New Oral Anticoagulant A practical guide on behalf of the Australasian Society of Thrombosis and Haemostasis (ASTH)

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1 New Oral Anticoagulant A practical guide on behalf of the Australasian Society of Thrombosis and Haemostasis (ASTH) Huyen Tran 1, Joanne Joseph 2, Laura Young 3, Simon McRae 4, Jennifer Curnow 5, Harshal Nandurkar 6, Peter Wood 7, Claire McLintock 8 1 Haemostasis Thrombosis Unit,The Alfred Hospital, Melbourne, VIC, 2 Haematology Department, St Vincent s Hospital, Sydney, NSW, 3 Clinical Haematology, Auckland City Hospital, Auckland, New Zealand, 4 Haemostasis Thrombosis Unit, Royal Adelaide Hospital, Adelaide, SA, 5 Haematology Department, Concord Hospital, Sydney, NSW, 6 Haematology Department, St Vincent s Hospital, Melbourne, VIC, 7 Clinical Haematology, Princess Alexandra Hospital, Brisbane, Queensland, 8 National Women s Health, Auckland City Hospital, Auckland, New Zealand The prescription of new oralanticoagulants (NOAC) requires an in depth knowledge of the pharmacology of these drugs and strategies must be developed in hospitals to ensure optimal care for patientsreceiving these drugs, especially when they develop bleeding complications or require urgent surgery. The NOAC are renally excreted which requires that patients have their renal function checked prior to initiation of therapy and repeated periodically to avoid inadvertent overdose due to impaired clearance in renal dysfunction. Haematology laboratories should provide basiccoagulation tests such as APTT, PT and TT along with the establishment of specific assays to measure the anticoagulant effect of NOAC in certain circumstances. Development of local guidelines is essential to manage patients receiving NOAC who present with bleeding or require urgent surgery. This practical guide comprises of three sections: 1) Selection of the most suitable patient groups to receive NOAC, 2) Laboratory measurements of NOAC in appropriate circumstances, 3) Management of patients taking NOAC in the peri operative period, and strategies to manage bleeding complications or reverse the anticoagulant effects for urgent invasive procedures. 1

2 1. Selection of the most suitable patient groups to receive the new oral anticoagulants New oral anticoagulants have been approved in many countries for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), the treatment of new and secondary prevention of deep vein thrombosis (DVT), as well as the prevention of venous thrombosis in hip and knee arthroplasty.table 1 summarises the pharmacological characteristics of Dabigatran, Rivaroxaban and Apixaban; Table 2 compares patient suitability for NOACs versus warfarin; and Table 3 suggests which patients should NOT be prescribed NOACs. Table 1.Pharmacological characteristics of Dabigatran, Rivaroxaban, and Apixaban* Dabigatran (Pradaxa) 1, 2 Rivaroxaban (Xarelto) 3, 4 Apixaban (Eliquis) 5, 6 Action Direct thrombin inhibition, free and clot bound Direct Factor Xa inhibition Direct Factor Xa inhibition T max 2 hours hours 1 3 hours Half life hours 5 9 hours (healthy) 8 15 hours hours (elderly) Plasma protein binding 35% 95% 87% Renal clearance 80% 33% 27% Potential drug interactions P glycoprotein inhibitors Quinidine contraindicated, Avoid Verapamil reduce dose, Amiodarone no adjustment Caution Potent P gp inducers Potent inhibitors of both P gp and CYP3A4: Azole antimycotics HIV protease inhibitors Potent CYP3A4 inducers of both P gp and CYP3A4: Rifampicin, phenytoin, Contraindicated, except fluconazole which may be used as it is a less potent inhibitor Use with caution Use with caution Use with caution 2

