Download Managing patients on dabigatran

Guideline for managing patients on Dabigatran (Pradaxa®)
Statewide
Custodian: Medication Safety, Medicines
Regulation and Quality
[email protected]
Developed
by
Medication
Safety,
Medicines Regulation and Quality and the
Anticoagulant Working Party (membership
includes representation from General
Practice Queensland, Sullivan Nicolaides
Pathology, QML Pathology)
Version no: 2.0
Applicable To: All Queensland Health
staff involved with management of patients
who present to hospital on dabigatran
1.
Purpose
This Guideline is intended to assist clinicians with the
management of patients who are admitted to hospital
already taking dabigatran. It is not intended as a guideline
for initiation of treatment with dabigatran. Haematology
consultation is advisable in most clinical situations.
Within the first two years of dabigatran being on the
Australian market there were numerous incident reports of
haemorrhage and deaths in Queensland, nationally and
internationally. This prompted the need for a specific
guideline for the management of patients presenting to
hospital who are already taking the drug.
Approval Date: 21/05/2013
Effective Date: 21/05/2013
Next Review Date: 21/05/2015
Authority:
2.
Scope
This Guideline provides information for all Queensland
Health employees (permanent, temporary and casual)
and all organisations and individuals acting as its agents
(including Visiting Medical Officers and other partners,
contractors, consultants and volunteers).
Approving Officer
3.
……Signed…………………………………
Name
Dr Sue Ballantyne
Director, Medicines Regulation and Quality
Supersedes: Guidelines for managing
patients on Dabigatran (Pradaxa®) who
present to hospital (v1.0, 2011)
Related documents




Queensland Health List of Approved Medicines
Statewide Heparin Intravenous Infusion Order
and Administration – Adult form
Guidelines for Anticoagulation Using Warfarin
Guidelines
for
Managing
Patients
on
Rivaroxaban (Xarelto®)
Key Words: dabigatran, anticoagulant,
Pradaxa
Accreditation References:
EQuIP and other criteria and standards
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Disclaimer
This guideline has been prepared to promote and facilitate standardisation and consistency of practice,
using a multidisciplinary approach.
Information in this guideline is current at time of publication.
The Department of Health, Queensland Government does not accept liability to any person for loss or
damage incurred as a result of reliance upon the material contained in this guideline.
Clinical material offered in this guideline does not replace or remove clinical judgement or the professional
care and duty necessary for each specific patient case.
Clinical care carried out in accordance with this guideline should be provided within the context of locally
available resources and expertise.
This Guideline does not address all elements of standard practice and assumes that individual clinicians
have the responsibility to:
 Discuss care with consumers in an environment that is culturally appropriate and which enables
respectful confidential discussion. This includes the use of interpreter services where necessary.
 Advise consumers of their choice and ensure informed consent is obtained.
 Provide care within scope of practice, meet all legislative requirements and maintain standards of
professional conduct.
 Apply standard precautions and additional precautions as necessary, when delivering care.
 Document all care in accordance with mandatory and local requirements.
Guideline for Managing Patients on Dabigatran (Pradaxa®)
Published by the State of Queensland (Queensland Health), May, 2013
© State of Queensland (Queensland Health) 2013
This work is licensed under a Creative Commons Attribution Non-Commercial Share Alike 3.0 Australia
licence. In essence, you are free to copy, communicate and adapt the work for non-commercial purposes, as
long as you attribute Medicines Regulation and Quality, Department of Health, Queensland Government, you
distribute any derivative work only under this licence and you abide by the licence terms. To view a copy of
this licence, visit http://creativecommons.org/licenses/by-nc-sa/3.0/au/deed.en
For further information contact Medication Safety Officer, Medicines Regulation and Quality, Locked Bag 21,
Fortitude Valley BC Qld 4006, email [email protected].
For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health,
GPO Box 48, Brisbane Qld 4001, email [email protected], phone (07) 3234 1479.
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4.
Guideline
4.1
Indications
Dabigatran is an oral direct thrombin inhibitor. It is available as 75 mg, 110 mg and 150 mg tablets.
It is not currently listed on the Queensland Health List of Approved Medicines (LAM).
Table A: Approved indications for dabigatran
TGA approved indications
PBS listed
Prevention of venous thromboembolic (VTE) events in adult patients who have
undergone major orthopaedic surgery of the lower limb (elective total hip and knee
replacement)
Yes
Prevention of stroke and systemic embolism in patients with non-valvular atrial
fibrillation and at least one additional risk factor for stroke
(except 150 mg)
No
TGA = Therapeutic Goods Administration; PBS = Pharmaceutical Benefits Scheme
Dabigatran is primarily renally excreted and is contraindicated if creatinine clearance (CrCl) is
less than 30 mL/min. Note: Calculation of CrCl should be determined using ideal body weight with
the Cockcroft-Gault equation as it is more accurate than eGFR for patients who are elderly or who
have low body weight (see online calculators available locally, on QHEPS or eTG Complete).
Risk factors for adverse events with dabigatran include age older than 75 years, low body weight
(less than 50 kg), and moderate or severe renal impairment (CrCl less than 50 mL/min).
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4.2
Monitoring / Pathology testing
There is currently no assay available for dabigatran levels in Queensland Health facilities. Advice
should be sought from local laboratories on availability of coagulation tests. Monitoring with
International Normalised Ratio (INR) is not recommended. The following tests are qualitative
indicators and can be influenced by concomitant use of other anticoagulants:

Activated partial thromboplastin time (APTT) is moderately sensitive to dabigatran, but it
becomes increasingly insensitive with higher levels. A trough (when the next dose is due)
APTT of 1.5 times the baseline value is seen with 150 mg twice daily of dabigatran in patients
with normal renal function. Trough APTT values greater than 80 seconds are associated with
increased bleeding risk.

Thrombin time (TT) is very sensitive to dabigatran, and a normal TT excludes the presence
of significant dabigatran levels but is not useful for monitoring or dose adjustment.
Routine testing is generally not conducted during treatment with dabigatran because it has a
predictable pharmacokinetic profile enabling a fixed-dose regimen. Laboratory testing is currently
limited but may be helpful in the following situations:
 the peri-operative setting
 acute coronary syndrome (ACS)
 in the event of bleeding or recurrent thrombosis
 elderly patients due to higher risk of bleeding
 when renal function is deteriorating or if renal impairment with CrCl less than 50_mL/min
 when parenteral anticoagulants are being considered for a patient taking dabigatran
 patients with extremes of body weight because low body weight has a high bleeding risk and
obesity may have poor efficacy
 patients on potentially interacting medications (i.e. concomitant administration of strong
inducers or inhibitors of P-glycoprotein)
 in case of overdose or if there are concerns about compliance.
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4.3
Drug interactions
Thrombolytic agents or antiplatelet agents (e.g. aspirin, clopidogrel, prasugrel, ticagrelor,
ticlopidine): Concomitant administration of these agents with dabigatran is a relative
contraindication as dual therapy is associated with higher risks of bleeding and anaemia, especially
if other risk factors (see section 4.1) are present.
Other Anticoagulants: Concomitant administration is not recommended with rivaroxaban,
warfarin, heparin, or low molecular weight heparin.
Non-steroidal anti-inflammatory drugs (NSAIDs): Monitor for risks of bleeding if dabigatran
used with NSAIDs, especially those with half-lives greater than 12 hours (e.g. naproxen,
piroxicam). NSAIDs with short half-lives less than 12 hours (e.g. ibuprofen) have not been shown
to be associated with increased bleeding risk.
Inhibitors of P-glycoprotein efflux transporter: The prodrug dabigatran exilate is a substrate for
the P-glycoprotein efflux transporter. Avoid use in combination with the following inhibitors which
may increase the levels of dabigatran.
 azoles (e.g. ketoconazole, itraconazole)
 calcium channel blockers (e.g. diltiazem, nifedipine, verapamil)
 immunosuppressants (e.g. cyclosporine, tacrolimus)
 macrolides (e.g. clarithromycin, erythromycin)
 protease inhibitors (e.g. ritonavir, saquinavir)
 others (e.g. amiodarone, dipyridamole, hydrocortisone, progesterone, propranolol, quinine,
tamoxifen).
Inducers of P-glycoprotein efflux transporter: Avoid concomitant use of dabigatran with the
following inducers of the P-glycoprotein efflux transporter which may reduce levels of dabigatran.
 carbamazepine
 rifampicin
 St John’s Wort.
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4.4
Management of bleeding
Currently, there is no known clinically proven antidote for dabigatran. In a human volunteer study,
prothrombin complex concentrates did not normalise the prolonged times of the relevant
coagulation tests. Vitamin K and fresh frozen plasma infusion have not been shown to be effective.
The effect of factor VIIa (Novoseven®) is currently uncertain.
Dabigatran associated bleeding
↓
If a patient is bleeding, discontinue dabigatran therapy and investigate for site of bleeding.
Initiate symptomatic treatment and optimise renal function.
Review all medications and discontinue all anticoagulants, anti-platelet agents and NSAIDs. Check for
possible drug interactions (see section 4.3).
For patients who have had warfarin in the last four days, administer 10 mg vitamin K intravenously.
↓
Check coagulation screen (APTT, TT and fibrinogen assay); indicate time of last dose on request form.
Check full blood count, renal function and electrolytes (including calcium).
Organise blood group and hold, and blood group antibody screen.
↓


