Warfarin

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rINN: Warfarin
Other Names
Coumadin, S-warfarin, R-warfarin
Pharmacological Information
Pharmacology Images
S-Warfarin Molecule at top, R-Warfarin at bottom
Warfarin.png
Web information on Warfarin
Metabolism & Interactions
S-warfarin primarily by CYP2C9 to 7-hydroxywarfarin. R-warfarin primarily by CYP1A2 to 6- and 8-hydroxywarfarin, by CYP3A4 to 10-hydroxywarfarin, and by carbonyl reductases to diastereoisomeric alcohols.
Mechanism of Action
Inhibition Vitamin K dependent carboxylation
Other Issues for Warfarin
Efficacy of warfarin is affected primarily when metabolism of S-warfarin is altered. Because of the low therapeutic index and complex metabolism it is necessary to dose based on the INR
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature
Other Wikis
Wikipedia on Warfarin (Less technical, ? quality control)

Warfarin is a coumarin oral anti-coagulant, named after the Wisconsin Alumni Research Foundation where Karl Link, its discoverer, worked. Investigations in 1922 into the cause of haemorrhage in cattle from sweet clover silage ingestion by Frank Schofield, a Canadian veterinarian, showed a chemical was involved. In 1940, Karl Link helped isolate the coumarin analogue responsible. In the USA, it is commonly known as Coumadin. It acts through inhibiting vitamin K dependent carboxylation of clotting factors II, VII, IX and X all of which are produced in the liver.

The response to warfarin is monitored by measuring the prothrombin time, a blood test that measures the speed of clotting under standard conditions. As different laboratories use different reagents, adjustments can be made to arrive at an International normalised ratio (INR), a standardised index of how long blood takes to clot after prothrombin activation.

Contents

Indications

Flag of the United Kingdom.png

British Guidelines on the use of Warfarin were last updated in 2011[1]


Effectiveness

  • In certain indications such as mechanical heart valves or in those with advanced renal disease it is the oral anticoagulant of choice and is likely to remain so.
  • In other indications such as non-valvular atrial fibrillation it is in equipoise with DOACs for most of the population in terms of clinical effectiveness but not convenience and once patents expire resources
  • Long term use is associated with a reduced risk of malignancy (lower age- and sex-adjusted incidence rate ratio, 0.84; 95% CI, 0.82-0.86)[2]. This may be through its actions on vitamin K dependent growth arrest-specific protein 6[3]. If this is the correct mechanism of action DOACs will not protect against malignancy and a 25% increase in malignancy risk in those over 50 years of age would have to be considered in net effectiveness.

Starting Warfarin

Several regimes for starting Warfarin exist. It is not possible to predict the eventual daily requirement of Warfarin from inspection of the patient and their metabolism in all patients but genomic based algorithms have been approved in the USA[4]. This does not mean they have any advantages in the first 4 weeks of therapy[5]. The only predictive factors for eventual dose in one study were the sex and the INR after 2 weeks on 2mg/day.(see Talk). A loading dose is commonly used on the first few days,[6] but this very commonly produces overshoots and swings. In recent years, a more leisurely approach has been introduced. See also Warfarin tables. The elderly benefit from a 5mg loading regime compared to a 10mg regime[7]

Warfarin increases coagulability in early stages of warfarin treatment due to disproportionate inhibition of protein C and S (both are anti-coagulant factors). This can result in adverse sequelae such as warfarin necrosis. Therefore, where there is an active clotting process such as a DVT, the first few days of warfarin treatment should be overlapped with another anti-coagulant such as heparin. Heparin is also more appropriate when an immediate anti-coagulant effect is required.

Genetic testing

  • Never going to be economically viable in low risk of haemorrhage patients as clinically would prolong life of an otherwise fit 69 year old man in atrial fibrillation by no more than one day[8]
  • May be useful for those that will need low warfarin dose and where other parameters such as race not practicable in determining regime.

Keeping People in Range With Warfarin

LogoKeyPointsBox.pngWarfarin produces hypercoagulability not reflected in INR in the first few days and in VTE you should cover with heparin for about 3 days after therapeutic INR reached

There is general consensus that with warfarin the total dose taken in a week is the way to go. You have to use an algorithm validated for your country and population. For example in the UK there are 3 computer programs commonly available:

  • RAT
  • INR Star
  • DAWN

However a good paper algorithm is as good as a computerised system[9]. RE-LY showed[10] that adherence to a simple warfarin dosing algorithm predicts improved TTR. The algorithm used in RE-LY is reproduced here for desired INR 2.0-3.0 as it has been internationally validated:

  1. Dose is calculated on a weekly, rather than daily, basis
  2. Increase, decrease, or no change in the weekly warfarin dose based only on the current INR.
    • no change for INR 2.00 to 3.00
    • +15% change for INR 1.50 or less
    • +10% for INR 1.51 to 1.99
    • -10% for INR 3.01 to 4.00
    • For INR 4.00 to 4.99, hold the dose for 1 day and then reduce it by 10%
    • For INR 5.00 to 8.99 withold dose until the INR was therapeutic and then decreased by 15%
  3. Weekly INR monitoring was recommended for out-of-range INR values.

