Direct Oral Anticoagulants (DOACs) for treatment of DVT or PE, or prevention

against recurrent DVT or PE (in Adults)

V1.2 Last reviewed: 09/12/2021 Review date: 31/10/2024

There are four DOACs available for the treatment of DVT or PE, and prevention of recurrent DVT or PE, these are:
• Apixaban (Eliquis®)
• Dabigatran etexilate (Pradaxa®)
• Edoxaban (Lixiana®)
• Rivaroxaban (Xarelto®)
Clinical trials have shown that DOACs are all non-inferior to vitamin K antagonists such as Warfarin for treatment of DVT and PE, as well as evidence for their
long-term use for protection against recurrent DVT or PE.
There are no clinical trials comparing the DOACs, so there is no evidence that one DOAC is superior to any other with respect to efficacy or side effects.

The updated NICE guideline published in March 2020 (NG158) recommends that patients with a suspected DVT or PE should receive interim anticoagulation
that can be continued if DVT or PE is subsequently confirmed. This means that it is now acceptable to use either Apixaban (Eliquis®) or Rivaroxaban (Xarelto®)
as an alternative to Low Molecular Weight Heparin (LMWH) injections (e.g. Enoxaparin) for suspected DVT or PE whilst investigations are being carried out.
Although it is imperative that baseline blood tests including FBC, UE, LFT and clotting screen are taken, the results do not need to be known prior to starting
anticoagulation, as long as they are reviewed within 24 hours.

Secondary care will:

• Ensure that patient continues on an appropriate anticoagulant if subsequently confirmed to have a DVT or PE.
• Guide the planned duration of anticoagulation.

A switch between anticoagulants would be required in certain situations, such as:

• Intolerance of vitamin K antagonists or one of the DOACs,
• Poor INR control or time in therapeutic range with vitamin K antagonists,
• Change in other medication meaning that current anticoagulant no longer suitable,
• Patient choice.

This information sheet is intended to assist primary care clinicians in initiating interim anticoagulation for suspected DVT or PE, or when switching between
anticoagulants.
Full guidance about how to switch between parenteral anticoagulants or Warfarin and DOACs can be found on the summary of product characteristics (SPC) of
the DOAC being initiated. For DOAC to DOAC switches, initiate the new medicine when the next dose is due. This is all summarised in Appendix 1 on page 8.
 When starting or switching to a DOAC it is important to consider certain factors such as:
• body weight (initial clinical trials only included patients between 50kg and 120kg), there is increasing evidence to support the use of DOACs in patients
weighing above 120kg, and recent ISTH guidance suggests that Rivaroxaban (Xarelto®) or Apixaban (Eliquis®) can be used for the management of DVT or PE in
patients with obesity irrespective of weight (although this guidance does not cover the use of these agents in the context of Atrial Fibrillation); this ISTH guidance
has been adopted locally by the NUH Anticoagulation Service for patients coming through the DVT pathway.
• renal function (see below prescribing information),
• interacting medications (see below prescribing information),
• the differences between dosing regimens (e.g. once daily or twice daily, whether taken with food or not; see below prescribing information).
Reversibility may be an important consideration in certain cases (e.g. high risk of bleeding or patient choice). There is a specific reversal agent available for:
• Warfarin,
• Dabigatran etexilate (Pradaxa®),
• Apixaban (Eliquis®) – although only approved for use in the context of major bleeding related to gastrointestinal tract,
• Rivaroxaban (Xarelto®) – although only approved for use in the context of major bleeding related to gastrointestinal tract.
Although the risk of bleeding is lower than Warfarin, there is no specific reversal agent yet available for Edoxaban (Lixiana®), although there are strategies
available to manage patients in the context of major bleeding (which would also be adopted in patients on Apixaban (Eliquis®) or Rivaroxaban (Xarelto®) in the
context of major bleeding not related to the gastrointestinal tract).
With respect to anticoagulation used long term as prevention against recurrent DVT or PE, the updated NICE guidance published in March 2020 (NG158)
recommends that patients are offered continued treatment with the anticoagulant they started when DVT or PE was confirmed, or consider switching to
Apixaban (Eliquis®) if the current anticoagulant isn’t well tolerated. This assessment of choice of anticoagulant for those patients continuing long term
anticoagulation will usually be made in secondary care as part of a follow up appointment.

