, a combination of clinical evaluation and laboratory testing will best ensure the accuracy of diagnosis.
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http://dx.doi.org/10.1016/j.pathol.2017.11.089DOI Listing
June 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

Impact of salvage treatment modalities in patients with positive FDG-PET/CT after R-CHOP chemotherapy for aggressive B-cell non-Hodgkin lymphoma.

J Med Imaging Radiat Oncol 2018 Jun 25;62(3):432-439. Epub 2018 Mar 25.

Department of Radiation Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia.

Introduction: To compare outcomes of different salvage treatment modalities in patients with aggressive B-cell non-Hodgkin lymphoma (NHL) who remain FDG-PET positive after R-CHOP chemotherapy. Existing data on these patients with FDG-PET primary refractory disease are limited.

Methods: Patients with diffuse large B-cell lymphoma or grade 3 follicular lymphoma were retrospectively reviewed from the Prince of Wales Hospital databases. Eligibility criteria were: age≥18 years, treated with R-CHOP, with positive post-chemotherapy FDG-PET. Salvage treatment modalities were: radical radiotherapy (RT, dose≥30 Gy), high dose chemotherapy and autologous stem cell transplant (ASCT), or non-radical management. Survival was calculated from date of post-chemotherapy FDG-PET to last follow-up.

Results: Twenty-six patients from 2003-2015 met the inclusion criteria. Median age was 60 (range 19-84). Most had adverse baseline features: 21 (81%) stage III-IV, 24 (92%) bulky disease and nine (35%) skeletal involvement. Characteristics of PET-positivity post-chemotherapy were single site in 16 (62%), sites of prior bulk in 24 of 24, skeletal sites in five of nine, and able to be encompassed by RT in 21 (81%). Salvage treatment was: radical RT in 17 (65%), ASCT in four (15%) and non-radical in five (20%). Median follow-up of surviving patients was 31 months. Kaplan-Meier estimates of 3-year PFS and OS were 41% and 52%, respectively. By salvage modality, 3-year PFS was 51% for RT, 25% for ASCT and 20% for non-radical treatment, (P = 0.453); 3-year OS was respectively 65%, 25% and 40% (P = 0.173).

Conclusion: Patients with FDG-PET positive disease after R-CHOP for aggressive B-cell NHL are salvageable with radiotherapy.
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http://dx.doi.org/10.1111/1754-9485.12719DOI Listing
June 2018

Role of radiotherapy in management of gingival infiltration of chronic myelomonocytic leukaemia.

Intern Med J 2018 02;48(2):223-224

Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Faculty of Medicine, UNSW, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/imj.13701DOI Listing
February 2018

Initial strides for invent-VTE: Towards global collaboration to accelerate clinical research in venous thromboembolism.

Thromb Res 2018 03 31;163:128-131. Epub 2018 Jan 31.

International Network of Venous Thromboembolism Clinical Research Networks (INVENT), Canada; Respiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de Alcalá (IRYCIS), Madrid, Spain.

Venous thromboembolism (VTE) represents a major global burden of disease and requires collaborative efforts to conduct large, high-quality investigator-initiated and academically sponsored studies addressing the most relevant clinical questions. Owing to increasing regulatory requirements, the highly competitive nature of peer-reviewed funding and costs associated with conducting large, multinational clinical trials, completing practice-changing research constitutes a growing challenge for clinical investigators. As clinical trialists interested in VTE, we founded INVENT (International Network of Venous Thromboembolism Clinical Research Networks) in an effort to promote and accelerate patient-oriented, investigator-initiated, international collaborative research, to identify, prioritize and answer key clinical research questions for patients with VTE. We report on our activities to formalize the INVENT network and our accomplishments in our first year.
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http://dx.doi.org/10.1016/j.thromres.2018.01.050DOI Listing
March 2018

Long-term risk of recurrence after discontinuing anticoagulants for a first unprovoked venous thromboembolism: protocol for a systematic review and meta-analysis.

BMJ Open 2017 Sep 21;7(9):16950. Epub 2017 Sep 21.

Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Introduction: For patients with a first unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is a crucial clinical dilemma which has yet to be resolved. The decision to stop anticoagulant therapy (AT) after the initial 3-6 months or to continue AT indefinitely, is primarily governed by the long-term risk of recurrence when treatment is discontinued. This risk however, is not well established, hindering decision making.