3 carbamazepine, phenobarbital, St John s wort Contraindications Known hypersensitivity Clinically significant active bleeding Spontaneous or pharmacological impairment of haemostasis Hepatic disease with coagulopathy (incl Child Pugh C) Cr Cl < 30ml/min Organ lesions at risk bleeding, including ICH < 6 months Pregnancy, breast feeding Known hypersensitivity Clinically significant active bleeding Spontaneous or pharmacological impairment of haemostasis Hepatic disease with coagulopathy (incl Child Pugh C) Cr Cl < 30ml/min Organ lesions at risk bleeding, including ICH < 6 months Pregnancy, breast feeding Known hypersensitivity Clinically significant active bleeding Spontaneous or pharmacological impairment of haemostasis Hepatic disease with coagulopathy (incl Child Pugh C) Cr Cl < 15ml/min Organ lesions at risk bleeding, including ICH < 6 months Pregnancy, breast feeding Special considerations Renal impairment Contra indicated if Cr Cl < 30ml/min, AUC plasma drug concentration increased 2.7 fold for Cr Cl 30 50ml/min; use with caution Contra indicated if Cr Cl < 30ml/min Contra indicated if Cr Cl < 15ml/min Hepatic impairment Child Pugh A or B Use with caution Child Pugh A or B Use with caution Child Pugh A or B Use with caution Weight < 50 kg or > 120kg, less than 25% change in plasma drug concentration, no dose adjustment < 50 kg or > 120kg, less than 25% change in plasma drug concentration, no dose adjustment < 50 kg or > 120kg, less than 25% change in plasma drug concentration, no dose adjustment Age AUC for plasma drug concentration up to 2.0 fold higher after 65 years, use 110mg AUC for plasma drug concentration 1.5 fold higher after 65 years, no dose adjustment though AUC 32% higher after 65 years, no dose adjustment though 3

4 BD dose after 75 years (recommendation based on RE LY data) Concomitant antiplatelet agents Aspirin alone caution Dual agents increased bleeding risk Aspirin alone caution Dual agents increased bleeding risk Aspirin alone caution Dual agents increased bleeding risk Australian Approval by indication Stroke prevention in nonvalvular AF with >= 1 risk factor (SPAF) TGA registered R PBS authority TGA registered Awaiting TGA approval Prevention VTE after elective total hip or knee replacement (VTE Prx) Treatment DVT and prevention of recurrent DVT and PE (VTE Rx) PBS authority PBS authority PBS authority Not registered PBS authority Not registered *Patients who met study exclusion criteria have not been adequately studied and may not be suitable candidates for NOAC. Some of these specific exclusions were intended to identify patients at increased bleeding risk and thus they may not be suitable for warfarin either. 4

5 Table 2.Patient selection for suitability for NOAC or warfarin May be suitable for NOAC May be suitable for warfarin Recent stroke Disabling < 6 months Any stroke < 14 days except Apixaban, only excluded stroke < 7 days Treatment VTE Prevention recurrent VTE Patient preference Heart valve disorders, including mechanical valves Increased bleeding risk Surgery < 1 month Assess risk versusbenefit Any Hx ICH, Intra ocular, spinal, retroperitoneal or atraumatic intra articular bleeding Assess risk versus benefit * Assess risk versusbenefit GI bleed < 12 months, ulcer < 30 days Assess risk v benefit Recent malignancy or radiation Anaemia Hb < 100g/L Thrombocytopenia < 100 x 10 9 /L Planned major surgery/procedure Assess risk v benefit * Assess risk versus benefit * Assess risk v benefit Assess risk versusbenefit Assess risk versusbenefit Assess risk versusbenefit Planned cardioversion Excluded from ROCKET AF only Fibrinolytic treatment within 2 10 days Dual antiplatelet therapy Creatinine clearance < 30 ml/min Liver disease 5

6 Pregnancy Lactating VTE with active cancer (use LMWH) VTE with known APLS Practical considerations Poor venous access Patients living in remote areas where INR monitoring cannot be readily accessed Unpredictable dietary intake of Vitamin K Treatment with drugs likely to make warfarin control difficult eg. Azoles, thyroxine and anticonvulsants ICH=intracranial haemorrhage * Patients with this criterion were excluded from clinical trials evaluating NOAC Table 3. Who should not be on NOAC Active significant bleeding At risk of bleeding Disorder of haemostasis (e.g., von Willebrand disease or coagulation factor deficiency) Prosthetic heart valve Poor renal function (CrCl <30ml/min) Known hypersensitivity to a NOAC preparation Concomitant medication known to affect pharmacokinetics (e.g., Rivaroxaban and azole antimycotic, or HIV protease inhibitors) Pregnant and breast feeding Liver disease with an ALT >3times upper limit of normal Stably anticoagulated on warfarin (Warfarin Time in Therapeutic Range >65% over a three month period) 6