Mild bleeding
Withhold next dose
of dabigatran or
discontinue
treatment as
appropriate.
Apply local
measures and treat
any aggravating
factors.
↓






#
Moderate bleeding#
Discontinue dabigatran.
Consult Haematology
Service.
Mechanical compression, or
consider surgical
intervention or wound
packing.
Administer fluid replacement
to maintain good urine
output as dabigatran is
renally excreted.
Consider platelets if levels
9
less than 70-80 x 10 /L or
patient on anti-platelet
agent.
Administer oral activated
charcoal if dabigatran
ingested in last two hours.
↓
Severe to life threatening bleeding*
Implement all measures for
moderate bleeding.
 Consider anti-fibrinolytic agent
tranexamic acid† IV 15-30 mg/kg,
followed by a continuous infusion at
1 mg/kg/hr until bleeding is under
control.
 Recombinant factor VIIa
(Novoseven®) IV bolus 50 microg/kg
may be trialled if critical. Repeat if
necessary with Haematology
guidance.Φ Note factor VIIa half-life
is significantly shorter than
dabigatran and so this will require
further close monitoring of the
patient.
 Haemodialysis (especially if renal
failure present) may remove
approximately 60% of dabigatran.

Moderate bleeding: non-trivial bleeding with a reduction in haemoglobin of less than 20 g/L, or requiring transfusion of
less than two units of red blood cells.
* Severe to Life-threatening bleeding: bleeding with a reduction in haemoglobin of greater than or equal to 20 g/L, or
requiring transfusion of greater than or equal to two units of red blood cells, or involving a critical site.
†
There is limited evidence of the clinical benefit for tranexamic acid in this setting and treatment should not delay
resuscitation and adequate factor replacement.
Φ
NB: Individual Patient Approval should be obtained as per Hospital and Health Service or local procedure for
recombinant factor VIIa ‘For the management of life-threatening bleeding and coagulopathy in non-haemophiliac
patients who have failed to respond to conventional therapy.’ (See Appendix 9 of the LAM)
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4.5
Management peri-operatively of patients admitted to hospital on dabigatran
Semi-acute or elective surgery



Assess the risk of bleeding against the risk of thrombosis as dabigatran may not need to
be discontinued for minor procedures.
If dabigatran needs to be withheld, plan ahead as there is no known treatment available for
immediate reversal.
Consider bridging anticoagulant therapy if there is a high risk of thrombosis (see section 4.6).
As dabigatran is primarily renally excreted, renal function will determine the withholding time prior
to surgery and this should be checked pre-admission. The patient should be advised when to
withhold dabigatran pre-operatively. In situations where complete haemostasis is required,
APTT and TT should be checked pre-operatively.
Table B: Discontinuation of dabigatran prior to surgery
Renal function
(CrCl, mL/min)
NB. Use Cockcroft-Gault
equation with ideal body
weight (see section 4.1)
Dabigatran
half-life
Withholding time of dabigatran prior to surgery after last
dose
(range)
Low bleeding risk
High bleeding riskΨ
Greater than 80
13 (11-22) hours
48 hours
5 days
51 – 80
15 (12-34) hours
48 hours
5 days
31 - 50
18 (13-23) hours
At least 72 hours
5 days
Equal to or less than 30
27 (22-35) hours
5 days – do not restart
Greater than 5 days – do not restart
Ψ
Types of surgery associated with high risk of bleeding include cardiac surgery, neurosurgery, abdominal surgery,
surgery involving a major organ, or in major surgery where complete haemostasis may be required. Other procedures
such as spinal anaesthesia may require complete haemostasis. Other risk factors for bleeding include advancing age,
co-morbidities (e.g. major cardiac, respiratory or liver disease) and concomitant use of anti-platelet therapy.
Urgent surgery







