Guidance for management of bleeding in patients taking the new oral anticoagulant drugs: rivaroxaban, dabigatran or apixaban Purpose The aim of this guidance is to outline the management of patients presenting with bleeding who are anticoagulated with the new oral anticoagulant drugs (NOACs): rivaroxaban, dabigatran or apixaban. The guideline contains general information followed by additional drug-specific details. General points for patients presenting with bleeding 1. Stop medication 2. Document the time of the last dose of NOAC and previously performed renal tests results when available. Consider giving activated charcoal if ingestion of drugs is within 2 hours. 3. Send blood samples for: Coagulation tests (including thrombin time (TT) (see below) and fibrinogen (one green tube) Full Blood Count and Group & Save (EDTA 1 small and EDTA 1 large tube) Renal profile (urea & electrolytes), Calcium (1 Brown gel tube (serum)) 4. Give fluid replacement to maintain urine output; adequate diuresis will help renal clearance of NOAC. 5. In cases of major bleeding, resuscitation measures and local control of haemostasis is required. This document should be read in conjunction with the appropriate policy for management of haemorrhage. 6. Once bleeding is controlled the on-going need for anticoagulation should be reviewed. 7. NOACs are currently black-triangle drugs and any bleeding events should be reported to the Medicines and Healthcare Products regulatory Agency (MHRA). There is no defined reversal agent for any of the NAOCs. Coagulation tests i.e. partial thromboplastin time (aptt), prothrombin time (PT) or thrombin time can help decide whether or not an anticoagulant effect remains (see under individual drug sections below). A normal aptt is likely to exclude a therapeutic intensity due to anticoagulant effect of the NOAC. Coagulation tests are not standardised for monitoring and cannot be used to indicate levels or to quantify the anticoagulant effect, but serial measurements may indicate the degree of clearance of the NOAC. Measurement of international normalised ratio (INR) is not helpful. Use of the antifibrinolytic drug tranexamic acid is expected to reduce bleeding but clinical experience in patients taking NOACs is lacking. 1
In cases of life-threatening bleeding, the use of factor concentrates may be considered (see under individual drugs). Consider platelet transfusion if patient has thrombocytopenia or taking long acting antiplatelet drugs e.g. aspirin, clopidogrel. RIVAROXABAN Rivaroxaban (Xarelto ) is an oral direct Factor Xa inhibitor with a half-life of 5-9 hours (can be up to 13 hours in the elderly). Prevention of stroke and systemic embolism in patients with atrial fibrillation, adult over 18 years, 20mg daily. Treatment of deep vein thrombosis and prophylaxis of deep vein thrombosis and pulmonary embolism, adult over 18 years, 15mg twice daily for 21 days then 20mg once daily. Prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery, adult over 18 years, 10mg once daily. There is NO REVERSAL agent for rivaroxaban. Rivaroxaban prolongs the prothrombin time but the degree is dependent on the assay used. A normal prothrombin time can occur in low levels of rivaroxaban. Consider anti Xa assay (if available) with a prolonged prothrombin time or normal prothrombin time within 24 48 hours after the last dose of rivaroxaban The APTT shows a curvilinear response to rivaroxaban but is less sensitive to low drug concentration. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban and should not be used. Due to the high plasma protein binding, rivaroxaban is not expected to be dialysable. DABIGATRAN Dabigatran etexilate (Pradaxa ) is an oral reversible direct thrombin inhibitor with a half-life of 12-14 hours. Dabigatran is primarily renally excreted and the half-life is prolonged in renal impairment. Prevention of stroke and systemic embolism in patients with atrial fibrillation, adults over 18 years, 150mg twice daily (elderly over 75 years, at high risk of bleeding or taking verapamil or amiodarone, 110mg twice daily) 2
Prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery, adults over 18 years, 220mg daily (elderly, renal impairment or taking verapamil or amiodarone, 150mg daily). There is NO REVERSAL agent for dabigatran. In emergency situations the aptt is the more accessible test (TT is the most sensitive method of monitoring the anticoagulant effect). High aptt results indicate supratherapeutic levels but need to be interpreted with caution as the anticoagulant effect may be underestimated. A normal TT or aptt would indicate no pharmacologically relevant anticoagulant effect. Prothrombin time (PT) is less sensitive and cannot be recommended. Protamine sulphate and vitamin K are not expected to affect the anticoagulant effect of dabigatran and should not be used. There is experimental evidence, but no clinical experience, for the use of factor concentrates prothrombin complex concentrate (PCC), activated prothrombin concentrate (FEIBA) or recombinant activated factor VII (rfviia). Fresh frozen plasma (FFP) may be also administered. Consider platelet concentrates when thrombocytopenia is present or if the patient is also taking long-acting antiplatelet drugs. Dabigatran can be eliminated by haemodialysis, haemofiltration or emergency charcoal filtration (no clinical evidence for charcoal filtration) APIXABAN Apixaban (Eliquis ) is an oral factor Xa inhibitor. It has a half-life of about 12 hours and is eliminated by various routes. It is highly protein bound and therefore not expected to be dialysable. Prevention of stroke and systemic embolism in patients with atrial fibrillation, adult over 18 years, 5mg twice daily (elderly, low body weight or renal impairment 2.5mg twice daily). Prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery, adult over 18 years, 2.5mg twice daily. There is NO REVERSAL agent for apixaban. At normal therapeutic doses, changes in aptt and PT are small and subject to a high degree of variability. The manufacture does not recommended measurement of aptt or PT as a method of measuring the anticoagulant activity of apixaban. Measurement of anti-factor Xa activity with anti-factor Xa chromogenic assay has been shown to be a more accurate method monitoring apixaban plasma concentrations and may be useful in some situations. 3
Factor concentrates (FEIBA,rFVIIa and PCC) have not been studied for treatment of apixaban related bleeding but Protamine sulphate and vitamin K will not affect the anticoagulant activity of apixaban and should not be used. Patients receiving apixaban who have an invasive procedure within 24 hours of the last dose of apixaban and have significant peri-procedural bleeding may be treated with fresh frozen plasma (e.g. 2 units IV every 6 hours) 4
Algorithm for management of bleeding in patients taking rivaroxaban, dabigatran or apixaban Patient bleeding on the new anticoagulant drugs (NOACs): rivaroxaban, dabigatran or apixaban STOP NOAC o o Assess bleeding and resuscitate as appropriate Initiate massive haemorrhage pathway (MHP) if appropriate Use local haemostatic measures to control bleeding mechanical compression or wound packing surgical intervention Request: FBC, renal profile, calcium, group & save, and clotting screen for PT, aptt, TT and fibrinogen. (State when last dose of anticoagulant was given when requesting test) Consider oral activated charcoal if ingestion less than 2 hours especially in case of overdose Mild Bleeding Delay next dose of NOAC or discontinue treatment if appropriate Consider risk / benefits and contra-indications to restarting anticoagulation. Check renal function. In case dabigatran or apixaban consider restarting at lower licensed dose if appropriate. Moderate / Severe Bleeding Give fluid replacement to maintain good urine output Blood product support to keep: Hb > 8.0g/dL Plt > 50 x 10 9 /L Fibrinogen >1.0g/L aptt<1.5 x normal Consider IV tranexamic acid (1g bolus over 10mins) and then 1g over 8 hours Consider FFP 4 units Life-threating Bleeding Implement measures for moderate to severe bleeding plus: Rivaroxaban: consider PCC,rFVIIa Dabigatran consider: PCC or rfviia (FEIBA) haemodialisis Apixaban Consider FFP if bleeding is post procedure within 24 hours of last dose Moderate to severe bleeding- reduction in Hb 20g/L, transfusion * of 2 units of red cells or symptomatic bleeding in a critical area/organ (e.g. intraocular, intracranial, intra-articular, intraspinal, pericardial, intramuscular with compartment syndrome) Life-threatening bleeding symptomatic intracranial bleed, reduction in Hb 50g/L, transfusion * of 4 units of red cells, hypotension requiring inotropic agents or bleeding requiring surgical intervention. * Red cell transfusion according to haemorrhage protocols 5