The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on Antithrombotic
Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 1 of 20
A Clinical Guideline For use in:
Organisation-wide
By: All medical and nursing staff
For: For all adult patients on antithrombotic drugs that have
been over anticoagulated or are bleeding.
Division responsible for document:
Core services including Outpatient services
Key words:
Antithrombotic drugs, warfarin, dabigatran,
rivaroxaban, apixaban, edoxaban, aspirin, clopidogrel, bleeding, overanticoagulation, Beriplex, FFP,
Idarucizumab.
Name of document author: Dr M D Lewis
Job title of document author: Consultant Haematologist
Name of document author’s Line Manager: Hugh Warren
Job title of author’s Line Manager: Divisional Director
Supported by: Sr E Macleod-Collins, Anticoagulation Advanced Nurse Practitioner
Pat Fysh, Coagulation Co-ordinator
Assessed and approved by the:
Hospital Thrombosis Committee / Clinical Governance Meeting Drugs and Therapeutics Committee If approved by committee or Governance Lead Chair’s Action; tick here
Date of approval: April 2020
Ratified by or reported as approved to: Clinical Guidelines Committee
Final Approval By and Date: Dr H Altemimi 29/06/2020
To be reviewed before:
This document remains current after
this date but will be under review April 2023
To be reviewed by: Dr M D Lewis, Consultant Haematologist
Reference: A0.8
Version No: v3
Description of changes: Put into new Trust format and updated with antidote
information of dabigatran etexilate (Pradaxa)
Compliance links: NICE
If Yes - does the guidance deviate from the recommendations of NICE? If so why?
No
This guideline has been approved by the Trust's Clinical Guidelines Group as an aid to the diagnosis and management of relevant patients and clinical circumstances. Not every patient or situation fits neatly into a standard guideline scenario and the guideline must be interpreted and applied in practice in the light of prevailing clinical circumstances, the diagnostic and treatment options available and the professional judgement, knowledge and expertise of relevant clinicians. It is advised that the rationale for any departure from relevant guidance should be documented in the patient's case notes. The Trust's guidelines are made publicly available as part of the collective endeavour to continuously improve the quality of healthcare through sharing medical experience and knowledge. The Trust accepts no responsibility for any misunderstanding or misapplication of this document.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on Antithrombotic
Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 2 of 20
1. Contents page Page
2 Definitions of terms used 4
3 Quick reference 5
4 Objective 6
5 Rationale 6
6 Processes to be followed: 6
General measures to stop bleeding in all patients taking antithrombotic drugs 6
Non-pharmacological measures 6
General haemostatic agents 7
Management of over anticoagulation on warfarin 8
Management of major or life threatening bleeding on warfarin 9
Beriplex 10
Important dosing advice 11
Management of significant bleeding without haemodynamic compromise 11
Active non-life threatening bleeding requiring rapid reversal of warfarin 11
Minor bleeding 12
High INR (>4.0) with no bleeding 12
Reversal of low molecular weight heparin or unfractionated heparin 13
Direct oral anticoagulants (DOACs) 14
Dabigatran 14
Reversal of Dabigatran with Idarucizumab (praxbind) 15
Restarting antithrombotic therapy 15
Direct oral factor Xa inhibitor – rivaroxaban (Xarelto), apixaban (Eliquis) and
edoxaban (Lixiana)
16
Bleeding on aspirin or clopidogrel 17
Other drugs 17
7 Summary of development and consultation process undertaken 18
8 References 18
9 Equality impact assessment 19
10 Monitoring compliance 21
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on Antithrombotic
Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 3 of 20
2. Definitions of Terms Used
Antithrombotic/Anticoagulant drugs:
Vitamin K Antagonist (VKA) – Warfarin, Acenocoumarol (Sinthrome)
Direct thrombin inhibitor – Dabigatran (Pradaxa)
Direct Factor Xa inhibitor – Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Lixiana)
Low Molecular Weight Heparin (LMWH) – Enoxaparin, Dalteparin, Tinzaparin
Unfractionated Heparin (UFH)
Reversal agents:
Prothrombin Complex Concentrate (PCC) - Beriplex
FFP – fresh frozen plasma
Protamine Sulphate
Praxbind (Idarucizumab).