Monitoring

UKMI recommend [1] baseline measurement of prothrombin time (PT) and activated partial thromboplastin time (APTT). They also recommend platelet count and LFTs, if possible, but this should not delay treatment. Once the INR level is within therapeutic range, INR should be monitored weekly until stable, and then at longer intervals (up to every 12 weeks). However, if there are any changes in the patients condition (e.g. liver disease, illness) more frequent monitoring may be required.

Interactions

LogoKeyPointsBox.pngSelected common potentiation interactions:

These are essentially predictable from the known pharmacology of the drug but to use this knowledge to predict you need to know a fair bit of pharmacology of not only warfarin but also of other drugs and even foods. The short term risk is with potentiation so this is the most important area with new or intermittent therapy. Many find it simpler to learn the common interactions and of course this should be done for a selected few drugs and food substances by every prescribing doctor. A white list approach is also useful, so the knowledge that a short course of amoxicillin does not significantly impact on the INR is useful in routine prescribing and deciding that monitoring not indicated.


Determining the time spent in the desired range(TTR)

This is a non-trivial computation. Automated systems should include an algorithm to estimate this for comparison and audit purposes.

Adjusting Dose

Adjustments should not be made on the basis only of a current result and current dose. Adjustments should usually be rather small.

Measurement should occur when there has been time for the adjustment to accomplish a change in state - after an adjustment of half a mg per week, a measurement in 2 weeks time will have seen only one additional mg of drug given or withheld. Measurements should be frequent while the state is changing.

Deming's work on process control is highly relevant to considering the frequency of testing, and the size of response to the results.

Risks

The risk of bleeding increases exponentially with the INR. And it seems adult trauma patients using warfarin at the time of their injury are at increased risk of poor outcomes compared with those not taking the anticoagulant. The odds ratio of increased mortality is 1.72(95% CI, 1.63-1.81). This association is not really explained by pre-existing pathology[11]. There is little doubt that prescribers should consider using a well validated risk score such as the HAS-BLED score. Issues such as some types of substance abuse that are not common enough to be accounted for in such scores are important[12].

Time in therapeutic range (TTR)

Time in therapeutic international normalized ratio range is a useful measure as both under anticoagulation and over anticoagulation are associated with adverse outcome. One study found that high-quality anticoagulation was associated with[13]:

  1. No use of alcohol
  2. Functional and cognitive ability to take medications as prescribed
  3. Presence of family support
  4. Erratic dietary vitamin K intake
  5. Sex
  6. Duration of anticoagulation treatment


And Aspirin?

Warfarin and Aspirin do not do the same job.

LogoWarningBox4.pngWarfarin + Aspirin: This is at least almost always a bad idea

Random aspirin for patients on warfarin is warned against in the patient-carried record booklet and is clearly a bad idea. However there remains space for discussion over combining aspirin and warfarin in certain high potential benefit patients. It is not and should not be a common occurrence, and every instance should have a clear rationale. See therapeutic bleeding risk for fuller context of the issues.

Aspirin combined with warfarin at therapeutic INR has a moderate harm ratio of one serious upper GI bleed per 184 patient years of treatment.[14]. It is therefore likely to be beneficial relative to the particular harm of bleeding in selected indications such as after a myocardial infarction [15] and acute coronary syndromes.[16] In practice, given other harms and as the evidence base after myocardial infarction is distinctly mixed, [17][18][19] unless your patient actually has characteristics of the recruitment population of the successful trials, a prescriber is likely to be doing net harm. Thus, few would consider using this proven therapeutic combination in the majority of elderly patients and, indeed, dangerous extrapolation from the clinical trials to subgroups excluded from the trials such as the very old, patients in renal failure and non-compliant is to be deprecated.

In patients with atrial fibrillation and ischaemic stroke the SPORTIF trials show that aspirin and warfarin is likely to be ineffective or harmful with no reduction in stroke, systemic embolism, or myocardial infarction compared to warfarin alone and an incremental rate of major bleeding of 1.6% per year over warfarin alone[20] In peripheral vascular disease we also know the combination is likely to be ineffective or harmful[21] being no more effective than antiplatelet therapy alone in preventing major cardiovascular complications and associated with an increase in life-threatening bleeding.