When switching from Warfarin onto a DOAC in a patient where the plan for long term anticoagulation was made historically, the above considerations (i.e. body
weight, renal function, interacting medications and the differences between dosing regimens) apply, and there are scenarios where specific DOACs may be
preferred to Apixaban (Eliquis®):
• Once a day dosing regimen: Rivaroxaban (Xarelto®) 10mg od
• Concerns related to high thrombotic risk: Rivaroxaban (Xarelto®) 20mg od, Dabigatran etexilate (Pradaxa®) or Edoxaban (Lixiana®)
If advice about which DOACs to consider for an individual patient is required, please liaise with Consultant Haematologist (e.g. via Advice and Guidance service).
There are certain scenarios where anticoagulation for prevention against recurrent DVT or PE should not be changed without consultation with secondary care:
• Renal impairment (i.e. creatinine clearance below 30ml/min)
• Active cancer
• Established triple positive antiphospholipid syndrome
• Extremes of body weight (i.e. body weight less than 50kg, or greater than 150kg)
2
Prescribing information for Direct Oral Anticoagulants (DOACs) for DVT or PE
See product SPCs for full prescribing information

Medicine Rivaroxaban (Xarelto®▼) Apixaban (Eliquis®) Dabigatran etexilate (Pradaxa®) Edoxaban (Lixiana®▼)

Licensed Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
indication Not recommended in PE patients who are haemodynamically unstable or may receive thrombolysis.
Standard Dosing Day 1-21 15 mg BD Day 1-7 10 mg BD After at least 5 days of parenteral After at least 5 days of parenteral
for DVT / PE Day 22 + 20 mg OD Day 8+ 5mg BD anticoagulation: anticoagulation:
After 6 months 10 mg OD After 6 months 2.5mg BD 150mg BD 60mg OD
or 20 mg OD if risk of Reduced to 110mg BD if: Reduced to 30mg OD if:
recurrent DVT/PE is NB: 5mg BD is ->80yrs -CrCl 15-50ml/min
high not a licenced -taking verapamil -low body weight (≤60kg)
(See SPC) long-term dose -increased risk of bleeding -concomitant use of potent P-gp inhibitors
for DVT/PE (See SPC) (e.g. Dronedarone, Erythromycin,
Ketoconazole, Ciclosporin)
(See SPC)
It is worth bearing in mind that Apixaban (Eliquis®) and Rivaroxaban (Xarelto®) drop to a lower dose after 6 months of treatment as the respective clinical trials highlighted a reduction in bleeding risk with
this strategy (although Rivaroxaban (Xarelto®) has the option to remain on the higher dose for those deemed to be at high risk of recurrence), whereas Dabigatran etexilate (Pradaxa®) and Edoxaban
(Lixiana®) have one dose throughout the duration of treatment.
Presentation 10, 15 and 20mg film coated tablets 2.5 and 5mg film coated tablets 110mg and 150mg hard capsules 15, 30 and 60mg film coated tablets

NB: 75mg capsules are not licensed for

DVT/PE.
Administration The tablet is taken with food Swallowed with water, with or without Take with or without food. Swallow Take with or without food. Swallow whole
food whole with a glass of water, to facilitate with a glass of water, to facilitate delivery
delivery to the stomach to the stomach
Use in Renal • DOACs can be used in patients with renal impairment in line with the SPC of the specific agent (as below).
Impairment • Patients who develop acute renal failure should discontinue the DOAC and seek specialist advice
• Creatinine clearance must be calculated (see here for calculator), eGFR is NOT considered a suitable alternative.
CrCL 30-50ml/min Limited clinical data: maintenance dose may Consider 110mg BD in moderate renal
be reduced to 15 mg OD based on bleeding No dosage adjustment
impairment CrCl 15-50ml/min: 30mg OD
risk and risk of recurrent VTE
CrCL 15-30ml/min Use with caution
CrCl < 30ml/min: Contraindicated
CrCL <15ml/min Contraindicated Contraindicated Contraindicated

3
Medicine Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Dabigatran etexilate (Pradaxa®) Edoxaban (Lixiana®)
Use in Hepatic Contraindicated in patients with hepatic Contraindicated in patients with Contraindicated in hepatic impairment Contraindicated in patients with
Impairment disease associated with coagulopathy and hepatic disease associated with or liver disease expected to have any hepatic disease associated with
clinically relevant bleeding risk including coagulopathy and clinically relevant impact on survival. coagulopathy and clinically relevant
cirrhotic patients with Child Pugh B and C bleeding risk. bleeding risk.

Not recommended in patients with Not recommended in mild-moderate Not recommended in patients with
severe hepatic impairment. hepatic impairment with liver enzymes severe hepatic impairment. Use with
Caution in patients with mild or >2 ULN. caution in patients with mild-moderate
moderate hepatic impairment hepatic impairment with liver enzymes >2
(Child Pugh A or B), but no dose ULN or total bilirubin >1.5 ULN.
adjustment is required.

