Warfarin and other oral anticoagulants

This chapter is relevant to Section Q2(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to "understanding of the pharmacology of anti-coagulants, anti-platelet drugs, thrombolytic drugs and anti-fibrinolytic drugs". It is specifically relevant to three SAQs:

None of these questions were especially inventive in their cruelty, making this a fairly straightforward exercise in pharmacology. Additionally, Question 21 from the first paper of 2014  asked the trainees to compare dabigatran and warfarin; and that seems like an excellent excuse to drag these substances under the light. They were also used in the Fellowship exam, also in the first paper of 2015 (Question 4), except the Second Part candidates were being asked about the various advantages and disadvantages of their use in atrial fibrillation.

  Warfarin Dabigatran
Class Vitamin K antagonist Direct thrombin inhibitor
Chemistry Coumarin derivative Small molecule polypeptide
Routes of administration Oral only Oral only
Absorption Rapidly absorbed
High oral bioavailablility (~ 100%)
Maximum blood concentration about 90 minutes after administration
Available as dabigatran etexilate, which is a pro-drug; dabigatran on its own is mch too polar to be absorbed effectively.
The exetilate is rapidly absorbed
High oral bioavailablility (~ 100%)
Maximum blood concentration about 90-180 minutes after administration
Solubility pKa 5.87; practically insoluble in water pKa 4.0, solubility in water is not very good
Distribution VOD=0.08-0.12, 99% protein-bound VOD=1.0L/kg; 35% protein-bound
Target receptor vitamin K epoxide reductase complex 1 Thrombin
Metabolism The more potent S-isomer is metabolised by hepatic CYP2C9 to 7-hydroxywarfarin, an inactive hydroxylated metabolite.
Another route is through reductases, into reduced metabolites (warfarin alcohols) with minimal anticoagulant activity.
Mainly renally excreted as unchanged drug; but about 20% is conjugated
with glucuronic acid to form acylglucuronides.
These conjugates are pharmacologically active and demonstrate almost identical properties of free, unconjugated dabigatran.
Elimination All of the metabolites ultimately make their way out in the urine. 92% of the radiolabelled dose is recovered in urine after 1 week.
Minimal free warfarin is renally excreted
80% renal excretion of unchanged drug
20% biliary excretion of acylglucouronides
Time course of action Terminal half-life of warfarin after a single dose is approximately 1 week;
Effective half-life ranges from 20 to 60 hours
Mean half-life is about 36-42 hours.
Half life = 12-14 hours
Mechanism of action Warfarin interferes with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the γ-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins.Vitamin K-dependent coagulation factors II, VII, IX, and X require γ-carboxylation for their procoagulant activity; thus warfarin therapy results in the hepatic synthesis of ineffective factors. Dabigatran interacts with the active site of thrombin, and acts as a competitive inhibitor of thrombin. It inactivates thrombin, including fibrin-bound thrombin.
This is a reversible reaction.
Some thrombin remains active to produce haemostasis.
Clinical effects Bleeding, skin necrosis, systemic microemboli, calciphylaxis Bleeding, insomnia, fever, periphral oedema
Single best reference for further information TGA PI document TGA PI document

For a bit of contrast, specific sources for this information that have some kind of scientific credibility include:

Chemical properties and chemical relatives of warfarin

Warfarin is a derivative of coumarin, presented as a racemate of two active enantiomers, of which the S-enantiomer is the most active. Coumarin is a benzopyrone commonly found in all sorts of plants, and it has no anticoagulant effects on its own. Warfarin itself is a derivative of a derivative, originating from dicoumarol (the clover-derived toxin responsible for millions of cattle deaths in the 1920s). There are multiple other coumarin-based rodenticides and anticoagulants (the two categories overlap to a surprising degree), of which the most familiar names will probably be acenocoumarol, ethyl biscoumacetate, phenprocoumon and the newer more lethal long-acting versions like bromadiolone and brodifacoum.  All of these drugs are related both by their chemical structure and by their mechanism of action, which is often referred to (inaccurately) as "vitamin K antagonism".

