Supratherapeutic INR

aka Toxicology Conundrum 021

A 70 year-old man has presented to your emergency department to get his INR checked. He has been traveling around the country in a camper van for the past month and has had trouble getting regular blood tests. He has taken warfarin regularly for 5 years as he has a mechanical prosthetic heart valve following a mitral valve replacement.

Questions below — but first, let’s see what Minnesota’s ‘Governing Body’, Jesse Ventura, has to say about anticoagulation:


Questions

Q1. What key issues may affect management in this case?

Answer and interpretation

Before treating a patient for potential supratherapeutic anticoagulation, the three most important things we need to know are:

  1. What is the INR?
  2. Is there evidence of active bleeding?
  3. Why is the patient taking warfarin?

Answers to the first two questions help us determine:

  • the severity of the supratherapeutic anticoagulation and the likely dose of reversal agents required.
  • the urgency with which treatment must be initiated.

Why the patient is taking warfarin is also important because:

  • all patients with anticoagulation problems should have the ongoing need for warfarin reviewed
  • there are potentional downsides to excessive correction of the INR — patients with mechanical heart valves are at high risk of thromboembolic complications so reversal with large doses of vitamin K  means the patient may require prolonged heparinisation until he becomes warfarin sensitive again. If vitamin K is given in this case, small doses should be administered and titrated according to serial INR results.

We also have to ask, “why the INR is high?“:

  • inadequate INR monitoring?
  • an intentional suicidal ingestion?
  • recently commence new medications? (e.g. antibiotics, analgesics, amiodarone)
  • lifestyle changes? (e.g. alcohol, diet)
  • inter-current illness?

Other factors important in elderly patients include:

  • elderly patients are less tolerant of significant hemorrhage:
    • they have less “physiological reserve”.
    • they are more likely to have other comorbidities that impair compensatory mechanisms.
  • elderly patients are more likely to have significant hemorrhage because:
    • they may be more prone to falls and other injury mechanisms, e.g. higher risk of intracranial hemorrhage should they sustain a head injury.
    • comorbidities (e.g. peptic ulcer disease) and other medications (e.g. clopidogrel, aspirin) are more likely to be present.

The target INR for patients with mechanical prosthetic hart valves is 3.0 to 4.5 (except for bileaflet mechanical aortic heart valves – the target INR is 2.5-3.5).


Q2. What are the likely sites of bleeding in the setting of warfarin-induced anticoagulation?

Answer and interpretation

Hematuria due to hemorrhage from the urinary tract is the most common site of bleeding from supratherapeutic anticoagulation.

Other sites include epistaxis, gingival bleeding, hemorrhage from minor wounds, subcutaneous bruising, and gastrointestinal hemorrhage. An intracranial bleed, the most devastating complication, should be suspected if there is a history of a fall or evidence of head injury or altered mental status. Retroperitoneal hemorrhage should be suspected there is back or loin pain. Investigations will depend on the clinical presentation.

The bottom line: bleeding can occur anywhere…

An adrenal hemorrhage is the most puzzling site I’ve encountered. Also, make sure you don’t miss spinal epidural hematomas, rectus sheath hemoatomas, hemarthroses and compartment syndrome from warfarin-induced hemorrhage.


Q3. How would you manage this case if this man’s INR is 4.9 and he has no evidence of bleeding?

Answer and interpretation
  • Resuscitation, supportive care and monitoring
    • No resuscitation issues. Cardiac monitoring not required. Can be assessed in a supportive ward environment.
  • Risk assessment
    • Potential for ongoing supratherapeutic anticoagulation and potentially lethal hemorrhage.
    • Peak effects of warfarin ingestion are observed within 72 hours of last dose.
  • Investigations – 
    • recheck INR within 24 hours.
  • Decontamination, enhanced elimination, and antidotes
    • Nil.
    • INR <5.0 requires no specific reversal treatments.
    • Vitamin K should only be given if the INR is sufficiently elevated and the bleeding risk is sufficiently high – i.e. not in this setting.
  • Disposition
    • Withold warfarin for one night, or decrease the dose until INR is in the high-normal (therapeutic) range. If INR is only 10% above normal, dose reduction may not be necessary if appropriate monitoring can be arranged.
    • Patient education regarding warfarin dosages and blood tests.
    • A review of medications and OTC/ alternative therapies that may interact with warfarin.
    • He could be treated on an outpatient basis if appropriate follow up is arranged, e.g. patient is discussed with GP (in this case, follow up could be tricky!)

