CHHS18/146

Canberra Hospital and Health ServicesClinical GuidelineApixaban Use in Adults with Severe Kidney DiseaseContents

Contents....................................................................................................................................1

Guideline Statement.................................................................................................................2

Background........................................................................................................................... 2

Key Objective........................................................................................................................ 2

Alerts.....................................................................................................................................2

Scope........................................................................................................................................ 2

Section 1 – Apixaban Target Trough Levels and Dosage...........................................................3

Section 2 – Planned Elective Surgery........................................................................................3

Section 3 – Haemorrhage..........................................................................................................4

Implementation........................................................................................................................ 4

Related Policies, Procedures, Guidelines and Legislation.........................................................5

References................................................................................................................................ 5

Definition of Terms...................................................................................................................6

Search Terms............................................................................................................................ 6

Attachments..............................................................................................................................6

Attachment 1 – Apixaban Clinician Discussion Points...........................................................7

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Guideline Statement

BackgroundNovel Oral Anticoagulants (NOACs) are a warfarin alternative that are indicated by preventing recurrent venous thromboembolism and arterial thromboembolism related to atrial fibrillation. In Australia, use at a creatinine clearance below 25 mL/min is listed as a contraindication by the Therapeutic Goods Administration. This contra-indication pre-dates more recent data on the pharmacokinetics of NOACs in dialysis patients.

Apixaban has the least renal excretion of any NOAC. A multi-dose study in dialysis patients indicated that a dose of apixaban 2.5mg twice daily resulted in a predicted drug exposure equivalent to a 5mg twice daily dose in subjects with normal renal function6-8 Target apixaban trough levels appear to be a median of 80 to 100ng/mL for atrial fibrillation (95% range 41 to 230 ng/mL) and 63 (95% range 22 to 167) for VTE. Apixaban is not removed by haemodialysis.9

Key ObjectiveTo provide Canberra Hospital and Health Services (CHHS) staff with information regarding the administration of apixaban to patients with severe chronic kidney disease.

Alerts Apixaban increases the risk and severity of bleeding. Concurrent use of medication that is strong inhibitors or inducers of CYP3A4 since these

will affect the intensity of apixaban on the clotting system. Current use of apixaban is a contraindication to transplantation. It should not generally

be used in patients active on the deceased donor renal transplant waiting list.

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Scope

This Clinical Guideline applies to medical staff of Canberra Hospital Health Service (CHHS).

Prescription of apixaban to patients with estimated creatinine clearance <25mL/min must occur only with the express permission of a renal physician and after the patient has provided informed consent for use. Clinicians prescribing apixaban are to ensure patients receive appropriate counselling (see attachment).

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Section 1 – Apixaban Target Trough Levels and Dosage

The target trough level 50 to 200ng/mL when measured at ACT Pathology.

Indication Patient Group Apixaban Initial Dose (for 7 days)

Subsequent Apixaban Dose

Apixaban Dose after 6 months

Measure trough anti-Xa levels*

Non-massive venous thromboembolism

Non-dialysis 10mg bd 5 mg bd 2.5mg bd 7 days, 14 days then every 3 months

Non-massive venous thromboembolism

Dialysisand non-dialysis

10mg bd 2.5 mg bd 2.5mg bd 7 days, 14 days then every 3 months

Non valvular Atrial fibrillation

Dialysis and non-dialysis with, age ≥80 years or body weight ≤60 kg

2.5 mg bd 2.5 mg bd 2.5 mg bd 7 days then every 3 months

Non valvular Atrial fibrillation

Non-dialysis with, age <80 years and body weight >60 kg

5 mg bd 5 mg bd 5 mg bd 7 days then every 3 months

Apixaban trough levels are based on measurement immediately prior to dosing on a 12 hour dosing regimen. The pathology request form must specify “anti-Xa level (apixaban).”

Current American Food and Drug Administration advice is not to alter the apixaban dose in patients on dialysis. The above table takes into account more recent information (discussed in the Background above)

Apixaban concentration is affected by strong inducers and inhibitors of CYP3A4 Exercise clinical judgment regarding dosing in the very elderly (age >80 years) and very

small patients (<45 kg).

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Section 2 – Planned Elective Surgery

Patients taking apixaban who require elective surgery should not take the apixaban for 48 – 72 hours prior to the surgery. The anticoagulant effect will usually be negligible after withholding apixaban for 48-72 hours or if the anti-Xa activity (apixaban) is <20 U/mL. Depending on the perceived risk of clotting and bleeding, withholding apixaban for up to 5 days prior to procedure may be appropriate. The use of bridging doses of heparin should be considered on a case by case basis, taking into account the risk of bleeding and of thrombosis.

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Section 3 – Haemorrhage

In the event of clinically significant active bleeding take a sample of the patient’s blood from either a vein or artery as seems most clinically appropriate at the time. The sample may be taken from a peripheral or central blood sampling device and should be sent for coagulation studies including anti-Xa activity (apixaban). Give the patient a systemic dose of prothrombinex 30-50units/kg ideal body weight.

After the administration of prothrombinex in some circumstances a second sample may be taken for the purposes of quality assurance. This should not be used for acute management of the patient. The sample may be taken from a peripheral or central blood sampling device (as seems most clinically appropriate at the time) and should be sent for coagulation studies including anti-Xa activity (apixaban). The sample should not be sent earlier than 20 minutes after completion of the prothrombinex infusion or more than 2 hours after.