Non-warfarin oral anticoagulants

To call these drugs "NOACs" would be to show one's age, as they are no longer Novel by any means. "DOACs", or "Direct oral anticoagulants", might seem more accurate, as their mechanism is more direct than warfarin (i.e. they usually directly interact with the clotting cascade instead of trying to undermine it by sabotaging the synthesis of critical factors. Chemically, they are a rather diverse group. Dabigatran is a small molecule polypeptide similar to argatroban, whereas apixaban and rivaroxaban are oxazolidinones, chemically related to linezolid.

Pharmacokinetics of oral anticoagulants

For such a chemically diverse group of agents, they are remarkably similar in their pharmacokinetics. The reasons for this are an accident of marketing, and they make all of their properties highly predictable. All of these oral agents would have to be well absorbed orally and to have a decent oral bioavailability to be sold as tablets, which means they would all have to be highly lipid soluble (and poorly water soluble), and this lipophilicity would make them all highly protein bound. 

Name Absorption and bioavailability
Warfarin Rapidly absorbed
High oral bioavailablility (~ 100%)
Maximum blood concentration about 90 minutes after administration
Dabigatran Available as dabigatran etexilate, which is a pro-drug; dabigatran on its own is mch too polar to be absorbed effectively.
The exetilate is rapidly absorbed
High oral bioavailablility (~ 100%)
Maximum blood concentration about 90-180 minutes after administration
Rivaroxaban Rapidly absorbed
High oral bioavailability (~ 80-100%)
Maximum blood concentration about 120-240 minutes after administration
Apixaban Rapidly absorbed
Oral bioavailability ~50%
Maximum blood concentration about 90-200 minutes after administration

Absorption and bioavailability for most of these drugs is not a problem. Warfarin is rapidly and completely absorbed in the intestine, reaching its maximum concentration rather quickly. Unfortunately, because of its pharmacodynamics, this does not really translate into any sort of speed advantage when it comes to the onset of its effect. The only exception is dabigatran: itself, the drug  would not be absorbed at all unless it was presented as an etexilate: otherwise, it would be fully ionised at gastric and intestinal pH, making it very difficult for it to cross into the bloodstream. The etexilate however gets absorbed effortlessly, giving dabigatran an effective bioavailability of basically 100%.

 pKa for all of the oral anticoagulants is unfavourable to good water solubility. None of them are especially soluble in water, and none have a conveniently available mechanism of parenteral delivery. 

Name pKa and solubility Volume of distribution and protein binding
Warfarin pKa 5.87; practically insoluble in water VOD=0.08-0.12, 99% protein-bound
Dabigatran pKa 4.0, solubility in water is not very good VOD=1.0L/kg; 35% protein-bound
Rivaroxaban pKa 13; practically insoluble in water VOD=0.7L/kg; 95% protein-bound
Apixaban pKa 13.1; practically insoluble in water VOD=0.3L/kg; 87% protein-bound

Distribution and protein binding:  All oral anticoagulants have a fairly small volume of distribution, as most of them are highly protein-bound to plasma proteins. 

Metabolism and elimination for warfarin and rivaroxaban is mainly hepatic, resulting in inactive metabolites which are really excreted. In contrast, dabigatran and apixaban rely considerably (for dabigatran, entirely) on renal clearance.

Name Metabolism Elimination Half life
Warfarin The more potent S-isomer is metabolised by hepatic CYP2C9 to 7-hydroxywarfarin, an inactive hydroxylated metabolite.
Another route is through reductases, into reduced metabolites (warfarin alcohols) with minimal anticoagulant activity.
All of the metabolites ultimately make their way out in the urine. 92% of the radiolabelled dose is recovered in urine after 1 week.
Minimal free warfarin is renally excreted
Terminal half-life of warfarin after a single dose is approximately 1 week;
Effective half-life ranges from 20 to 60 hours
Mean half-life is about 36-42 hours.
Dabigatran Mainly renally excreted as unchanged drug; but about 20% is conjugated
with glucuronic acid to form acylglucuronides.
These conjugates are pharmacologically active and demonstrate almost identical properties of free, unconjugated dabigatran.
80% renal excretion of unchanged drug
20% biliary excretion of acylglucouronides
Half life = 12-14 hours
Rivaroxaban 66% is metabolised in the liver: a substrate of CYP3A4 and CYP2J2.
Inactive metabolites are excreted by biliary (50%) and renal (50%) routes
33% renal excretion of unchanged drug
66% hepatic metabolism
Half life = 7-12 hrs
Apixaban 33% is metabolised in the liver: a substrate of CYP3A4/5
Inactive sulfate conjugates are renally excreted
Hepatic metabolism, renal excretion and biliary secretion are each responsible for elimination of approximately one-third of dose.
33% renal excretion of unchanged drug
33% biliary and intestinal secretion of unchanged drug
33% hepatic metabolism
Half life = 12 hours

