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

simone.taylor@austin.org.au

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