Guideline for managing patients on Dabigatran (Pradaxa ) Statewide

Guideline for managing patients on Dabigatran (Pradaxa ) Statewide Custodian: Medication Safety, Medicines Regulation and Quality medicationsafety@health.qld.gov.au 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 Approval Date: 21/05/2013 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. Effective Date: 21/05/2013 Next Review Date: 21/05/2015 Authority: Approving Officer 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) 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). 3. 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 Version No.: 2.0; Effective From: 21/05/2013 Page 1 of 12

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 MedicationSafety@health.qld.gov.au. For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane Qld 4001, email ip_officer@health.qld.gov.au, phone (07) 3234 1479. Version No.: 2.0; Effective From: 21/05/2013 Page 2 of 12

4. Guideline 4.1 Indications Queensland Health: Guideline for managing patients on Dabigatran (Pradaxa ) 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) Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke Yes (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). Version No.: 2.0; Effective From: 21/05/2013 Page 3 of 12

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. Version No.: 2.0; Effective From: 21/05/2013 Page 4 of 12

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. Version No.: 2.0; Effective From: 21/05/2013 Page 5 of 12

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 Moderate bleeding # Severe to life threatening bleeding* Withhold next dose Discontinue dabigatran. Implement all measures for of dabigatran or Consult Haematology moderate bleeding. discontinue Service. Consider anti-fibrinolytic agent treatment as Mechanical compression, or tranexamic acid IV 15-30 mg/kg, appropriate. consider surgical followed by a continuous infusion at Apply local intervention or wound 1 mg/kg/hr until bleeding is under measures and treat packing. control. any aggravating factors. Administer fluid replacement to maintain good urine output as dabigatran is renally excreted. Consider platelets if levels less than 70-80 x 10 9 /L or patient on anti-platelet agent. Administer oral activated charcoal if dabigatran ingested in last two hours. 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) Version No.: 2.0; Effective From: 21/05/2013 Page 6 of 12

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 (range) Withholding time of dabigatran prior to surgery after last dose Low bleeding risk High bleeding risk Ψ 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. Version No.: 2.0; Effective From: 21/05/2013 Page 7 of 12

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. Version No.: 2.0; Effective From: 21/05/2013 Page 8 of 12

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) APTT 12 hours after last dabigatran dose Instructions Greater than or equal to 30 ml/min Less than 30 ml/min # Less than 60 seconds Greater than 60 seconds Less than 60 seconds Greater than 60 seconds 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. 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. 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. 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. Version No.: 2.0; Effective From: 21/05/2013 Page 9 of 12

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) Low risk of thrombosis Options for conversion 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. Version No.: 2.0; Effective From: 21/05/2013 Page 10 of 12

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. Version No.: 2.0; Effective From: 21/05/2013 Page 11 of 12

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: Statewide General Medicine Clinical Network Statewide Cardiac Clinical Network 8. Guideline Revision and Approval History Version Modified by Amendments authorised by Approved by No. 1.0 Sarah Mathers Queensland Health Dr Julie Stokes Statewide Anticoagulant Working Party 2.0 Sarah Mathers Queensland Health Statewide Anticoagulant Working Party Dr Sue Ballantyne Version No.: 2.0; Effective From: 21/05/2013 Page 12 of 12