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.