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on Antithrombotic
Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 4 of 20
3. Quick reference
▪ General Measures to Stop Bleeding – page 6
▪ Management of major or life threatening bleeding on warfarin - page 9
▪ Management of significant bleeding without haemodynamic compromise - page 11
▪ Reversal of LMWH or UFH - page 13
▪ Reversal of DOACs – page 14-16
▪ Bleeding on aspirin or clopidogrel - page 17
▪ Other drugs –page 17
For full information / further details: please see rest of document.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on Antithrombotic
Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 5 of 20
4. Objective
To provide management advice for adult patients experiencing bleeding symptoms or over-
anticoagulation while taking antithrombotic drugs. 5. Rationale
To provide management advice for adult patients on antithrombotic drugs who have been over-
anticoagulated or have bleeding using evidence based recommendations. It includes general
measures to stop bleeding and information for rapid reversal of Warfarin, and Dabigatran where a
specific antidote exists, plus guidance for the other Direct Oral AntiCoagulants (DOACs) and LMWH.
Oral vitamin K will take approximately 24 hours to counteract the effect of warfarin.
IV Vitamin K will take approximately 6-8 hours to counteract the effect of warfarin.
Beriplex will begin to work immediately.
Idarucizumab (Praxbind) will begin to work immediately. 6. Processes to be followed
• Establish indication for anticoagulation (with dates of events)
• Establish when the last dose of antithrombotic drug was taken and how much.
• Check renal function, LFT, FBC, PT, APTT, INR (for warfarin ONLY), APTTR (for UFH ONLY)
• General measures. General Measures to Stop Bleeding in All Patients Taking Antithrombotic Drugs
For all patients, it is important to balance bleeding risk and thrombotic risk. To do this, you must
document the indication for anticoagulation (including dates of VTE, stroke), antithrombotic used
(including target INR if warfarin), drug dose and timing of last dose. If anticoagulation is to be
reversed, thrombotic risk factors should be acknowledged.
Non-pharmacological measures
In many cases, simple non-pharmacological measures and stabilisation of the patient whilst the
antithrombotic is eliminated are sufficient to treat or prevent bleeding (see table below).
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 6 of 20
General non-pharmacological measures
1. Stop the antithrombotic drug
2. Document the timing and dose of the last drug dose and presence of pre-existing renal or
hepatic impairment
3. Estimate the half-life and length of functional defect induced by the drug
4. Assess the source of the bleeding
5. Request full blood count, prothrombin time, activated partial thromboplastin time,
thrombin time, fibrinogen concentration, serum creatinine levels
6. If available, request a specific laboratory test to measure the antithrombotic effect of the
drug (warfarin – INR, LMWH – Anti-Xa, UFH – APTTR or Anti-Xa)
7. Correct haemodynamic compromise with intravenous fluids and red cell transfusion
8. Apply mechanical pressure, if possible
9. Use endoscopic, radiological or surgical measures
General haemostatic agents
Specific antidotes are not always available to reverse antithrombotic drugs in emergencies.
However, general prohaemostatic agents, such as Tranexamic acid, may be useful in some
circumstances. Recombinant activated factor VII (rFVIIa, Novoseven®), prothrombin
complex concentrates (PCC) and activated PCC [APCC; e.g. factor VIII inhibitor bypass
activity (FEIBA)] are often considered as agents for reversal of the effect of antithrombotic
drugs. However, off-label use of rFVIIa for critical bleeding was associated with arterial
thrombosis in 5.5% vs. 3.2% in placebo in all patient groups and 10.8% vs. 4.1% in placebo
in patients >75 years. Reversal of the effect of an antithrombotic is an unlicensed
indication for rFVIIa but this agent is often considered as a last resort when all other
measures have failed and the risks and benefits are carefully documented.
If the patient is likely to have therapeutic levels of anticoagulation in circulation, reversal
should be considered for major/life threatening bleeding or when emergency surgery is
required.
Drug Half-life
Dabigatran 12-14 hours if CrCl ≥80
~15 hours if CrCl ≥50 - <80
~18 hours if CrCl ≥30 - <50
~27 hours if CrCl <30
Rivaroxaban 5-9 hours in young patients
11-13 hours in elderly patients
Apixaban 12 hours
Edoxaban 10-14 hours
Low molecular weight
heparin
4-7 hours
Warfarin 40 hours
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 7 of 20
NB: FFP (FRESH FROZEN PLASMA) SHOULD NEVER BE USED FOR THE REVERSAL OF
WARFARIN (WHEN PCC IS AVAILABLE IE BERIPLEX). MANAGEMENT OF OVER-ANTICOAGULATION ON WARFARIN
A precipitating factor must be identified as a cause of the over-anticoagulation.
eg infection, new medication, liver dysfunction) so that the warfarin be dosed accordingly
in the future.
