MI L

Volume 8 , No. 1 January 2018

This Medicines Information Leaflet is produced locally to optimise the use of medicines by encouraging prescribing that is safe,
clinically appropriate and cost-effective to the NHS.

Treatment of venous thromboembolism (VTE) with apixaban or rivaroxaban in adults

This guideline sets out the use of apixaban and Summary of Product Characteristics (SPCs) do not
rivaroxaban in the acute treatment and secondary have an upper limit for body weight, the
prevention of venous thromboembolism (VTE), International Society on Thrombosis and
both deep vein thrombosis (DVT) and pulmonary Haemostasis (ISTH) suggest that DOACs should not
embolism (PE). Both oral anticoagulants are direct be used in patients with a weight of more than
inhibitors of factor Xa with apixaban being our 120kg. This is because there are limited clinical data
agent of choice. available for patients at the extreme of weight, and
the available pharmacokinetic/pharmacodynamic
Choice of anticoagulant drug evidence suggests that decreased drug exposures,
Treatment of DVT and PE can be with one of the reduced peak concentrations and shorter half-lives
following options: occur with increasing weight, which raises concerns
about under-dosing.
1. Warfarin
Warfarin may be preferred by some patients on the 3. Dalteparin
basis that there are decades of experience and an Dalteparin remains the gold standard treatment for
antidote. It is preferred in patients with liver cancer-related VTE and further information is
dysfunction or significant renal impairment. It can available in MIL volume 7, number 10.
also be an advantage to have a monitored
treatment in the poorly compliant. For further Whilst it is recognised that dabigatran (an oral
information see MIL volume 5, number 8. thrombin inhibitor) and edoxaban (a factor Xa
inhibitor) are also licensed for VTE they are not
2. Factor Xa inhibitors considered within these guidelines because they
Apixaban and rivaroxaban are convenient for are deemed a less practical option; parenteral
initiation of treatment as the quick onset of action anticoagulation for at least five days is required
negates the need for parenteral therapy. before dabigatran or edoxaban can be initiated.

The efficacy of apixaban and rivaroxaban are Contraindications to anticoagulation

similar to that of warfarin for acute VTE. However, The following substantially increase the risk of
compared to warfarin, both are significantly less major bleeding:
likely to cause major bleeding. Additionally,  Current or recent gastrointestinal ulceration
apixaban is significantly less likely to cause clinically  Presence of malignant neoplasm at high risk of
relevant non-major bleeding. Rivaroxaban (but not bleeding
apixaban) had an increased risk of GI bleeding  Recent brain or spinal injury
compared with warfarin. When used for long-term  Recent brain, spinal or ophthalmic surgery
secondary prevention the prophylactic dose of  Recent intracranial haemorrhage
apixaban (2.5 mg bd) had no more bleeding than  Known or suspected oesophageal varices
placebo. The treatment dose of rivaroxaban (20 mg  Arteriovenous malformation
od) had a significantly increased risk of bleeding  Vascular aneurysms, major intraspinal or
over placebo but the prophylactic dose (10 mg od) intracerebral vascular abnormalities
has been shown to be similarly effective and has a  Acute stroke (contact stroke team)
bleeding risk similar to aspirin. Although the

Medicines Management and Therapeutics Committee January 2018

Oxford University Hospitals
If anticoagulation is felt to be contraindicated, the patient should be discussed with Haematology (bleep
5529) and an IVC filter considered.

Starting apixaban and rivaroxaban and therapy

Prior to starting treatment, a baseline coagulation screen, full blood count, U&Es (including renal function)
and liver function must be performed. Table 1 provides guidance on the recommended doses. Patients should
be started on a therapeutic dose of anticoagulation if diagnostic investigations are suspected to take longer
than 1 hour (PE) or 4 hours (DVT). It will usually be simplest to give a treatment dose of
dalteparin to provide 24 hours of cover. If the risk of therapy is felt to outweigh the benefit, this should be
documented in the medical notes.