7 2. Monitoring of new oral anticoagulants The following comments focus on thenoac Dabigatran (Pradaxa; direct thrombin inhibitor) and Rivaroxaban (Xarelto; direct Xa inhibitor) as both agents are available for thromboprophylaxis post hip and knee arthroplasty and anticoagulation for nonvalvular AF to prevent systemic thromboembolism. In addition, Rivaroxaban is available for treatment of DVT. A third drug Apixaban (Eliquis; a direct Xa inhibitor) is currently only available for thromboprophylaxis post hip and knee arthroplasty. CAUTION: 1) Neither rivaroxaban nor dabigatran should be used in the presence of severe renal impairment (GFR< 30ml/min). Patients previously stabilised on these drugs may be at risk of bleeding if there is deterioration of renal function since its commencement. 2) Rivaroxaban is metabolised by the liver and moderate severe liver impairment will increase drug levels. 3)Overall with NOAC there arefewer drug interactions than with warfarin. However, with Rivaroxaban drugs that interfere with CYP3A4, such as azole antifungals agents, HIV protease inhibitors and rifampicin,have significant interaction. For Dabigatran, drugs that inhibit p glycoprotein such as Verapamil can increase drug levels. Table 4shows the important drug interactions that will result in at least a 50% change in exposure to Dabigatran or Rivaroxaban but we also refer the reader to the product information for a comprehensive list of drug interactions. Table 4. Drug interactions with at least 50% change in the exposure to Dabigatran or Rivaroxaban.Reproduced with permission from Blood 2012; 119(13): Dabigatran Rivaroxaban Mechanism Interacting drug Exposure, % Interacting drug Exposure, % P gp inhibition Ketoconazole* 150 Ketoconazole* 160 Quinidine 53 Amiodarone 60 Verapamil 50 P gp induction Rifampicin 67 Rifampicin 50 St John s wort ND St John s wort ND CYP3A4 inhibition Ketoconazole* 160 Clarithromycin 50 Ritonavir 50 CYP3A4 induction Rifampicin 50 St John s wort ND * Contraindicated Variable depending on verapamil formulation ND = not determined 7

8 NOAC generally DO NOT require monitoring when used for thromboprophylaxis or for therapeutic anticoagulation. Routine coagulation tests can be useful as screening tests to determine residual anticoagulant effect. Assay for specific drug level may need referral to a specialised laboratory. The anticoagulant effect of NOAC should be measured in the following clinical situations: 1. Bleeding: Is there an overdose or is therapeutic anticoagulation due to a NOAC contributing the bleeding? 2. Change in clinical scenario: Patients requiring urgent surgery, new or worsening renal failure, lack of adherence, and recurrence or extension of thromboembolism. Recommended Assays in the presence of bleeding: Dabigatran: The Thrombin Time(TT) is the most sensitive assay for determining if any Dabigatran is present 8 11.A normal APTTsuggests that it is unlikely that a high level ofdabigatran is contributing to bleedingand anormal TT excludes the presence of Dabigatran. Rivaroxaban:The (prothrombin time) PT is the most sensitive assay for detecting Rivaroxaban 12. A normal PT value using a thromboplastinthat is sensitive to Rivaroxaban (such as Triniclot PT Excel S, Neoplastin R and Recombiplastin) suggeststhat the Rivaroxaban level is not high. As with thelow molecular weight heparins (LMWH), the APTT and INR cannot predict the anticoagulant effect. Rivaroxaban doesn t prolong the TT. Recommended Assays with Changes in clinical scenario: The relatively short half life of Dabigatran and Rivaroxaban mean that recording the time of the last dose taken by the patient will be important in interpretation the assay results. Dabigatran:A dilute thrombin clotting time assay such as the HEMOCLOT Thrombin Inhibitor assay is the recommended assay to determinedabigatran drug level. The C max 2 hours after Dabigatran from patients in the RE LY Study is between ng/ml 8, 11. Population pharmacokinetic modelling of patients receiving dabigatran 150 mg twice daily demonstrates a median (with 5 th and 95 th percentiles) peak level of 184 ng/ml (64 443) and trough of 90 ng/ml (31 225). 11 Rivaroxaban: A specific anti factor Xachromogenic assay is specific and sensitive for quantitative measurements of rivaroxaban with an expected therapeutic range of between ng/ml 2 hours after Rivaroxaban. 35 Population pharmacokinetic modelling of patients receiving Rivaroxaban 20 mg once daily demonstrated a median peak level of 290ng/ml (95% CI: 170 to 400) and trough of 32ng/ml (95% CI: 0 to150). 13 The clinical relevance of drug level is unknown and should not be used to modify maintenance drug dose. 8