Stop dabigatran.
Administer oral activated charcoal if dabigatran ingested in the last two hours.
Check full blood count, electrolytes (including calcium), renal function and coagulation screen
(APTT, TT and fibrinogen assay); indicate time of last dabigatran dose on request form.
Consider delaying surgery, if appropriate, until coagulation screen is normal or until sufficient
time for drug clearance (four half-lives).
Where urgent life-saving surgery cannot be delayed, consult with Haematology Service over
measures to control bleeding perioperatively.
Epidural and spinal anaesthesia are contraindicated.
Cross-match blood.
Recommendations regarding epidural and spinal catheter



Epidural and spinal anaesthesia are contraindicated unless dabigatran has been eliminated as
indicated by a normal TT.
Dabigatran should not be recommenced in patients who have an epidural or spinal catheter in
place.
Dabigatran should not be restarted within 24 hours of removal of spinal or epidural catheter; a
longer delay should be considered if there are multiple punctures or traumatic insertion of
spinal or epidural catheter.
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Restarting dabigatran after surgery





Discuss with Haematology Service based on nature of surgery, haemostatic state and urgency
of restarting anticoagulant therapy.
Do not restart dabigatran in severe renal impairment (i.e. if CrCl is less than 30 mL/min).
In elective surgery where haemostasis is satisfactory, it is suggested that dabigatran is
restarted after at least 12 hours if the surgeon considers it safe to do so.
If haemostasis is not satisfactory and clinically significant bleeding is present, a delay in
restarting dabigatran is appropriate.
Consider using an alternative reversible anticoagulant (e.g. unfractionated heparin) if the risk of
thrombosis is greater than the risk of wound bleeding.
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4.6
Bridging or switching to or from other anticoagulants
Conversion from dabigatran to a parenteral anticoagulant
Table C: Converting dabigatran to parenteral anticoagulants
Creatinine
clearance (CrCl)
Greater than or
equal to 30 mL/min
APTT 12 hours
after last
dabigatran dose
Less than 60
seconds
Instructions
Start treatment dose of low molecular weight heparin (LMWH)
when next dose of dabigatran would have been due.
OR
Start unfractionated heparin (UFH)* intravenous infusion without
a bolus. Measure APTT six hours after infusion has started, then
as per the Queensland Health Heparin Intravenous Infusion
Order and Administration – Adult form guidelines.
Greater than 60
seconds
Repeat APTT every six hours until APTT is less than 60
seconds, then:
Start treatment dose of low molecular weight heparin (LMWH)
when next dose of dabigatran would have been due.
OR
Start unfractionated heparin (UFH)* intravenous infusion without
a bolus. Measure APTT six hours after infusion has started, then
as per the Queensland Health Heparin Intravenous Infusion
Order and Administration – Adult form guidelines.
Less than
30 mL/min
#
Less than 60
seconds
Start unfractionated heparin (UFH)* intravenous infusion without
a bolus. Measure APTT six hours after infusion has started, then
as per the Queensland Health Heparin Intravenous Infusion
Order and Administration – Adult form guidelines.
Greater than 60
seconds
Repeat APTT every six hours until APTT is less than 60
seconds, then:
Start unfractionated heparin (UFH)* intravenous infusion without
a bolus. Measure APTT six hours after infusion has started, then
as per the Queensland Health Heparin Intravenous Infusion
Order and Administration – Adult form guidelines.
* Note: Loading doses of UFH should not be given. The Queensland Health Heparin Intravenous Infusion Order and
Administration – Adult form should only be used as a guide for dose adjustment.
#
Note: Dabigatran is contraindicated if CrCl is less than 30 mL/min. Do not restart.
Conversion from a parenteral anticoagulant to dabigatran
Check renal function prior to re-starting dabigatran. If renal impairment, dabigatran may require
dose adjustment or should not be used, depending on its indication (avoid if CrCl is less than 30
mL/min).
 For conversion from an UFH infusion to dabigatran, start dabigatran when infusion ceased.
 For conversion from low molecular weight heparin (LMWH) such as enoxaparin to
dabigatran, start dabigatran 12 hours after the last dose of LMWH.
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Conversion from dabigatran to warfarin



