Management of Bleeding in Patients on Direct Oral Anticoagulants (DOACs)

• Summary of Guideline/Protocol
• Aims
• Background
• Diagnosis
• Investigation
• Treatment / Management

Summary of Guideline/Protocol

Pertinent aspects of history and examination
Key diagnostic criteria
Investigations required
Treatment
Management

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Aims

To improve the diagnosis and management of bleeding in patients taking a direct oral anticoagulant (DOAC), apixaban, dabigatran, edoxaban or rivaroxaban (previously called NOACs)

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Background

The DOACs have been introduced as an alternative to vitamin K antagonists (VKAs i.e. warfarin) for patients requiring anticoagulation for venous thromboembolism (VTE) prevention after hip and knee replacements, for the prevention of stroke in patients with non-valvular atrial fibrillation (AF) and for the acute treatment and prevention of recurrence for patients with VTE.

This document provides recommendations for the management of bleeding in patients on apixaban, dabigatran, edoxaban and rivaroxaban.

An antidote for dabigatran has been licensed.

An antidote for apixaban and rivaroxaban for patients with a life threatening or uncontrolled gastro-intestinal bleeding has been licensed and approved by NIC

There is no licensed antidote for use in patients on edoxaban with major or life-threatening bleeding.

Dabigatran

Small molecule prodrug which does not exhibit any pharmacological activity.

Dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver.

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Diagnosis

• If a patient taking a direct oral anticoagulant drug (DOAC) presents with bleeding, assess if the bleeding is minor or major. 
• Establish usual resuscitative measures as appropriate for the severity of the bleeding. 
• Take a history regarding dose, indication for the drug and time of last ingestion. Establish whether there is any known history of renal impairment.
• Establish full medication history including use of any antiplatelet agents, recent non-steroidal anti-inflammatory drugs or drugs that may interact with the DOACs.

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Investigation

• Send blood to the laboratory for urgent full blood count (FBC), urea and electrolyties (U/E) and liver function tests (LFTs), coagulation screen (and thrombin clotting time for dabigatran only), Klaus fibrinogen and group and save. Mark clearly on the form which drug the patient is on, that they are bleeding and that the sample should be saved following processing of the coagulation screen. 
• Please refer to Table 1 for the predicted effects of the DOACs on coagulation screening tests. Please note that effects are variable and the tests cannot be interpreted in the same way as for warfarin or for heparin. Please seek haematology advice for interpretation of results. Note that the effects on coagulation screening tests vary as to when the sample was taken in relation to the peak plasma concentration of the drug.  A standard coagulation screen is most useful in combination with a specific assay for the drug. Remember that coagulation abnormalities may not always be due to the drug and a normal coagulation screen does not exclude significant drug effect.  
• For rivaroxaban the prothrombin time (PT) in LTHT may give an indication as to whether significant residual drug effect remains in the patient’s plasma (note other centres may use different reagents so this is not applicable if the test was done elsewhere). If the prothrombin time is in the normal range it is unlikely that an excessive amount of anti Xa activity due to rivaroxaban is present. This means that it is unlikely that bleeding is entirely due to rivaroxaban. If the prothrombin time is prolonged, or bleeding is severe, seek haematology advice and request urgent assessment of rivaroxaban anti Xa activity as a measure of rivaroxaban in the patient’s plasma.  
• The effects of apixaban on PT and activated partial thromboplastin time (APTT) are highly variable between laboratories and in general apixaban has less effect on conventional coagulation screening tests than rivaroxaban. It must not be assumed that normal coagulation screening tests exclude a significant circulating concentration of apixaban. Please seek advice from a senior haematologist if a patient has significant bleeding on apixaban.
• For dabigatran, the APTT gives an indication as to whether significant residual drug effect remains in the patient’s plasma. If the APTT is normal; it is therefore unlikely that an excessive amount of thrombin (anti IIa) activity due to dabigatran is present. A normal thrombin time (TT) suggests the level of dabigatran is very low.  If the APTT is prolonged or bleeding is major, consult haematology and consider a dabigatran level
• Edoxaban prolongs clotting time in tests such as prothrombin time (PT), and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests are expected at the therapeutic dose, however, these changes are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of edoxaban.

• Investigate patients appropriately for causes of local bleeding e.g. upper GI endoscopy. Use all appropriate local measures (e.g. nasal packing for epistaxis) to help secure haemostasis.  

Table 1

¶ Results are variable according to the coagulation reagent used.

‡ TT is very sensitive to presence of dabigatran and even low (potentially negligible) plasma levels may lead to elevated TT

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Treatment / Management

MINOR Bleeding;

1        Withhold further doses of the drug until bleeding has settled.

2        Withhold antiplatelet agents also unless the patient has had placement of a coronary stent recently (within 3 months for a bare metal stent, within 12 months for a drug eluting stent), consult cardiology for such patients.

3        Consider activated charcoal if ingestion < 2 hours previously and the bleed is not from the upper GI tract.

4        Monitor the patient clinically and be prepared for resuscitative measures if bleeding worsens.

5        See background section for the elimination half-lives of each DOAC. Note that compared with warfarin, all have shorter half-lives, therefore it is often sufficient to discontinue the drug, monitor and support the patient.

6        Avoid invasive procedures that are not directed at stopping bleeding eg avoid intra-muscular (IM) injections, arterial blood gases. Avoid starting any medication that may further impair haemostasis e.g. low molecular weight heparin (LMWH), antiplatelet agents or non-steroidal anti-inflammatory drugs. For in-patients, use anti-embolic stockings for thromboprophylaxis unless contraindicated.

