Friday 23 June, 2006

How to reverse warfarin

Posted in Emergency, Emergency Dept., General Practice, Medicine, Michael Tam, Wards at 16:44 by Michael Tam

Index: Anticoagulation :: Printer friendly

Original article by: Michael Tam

Resources

Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis [Position Statement]

Warfarin is an increasingly commonly used medication in Australia. It is invaluable as an oral anticoagulant and until the oral direct antithrombin agents (e.g., ximelagatran) (1) are released, it is the only oral medication that can provide “therapeutic” levels of anticoagulation.

Unfortunately, with its increased use, over-anticoagulation has become a common presentation to the emergency department. A high INR with or without bleeding complication is not an uncommon scenario for hospital inpatients as well (IMHO due in part due to poor warfarin initiation and management).

Guideline for raised INR (adapted from the consensus guidelines) (2):

Clinical setting Action
INR higher than the therapeutic range but < 5.0; bleeding absent Lower the dose or omit the next dose of warfarin. Resume therapy at a lower dose when the INR approaches therapeutic range.

If the INR is only minimally above therapeutic range (up to 10%), dose reduction may not be necessary.

INR 5.0–9.0; bleeding absent Cease warfarin therapy; consider reasons for elevated INR and patient-specific factors.

If bleeding risk is high, give vitamin K (1.0–2.0 mg orally or 0.5–1.0 mg intravenously).

Measure INR within 24 hours, resume warfarin at a reduced dose once INR is in therapeutic range.

INR > 9.0; bleeding absent Where there is a low risk of bleeding, cease warfarin therapy, give 2.5–5.0 mg vitamin K orally or 1.0 mg intravenously. Measure INR in 6–12 hours, resume warfarin therapy at a reduced dose once INR < 5.0.

Where there is high risk of bleeding, cease warfarin therapy, give 1.0 mg vitamin K1 intravenously. Consider Prothrombinex-HT (25–50 IU/kg) and fresh frozen plasma (150–300 mL), measure INR in 6–12 hours, resume warfarin therapy at a reduced dose once INR < 5.0.

Any clinically significant bleeding where warfarin-induced coagulopathy is considered a contributing factor Cease warfarin therapy, give 5.0–10.0 mg vitamin K intravenously, as well as Prothrombinex-HT (25–50 IU/kg) and fresh frozen plasma (150–300 mL), assess patient continuously until INR < 5.0, and bleeding stops.

or

If fresh frozen plasma is unavailable, cease warfarin therapy, give 5.0–10.0 mg vitamin K intravenously, and Prothrombinex-HT (25–50 IU/kg), assess patient continuously until INR < 5.0, and bleeding stops.

or

If Prothrombinex-HT is unavailable, cease warfarin therapy, give 5.0–10.0 mg vitamin K intravenously, and 10–15 mL/kg of fresh frozen plasma, assess patient continuously until INR < 5.0, and bleeding stops.

Prevention: reduce the risk of high INR

The best way to avoid warfarin reversal is to try to prevent the scenarios that lead to a high INR. The following should be considered:

  • As per my article on “how to start warfarin therapy” avoid loading doses of warfarin and initiation schemes designed to reach an INR of 2.0 as quickly as possible for discharge; it is a sure fire recipe for a high INR one to two weeks post discharge in the community (3).
  • Patience is importance – unless there is a very good reason, INR need only be tested no more than once a week and each dosage change should be small and well considered.
  • Continuing patient education is important.
  • Ensure medication compliance before increasing the dose.
  • Aim for an INR of 2.5 (the therapeutic range for most conditions is between 2.0 and 3.0 and for mechanical heart valves 2.5 to 3.5 – either way, aiming for 2.5 covers both bases).

There has recently been some discussion about low-intensity warfarin therapy with a target INR of 1.5 to 2.0. However, the “Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators” found in 2003 that low-intensity warfarinisation was not as good as standard warfarinisation and did not reduce the rate of bleeding complications (4). As such this practice cannot be recommended.

What to do for INR < 3.5

The increased risk of bleeding is around twice that of an INR from 2.0-3.0. Keep this in perspective. If there is a 1% per annum risk of serious bleed, an INR of 3.5 means approximately 2% per annum risk; or a miniscule risk that they will have a serious bleed within the next week.

What you will do somewhat depends on the scenario.