Q4. How would you manage this case if this man’s INR is 8.4 and he has no evidence of bleeding?

Answer and interpretation
  • Resuscitation, supportive care and monitoring
    • No resuscitation issues. Cardiac monitoring not required. Can be assessed in a supportive ward environment.
  • Risk assessment
    • Potential for ongoing supratherapeutic anticoagulation and potentially lethal hemorrhage.
    • Peak effects of warfarin ingestion are observed within 72 hours of last dose.
  • Investigations
    • recheck INR within 24 hours.
  • Decontamination and enhanced elimination — Nil.
  • Antidotes – see resuscitation.
    • Vitamin K should only be given if the INR is sufficiently elevated and the bleeding risk is high (see Q5 Toxicology Conundrum #016) If INR 5-9 and bleeding risk is:
      • low – monitor INR, no vitamin K required.
      • high – monitor INR, administer 0.5-1mg vitamin K IV or 1-2mg po.
  • Disposition —
    • Withold warfarin. Restart at a lower dose once INR is in the high-normal (therapeutic range.
    • Patient education regarding warfarin dosages and blood tests.
    • A review of medications and OTC/ alternative therapies that may interact with warfarin.
    • He could be treated on an outpatient basis if low risk and appropriate follow up is arranged, e.g. patient is discussed with GP (in this case, follow up could be tricky!)
    • However, given this man is living out of a camper van, a stay in hospital overnight to get things sorted may be reasonable.


Q5. How would you manage this case if this man’s INR is 12.0 and he has no evidence of bleeding?

Answer and interpretation
  • Resuscitation, supportive care and monitoring
    • No resuscitation issues. Cardiac monitoring not required. Can be assessed in a supportive ward environment.
  • Risk assessment
    • Potential for ongoing supratherapeutic anticoagulation and potentially lethal hemorrhage.
    • Peak effects of warfarin ingestion are observed within 72 hours of last dose.
  • Investigations — 
    • recheck INR in 6-12 hours, and repeat as necessary.
  • Decontamination and enhanced elimination — Nil.
  • Antidotes
    • Vitamin K is indicated if INR is >9. If bleeding risk is high (see Q5 Toxicology Conundrum 016), FFP and/or prothrombin complex concentrate should be ‘considered’ :If INR >9 and bleeding risk is:l
      • ow – monitor INR, administer vitamin K 1mg IV or 2.5-5.0 mg po.
      • high – monitor INR, administer 1mg vitamin K IV, ‘consider’ the administration of FFP/ prothrombinex.
  • Disposition
    • Patient education regarding warfarin dosages and blood tests.
    • A review of medications and OTC/ alternative therapies that may interact with warfarin.
    • Patients with an INR>9 may be admitted to a hospital ward for monitoring and supportive care.

Q6. Describe your management plan if there is evidence of active bleeding.