Caution in patients with elevated

liver enzymes (ALT/AST >2 x ULN)
or total bilirubin ≥1.5 x ULN as
these patients were excluded in
clinical trials.

Suitability for May be given via gastric tube or crushed Tablets may be crushed and dispersed Capsules should not be opened- Tablets may be crushed and mixed with
patients with and mixed with water or apple puree for in dextrose 5% (unlicensed, info from increased risk of bleeding (oral water/apple puree and immediately
swallowing patients with swallowing difficulties personal communication with bioavailability may be increased by 75% administered. Alternatively, tablets may be
(licensed route of admin) manufacturer) when the pellets are removed from the crushed and suspended in water and
difficulties/
capsule shell) immediately delivered through a gastric
enteral tubes tube followed by flushing with water.

Suitability for The shorter half-life of all DOACs may mean missed doses result in a lack of anticoagulation more quickly compared to warfarin. Also, as the therapeutic effect of DOACS is not
patients with easily measurable through routine clotting screens, it is difficult to objectively measure concordance in individuals suspected of poor adherence to therapy.
compliance May be put in MCAs (no special storage May be put in MCAs (no special storage Not suitable for use in MCAs (unstable May be put in MCAs (no special storage
problems / multi- conditions required) conditions required) out of original packaging) conditions required).
compartment
compliance aids
(MCAs)

4
Contraindications • Hypersensitivity to drug or excipients
• Active clinically significant bleeding
• Risk factors for major bleeding e.g. current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent
brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major
intraspinal or intracerebral vascular abnormalities, uncontrolled severe hypertension
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
• Dabigatran is contraindicated and neither rivaroxaban, apixaban nor edoxaban are not recommended in patients with prosthetic heart valves
• Pregnancy or breast feeding

Drug interactions Interactions with common medicines listed below (See SPC or specialist source for more detailed list)
• Anticoagulants – all DOACs contraindicated with other anticoagulants
• Antiplatelets (e.g. aspirin, clopidogrel, prasugrel, ticagrelor etc) and NSAIDs – caution, increase bleeding risk
• Azole antimycotics (e.g. ketoconazole, itraconazole, voriconazole) - contraindicated with dabigatran, not recommended with rivaroxaban or apixaban (increased
plasma levels and bleeding risk), dose adjustment required with edoxaban (see above)
• HIV protease inhibitors (e.g. ritonavir) - contraindicated with dabigatran, not recommended with rivaroxaban or apixaban (increased plasma levels and bleeding risk)
• Rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's Wort - should be avoided with rivaroxaban and dabigatran, use with caution with apixaban or
edoxaban
• Dronedarone - contraindicated with dabigatran, avoid with rivaroxaban, dose adjustment with edoxaban (see above)
• Posaconazole – not recommended with apixaban and rivaroxaban, use with caution with dabigatran (dose reduction required)
• Ciclosporin – contraindicated with dabigatran (increased plasma levels of dabigatran expected), use with caution with rivaroxaban or apixaban (possible increased plasma levels
and bleeding risk), dose adjustment with edoxaban (see above)
• Tacrolimus – contraindicated with dabigatran (increased plasma levels of dabigatran expected), use with caution with rivaroxaban or apixaban (possible increased plasma levels
and bleeding risk)
• SSRIs / SNRIs – caution
• Clarithromycin – caution with dabigatran especially in renal impairment, caution with rivaroxaban in renal impairment
• Erythromycin – caution with rivaroxaban if renal impairment, dose adjustment with edoxaban (see above)
• Verapamil – reduce dabigatran dose (see above)
• Amiodarone and quinidine – caution with dabigatran, monitor for signs of bleeding / anaemia
• Fluconazole - caution if renal impairment and concomitant rivaroxaban

5
 Monitoring of DOACs

Baseline blood tests

U + Es Full blood count Coagulation screen Liver function tests
Patient group (Creatinine clearance)
All
Follow up tests
U + Es Full blood count Coagulation screen Liver function tests
Patient group (Creatinine clearance)
Creatine Clearance
Annually
> 60ml/min
Annually
X Inappropriate without Annually
Creatine Clearance correct reagent
Six Monthly
30-60ml/min
* In addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate

• Clinical trials have demonstrated that the therapeutic anticoagulation effect of DOACs does not require routine monitoring.
• Unlike warfarin, a prothrombin time may not be sensitive to their anticoagulant effect. Likewise, an INR will not demonstrate the level of anticoagulation.
• As DOACs are predominantly eliminated by the renal route, it is prudent to monitor the renal function of a patient taking a DOAC. The following regimen is
broadly in line with NICE guidance on Chronic Kidney Disease and based on consensus clinician opinion. This may recommend more frequent monitoring
than that advised in the manufacturer’s summary of product characteristics (SPC).
• Creatinine clearance must be used for calculating renal function using the Cockcroft and Gault equation (see below). eGFR is not a suitable alternative:
CrCl (ml/min) = (140 – age) x weight (kg) x 1.04 (female) or 1.23 (male)
serum creatinine (micromol/l)
Should the individual patient be deemed at a greater risk of developing renal dysfunction, more frequent monitoring may be warranted. The frequency of
testing will need to be increased if there is rapid progression, or during intercurrent illness and perioperatively in all patients with CKD.

6
 Criteria for review and discontinuation of DOACs

Event Action
Haemorrhage Refer patient immediately to Emergency Department if serious bleeding occurs e.g. GI bleeding,
epistaxis lasting more than 1 hr.
Dyspepsia Common with dabigatran. Consider a proton pump inhibitor. If persists, consider alternative
anticoagulant.
Unexplained acute fall in haemoglobin or blood pressure Refer patient immediately to the Emergency Department for investigation.

Trauma (especially to the head) Consider referral to Emergency Department.

Excessive bruising Check FBC and U+Es. Consider discussion with Haematologist.
Any acute illness that MAY affect renal function Measure U+Es and calculate creatinine clearance. Reduce dose or withhold treatment if required.

Significant reduction in renal function (and see below) Reduce dose as appropriate according to the medicine’s recommended dosing schedule in renal
impairment (see above for CrCl calculation). If renal function continues to worsen consider
alternative anticoagulant.
Fall in creatinine clearance to <30ml/min with Stop DOAC, assess for bleeding and seek advice as to whether specific assays are indicated /
dabigatran or <15ml/min with rivaroxaban, apixaban or alternative anticoagulant required.
edoxaban

7
 Appendix 1: Switching between anticoagulants
Drug switch To Apixaban To Dabigatran To Edoxaban To Enoxaparin To Rivaroxaban To Warfarin

From Apixaban X Stop apixaban and Stop apixaban and Stop apixaban and give Stop apixaban and Load with warfarin as per loading
commence dabigatran at commence edoxaban at enoxaparin at same time as commence rivaroxaban at guide, take INR prior to next dose
same time as next same time as next next scheduled apixaban same time as next of apixaban, continue apixaban
scheduled apixaban dose scheduled apixaban dose dose scheduled apixaban dose until INR in range
From Stop dabigatran and X Stop dabigatran and Stop dabigatran and Stop dabigatran and Load with warfarin as per loading
Dabigatran commence apixaban at commence edoxaban at commence enoxaparin at commence rivaroxaban at guide, take INR prior to next dose
same time as next same time as next same time as next same time as next of dabigatran, continue
scheduled dabigatran dose scheduled dabigatran scheduled dabigatran dose scheduled dabigatran dabigatran until INR in range
dose dose
From Edoxaban Stop edoxaban and Stop edoxaban and X Stop edoxaban and Stop edoxaban and Load with warfarin as per loading
commence apixaban at commence dabigatran at commence enoxaparin at commence rivaroxaban at guide, take INR prior to next dose
same time as next same time as next same time as next same time as next of edoxaban, continue edoxaban
scheduled edoxaban dose scheduled dabigatran dose scheduled edoxaban dose scheduled edoxaban dose at half of usual daily dose until
INR in range.
From Stop enoxaparin and Stop enoxaparin and Stop enoxaparin and X Stop enoxaparin and Load with warfarin as per loading
Enoxaparin commence apixaban at commence dabigatran at commence edoxaban at commence rivaroxaban at dose guide and continue
same time as next same time as next same time as next same time as next enoxaparin until INR in range
scheduled enoxaparin dose scheduled enoxaparin dose scheduled enoxaparin scheduled enoxaparin
dose dose
From Stop rivaroxaban and Stop rivaroxaban and Stop rivaroxaban and Stop rivaroxaban and give X Load with warfarin as per loading
Rivaroxaban commence apixaban at commence dabigatran at commence edoxaban at enoxaparin at same time as guide, take INR prior to next dose
same time as next same time as next same time as next next scheduled rivaroxaban of rivaroxaban, continue
scheduled rivaroxaban dose scheduled rivaroxaban dose scheduled rivaroxaban dose rivaroxaban until INR in range
dose
From Warfarin Stop warfarin and start Stop warfarin and start Stop warfarin and start Stop warfarin and Stop warfarin and start X
apixaban when INR<2 dabigatran when INR<2 edoxaban when INR<2.5 commence enoxaparin rivaroxaban when INR<3
when INR<2 (or below (AF) or <2.5 (DVT/PE)
usual range)

