Appendix 2H - SECONDARY CARE CONVERSION GUIDELINES ORAL ANTICOAGULANTS

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1 Appendix 2H - SECONDARY CARE CONVERSION GUIDELINES ORAL ANTICOAGULANTS Please note that newer oral anticoagulants e.g. rivaroxaban, dabigatran and apixiban should be only be considered in patients with AF where there is poor INR control despite complying with warfarin or in those where warfarin / other coumarins are not tolerated. Rivaroxaban is the preferred agent in NHS Fife in those circumstances. Rivaroxaban is the 1 st line treatment choice for a first episode of DVT or PE where treatment duration is expected to be no longer than 6 months. It is started without heparinisation. Rivaroxaban (Xarelto ) Conversion from Warfarin to Rivaroxaban For patients treated for prevention of stroke and systemic embolism, warfarin treatment should be stopped and rivaroxaban therapy should be initiated when the INR is 3.0 or less. For patients treated for DVT and prevention of recurrent DVT and PE, warfarin treatment should be stopped and rivaroxaban therapy should be initiated once the INR is 2.5 or less. When converting patients from warfarin to rivaroxaban, INR values will be falsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity of rivaroxaban, and therefore should not be used. Conversion from Rivaroxaban to Warfarin There is a potential for inadequate anticoagulation during the transition from rivaroxaban to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that rivaroxaban can contribute to an elevated INR. In patients converting from rivaroxaban to warfarin, warfarin should be given concurrently until the INR is 2.0. For the first two days of the conversion period, standard initial dosing of warfarin should be used followed by warfarin dosing guided by INR testing. While patients are on both rivaroxaban and warfarin the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of rivaroxaban. Once rivaroxaban is discontinued INR testing may be done reliably at least 24 hours after the last dose. Conversion from Parenteral Anticoagulants to Rivaroxaban For patients currently receiving a parenteral anticoagulant, rivaroxaban should be started 0 to 2 hours before the time of the next scheduled administration of the parenteral medicinal product (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin). Conversion from Rivaroxaban to Parental Anticoagulants Give the first dose of parenteral anticoagulant at the time the next rivaroxaban dose would be taken.

2 Management of bleeding Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours. Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets. If bleeding cannot be controlled by the above measures, administration of a specific procoagulant reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-fviia). However, there is currently very limited clinical experience with the use of these products in individuals receiving rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding. If an invasive procedure or surgical intervention is required, rivaroxaban should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. Rivaroxaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established

3 Dabigatran (Pradaxa ) Please note that Dabigatran is not recommended in NHS Fife Conversion from Warfarin to Dabigatran When converting patients from warfarin therapy to dabigatran, discontinue warfarin and start dabigatran when the INR is below 2.0 (this usually occurs 3-5 days after discontinuing warfarin when a patient has been stable in INR range 2-3). Conversion from Dabigatran to Warfarin When converting from dabigatran to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows: For CrCl>50mL/min, start warfarin 3 days before discontinuing dabigatran. For CrCl 31-50mL/min, start warfarin 2 days before discontinuing dabigatran. For CrCl 15-30mL/min, start warfarin 1 day before discontinuing dabigatran For CrCl<15mL/min, no recommendations can be made consult with on call haematologist. Because dabigatran can contribute to an elevated INR, the INR will better reflect warfarin s effect after dabigatran has been stopped for at least 2 days. Conversion from Parenteral Anticoagulants to Dabigatran For patients currently receiving a parenteral anticoagulant (e.g. LMWH), start dabigatran 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g. intravenous unfractionated heparin). Conversion from Dabigatran to Parenteral Anticoagulants For patients currently taking dabigatran, wait 12 hours (CrCl>30mL/min) or 24 hours (CrCl<30mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant. Management of Bleeding There is no antidote to dabigatran. In the event of haemorrhagic complications: Discontinue treatment with dabigatran (half life 13 hours with normal renal function). Consult the on call haematologist/blood transfusion. Initiate appropriate clinical support, e.g. surgical or local haemostasis, transfusion of red cells, volume substitution, inotropic drugs. Consider administration of platelet concentrates in case where thrombocytopenia is present or long acting antiplatelet drugs have been used. Investigate the source of bleeding.

4 Around 85% of dabigatran clearance is renal; therefore, maintain adequate diuresis. Dabigatran can be dialysed (protein binding is low), and it may take 6-8 hours to clear dabigatran this way; however, data supporting this approach is limited. The duration of dialysis may be best guided by normalisation of aptt. There is some experimental evidence to support the role of activated prothrombin complex concentrates. However, their usefulness in clinical settings has not been evaluated and therefore these alternatives cannot be relied upon. Measurement of aptt may help guide therapy to the extent that therapeutic levels of dabigatran will cause a prolongation. Timing of discontinuation after last dose of dabigatran before surgery Renal function Half life (hours) Standard risk of High risk bleeding (see c) (Crcl ml/min) (see b) bleeding >80 13 (11-22) 24 hours 2-4 days >50 to <80 15 (12-34) hours 2-4 days >30 to <50 18 (13-23) hours 4 days <30 (see a) 27 (22-35) 2-5 days >5 days Crcl = creatinine clearance a) Dabigatran etexilate is contraindicated for use in these patients. b) Half life data from renal impairment study in healthy volunteers (Strainger et al). c) Types of surgery associated with a high risk of bleeding (or in major surgery where complete haemostasis may be required) include but is not limited to cardiac surgery, neurosurgery, abdominal surgery or those involving a major organ. Other procedures such as spinal anaesthesia may also require complete haemostatic function. Other important determinants of bleeding risk include advancing age, co-morbidities (e.g. major cardiac, respiratory or liver disease), low body weight (<50kg) and concomitant use of antiplatelet therapy. Apixaban (Eliquis ) Please note that Apixaban is not recommended in NHS Fife Conversion from Warfarin to Apixaban For patients treated for prevention of stroke and systemic embolism, warfarin treatment should be stopped and apixaban therapy should be initiated when the INR is 2.0 or less. Conversion from Apixaban to Warfarin There is a potential for inadequate anticoagulation during the transition from apixaban to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. When converting patients from apixaban to warfarin, continue administration of apixaban for at least 2 days after beginning warfarin therapy. After 2 days of co-administration, obtain an INR prior to the next scheduled dose of warfarin. Continue coadministration of apixaban and warfarin until the INR is 2.0 and then stop apixaban.

5 Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable. Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. Management of bleeding There is no antidote to apixaban. Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets. If life-threatening bleeding cannot be controlled by the above measures, administration of recombinant factor VIIa may be considered. However, there is currently very limited clinical experience with the use of these products in individuals receiving apixaban. The recommendation is also based on limited non-clinical data. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of bleeding. References Acknowledgements Dr Ron Kerr - Consultant Haematologist, Ninewells Hospital, Dundee. Dr Steve Rogers - Consultant Haematologist, VHK