Satarupa Choudhuri

BACKGROUND: Patients with chronic kidney disease (CKD) have an increased risk of venous thromboembolism (VTE) and atrial fibrillation (AF). Anticoagulants have not been studied in randomised controlled trials with CrCl < 30 ml/min. The objective of this review was to identify the impact of different anticoagulant strategies in patients with advanced CKD including dialysis. METHODS: We conducted a systematic review of randomized controlled trials and cohort studies, searching electronic databases from 1946 to 2022. Studies that evaluated both thrombotic and bleeding outcomes with anticoagulant use in CrCl < 50 ml/min were included. RESULTS: Our initial search yielded 14,503 papers with 53 suitable for inclusion. RCTs comparing direct oral anticoagulants (DOACs) versus warfarin for patients with VTE and CrCl 30-50 ml/min found no difference in recurrent VTE events (RR 0.68(95% CI 0.42-1.11)) with reduced bleeding (RR 0.65 (95% CI 0.45-0.94)). Observational data in haemodialysis suggest lower risk of recurrent VTE and major bleeding with apixaban versus warfarin. Very few studies examining outcomes were available for therapeutic and prophylactic dose low molecular weight heparin for CrCl < 30 ml/min. Findings for patients with AF on dialysis were that warfarin or DOACs had a similar or higher risk of stroke compared to no anticoagulation. For patients with AF and CrCl < 30 ml/min not on dialysis, anticoagulation should be considered on an individual basis, with limited studies suggesting DOACs may have a preferable safety profile. CONCLUSION: Further studies are still required, some ongoing, in patients with advanced CKD (CrCl < 30 ml/min) to identify the safest and most effective treatment options for VTE and AF.

A survey to gain insight into anticoagulant prescribing practice in the setting of chronic kidney disease (CKD) across the UK was disseminated via renal and haematology networks. Areas of anticoagulant use included patients with venous thromboembolism (VTE), requiring thromboprophylaxis for VTE, Atrial Fibrillation (AF) and nephrotic syndrome.An online-survey was disseminated via British Haematology Society, UK Kidney Association, and Renal Pharmacy Group over a five month period. All responses were voluntary and anonymous.Among 117 responses there were 49 nephrology doctors, 47 renal pharmacists and 20 haematology clinicians. A specialist multidisciplinary team to discuss the specific anticoagulant management of these patients was only available to 3% (4/117) respondents. Renal function estimate used for anticoagulant dosing was mainly Cockcroft-Gault for pharmacists and haematology but lab-based estimates were used by nephrology doctors. Therapeutic dose of Low Molecular Weight Heparin was mostly likely to be reduced by one-third when used for VTE treatment, with the majority of units undertaking anti-Xa monitoring in CKD stage 5 and dialysis. Direct-acting Oral Anticoagulants are being used in patients with nephrotic syndrome, those with CKD stage 5 and on dialysis for VTE and AF in the absence of license in these indications.This survey highlighted the significant differences between anticoagulant prescribing in CKD between two professional specialties and marked variation between centres in anticoagulant management strategies employed for these patients. With gaps still existing in the evidence base and answers to these not expected within the next few years, development of a best-practice guideline would be warranted to support clinicians in this field.

OBJECTIVE: Cancer patients are at high risk of venous thromboembolism (VTE), a significant cause of cancer-related death. Historically, low molecular weight heparins (LMWH) were the gold standard therapy for cancer-associated VTE, but recent evidence supports the use of direct factor Xa inhibitors in cancer-associated VTE and this is now reflected in many guidelines. However, uptake of direct factor Xa inhibitors varies and guidance on the use of direct factor Xa inhibitors in specific cancer sub-populations and clinical situations is lacking. This review presents consensus expert opinion alongside evaluation of evidence to support healthcare professionals in the use of direct factor Xa inhibitors in cancer-associated VTE. METHODS: Recent guidelines, meta-analyses, reviews and clinical studies on anticoagulation therapy for cancer-associated VTE were used to direct clinically relevant topics and evidence to be systematically discussed using nominal group technique. The consensus manuscript and recommendations were developed based on these discussions. RESULTS: Considerations when prescribing anticoagulant therapy for cancer-associated VTE include cancer site and stage, systemic anti-cancer therapy (including vascular access), drug-drug interactions, length of anticoagulation, quality of life and needs during palliative care. Treatment of patients with kidney or liver impairment, gastrointestinal disorders, extremes of bodyweight, elevated bleeding or recurrence risk, VTE recurrence and COVID-19 is discussed. CONCLUSION: Anticoagulant therapy for cancer-associated VTE patients should be carefully selected with consideration given to the relative benefits of specific drugs when individualizing care. Direct factor Xa inhibitors are typically the treatment of choice for preventing VTE recurrence in non-cancer patients and should also be considered as such for cancer-associated VTE in most situations.

