1 Clinical recommendations for treatment with New oral anticoagulants These recommendations on new oral anti-coagulants have been developed on behalf of the Swedish Society on Thrombosis and Haemostasis (SSTH), specialist associations within the Swedish Society of Medicine, and nurses with special expertise in anti-coagulation.
2 Consolidation process These recommendations has been submitted for consultation to the following specialist associations in Sweden to give them the opportunity to present their views: Emergency medicine. Family Medicine. Anaesthesiology and Intensive Care. Cardiology. Gastroenterology. Haematology. Internal Medicine. Surgery. Clinical Chemistry. Vascular Surgery. Neurology. Neurosurgery. Nephrology. Obstetrics and Gynaecology. Oncology. Orthopaedics. Thoracic surgery.transfusion Medicine. Urology. Ear, nose and throat. Otolarygology. A working group led by Associate Professor Peter J. Svensson has worked with the recommendations in the programme. Recommendations will include all new oral anticoagulants. The scientific basis for recommendations is composed of presented studies, clinical experience and consensus discussions. In many of the situations described, there are no clear studies on which to base the advice. Graphic design: Petter Grafisk Design 2011
3 CONTENTS New oral anticoagulants Page 1. General information 5 2. Surgery Anaesthesia Minor surgery/dental surgery Medical procedures requiring dose adjustment Cardiology Neurology/Stroke/Cerebral haemorrhage Bleeding/risk of bleeding Immobilized patients/cancer patients Switching between different anticoagulants Intoxications/Overdose/Interactions Follow-up/Compliance Renal insufficency and calculation of egfr APTT/PT (INR) Managing severe bleeding Working group References 39 3.
5 1. General information Pradaxa (dabigatran etexilate) is a prodrug with approx. 6 % bioavailability after oral administration. It is hydrolyzed in the liver to the active substance dabigatran, which is mainly (80 85 %) renally excreted. Dabigatran etexilate Comment Other Coagulation effect Direct-acting and reversible Thrombin inhibitor Bioavailability after oral administration Gastrointestinal uptake is regulated via a transport protein. Dabigatran is a substrate for the transport protein P-gp. Drugs that inhibit this protein (verapamil, cordarone, dronedarone) or stimulate it (rifampicin) affect plasma concentrations. Uptake can vary post-operatively or after other changes in gastrointestinal motility and function. Maximal plasma concentration occurs approx. 1½ hours after administration of a given dose at normal absorption. Approx. 6 % Metabolism Dabigatran use is discouraged in patients with reduced liver function, e.g. transaminases >2 times the reference range. Dabigatran etexilate is hydrolyzed in the liver to the active substance dabigatran. Excretion Dose reduction is recommended for patients with reduced renal function (egfr ml/min/1.73 m2), and contraindicated with severe renal impairment (egfr <30 ml/min) % of the active substance is excreted unchanged through the kidneys (egfr is stated as ml/min/1.73 m2). In this document, either ml/min or the numerical value only will be stated for egfr for reasons of space). 5.
6 Half-life Renal function, egfr ml/min >50 15 hours >30 <50 18 hours <30 27 hours Estimated glomerular filtration rate (egfr) has been used throughout this document as it is considered to most accurately reflect the patient s kidney function in these clinical settings. For dose calculations, calculating absolute glomerular filtration may be necessary. See Panel 1 on how to calculate this. Guidelines for calculating how long the anticoagulant effect will be maintained after the last given dose In patients with hepatic impairment (egfr ml/min), the half-life times indicated above should be doubled, and doubled again at egfr <30 ml/min. It is estimated that 25 30% of the anti-coagulation effect remains after hours and approx. 5 % after hours, depending on renal function. Rebound effect after stopping treatment No rebound effect has been described. Other concomitant antithrombotic treatment Concomitant treatment with heparin, low molecular weight heparin, warfarin and certain antiplatelet drugs (GP IIb/IIIa inhibitors, ticlopidin, clopidogrel) is discouraged due to increased bleeding risk and difficulties in reversing the effects before surgery or in the case of bleeding. Concomitant use of aspirin in connection with orthopaedic surgery or as combination therapy for atrial fibrillation has not significantly increased the bleeding risk in studies on selected patients without additional risk factors for bleeding. If aspirin is indicated, combination treatment can be used with increased observation of the patient. Poorly investigated. 6.