INR Presence of bleeding Action required
INR 5.0 - 8.0 No bleeding 1) Stop warfarin
2) Restart a lower dose
when INR <5.0
INR 5.0-8.0 Minor bleeding or risk factors
for bleeding
1) Stop warfarin
2) Give vitamin K 1mg
orally
3) Restart at a reduced
dose when INR<5.0
INR >8.0
ALL patients with an INR
greater than 8.0 require
reversal
No bleeding or minor bleeding 1) Stop warfarin
2) Give phytomenadione
(vitamin K1)1-5mg orally
using the IV preparation
(Konakion® MM) or
Menadiol 10mg tablets
to be SUCKED and NOT
to be swallowed, for
partial reversal. Higher
doses are required for
full reversal.
3) Restart warfarin at a
lower dose when INR
<5.0 if no risk factors for
bleeding
Oral vitamin K will take approximately 24 hours to counteract the effect of warfarin.
IV Vitamin K will take approximately 6-8 hours to counteract the effect of warfarin.
Beriplex will begin to work immediately.
NB: FFP should NOT be used for the reversal of warfarin.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 8 of 20
Other risk factors for bleeding:
Age >70 years
Previous bleeding complications
Uncontrolled Hypertension
Diabetes
Renal/Liver failure
Concurrent use of anti-platelet agents
Unexpected bleeding at therapeutic levels – Always investigate the possibility of
underlying cause (e.g. unsuspected renal or GI tract pathology)
MANAGEMENT OF MAJOR OR LIFE-THREATENING BLEEDING ON WARFARIN
Definition of life-threatening bleeding – examples include:
Intracranial or rapid onset neurological signs
Significant head injury
Intra-ocular (not conjunctival) bleeds
Compartment syndrome
Pericardial bleed
Active bleeding with shock
Send blood for urgent clotting assessment
FBC, INR
Prothrombin time, APTT, Fibrinogen
Baseline renal and liver function
Group and Save with X match (remember may need a 2nd sample if first time
patient)
Contact the consultant haematologist on-call if required at this stage
Oral vitamin K will take approximately 24 hours to counteract the effect of
warfarin.
IV Vitamin K will take approximately 6-8 hours to counteract the effect of warfarin.
Beriplex will begin to work immediately.
Stop warfarin and reverse anticoagulation
1) Give vitamin K1 5-10 mg IV slowly (over 10-15 minutes) – can cause
anaphylaxis if given too quickly
**In patients admitted with a fractured neck of femur (NOF) who will
require surgery, 10mg iv has been shown to be more effective than 5mg
(source: local audit).**
2) Give Prothrombin Complex Concentrate – BERIPLEX – dose according to INR
– See table below
a. Kept in pharmacy night store
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 9 of 20
b. Fast onset of action <10 mins
c. Reconstitute according to instructions in pack and give over 15 – 20
minutes (For patients <70kg maximum 0.12ml/kg/min, top maximum
rate is 8.0 ml/min)
d. Has half-life of ONLY 6 hours – essential to give vitamin K at the same
time
3) Recheck INR - 20 minutes and 6 hours post infusion of Beriplex
4) Seek further advice if no improvement in INR
5) The degree of reversal must be decided on an individual basis. All patients
with bleeding should be evaluated to identify if there is a local anatomical
reason for bleeding, which must also be addressed.