9 Table 5summarises the laboratory tests and patterns when monitoring NOAC. Figure 1 is a suggested algorithm when monitoring of NOAC is necessary. Table 5: A summary of laboratory tests and patterns for monitoring NOAC Test Dabigatran Rivaroxaban Prothrombin time (PT) / International Normalised Ratio (INR) Activated Partial Thromboplastin Time (APTT). Thrombin time (TT) Insensitive. Somewhat sensitive (curvi linear) but may underestimate high levels. Standard TT is oversensitive; dilute TT or commercial method (HEMOCLOT) appear suitable options Marked variations with different thromboplastins, and low dose response may be poor. Discuss sensitivity with your local laboratory.conventional INR does not correct for the variations and must not be used. Current INR system not recommended for use. APTT is prolonged dose dependently, but is less sensitive than the PT. Insensitive. Chromogenic anti Xa assay Insensitive Standard assay as used for monitoring heparin is too sensitive. Modified anti Xa (Rivaroxaban) assay appears suitable. Recommendation Test with PT, APTT, TT. If any tests prolonged, extend testing and/or refer to algorithm for possible scenarios. Expected overall test patterns: a. Significant anticoagulant effect unlikely b. Anticoagulant effect present (screening tests) c. Drug effect likely (confirmatory tests) APTT & TT normal TT prolonged or no clot obtained; APTT prolonged Dilute thrombin clotting time assay (HEMOCLOT) prolonged PT normal (using a sensitive thromboplastin) PT prolonged (> APTT) Modified anti Xa positive (Rivaroxaban level) 9

10 Figure 1. Suggested laboratory algorithm for NOACevaluation. Modified with permission from Pathology 2013; 45(4): Basic coagulation tests: APTT, PT, TT Consider timing of tests in relation to last dose of NOAC ingested All normal Significant anticoagulant activity unlikely PT prolonged > APTT prolonged; TT normal Suggestive of direct factor Xa inhibitor effect (e.g., Rivaroxaban), if warfarin, & liver disease are excluded Confirmatory assay: Drug specific Anti Xa assay (e.g., Rivaroxaban assay to provide drug level) APPT prolonged > PT prolonged; TT prolonged Suggestive of Dabigatran effect, if heparin, low fibrinogen are excluded Confirmatory assay: Hemoclot assay (provides Dabigatran level) APTT = activated partial thromboplastin time PT = prothrombin time TT = thrombin time 10

11 3. Peri operative Management of Patients on NOAC undergoing Elective Surgery or Procedures Elective surgery As with all patients receiving other anticoagulant agents, an important factor in determining management in the perioperative period of patients receiving NOAC is the riskof thrombosis if the drug is stopped relative tothe risk of bleeding if it is continued. As with warfarin, it may not be essential to discontinue NOAC in patients undergoing minor procedures, although firm evidence to support this practice is not established 15. Surgery should be timed to avoid peak drug levels 16. If the bleeding risk with the procedure is high and the NOAC needs to be stopped, advance planning is essential as, unlike warfarin, there are no established strategies for immediate reversal of the anticoagulant effect. The short half life of NOAC with rapid onset and offset of anticoagulant effect should allow for safe andshorter period of drug cessation prior to procedures in patients with normal renal and hepatic function7, 17 The timing of preoperative NOAC interruption toensure a minimal or no residual anticoagulant effect at surgery is based on the elimination half life of NOAC,patient renal function (based on calculated CrCl) and its effect on NOAC elimination, and planned surgery and anaesthesia. For example, patients on Rivaroxaban 20mg once daily (half life 5 9h in patients with normal renal function Table 1) who are to undergo abdominal surgery are recommended to skip3 doses whereas the same patient undergoing a minor procedure could skip only one dose prior to the procedure(table 6) 17. Neuraxial anaesthesia in patients receiving NOAC As with all patients on anticoagulants, those receiving NOAC are at risk of developing epidural or spinal haematoma when neuraxial anaesthesia is used while anticoagulated. Patients should be monitored carefully for symptoms and signs of neurological impairment. For patients receiving Rivaroxaban 10mg daily for VTE prevention post elective hip or knee arthroplasty the following strategy is recommended 18 : The last dose of Rivaroxaban is 24 hours before catheter insertion or removal The first dose of Rivaroxaban is hours post catheter insertion in case of traumatic puncture First dose of Rivaroxaban is no earlier than 6h after catheter removal Similar strategies have been suggested for Dabigatran and Apixaban (Table 7). There is no available evidence regarding the use of treatment doses of NOACs and neuraxial anaesthesia. In this situation it may be useful to utilise laboratory tests to guide the periprocedural timeframes. For example, in the case of Rivaroxaban 15mg twice daily or 20mg once daily, a normal PT suggests a significant level of anticoagulation is unlikely, but some residual effect cannot be excluded (similar to prophylactic LMWH). Rivaroxaban drug level (modified anti Xa) measurements may also provide further reassurance (Refer to Monitoring NOAC Section). 11

