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Background Treatment of low-risk patients with isolated symptomatic distal deep vein thrombi (IDDVT) is uncertain. Objective: assess whether two weeks of therapeutic anticoagulation is efficacious/safe for IDDVT. Primary outcome: symptomatic three-month venous thromboembolism (VTE) incidence in the two-week anticoagulation group. Secondary outcomes included post-thrombotic syndrome (PTS) and bleeding. Methods Prospective multicentre cohort study. Consecutive low-risk IDDVT patients enrolled within 72 h of diagnosis and treated with therapeutic dose enoxaparin or rivaroxaban. At two weeks, patients had repeat complete whole leg compression ultrasound (CUS)/clinical review. If resolution of leg symptoms AND no radiological evidence of thrombus extension, anticoagulation was stopped. If ongoing symptoms and/or radiographic extension within distal veins, anticoagulation was continued for four more weeks. Patients with extension into the popliteal vein on two-week ultrasound were treated off-study. Patients were reviewed at three and six months. Findings/interpretation 241 eligible patients received ≥2 weeks anticoagulation. 167/241 (69%) were assigned to the 2-week anticoagulation group; 71/241 (30%) to the six-week anticoagulation group; 3/241 patients (1%) had extension into the popliteal vein on two-week CUS. Two patients in the two-week anticoagulation group had symptomatic IDDVT recurrence in ≤3 months; VTE recurrence 2/156; 1.3%(95% CI 0.05–4.85%). 69% of patients had complete resolution of symptoms within two weeks. Six-month PTS rates were 8/184, 4.4%(95% CI 2.1–8.5%). No major bleeding was reported. Our findings suggest it's safe/efficacious to stop therapeutic anticoagulation at two weeks in low-risk IDDVT patients with resolution of symptoms/no extension on ultrasound. This could replace 6–12 weeks of anticoagulation for ambulatory, low-risk IDDVT patients. Trial registration ClinicalTrials.gov NCT01252420

Summary Background Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide–dexamethasone and carfilzomib–dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone in patients with relapsed multiple myeloma. Methods This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib–dexamethasone (isatuximab group) or carfilzomib–dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. Findings Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77–not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32–0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. Interpretation The addition of isatuximab to carfilzomib–dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. Funding Sanofi. Video Abstract Video abstractYouTube link: https://youtu.be/5kXtQQlzRh4

Background Conflicting recommendations exist addressing the management of direct oral anticoagulants (DOACs) for invasive dental procedures. Objectives To determine the safety of DOAC continuation compared to warfarin continuation for dental extractions with regards to bleeding outcomes. Methods A single-center, prospective, cohort study was performed to compare 7-day bleeding outcomes between patients who continued their DOAC, and patients on warfarin with an International Normalized Ratio (INR) between 2.0 and 4.0. Blood tests including oral anticoagulant drug levels were measured immediately prior to extraction. The gauze used to apply pressure to the socket was weighed before and after extraction to estimate blood loss. Patients were contacted by phone 2 and 7 days after extraction. Results Eighty-six patients on a DOAC had a total of 145 teeth extracted, and 21 patients on warfarin had 50 teeth extracted. There were no major bleeding events. The rate of minor plus clinically relevant nonmajor bleeding was comparable between the DOAC and warfarin cohorts (36% and 43%, respectively; odds ratio, 0.75; 95% confidence interval, 0.29-1.98). Preextraction apixaban and dabigatran levels were comparable between bleeders and nonbleeders, while rivaroxaban levels were higher in those who bled. The weight change of gauze used to tamponade the socket was similar between the 2 cohorts. Conclusion Dental extractions on patients continuing DOACs led to bleeding rates similar to patients on warfarin with an INR between 2.0 and 4.0. There is no need to adjust DOAC dosing prior to dental extractions.