** TRANSFUSION TRANSMITTED INFECTION: Both FFP and Beriplex are plasma products THEY CARRY THE RISK OF TRANSFUSION TRANSMITTED INFECTION AND OTHER
TRANSFUSION RELATED COMPLICATIONS. IT IS IMPORTANT THAT THEY ARE USED
APPROPRIATELY AND THEIR PRESCRIPTION AND RATIONALE FOR USE ARE RECORDED IN
THE PATIENT’S NOTES
BERIPLEX
Indications ►Treatment and perioperative prophylaxis of bleeding in acquired deficiency of the prothrombic complex coagulation when rapid correction of the deficiency is required. ►Serious bleeding secondary to Vitamin K antagonists ►Reversal of warfarin when emergency surgery is required within 6 hours
Contraindications ►Known hypersensitivity ►Risk of thrombosis, angina, recent AMI (exception: life threatening haemorrhage secondary to warfarin over dosage & before induction of fibrinolytic therapy ►Caution severe liver failure ►DIC – Beriplex maybe used after termination of the consumptive state ►History of heparin-induced thrombocytopenia
Side-effects ►Allergy or anaphylactic type reactions – discontinue Beriplex immediately ►Fever ►Antibody development to one or more clotting factors ►Heparin induced thrombocytopenia ►Risk of thromboembolic episodes
Please note: ► The action of warfarin may last longer than the action of Beriplex ► Check INR at 20 minutes and 6 hours post infusion ► Use clinical judgement on a case-by-case basis to decide if the potential benefit of treatment with Beriplex outweighs the potential thrombotic complications in certain patients
Patient’s INR Recommended dose of Beriplex Maximum dose (cap at 100kg body weight (see next page)
2.0 – 3.9 25 units/ kg body weight 2,500 unit
4.0 – 6.0 35 units/ kg body weight 3,500 units
> 6.0 50 units/ kg body weight 5,000 units
** The single dose should not exceed 5,000 IU (200ml of Beriplex). Vial sizes = 250 IU, 500 IU) **
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 10 of 20
IMPORTANT DOSING ADVICE
1. For the purposes of dose calculation, patients should have their weight
capped at 100kg. For example, if a patient weighs 130kg, with an INR of 5.0,
they should still only receive 3500iu of Beriplex (NOT 4550iu).
2. The maximum single dose is 5,000iu Beriplex, which must not be exceeded.
Taken with point 1, if a patient had an INR of greater than 6, and weighed
100kg or above, they would still receive the same maximum dose of 5,000iu.
If there is any question about the interpretation of dosing guidance, the case should be
discussed with the Haematologist on-call.
MANAGEMENT OF SIGNIFICANT BLEEDING WITHOUT HAEMODYNAMIC COMPROMISE
Active non-life threatening bleeding – requiring rapid reversal of warfarin
Oral vitamin K will take approximately 24 hours to counteract the effect of warfarin.
IV Vitamin K will take approximately 6-8 hours to counteract the effect of warfarin.
Beriplex will begin to work immediately.
Ascertain the following information: -
1) The indication for anticoagulation, noting dates of any previous thromboembolic
events.
2) The target INR range.
3) The usual dose of warfarin therapy.
4) From this ascertain the thrombotic risk of reversing anticoagulation - high or low. DISCUSS WITH A HAEMATOLOGIST IF IN ANY DOUBT.
Establish INR
Withhold warfarin
Give vitamin K 5-10 mg by slow intravenous injection
Consider using Beriplex
Recheck clotting screen at 4 hours or sooner if there is clinical deterioration
Repeat if necessary and seek haematological advice
Bleeding may occur with INR in the therapeutic range. In these circumstances it may be
still necessary to reverse anticoagulation to allow treatment of bleeding.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 11 of 20
Minor bleeding (eg epistaxis or haematuria)
Establish INR
Withhold warfarin
If no other risk factors for haemorrhage, withhold warfarin until INR <5.0
If risk factors for haemorrhage or minor bleeding (e.g. age >70 years,
previous bleeding complications, epistaxis), consider giving Vitamin K1 2mg
oral or 1mg by slow IV injection (i.e. to bring the INR down faster)
Recheck clotting screen at 24 hours or sooner if clinical deterioration
Restart warfarin once bleeding risk has subsided
High INR (>4.0) with no bleeding
If INR > 4.0 withhold warfarin for 1 day then continue with lower dose.
If INR >5.0 withhold warfarin for 2 days. Re-check INR to ensure it has fallen,
If <3.5 restart warfarin at lower dose.
If INR >6.0 withhold warfarin for 3 days. Re-check INR to ensure it has fallen,
If <3.5 restart warfarin at lower dose.
If INR >8.0 give 1-5mg vitamin K1 orally (using the IV preparation) or
menadiol 10mg tablet SUCKED - DO NOT SWALLOW WHOLE for partial
reversal. Recheck INR 12-18 hours post dose. Restart warfarin at reduced
dose.
