Introduction
Vitamin K antagonists (VKA) are
used in long-term treatment and prevention of thromboembolic events.
They exhibit their anticoagulant effect by interfering with the
vitamin K dependent
γ-carboxylation of blood coagulation factors including factor
II,
VII and
X. The anticoagulant effect is
monitored by measurement of one of the following two blood tests; the
international normalized ratio (INR) or the Prothrombin Time (PTT). It
is essential to achieve INR levels within the therapeutic range to avoid
thromboses as well as bleedings.[1, 2] The use of VKA can be
challenging, due to a narrow therapeutic index and substantial
interindividual variation in dose-response.[1] Furthermore, the
anticoagulant effect of VKA can be influenced by drug-drug interactions,
certain food, genetic variation, and other factors (e.g. fever).[3]
Warfarin is the most widely prescribed VKA, but
acenocoumarol and
phenprocoumon
are also commonly used, especially in some European countries.[4]
The
cytochrome
P450 enzymes CYP2C9 and
CYP3A4 are responsible for the
metabolism of S-warfarin and R-warfarin, respectively, with CYP2C9 being
the most important metabolic pathway for warfarin.[2-4]
Phenprocoumon is primarily metabolized by CYP2C9 while acenocoumarol is
metabolized by both CYP2C9 and
CYP2C19.[2, 4]
Cholesterol-lowering treatment with
HMG-CoA reductase inhibitors
(statins) comprises one of the most frequent drug treatments, with more
than 200 million statin users worldwide.[5] The metabolism of
statins also involves CYP3A4
(simvastatin,
atorvastatin, and
lovastatin) and CYP2C9
(fluvastatin and
rosuvastatin).[6] Furthermore,
the membrane transport protein; organic anion transporting polypeptide
1B1 (OATP1B1), is also involved in
the metabolism of the majority of statins.[6] Coadministration of
VKA and statins is common with approximately 50% of warfarin users
taking statins in Denmark.[7]
Despite the widespread concomitant use of statins and VKA and the
overlapping metabolic pathways, data about potential drug-drug
interactions between the two drug groups are limited and conflicting.
Studies have both reported that statin initiation leads to moderate INR
increases potentially associated with increased anticoagulant effects
well as small INR changes of limited clinical relevance. Nevertheless,
it is recommended by commonly used online drug-drug interaction
databases to increase the frequency of INR monitoring when initiating or
discontinuing statin treatment and following dose changes.[8-10] To
assess the clinical relevance of the potential drug-drug interactions
between VKA and statins, we conducted a systematic literature review of
the collectively available evidence on the effect of statin initiation
on the anticoagulant effect of VKAs.