MANAGEMENT OF OVERANTICOAGULATION AND PREOPERATIVE MANAGEMENT OF WARFARIN DOSE 1. GUIDELINES FOR THE MANAGEMENT OF AN ELEVATED INR

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1 MANAGEMENT OF OVERANTICOAGULATION AND PREOPERATIVE MANAGEMENT OF WARFARIN DOSE 1. GUIDELINES FOR THE MANAGEMENT OF AN ELEVATED INR 1.1 Time to lower INR Prothrombinex-VF - 15 minutes Fresh Frozen Plasma - 15 minutes after infusion completed Oral vitamin K 1 - effect on INR can be expected within 6-12 hours, maximum effect within 24 hours Intravenous vitamin K 1 - effect on INR can be expected between 4-6 hours, maximum effect within 12 hours 1.2 Important Considerations Expert advice should be sought on management of bleeding patients who are on warfarin if there is a high risk of a thromboembolic event without anticoagulation therapy Determine the cause of overanticoagulation if possible, to aid decision making regarding dose adjustment. If the cause will be reversed in the near future (e.g. antibiotic course, poor diet, acute disease exacerbation, especially CCF) this needs to be factored into decision making regarding dose changes Bleeding risk increases exponentially when INR exceeds 4.5 If INR > 4.5 extra INR monitoring should be performed over the following 2 weeks 1.3 Vitamin K 1 Vitamin K 1 injection administered as IV push over 2-3 minutes Vitamin K 1 effect on INR can be expected in 6-12 hours. The full effect of vitamin K 1 in reducing the INR takes up to 24 hours to develop, even when given in larger doses with the intention of complete reversal The vitamin K 1 injection solution can be given orally (the 10mg tablet is not easily divided into smaller doses) When using fresh frozen plasma, vitamin K 1 is concurrently required to prevent possible rebound anticoagulation 1.4 Prothrombin complex concentrate (PCC Prothrombinex-VF) and fresh frozen plasma (FFP) For immediate reversal of clinically significant bleeding, the combination of Prothrombinex-VF and FFP covers the period before vitamin K 1 has reached its full effect Prothrombinex-VF (25U/ml, 20 ml), one 20 ml bottle = 500 units. INR can be measured within 15 minutes of dose completion and doses repeated as necessary depending on INR. For an INR <4.5 use a dose closer to 25IU/kg, for INR> 4.5 use a dose closer to 50IU/kg. As with FFP, vitamin K 1 is concurrently required to prevent possible rebound anticoagulation Prothrombinex-VF is the only PCC approved in Australia and New Zealand for warfarin reversal. It is a three-factor concentrate, containing factors II, IX and X, but only low levels of factor VII. Therefore, the adjunctive use of FFP should be considered as a source of factor VII Consult with your Haematologist for the requirements for ordering and administration of Prothrombinex-VF and fresh frozen plasma 1 IE.EL.INR.1.v5 Issue date: Review date:

2 INR Higher than the therapeutic range but INR < 4.5 CLINICAL STATUS Bleeding Absent and low risk of bleeding TABLE 1: GUIDELINES FOR THE MANAGEMENT OF AN ELEVATED INR 1 WARFARIN VITAMIN K 1 DOSE Reduce or omit the next warfarin dose INR No bleeding STOP warfarin therapy, consider reasons for elevated INR & patientspecific factors PROTHROMBINEX OR FFP CHECK INR COMMENTS Nil Nil Next INR in 24 hours or less Resume therapy at lower warfarin dose when INR approaches therapeutic range. If the INR is only minimally above therapeutic range (up to 10%) dose reduction is generally not necessary If bleeding risk is high, consider Vitamin K 1 1-2mg orally or mg IV INR > 10.0 No bleeding STOP warfarin therapy Vitamin K mg orally or IV Nil Within 24 hours Resume therapy at a lower dose once INR approaches therapeutic range Nil Measure INR in hours then daily or every 2 nd day over next week Resume Warfarin therapy at reduced dose when the INR approaches the therapeutic range INR > 10.0 High risk of bleeding STOP warfarin therapy Vitamin K mg orally or IV Consider Prothrombinex-VF IU/kg Measure INR in hours then daily or every 2 nd day over next week Resume Warfarin therapy at reduced dose when the INR approaches the therapeutic range. If fresh frozen plasma and/or Prothrombinex -VF not available, contact Haematologist INR 1.5 Life-threatening (critical organ) bleeding STOP warfarin therapy Vitamin K mg IV Prothrombinex-VF 50 IU/kg and FFP ml. If Prothrombinex-VF unavailable, administer FFP 15 ml/kg Assess patient continuously until bleeding stops If fresh frozen plasma and/or Prothrombinex -VF not available, contact Haematologist INR 2.0 Clinically significant bleeding (not lifethreatening) STOP warfarin therapy Vitamin K mg IV Prothrombinex-VF IU/kg according to INR. If Prothrombinex-VF unavailable, administer FFP 15 ml/kg Assess patient continuously until bleeding stops If fresh frozen plasma and/or Prothrombinex -VF not available, contact Haematologist Any INR Minor bleeding STOP warfarin therapy If bleeding risk is high, consider Vitamin K 1 1-2mg orally or mg IV Nil Repeat INR the following day Adjust warfarin dose to maintain INR within therapeutic range 2 IE.EL.INR.1.v5 Issue date: Review date:

3 Description Contraindications Specifications Availability Considerations for use TABLE 2: CHARACTERISTICS OF PROTHROMBINEX-VF* AND FRESH FROZEN PLASMA (FFP) 2 PROTHROMBINEX-VF FRESH FROZEN PLASMA Prepared from plasma collected from voluntary donors. Sterile freeze-dried powder containing coagulation factors II, IX and X and low levels of factor VII Patients showing signs of thrombosis or disseminated intravascular coagulation Available in vials containing 500 IU of factor II, IX and X to be reconstituted in 20 ml of water for injections. Each vial also contains 25 IU of antithrombin and 192 IU of heparin From relevant blood service or hospital blood bank. No need to consider ABO group Known allergies to prothrombin complex concentrates. Predisposition to venous thrombosis, disseminated intravascular coagulation and myocardial infarction. Heparin-induced thrombocytopenia. Separated and frozen within 18 hours of collection from volunteer donors. Contains all coagulation factors Do not use when coagulopathy can be corrected more effectively with specific therapy, such as vitamin K 1, cryoprecipitate or other specific factor concentrates Available in ml sizes. May be stored in monitored blood refrigerator at 2 6 C for up to 5 days once thawed, and relabeled thawed plasma. Thawed plasma has levels of factors II, VII, IX and X adequate for warfarin reversal From relevant blood service or hospital blood bank. Available in all ABO groups and should be ABO-group compatible with patient s red cells (or use AB plasma) Most common adverse events allergic reactions and volume overload. Potential for transmission of infections, transfusion- related acute lung injury (TRALI) and other transfusion reactions, including transmission of infection *CSL Bioplasma For more comprehensive information on these products, refer to approved product information and blood service data Thrombotic complications of prothrombin complex concentrates appear to be rare. Since 1993 thrombotic episodes with Prothrombinex-VF or its predecessor, Prothrombinex-HT, have been rarely reported to CSL Bioplasma. 3 IE.EL.INR.1.v5 Issue date: Review date:

4 2. RISK FACTORS FOR BLEEDING COMPLICATIONS OF ANTICOAGULATION THERAPY 2.1 Management of over-anticoagulation depends on: The INR The risk of bleeding history The clinical significance of the bleed (if bleeding occurs) RISK FACTOR CATEGORY Age Cardiac Gastrointestinal Haematologic/Oncologic Neurologic Renal Trauma Alcohol Medications* TABLE 3: RISK FACTORS FOR BLEEDING COMPLICATIONS OF ANTICOAGULATION THERAPY 2 SPECIFIC RISK FACTORS 75 years Uncontrolled hypertension History of gastrointestinal haemorrhage, active peptic ulcer, hepatic insufficiency Thrombocytopenia (platelet count, < 50 x 10 9 /L), platelet dysfunction, coagulation defect, underlying malignancy History of stroke, cognitive or psychological impairment Severe renal insufficiency Recent trauma, increased falls (within previous treatment year or recurrent, injurious falls) Excessive alcohol intake Aspirin, non- steroidal anti-inflammatory drugs * Careful monitoring of warfarin effect is critical to minimise risk in patients taking multiple medications 4 IE.EL.INR.1.v5 Issue date: Review date:

5 3. MANAGING ORAL ANTICOAGULATION DURING INVASIVE PROCEDURES ACCORDING TO RISK OF THROMBOEMBOLISM 3.1 Pre- and post-operative management of anticoagulation 2 Opinion varies about how to manage anticoagulation in patients who have been taking warfarin long-term and who need to undergo surgery, as the evidence is mainly anecdotal. For most patients, warfarin can be withheld 5 days before elective surgery; the INR usually falls to below 1.5 in this time, and surgery can be conducted safely. An INR should always be performed in the 24 hours prior to surgery. It is important to consider the risk of thrombosis if warfarin is temporarily stopped and the possible need for peri-operative bridging anticoagulation Some procedures entail a low risk of bleeding and do not require interruption to warfarin therapy if the INR is within the therapeutic range. Examples include simple dental procedures, periodontal therapy, and minor dermatological procedures where pressure can be applied if required. If withholding warfarin preoperatively is necessary, a number of issues need to be considered. These include: Prolonged immobility during surgery and afterwards increases the risk of venous thromboembolism The need for bridging therapy depends on the risk of the thrombosis recurring during the period that patients are not receiving anticoagulation therapy. This risk is a combination of the risk associated with the patients themselves e.g. history of DVT and the risk of thrombosis associated with the type of surgery e.g. hip or knee replacement poses a greater risk than arthroscopy. Unfractionated heparin (UFH) offers some advantages for bridging anticoagulation in the 24 hours preceding surgery because of its faster onset and offset of action. There is no clear consensus regarding who should and should not receive bridging anticoagulation, due to a lack of randomised control trial data. In some situations, bridging anticoagulation may not be required. Patients who take anticoagulants because of low-moderate risk atrial fibrillation, or in whom the index event requiring anticoagulation occurred more than 3 months ago, can be safely managed without bridging anticoagulation. These patients are at relatively low risk of thromboembolism. Patients with prosthetic valves and those who have suffered an acute thrombosis within the preceding 3 months should receive bridging anticoagulation in the perioperative and postoperative period. This should be done in consultation with the relevant experts in this area. 5 IE.EL.INR.1.v5 Issue date: Review date:

6 TABLE 4: MANAGING ORAL ANTICOAGULATION DURING INVASIVE PROCEDURES ACCORDING TO RISK OF THROMBOEMBOLISM 2 TIME PATIENTS AT RELATIVELY LOW RISK PATIENTS AT RELATIVELY HIGH RISK Before surgery After surgery Withhold warfarin therapy 4 5 days before surgery Day before surgery - Check INR. If INR 2-3, administer 3 mg vitamin K 1 IV Day of surgery - If INR 1.5 surgery can proceed - If INR > 1.5, defer surgery or if urgent, give Prothrombinex-VF (according to Table 1) or if Prothrombinex-VF is not available, use FFP ml/kg - Consider preoperative thromboprophylaxis with LMWH if immobilized - For procedures with low risk of bleeding (e.g. cataracts, dental or dermatological), continue warfarin - Recommence warfarin on the night of surgery, at the previous maintenance dose - Employ thromboprophylaxis as per local practice Option 1 - Withhold warfarin 4-5 days before surgery - Once INR < 2.0, start LMWH 1.5 mg/kg once daily or 1 mg/kg twice daily, or UFH infusion at treatment doses o LMWH last dose should be 24 hours before surgery o UFH cease 4-6 hours before surgery Option 2 - If INR stable at 2-3 in preceding 2-4 weeks, administer vitamin K 1 3 mg IV day before surgery - Day of Surgery o o If INR 1.5, surgery can proceed If INR > 1.5, defer surgery or if urgent, administer Prothrombinex-VF according to table 1 or if not available use FFP ml/kg Option 3 - For urgent surgery, check INR before and administer Prothrombinex-VF according to table 1 - For procedures with a low risk of bleeding (eg cataracts, dental or dermatological) continue warfarin - Recommence warfarin the night of surgery at the previous maintenance dose. Consider bleeding risk against thrombosis - Start LMWH or UFH hours postoperatively - If using LMWH, begin with prophylactic dose: if UFH infusion is used, avoid bolus and aim to prolong the APTT by 1.5 times - Delay resumption of the therapeutic dose LMWH for hours after surgery in absence of bleeding - Continue LMWH or UFH for minimum of 5 days and cease 48 hours after target INR is reached. In surgery with high bleeding risk, consider using prophylactic dose LMWH or UFH only and cease 48 hours after target INR is reached. INR = international normalised ratio. aptt = activated partial thromboplastin time. FFP= fresh frozen plasma. LMWH=low molecular weight heparin. UFH=unfractionated heparin. * Exercise caution in patients with impaired renal function (calculated creatinine clearance rate < 30 ml/hr). LMWH can accumulate and contribute to bleeding 6 IE.EL.INR.1.v5 Issue date: Review date:

7 REFERENCES 1. Tran HA, Chunilal SD, Harper PL, et al. An update of consensus guidelines for warfarin reversal, Med J Aust 2013;198:198-9 [PubMed ( 2. Department of Haematology, Department of Pharmacy RGH,Pharmacy Division FMC. Dec 2010, Treatment Strategy for Warfarin Overanticoagulation, Southern Area Health Service Protocol,viewed , < nticoagulation&type=and&xcid=2> 3. Baker R I et al, 2004, Warfarin Reversal: Consensus Guidelines, On Behalf of the Australasian Society of Thrombosis and Haemostasis MJA Volume 181 (9): , Viewed Feb Meehan R, Tavares M, Sweeney J Clinical experience with oral versus intravenous vitamin K for warfarin reversal, Transfusion Mar; 53(3):491-8; quiz 490. doi: /j x. Epub 2012 Jun 28. From the Blood Bank and Department of Medicine, Roger Williams Hospital, Providence, Rhode Island. 7 IE.EL.INR.1.v5 Issue date: Review date: