ClinicalClinical focus focus Guidelines An update of consensus guidelines for warfarin reversal Huyen A Tran MB BS, MClinEpi, FRACP, arfarin is effectively used in a wide range of Summary Haematologist1,2 thromboembolic disorders for primary and sec- • Despite the associated bleeding risk, warfarin is the most ondary prevention. Patients on long-term ther- Sanjeev D Chunilal W commonly prescribed anticoagulant in Australia and New MB ChB, FRACP, FRCPA, apy have a risk of 1%–3% per year for haemorrhage leading Zealand. Warfarin use will likely continue for Haematologist2 1,2 to hospitalisation or death. Therefore, strategies to manage anticoagulation indications for which novel agents have Paul L Harper over-warfarinisation and warfarin during invasive procedures not been evaluated and among patients who are already MD, FRCP, FRACP, 3,4 stabilised on it or have severe renal impairment. Haematologist3 are important. Despite the associated bleeding risk, warfa- rin remains the most commonly prescribed anticoagulant in • Strategies to manage over-warfarinisation and warfarin Huy Tran during invasive procedures can reduce the risk of MB BS, FRACP, FRCPA, Australia and New Zealand. Common indications for the use Clinical and Laboratory of warfarin in the community include stroke prevention in haemorrhage. Haematologist4 atrial fibrillation (AF), preventing thrombus formation in • For most warfarin indications, the target international Erica M Wood patients with mechanical heart valves (MHV), and treatment normalised ratio (INR) is 2.0–3.0 (venous MB BS, FRACP, FRCPA, thromboembolism and single mechanical heart valve Haematologist2,5,6 of venous thromboembolism (VTE). For most warfarin indi- excluding mitral). For mechanical mitral valve or combined cations, the target international normalised ratio (INR) is 2.0– Alex S Gallus mitral and aortic valves, the target INR is 2.5–3.5. MB BS, FRACP, FRCPA, 3.0 (VTE and single MHV excluding mitral). For mechanical Haematologist,7 and • Risk factors for bleeding with warfarin use include Professor of Haematology8 mitral valve or combined mitral and aortic valves, the target 5 increasing age, history of bleeding and specific INR is 2.5–3.0. New anticoagulants such as oral direct factor comorbidities. on behalf of the Xa inhibitors and direct thrombin inhibitors are becoming • Australasian Society 6-8 For patients with elevated INR (4.5–10.0), no bleeding and of Thrombosis and available as alternatives to warfarin. However, it is likely no high risk of bleeding, withholding warfarin with careful Haemostasis that warfarin will continue to be widely used in the commu- subsequent monitoring seems safe. nity among patients who are already stable on warfarin or • Vitamin K1 can be given to reverse the anticoagulant effect 1 Clinical Haematology, have severe renal impairment (creatinine clearance, <30mL/ The Alfred Hospital, of warfarin. When oral vitamin K1 is used for this purpose, Melbourne, VIC. min), and for anticoagulation indications for which these the injectable formulation, which can be given orally or 9,10 2 Haematology, novel agents have not been evaluated, such as MHV. intravenously, is preferred. Monash Medical Centre, 11 Melbourne, VIC. This update of the previous consensus guidelines is • For immediate reversal, prothrombin complex 3 Clinical Haematology, again on behalf of the Australasian Society of Thrombosis concentrates (PCC) are preferred over fresh frozen plasma Palmerston North Hospital, and Haemostasis (ASTH) and offers advice on strategies to (FFP). Prothrombinex-VF is the only PCC routinely used for Palmerston North, warfarin reversal in Australia and New Zealand. It contains New Zealand. prevent over-anticoagulation, the principles of warfarin factors II, IX, X and low levels of factor VII. FFP is not 4 Haematology, reversal, and bridging anticoagulation therapy in different Dorevitch Pathology, routinely needed in combination with Prothrombinex-VF. Melbourne, VIC. clinical settings. In particular, the focus is on managing: FFP can be used when Prothrombinex-VF is unavailable. 5 Diagnostic Haematology, • warfarin therapy complicated by bleeding; Vitamin K1 is essential for sustaining the reversal achieved Royal Melbourne Hospital, Melbourne, VIC. • a supratherapeutic INR with no bleeding; and by PCC or FFP. 6 Monash University, • warfarin therapy during invasive procedures. • Surgery can be conducted with minimal increased risk of Melbourne, VIC. bleeding if INR р 1.5. For minor procedures where bleeding 7 Haematology, The recommendations draw on available evidence and risk is low, warfarin may not need to be interrupted. If SA Pathology at Flinders the clinical experience of the panel of author–practitioners. Medical Centre, necessary, warfarin can be withheld for 5 days before Adelaide, SA. surgery, or intravenous vitamin K1 can be given the night 8 Flinders University, Guideline development before surgery. Prothrombinex-VF use for warfarin reversal Adelaide, SA. should be restricted to emergency settings. Perioperative huyen.tran@ As Australian and New Zealand-based experts in the field management of anticoagulant therapy requires an monash.edu evaluation of the risk of thrombosis if warfarin is of thromboembolic disorders, we were invited to join the temporarily stopped, relative to the risk of bleeding if it is panel leading guideline development. The process doi: 10.5694/mja12.10614The Medical Journal of Australia ISSN: 0025-729X 4 March 2013 198 continued or modified. 4 1-7 included reviewing up-to-date evidence and existing high- ©The Medicalquality Journal evidence-based of Australia 2013 internat www.mja.com.auional guidelines for warfa- Clinical Focusrin (guidelines) reversal. We conducted a face-to-face meeting on 21 We based our recommendations on the body of evi- March 2011 at which specific questions and drafting of the dence, with consideration of the strength of evidence, guidelines were discussed. Further revisions were made by consistency across studies, likely clinical impact, and gen- An abridged version of this article appeared in consensus via email. All six members of the panel are the eralisability and applicability of study findings in the local the printed journal authors of this article. setting. 1 MJA 198 (4) · 4 March 2013 Clinical focus Relevant clinical questions guided systematic review of 1 Grades of guideline recommendations the evidence. We followed the GRADE (Grading of Rec- ommendations Assessment, Development and Evalua- Grade of recommendation Quality of supporting evidence tion) method to generate recommendations. The strength Strong recommendation, Evidence obtained from a systematic review of all of recommendations, designated strong (1) or weak (2), is high-quality evidence (1A) relevant randomised controlled trials (RCTs) or based on the quality of the body of evidence, which can be exceptionally strong evidence from observational high (A), moderate (B) or low (C).12 For recommendations studies where the quality of evidence was not sufficient to allocate Strong recommendation, Evidence from at least one RCT or very strong a grade, the term “good practice point” (GPP) indicates moderate-quality evidence (1B) evidence from observational studies the recommendation is based on the consensus opinion of Strong recommendation, Evidence for at least one critical outcome from the ASTH writing panel (Box 1). Consensus recommenda- low-quality evidence (1C) observational studies, case series, or RCTs, with tions were reached in an equitable manner. Agreement of serious flaws or indirect evidence all members of the expert panel was required in order to Weak recommendation, Evidence obtained from a systematic review of all proceed with making the recommendation. high-quality evidence (2A) relevant RCTs or exceptionally strong evidence from Potential conflicts of interest were declared and observational studies recorded. Funding for this update was provided by a Weak recommendation, Evidence from at least one RCT or very strong restricted educational grant from CSL Bioplasma that was moderate-quality evidence (2B) evidence from observational studies administered by the ASTH. Weak recommendation, low or Evidence for at least one critical outcome from very low-quality evidence (2C) observational studies, case series, or RCTs, with Bleeding complications of warfarin therapy serious flaws or indirect evidence Good practice point (GPP) Supporting evidence is insufficient to meet even Bleeding is the most common complication of warfarin the lowest grade of evidence. Recommendation is therapy and is related to the INR value. Although incre- therefore based on consensus opinion of the writing panel of Australasian Society of Thrombosis and mental rises in INR increase the risk of bleeding, most Haemostasis ◆ intracranial bleeds are in patients with an INR in the therapeutic range; they occur in 0.5%–1.0% of patients with AF per year.13,14 Bleeding risk is also related to patient 2 Principles for preventing high international normalised ratio (INR)* factors including age, a prior bleeding history and specific • When starting warfarin therapy, avoid high loading doses of warfarin. In general, it is comorbidities. Elderly patients are generally more sensitive preferable to start treatment using an initial daily dose of 5 mg, or even lower in elderly 15,16 to warfarin and need a lower mean daily dose. Bleed- patients.19-21 However, some guidelines have suggested that patients who are ing risk is greatest in the first 3 months after starting considered