Note: prothrombinex does not reduce the concentration of apixaban and normalisation of the prothrombin time does not indicate the absence of anti-Xa effect. For this reason local haemostatic measures are essential whenever possible. Local haemostatic measures include local pressure (such as with use of finger, hand or sandbag to the area, use of a tourniquet or inflation of a blood pressure cuff above systolic blood pressure), closure of any actively bleeding vessels through endoscopic, angiographic or surgical techniques.

Use of intravenous desmopressin (DDAVP), 0.3 mcg/kg, may help reduce bleeding for those taking antiplatelet agents and those with possible uraemic bleeding.

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Implementation

Following approval of this Guideline an education session will be provided to renal unit doctors.

The clinical guideline will be available to all staff on the policy register. It will be communicated to affected staff via team meetings.

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Related Policies, Procedures, Guidelines and Legislation

Policies Consent and Treatment Patient Identification and Procedure Matching Policy

Procedures Patient Identification and Procedure Matching Procedure Patient Identification – Pathology Specimen Labelling Procedure

Legislation Health Records (Privacy and Access) Act 1997 Human Rights Act 2004

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References

1 Van Der Meersch H, De Bacquer D, De Vriese AS. Vitamin K antagonists for stroke prevention in hemodialysis patients with atrial fibrillation: A systematic review and meta-analysis. American Heart Journal. 2017; 184: 37-46.

2 Tanner NC, Da Silva A. Medical adjuvant treatment to increase patency of arteriovenous fistulae and grafts. Cochrane Database of Systematic Reviews. 2015.

3 Brandenburg VM, Kramann R, Rothe H, Kaesler N, Korbiel J, Specht P, et al. Calcific uraemic arteriolopathy (calciphylaxis): data from a large nationwide registry. Nephrol Dial Transplant. 2017; 32: 126-32.

4 FDA Apixaban Labelling. Vol. 2017.5 Chan KE, Giugliano RP, Patel MR, Abramson S, Jardine M, Zhao S, et al. Nonvitamin K

Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF. J Am Coll Cardiol. 2016; 67: 2888-99.

6 Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients. J Am Soc Nephrol. 2017; 28: 2241-48.

7 Leil TA, Feng Y, Zhang L, Paccaly A, Mohan P, Pfister M. Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose. Clinical pharmacology and therapeutics. 2010; 88: 375-82.

8 Pfizer Canada Inc. & Bristol-Myers Squibb Canada. Product Monograph. Eliquis Apixaban Tablets 2.5 mg and 5 mg Anticoagulant. 2016.

9 Wang X, Tirucherai G, Marbury TC, Wang J, Chang M, Zhang D, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. The Journal of Clinical Pharmacology. 2016; 56: 628-36.

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Definition of Terms

NOAC: Novel oral anticoagulant.CKD: Chronic kidney failureBd: twice a dayCYP3A4: Cytochrome P-450 subtype 3A4Ideal body weight in kg: is 22 multiplied by the square of the patient’s height in meters. (height2 x 22)ng: Nanogram

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Search Terms

Apixaban, anticoagulant, dialysis, chronic kidney disease

Attachments

Attachment 1 – Apixaban Clinician Discussion Points

Disclaimer: This document has been developed by ACT Health, Canberra Hospital and Health Services specifically for its own use. Use of this document and any reliance on the information contained therein by any third party is at his or her own risk and Health Directorate assumes no responsibility whatsoever.

Policy Team ONLY to complete the following:Date Amended Section Amended Divisional Approval Final Approval 25/05/2018 New Document Girish Talulikar, ED,

MedicineCHHS Policy Committee

This document supersedes the following: Document Number Document Name

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Attachment 1 – Apixaban Clinician Discussion Points

Apixaban (Eliquis) checklist of information to be conveyed to patients with severe kidney failure prior to obtaining informed consent.

Apixaban is a drug that reduces blood clotting. It is licensed for use in Australia for patients at risk of blood clots from atrial fibrillation (an irregular heart beat) and for patients that have had a clot in a deep vein (DVT) or lungs (PE). It can also be used to prevent clots in your veins after a hip or knee replacement surgery.

Apixaban is not licensed for use in people with severe kidney failure in Australia. This is because there is limited information available on its use in this patient group. Drugs are sometimes prescribed for unlicensed (“off label”) use by doctors and when this occurs informed consent from the patient is important.

All medications that reduce blood clotting, including apixaban, can increase the risk of bleeding. The bleeding can be minor resulting in things such as bruising or more severe and potentially life threatening. We do not know if this risk is greater for patients with severe kidney disease.

An alternative to apixaban may be warfarin, which also reduces the risk of blood clots but can also increase the risk of bleeding. Unlike apixaban, warfarin has numerous food and drug interactions, and the need for regular monitoring and dose adjustments can be difficult for patients. In addition, the variable levels of warfarin in the blood may result in the blood being either over or under anticoagulated some of the time potentially making it less effective. There is also very limited or consistent data for the effectiveness or risks of warfarin in patients with severe kidney failure.

Apixaban has a relatively consistent anticoagulant effect so a particular dose usually leads to the desired level of anticoagulation – neither too much, nor too little. It is not affected by changes in diet and is affected by only a limited number of other medications. Information is available on how kidney function or dialysis affects the levels of apixaban in the blood so we are able to determine what dose is likely to give the same blood levels seen in healthy people taking the recommended dose without kidney disease.

The effects of warfarin can be reversed with vitamin K. Vitamin K is an antidote to warfarin. This reversal is not immediate, but if severe bleeding occurs, it can often be reduced within a few hours. Currently apixaban effects cannot be reliably reversed and there is no antidote. The anticoagulant effect usually wears off within 2 days of stopping the medication. If severe bleeding occurs measures can be taken to control this.

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