Is warfarin on its way out?

Image via Wikipedia

A few weeks back, a drug rep came to see us to provide more information on a new drug just added to the hospital formulary. This drug was dabigatran (Pradaxa ® ),  a direct thrombin inhibitor licensed for the prophylaxis of  venous thromboembolism in adults after total hip replacement or total knee replacement surgery. This talk made me think… ” will warfarin still be used in 10 years time?”

Warfarin has been around since the 1950′s . It is licensed for the prophylaxis of embolisation in rheumatic heart disease and atrial fibrillation; prophylaxis after insertion of prosthetic heart valve; prophylaxis and treatment of venous thrombosis and pulmonary embolism and transient ischaemic attacks (BNF 60).

Although the two newer oral anticoagulants dabigatran and rivaroxaban (Xarelto®  ) available in the UK are not licensed for use in AF or treatment of venous thrombosis, pulmonary embolism  and in valve patients,  its only a matter of time before they are licensed for these indications once trial data is available.

Dabigatran  as mentioned above is a direct thrombin inhibitor and rivaroxaban is a direct inhibitor of activated factor X. They are given orally but unlike warfarin do not require dose adjustments, and therapeutic drug monitoring (INR testing).  They also do not have a narrow therapeutic range or have the same long list of drug and food interactions.

from http://www.australianprescriber.com/magazine/33/2/38/41/#t1
Comparison of oral anticoagulants
Property	Warfarin	Rivaroxaban	Dabigatran etexilate
Anticoagulant action	Reduced synthesis of functional clotting factors II, VII, IX and X	Direct competitive reversible inhibition of activated factor X	Direct competitive reversible inhibition of thrombin
Prodrug	No	No	Yes
Bioavailability	Almost 100%	80%	6.5%
Onset of anticoagulant action	36–72 hours	Within 30 minutes Tmax 2.5–4 hours	Within 30 minutes Tmax 0.5–2 hours
Duration of anticoagulant action	48–96 hours	24 hours	24–36 hours
Elimination half-life (anticoagulant activity)	20–60 hours	5–9 hours in young adults 11–13 hours in older adults	7–9 hours in young adults 12–14 hours in older adults
Predictable pharmacokinetics	No	Yes	Yes
Interactions with diet or alcohol	Yes, clinically significant	Low potential	Low potential
Drug interactions	Numerous clinically significant interactions	Potent cytochrome P450 3A4 and P-glycoprotein inhibitors augment anticoagulant effect (e.g. ketoconazole, clarithromycin, ritonavir)	Proton pump inhibitors reduce absorption Possible interactions with P-glycoprotein inhibitors and inducers
Dosing and dose adjustments	Dose individualised for each patient, requires frequent INR monitoring and adjustment	Fixed according to clinical indication	Fixed according to clinical indication
Monitoring	INR every 1–2 weeks	No routine monitoring required	No routine monitoring required
Use in liver failure	Contraindicated or caution advised	Contraindicated as hepatic metabolism	Possibly safe as no hepatic metabolism but caution advised
Use in severe renal impairment	No dose adjustment required	Increased drug exposure and elimination half-life in renal impairment Safety and dosing not yet established Contraindicated in severe renal impairment	Increased drug exposure and elimination half-life in renal impairment Safety and dosing not yet established Contraindicated in severe renal impairment
Use in pregnancy	Category D Teratogenic in first trimester	Contraindicated as safety not established (excluded from clinical trials)	Contraindicated as safety not established (excluded from clinical trials)
Reversibility after cessation	Several days, requires synthesis of clotting factors	24 hours, dependent on plasma concentration and elimination half-life	24–36 hours, dependent on plasma concentration and elimination half-life
Antidote	Immediate reversal with plasma or factor concentrate Reversal within hours with vitamin K	None available	None available
INR international normalised ratio  Tmax time to maximum concentration

So will they replace warfarin?  Although the dosing regimens are simpler  it can be argued that since intensive monitoring is not required, compliance may become an issue if they replace warfarin . I think until the costs of these new anticoagulants decrease and their safety and efficacy is proven in AF and the treatment of PEs and DVTs  and heart valve patients, warfarin (and the other vitamin K antagonists, acenocoumarol and phenindione) will be around for a good few years yet.

see also

• National Patient Safety Agency (NPSA) http://www.nrls.npsa.nhs.uk/resources/?entryid45=59814&q=0%C2%ACanticoagulants%C2%AC
• Blog: The Redheaded Pharmacist, Respect Coumadin http://www.theredheadedpharmacist.com/?p=1836
• RE-LY trial,  Dabigatran versus Warfarin in Patients with Atrial Fibrillation http://www.nejm.org/doi/full/10.1056/NEJMoa0905561

Advertisement