12 Table 6. Preoperative interruption of new oral anticoagulants: a suggested management approach. Modified with permission from Blood 2012; 120(15): Drug (doses)* Renal function Low bleeding risk surgery (2 or 3 drug halflives betweenlast dose and surgery) High bleeding risk surgery (4 or 5 drug halflives betweenlast dose and surgery) Dabigatran (150 mg twice daily) t1/ h Normal or mild impairment (CrCl 50 ml/min) Last dose: 2 days (skip 2 doses) Last dose: 3 days (skip 4 doses) Moderate impairment (CrCl ml/min) Last dose: 3 days (skip 4 doses) Last dose: 4 5 days (skip 6 8 doses) Rivaroxaban (20 mg once daily) t1/2 5 9 h (healthy) hours (elderly) Normal or mild impairment (CrCl 50 ml/min) Last dose: 1 day (skip 1 dose) Last dose: 3 days (skip 3 doses) moderate impairment (CrCl ml/min) Last dose: 1 day Last dose: 3 days (skip 1 dose) (skip 3 doses) Apixaban (5 mg twice daily) t1/ h Normal or mild impairment (CrCl 50 ml/min) Moderate impairment (CrCl ml/min) *Estimated t1/2 based on renal clearance. Last dose: 1 day (skip 2 doses) Last dose: 3 days (skip 4 doses) Last dose: 3 days (skip 4 doses) Last dose: 4 days (skip 6 doses) Aiming for mild to moderate residual anticoagulant effect at surgery (<12% 25%) Aiming for no or minimal residual anticoagulant effect (<3% 6%) at surgery 12

13 Table 7. Recommendations for NOAC use for VTE prophylaxis in the setting of neuraxial Anesthesia. Dabigatran Rivaroxaban Apixaban Time of last NOAC dose before catheter insertion or removal Time of NOAC dose after catheter insertion Time between removal of catheter and next NOAC dose 24 hours 24 hours 24 hours NR* hours hours 6 hours 6 hours 6 hours *Dabigatran is not recommended in patients undergoing anesthesia with postoperative indwelling catheters Restarting NOAC after surgery7, 17 Bleeding risk can be minimised after major surgery byadjusting the time when anticoagulant is resumed, accordingto the anticipated surgical bleeding risk and the extentof intraoperative or immediate postoperative bleeding.this means that for major surgery, therapeutic anticoagulation shouldbe delayed for at least 48 hours, preferably 72hours (Table 8).For patients at high risk for thromboembolism, consider administering a reduced dose of Dabigatran, mg once daily or Rivaroxaban 10mgonce daily, starting the evening after surgery and continue until it is safe to resume therapeutic anticoagulation. Patients who are unable to tolerate oral intake can receive prophylactic LMWH (e.g., Enoxaparin 40mg once daily). For patients at low risk for thromboembolism associated with a high bleeding risk, therapeutic anticoagulation can be delayed for greater than 72 hours, particularly in view of a lack of an antidote for NOAC. Following minor surgerywhere the bleeding risk is low, therapeutic dose of doses of NOACcan be started about 24 hours after surgery. Ensure that hepatic and renal functions are normal before recommencing NOAC postoperatively. NOAC and Urgent surgery Consider delaying surgery, if appropriate, until coagulation screen is normal or until sufficient time has passed for drug clearance. For Dabigatran, haemodialysis for 4 hours can be considered to enhance drug elimination 19. When urgent life saving surgery cannot be delayed, consult with Haematology Service to discuss measures to control bleeding prior to and during surgery. For Dabigatran,no haemostatic agent is known to effectively reverse its anticoagulant effect and evidence of potential benefit is based largely on animal studies Laboratory tests in healthy volunteers suggest that the impact of Rivaroxaban on laboratory assays of haemostasis may be reversible with prothrombin complexconcentrate (PCC) or activated PCC (such as FEIBA) 25, 26, however 13

