Vitamin K antagonists are used for the prevention of arterial and venous thrombosis
since more than 60 years and were the most widely prescribed anticoagulants in the
world.[1] Despite their unexcelled efficacy, the narrow therapeutic window is associated with
many challenges in clinical practice.
Warfarin, a racemic mixture of (R)- and (S)-enantiomers, is metabolized by seven different
isoenzymes of the cytochrome P450 system, making it prone to many food and drug interactions.
Furthermore, other factors such as genetic polymorphisms (specifically CYP2C9 variants),
age, concomitant diseases and renal function may reduce drug efficacy and increase
the possibility of over- and under-dosing, associated with an enhanced risk of bleeding
or thrombotic complications predominantly in the early phase of warfarin therapy.[2] Not least the inconvenient need for a dense monitoring of the international normalized
ratio (INR) has spurred the development of newer anticoagulant agents.[3]
Unlike vitamin K antagonists, the direct oral anticoagulants target one specific factor,
currently either factor IIa or factor Xa, and are more convenient to administer due
to a fixed dose without routine monitoring.[4] Nonetheless, in some critical circumstances, for example, in emergency surgery or
acute renal failure, the measurement of drug levels and the anticoagulant effect may
become necessary.[5]
While non-vitamin K antagonist oral anticoagulants are as effective as warfarin to
prevent stroke in non-valvular atrial fibrillation patients,[6] apixaban and dabigatran initiation was associated with significantly less major
bleeding complications than warfarin in the early phase. In contrast to apixaban,
initial rivaroxaban intake resulted in a higher bleeding risk.[7] Notably, some of the newer agents are associated with a higher incidence of gastrointestinal
bleeding, which however can often be controlled by temporarily withholding treatment
due to their relatively short half-lives. Dabigatran was less effective than warfarin
in patients with mechanical heart valves[8] and also associated with an increased rate of bleeding events.[9]
In general, minimizing the bleeding risk includes precautions such as dose reduction
in higher-risk populations (e.g., renal impairment) and to avoid non-vitamin K antagonist
oral anticoagulants in patients with contraindications such as severe chronic kidney
disease (creatinine clearance rate [CrCl] < 15 mL/min, for dabigatran < 30 mL/min).[5]
Chronic kidney disease is a circumstance that per se complicates anticoagulation.
On the one hand, it occurs more frequently in patients with venous thromboembolism
and arterial fibrillation. On the other hand, a low glomerular filtration rate (eGFR) < 60
mL/min/1.73 m2 vice versa increases the risk of stroke and venous thromboembolism. Oral anticoagulants
are known to be beneficial in patients with chronic kidney disease, but despite the
recommendation to use vitamin K antagonists in severe CKD there are several concerns
regarding their safety in this patient population. Among others, comorbidities may
increase the risk for thrombotic and bleeding complications, and concomitant drugs
and uremic toxins are likely to interfere with the metabolism of (S)- and (R,S)-warfarin
mediated by the CYP450 system, requiring dose adaptions according to GFR-dependent
algorithms. Regarding all these drawbacks, there is a strong need for an alternative
to warfarin in this clinical setting.[10]
One possible alternative is presented in this issue of Thrombosis and Haemostasis: Albrecht and colleagues describe the pharmacokinetics of tecarfarin—a novel vitamin
K antagonist under development—in patients with severe chronic kidney disease.[10]
Tecarfarin (ATI-5923) is a structural analogue of warfarin with the same mechanism
and duration of action. As a non-competitive vitamin K epoxide reductase (VKOR) antagonist,
tecarfarin impairs the activation of the vitamin K–dependent clotting factors II,
VII, IX and X. Like for warfarin, anticoagulant efficacy is monitored using the INR.