7        In cases where bleeding is not stopping readily, please discuss with the on call haematology team. It may be appropriate to consider platelet transfusion if the patient is on concomitant anti platelet therapy. It may be possible to measure the level of the drug in the patient’s plasma. This should be considered after discussion with clinical haematology in cases of difficulty and by arrangement with the specialist coagulation laboratory. This may be particularly useful if the patient has impaired renal function.

8        Consider tranexamic acid particularly for mucosal bleeding.

9        Review reasons for treatment and dose and do not restart until at least 24 hours after bleeding has ceased, the risk of re-bleeding is low and, if drug levels have been checked, the level has returned to therapeutic range or less (discuss with haematology).

MAJOR Bleeding;

1        Apply all measures as for management of minor bleeding. Consult clinical haematology on call service as soon as major bleeding is recognised.

2        Focus initially on adequate resuscitation with crystalloid, colloid, red cells and other component therapy as per the Trust’s major haemorrhage protocol (link).

3        Correct any other causes of coagulopathy (e.g. disseminated intravascular coagulation (DIC), thrombocytopenia).

4        Use all possible local measures to secure haemostasis.

5        If the patient is also on antiplatelet therapy give one adult dose of platelets irrespective of the platelet count and consider further platelet transfusion if bleeding is continuing as per usual haemorrhage guidelines.

6        For major mucosal bleeding, give 1g tranexamic acid intravenously (IV)

7        Fresh frozen plasma (FFP) should not be used to attempt to “reverse” the effects of DOACs but may be used if there is an additional dilutional coagulopathy or DIC (diagnosis may be complex: consult haematology)

8        Apixaban, edoxaban and rivaroxaban only : In the event of continuing uncontrolled haemorrhage, or if bleeding is major give prothrombin complex concentrate (PCC) 25-50 units/kg (Octaplex is the preparation of first choice). There is anecdotal evidence that this may have some effect in securing haemostasis in the presence of apixaban, edoxaban and rivaroxaban. This must be given after consultation with haematology and after due consideration of the balance of risks of continuing bleeding versus thrombosis. PCC and activated PCC (see below) are not DOAC antidotes and do not affect the inhibitory effect of these drugs on coagulation factors IIa (thrombin) and Xa. These agents may reduce DOAC-associated bleeding by providing large amounts of factors II and X. They may be associated with a small increased thrombotic risk.

9        Apixaban or rivaroxaban and life threatening or uncontrolled gastro-intestinal bleeding : Andexanet Alfa is the antidote for apixaban and rivaroxaban and has been licensed and approved by NICE for the management of life threatening or uncontrolled GI bleeding only. Its use can only be authorised by  a senior haematologist. It is kept in the fridge in resus in ED at SJUH and LGI. The recommended dose depends on the drug, dose and time of ingestion

Summary of dosing for reversal of apixaban

Summary of dosing for reversal of rivaroxaban

Andexanet alfa is a specific reversal agent for FXa inhibitors. The predominant mechanism of action is the binding and sequestration of the FXa inhibitorAndexanet alfa binds direct FXa inhibitors with high affinity, making them unavailable to exert their anticoagulant effects.

MRHA/CHM advice: Ondexxya® (andexanet alfa): Commercial anti-FXa activity assays are unsuitable for measuring anti-FXa activity following administration of andexanet alfa (July 2020)

Treatment monitoring after administration of andexanet alfa should not be based on anti-FXa activity assays. In these assays, the FXa inhibitor dissociates from andexanet alfa, resulting in the detection of falsely elevated anti-FXa activity levels, and consequently a substantial underestimation of the reversal activity of andexanet alfa. Healthcare professionals are advised to monitor treatment using clinical parameters indicative of appropriate response (i.e. achievement of haemostasis), lack of efficacy (i.e. re-bleeding), and adverse events (i.e. thromboembolic events).

10     For dabigatran, in the event of life threatening bleeding, contact Haematology. Idarucizumab is the specific antidote for dabigatran and is kept in the fridge in ED at LGI and SJUH. A senior haematologist must approve its use. The recommended dose of Idarucizumab is 5 g (2x2.5 g/50 mL). Idarucizumab (2x2.5 g/50 mL) is administered intravenously as two consecutive infusions over 5 to 10 minutes each or as a bolus injection. Idarucizumab is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran with very high affinity, approximately 300-fold more potent than the binding affinity of dabigatran for thrombin. The idarucizumab-dabigatran complex is characterised by a rapid on-rate and extremely slow off-rate resulting in a very stable complex. Idarucizumab potently and specifically binds to dabigatran and its metabolites and neutralises their anticoagulant effect.

In the event of bleeding continuing in the presence of raised plasma concentrations of dabigatran or in the presence of renal impairment, haemodialysis should be considered. There is evidence for efficacy in clearing dabigatran by dialysis. The practicalities of setting up dialysis in the context of major bleeding are considerable. The balance of risks in a potentially haemodynamically unstable patient require careful individual consideration. However, there is more evidence for this measure in clearing dabigatran than there is for any attempts to reverse the effects of dabigatran with PCC.

11     Apixaban, edoxaban and rivaroxaban are highly protein bound and dialysis is generally ineffective in clearing the drug but may be indicated in a critically ill patient with severe renal impairment in any case (consult renal team).

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Follow up

The patients GP should be informed of the bleed and the recommendations for continuing or stopping anticoagulation, including whether the DOAC should be restarted (if not already done so) or whether the use of the agent is not advisable again. Cases where the decision is not straight-forward should be discussed with Haematology and appropriate follow up planned.

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Patient taking Apixaban, Edoxaban or Rivaroxaban presenting with bleeding;

Patients taking Dabigatran who present with bleeding;

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