Methods And Analysis: We will conduct a systematic review and a meta-analysis of studies involving patients diagnosed with a first, symptomatic unprovoked VTE or VTE provoked by minor transient risk factors, who have completed at least 3 months of initial AT; and who were followed-up for standardised time intervals of 1, 2, 5, 10 and 20 years (±3 months) after stopping AT. We will search (from inception to January 2017) MEDLINE, Embase and the Cochrane library for randomised controlled trials and prospective observational studies. Two reviewers will conduct all screening and data collection independently. The primary outcome of the rate of recurrent VTE at the standardised time intervals will be calculated for each study from the total number of recurrent events and the corresponding number of patient-years of follow-up. We will use a random-effects model to pool study results and report a weighted estimate of the absolute rate of recurrent VTE (events per 100 patient-years) over standardised time intervals of 1, 2, 5, 10 and 20 years after discontinuing anticoagulants.

Ethics And Dissemination: Ethical approval is not applicable for this study. Findings from this study will be disseminated through peer-reviewed journal publication as well as relevant national and international conference presentations.

Prospero Registration Number: CRD42017056309.
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http://dx.doi.org/10.1136/bmjopen-2017-016950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623531PMC
September 2017

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

Prekallikrein deficiency.

Pathology 2016 Oct 29;48(6):634-7. Epub 2016 Aug 29.

Haematology Department and SEALS Pathology, Prince of Wales Hospital, Randwick, NSW, Australia.

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http://dx.doi.org/10.1016/j.pathol.2016.07.005DOI Listing
October 2016

Long-term Anticoagulation With Rivaroxaban for Preventing Recurrent VTE: A Benefit-Risk Analysis of EINSTEIN-Extension.

Chest 2016 Nov 1;150(5):1059-1068. Epub 2016 Jun 1.

Bayer AG, Wuppertal, Germany.

Background: Short-term anticoagulant treatment for acute DVT or pulmonary embolism (PE) effectively reduces the risk of recurrent disease during the first 6 to 12 months of therapy. Continued anticoagulation often is not instituted because of the perception among physicians that the risk of major bleeding will outweigh the risk of new venous thrombotic episodes.

Methods: The authors performed a benefit-risk analysis by using the randomized EINSTEIN-Extension trial, which compared continued rivaroxaban with placebo in 1,197 patients with symptomatic DVT or PE who had completed 6 to 12 months of anticoagulation and in whom physicians had equipoise with respect to the need for continued anticoagulation. One-year Kaplan-Meier rates and rate differences of recurrent VTE and major bleeding were calculated. Benefits and risks were assessed using rate differences scaled to a population size of 10,000 patients treated for 1 year.

Results: Recurrent VTE occurred in eight recipients of rivaroxaban and 42 patients receiving placebo. In a population of 10,000 patients treated for 1 year, rivaroxaban treatment would have resulted in 665 (95% CI, 246-1,084) fewer recurrent VTEs than would placebo (number needed to treat = 15). Major bleeding occurred in four (0.7%) and zero patients, respectively. Rivaroxaban treatment would have resulted in 68 (95% CI, 2-134) more major bleeding events than would placebo (number needed to harm = 147). Kaplan-Meier analysis showed early recurrent VTE reduction with rivaroxaban that continued to improve throughout treatment; major bleeding increased gradually, plateauing at approximately 100 days.

Conclusions: A clinically important benefit and a favorable benefit-risk profile of continued rivaroxaban anticoagulation was observed.

Trial Registry: ClinicalTrials.gov; No.: NCT00439725; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2016.05.023DOI Listing
November 2016

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use.

Blood 2016 Mar 22;127(11):1417-25. Epub 2015 Dec 22.

Maastricht University Medical Center, Maastricht, The Netherlands.

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration.
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http://dx.doi.org/10.1182/blood-2015-08-665927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832477PMC
March 2016

Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1.

Blood 2015 Oct 27;126(17):2027-30. Epub 2015 Aug 27.

Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia; Northern Blood Research Centre, Kolling Institute of Medical Research.

Hemizygous deletion of a variable region on chromosome 11q containing FLI1 causes an inherited platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. These multisystem disorders are also characterized by heart anomalies, changes in facial structure, and intellectual disability. We have identified a consanguineous family with autosomal recessive inheritance of a bleeding disorder that mimics Paris-Trousseau thrombocytopenia but has no other features of the 11q23 deletion syndrome. Affected individuals in this family have moderate thrombocytopenia; absent collagen-induced platelet aggregation; and large, fused α-granules in 1% to 5% of circulating platelets. This phenotype was caused by a FLI1 homozygous c.970C>T-point mutation that predicts an arginine-to-tryptophan substitution in the conserved ETS DNA-binding domain of FLI1. This mutation caused a transcription defect at the promoter of known FLI1 target genes GP6, GP9, and ITGA2B, as measured by luciferase assay in HEK293 cells, and decreased the expression of these target proteins in affected members of the family as measured by Western blotting of platelet lysates. This kindred suggests abnormalities in FLI1 as causative of Paris-Trousseau thrombocytopenia and confirms the important role of FLI1 in normal platelet development.
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http://dx.doi.org/10.1182/blood-2015-06-650887DOI Listing
October 2015

Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study.

