Tinzaparin for Venous Thromboembolism in Patients with Renal Impairment – a Single-Centre, Prospective Pilot Study

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

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.

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 nearest𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 syringe strength𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 size𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶. SAS𝑥𝑥 applications𝐵𝐵𝐵𝐵𝐵𝐵 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

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 malignancy. Three individuals with CA-VTE were included despite being outside inclusion criteria: (1) obese patient CKD-EPI enrolled with eGFR 56mL/min/1.73m2 and background of metastatic breast cancer and fluctuating renal function. The patient also experienced both extension of DVT and a clinically relevant bleeding episode on therapeutic enoxaparin while eGFR was 30mL/min/1.73m2; (2) patient with DVT and progressive multiple myeloma and concern for imminent kidney injury; (3) patient with advanced ovarian cancer, CA-VTE and CrCl of 18mL/min. Other indications for anticoagulation and baseline information are listed in Table 1. Two dose adjustments were made: one due to persistent low anti-FXa level (0.19 units/mL), one patient was dose-reduced at physician discretion, after an episode of minor bleeding (epistaxis) on day 2, despite an anti-FXa level within acceptable range of 1.25 units/mL. No patients required dose adjustments were required for high anti-FXa levels. Eight patients transitioned to oral anticoagulant therapy (six to warfarin, one to apixaban and one to rivaroxaban), and one patient transitioned to enoxaparin as renal impairment improved.

Complications: Over the fifteen-month period, no incidences of recurrent VTE were reported. Major bleeding occurred in two patients: one gastrointestinal hemorrhage and one abdominal hematoma. The episode of gastrointestinal hemorrhage complicated an intensive care unit stay for type 2 respiratory failure and acute kidney injury, tinzaparin was ceased and the patient ultimately died from respiratory failure. The episode of abdominal hematoma occurred after 8 months of tinzaparin therapy for breakthrough PE on warfarin and high-risk atrial fibrillation (CHA2DS2-Vasc score of 6). Tinzaparin was ceased and warfarin was restarted. Three patients experienced minor bleeding: one grade 2 epistaxis and two grade 1 abdominal hematomas.

Of patients prescribed extended duration tinzaparin, five patients continue on tinzaparin with median treatment duration of 6.3 months (range 0.2 – 15.1 months). Two patients ceased tinzaparin therapy – one due to exacerbation of pre-existing hematuria, and one was withdrawn as part of end-of-life care. Four patients died during follow-up, all attributable to the patients’ comorbidities.

This article is protected by copyright. All rights reserved. Tinzaparin levels: Tinzaparin anti-FXa level at each time point was found to have normal distribution using the D’Agostino and Pearson normality test (p > 0.05). Figures 1 and 2 show the distribution of tinzaparin anti-FXa levels and highlighted patients with adverse events. No evidence of accumulation was seen by day 14 (Figure 1). One patient received a dose reduction for epistaxis, however the tinzaparin anti-FXa level remained within the expected range. No measure of creatinine clearance (CrCl, eGFR or St-CrCl) significantly correlated with anti-FXa levels at any of the three time points. There was a positive correlation between weight and anti-FXa levels on day 2 (r = 0.49, p = 0.02) and day 7 (r = 0.52, p = 0.046), but not on day 14 (r = 0.4, p = 0.13). Scatterplots highlighting patients with adverse events demonstrate that tinzaparin anti-FXa level did not predict adverse events (Figure 2). None of CrCl, eGFR or St-CrCl correlated with duration of therapy.

Discussion Our small cohort shows the deliverability of tinzaparin within the Australian context and confirms previous pharmacological studies of its use in patients with CrCl between 20-50mL/min, showing no signal for accumulation. While steady state was not expected at day 2 for tinzaparin, day 2 levels were collected in line with previous pharmacokinetic studies for comparison with day 7 and day 14.11, 16 We found that no measure of creatinine clearance correlated with anti-FXa levels at day 7 or 14. While there was a positive correlation between weight and anti-FXa levels at day 2 and 7, the association was not present at day 14. Thus, similar to previous pharmacokinetic studies and recommendations, our study supports the simple weight-based dosing without adjustment for renal function.11 Of note, the TRIVET study used trough levels to show increased rates of accumulation in patients with CrCl <30mL/min not on dialysis. We did not measure trough levels, however trough levels may be of benefit for patients with creatinine clearance 20-30mL/min.8

