Tinzaparin for venous thromboembolism in patients with renal impairment – a single-centre, prospective pilot study Author details: James Yeung1,2, Caroline H. K. Dix1,2, Angus G. Ritchie3,4,5, Marian Kow6, Vivien M. Y. Chen1,4 1. Department of Haematology, Concord Cancer Centre, Concord Repatriation General Hospital, Concord West, NSW 2139 2. Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, NSW 2050 3. Department of Renal Medicine, Concord Repatriation General Hospital, Concord West, NSW 2139 4. Concord Clinical School, The University of Sydney, Sydney, NSW 2006 5. Menzies Centre for Health Policy, The University of Sydney, Sydney, NSW 2006 6. Pharmacy Department, Concord Repatriation General Hospital, Concord West, NSW 2139 Corresponding author: James Yeung Address: Department of Haematology, Concord Cancer Centre, Concord Repatriation General Hospital, Concord West, NSW 2139 Telephone: +61 2 9767 6648 Email: [email protected] Acknowledgements: No financial grants, funding, industrial links or conflicts of interest to declare This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/imj.15010 This article is protected by copyright. All rights reserved. Abstract Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin, and standard of care in cancer-associated VTE. Tinzaparin has the highest molecular weight of all LMWH, and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20ml/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20ml/min and in cancer-associated VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50ml/min with an indication for anticoagulation. Tinzaparin anti-Xa levels were tested at days 2, 7 and 14 (+/- one day) and transition to oral anticoagulants were allowed at clinician discretion. No accumulation of tinzaparin was seen into day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor), and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and BSA-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on day 2, and this effect was lost when patients with CrCl >50ml/min were excluded. Data from our cohort confirms previous pharmacokinetic studies using therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50ml/min with no signs of accumulation. Bleeding and death outcomes were also comparable to other trials using tinzaparin in cancer-associated VTE. Tinzaparin is an attractive alternative anticoagulant with once-daily administration in a range of potential indications. This article is protected by copyright. All rights reserved. Introduction Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin, and until recently, as sole standard of care in cancer- associated VTE (CA-VTE). There is an unmet need for appropriate LMWH use in patients with CA-VTE and chronic kidney disease (CKD), particularly towards creatinine clearance of 30mL/min where accumulation may occur. In Australia, enoxaparin and dalteparin are widely available and standard dosing is recommended in patients with Cockcroft-Gault creatinine clearance (CrCl) >30mL/min with some centers recommending dose adjustment in moderate renal impairment (CrCl 30-50mL/min).1 Dose-reductions and anti-factor Xa (anti-FXa) monitoring are recommended for CrCl <30mL/min within the product information for enoxaparin.2 Tinzaparin has the highest molecular weight of all LMWH at 6500 Da, resulting in a lower reliance on renal clearance than other LMWHs.3 This expands the use of tinzaparin to CrCl 20mL/min without requirement for dose-adjustment.4 Direct comparison between enoxaparin and tinzaparin in patients with renal impairment (CrCl 20-50mL/min) within the prophylaxis setting demonstrated accumulation of enoxaparin but not tinzaparin.4 Outside of Australia, tinzaparin is widely used in both CA-VTE and CKD, with multiple trials showing safety and efficacy in both settings. In CA-VTE, the CATCH and LITE trials compared tinzaparin to warfarin, demonstrating reduced clinically-relevant, non-major bleeding (CRNMB) and reduced CA-VTE recurrence in the tinzaparin arms respectively.5, 6 In CKD, the TRIVET trial showed no accumulation using tinzaparin for patients with CrCl >20mL/min, but there remains concern over elderly patients with diminished renal function.7, 8 Another trial, IRIS, evaluated elderly patients with CKD and VTE using tinzaparin as a bridge to vitamin K antagonist and initially there was concern about increased deaths in the tinzaparin arm.9 This was later attributed to an uneven distribution of risk factors, and a sub-study from IRIS showed no accumulation of tinzaparin and no signal for increased bleeding.10 Further prospective trials in patients aged 75 and above with CKD (mean CrCl 35mL/min) showed no evidence of accumulation using prophylactic dose, and use in patients aged 70 and above with CKD (mean CrCl 51mL/min) also demonstrated safety at therapeutic dose for 30 days.4, 11 However, in Australia, tinzaparin is not widely available – it can be accessed via the Special Access Scheme (SAS), but is not subsidized by the Pharmaceutical Benefits Scheme (PBS) and is not generally available on formulary in NSW hospitals. This article is protected by copyright. All rights reserved. In our ageing population, there is an increasing demand for anticoagulation in patients with CKD, with longer-term anticoagulation required in CA-VTE. We explored the ability to deliver short and long term therapeutic tinzaparin in patients with CrCl 20-50mL/min using a prospective study at Concord Hospital, with measurement of anti-FXa levels to test for accumulation within the first fourteen days and outcomes of bleeding, recurrent thrombosis and mortality. Methods A tinzaparin pilot program was implemented at Concord Repatriation General Hospital, Sydney under ethics approval (CH62/6/2018-077). Inclusion criteria were requirement for therapeutic anticoagulation with CrCl between 20- 50mL/min or Chronic Kidney Disease Epidemiology (CKD-EPI) estimated glomerular filtration rate (eGFR) 20- 50mL/min/1.73m2. Patients with CrCl or CKD-EPI eGFR outside this range were included at physician discretion. Patients were excluded if they had a history of allergy or anaphylaxis to heparin or other LMWH products, a history of heparin induced thrombocytopenia, or if subcutaneous injections could not be administered for the duration of the treatment. Patients were selected via recommendations from inpatient hematology consultation or the outpatient thrombosis management clinic. CrCl was calculated using the Cockcroft-Gault equation, and estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation.12, 13 Body surface area was calculated using the Du Bois formula.14 CrCl was standardized (St-CrCl) against the patient’s BSA using the following equation – = 1.73/ . A dose level of 175units/kg once daily tinzaparin was used rounded to nearest syringe strength size. SAS applications were submitted to the Therapeutic Goods Administration (TGA) for approval. After commencement, tinzaparin anti-FXa levels were taken at days 2, 7 and 14 (+/- one day), 3-5 hours after dosing. Choice of day and peak levels were in line with Pautas et al.11 These were measured according to local protocols using the Stago STA-R Max (Diagnostica Stago, Paris, France) with a chromogenic anti-FXa assay. Dose-adjustment was made at the physician’s discretion or outside the therapeutic tinzaparin anti-FXa level of 0.5-1.5 units/mL.11 Further tinzaparin anti-FXa levels were taken after dose-adjustment to ensure ongoing safety and efficacy. Physicians had the option to transition patients to warfarin or direct oral anticoagulants (DOACs) depending on the degree and progress of renal impairment. Data on baseline characteristics (age, gender, height, weight and serum creatinine) and follow-up (duration of treatment, complications, outcomes and cause of death) were collected and analyzed using Prism 7 (GraphPad Software, La Jolla, California, USA). Complications were assessed by Common Terminology Criteria for Adverse Events (version 5.0) using electronic medical record review.15 This article is protected by copyright. All rights reserved. Results Twenty patients (ten males and ten females) received tinzaparin between June 2017 and September 2018. Demographic data is summarized in Table 1. Median age was 78 years (range 60-90 years). Eight patients were placed on tinzaparin until bridged to an alternative anticoagulant with a median duration of 0.2 months, and twelve patients were placed on extended duration LMWH therapy (median 6.3 months, range 0.2 – 15.1 months). Seventeen patients had CrCl or CKD-EPI eGFR 20-50mL/min/1.73m2 between 20-50mL/min, and within this group, five patients had active