Answer and interpretation
  • Resuscitation
    • Manage in an appropriately resourced resuscitation setting with continuous monitoring
    • Address ABCs along conventional lines
      • ensure IV access with 2 x large bore cannulae (e.g. 14G) and obtain crossmatch
      • consider insertion of a rapid infusion catheter, e.g. using a guidewire through a cannula of minimum 20G size.
    • Identify and control source of hemorrhage 
      • e.g. elevate body part, direct pressure
      • hemorrhage is often internal (e.g. intracranial, retroperitoneal), and may be difficult to control
    • Treat hypotension
      • fluid resuscitation (e.g. 10-20 mL/kg crystalloid)
      • packed RBC transfusion (if bleeding is ongoing a target Hb ~100 may be appropriate)
      • consider activation of massive transfusion protocol
    • Treat active uncontrolled hemorrhage by administering
      • fresh frozen plasma (10-15mL/kg)
      • prothrombinex HT (25-50 IU/kg)
      • vitamin K 5-10mg IVLiaise with hematology team and transfusion medicine as required
  • Risk assessment
    • Potential for life-threatening hemorrhage that may be difficult to control.
  • Supportive care and monitoring
    • Routine measures.
  • Investigations — 
    • Check INR on arrival (should be normal if performed within 6 hours of ingestion) and periodically thereafter according to INR and bleeding risk.
  • Decontamination and enhanced elimination — Nil.
  • Antidotes — see resuscitation.
  • Disposition
    • Withold warfarin.
    • Disposition with depend on the source of bleeding and measures required to control hemorrhage: potential ward admission, intensive care, or direct to the operating theatre or interventional radiology for angiography +/- embolisation of a bleeding vessel (interventional procedures are not usually required)
    • Patient education regarding warfarin dosages and blood tests.
    • A review of medications and OTC/ alternative therapies that may interact with warfarin.
    • Anticoagulation (e.g. heparin infusion) may be restarted when the INR is in the “normal/therapeutic” range and bleeding has been controlled. The risk of rebleeding must be weighed against the risk of thromboembolic heart valve complications.

Q7. What aspects of warfarin therapy should patients taking warfarin be educated about?

Answer and interpretation

Patients on warfarin therapy should have the following explained:

  • Reason for treatment
  • Mechanism of action of warfarin
  • Time of day to take warfarin (same time of day)
  • The INR, target range and need for regular testing
  • Signs and symptoms of bleeding
  • Effect of illness, injury or any changes in physical status
  • Potential effect of invasive procedure, surgery or dental work
  • The effects of common over-the-counter (OTC) medication interactions
  • The need for consistent intake of vitamin K-rich foods
  • Effects of alcohol intake
  • Appropriate action if diarrhoea or vomiting occurs

Some patients may consider the use of a Medic Alert bracelet/necklace and warfarin identification card.


References
  • Baker RI, Coughlin PB, Gallus AS et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Medical Journal of Australia 2004; 181(9):492-487. [fulltext]
  • Gallus AS, Baker RI, Chong BH,  et al. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Medical Journal of Australia 2000; 172: 600-605. [fulltext]

CLINICAL CASES

Toxicology Conundrum

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

2 Comments

  1. Hi Chris. First of all, thank you for the recent update on this topic.
    I am wondering about the target INR for patients with mechanical prosthetic heart valves. Is the 3.0 to 4.5 an updated Australian recommendation? The ESC and AHA recommend different targets. I am now slightly confused about what to follow in the Ozzy land and I would highly appreciate your guidance. Thank you.

    • Hi

      This is actually an old post reposted!

      I don’t think there have been any Australian national guidelines since 2000 (https://www.mja.com.au/journal/2000/172/12/consensus-guidelines-warfarin-therapy): which state that:

      “The American College of Chest Physicians recommends an INR of 2.0-3.0 for recent-model bileaflet or tilting disc valves, and 2.5-3.5 for older and more thrombogenic valves that have a caged ball or disc; patients with a newly placed bioprosthetic (tissue) valve require three months of warfarin and an INR of 2.0-3.0. However, in our view, because the evidence is incomplete, it remains prudent to retain a target range of 2.5-3.5 for most (“low-risk”) prosthetic valves while aiming higher (3.0-4.5) for older and more thrombogenic models, provided there is no contraindication.”

      I think most local Australian hospital protocols would now be more in line with ACCP/ AHA guidelines – as suggested by the 2013 MJA guidelines on warfarin reversal (https://www.mja.com.au/journal/2013/198/4/update-consensus-guidelines-warfarin-reversal):

      “For most warfarin indications, the target international normalised ratio (INR) is 2.0–3.0 (VTE and single MHV excluding mitral). For mechanical mitral valve or combined mitral and aortic valves, the target INR is 2.5–3.0.”

      The protocol at my hospital (currently) states for mechanical valves:
      – aortic: INR 2-3
      – mitral: INR 2.5-3.5

      Follow your local guideline! 🙂

      Cheers

      Chris

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