Mechanism of the anticoagulant effect

"Vitamin K inhibitors" are so named because it would probably be inconvenient to call them "vitamin K epoxide reductase complex inhibitors". They sure don't inhibit vitamin K in any meaningful sense. Vitamin K is an essential cofactor for the activation of factors II, VII, IX, and X. These factors are synthesized as precursors, and require post-translational carboxylation by gamma glutamyl carboxylase. Reduced vitamin K is required as a cofactor for this reaction. In its absence, the secreted factors are inactive, and the extrinisic pathway is affected.

The lack of factor 7 does not disturb the intrinsic pathway overmuch; or at least when it is tested using various clay-based surrogates, it is still possible to have a relatively normal clotting time. As the result, PT (and its normalised version, the INR) are used to monitor the effects of warfarin. Still, APTT can be affected, as it tests the function of factors II, X and IX. Kearon et al (1998) found that on average it tends to increase by about 16 seconds for every 1.0 increment in INR.

Direct thrombin inhibitors interact with the active site of thrombin and inactivate it. The result is that thrombin, including fibrin-bound thrombin, is not able to do any of its normal duties. We may recall that those duties are central to the clotting cascade. Thrombin is the final common step for both the intrinsic and the extrinsic pathway, as it is responsible for multiple essential steps:

  • It mediates the conversion of fibrinogen to fibrin.
  • It is also a potent stimulant of platelet activation
  • It enhances clot stability by activating the intrinsic pathway
  • It cleaves Factor VIII off from Von Willebrands Factor  

Dabigatran and argatroban attack this central factor, disabling the clotting cascade. PT and APTT do not work particularly well to monitor the effect, as they tend to remain normal while the patient is clinically fully anticoagulated. Di Nisio et al (2005) propose ecarin time as a better option.

Factor Xa inhibitors attack the pre-thrombin step in the clotting cascade. Factor Xa is the final form of Factor X, which is activated by either the extrinsic or intrinsic pathway in the course of the "amplification" stage of haemostasis.  Factor Xa then joins Factor Va to form the prothrombinase complex, which converts prothrombin into thrombin and the rest is a well-known cascade of events that leads to the formation of fibrin (Yeh et al, 2012, probably explain it better). In effect, to disable the function of prothrombinase would be the same as to disable thrombin itself. 

Reversal agents

Reversal of warfarin

Time. Literally waiting for some halflives to wear down may be enough. Patients with an elevated INR and no actual bleeding can be managed conservatively.  The problem with giving any dose of vitamin K is that eventually, you will probably need to rewarfarinise the patient, and it will be more difficult to titrate their dose if their bloodstream ends up being full of active factors, so waiting is often a reasonable option. However, that is too boring for the CICM examiners and they typically ask for the pharmacological measures. In other words, read the question carefully: this safe and reasonable approach may not score any marks.

Vitamin K (phytomenadione) is the reversal agent for warfarin. It increases the availability of the reduced substrate for the activation of clotting factors, which means you are not as reliant on the blocked epoxide reductase. Do not be fooled, the reductase remains blocked, but at least now you have some factors getting activated, which means normal clotting function will be possible as soon as the liver produces enough of them. That is the main caveat: this is not an instant solution. It is more rapid than just waiting for the warfarin to wear off, but the acutely bleeding patient may require something more.