Triple therapy

LogoWarningBox4.pngWarfarin + Aspirin + another antiplatelet: This is at least almost always a very bad idea, but a fair one when the patient has acute or subacute unstable coronary arteries

Unhappily the safety of concomitant aspirin, clopidogrel, and warfarin therapy after percutaneous coronary intervention is a function of the warfarin therapy with a hazard ratio of 5 and number needed to harm of 7[22]. Short term triple therapy in those with a strong indication to be on warfarin is accepted, with until 2016 atrial fibrillation being one of these strong indications, as overall all cause mortality is reduced[23]. PIONEER AF-PCI defined that after PCI with stent placement either low dose rivaroxaban combined with dual antiplatelet therapy or moderate dose rivaroxaban combined with a P2Y12 inhibitor was superior to the then standard of care which was 'triple' therapy with warfarin and dual antiplatelet therapy[24]. Accordingly a move away from warfarin in this indication is to be expected. ESC consensus guidelines on what to do in patients on prior antithrombotic therapy for atrial fibrillation, who present with acute coronary syndrome and/or undergo percutaneous coronary intervention/coronary stenting exist. [25] Essentially the antiplatelet agents are given as well as the anticoagulant for the period of highest thrombotic risk with some modification if the risk of haemorrhage is high. In acute coronary syndrome, standard therapy is used with oral anticoagulation generally being withheld while INR > 2.0. Triple therapy is now recommended for 3 to 6 months, possibly longer in those at highest coronary artery disease risk. However the INR control must be tight between 2 to 2.5. It is noted that those at highest risk of embolic event (eg metal heart valves) INR up to 3 does not contraindicate radial artery access PCI. For elective metal stents offer 1 month of triple therapy, elective 'olimus coated stents get 3 months triple therapy and to 12 months an antiplatelet and anticoagulant, while elective paclitaxel coated stents get 6 months triple therapy, then up to 12 months an antiplatelet and anticoagulant. This last regime also applies to all stents used in primary PCI. If risk of haemorrhage is high, use bare metal stents in all indications and up to 4 weeks of triple therapy, then in elective patients revert to warfarin but in primary PCI acute coronary syndrome patients give 6 months antiplatelet and anticoagulant before reverting to anticoagulation alone.

Anticoagulation/Warfarin and surgical or medical procedures

There is a balance between risk of the condition the anti-coagulation is to prevent, and of bleeding, which should be individualised for various conditions, procedures and patients. Conferring is often indicated and the problem should be presented to the patient as being an intelligent balancing of risks. See main article anticoagulation and procedures
Relation between INR and risk bleeding (note log scale)

Overdose

See Warfarin toxicity

Can be intentional (e.g. suicide attempt) or accidental (ingestion by child, or mistaking different coloured tablets). Often iatrogenic due to misjudged dosage, inadequate monitoring, or failure to appreciate interactions with other drugs.

Can be rapidly reversed with FFP or specific recombinant factors, e.g. Beriplex™, but this is a relatively short-lived effect as the half-life of many of these factors is in the order of several hours. More lasting reversal requires vitamin K, but this can take 8-12 hours to become effective.

If the level is moderately high, and the indication for anticoagulation remains good, using a small dose of vitamin K may be preferable to a large one.

Alternative anticoagulant drugs

In the UK phenindione is the usual second choice coumarin. It is suitable for use in the few patients with definite allergy to Warfarin. A third coumarin is nicoumalone.

In Holland phenprocoumon and acenocoumarol are used rather than warfarin. They differ subtly in pharmacokinetics which may affect the timing of monitoring. The usual drug in Germany is phenprocoumon.

Non-coumarin oral anticoagulants

Rivaroxaban, apixaban and dabigatran etexilate are under trial. The last was recently introduced for postoperative prophylaxis (studies in Lancet 2007) and is reported to have few interactions and not require routine monitoring. A previous drug of this type was withdrawn due to toxicity.