Abstract Introduction: The COVID-19 pandemic hit the United Kingdom in early 2020. High infection rates prompted concern for immunocompromised patients, including patients with AML receiving intensive chemotherapy. CPX-351 (Europe: Vyxeos ® Liposomal; US: Vyxeos ®), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults in Europe and in adults and pediatric patients aged ≥1 year in the United States. Despite concerns about intensive chemotherapy-related myelosuppression, the National Cancer Research Institute AML Working Group recommends that CPX-351 should continue to be administered in patients with adverse-risk cytogenetics and/or secondary AML during the pandemic. We report 2 patients with AML who were successfully treated with CPX-351 in the United Kingdom during the COVID-19 pandemic. Methods: The patients were diagnosed and managed per institutional guidelines. Two patients received CPX-351 induction (daunorubicin 44 mg/m 2 + cytarabine 100 mg/m 2) on Days 1, 3, and 5 (Days 1 and 3 for second induction) and CPX-351 consolidation (daunorubicin 29 mg/m 2 + cytarabine 65 mg/m 2) on Days 1 and 3, all by 90-minute IV infusion, during the pandemic. Results: The first patient was a 67-year-old male who presented with generalized fatigue in June 2020 with comorbidities of type 2 diabetes, diabetic nephropathy, and leg ulcers. Blood counts demonstrated a hemoglobin count of 79 g/L, white blood cell count of 0.7×10 9, platelet count of 58×10 9/L, and neutrophil count of 0.2×10 9/L. A bone marrow biopsy revealed AML-MRC with 40% blasts, and the patient had wild-type FLT3, NPM1, and SRSF2. The patient achieved morphologic and cytogenetic remission after 2 CPX-351 induction cycles. The patient then received 1 CPX-351 consolidation cycle but was not a candidate for transplant due to diabetic nephropathy. Tolerability improved with each cycle; the patient experienced neutropenic sepsis during the first induction, a flare up of leg ulcers and cellulitis during the second induction, and no tolerability concerns during the consolidation cycle. After the first induction, recovery of neutrophils and platelets occurred around Day 35 and Day 28, respectively (Figure 1), and counts recovered more quickly with each cycle. This patient was managed without contracting COVID-19 or experiencing any pandemic-related complications. The second patient was a 69-year-old female who presented with pancytopenia in February 2020 with no significant past medical or drug history. Her hemoglobin count was 66 g/L, white blood cell count was 0.6×10 9/L, platelet count was 17×10 9/L, and neutrophil count was 0.3×10 9/L. The patient was diagnosed with AML-MRC with mutated NPM1, SRSF2, IDH2, and JA2. During the first CPX-351 induction cycle, the patient contracted COVID-19. Some symptoms were present, but the patient did not become significantly unwell from COVID-19. Despite count recovery, the patient remained positive by nasal/oral PCR swab test for several weeks, delaying the delivery of the second CPX-351 induction cycle. After the second CPX-351 cycle began, the patient once again became positive for COVID-19 by PCR swab. The patient remained positive for longer than the first infection but was largely asymptomatic during the cycle (apart from a bout of sepsis). After a period of approximately 3 months from the previous CPX-351 cycle, the patient received a CPX-351 consolidation cycle and achieved complete remission with no measurable residual disease by NPM1 mutation in the bone marrow (Figure 2). The patient was eligible for transplant but declined. Conclusions: Two patients with AML-MRC were successfully treated with CPX-351 during the COVID-19 pandemic, despite one of the patients contracting and variably testing positive for the disease. During the pandemic, it is important to weigh the benefits of treating AML with curative intent versus the risks of immunosuppression and potential COVID-19 infection. Individualized decisions must be made for each patient based on disease, treatment, and COVID-19 risk factors through discussion with a multidisciplinary team. Although treating patients with AML with CPX-351 during the pandemic can be challenging, it remains an option for appropriate patients with newly diagnosed t-AML or AML-MRC. Figure 1 Figure 1. Disclosures Munisamy: Roche: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Choudhuri: AstraZeneca, Bristol-Myers Squibb, Jazz Pharmaceuticals, and Pfizer: Consultancy.