Table 1: Dosing advice for apixaban and rivaroxaban

Apixaban Rivaroxaban
Standard Dose Days 1-7: 10mg bd Days 1-21: 15mg bd with food
Days 8 onwards: 5mg bd Day 22 onwards: 20mg od with food
After 6 months: 2.5mg bd* (see below) After 6 months, 10mg od* (see below)
Renal Warfarin preferred if CrCl less than 30ml/min Warfarin preferred if CrCl less than 30ml/min
impairment Do not use if CrCl less than15ml/min Do not use if CrCl less than 15ml/min
Day 22 onwards if CrCl 30-49ml/min; consider
reducing to 15mg od if the patient’s risk of
bleeding outweighs the risk of recurrence
Hepatic Contraindicated in patients with hepatic disease Contraindicated in patients with hepatic disease
impairment associated with coagulopathy and clinically associated with coagulopathy and clinically
relevant bleeding risk. Use with caution in mild relevant bleeding risk including cirrhotic patients
and moderate hepatic impairment (Child Pugh A with Child Pugh B and C.
or B). Not recommended in severe hepatic
impairment.
Switching from Apixaban should be started instead of the next Rivaroxaban should be started instead of the next
dalteparin scheduled administration of dalteparin (if a scheduled administration of dalteparin
patient has receives 7 days or more of dalteparin,
then apixaban can be started at 5mg bd (as for
day 8 onwards).
Switching to Give the first dose of dalteparin at the time the Give the first dose of dalteparin at the time the
dalteparin next apixaban dose would have been due next rivaroxaban dose would have been due
Switching from Stop warfarin and start apixaban once INR is less Stop warfarin and start rivaroxaban once INR 2.5
warfarin than 2 or less (not forgetting higher initial dosing when
within three weeks of an acute event)
Switching to Co-administer apixaban and warfarin for 2 days. Co-administer rivaroxaban and warfarin until INR
warfarin After 2 days, check INR prior to next apixaban 2 or greater.
dose and continue until INR 2 or greater

*For patients taking long-term apixaban or rivaroxaban as secondary prevention the manufacturers indicates
the dose should be reduced following completion of 6 months of treatment. A risk-benefit assessment might
suggest that this decrease in dose could take place after 3 months. For rivaroxaban in patients in whom the
risk of recurrent DVT or PE is considered high continuing 20 mg once daily should be considered. Although not
licenced continuing 5 mg bd apixaban could also be considered in this group.

Medicines Management and Therapeutics Committee January 2018

Oxford University Hospitals
 3 Medicines Information Leaflet

Missed doses contraindicated (except when UFH is being used

1. Apixaban to maintain patency of a central venous or arterial
If a dose is missed, the patient should take the catheter)
apixaban immediately and then continue with
twice daily intake as before. Monitoring
Patients with poor compliance need careful
2. Rivaroxaban assessment. INR monitoring enables assessment of
If a dose is missed during the 15 mg twice daily compliance with warfarin and therefore is the
treatment phase (day 1 - 21), the patient should preferred option in such patients. Given no
take the missed dose immediately and take the monitoring is required for DOACs, assessment and
next dose on time (if the next dose is due two 15 reinforcement of compliance do not take place. In
mg tablets can be taken together). The patient addition, the anticoagulant effects from DOACs
should then continue with 15 mg twice daily. wear off much quicker than those of warfarin due
to a much shorter half-life.
If a dose is missed during the once daily treatment
phase (day 22 and onwards), the patient should Pregnancy & Breast feeding
take the missed dose immediately, and continue Apixaban and rivaroxaban should be avoided in
on the following day with the once daily intake as pregnant patients and those who are breast
recommended. The dose should not be doubled feeding. Women of child-bearing potential should
within the same day to make up for a missed dose. be counselled appropriately.

Interactions Duration of therapy

The use of factor Xa inhibitors is not Patients with proximal DVT or PE should be
recommended in patients receiving concomitant treated for at least 3 months. For a first proximal
systemic treatment with azole-antimycotics (such DVT or a PE associated with transient risk factors
as ketoconazole, itraconazole, voriconazole and treatment will usually stop at three months. Long
posaconazole) or HIV protease inhibitors (such as term treatment will be considered for recurrent
ritonavir). These active substances are strong thrombosis, patients with an on-going risk factor,
inhibitors of both CYP3A4 and P-gp and therefore or unprovoked proximal DVT or PE. It may be
may increase apixaban and rivaroxaban plasma possible to decide on finite (3 months) or
concentrations to a clinically relevant degree. Co- indefinite anticoagulation when treatment is
administration of factor Xa inhibitors with strong started but many patients (e.g. those with a first
CYP3A4 inducers e.g. rifampicin, phenytoin, unprovoked proximal DVT or PE) will need to be
carbamazepine, phenobarbital or St. John’s Wort, reviewed at three months to decide whether to
may lead to reduced apixaban and rivaroxaban stop anticoagulation or whether to continue
plasma concentrations. We therefore recommend indefinitely.
that strong CYP3A4 inducers should not be co-
administered with factor Xa inhibitors when Patient or carer education
treating acute venous thromboembolism. It is vital that all patients newly started on
Macrolide antibiotics, such as clarithromycin and anticoagulation therapy receive written and verbal
erythromycin, may inhibit metabolism of factor Xa information from a healthcare professional before
inhibitors and therefore caution should be applied discharge. Patient booklets containing alert cards
if co-prescribed. Co-administration of rivaroxaban are available from pharmacy to all staff for both
with dronedarone should be avoided given limited apixaban and rivaroxaban. Patients should be
clinical data. Care should also be taken if patients encouraged to carry the alert cards with them at
are treated concomitantly with medicinal products all times. Further counselling advice can be found
affecting haemostasis (e.g. NSAIDS, aspirin, on the Anticoagulation & Thrombosis website.
platelet aggregation inhibitors or other
antithrombotic agents). Further information for Discharge arrangements
cardiac patients, can be found in MIL Vol 8, No 5. Patients should be provided with enough supply of
Concomitant treatment with unfractionated apixaban or rivaroxaban to complete the first 3
heparin (UFH), dalteparin or fondaparinux is weeks of treatment. GPs will then take over the
 4 Medicines Information Leaflet

prescribing to provide further supplies of Pharmaceutical Society of Great Britain

medication. State on the discharge summary how London, UK. September 2014- March 2015
long the patient should be anticoagulated for; this 2. Summary of Product Characteristics (SPC) for
will usually be three months or to continue rivaroxaban (Xarelto®), Bayer plc accessed via
indefinitely. Many patients will need a three www.medicines.org.uk.
month review to make this decision. Patients can 3. Summary of Product Characteristics (SPC) for
be referred to the thrombosis consultants at the apixaban (Eliquis®), Bristol-Myers Squibb-Pfizer
Oxford Haemophilia and Thrombosis Centre for accessed via www.medicines.org.uk.
this three month review if required. 4. Bauersachs R et al. Oral Rivaroxaban for
Symptomatic Venous Thromboembolism – The
Reversal Einstein Investigators. NEJM 363: 2499-2510
There is currently no specific antidote to apixaban 5. Agnelli G et al. Oral Apixaban for the Treatment
or rivaroxaban. of Acute Venous Thromboembolism. NEJM
369: 799-808
Effect on coagulation tests 6. Medicines and Healthcare products Regulatory
If the PT and/or APTT are prolonged, levels are Agency (MHRA). Drug Safety Update October
likely to be significant but a normal PT and APTT 2013 accessed via www.mhra.gov.uk
do not exclude significant drug levels (especially 03/12/2013
with apixaban). If necessary drug levels can be 7. Weitz JI et al. Rivaroxaban or Aspirin for
measured with a specific assay (based on Xa Extended Treatment of Venous
inhibition). Further information is available on the Thromboembolism. NEJM 376: 1211-1222
Anticoagulation & Thrombosis website under
section 5.
Prepared by:
Vicki Price, Lead Anticoagulation & Thrombosis
Elective surgery Pharmacist and Dr David Keeling, Haematology
For patients undergoing elective surgery, apixaban Consultant.
and rivaroxaban should be discontinued at least 24
hours before the surgery is planned and for high Review date: March 2019
bleeding risk surgery this should be 48-72 hours,
see MIL Vol 10, No 5 for further details. In
patients undergoing a procedure which carries a
low bleeding risk, full dose anticoagulation can be
resumed 24 hours post-procedure assuming
adequate haemostasis was achieved at surgery
(discuss with operating surgeon). In patients
undergoing a procedure which carries a high
bleeding risk, re-institution of full dose post-
operative anticoagulation should not be until 48-
72 hours after the procedure. The decision on
when to reinstate therapeutic anticoagulation
post-operatively should be made by the operating
surgeon.

Bleeding, overdose and emergency surgery

Please refer to MIL Vol 10, No 6 on apixaban and
rivaroxaban.

References
1. British National Formulary (BNF) 68th Edition
British Medical Association and the Royal