14 whether this results in a reduction in bleeding risk is unknown (Figure 2). Presently there is no standard of care for the administration of haemostatic agents to achieve haemostasis with NOACs. Refer to the section on Management of patients bleeding while receiving NOAC. Table8. Postoperative resumption of new oral anticoagulants: a suggested management approach.reproduced with permission from Blood 2012; 120(15): Drug Low bleeding risk surgery High Bleeding risk Surgery Dabigatran Rivaroxaban Resume 24h after surgery,150 mg twice daily Resume 24h after surgery,20 mg once daily Resume h after surgery,150 mg twice daily* Resume h after surgery, 20 mg once daily Apixaban Resume 24h after surgery,5 mg twice daily Resume h after surgery,5 mg twice daily *For patients at high risk for thromboembolism, consider administering a reduced dose of Dabigatran (eg, mg once daily) on the evening after surgery and on the following day (first postoperative day) after surgery. Consider a reduced dose (i.e., Rivaroxaban 10 mg once a day or Apixaban 2.5 mg twice a day) in patients at high risk for thromboembolism LMWH such as enoxaparin 40mg once daily or mechanical prophylaxis such as Intermittent Pneumatic Compression (IPC) can be considered until therapeutic anticoagulation can be re introduced. 14

15 Figure 2. Suggested management of patients receiving NOAC requiring urgent surgery. NOACs and Urgent surgery DABIGATRAN NORMAL APTT & TT STOP NOAC NORMAL APTT & PROLONGED TT RIVAROXABAN NORMAL PT NOAC LEVEL LOW OR ABSENT DABIGATRAN APTT & TT PROLONGED RIVAROXABAN PT (& APTT) PROLONGED Significant Anticoagulant effect Maintain BP & Urine Output Control bleeding Transfusion support DISCUSS IF SURGERY CAN BE DELAYED SURGERY CAN BE DELAYED >12H SURGERY CAN BE DELAYED 4 12 IMMEDIATE SURGERY REFER TO ELECTIVE SURGERY STRATEGY CONSIDER HAEMODIALYSIS FOR DABIGATRAN DISCUSS WITH HAEMATOLOGY IF CONSIDERING HAEMOSTATIC AGENT PCC/aPCC/rFVIIa 15

16 4. Switching to or from other anticoagulants Conversion with a parenteral anticoagulant For conversion from LMWH, start the NOAC when the next LMWHdose is due. For conversion from a continuous heparin infusion to NOAC, start NOAC immediately when infusion ceased. For conversion from Rivaroxaban or Apixaban, start UFH or LMWH 12 24h after the last dose(1 2half lives of the NOAC). No bolus dose of UFH is required. For conversion from Dabigatran, wait hours where CrCL greater than or equal to 30mL/min, or 48 hours where CrCL less than 30mL/min, after the last dose of Dabigatran before starting the parenteral anticoagulant (see above table). Note LMWH are also predominantly renally excreted. Conversion with Warfarin Conversion from warfarin to a NOAC Patients who are stably anticoagulated on warfarin may prefer to remain on warfarin. However, the added convenience and thepotential for enhanced efficacy and reduced risk for intracranialbleeding of Dabigatran,Rivaroxaban or Apixaban, may mean that many patients will choose totransition from warfarin to one of the new anticoagulants 7. For conversion from warfarin to a NOAC (Dabigatran,Rivaroxaban or Apixaban), discontinue warfarin and start NOAC the next day when INR is 2.3 or less. Conversion from a NOAC to warfarin Some patients will not be able to continue with a NOAC. When switching from a NOAC to warfarin, it is necessary to take into account that the elimination half life of a NOAC is affected by renal function, the delay in the onset of warfarin (typically 5 days) and the INR readout is affected by both the NOAC and warfarin. Table 9shows suggested transitionstrategies. We recommend starting with a warfarin dose of 5mg or less. The first INR should be measured on day 3 after starting warfarin, with the main purpose to identify high levels thereby maintaining caution with ongoing warfarin dosing. Point of careinr monitors should not be used to assess the INR duringtransitions between a NOAC and warfarin. Stop the NOAC when INR has been 2.0 on two consecutive days taking into account the NOAC effect on INR 7. Discuss with your local haematology laboratory for further advice. 16