7 Laboratory monitoring Laboratory control APTT is prolonged, but the doseresponse curve is flat and in part dependent on the APTT reagent used in the respective hospital laboratory. A slightly prolonged APTT indicates that dabigatran is present in plasma. APPT >70 90 seconds indicates a high concentration. APTT >90 seconds indicates probable overdose or accumulation. PT (INR) (Owren method) is only affected at high plasma concentrations of dabigatran. PT (INR) >1.5 indicates probable overdose or accumulation. Table 2 (page 35) shows the co-variation between APTT and PT (INR). Assessment should be based on both these analyses. All coagulation factor tests that are dependent on thrombin generation in plasma are affected and cannot be assessed (falsely low values). Antithrombin may be falsely high with some reagents. Note! At normal APTT, a small amount of dabigatran, <50 ug/l, may be found in plasma. Hemoclot Thrombin Inhibitor Assay Ecarin Clotting Time (ECT) Activated Clotting Time (ACT) Lack of established method for determining individual clinical effect and bleeding risk. Today ( ) only available at specialist laboratories in Sweden (more information will be added) Antidote Recombinant factor VIIa (Novo Seven ) has shown some neutralizing effect in vitro. Case reports indicate a clinical effect. Prothrombin complex concentrates (PCCs), (Confidex Octaplex /Ocplex ) are available in Sweden and have demonstrated some neutralizing effect in vitro but have not been investigated in clinical studies. Fresh frozen plasma and Protamin have no proven neutralizing effect. For massive overdose or serious bleeding, haemodialysis may be one possibility. Activated charcoal may also have effect if administered within 2 hours of ingestion. No clinically proven antidote is available. Dabigatran is a small molecule with low-grade protein binding. Hemodialysis may be a possible treatment for severe overdose. 7.
8 Current indications Pradaxa (dabigatran etexilate) is available as 75 mg, 110 mg and 150 mg capsules. 1. Prevention of venous thrombosis/pulmonary embolism after elective hip and knee replacement. Recommended dosing: First dose 110 mg 1 4 hours after surgery, from day 1 post-operatively 220 mg x 1, with dose reduction to 150 mg x 1 in elderly patients (>75 years) and patients with reduced renal function (egfr ml/min). 2. Prevention of TIA/stroke and peripheral arterial embolism in patients with atrial fibrillation. Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation and one or more of the following risk factors: Previous stroke, transient ischemic attack (TIA), or systemic embolism (SEE) Reduced left ventricular function, ejection fraction <40% Symptomatic heart failure, New York Heart Association (NYHA) class 2 Age 75 years Age 65 years with one of the following risk factors: diabetes mellitus, coronary heart disease or hypertension. For patients aged >80 years and above, 110 mg 1x2 is recommended. Contraindication(s) for dabigatran: Hypersensitivity to dabigatran Severe renal impairment (CrCL < 30 ml/min) ( egfr <30) Panel 1 Pregnancy Active bleeding Increased risk of bleeding; congenital, acquired or due to organ damage. Hepatic impairment or liver disease expected to impact survival Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole or tacrolimus. Patients who should not be treated with dabigatran: Reduced renal function, or obvious risk for reduced renal function (egfr <30mL/min), elevated liver enzymes (2 x reference), previous stroke without any strong indication for treatment, un controlled hypertension, thrombocytopenia (<75 x 109/L), breast-feeding, substance abuse uncontrolled eller un-controlled mechanical heart valve and current VTE. 8.
9 Clinical situations in which dabigatran etexilate is used The need to develop practical advice for dabigatran (Pradaxa ) has been considered to be great. In the clinical situations described, advice is based on presented studies, assessments and advice from the U.S. Food and Drug Administration (FDA) and European Medical Agency (EMA), as well as clinical experience and consensus discussions in the Working Group. Colleagues both domestic and abroad have also been consulted. Few of these clinical situations have been evaluated in the study programmes, but they are common in routine healthcare. The recommendations are deliberately brief to make them easy to use in clinical practice. The attached reference list presents background documentation available The document and recommendations will be continuously updated as new information emerges. Accepted abbreviations are used in the document. These recommendations apply to patients treated with dabigatran (Pradaxa ) for the indication primary and secondary prevention of systemic thromboembolism in atrial fibrillation. 9.