  • If someone’s INR is known to fluctuate up and down but has otherwise been fairly stable on a particular dose, then it would not be unreasonable to keep them on the current dose and repeat the INR in a week.
  • Similarly, if there is a good reason for the increase (e.g., commencement of a short course of oral antibiotics), then there is no particular reason to change the existing dose.
  • If it appears that the raised INR is likely to remain raised on their current maintenance dose of warfarin, then it would be reasonable to reduce the regular dose to what is estimated to be the correct dose (example, approximately a 10-20% dose reduction) and then recheck the INR in 1-2 weeks.
  • Avoid the (IMHO, bad) practice of withholding doses at this INR range.

What to do for INR 3.5 – 5.0

The risk of bleeding is up to quadrupled from an INR of 2.0-3.0. Again keep this in perspective. The absolute risk of a serious bleed in the next few days to week when you will be managing it is very low if the patient doesn’t have risk factors.

  • Consider precipitating factors, e.g., drug interactions, medication compliance issues. If the INR of 5.0 was unexpected, then it may be reasonable to repeat the INR daily for the next few days to monitor the trend.
  • If the patient is otherwise relatively stable, reduce the dose to what would be expected to be the “correct” dose (approximately 20% dose reduction) and check again in a week.
  • For some patients who may have higher risk, it is reasonable to repeat the INR on a daily basis and withholding warfarin until the INR falls to below 3.5. At that time, restart at what is estimated as the appropriate dose.

What to do for INR 5.0 – 9.0

The risk of acute bleeding is now raised significantly enough that warfarin should be ceased immediately. The cause of the raised INR should be carefully considered.

  • I would advise daily INRs and restarting warfarin once the INR is below 3.5. The dose chosen should be the estimated maintenance dose.
  • Try to avoid the inevitable INR “undershoot” by restarting warfarin sooner rather than later once the INR trend is clearly downwards.
  • If bleeding risk is high, give a low dose of vitamin K:
    • 1-2 mg orally or;
    • 0.5-1.0 mg intravenously.
  • Avoid high doses of vitamin K as it results in “resistance” during re-warfarinisation. Even a small dose intravenously often leads to completely reversal.
  • If INR is sub-therapeutic after reversal, then remember to provide alternate forms of anticoagulation (e.g., with low molecular weight heparin) if indicated.

What to do for INR > 9.0

There is marked increased risk for acute bleeding at this level.

  • Again, consider why the INR is raised.
  • Immediately cease warfarin therapy.
  • Where bleeding risk is low, give vitamin K:
    • 2.5-5.0 mg orally or;
    • 1 mg intravenously.
  • Where bleeding risk is high:
    • vitamin K 1 mg intravenously or;
    • Prothrombinex 25-50 units/kg intravenously or;
    • fresh frozen plasma (FFP) 150-300 mL (1 unit) intravenously.
  • Check the INR in 6 hours and monitor with daily INRs for the next few days.
  • Restart warfarin at the estimated appropriate dose for maintenance when the INR < 5.0.

How to give intravenous vitamin K

In the hospitals I worked in, phytomenadione (vitamin K) (Konakion) tablets were simply not stocked. However, intravenous vitamin K is almost universally available.

Be aware that intravenous vitamin K (also Konakion) comes in both paediatric (2 mg/0.2 mL) and adult (10 mg/1 mL) sizes.

Firstly, insert an intravenous cannula, preferable 21 gauge or larger. Make sure that the line is patent by giving it a flush with sterile saline.

Secondly, ensure that resuscitation equipment is available as intravenous vitamin K can provoke anaphylactic reactions.

Now, the usual dose for intravenous vitamin K is 1 mg, or 0.1 mL. That is impossible to infuse slowly. So:

Draw 10 mg (1 mL) of vitamin K into a 10 mL syringe

Then draw up sterile 0.9% NaCl solution into the syringe to make up 10 mL

Slowly infuse 1 mg (1 mL) of the diluted solution through the cannula over 30-60 seconds

Afterwards, flush with 5-10 mL of saline – again, slowly over 30-60 seconds. For larger doses of vitamin K, infuse the appropriate amount. When diluted up to 10 mL, the concentration of vitamin K is 1 mg/mL.

The INR should always be checked after 6 hours to ensure adequate reversal of anticoagulation.

