Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Contact Name and Job Title (author) Guideline on the management of excessive coumarin anticoagulation in adults Julian Holmes (Haemostasis and Thrombosis Pharmacist) Joannes Hermans (Haemostasis and Thrombosis Consultant) Directorate & Speciality Diagnostics and Clinical Support Date of submission October 2018 Date on which guideline must be reviewed (this should October 2021 be one to three years) Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Patients requiring management of excessive coumarin anticoagulation Abstract Key Words Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? Evidence base: (1-5) 1a meta analysis of randomised controlled trials 1b at least one randomised controlled trial 2a at least one well-designed controlled study without randomisation 2b at least one other type of well-designed quasi-experimental study 3 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 4 expert committee reports or opinions and / or clinical experiences of respected authorities 5 recommended best practise based on the clinical experience of the guideline developer Consultation Process Target audience This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. Warfarin, vitamin K, acenocoumarol, phenindione, phytomenadione 4,5 Based on BCSH guideline on anticoagulation with warfarin 4 th edition 2011 and update of previous versions Consensus opinion with input from Haemostasis/Thrombosis Consultants (Dr Gill Swallow, Dr Charlotte Grimley, Dr Cherry Chang) and Cardiac surgeons (Mr Adam Szafranek) Haemostasis and Thrombosis Service Drugs and Therapeutics Committee All wards and clinical areas Page 1 of 11
Management of Excessive Coumarin Anticoagulation in Adults This guideline provides guidance for the management of excessive anticoagulation with coumarins; this includes warfarin, acenocoumarol and phenindione. Exclusions to this guideline; Patients taking direct oral anticoagulants (which include rivaroxaban, apixaban, dabigatran and edoxaban). Please refer to the relevant guideline for patients receiving direct oral anticoagulants requiring emergency surgery or treatment for haemorrhage. Guidelines are available from the Trust s Clinical Guideline Page on the intranet. Paediatric patients in hours please contact paediatric haematologist for advice; out of hours please contact on call haematologist for advice. N.B. All INR's over 8 require active intervention in view of the very high risk of intra-cranial bleeding over this level. For management of major bleeding please see page 6 Page 2 of 11
Management of excessive oral anticoagulation in adult Non Bleeding patients in whom anticoagulation is to be continued 1. OUT PATIENTS (non-bleeding) The following applies ONLY to out patients dosed by the NUH anticoagulation service. Patients who are dosed by their own GP should be discussed directly with their GP or, out of hours, the on call GP service. Oral vitamin K (phytomenadione) has been shown to reduce the INR of patients over anticoagulated by warfarin or other coumarin anticoagulants (but not the direct oral anticoagulants). Investigate for cause of high INR (e.g. drug interactions, alcohol intake, liver disease, cardiac failure). If INR>8 patient contacted by anticoagulation clinic and attends NEMS at Platform One Surgery for repeat INR and FBC and administration of vitamin K as below Page 3 of 11
INR INR 3-6 (range 2-3) INR 4-6 (higher range) INR 6-8 INR >8 (Excluding patients with Mechanical Valves) Recommended action Reduce warfarin dose Reduce warfarin dose Stop warfarin for 1-2 days, reduce dose and check INR on day 3 Stop warfarin. Patient to attend NEMS for repeat INR and FBC Give oral vitamin K (phytomenadione) 2mg (Konakion MM Paediatric 2mg in 0.2ml) diluted in water Check INR the following day and re-start warfarin only when INR in therapeutic range. Follow up by anticoagulation clinic. INR >8 (Patients with Mechanical Valves only) Stop warfarin. Patient to attend NEMS for repeat INR and FBC Give oral vitamin K (phytomenadione) 1mg (Konakion MM Paediatric 1mg in 0.1ml) diluted in water INR must be checked the following day (even if falls at a weekend) and re-start warfarin only when INR in therapeutic range. Follow up by anticoagulation clinic. Page 4 of 11
2. INPATIENTS (non-bleeding) Oral vitamin K (phytomenadione) has been shown to reduce the INR of patients over anticoagulated by warfarin or other coumarin anticoagulants (but not the direct oral anticoagulants). Investigate for cause of high INR INR INR 3-6 (range 2-3) INR 4-6 (higher range) INR 6-8 INR >8 (Excluding patients with Mechanical Valves) Recommended action Reduce warfarin dose Reduce warfarin dose Stop warfarin for 1-2 days, reduce dose and check INR on day 3 Stop warfarin. Patient to attend NEMS for repeat INR and FBC Give oral vitamin K (phytomenadione) 2mg (Konakion MM Paediatric 2mg in 0.2ml) diluted in water Check INR the following day and re-start warfarin only when INR in therapeutic range. Follow up by anticoagulation clinic. INR >8 (Patients with Mechanical Valves only) Stop warfarin. Patient to attend NEMS for repeat INR and FBC Give oral vitamin K (phytomenadione) 1mg (Konakion MM Paediatric 1mg in 0.1ml) diluted in water INR must be checked the following day (even if falls at a weekend) and re-start warfarin only when INR in therapeutic range. Follow up by anticoagulation clinic. Page 5 of 11
Management of excessive oral anticoagulation in adult Bleeding PATIENTS or those at high risk of bleeding or invasive procedure anticipated If the patient is an outpatient and bleeding, they should be advised to come to the hospital for assessment Check INR urgently If suspected, intracerebral or intraspinal haemorrhage is an emergency give iv vitamin k (phytomenadione) 10mg by direct injection over at least 30 seconds but usually over 3-5 minutes and contact the neurosurgeon on call for advice regarding further investigation/management and/or need for immediate reversal of anticoagulation with prothrombin complex concentrate. Always investigate for underlying cause of bleeding and cause of high INR Further action depends on clinical situation and INR. INR INR <4 INR 4-8 Minor Bleed (e.g. minor trauma, minor nose bleeds etc) Recommended action Reduce warfarin dose Stop warfarin for 2 days Restart at appropriate dose when INR in therapeutic range INR >8 (Excluding patients with Mechanical Valves) Or if other risk factors for bleeding (e.g. age>70 years, previous history of bleeding, abnormal LFT s, malignancy, tendency to falls) INR >8 (Patients with Mechanical Valves only) Stop warfarin. Check FBC Give iv vitamin K (phytomenadione) 2mg (Konakion MM Paediatric 2mg in 0.2ml) by direct injection over at least 30 seconds but usually over 3-5 minutes Check INR in 6-8 hours and re-start warfarin only when INR in therapeutic range Stop warfarin. Check FBC Give iv vitamin K (phytomenadione) 1mg (Konakion MM Paediatric 1mg in 0.1ml) by direct injection over at least 30 seconds but usually over 3-5 minutes Check INR in 6-8 hours and re-start warfarin only when INR in therapeutic range Page 6 of 11
Major Bleed Give iv vitamin K (phytomenadione) 10mg (Konakion MM 10mg in 1ml) immediately by direct injection over at least 30 seconds but usually over 3-5 minutes Do not wait for INR result Stop warfarin If intracranial or intraspinal haemorrhage discuss with neurosurgeon on call for advice regarding further investigation/management and/or need for immediate reversal of anticoagulation Other patients discuss with haematology registrar or consultant Consider prothrombin complex concentrate in discussion with the haematologists (see appendix for further information) NB: If anticoagulation is reversed for patients with mechanical valves, a plan for post reversal re-anticoagulation once the situation has stabilised MUST be discussed with Cardiac Surgery. Page 7 of 11
Appendix: Prothrombin Complex Concentrate (PCC) PCC is a pooled factor concentrate licensed for emergency reversal of vitamin K antagonists (e.g. warfarin), when the clinical situation does not allow for the 4-8 hours for vitamin K to take full effect. It is not used to enable elective invasive procedures where warfarin should be discontinued in advance (http://nuhnet/nuh_documents/guidelines/cancer%20and%20associated%20specialties/ Clinical%20Haematology/2854.pdf) or in situations where reversal with Vitamin K will suffice. It contains factors II, VII, IX and X (plus small amounts of Proteins C, S and antithrombin, as well as heparin), is virally inactivated, and is not blood group specific. PCC has a baseline thrombotic risk of 5-7%. It should be used with extreme caution in patients at high risk of thrombosis and is not recommended for use in patients with disseminated intravascular coagulation or a history of heparin-induced thrombocytopenia (HIT). If there is major bleeding, discuss with the relevant clinical team about whether immediate reversal is indicated (unless in the context of non-traumatic intracranial haemorrhage in which case it can be ordered directly from the blood transfusion laboratory (http://nuhnet/nuh_documents/guidelines/acute%20medical/emergency%20department %20-%20EDIS/2303.pdf). In the context of intracranial or intraspinal haemorrhage, the case needs to be discussed with the neurosurgeon on call to assess whether immediate reversal is required or not, as in some cases vitamin K alone is clinically sufficient. In all other situations, the case should be discussed with the haematology registrar or consultant on call for advice and authorisation. NB: Vitamin K must always be given prior to PCC to prevent the INR from rising again after 6-12 hours. If the use of PCC is required, then the appropriate dose (see below) should be requested and collected from the blood transfusion laboratory. Octaplex is the prothrombin complex concentrate currently being used at NUH, but this is subject to change, and so please request prothrombin complex concentrate (as opposed to octaplex ) to prevent potential confusion and delays. Dosing The dose of PCC used within NUH for the reversal of vitamin K antagonists is based on INR as shown in the table below (and differs from the dose used in other indications, which is weight-based). If there is major, life-threatening bleeding and an INR is not available, 1000 units may be given. An additional top-up dose when the INR result is available may be given if clinically required. Page 8 of 11
The maximum dose of PCC is 3000 units. INR 1.6-2.9* 3.0-5.0 >5.0 Dose of octaplex 1000 units 2000 units 3000 units *Prothrombin complex concentrate is not indicated if INR 1.5 Requesting, Prescribing and Administering PCC PCC is requested on Medway through Blood Products/Components (Prothrombin Complex Concentrate) or on a Blood Transfusion request form. It must be collected immediately from the blood transfusion laboratory. If it is not collected within 2 hours of issue, it will be returned to stock and re-authorisation will be required. PCC must be prescribed on the Transfusion Record Sheet (TRS) and the infusion documented as per the TRS. It can also be given as a rapid IV infusion or slow IV bolus. As this is an emergency drug, it should be given immediately. If more than 3 hours has passed since the administration of Vitamin K and the commencement of PCC, then consideration should be given as to whether it is still clinically necessary, and a repeat INR checked to confirm dose of PCC is still appropriate. Reconstitution and administration guidelines are available on the Specific Product Characteristics (SPC) leaflet accompanying the product. Instructions are also available on the Blood Transfusion webpage on the NUH intranet (http://nuhnet/diagnostics_clinical_support/blood_transfusion/pages/reversal_warfarin.a spx) The blood transfusion laboratory will NOT accept PCC back in the event of failure to reconstitute. This is rarely a product malfunction and there is usually a solution to this problem. Please contact the haematologist for advice. Post dose monitoring Since dose effect is not universally applicable, efficacy of dosing must be determined using the surrogate marker of an INR 10-30 minutes post administration of PCC. If the INR is not 1.5 and the patient is still bleeding, an additional dose may be required so discuss with the haematologist. NB: Be aware that the risk of thrombosis can extend to up to 30 days post dose, and so it is important to be vigilant for thrombosis during this period. References RECOMMENDATIONS FOR USE OF PROTHROMBIN COMPLEX CONCENTRATES IN CANADA Recommendations for the use of prothrombin complex concentrates in Canada, National Advisory Committee on Blood and Blood Products, May 2014 Page 9 of 11
Equality Impact Assessment Report 1. Name of Policy or Service Response to external best practice policy 2. Responsible Manager Owen Bennett (Clinical Quality, Risk and Safety Manager) 3. Name of person Completing EIA Julian Holmes 4. Date EIA Completed 24.5.18 5. Description and Aims of Policy/Service Management of excessive coumarin anticoagulation in adults 6. Brief Summary of Research and Relevant Data BCSH guideline on anticoagulation with warfarin 4 th edition 2011 7. Methods and Outcome of Consultation N/A 8. Results of Initial Screening or Full Equality Impact Assessment: Equality Group Age Gender Race Sexual Orientation Religion or belief Disability Dignity and Human Rights Working Patterns Social Deprivation Assessment of Impact Page 10 of 11
9. Decisions and/or Recommendations (including supporting rationale) From the information contained in the procedure, and following the initial screening, it is my decision that a full assessment is not required at the present time. 10. Equality Action Plan (if required) N/A 11. Monitoring and Review Arrangements Review October 2021 Page 11 of 11