Warfarin associated bleeding
and high INR:
Management in ED and preventing
recurrence
Dr Simone Taylor Senior Pharmacist:
Emergency Medicine and Research Austin Health, Melbourne, Australia
Background
• Warfarin still most commonly used anticoagulant in Australia
• Despite newer options, warfarin still expected to be used for • Patients already stable on warfarin (Time in Therapeutic Range > ~65%)
• Patients with severe renal dysfunction (CLCR < 30 ml/min)
• Indications not included in studies of new agents e.g. thrombus prevention in mechanical heart valves
• 1-3% risk of haemorrhage resulting in hospitalisation or death • Greatest risk in first 3 months after initiation
• Bleeding risk related to patient age, prior history of bleeding and specific co-morbidities.
• Most intracranial bleeds occur with INR in therapeutic range
Overview
• Managing high INR and warfarin associated bleeding in ED
• Answer the question “Why now?” to reduce risk of it happening again
• Communicate your findings, interventions and plan to the patient’s next health provider
Reversal options
• Vitamin K (phytomenadione)
• Available as oral tablets and injection
• In setting of warfarin reversal, use injection orally
• Prothrombin complex concentrates*
• Contain 3 factors (II, IX, X) or 4 factors (II, VII, IX, X)
• Prothrombinex-VK (3 factors) is the only option routinely used in Australia
• Fresh frozen plasma*
• Contains all coagulation factors present in whole blood
* Obtain from Hospital Blood Bank or blood service
Vitamin K
• IV has onset of 6-8 hours
• After 24 hours, IV and oral achieve similar correction of INR
• Not to be given subcut or IM • Subcut is no more effective than placebo
• IM has variable absorption and risk of haematoma/bleeding
• Anaphylaxis when given IV is very rare • Incidence not accurately known
• Current micelle formulation felt to be safer than the older formulation
Prothrobinex-VK • Advantages
• Small volume, infused over 20-30 minutes
• Fast onset – completely correcting INR in about 15 minutes
• No need to check blood group, minimal risk of viral transmission, transfusion associated circulatory overload and TRALI
• Other notes • Contains small amount of heparin; need to be cautious in patients with a
history of heparin-induced thrombocytopenia
• Similar duration of effect to endogenous clotting factors
• Lasts 6-8 hours; must also give vitamin K
• Low levels of factor VII
• Old MJA guidelines suggested routine FFP supplementation
• 2013 – FFP supplementation not necessary in all cases
• Only if INR > 10 or major life-threatening bleed
Prothrombinex-VK dosing
Target INR
Initial INR 1.5 – 2.5
Initial INR 2.6 – 3.5
Initial INR 3.6 - 10
Initial INR > 10
0.9 – 1.3 30 units/kg 35 units/kg 50 units/kg
50 units/kg
1.4 – 2.0 15 units/kg 25 units/kg
30 units/kg
40 units/kg
• Previously, dose was 25 – 50 units/kg
• New guidelines base dose on initial and target INR
• Each vial contains 500 units
Fresh frozen plasma
• Is not a coagulation factor concentrate • Each unit contains 250 – 334 mL
• Multiple units may be needed
• 300 mL is usually given over about 1 hour
• Monitor for volume overload – diuretic cover may be needed in heart failure and renal dysfunction
• Carries all of the routine risks of blood products
• Indications • If Prothrombinex-VK is not available
• In addition to Prothombinex-VK, only if INR > 10 or major life threatening bleeding
Managing elevated INR with no bleeding
Clinical setting Recommendations
INR higher than therapeutic range but < 4.5 and no bleeding
• Lower or omit the next dose of warfarin • Resume warfarin at lower dose when INR approaches therapeutic
range • If INR only minimally above therapeutic range (up to 10%) dose
reduction is generally not necessary
INR 4.5 – 10 and no bleeding • Cease warfarin; consider reasons for elevated INR and patient specific factors
• Vitamin K is usually unnecessary. If bleeding risk is high* consider vitamin K 1 -2 mg IV
• Measure INR within 24 hours. Resume warfarin at reduced dose once INR approaches therapeutic range
INR > 10 and no bleeding • Cease warfarin, administer 3 -5 mg vitamin K orally or IV
• Measure INR in 12 – 24 hours. Closely monitor INR daily or every second day over the following week. Resume warfarin at a reduced dose once INR approaches therapeutic range
• If bleeding risk is high* consider Prothrombinex-VK 15-30 units/kg and measure INR in 12-24 hours. Monitor closely over the following week and resume warfarin at reduced dose once INR approaches therapeutic range
* Recent major bleed (within previous 4 weeks) or major surgery (within previous 2 weeks),
thrombocytopenia (platelet count, < 50 109/L), known liver disease or concurrent antiplatelet therapy
Managing bleeding associated with warfarin^
(irrespective of INR)
Clinical setting Recommendations
INR > 1.5 with life-threatening bleeding (critical organ and intracranial haemorrhage)
• Cease warfarin • Administer: Vitamin K 5 – 10 mg IV, and Prothrombinex-VF 50 units/kg IV,# and Fresh frozen plasma 150 - 300 mL If Prothrombinex-VK is unavailable, administer FFP 15 mL/kg
INR > 2.0 with clinically significant bleeding (non-life-threatening)
• Cease warfarin • Administer: Vitamin K 5 – 10 mg IV, and Prothrombinex-VF 35-50 units/kg IV, depending on INR If Prothrombinex-VK is unavailable, administer FFP 15 mL/kg
Any INR with minor bleeding
• Omit warfarin, repeat INR the following day and adjust warfarin dose to maintain INR in target range
• If bleeding risk is high* or INR > 4.5, consider vitamin K 1-2 mg orally or 0.5-1 mg IV
^The need for warfarin should be re-considered. # Consider giving Prothrombinex dose less than 50 units/kg when INR 1.5-
1.9 *Recent major bleed (within previous 4 weeks) or major surgery (within previous 2 weeks), thrombocytopenia (platelet
count, < 50 109/L), known liver disease or concurrent antiplatelet therapy.
High INR/bleed: “Why now?”
• Adherence/dose confusion
• Intercurrent illness • Reduced vitamin K intake, antibiotics, vomiting/nausea/diarrhoea
• Drug interactions • Starting, ceasing or dose change
• Certain antibiotics, amiodarone, statins, anticonvulsants, some herbal products e.g. St John’s wort
• Major dietary changes • Maintain consistent vitamin K intake
• Useful information on National Prescribing Service website • Decision tools, warfarin safety check-list
Communicate – continuum of care issues
• Warfarin discharge plan • What was done in ED?
• When/where is next INR to be checked?
• Who will review INR and advise patient?
• Don’t rely on the patient to verbally communicate changes to dosing service
Useful resources
• Australasian Society of Thrombosis Haemostasis Guidelines • Tran HA. An update of consensus guidelines for warfarin reversal. Med
J Aust. 2013;198:1-7
• Drug and food interactions • Australian Medicines Handbook – on Clinicians Health Channel
• National Prescribing Service website http://www.nps.org.au/medicines/heart-blood-and-blood-vessels/anti-clotting-medicines/for-individuals/anticoagulant-medicines/for-health-professionals/decision-tools
• Holbrook AM, et al. Systematic overview of warfarin and its drug and food interactions. Archives of Internal Medicine 2005;165:1095–106
• Your pharmacy department/medicines information service
• Patient education materials • National Prescribing Service website
• Warfarin Dose Tracker, Living with warfarin fact sheet