Thromb Haemost 2015 Aug 21;114(3):645-50. Epub 2015 May 21.

Jeffrey I. Weitz, Thrombosis & Atherosclerosis Research Institute, and McMaster University, Hamilton, Ontario, Canada, E-mail:

Patients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6-12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).
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http://dx.doi.org/10.1160/TH15-02-0131DOI Listing
August 2015

Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration.

Circulation 2014 Sep 25;130(13):1062-71. Epub 2014 Aug 25.

From the National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., A.C.K., R.M.); the Division of Internal and Cardiovascular Medicine and Stroke Unit, Department of Internal Medicine, University of Perugia, Perugia, Italy (C.B., G.A.); the Population Health Research Institute, McMaster University, Hamilton, ON, Canada (J.W.E.); the Department of Cardiothoracic and Vascular Sciences, University of Padua, Padua (P.P.); and the Department of Haematology, South Eastern Area Laboratory Services (SEALS), Prince of Wales Hospital, Sydney, Australia (T.A.B.).

Background: In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued. The Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed that aspirin reduces this risk, but they were not individually powered to detect treatment effects for particular outcomes or subgroups.

Methods And Results: An individual patient data analysis of these trials was planned, before their results were known, to assess the effect of aspirin versus placebo on recurrent VTE, major vascular events (recurrent VTE, myocardial infarction, stroke, and cardiovascular disease death) and bleeding, overall and within predefined subgroups. The primary analysis, for VTE, was by intention to treat using time-to-event data. Of 1224 patients, 193 had recurrent VTE over 30.4 months' median follow-up. Aspirin reduced recurrent VTE (7.5%/yr versus 5.1%/yr; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90; P=0.008), including both deep-vein thrombosis (HR, 0.66; 95% CI, 0.47-0.92; P=0.01) and pulmonary embolism (HR, 0.66; 95% CI, 0.41-1.06; P=0.08). Aspirin reduced major vascular events (8.7%/yr versus 5.7%/yr; HR, 0.66; 95% CI, 0.50-0.86; P=0.002). The major bleeding rate was low (0.4%/yr for placebo and 0.5%/yr for aspirin). After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR, 0.58; 95% CI, 0.40-0.85; P=0.005). Prespecified subgroup analyses indicate similar relative, but larger absolute, risk reductions in men and older patients.

Conclusions: Aspirin after anticoagulant treatment reduces the overall risk of recurrence by more than a third in a broad cross-section of patients with a first unprovoked VTE, without significantly increasing the risk of bleeding.

Clinical Trial Registration Url: www.anzctr.org.au. Unique identifier: ACTRN12611000684921.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.008828DOI Listing
September 2014

Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin.

JAMA Intern Med 2014 Jun;174(6):947-53

Maastricht University Medical Centre, Maastricht, the Netherlands.

Importance: Combined anticoagulant and aspirin therapy is associated with increased bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented.

Objective: To estimate the bleeding risk of combined anticoagulant (rivaroxaban or enoxaparin-vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous thromboembolism.

Design, Setting, And Participants: Prospective analysis of observational data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246 patients enrolled from 2007 to 2009.

Exposure: Bleeding event rates during exposure to NSAID and aspirin therapy were compared to time without exposure.

Main Outcomes And Measures: Days of NSAID or aspirin use and nonuse, clinically relevant bleeding event and major bleeding event rates by patient-years, and hazard ratios.

Results: During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding during NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years, compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95% CI, 1.51-3.75]). For aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during aspirin nonuse (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100 patient-years during aspirin nonuse (HR, 1.50 [95% CI, 0.86-2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA anticoagulation regimens.

Conclusions And Relevance: Among patients with venous thromboembolism receiving anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased risk of clinically relevant and major bleeding.
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http://dx.doi.org/10.1001/jamainternmed.2014.946DOI Listing
June 2014

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies.

Thromb J 2013 Sep 20;11(1):21. Epub 2013 Sep 20.

Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects.

Methods: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75.

Results: A total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority < 0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p = 0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots, and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban were similar compared with standard-therapy.