Unlike warfarin, which is metabolized by the CYP450 pathway, tecarfarin undergoes
hydrolysis mediated by human carboxylesterase 2 (hCE-2), yielding a single inactive
carboxylic acid metabolite (ATI-5900),[3]
[11] which is excreted by the kidney. Since hCE-2 is unlikely inhibited by renal failure
and chronic kidney failure is not expected to affect tecarfarin clearance, probably
a more stable anticoagulation could be achieved in this specific patient population,[10] while drug interactions mediated by the CYP450 system may be eliminated.[11]
Furthermore, anticoagulant activity of tecarfarin is unaffected by genetic variations
in CYP2C9. Reducing the early dosing inter-subject variability in plasma levels and
in therapeutic response, tecarfarin may decrease the risk of bleeding and minimize
adverse effects due to over- and under-dosing. Although there was no significant difference
in maintenance doses between CYP2C9 genotypes, doses varied between VKORC1 genotypes.
Plasma concentrations of tecarfarin correlated with VKORC1 genotype, with the GG genotype
having twofold higher plasma concentrations than the AA genotype, resulting in twofold
difference in maintenance dose. Importantly, there was no relationship between plasma
concentrations of tecarfarin and INR. Therefore, tecarfarin does not appear to have
any special advantages over warfarin in subjects with VKORC1 polymorphisms and a genotype-guided
initial dosing may be useful in this subset of patients.[12]
Beyond the reduced probability for CYP450-mediated drug interactions and the promising
results in chronic kidney disease, it remains questionable if tecarfarin exhibits
any further advantages over warfarin ([Table 1]). In the EmbraceAC trial, tecarfarin did not meet the primary endpoint so that superiority
of tecarfarin over warfarin for time in therapeutic range (TTR) was not demonstrated
in patients who require chronic oral anticoagulation. Treatment emergent adverse events
were reported for 88% of patients on warfarin and 90% on tecarfarin. Both drugs exhibited
comparable TTR, which correlates with clinical outcome, and no difference in the frequency
of clinical events, concluding that only patients with CYP2C9-variant alleles or taking
CYP2C9-interacting drugs may benefit from tecarfarin.[13]
Table 1
Major differences between the oral anticoagulants tecarfarin and warfarin
|
Tecarfarin
|
Warfarin
|
|
Structural formula
|
|
|
|
Monitoring
|
International normalized ratio (INR)
|
INR
|
|
Metabolism
|
Hydrolysis mediated by hCE-2
|
CYP450 pathway (seven different enzymes)
|
|
Genetic variations
|
No relevant variations known
|
CYP2C9
|
|
Food and drug interactions
|
Unlikely
|
Prone to many interactions
|
Abbreviations: CYP450, cytochrome P450; CYP2C9, cytochrome P450 2C9; hCE-2, human
carboxylesterase 2.
A second study performed by Albrecht and colleagues published in Thrombosis and Haemostasis describes the pharmacokinetics and pharmacodynamics of tecarfarin after single and
multiple dosing in healthy volunteers. Single doses of tecarfarin up to 40 mg are
associated with a dose proportionality in drug concentrations and half-life. The maintenance
dose required to keep the target INR range of 1.7 to 2 varies between 10 and 20 mg,
and the INR declines within 1 to 3 days after cessation of tecarfarin.[14] However, further studies are required to investigate the effects of tecarfarin after
multiple dosing in chronic kidney disease and patients with mechanical heart valves.
The inactive metabolite (ATI-5900), which is excreted by the kidney, was present at
concentrations approximately 10% of the parent drug in healthy volunteers[14] and at twofold higher concentrations in chronic kidney disease as compared with
healthy volunteers.[10] Hence, there is a need to characterize its detailed profile and to exclude any toxic
effect of the metabolite, particularly after multiple dosing in high-risk populations
such as chronic kidney patients.
Furthermore, tecarfarin is known to inhibit CYP2C9-mediated metabolism, at least in
transfected cells,[12] and it remains to be answered if the metabolite also has an inhibitory effect on
CYP450 enzymes. Therefore, it should not be forgotten that a potential to cause drug–drug
interactions in any manner can definitively not be excluded for tecarfarin.
Once all of these issues have been addressed in subsequent trials, tecarfarin may
become an interesting alternative to achieve a stable anticoagulation in patient populations,
which cannot be satisfactorily treated with good old warfarin.