Additionally, the dose matters. A non-urgent situation may call for a smaller dose, potentially delivered as a tablet. Oral Vitamin K has enough oral bioavailability to be effective in this setting. The college examiners laboured the point that this fat-soluble vitamin will require bile salts to absorb, which excludes some people from being able to benefit (eg. those who have undergone a cholecystectomy, or those with end-stage liver disease). A larger dose is called for if the patient is at considerable risk of bleeding to death. The IV formulation may be called in if time is of the essence or if the patient is unable to absorb it enterally; in which case it is still usually well tolerated apart from occasional case reports of anaphylaxis to the benzyl alcohol excipient (Aziz et al, 1996

Prothrombinex contains factors II, IX, X and low levels of factor VII. The dose is 25 – 50 IU/kg. This blood product concentrate rapidly restores the circulating levels of the necessary factors, and with a lot less infused volume than the next best option, which is...

 FFP of which the maximum dose is 15ml/kg. Consider that this could be 1000ml of a highly hyperoncotic solution, funnelled into the patient rapidly to reverse their coagulopathy. The outcome may be TACO, transfusion-associated circulatory overload. For this reason, and damn the expense, prothrombinex is a much better option in virtually every case.

References

Tran, Huyen, et al. "New oral anticoagulants: a practical guide on prescription, laboratory testing and peri‐procedural/bleeding management." Internal medicine journal 44.6 (2014): 525-536.

Yeh, Calvin H., James C. Fredenburgh, and Jeffrey I. Weitz. "Oral direct factor Xa inhibitors.Circulation research 111.8 (2012): 1069-1078.

Ansell, Jack, et al. "The pharmacology and management of the vitamin K antagonists." Chest 126.suppl 3 (2004): 204S-233S.

January, Craig T., et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary." J Am College Cardiol (2014).

Stangier, Joachim, and Andreas Clemens. "Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor." Clinical and Applied Thrombosis/Hemostasis (2009).

Kreutz, Reinhold. "Pharmacodynamic and pharmacokinetic basics of rivaroxaban." Fundamental & clinical pharmacology 26.1 (2012): 27-32.

Perzborn, Elisabeth, et al. "Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro." Thrombosis research 133.4 (2014): 671-681.

Scaglione, Francesco. "New oral anticoagulants: comparative pharmacology with vitamin K antagonists." Clinical pharmacokinetics 52.2 (2013): 69-82.

Frost, Charles, et al. "Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects." British journal of clinical pharmacology 75.2 (2013): 476-487.

Ward, Christopher, et al. "Practical management of patients on apixaban: a consensus guide." Thromb J 11.1 (2013): 27.

Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal." New England Journal of Medicine 373.6 (2015): 511-520.

Almegren, Mosaad. "Reversal of direct oral anticoagulants." Vascular health and risk management 13 (2017): 287.

Cohen, Oliver, Lucy-Anne Frank, and Susan Bradley. "Reversal of direct oral anticoagulants." British Journal of Hospital Medicine 79.5 (2018): C70-C73.

Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine373.25 (2015): 2413-2424.

Galliazzo, S., M. P. Donadini, and W. Ageno. "Antidotes for the direct oral anticoagulants: What news?." Thrombosis research164 (2018): S119-S123.

Keller, Christina, Axel C. Matzdorff, and Bettina Kemkes-Matthes. "Pharmacology of warfarin and clinical implications." Seminars in thrombosis and hemostasis. Vol. 25. No. 01. Copyright© 1999 by Thieme Medical Publishers, Inc., 1999.

Ufer, Mike. "Comparative pharmacokinetics of vitamin K antagonists." Clinical pharmacokinetics 44.12 (2005): 1227-1246.

Kearon, Clive, et al. "Effect of warfarin on activated partial thromboplastin time in patients receiving heparin." Archives of internal medicine 158.10 (1998): 1140-1143.

Di Nisio, Marcello, Saskia Middeldorp, and Harry R. Büller. "Direct thrombin inhibitors." New England Journal of Medicine 353.10 (2005): 1028-1040.

Hirsh, Jack. "Reversal of the anticoagulant effects of warfarin by vitamin K1.Chest 114.6 (1998): 1505-1508.

Aziz, Noorizan Abdul, et al. "Vitamin K1-induced anaphylactic shock." Journal of Pharmacy Technology 12.5 (1996): 214-216.