IMPORTANT - Ascertain any possible reason for INR elevation (e.g. antibiotic
therapy, illness, alcohol, medication change etc.)
• If cause established, which has now passed restart warfarin at usual
dose.
• If reason persists, restart warfarin at lower dose (reduce by
approximately 10%)
• If INR elevation is due to heart failure, major medical illness or increase
in liver enzymes, seek advice before restarting warfarin.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 12 of 20
REVERSAL OF LMWH OR UNFRACTIONATED HEPARIN
ESTABLISH LAST DOSE AND HALF-LIFE OF ANTITHROMBOTIC DRUG
NB Half life of IV UFH is 60-90 minutes; Half life of enoxaparin is approx. 7 hours
(Other LMWH may vary)
The anticoagulant effects of enoxaparin can be largely neutralised by the slow intravenous injection of Protamine, but even with high doses of Protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about 60%). ** Decisions regarding the necessity and dose of subsequent Protamine injections should be based on clinical response rather than measurement of anti Xa results. The physician should also consider that the amount of enoxaparin in the body drops to 50% after 8 hours and 33% or less after 12 hours
FULL REVERSAL OF UNFRACTIONATED HEPARIN WITH PROTAMINE
1mg of Protamine will neutralise 100 units of unfractionated heparin
(NB: maximum single dose of Protamine 50mg)
PARTIAL REVERSAL OF LMWH (eg enoxaprin) WITH PROTAMINE
Time since last dose of enoxaparin -
< 8 hours: 1mg Protamine per 1mg of enoxaparin (Max dose 50mg)
8 – 12 hrs: 0.5mg Protamine per 1mg of enoxaparin (Max dose 50mg)
> 12 hrs: May not be required
ADMINISTRATION OF PROTAMINE
Administer as slow IV push over 10 minutes
Do not give more than 50mg of Protamine in a single dose
Rapid administration can cause hypotension and anaphylactoid
reactions
Onset of action, neutralisation of UFH ~ 5 minutes
Excessive doses (>100mg) can cause paradoxical anticoagulation
For full details see Product information
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 13 of 20
DIRECT ORAL ANTICOAGULANTS (DOACS)
IMPORTANT: the PT, APTT, INR and APTTR CANNOT BE USED to quantify the anticoagulant effect of DOACs. (limited interpretation may be possible in certain circumstances - and should be discussed with a Haematologist) Dabigatran (Pradaxa) a Direct oral thrombin inhibitor
Rationale
Following oral administration, plasma levels peak within 2–3 h. In individuals with normal
renal function, the half-life is 13 h. Dabigatran etexilate is 80% eliminated by the kidneys
and has a prolonged plasma half-life in patients with renal impairment (plasma half-life
22–35 h with creatinine clearance < 30 ml/min). In the RE-LY trial of dabigatran etexilate in
atrial fibrillation the annual risk of major bleeding was 2.71% and 3.11% with the 110 and
150 mg dabigatran etexilate doses, respectively, in comparison to 3.36% for patients
treated with warfarin. It must be appreciated, however, that both these figures are
conservative as this pivotal trial excluded many real-life situations of patients with
extreme body weights, significant renal impairment or multiple co-morbidities.
A normal thrombin time and a normal APTT suggest that a high level of dabigatran
etexilate is unlikely. A degree of anticoagulation cannot be excluded but the intensity
might be regarded as no more than that achieved with a prophylactic dose of low
molecular weight heparin.
Reversal
• Establish indication for anticoagulation.
• Establish when last dose was taken and how much.
• Check renal function.
• General measures.
Oral activated charcoal – in bleeding patients who have taken a dose of dabigatran
etexilate in the last 2 hours, this should be considered to prevent further absorption.
Minor bleeding – In view of the relatively short dabigatran half-life, this should be
managed by withholding further doses of the drug and using standard measure, such as
direct pressure, simple surgical intervention and fluid replacement.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 14 of 20
Reversal of Dabigatran (Pradaxa) with IDARUCIZUMAB (Praxbind)
Praxbind (Idarucizumab) is a specific reversal agent for Pradaxa (dabigatran etexilate) and
is indicated in adults (there is not data for its use in the paediatric population) when rapid
reversal of its anticoagulant effects is required, i.e.:
For emergency surgery/urgent procedures
In life-threatening or uncontrolled bleeding.