8
References
1. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the
SSC of the ISTH. Journal of thrombosis and haemostasis aemos. 2016; 14(6):1308-1313. doi.org/10.1111/jth.13323
2. De Caterina R, Lip GYH. The non-vitamin K antagonist oral anticoagulants (NOACs) and extremes of body weight-a systematic literature review. Clin Res
Cardiol. 2017 Aug; 106(8):565-572. doi: 10.1007/s00392-017-1102-5. Epub 2017 Apr 10. Review.
3. Tittl L, Endig S, Marten S, Reitter A, Beyer-Westendorf I, Beyer-Westendorf J. Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of
the prospective Dresden NOAC Registry (NCT01588119). Int J Cardiol. 2018 Jul 1; 262:85-91. doi: 10.1016/j.ijcard.2018.03.060. Epub 2018 Mar 14
4. Spyropoulos AC, Ashton V, Chen Y, Wu B, Peterson ED. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous
thromboembolism: Comparative effectiveness, safety and costs. Thrombosis Research. 2019; 182:159-166. doi: 10.1016/j.thromres.2019.08.021
5. Elshafei M, Mohamed M, El-Bardissy A, Ahmed M, Abdallah I, Elewa H, Danjuma M. Comparative effectiveness and safety of direct oral anticoagulants
compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and meta-analysis. Journal of Thrombosis and
Thrombolysis. 2020. doi: 10.1007/s1123 9-020-02179 -4 Epub 18 June 2020
6. Martin AC, Thomas W, Mahir Z, Crowley MP, Dowling T, Breen K, Collings V, Moore GW, MacDonald S, Hunt BJ, Cohen AT. Direct oral anticoagulant
concentrations in obese and high body weight patients: a cohort study. Thrombosis and Haemostasis. 2021 Feb;121(2):224-233. doi: 10.1055/s-0040-
1715834. Epub 2020 Aug 30
7. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the
ISTH SSC Subcommittee on Control of Anticoagulation, Journal of Thrombosis and Haemostasis, 2021, doi: 10.1111/jth.15358
8. Xarelto Summary of Product Characteristics. Last updated 13/06/2018 see www.medicines.org.uk
9. Eliquis Summary of Product Characteristics. Last updated 13/06/2018 see www.medicines.org.uk
10. Pradaxa Summary of Product Characteristics. Last updated 26/06/2018 see www.medicines.org.uk
11. Lixiana Summary of Product Characteristics. Last updated 31/07/2017 see www.medicines.org.uk
12. The Renal Drug Database. Accessed 13/08/2014
13. NICE CG144: Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. June 2012
14. NICE NG 158: Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. March 2020
15. BNF July 2015. Available from www.bnf.org
16. NICE Clinical Guideline 73: Chronic Kidney Disease. September 2008
17. NICE Clinical Guideline 182: Chronic Kidney Disease. July 2014
18. NICE: Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism (TA341) June 2015. Available at
http://www.nice.org.uk/guidance/TA341
19. NICE: Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (TA261) July
2012. Available at http://www.nice.org.uk/guidance/TA261
20. NICE: Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism (TA287) June 2013. Available at
http://www.nice.org.uk/guidance/TA287

9
21. NICE: Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism (TA327) December 2014.
Available at http://www.nice.org.uk/guidance/TA327
22. NICE: Edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism (TA354) August 2015. Available at
http://www.nice.org.uk/guidance/TA354
23. MHRA Drug Safety Update October 2013: New oral anticoagulants apixaban (Eliquis▼), dabigatran (Pradaxa) and rivaroxaban (Xarelto▼): risk of
serious haemorrhage—clarified contraindications apply to all three medicines. Available at:
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON322347

V1.1 -Direct Oral Anticoagulants (DOACs) for treatment of DVT or PE, or prevention against recurrent DVT or PE (in Adults)
Version Author(s) Date Changes
th
1.1 Updated by Irina Varlan in collaboration 26 Oct 2021 Update on dosing for rivaroxaban and apixaban in treating
with Consultant Haematologists at NUH patients with obesity for DVT/PE.
(Dr Joannes Hermans, Dr Gill Swallow
and Dr Charlotte Grimley).
1.2 Jill Theobald 9th Dec 2021 Edoxaban licensed to administer via enteral feeding tube –
added to prescribing information table on page 5.
Corrected minor typos and added standard header

10