A brief summary of oral anticoagulant agents

By Alex Yartsev - 11/10/2015

This is meant as a brief revision of oral anticoagulant drug pharmacology. The college used these agents (and their relative novelty) against the candidates in Question 4 from the first paper of 2015. Specifically, the question was in part regarding the various advantages and disadvantages of these agents in the management of AF, which seems to be a very "physicianly" question. The other parts of it - more intersting to ICU trainees - were about testing to assess coagulation status, and managing life-threatening bleeding. Something similar appeared in Question 7 from the second paper of 2020, where the focus was rivaroxaban.

FOAM resources:

Non-FOAM resources, which still happen to be free and online:

Tran et al (2014) - an excellent overview of oral anticoagulants
Ansell et al (2004) - a brief tour of warfarin and its chemical relatives
AHA/ACC/HRS Guidelines for AF (2014) - mainly to help answer Question 4 from the first paper of 2015 with some specific recommendations.
Stangier et al (2009) - pharmacology of dabigatran
Kreutz (2010) - pharmacology of rivaroxaban
Frost et al (2013) - pharmacology of apixaban

Since Question 4 from the first paper of 2015 was written, we have had some new developments. Excellent overviews by Almegren (2017, free) and Cohen et al (2018, paywalled) are available, and have been integrated into the updated version of this article. The advent of the "broad spectrum" reversal agent ciraparantag (Galliazzo et al, 2018) is anticipated to significantly alter the character of this article, but at this stage it is not yet available for widespread use.

Warfarin
	Mechanism	Vitamin K antagonist is the short version. More accurately, warafarin 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.
	Chemistry	Warfarin is a racemic mixture of two isomers, the R and S forms It is a a synthetic derivative of dicoumarol, a mycotoxin
	Absorption	Rapidly absorbed High oral bioavailablility (~ 100%) Maximum blood concentration about 90 minutes after administration
	Distribution	99% protein bound (albumin) Volume of distribution is small: 0.14 L/kg
	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.
	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
	Half-life	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.
	Advantages	Easily reversed Cheap Familiar Easy to monitor (INR can even be done as a point-of-care test) Unaffected by even severe renal failure
	Disadvantages	Narrow therapeutic window Patients vary considerably in dose response Many interactions with drugs and diet
	Interactions	In short, everything. See Table 2 from the Ansell paper.
	Monitoring	PT (INR)
	Reversal	Vitamin K: from 1mg to 10mg Fresh frozen plasma (FFP) up to 15ml/kg Prothrombinex 25-50 IU/kg

Dabigatran
	Mechanism	Direct thrombin inhibitor is the short version. Thrombin is a serine protease which catalyses the conversion of fibrinogen to fibrin 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.
	Chemistry	Small nonpeptide molecule Chemically related to argobatran and ximelagatran
	Absorption	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
	Distribution	35% protein bound (albumin) Volume of distribution is 1.0 L/kg
	Metabolism	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	80% renal excretion of unchanged drug 20% biliary excretion of acylglucouronides
	Half-life	12-14 hours
	Advantages	Rapid onset and offset No food interactions Wide therapeutic window Convenient (no need to monitor) Lower risk of bleeding complications than warfarin
	Disadvantages	Contraindicated in renal failure Difficult to monitor Rapid decline of efficacy with missed doses Expensive Without immediate antidote
	Interactions	In short, nothing. Amiodarone and quinidine will "interact" by competing for the P-glycoprotein efflux transporter. Dabigatran loses the competition, and its accumulation may result.
	Monitoring	Thrombin time (TT) Ecarin clotting time (ECT) Both tests directly assay the activity of thrombin APTT increases 2-3fold in high doses (eg. in overdose)
	Reversal	Severe bleeding may be controlled by FFP. prothrombinex or activated Factor VII Worst case scenario: its a small polar molecule, susceptible to removal by dialysis: apparently, 60% of the drug is removed over 2-3 hours. Since 2015 or so, we also have idarucizumab (Pollack et al, 2015) - it is a monoclonal antibody fragment which binds both free and thrombin-bound dabigatran to neutralise it. A 5g dose of idarucizumab rapidly and completely normalises TT and ECT.