17 Table 9. Suggested strategy for conversion from Rivaroxaban or Dabigatran to warfarin.modified with permission from Blood 2012; 119(13): Calculated Creatinine clearance Greater than 50 ml/min Rivaroxaban: Time from warfarin initiation Continue Rivaroxaban 4 days before stopping Dabigatran: Time from warfarin initiation Continue Dabigatran 3 days before stopping 31 to 50 ml/min Continue Rivaroxaban 3 days before stopping 15 to 30 ml/min Continue Rivaroxaban 2 days before stopping Continue Dabigatran 2 days before stopping Continue Dabigatran 1 days before stopping Less than 30mL/min Consult with Haematology Service Consult with Haematology Service 5.Managing NOAC related Bleeding General principles in management of patients bleeding while receiving NOAC11, 27 29, Drug discontinuation anticoagulant should be ceased at least temporarily in all patients presenting with significant bleeding. The timing of recommencement will be influenced by the severity of the bleeding event, the presence of ongoing risk factors for bleeding (e.g. anatomical lesions, persisting renal dysfunction), and the initial indication for anticoagulant therapy. 2. Baseline laboratory assessment Baseline assessment of haemoglobin should be performed to assess bleed severity. Standard coagulation testing (APTT, PT and TT) and where available specific drug levels should be performed to assess the contribution of excess drug to the bleeding event and to guide the need for intervention to either reduce drug level or counteract the anticoagulant effect of the drug (see drug monitoring section). Creatinine level should be measured to assess renal function and allow prediction of the expected rate of anticoagulant drug clearance. 3. General supportive care measures Surgical and radiological procedures to identify the source of bleeding and to limit ongoing bleeding should be performed as appropriate, taking into account the risk of procedure related bleeding in an anticoagulated patient. Adequate hydration should be maintained to enhance renal clearance of both Dabigatran and Rivaroxaban. Transfusion of red cells should be administered as appropriate guided by haemoglobin level. Platelet transfusion should be considered in patients on concurrent anti platelet therapy or with significant thrombocytopenia (platelet <50x10 9 /L). 17

18 4. Activated charcoal Administration of activated charcoal should be considered in patients with moderate and severe bleeding who present within 4 hours of the last oral dose of Dabigatran or Rivaroxaban. 5. Administration of haemostatic agents Current evidence on the use of prohaemostatic agents in patients with Dabigatran or Rivaroxaban is limited. Recombinant factor VIIa (rfviia), the activated prothrombin complex concentrate (FEIBA) and 4 factor prothrombin complex concentrates (PCC) have all been shown to reduce bleeding in animal models with variable effect on coagulation parameters in animals and healthy volunteers 20 26, 30, 31. In Australia and New Zealand, only three factor PCC (Prothrombinex VF) is available and its efficacy in reversing Dabigatran or Rivaroxaban has not evaluated. The risk and benefit of administration of such agents should be assessed in each individual patient. Until further information is available it is reasonable to consider their use in patients with life or limb threatening bleeding. 6. Dialysis Dialysis may be considered where available in patients receiving Dabigatran with life threatening bleeding, particularly if renal function is impaired or Dabigatran is present in excess (APTT > 80 sec or Dabigatran level > 500 ng/ml) 19. There is no role for dialysis in Rivaroxaban and Apixaban related bleeding. 7. There is no published data on Apixaban reversal therefore specific advice is not given on managing bleeding in patients on this agent. Figures 3 and 4 show the suggested algorithms to manage Dabigatran and Rivaroxaban related bleeding, respectively. 18

