How Can We Bridge the Results of Global Clinical Trials and Region/Country Specific Clinical Practice by Region/Country Specific Registry Data?

摘要

In this issue of the Journal, Kodani et al present an interesting report regarding the thrombotic and bleeding event rates in patients in Japan treated with warfarin in realworld practice against atrial fibrillation (AF) with valvular heart disease (the majority was mitral stenosis). Warfarin is recommended for primary and secondary stroke prevention in cases of valvular and non-valvular AF in various clinical practice guidelines, including those published in Japan.4 Recommendation is based on the consensus that the risk of bleeding events caused by warfarin therapy is lower than that of thrombotic events prevented by the use of warfarin. Indeed, absolute merit is high in patient populations facing higher thrombotic event risk.5 In patients with AF, there are subpopulations at high risk of thrombosis, such as patients with mitral stenosis, heart failure, diabetes, etc. Of these risk factors for thrombotic events in AF patients, mitral stenosis is by far the most important.8 Thus, we have reached the consensus that anticoagulation therapy in mitral stenosis is needed no matter whether the patient has AF or not if that patient has severe mitral stenosis with an enlarged left atrium or a previous history of embolic events. There are several direct oral coagulation factor inhibitors, such as direct thrombin inhibitor and direct Xa inhibitor, registered for the prevention of stroke and systemic embolism in patients with non-valvular AF. Of note, patients with mitral stenosis, which has a clinically meaningful high risk of thrombotic events, have been excluded from all the phase III trials of these direct anticoagulants.10–13 Furthermore, except for the J-ROCKET trial of rivaroxaban,14 the efficacy and safety of new generation direct oral anticoagulants have been compared with warfarin targeting an international normalized ratio (INR) 2–3. This INR target (target INR 2.5) originally comes from the recommendation for mitral stenosis and chronic phase of artificial heart valve. Failure of one clinical trial comparing the efficacy and safety of dabigatran with warfarin in patients with mechanical heart valve led to us consider the difference in the mechanisms of direct enzyme inhibition by new-generation direct oral anticoagulants and the complex multi-target anticoagulation of warfarin.15 Nevertheless, the present report is the first demonstration of thrombotic and bleeding events in Japanese AF patients with valvular heart disease (mostly mitral stenosis), thus providing important insight for the treatment of these patients in Japan.