Reference articles

(1) Brighton TA. The direct thrombin inhibitor melagatran/ximelagatran. MJA 2004; 181: 432–437 [download PDF :: 344 Kb]

(2) Baker RI., Coughlin PB., Gallus AS., et al.; the Warfarin Reversal Consensus Group. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis [Position Statement]. MJA 2004; 181 (9): 492-497 [download PDF :: 183 Kb]

(3) Tam M. How to start warfarin therapy [electronic article]. The Medicine Box. Last updated 20 July 2006. [Link]

(4) Kearon C., Ginsberg JS., Kovacs MJ., et al.; Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. New England Journal of Medicine. 349(7):631-9, 2003 Aug 14 [download PDF :: 910 Kb]

Please read the disclaimer

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16 Comments »

  1. Michael Tam said,

    Unfortunately, it appears that warfarin will be staying with us for a while. The new direct antithrombin drugs (melagatran/ximelagatran) which had reached human therapeutic trials were withdrawn from the market by AstraZeneca due to evidence of hepatotoxicity (1).

    Reference article

    (1) AstraZeneca Decides to Withdraw Exanta [press release]. AstraZeneca Website. 14 February 2006. http://www.astrazeneca.com/pressrelease/5217.aspx

  2. april Dilorenzo said,

    I am on coumidin for a pulminary embolisim in my left lung after having surgery and i am currently on 20 mg of coumidin every day and 80 mg of lovenox 2x per day is this normal

  3. Michael Tam said,

    Firstly: please read the disclaimer

    I am not your regular medical practitioner and I do not have all the clinically relevant information here. The following is my opinion on the information you have provided me.

    Warfarin (Coumadin) would be the appropriate oral anticoagulant for treatment of a pulmonary embolus. It would be common for anticoagulation to be achieved in the short term with enoxaparin sodium (Lovenox). A dose of enoxaparin sodium 80 mg twice daily would be appropriate if your weight was approximately 80 kg.

    As for your dose of warfarin, it does seem unusually high. You should be regularly monitored with blood tests for INR (international normalised ratio) and your target INR is between 2.0 and 3.0. Once the INR has reached the therapeutic range, the enoxaparin should be ceased.

  4. Muzzammal k qureshi said,

    Warfarin (Coumadin)
    It is usefull artical for a G.P
    thank

  5. Sneha Tamhankar said,

    My brother, aged 57 is a stroke patient for last 30 years with left side paralysed (at the age of 27). Now 4 months back he had symptoms of stroke (TIA – transient ischemic attacks) and was admitted to hospital, was on injection heparin for few days. Due to very high INR (it was between 12-15 at times) he was given Vit K injection, the very next day he suffered a severe storke. TPA treatment was given in time (within 3 hours of stroke) and his life was saved. He was in ICU and Tracheostomy was done & feeding tube (ryles tube) was inserted. After that he suffered one more severe stroke and unfortunately the next day vascular surgeon had to operate him for radial artery annurism on his wrist. After the operation, he is still in semi-conscious state for last 3 months. He has been advised to maintain 1/2 mg daily dose of warfarin to maintain INR between 2-3. Is his life at risk again?

  6. Michael Tam said,

    Dear Sneha,

    The underlying risk factors that led to your brother having multiple strokes are likely to be still there. Warfarin reduces the risk of a subsequent event by approximately 70%. From the story that you have given, the possibility of further cerebrovascular events is high even with optimal medical treatment.

    Best regards,
    Michael Tam

  7. Sneha Tamhankar said,

    Thanks a lot for your prompt response and you opinion !!

  8. Anica said,

    Hi
    I have a friend who broke her leg and while she was in cast complained of chest pain, she was taken ro ED and there she was given heparin and discharged as low risk. Two weeks later she again became extremely SOB and chest pain, taken to After Hours they admitted her to Ed and discovered two pulmonary embolisms, discharged a week later with inr not exactly controlled. Friend departed for France and under went scan of whole body and another clot discovered in fractured leg, pt was given heparin injection to admnister a home for a while as well as warfarin dosis, pt then had very high inr >5 later stabilised ,but pt has just been admitted with lower back pain and apparently unreadable INR / >9, scan cannot explain lower back pain. pt says she was given Vit K and be observed over night.
    Could there be another underlying problem PT is 25 slightly obese family history of Anuerism and Embolism and Hypothyroidism
    There seems to be a mismanagement of meds by both hospital staff and pt.
    What are the precautions for efficient management of pt,She has ben misdiagnosed in NZ twice by GP and Ed staff, now in france there also sems difficulty in effiecient treatment.
    Sincerly
    Anica

  9. Michael Tam said,

    There are many complicated issues here and I cannot make a valid comment without the complete record of the recent history.