External Links

References

  1. BCSH Guidelines on oral anticoagulation (warfarin): forth edition –2011 update
  2. Haaland GS, Falk RS, Straume O, Lorens JB. Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years. JAMA internal medicine. 2017 Nov.(Print-Electronic) (Link to article – subscription may be required.)
  3. Kirane A, Ludwig KF, Sorrelle N, Haaland G, Sandal T, Ranaweera R, Toombs JE, Wang M, Dineen SP, Micklem D, Dellinger MT, Lorens JB, Brekken RA. Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis. Cancer research. 2015 Sep; 75(18):3699-3705.(Print-Electronic) (Link to article – subscription may be required.)
  4. Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. Journal of the American College of Cardiology. 2011 Feb 1; 57(5):612-8.(Link to article – subscription may be required.)
  5. Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM, Yale S, Mohler ER, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH. A pharmacogenetic versus a clinical algorithm for warfarin dosing. The New England journal of medicine. 2013 Dec 12; 369(24):2283-93.(Link to article – subscription may be required.)
  6. SIGN Guidelines Table on Starting Warfarin
  7. Mahtani KR, Heneghan CJ, Nunan D, Bankhead C, Keeling D, Ward AM, Harrison SE, Roberts NW, Hobbs FD, Perera R. Optimal loading dose of warfarin for the initiation of oral anticoagulation. The Cochrane database of systematic reviews. 2012; 12:CD008685.(Epub) (Link to article – subscription may be required.)
  8. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Annals of internal medicine. 2009 Jan 20; 150(2):73-83.
  9. Nieuwlaat R, Hubers LM, Spyropoulos AC, Eikelboom JW, Connolly BJ, Van Spall HG, Schulze KM, Cuddy SM, Stehouwer AC, Schulman S, Connolly SJ. Randomised comparison of a simple warfarin dosing algorithm versus a computerised anticoagulation management system for control of warfarin maintenance therapy. Thrombosis and haemostasis. 2012 Dec; 108(6):1228-35.(Link to article – subscription may be required.)
  10. Van Spall HG, Wallentin L, Yusuf S, Eikelboom JW, Nieuwlaat R, Yang S, Kabali C, Reilly PA, Ezekowitz MD, Connolly SJ. Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation. 2012 Nov 6; 126(19):2309-16.(Link to article – subscription may be required.)
  11. Dossett LA, Riesel JN, Griffin MR, Cotton BA. Prevalence and Implications of Preinjury Warfarin Use: An Analysis of the National Trauma Databank. Archives of surgery (Chicago, Ill. : 1960). 2011 Jan 17.(Epub ahead of print) (Link to article – subscription may be required.)
  12. Efird LM, Miller DR, Ash AS, Berlowitz DR, Ozonoff A, Zhao S, Reisman JI, Jasuja GK, Rose AJ. Identifying the risks of anticoagulation in patients with substance abuse. Journal of general internal medicine. 2013 Oct; 28(10):1333-9.(Link to article – subscription may be required.)
  13. Costa GL, Lamego RM, Colosimo EA, Valacio RA, Moreira Mda C. Identifying potential predictors of high-quality oral anticoagulation assessed by time in therapeutic international normalized ratio range: a prospective, long-term, single-center, observational study. Clinical therapeutics. 2012 Jul; 34(7):1511-20.(Link to article – subscription may be required.)
  14. Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM, Andersen M, Lassen AT. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ (Clinical research ed.). 2006 Oct 7; 333(7571):726.(Link to article – subscription may be required.)
  15. Warfarin or aspirin or both after myocardial infarction Bandolier 02/14/06 update accessed 1/10/06
  16. van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002 Jul 13; 360(9327):109-13.(Link to article – subscription may be required.)
  17. Herlitz J, Holm J, Peterson M, Karlson BW, Haglid Evander M, Erhardt L. Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction; the LoWASA Study. European heart journal. 2004 Feb; 25(3):232-9.(Link to article – subscription may be required.)
  18. Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P. Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation. 2002 Feb 5; 105(5):557-63.
  19. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. The New England journal of medicine. 2002 Sep 26; 347(13):969-74.(Link to article – subscription may be required.)
  20. Flaker GC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, Halinen MO, Horrow J, Halperin JL. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. American heart journal. 2006 Nov; 152(5):967-73.(Link to article – subscription may be required.)
  21. Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, Sussex B, Liu L, Guzman R, Cina C, Crowell R, Keltai M, Gosselin G. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. The New England journal of medicine. 2007 Jul 19; 357(3):217-27.(Link to article – subscription may be required.)
  22. DeEugenio D, Kolman L, DeCaro M, Andrel J, Chervoneva I, Duong P, Lam L, McGowan C, Lee G, DeCaro M, Ruggiero N, Singhal S, Greenspon A. Risk of major bleeding with concomitant dual antiplatelet therapy after percutaneous coronary intervention in patients receiving long-term warfarin therapy. Pharmacotherapy. 2007 May; 27(5):691-6.(Link to article – subscription may be required.)
  23. Ruiz-Nodar JM, Marín F, Hurtado JA, Valencia J, Pinar E, Pineda J, Gimeno JR, Sogorb F, Valdés M, Lip GY. Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation implications for bleeding risk and prognosis. Journal of the American College of Cardiology. 2008 Feb 26; 51(8):818-25.(Link to article – subscription may be required.)
  24. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, Birmingham M, Ianus J, Burton P, van Eickels M, Korjian S, Daaboul Y, Lip GY, Cohen M, Husted S, Peterson ED, Fox KA. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. The New England journal of medicine. 2016 Nov.(Print-Electronic)
  25. Lip GY, Huber K, Andreotti F, Arnesen H, Airaksinen KJ, Cuisset T, Kirchhof P, Marín F. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/ stenting. Thrombosis and haemostasis. 2010 Jan; 103(1):13-28.(Link to article – subscription may be required.)
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