For conversion from dabigatran to warfarin, adjust the starting time of warfarin based on renal
function (see Table D) and start dosing as per the Queensland Health Guidelines for
Anticoagulation Using Warfarin - Adult.
As dabigatran can contribute to an elevated INR, the INR will better reflect the effect of
warfarin after dabigatran has been ceased for two days.
If patient has previously been on warfarin restart on usual dose.
Table D: Converting dabigatran to warfarin
Creatinine
clearance (CrCl)
Options for conversion
Low risk of thrombosis
#
High risk of thrombosis
Greater than or
equal to 50 mL/min
Stop dabigatran and start warfarin at
the next standard administration time.
Start warfarin at next standard administration
time three days before discontinuing
dabigatran
31 to 50 mL/min
Stop dabigatran and start warfarin at
the next standard administration time.
Start warfarin for two days before discontinuing
dabigatran
Less than or equal
to 30 mL/min#
Stop dabigatran and start warfarin at
the next standard administration time.
Stop dabigatran and start warfarin at next
standard administration time.
Note: Dabigatran is contraindicated if CrCl is less than 30 mL/min. Do not restart.
Conversion from warfarin to dabigatran
Check renal function prior to re-starting dabigatran. If renal impairment, dabigatran may require
dose adjustment or should not be used, depending on its indication (avoid if CrCl is less than 30
mL/min).
 For conversion from warfarin to dabigatran, discontinue warfarin and start dabigatran when
INR is below two.
4.7
Venous Thromboembolism (VTE) prophylaxis
Do not commence pharmacological VTE prophylaxis (e.g. heparin, enoxaparin, dalteparin) if
patient is taking dabigatran. If dabigatran is ceased, and VTE prophylaxis is indicated, start
pharmacological prophylaxis when APTT is less than 60 seconds.
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4.8
Acute coronary syndrome (ACS)
There is currently no published literature available for ACS management in patients who are on
dabigatran, rivaroxaban or apixaban. The following information is suggested guidance only and it
may be modified in the future depending on accumulating clinical experience. Further advice
should be sought from a cardiologist.
Note: For patients with stents requiring dual antiplatelet therapy, dabigatran should only be
considered by a cardiologist.
Table E: Acute coronary syndrome management in patients on dabigatran





ST Elevation Myocardial Infarction (STEMI)
For parenteral anticoagulation for ACS in dabigatran treated patients, unfractionated heparin (UFH) is
preferred to low molecular weight heparin.
For patients receiving dabigatran, primary percutaneous coronary intervention (PCI) is preferred (if
available) to thrombolysis.
The decision to thrombolyse should be based on an assessment of the perceived benefit (e.g. anterior
versus inferior myocardial infarction, time to presentation) versus the perceived risk of a bleeding
complication (e.g. elderly, reduced renal function, presence of other relative contraindications).
If thrombolysis is administered, do not start UFH within 12 hours of last dabigatran dose or longer if
impaired renal function (see likely half life-lives with renal impairment in Table B).
Loading doses of UFH should not be given. See Table C, section 4.6 for information on UFH dosing.
Non-ST Elevation Acute Coronary Syndrome (NSTEACS)



(e.g. Non-ST Elevation Myocardial Infarction (NSTEMI) and Unstable Angina)
For parenteral anticoagulation for ACS in dabigatran treated patients, unfractionated heparin (UFH) is
preferred to low molecular weight heparin.
Do not start UFH within 12 hours of the last dose of dabigatran or longer if impaired renal function (see
likely half life-lives with renal impairment in Table B).
Loading doses of UFH should not be given. See Table C, section 4.6 for information on UFH dosing.
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5.
Definition of Terms
Definitions of key terms are provided below.
Term
Definition / Explanation / Details
TGA
Therapeutic Goods Administration
PBS
Pharmaceutical Benefits Scheme
LAM
Queensland Health List of Approved Medicines
CrCl
Creatinine clearance which is an indicator for renal function
INR
International normalised ratio
APTT
Activated partial prothrombin time
TT
Thrombin time
ACS
Acute coronary syndrome
NSAIDs
Non-steroidal anti-inflammatory drugs
LMWH
Low molecular weight heparin
UFH
Unfractionated heparin
VTE
Venous thromboembolism
STEMI
ST elevation myocardial infarction
NSTEACS
Non-ST elevation acute coronary syndrome
6.
References and Suggested Reading
References are available on request.
7.
Consultation (optional)
Key stakeholders who reviewed this version are:
8.

Statewide General Medicine Clinical Network

Statewide Cardiac Clinical Network
Guideline Revision and Approval History
Version
No.
1.0
Modified by
Amendments authorised by
Approved by
Sarah Mathers
Dr Julie Stokes
2.0
Sarah Mathers
Queensland Health
Statewide Anticoagulant
Working Party
Queensland Health
Statewide Anticoagulant
Working Party
Version No.: 2.0; Effective From: 21/05/2013
Dr Sue Ballantyne
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