11 2. Surgery Clinical situation Recommendation 1 Acute surgery (within 1 2 hours) 1 Contact the coagulation consultant on call. 2 Check PT (INR), APTT, creatinine, thrombocytes and Hb 3 When did the patient last take dabigatran? 4 Experienced surgeon if possible, specialist case 5 Early contact with blood bank Great risk for bleeding complications. Try to optimize hemostasis, reverse the effect of dabigatran with PCC and monitor according to the directions below (Table 2 and Panel 2). If possible, reverse other concomitant anticoagulation treatment or treatment with antiplatelet drugs. 2 Semi-acute surgery (within 2 12 hours) 1 Contact the coagulation consultant on call. 2 Check PT (INR), APTT, creatinine, thrombocytes and Hb 3 When did the patient last take dabigatran? Assess renal function, APTT. If possible, postpone the operation for one half-life, i.e hours depending on egfr or until APTT is normalized (Table 2). If possible, reverse other concomitant anticoagulation treatment or treatment with antiplatelet drugs. 3 Elective surgery 1. For major surgery, discontinue dabigatran treatment according to the following (see page 33, Table 1). egfr >80 discontinue 2 days egfr discontinue 2 days egfr discontinue 4 days egfr <30 discontinue at least 5 days Preferably initiate prevention of venous thrombosis according to normal procedures within 6 hours postoperatively. Treatment with dabigatran can be resumed post-operatively on the third day if there is no increased risk of bleeding. 150 mg x 2 or 110 mg x
12 2. For minor surgery, discontinue dabigatran treatment according to the following (see page 33, Table 1). egfr >80 egfr egfr egfr <30 discontinue 1 day discontinue 1 day discontinue 2 days discontinue at least 5 days Dabigatran can be restarted the day after surgery if there is no increased risk of bleeding. LMWH is not recommended. Do not remove this patient group from the surgery schedule. 4 Thoracic surgery See paragraph 3. 5 Vascular surgery See paragraph 3. 6 Bridging situations (temporary discontinuation) due to temporary high risk of bleeding CHADS 4: consider LMWH (low molecular weight heparin) if discontinuation is long (>7 10 days) e.g. post-operatively. 12.
13 3. Anaesthesia Clinical situation Recommendation 7 Regional anaesthesia in patients on dabigatran Discontinue Pradaxa at least 48 hours before regional anaesthesia depending on renal function see page Spinal/epidural anaesthesia during ongoing treatment with dabigatran for atrial fibrillation See paragraph 7, Regional anaesthesia. 13.
15 4. Minor surgery/dental surgery Clinical situation Recommendation 9 Scopy with/without biopsy 1. Without biopsy no action. 2. With biopsy treat like minor surgery, see page Punctures/biopsies/IM/IA Central venous catheter(cvc), Port-a-Cath installation Treat like minor surgery, see page Tartar removal, tooth extraction 1. Maintain dabigatran Soak a gauze pad in tranexamic acid (1 gram tablet dissolved in 10 ml water) and apply over the surgical site. The patient should bite on this for 1 hour. Avoid rinsing with tranexamic acid solution as it may wash away the thrombus. 2. Avoid hot drinks during the first day. 12 Major dental procedures Treat like minor surgery, see page
17 5. Medical procedures requiring dose adjustment Clinical situation Recommendation 13 Lumbar puncture Treat like minor surgery, see page Crista biopsy Treat like minor surgery, see page Acupuncture Treat like minor surgery, see page Pleural tap Treat like minor surgery, see page Tattooing Treat like minor surgery, see page Pacemaker device, event recorder Treat like minor surgery, see page EMG Treat like minor surgery, see page Cataract surgery No action. 21 Prostate biopsy Treat like minor surgery, see page Liver biopsy Treat like minor surgery, see page Transesophageal ECG/ ultrasound No action. 24 Cardiac catheterization Treat like minor surgery, see page Skin excision Treat like minor surgery, see page Angiography Treat like minor surgery, see page Botox injections Treat like minor surgery, see page Sty or eyelid surgery Treat like minor surgery, see page Partial skin grafting Treat like minor surgery, see page ECT (electroconvulsive therapy) Treat like minor surgery, see page
19 6. Cardiology Clinical situation Recommendation 31 PCI and triple therapy 1. Discontinue as for elective minor surgery (if possible), see page After stent: In case of continued indication for anticoagulation, warfarin is the most studied. If dabigatran is used: Give triple therapy with aspirin, clopidogrel and dabigatran 110 mg x 2 for 1 month, followed by dabigatran and aspirin. 3. Avoid DES in patients with indication for dabigatran. After 1 month, consider the higher dabigatran dose of 150 mg x 2 if the patient s risk for thrombosis is high. 32 Acute coronary syndrome 1. NST-ACS: Discontinue dabigatran. Give aspirin and clopidogrel immediately. After 12 hours (if GFR <30, wait 24 hours), give subcutaneous anticoagulation (fondaparinux or LMWH). 2. NST-ACS directly to angio/pci: Discontinue dabigatran. Give aspirin and clopidogrel immediately. Give low-dose, weight-adjusted heparin (70 U/kg) or bivalirudin. 3. STEMI with primary PCI: Discontinue dabigatran. Give aspirin and clopidogrel immediately. Give lowdose, weight-adjusted heparin (70 U/kg) or bivalirudin, possibly with the addition of a Gp IIb/IIIa inhibitor. 4. STEMI with thrombolysis (consider PCI if possible): Discontinue dabigatran. Give aspirin and clopidogrel. Analyze APTT, PT (INR), creatinine, egfr. Tablet intake <3 hours, possibly refrain, evaluate risk-benefit with thrombolysis. Refrain from other anticoagulants. Note! There are no studies supporting thrombolysis during ongoing dabigatran treatment. 33 Electric cardioversion Can be carried out after 3 weeks of continuous dabigatran 150 mg x 2 or 110 mg x 2. Continue anticoagulant therapy for at least 4 weeks after electric cardioversion. 19.
21 7. Neurology/Stroke/Cerebral haemorrhage Clinical situation Recommendation 34 Embolic ischaemic stroke Acute APTT and PT (INR) tests to determine if treatment is ongoing and grade anticoagulation effect. 35 Thrombolysis in acute ischaemic stroke Scientific data are lacking. 1. Medical history 2. Check PT (INR), APTT, creatinine 3. When did the patient last take dabigatran? Consider thrombolysis if dabigatran values are normal and the benefit outweighs the risk. Note! There are no studies supporting thrombolysis during ongoing dabigatran treatment. Thrombolysis is discouraged if APTT is prolonged or tablet intake was within 3 4 hours (Table 2). Note! Consider catheter intervention if available. 36 Cerebral haemorrhage 1. Check PT (INR), APTT, creatinine. 2. Discontinue dabigatran and reverse and monitor the anti-coagulant effect see page Contact the coagulation consultant on call. 4. NovoSeven: If not available, consider PCC (Panel 2) (see page 7, Antidote). 21.