In keeping with the known risk of bleeding complications in anticoagulated patients with renal impairment, bleeding rates were high in this cohort. No deaths were attributable to tinzaparin use, but the twelve month mortality rate in our cohort of 20% (n = 4) is comparable to the IRIS study and reflects the high level of comorbidity in these patients .9 Two patients died of progressive malignancy – one multiple myeloma, and the other a combination of transitional cell carcinoma and prostate cancer. Of those without malignancy – one patient died of small bowel ischemia, and one due to type 2 respiratory failure. The patient with small bowel ischemia was not on tinzaparin at time of ischemia, as he had already transitioned to warfarin in an admission prior to the ischemic event. The presence of high-risk factors including active malignancy, indication for anticoagulation being VTE treatment rather than atrial fibrillation, and low CrCl (acute or chronic) likely reflects the higher mortality rate. Although direct comparison is not possible, the CATCH study comparing vitamin K antagonists with tinzaparin for treatment of CA-VTE reported 13.6% bleeding and 33.4%

This article is protected by copyright. All rights reserved. death in the tinzaparin arm after six months’ follow-up, and the IRIS study (tinzaparin treatment in older population) reported 11.9% bleeding and 11.5% death in the tinzaparin arm after 90 days’ follow-up.5, 9

No measurement of CrCl or eGFR predicted bleeding events. Further, method of measurement for creatinine clearance or eGFR did not correlate with adverse events or duration of therapy. Historically, studies involving heparin- based or DOACs included a patient on the basis of CrCl. CrCl is limited by variations in weight, muscle mass, protein restriction, inter-laboratory measurement amongst others.17 Standardization of CrCl with BSA is recommended for drug dosing.18 CKD-EPI is a reflection of steady-state eGFR and has become the new standard in routine reporting,18 but cannot be directly compared to CrCl, and is not accurate in acute kidney injury.19 Our analysis brings into question the optimal method for including patients for heparin-based anticoagulants and further comparative studies are required using CrCl, CKD-EPI or other methods of estimation and standardization. Anti-FXa levels taken within the first 14 days did not predict bleeding events. An unexpected positive correlation between weight with tinzaparin anti-FXa level was seen on day 2 and day 7 but not on day 14 – i.e. patients with higher weight had higher anti-FXa levels, which is the opposite to the usual concerns of using LMWH in those with low body weight. This effect may reflect the weight-based dosing of LMWH but no correlation was seen on multivariate analysis (data not shown).

Circumventing the need for unfractionated heparin (UFH) infusions in transitioning to vitamin K antagonists reduces hospital stays.20 Once-daily dosing tinzaparin provides a simpler alternative for selected patients and can be self- administered or provided via Hospital in the Home services. Based on local calculations at Concord Repatriation General Hospital, the daily cost of tinzaparin is similar to that of enoxaparin. Given the potential reduction in inpatient hospital stays, significant cost savings may be achieved.

Recent advances in the use of DOACs has created excitement in improving treatment for CA-VTE, especially in improving adherence to oral over subcutaneous therapy.21 The HOKUSAI VTE Cancer study demonstrated non- inferiority of oral edoxaban compared to subcutaneous dalteparin, with a lower rate of recurrent VTE offset by a higher rate of major bleeding.22 The SELECT-D study comparing oral rivaroxaban with subcutaneous dalteparin also showed no difference in VTE recurrence but higher clinically relevant, non-major bleeding.23 ADAM VTE using apixaban has also shown comparable results, and further use of DOACs in primary prophylaxis of CA-VTE have demonstrated encouraging findings.24, 25 However, all DOAC versus LMWH clinical trials have excluded patients with CrCl less than 30mL/min and current guidelines suggest avoidance of DOACs in patients with increased bleeding risk including those with renal impairment or lumen-based cancers.26 Thus tinzaparin is likely to still play a role in patients with CrCl <30mL/min, and may be preferred in patients with gastrointestinal or genitourinary solid malignancies and CrCl >30mL/min where an increased bleeding signal was identified for edoxaban in HOKUSAI.22

This article is protected by copyright. All rights reserved. Limitations: Our study was limited by low accrual rates during fifteen months of data collection, with a low proportion (20%; n = 4) of patients with CrCl between 20-30mL/min, and three patients outside CrCl range. Our cohort represents the real- world experience where high-risk patients may not be suitable for anticoagulation or may receive UFH owing to physician experience, and further studies in this patient group are required.

Conclusion

Tinzaparin can be used in patients with advanced CKD, down to Cockcroft-Gault creatinine clearance 20mL/min, and offers a once daily dosing regimen. Although small, our pilot study at Concord Repatriation General Hospital demonstrates tinzaparin as a deliverable low molecular weight heparin in a high-risk population, although with high rates of bleeding. Whilst DOACs are emerging as a convenient choice in CA-VTE, and UFH remains the standard of care in creatinine clearance <20mL/min, tinzaparin is an attractive alternative in selected patients within the Australian context.

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