Background: There is limited data to guide prescribing of all available anticoagulants in obese patients, in particular those weighing > 150kg or with a BMI > 40kg/m2. We aimed to examine anticoagulant prescribing patterns in obese patients in Australia and New Zealand including choice of agent and dosing, determine whether patients with obesity achieve appropriate direct oral anticoagulant (DOAC) levels and evaluate the efficacy and safety of anticoagulation in obese patients. Methods: Patients with a BMI > 35kg/m2 or weight > 120kg receiving anticoagulant therapy are prospectively identified at 7 sites in Australia and New Zealand. Demographic data, indication for anticoagulation and choice of anticoagulant are collected at baseline. At follow-up visits, drug specific levels, dose adjustments and clinical progress (symptoms, imaging, recurrent thrombosis and adverse events) are recorded. Results: 155 patients have been recruited across seven sites (recruitment ongoing). The median age of patients was 53 (range 22-85) and 49% of patients were male. 77 (50%) of patients were anticoagulated for pulmonary embolus (PE) while 40% were anticoagulated for deep vein thrombosis (DVT) without PE. Initial anticoagulant prescribed was apixaban in 37 patients, dabigatran in 4 patients, rivaroxaban in 57 patients, low molecular weight heparin (LMWH) in 29 patients and warfarin in 28 patients (Table 1). A subset of patients initially received LMWH for 5-14 days prior to transition to a DOAC (rivaroxaban in 7, dabigatran in 6). There was cross-over between agents during the study period. Table 2 demonstrates median peak and trough DOAC levels. All peak apixaban levels and 25 of 37 (68%) peak rivaroxaban levels were within the therapeutic ranges published by the International Council for Standardization in Haematology (Gosselin, Thromb Haemost. 2018). Assessment of appropriate trough levels was limited by the limit of detection at different laboratories. 27 patients receiving enoxaparin had at least one peak Anti-Xa level (target peak 0.5-1.2U/ml). The median enoxaparin dose to achieve therapeutic peak Anti-Xa was 0.9mg/kg (range 0.52-1.3). 15 patients weighing > 150kg had a recorded peak Anti-Xa, 10 of these patients were prescribed a capped dose of 150mg BD (weight range 155-290kg) and nine had a therapeutic Anti-Xa and one had a supratherapeutic Anti-Xa measurement. One patient had a PE on apixaban 5mg twice daily (in the setting of suspected non-compliance), one patient had a new confirmed PE after 4 days of non-compliance with rivaroxaban 20mg daily and another patient had a confirmed recurrence on therapeutic warfarin. 1 patient had a PE when warfarin was withheld for emergency surgery. An equivocal recurrence occurred on enoxaparin with a supratherapeutic Anti-Xa (1.76 U.ml) and 1 DVT occurred on dabigatran for a cardiac indication (no drug level available). One patient had recurrent superficial thrombophlebitis on rivaroxaban 20mg daily (peak 301ng/L and trough Conclusion: There is limited data to guide prescribing of all anticoagulants in obese patients, in particular in patients weighing > 150kg or BMI > 40kg/m2. There is increasing use of DOACs in Australia and New Zealand in patients with obesity given the ease of administration and lack of monitoring required. Despite the recommendation to perform DOAC levels in this group of patients, interpretation of levels is difficult due to a lack of well validated therapeutic ranges with clinical correlation. Further data regarding the clinical utility of DOAC levels, appropriate dosing strategy for enoxaparin, and clinical outcomes in this population is required. Our registry provides data regarding drug levels in this population, prescribing characteristics and clinical outcome data. Disclosures No relevant conflicts of interest to declare.

Rationale, aims and objectives Therapies utilized in patients with clinically significant haemoglobin disorders appear to vary between clinicians and units. This study aimed to investigate the processes of evidence implementation and medical decision making in the care of such patients in NSW, Australia. Methods Using semi-structured interviews, 11 haematologists discussed their medical decision-making processes with particular attention paid to the use of published evidence. Transcripts were thematically analysed by a single investigator on a line-by-line basis. Results Decision making surrounding the care of patients with significant haemoglobin disorders varied and was deeply contextual. Three main determinants of clinical decision making were identified - factors relating to the patient and to their illness, factors specific to the clinician and the institution in which they were practising and factors related to the notion of evidence and to utility and role of evidence-based medicine in clinical practice. Conclusions Clinicians pay considerable attention to medical decision making and evidence incorporation and attempt to tailor these to particular patient contexts. However, the patient context is often inferred and when discordant with the clinician's own contexture can lead to discomfort with decision recommendations. Clinicians strive to improve comfort through the use of experience and trustworthy evidence.

Aim To comprehensively review the health needs of patients living with clinically significant haemoglobinopathies (thalassaemia and sickle-cell disease (SCD)) in New South Wales, Australia. Methods A survey-based health needs assessment was undertaken in outpatients cared for at five tertiary institutions in metropolitan and regional centres. Sixty-three of 121 adults (approximately 80–90% of adult patients with transfusion-requiring haemoglobinopathies in New South Wales) completed an in-house and commercial health-related quality assessment survey (SF-36v2). Results Subjects came from more than eight world regions, with those with SCD being more likely to be born outside of Australia than subjects with thalassaemia (P 12 months = 27%) and surgical splenectomy (55.6%). Use of hydroxyurea in SCD was less than expected with only 46.6% of subjects having prior use. Lack of universal access to magnetic resonance imaging-guided chelation (international best practice) was evident, although 65.5% had been able to access magnetic resonance imaging through clinical trial, or self-funding. Conclusions Patients with SCD and thalassaemia experience considerable morbidity and mortality and require complex, multidisciplinary care. This study revealed both variance from international best practice and between specialist units. The results of this research may provide the impetus for the development of clinical and research networks to enable the uniform delivery of health services benchmarked against international standards.

Bergman and Diamond (2013) have articulately and accurately identified many of the reasons why, and the problems associated with, the identification of people with sickle cell disease (SCD) as “difficult patients.” In our view, however, by suggesting that this problem is best dealt with through an ethics service consultation (ESC), they misconstrue the source of the difficulties of SCD and fail to appreciate the limitations of bioethics in seeking to improve the health care experience of people living with SCD. We provide empirical data describing an Australian perspective of SCD care, which highlights not only the complex issues raised by this illness but the challenges it creates for medical decision making and for bioethics. We suggest that the difficulties of SCD are protean in nature and that more can be gained from thinking again about the limits of bioethics and contemporary medicine than it can by seeking solace in clinical ethics consultation.

Evidence-based medicine (EBM) has been rapidly and widely adopted because it claims to provide a method for determining the safety and efficacy of medical therapies and public health interventions more generally. However, as others have noted, EBM may be riven through with cultural bias, both in the generation of evidence and in its translation. We suggest that technological and scientific advances in medicine accentuate and entrench these cultural biases, to the extent that they may invalidate the evidence we have about disease and its treatment. This creates a significant ethical, epistemological and ontological challenge for medicine.