19 Figure 3. Management of Dabigatran Associated Bleeding Bleeding Patient on Dabigatran Initiate Standard Resuscitation Procedures as Required Take blood for FBC, creatinine, aptt, TT Dabigatran level. STOP DABIGATRAN THERAPY Mild Bleeding - Local haemostatic measures. - Delay next dose of Dabigatran or discontinue if felt appropriate by prescribing physician. Clinically Significant Bleeding - Administer oral charcoal if dabigatran ingestion <4 hrs prior. - Local haemostatic measures Mechanical compression Consider surgical or radiological intervention to identify and treat bleeding source - Maintain adequate hydration to aid drug clearance. - Transfusion support Red cell transfusion as indicated by Haemoglobin. Consider platelet transfusion if platelets< 50 x 10 9 /L or antiplatelet Rx. - Pro-haemostatic agent If bleeding persists and clinical instability develops consider pro-haemostatic measures as described for lifethreatening bleeding Life-threatening Bleeding - Institute measures as for Clinically Significant bleeding -Consider use of one of the following agents a) Prothrombinex-VF IU/kg b) FEIBA IU/kg c) rviia 90 ug/kg every 2 hours d) Tranexamic Acid 15-30mg/kg IV+/- infusion for mucosal bleeds - Consider dialysis - Neither pro-haemostatic agents or dialysis is likely to improve outcome in patientswith a normal aptt or adabigatran level of < 50 ng/ml Clinically Significant bleeding reduction in Hb 20g/L, transfusion of 2 units of red cells Life-threatening bleeding bleeding in critical area or organ (intraocular, intracranial, intraspinal, compartment syndrome, retroperitoneal or pericardial), hypotension not responding to resuscitation. This is an off license use of rviia, FEIBA and Prothrombinex-VF and the risk of thrombotic complications when rviia is used for this indication is unclear. The use of rviia is supported by laboratory data however clinical evidence supporting an improvement in clinical outcomes is still lacking. Dialysis is particularly indicated if high drug level as indicated by excessively prolonged aptt > 80 secs or Dabigatran level > 500 ng/ml and / or impaired renal function. Consider dose of rviia immediately prior to vascular access if significantly prolonged aptt. 4 hrs of haemodialysis will reduce drug level by ~ 60 %

20 25, 26, 30, 31 Figure 4. Management of Rivaroxaban Associated Bleeding Bleeding Patient on Rivaroxaban Initiate Standard Resuscitation Procedures as Required Take blood for FBC, creatinine, PT, Rivaroxaban level. STOP RIVAROXABAN THERAPY Mild Bleeding - Local haemostatic measures. - Delay next dose of rivaroxaban or discontinue if felt appropriate by prescribing physician. Clinically Significant Bleeding - Administer oral charcoal if rivaroxaban ingestion <4 hrs prior. - Local haemostatic measures Mechanical compression Consider surgical or radiological intervention to identify and treat bleeding source - Maintain adequate hydration to aid drug clearance. - Transfusion support Red cell transfusion as indicated by Hb. Consider platelet transfusion if platelets< 50 x 10 9 /L or antiplatelet Rx. - Pro-haemostatic therapy If bleeding persists and clinical instability develops consider pro-haemostatic measures as described for life-threatening bleeding Life-threatening Bleeding - Institute measures as for Clinically Significant bleeding - Consider use of one of the following agents a) Prothrombinex-VF IU/kg b) FEIBA IU/kg c) rviia 90 ug/kg d) Tranexamic Acid 15-30mg/kg IV+/- infusion for mucosal bleeds * Pro-haemostatic agents areunlikely to improve outcomein patients with normal PT. Clinically Significant bleeding reduction in Hb 20g/L, transfusion of 2 units of red cells Life-threatening bleeding bleeding in critical area or organ (intraocular, intracranial, intraspinal, compartment syndrome, retroperitoneal or pericardial), hypotension not responding to resuscitation. This is an off license use of rviia, FEIBA, and Prothrombinex-VF and the risk of thrombotic complications when these agents are used for this indication is unclear. 20

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