23 8. Bleeding/risk of bleeding Clinical situation Recommendation 37 Acute gastrointestinal bleeding 1. Discontinue dabigatran until the source of bleeding is identified and remedied. 2. Next: Decide whether to continue with dabigatran or an alternative treatment. 3. If resumed, consider dabigatran 110 mg x Minor bleeding from sites at which mechanical haemostasis is easy, e.g. minor nose bleed (stops within minutes when pressure is applied), wound, or single occasion of blood in the urine (should, however, be investigated) 39 Investigation of anaemia caused by bleeding, blood in the stool, vaginal bleeding, bleeding from urinary tract or hemoptysis 1. Discontinue dabigatran for 1 2 doses. 2. Creatinine, APTT, PT (INR), egfr see page Restart if the bleeding stops. 1. Discontinue dabigatran until the cause of bleeding is determined and, if necessary, remedied. The latter is a priority. 2. Alternatively, change to the lowest dose or to an anticoagulant for which there is more experience. 40 Anaemia not caused by bleeding or of unknown cause 1. Discontinue dabigatran until the cause of the anaemia is determined. 2. Alternatively, change to the lowest dose or to an anticoagulant for which there is more experience. Anaemia is a general risk factor for bleeding complications during anticoagulation treatment. Re-evaluate the indication for continued dabigatran treatment and use the lowest dose. 41 Heavy menstrual bleeding 1. Ask the patient to buy tranexamic acid at the pharmacy. 2. Make sure that contraceptives are optimal. 42 Severe trauma to the head or major muscle group with the risk of compartment syndrome, thoracic or abdominal 1. Tell the patient to seek emergency care. 2. Discontinue dabigatran for 1 2 doses. In patients with reduced renal function (egfr ml/min), discontinue dabigatran for 2 3 doses. 3. Keep the patient for prolonged observation, 24 hours; consider CT scan. 4. Check PT (INR), APTT, creatinine. 23.
25 9. Immobilized patients/cancer patients Clinical situation Recommendation 43 Immobilized patients in hospital ward 1. Maintain dabigatran. Discontinue dabigatran in case of bleeding risk. 2. Monitor renal function. 44 Cancer patients (i.e. if the patient gets cancer) 1. Maintain dabigatran. 2. Monitor renal function. 3. Assess chemotherapy in relation to the anticoagulation treatment, possibly reducing dabigatran dose. 25.
27 10. Switching between different anticoagulants Clinical situation 45 When to switch from one anticoagulant to another? Recommendation After an ischaemic stroke during warfarin treatment in therapeutic INR, consider switching to dabigatran if renal function is normal. After an ischaemic stroke during dabigatran treatment, consider adjusting the dose or switching to another anticoagulant. Dabigatran may be an alternative after an intracerebral bleeding during warfarin treatment and when continued anti-coagulant treatment is strongly indicated. Dabigatran may be an alternative when continued anticoagulant treatment is strongly indicated and PT (INR) fluctuates strongly (in spite of controls at an anti-coagulation clinic and good compliance). For patients with a high risk of bleeding, consider dabigatran 110 mg x Switching to and from warfarin 1. When switching from dabigatran to warfarin egfr >50 ml/min: Initiate warfarin therapy in the usual way for 2 3 days before stopping dabigatran treatment. egfr ml/min: Initiate warfarin therapy for 1 day before stopping dabigatran treatment. egfr ml/min: Initiate warfarin therapy for 1 day after stopping dabigatran treatment. egfr <15 ml/min: dabigatran is contraindicated due to risk of bleeding. Contact coagulation expertise. 2. When switching from warfarin to dabigatran Discontinue warfarin treatment and initiate dabigatran when PT (INR) is below Switching to and from heparin/lmwh 1. When switching from dabigatran to heparin/lmwh egfr >30: wait for 12 hours before initiating heparin/ LMWH therapy. egfr <30: wait for 24 hours before initiating heparin/ LMWH therapy. 2. When switching from heparin/lmwh to dabigatran Give the first dabigatran dose 0 2 hours before the next planned dose of LMWH or 0 2 hours after heparin infusion is completed. 27.
29 11. Intoxications/Overdose/Interactions Clinical situation Recommendation 48 Accidental overdose (double or triple dose by mistake) 1. Discontinue dabigatran for one or two doses. 2. For patients with reduced liver function (egfr ml/min), stop dabigatran for two or three doses. 49 Intoxication 1. Hospital case. 2. Level of care; intensive care or emergency department. 3. Blood typing. 4. Check PT (INR), APTT, creatinine, egfr and blood count. 5. Contact the coagulation consultant on call. 6. Activated charcoal if drug intake <2 hours For significantly prolonged values for APTT and PT (INR) with symptoms of bleeding, start by reversing with PCC (Panel 2) and follow the clinical course for the first 4 10 days, depending on renal function. For significantly prolonged values for APTT and PT (INR) without symptoms of bleeding, start with active surveillance and follow the clinical course the first 4 10 days, depending on renal function. Make regular measurements of APTT and PT (INR). Hemodialysis may be one possibility. Optimize blood pressure and other hemostasis parameters. Activated charcoal within 2 hours after drug intake may be one possibility. 50 Interactions with other drugs, including painkillers 1. Avoid combination with long-term NSAID treatment (short treatment courses are not a problem). Check renal function if this combination is used. 2. Avoid combination with rifampicin. Check renal function if this combination is used. 3. Avoid combination with other antithrombotic drugs like LMWH, heparin, thrombolytic drugs, warfarin. 4. Dose reduction may be needed with the following combinations: verapamil, clarithromycin. Check renal function if these combinations are used. 5. Verapamil: adjust dose to 110 mg x 2. For amiodarone, do not adjust dose for the atrial fibrillation indication. Dronedarone: too little data; concomitant use is not recommended at present. 4. Avoid natural remedies containing St. John s wort. 29.
30 51 Interactions with food and alcohol l. No known interactions with food or alcohol have as yet been reported. 2. Patients are encouraged to live life as usual, with a balanced diet and moderate alcohol intake. 30.
31 12. Follow-up/Compliance Clinical situation Recommendation 52 Compliance 1. Capsules should be taken twice daily, at approximately the same time in the morning and evening. 2. Capsules should not be chewed, crushed or opened, and should be stored in the original package (not in dosette boxes/pill organizers) as the capsule is moisture-sensitive. 53 Missed dabigatran capsule If a dose is missed 1. The missed dose may still be taken up to 6 hours prior to the next scheduled dose. 2. Skip the missed dose if there is less than six hours to the next scheduled dose. 54 Patient information 1. A patient information leaflet can be ordered from Boehringer-Ingelheim. 2. Give verbal information to all patients starting on dabigatran. 3. This should include the purpose of treatment, risks/ benefits, bleeding/clotting, what to do in the case of bleeding, side effects (GI symptoms), painkillers, diet, alcohol, surgery, minor surgery, follow-up, kidney function, fertile women, pregnancy and what to do if a dose is missed. For GI symptoms related to dabigatran, intake with food and a large glas of water is recommended. Conveying this information is estimated to take approx minutes. 55 Information card 1. Provide a card with information about dabigatran and hand it to the patient. 2. Tell patients to always carry the card with them. 31.
32 56 Follow-up 1. Follow-up in quality registers. 2. Reconsider the indication for dabigatran once yearly and consider changing dose. 3. Follow egfr every 3, 6 or 12 months depending on the baseline value. 4. Register complications yearly. Note! Do not forget to report any adverse events to the Medical Products Agency. 57 Effects of new anticoagulants on common coagulation assays A Swedish expert group on coagulation, Equalis, has investigated the effects of dabigatran on common coagulation assays in vitro. All coagulation analyses based on thrombine binding are probably affected, rendering thrombosis investigations in dabigatran-treated patients inappropriate. Effects of dabigatran see page 35. The expected trough is 50 μg/l, peak μg/l. APTT was prolonged for all reagents used in Sweden already at 100 μg/l. The effects of dabigatran on PT (INR) are small, with almost all results within the reference range at 100 μg/l. For a dabigatran-treated patient with APTT >90 seconds and Owren PT (INR) >1.5 or Quick-PT INR >2, consider overdosing and/or accumulation of dabigatran. 58 Tests to be taken before starting dabigatran (Pradaxa ) Haemoglobin, thrombocytes, APTT, PT (INR), s-creatinine or cystatin C and estimation of egfr see page 33 and liver function tests. 32.