    Of the information provided, there is nothing to suggest another underlying issue. The most likely sequence of events is that the lower limb fracture resulted in a deep venous thrombosis (DVT) in the leg. This subsequently resulted in the pulmonary embolism.

    Certainly, there appears to be a continuing problem with INR management. It should be noted that it is not the role of emergency services to manage warfarin dosing. INR management is best performed though the continuing care of a single family medicine physician or general practitioner.

  10. Michelle said,

    In 1995 my mother had a mild stroke and has since suffered from ME.

    My mom is 66 and has been on Warfarin since she had a Bi Fem Arterial bypass in October 2000 with lots of complecations and having to re do the by pass.

    In April 2008 she suffered bleeding with an INR of 7.7. She was taken off warfarin and put on Heparin (sp) as she had become Warfarin Toxic (it had built up) and spent a month in hospital with a mostly unreadable Blood Pressure which spent alot of time at around 60/40.
    She was put back on warfarin and in may 2008 was rushed to hospital with an ustoppable blood nose and again, no BP. She was taken off Warfarin again.

    The hospital has now decided that she needs to be back on Warfarin as they are concerned that she will clot and suffer a stroke.

    What can i do to lower the risks and manage the chances of her becoming Warfarin toxic again?

    She drinks 1 – 3 glasses of red wine per evening and uses arnica fro cramps.

  11. Michelle said,

    PS: We are in Cape Town, South Africa

  12. Michael Tam said,

    Dear Michelle,

    It sounds like there have been problems with the monitoring of warfarin in the community. Your mother will need a good General Practitioner who can help monitor her INR.

    The INR should probably be performed regularly (every few days to a week) until it is clear that it has stabilised on a particular dose of warfarin. After that, once monthly INRs (or fortnightly initially if there are still concerns) would be appropriate.

    Apart from taking the warfarin religiously it would be important that she has a stable consumption of vitamin K rich foods (e.g., green vegetables) as well as a consistent amount of alcohol.

  13. Jonny said,

    Hi, I just wanted to ask you for your opinion how you would treat a patient with a mechanical heart valve who is
    a.)actively bleeding or requiring emergency surgery.
    b.) in case the Warfarin reversal is fully (FFP/Prothrombinex/Vit K to an INR <2) to stop the bleeding/make the patient operable would you start Enoxaparin,Heparin or nothing – considering the patient nevertheless might require surgery?
    c.) How would you treat a mechanical heart valve patient on Warfarin for an elective Surgery?

    I thought IV Heparin might be a good option, however stopping the Heparin prior to surgery and restarting it after surgery is gonna cause problems for the valve though?

    Thank you very much for your answers!

  14. Michael Tam said,

    Dear Jonny,

    (A) If the patient is anticoagulated and actively bleeding then the anticoagulation will need to be reversed. Where the anticoagulation is for a mechanical heart valve, FFP for reversal would be preferable as there will not be a resistance to re-anticoagulation (compared to high dose intravenous vitamin K).

    If emergency surgery is required (but the patient is not haemorrhaging), it depends on the type of surgery (some low risk surgery can be performed with the patient anticoagulated, though this is dependent on the surgeon’s “comfort zone”). If reversal of anticoagulation is required, then it would make sense to use FFP and then re-anticoagulate after surgery (initially with LMWH or UFH).

    (B) Once the source of bleeding is controlled, then yes, full re-anticoagulation should be performed as soon as possible. The choice of agent to use would depend on the immediate and short term expectation of therapy.

    (C) See my article on how to stop warfarin for surgery

    Best regards,
    Michael Tam

  15. Mark said,

    I am late 40s, MS progrssive in bed most of time, got clot right lower lung, started injections of said drug and a pill of another kind. INR was 6.7 Tuesday and started to bleed in urin yesterday and today went to ER, was at 6.4 and they gave plasma two bags and stopped med but no K given. Sent home and still bleeding and to see Doct Friday in about less 24 hours now but scared of urinating blood. Insurance would not let them keep and monitor me overnight. I am alone at home just worried. Anyon else in this boat?

  16. LISA said,

    My mothers inr was a 12 and is in the icu. She has a home health care nurse that comes out to check this every week and on last monday they checked it and it was low 1.3 and within 5 days it was a 12 how can that go to a 12 that fast. Her dose was 1mg everyday except tuesday and saturday she gets 2mg. Thanks


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