1. The recommended dose of Praxbind (Idarucizumab) is 5 g (2x2.5 g/50 mL vials), given
intravenously as two consecutive infusions over 5 to 10 minutes each or as a bolus
injection.
No dose adjustments are required for renal/hepatic impairment.
In a subset of patients, recurrence of plasma concentrations of unbound dabigatran
etexilate and concomitant prolongation of clotting tests have occurred up to 24 hours
after administration of Praxbind (idarucizumab).
2. Administration of a second 5 g dose of Praxbind (idarucizumab) may be considered in
the following situations:
• recurrence of clinically relevant bleeding together with prolonged clotting times, or
• if potential re-bleeding would be life-threatening and prolonged clotting times are
observed, or
• patients require a second emergency surgery/urgent procedure and have prolonged
clotting times.
Haemodialysis, haemofiltration and charcoal haemoperfusion offer the possibility of
enhanced clearance of the active drug. However, while this may be of benefit in theory,
the difficulties of inserting a dialysis line in an unwell, anticoagulated patient, plus the
length of time required for the dialysis procedure, mean that this technique is expected to
be used very rarely. Restarting Antithrombotic Therapy
Dabigatran treatment can be re-initiated 24 hours after administration of Praxbind,
if the patient is clinically stable and the bleeding risk has passed. Other
antithrombotic therapy (e.g. low-molecular weight heparin) can be started at any
time, once safe to do so.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 15 of 20
Direct oral Xa inhibitors - Rivaroxaban (Xarelto), Apixaban (Eliquis) and Edoxaban (Lixiana)
Rationale
Following an oral dose, rivaroxaban, apixaban and Edoxaban reach a peak at 3 h and have
half-lives of 7–9, 9–14 and 10-14h respectively, in patients with normal renal function. The
Xa inhibitors are mostly metabolized by the liver with small amounts excreted unchanged
by the kidneys. In the ROCKET AF trial, the annual risk of major bleeding was 3.6% for 20
mg once daily rivaroxaban and 3.4% for warfarin. In the ARISTOTLE trial, which compared
apixaban 5 mg twice daily with warfarin in AF, the annual risks of major bleeding were
2.13% and 3.09%, respectively. As these clinical trials restricted recruitment of some
patient groups, such as at the extreme of body weight, significant renal impairment and
multiple comorbidities, the real risk of bleeding experienced in clinical practice is likely to
be higher.
A normal PT suggests against a therapeutic intensity of anticoagulation being
present from rivaroxaban therapy. Although some degree of anticoagulation
cannot be excluded by a normal PT, the intensity could be regarded as no more
than that achieved with a prophylactic dose of low molecular weight heparin. The PT has no role at all in assessing the anticoagulant effects of Apixaban and Edoxaban
No antidote is currently available at QEHKL for use in patients with major or life-
threatening bleeding.
There are no published clinical trials or other high quality evidence addressing the
management of bleeding on rivaroxaban or apixaban.
Other specific antidotes such as a recombinant Xa-analogue are still being
investigated in clinical trials.
Reversal
• Establish indication for anticoagulation.
• Establish when last dose was taken and how much.
• Check renal function.
• General measures.
For minor bleeding - in view of the short half-life, supportive measures, such as
direct pressure, minor surgical intervention and fluid replacement, should be tried.
Life-threatening bleeding - PCC (i.e. Beriplex 50u/kg) and rFVIIa 90mcg/kg should be
considered following discussion with the on call Haematologist.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 16 of 20
As these drugs show high plasma protein binding they would not be expected to be
dialysable. BLEEDING ON ASPIRIN OR CLOPIDOGREL.
Consider platelet transfusion (one unit) early in bleeding patient.
Discuss with Haematologist on call.
OTHER DRUGS
Danaparoid sodium
Danaparoid is a heparinoid used mainly in the treatment of Heparin Induced
Thrombocytopenia (HIT), consisting of a mixture of glycosaminoglycans with an anti-
Xa/anti-IIa ratio > 20. Danaparoid is excreted renally and has a plasma half-life of anti-Xa
activity of approximately 24 h. Danaparoid may be monitored by anti-Xa assay using a
danaparoid standard (must notify lab). Major bleeding occurred in 8.1% of patients
treated with danaparoid for HIT. An ex vivo study showed partial restoration of thrombin
generation when rFVIIa was added at supra-therapeutic doses to plasma spiked with
danaparoid, but not with addition of APCC and FFP.
There is no specific antidote for danaparoid. Management of bleeding should be
through cessation of treatment and general haemostatic measures
Plasmapheresis removes danaparoid effectively from the circulation and may be
considered for critical bleeding. Fondaparinux
Fondaparinux is a synthetic pentasaccharide with indirect anti-Xa activity that achieves
steady state antithrombotic activity after 3–4 d of use. The plasma half-life is significantly
longer than LMWH at 17–20 h (with normal renal function) and up to 72 h (when
creatinine clearance is <30 ml/min).
There is no specific antidote for fondaparinux. Management of bleeding should be
through cessation of treatment and general haemostatic measures.
Recombinant FVIIa 90mcg/kg may partially correct the haemostatic defect from
Fondaparinux, and should be considered for critical bleeding, but only after
discussion with a Consultant Haematologist, and only once other measures have
failed.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 17 of 20
8. Summary of development and consultation process undertaken before registration and dissemination
The authors listed above drafted this document on behalf of the Hospital Thrombosis Committee who has agreed the final content. During its development it has been
circulated for comment to: Hospital Thrombosis Committee and Drugs and Therapeutics committee.
This version has been endorsed by the Hospital Thrombosis Committee. 9. References
BRITISH COMMITTEE FOR STANDARDS IN HAEMATOLOGY (BCSH) (2012). Guideline on the
management of bleeding in patients on antithrombotic agents. 4th Edition.
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE (nice) 2016. Reversal of the
anticoagulant effect of dabigatran: Idarucizumab
BOEHRINGER INGELHEIM (2015). Praxbind 2.5g/50ml solution for injection/infusion,
summary of product characteristics (online, January 2017)
http://www.acepnow.com/article/options-approaches-outpatient-treatment-deep-vein-
thrombosis-emergency-physicians/?singlepage=1&theme=print-friendly
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 18 of 20
EQUALITY IMPACT ASSESSMENT
STAGE 1 - SCREENING
Name & Job Title of Assessor:
Dr M D Lewis, Consultant Haematologist
Date of Initial Screening: April 2020
Date of Review: April 2023
Policy or Function to be assessed:
Yes/No
Comments
1. Does the policy, function, service or project affect one group more or less favourably than another on the basis of:
Race & Ethnic background No
Gender including transgender No
Disability:- This will include consideration
in terms of impact to persons with
learning disabilities, autism or on
individuals who may have a cognitive
impairment or lack capacity to make
decisions about their care
No
Religion or belief No
Sexual orientation No
Age Yes Applies to adult patients only.
Patients under the age of 18 are to
be seen by a Paediatrician
2. Does the public have a perception/concern regarding the potential for discrimination?
No
If the answer to any of the questions above is yes, please complete a full Stage 2 Equality Impact Assessment.
Signature of Assessor: Dr M D Lewis Date: April 2020
Signature of Line Manager: Hugh Warren Date: April 2020
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 19 of 20
STAGE 2 – EQUALITY IMPACT ASSESSMENT
If you have indicated that there is a negative impact on any group in part one please complete the following, is that impact:
Yes/No Comments
1. Legal/Lawful under current equality legislation?
N/A
2. Can the negative impact be avoided? No Not desirable.
Clinically appropriate.
3. Are there alternatives to achieving the policy/guidance without the impact?
N/A
4. Have you consulted with relevant stakeholders of potentially affected groups?
No
5. Is action required to address the issues? No
It is essential that this Assessment is discussed by your management team and remains
readily available for inspection. A copy including completed action plan, if appropriate,
should also be forwarded to the Equality & Diversity Lead, c/o Human Resources
Department.
The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust Clinical Guideline for the Management of Over Anticoagulation and Bleeding on
Antithrombotic Drugs in Adults
Clinical Guideline Author: Dr M D Lewis Authors title: Consultant Haematologist Approved by: Hospital Thrombosis Committee Date approved: April 2020 Review date: April 2023 Page 20 of 20
MONITORING COMPLIANCE
Key elements Process for Monitoring
By Whom (Individual / group /committee)
Responsible Governance Committee /Dept
Frequency of monitoring