Rivaroxaban
	Mechanism	Factor Xa inhibitor is the short version. Factor Xa is the active form of Factor X (activated by either the intrinsic or extrinsic pathway); its job is to cleave prothrombin into thrombin. Rivaroxaban inhibits free factor Xa as well as prothrombinase-bound and clot-associated factor Xa, in contrast to drugs like fondaparinux which only act on free Xa. Thus, rivaroxaban prevents thrombin generation.
	Chemistry	Chemically related to linezolid: both share an oxazolidinone-derived core structure However, it has neither antibiotic properties, nor bone marrow toxicity
	Absorption	Rapidly absorbed High oral bioavailability (~ 80-100%) Maximum blood concentration about 120-240 minutes after administration
	Distribution	95% protein bound Volume of distribution is 0.7L L/kg
	Metabolism	66% is metabolised in the liver: a substrate of CYP3A4 and CYP2J2. Inactive metabolites are excreted by biliary (50%) and renal (50%) routes
	Elimination	33% renal excretion of unchanged drug 66% hepatic metabolism
	Half-life	7-12 hours
	Advantages	Rapid onset and offset No food interactions Wide therapeutic window Convenient (no need to monitor) Lower risk of bleeding complications than warfarin
	Disadvantages	Contraindicated in renal failure Contraindicated in severe liver failure Difficult to monitor Rapid decline of efficacy with missed doses Expensive Without immediate antidote: in fact accepted reversal agents have a maximal reversal effect of about 50%.
	Interactions	In short, nothing. Amiodarone and quinidine will "interact" by competing for the P-glycoprotein efflux transporter.
	Monitoring	Both PT and APTT increase, but these are not useful for monitoring. APTT may be useful in overdose Thrombin time (TT) will be normal Special PT assay with a rivaroxaban-sensitive thromboplastin may be the most sensitive test (i.e. a normal "special" PT suggests that the activity of rivaroxaban is within a normal therapeutic range) Anti-Factor Xa activity may be the best method of monitoring.
	Reversal	Too heavily protein-bound to be susceptible to dialysis. Prothrombinex and probably Factor VIIa are valid reversal agents, but the reversal effect reaches a plateau with a maximal effect of approximately 50%. Andexanet alfa is a specific reversal agent which binds to Xa with approximately the same or slightly higher activity as the Xa inhibitors, and therefore is a possible reversal agent for rivaroxaban and apixaban as well as enoxaparin and fondaparinux (Siegal et al, 2015). Chemically, it is a recombinant derivative of Xa which acts as a decoy receptor.

Apixaban
	Mechanism	Factor Xa inhibitor is the short version. Apixaban inhibits free factor Xa as well as prothrombinase-bound and clot-associated factor Xa, and thus prevents thrombin generation.
	Chemistry	Like rivaroxaban, it is chemically related to linezolid: both share an oxazolidinone-derived core structure.
	Absorption	Rapidly absorbed Oral bioavailability ~50% Maximum blood concentration about 90-200 minutes after administration
	Distribution	87% protein bound Volume of distribution is small: 0.3 L/kg
	Metabolism	33% is metabolised in the liver: a substrate of CYP3A4/5 Inactive sulfate conjugates are renally excreted
	Elimination	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	about 12 hours
	Advantages	Rapid onset and offset No food interactions Wide therapeutic window Convenient (no need to monitor) Lower risk of bleeding complications than warfarin
	Disadvantages	Difficult to monitor Rapid decline of efficacy with missed doses Expensive Without immediate antidote
	Interactions	In short, not much. Amiodarone and quinidine will "interact" by competing for the P-glycoprotein efflux transporter, but because apixiban is eliminated by several different pathways, this is unlikely to have a clinically significant effect on accumulation. Strong CYP450 inhibitors (eg. etoconazole, itraconazole, voriconazole, posaconazole) may delay clearance, particularly in renally impaired people.
	Monitoring	Both PT and APTT increase, but these are not useful for monitoring. Thrombin time (TT) will be normal Anti-Factor Xa activity may be the best method of monitoring: the relationship between apixaban plasma concentration and anti-FXa activity is linear over a wide dose range of apixaban.
	Reversal	The recent article by Ward et a (2013) recommends the following strategies: Prothrombinex 25-50 IU/kg Tranexamic acid Novoseven (Factor VIIa) Andexanet alfa is an option

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.

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.

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