Conclusion: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups.

Trial Registration Einstein-pe: ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193.
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http://dx.doi.org/10.1186/1477-9560-11-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850944PMC
September 2013

Low-dose aspirin for preventing recurrent venous thromboembolism.

N Engl J Med 2012 Nov 4;367(21):1979-87. Epub 2012 Nov 4.

Department of Haematology, South Eastern Area Laboratory Services (SEALS), Prince of Wales Hospital, Sydney, Australia.

Background: Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism.

Methods: We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism.

Results: During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P=0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P=0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P=0.22) or serious adverse events.

Conclusions: In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.).
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http://dx.doi.org/10.1056/NEJMoa1210384DOI Listing
November 2012

Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT: results of a large Australian study.

Thromb Haemost 2012 Mar 11;107(3):575-83. Epub 2012 Jan 11.

Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.

Heparin-induced thrombocytopenia (HIT) remains a challenge, with diagnosis confirmed only by functional assays. The gold standard 14C-serotonin release assay (SRA) is highly sensitive but technically challenging and unsuitable for routine use. We conducted a large study to validate whole blood impedance aggregometry (WBIA) as a suitable diagnostic tool for HIT. WBIA and SRA were used to test 181 samples positive for H-PF4 antibodies by PaGIA or ELISA. Using the same high responder donor, 77 samples were positive by WBIA (aggregation with low-dose but not high-dose heparin). Using the strict definition for SRA positivity, 72 samples were true HIT. In nine samples, serotonin release with high-dose heparin dropped by > 50% but was still >20%; these were retested after a one-half dilution and 8/9 became positive. Ten other samples were discrepant between the two assays: one strongly positive (89% release) and six weakly positive samples by SRA (average release 56%) were WBIA negative. When these samples were retested using a random donor, only two remained SRA positive. Three samples were strongly WBIA positive but SRA negative; two were retested by SRA with 0.5IU/ml heparin and one became positive. Under controlled conditions, using the same selected high-responder donor, WBIA and SRA performed similarly with slightly increased sensitivity of the WBIA when using the strict definition of SRA positivity. WBIA is easy to perform with rapid turn-around time and warrants a multi-laboratory trial to complete its validation as a confirmatory assay for platelet-activating HIT antibodies.
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http://dx.doi.org/10.1160/TH11-09-0631DOI Listing
March 2012

The direct factor Xa inhibitor rivaroxaban.

Med J Aust 2009 Apr;190(7):379-83

Gosford Hospital, Gosford, NSW, Australia.

Warfarin and heparin are the traditional mainstay anticoagulant therapies for treating thromboembolic disease. These drugs, with a documented history of utility, also have inherent difficulties in usage; in particular, the complicated monitoring and numerous drug-drug interactions of warfarin, and the need for parenteral administration of heparins. New agents have recently emerged that target specific elements of the clotting pathway. Rivaroxaban, which inhibits activated factor X (Xa), is currently in clinical trials and is the most advanced factor Xa inhibitor. The drug offers once-daily oral dosing, with no need for injections, dose titration, or frequent blood tests to monitor the international normalised ratio. It has a rapid onset of action and, although there is no specific antidote, it has a short plasma elimination half-life (about 5-9 hours). Evidence from recently published large-scale phase III clinical trials shows rivaroxaban to be superior to enoxaparin for prophylaxis of venous thromboembolism after major orthopaedic surgery. Studies have shown rivaroxaban to have a sound safety profile, with an incidence of bleeding similar to enoxaparin in phase III clinical trials. Few side effects and drug-drug interactions between rivaroxaban and common medications have been found thus far, although some interactions with potent cytochrome P450 3A4 inhibitors have been observed. It is hoped that rivaroxaban may be used as a first-line anticoagulant for prophylaxis of venous thromboembolic disease in postsurgical patients.
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http://dx.doi.org/10.5694/j.1326-5377.2009.tb02453.xDOI Listing
April 2009

Venous thromboembolism - management in general practice.

Aust Fam Physician 2009 Jan-Feb;38(1-2):36-40

St George Clinical School, University of New South Wales.

The diagnosis, treatment and management of venous thromboembolism prophylaxis are increasingly becoming the responsibility of the general practitioner. Effective treatments exist, as do guidelines for management of hospitalised patients. However, very little research has been done into the implementation of management strategies in community based patients. In 2008, an estimated 15 000-23 000 Australians experienced venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Retrospective studies report mortality rates following VTE of 5-23%, although in symptomatic patients with adequate anticoagulation, mortality is 1-2%.
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May 2009