33 13. Renal insufficency and calculation egfr Panel 1. Calculating egfr To correctly assess a patient s renal function and establish correct dosing of a renally excreted drug or contrast agent, the patient s glomerular filtration rate (GFR) must be established. This can be done by invasive procedures, such as measuring plasma clearance of inulin, iohexol or 51Cr-EDTA. Such procedures are, however, expensive, time-consuming and not entirely without risk to the patient. Therefore, GFR prediction equations have been designed based on cystatin C and/or creatinine levels in plasma or serum. If the egfr i lowered, calculation of the absolute glomerular filtration may be necessary to establish the correct dosing of the drug. Refer to Table 1. Dabigatran in connection with surgery and other invasive procedures egfr < >80 Op day ml/h Stopping > 5 days 4 days 2 days 2 days 0 Restarting dabigatran dabigatran 3rd day Major 150 mg x 2 surgery 110 mg x 2 LMWH 6 hours after o Stopping >5 days 2 days 1 days 1 days 0 Restarting day dabigatran dabigatran after op with Minor previous dose surgery LMWH Not needed LMWH may be an alternative for patients considered to suffer a major post-operative risk for venous thrombosis until dabigatran can be restarted, i.e. on the third day according to Table 1. Use the LMWH prophylactic dose. 33.
35 14. APTT/PT(INR) Table 2. Dabigatran and acquired effects on APTT and PT (INR) at different concentrations of dabigatran Dabigatran (μg/l) Normal level APTT s 45 (40-54) 63 (55-71) INR In Sweden, APTT may be considered to have a normal value of 42 seconds. PT (INR) has a normal value of Therapeutic levels of dabigatran; trough 50 µg/l and peak µg/l (therapeutic dose). Table 2 illustrates how APTT and PT (INR) (Owren method) change at different concentrations of dabigatran. Only consider these values in acute situations to indicate the drug concentration. At normal APTT levels, low concentrations of dabigatran may be present in plasma (< 50ug/L). (In vitro data, ref. 1.) 35.
37 15. Handling major bleeding Panel 2. Major or life-threatening bleeding associated with dabigatran A. Trauma or need for acute surgery within 1 2 hours or other major bleeding, e.g. GI bleeding. 1. Check APTT, PT (INR) and creatinine and assess the patient s renal function (egfr) other tests according to local routines - If APTT and PT (INR) are normal, the concentration of dabigatran is low and there is no need for any specific measure with factor concentrates - If the dabigatran dose was taken within 3 4 hours, APTT and PT (INR) may be normal in spite of the effect of the drug. Prothrombin complex concentrate (PCC) may therefore be relevant in this situation. - If APTT is prolonged and PT (INR) is elevated, the concentration of dabigatran can be estimated according to page If you cannot wait for APTT and PT (INR) and reversing is necessary, go directly to paragraph 2 below. 2. Prothrombin complex concentrate (PCC) Octaplex /Ocplex or Confidex (see page 7, Antidote) - <15 hours after the last dabigatran dose, give 1000 IU Octaplex /Ocplex or Confidex hours after the last dabigatran dose, give 500 IU Octaplex /Ocplex or Confidex - Retest minutes after injection. Additional Octaplex /Ocplex or Confidex may be appropriate depending on clinical response and laboratory analysis. B. Cerebral hemorrhage (Note! Especially important with minor bleeding and a conscious patient) 1. Check APTT, PT (INR) and creatinine and assess the patient s renal function (egfr) other tests according to local routines - If APTT and PT (INR) are normal, the concentration of dabigatran is low and there is no need for any specific measure with factor concentrates. - If the dabigatran dose was taken within 3 4 hours, APTT and PT (INR) may be normal in spite of the effect of the drug. Recombinant factor VIIa may therefore be relevant in this situation. - If APTT is prolonged and PT (INR) is elevated, the concentration of dabigatran can be estimated according to page If you cannot wait for APTT and PT (INR) (i.e. great likelihood of CNS hemorrhage) and reversing is necessary, go directly to paragraph 2 if dabigatran intake <15 hours. 2. Recombinant factor VIIa (rviia) NovoSeven (see page 7, Antidote) - <15 hours after the last dabigatran dose, give NovoSeven 100 μg/kg (round up to an appropriate packaging) hours after the last dabigatran dose, give NovoSeven 50 μg/kg (round up to an appropriate packaging) - Retest minutes after injection. Additional NovoSeven may be appropriate depending on clinical response and laboratory analysis. - NovoSeven is available in 1 mg, 2 mg, 5 mg and 8 mg vials. - Example: a patient weighing 80 kg should have 8 mg NovoSeven if <15 hours after the last dabigatran dose. 37.