Cardioembolic stroke related to nonvalvular atrial fibrillation is associated with a high recurrence rate and high mortality and morbidity. In this population, therefore, optimal anticoagulant therapy is required to prevent the occurrence of second stroke. Oral anticoagulant, warfarin has been traditionally used, but it is greatly limited by its narrow efficacy window, complex pharmacokinetics, and multiple drug interactions, thus requiring frequent blood monitoring. Recently, oral anticoagulants targeted for a specific coagulation component have been newly developed and tested in large clinical trials. Dabigatran, direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, inhibitors of factor Xa harbor great merits of rapid action time, short half-life, stable plasma concentration, and little drug interaction. Recently, large randomized clinical trials and meta-analyses have been published to show the efficacy and safety of the new oral anticoagulants compared with warfarin. Based on the results from recent clinical trials, we revised recommendations to apply optimal anticoagulant therapy in patients with nonvalvular atrial fibrillation and ischemic stroke or transient ischemic attack.
Large nationwide multicenter stroke registry studies in Korea have shown an increase in cardioembolic stroke, which accounts for 20% of all ischemic strokes,
The first edition of the secondary stroke prevention guidelines for patients with atrial fibrillation was published in 2009 and did not reflect evidence concerning the newly developed oral anticoagulants. The previous recommendations were as follows:
Warfarin treatment (INR 2.0-3.0) is recommended, unless contraindicated, in patients with ischemic stroke or transient ischemic attack coexisting with sustained or paroxysmal atrial fibrillation (Evidence level: Ia, Recommendation grade: A).
If anticoagulants cannot be used, aspirin can be used instead (Evidence level: Ia, Recommendation grade: A). The recommended daily dose of aspirin is 325 mg. In Korea, a prescribable dose of 300 mg may be considered (Evidence level: IV, Recommendation grade: GPP).
For the recurrence of ischemic stroke or transient ischemic attack in atrial fibrillation patients already receiving adequate anticoagulation therapy, increasing the therapeutic target to INR 2.5-3.5 or initiating combination therapy with antiplatelets may be considered (Evidence level: IV, Recommendation grade: C).
Recommendations of the Korean Clinical Practice Guidelines (CPG) for Stroke are generated by summarizing foreign and Korean published evidence modified to take the Korean health care system into account. The first edition was published in 2009 and reflects evidence published through June 30, 2007. Since then, the Steering Committee has monitored new clinical evidence and selected topics requiring guidelines updates. The Steering Committee makes a final decision regarding guideline updates and appoints a Writing Committee chair for each of the following three areas: primary stroke prevention, acute stroke management, and secondary stroke prevention. Each chair organizes writing members by referring to their specialty with the approval of the Steering Committee. Under the supervision of each chair, the Writing Committee members search, compile, and evaluate new evidence and make recommendations for each topic. With the advent of new evidence for antithrombotic management in atrial fibrillation, the Steering Committee decided to update the guideline for secondary stroke prevention in patients with atrial fibrillation and composed the Writing Committee. Disagreements among Writing Committee members were resolved by consensus. The Steering Committee reviewed the first draft and recommended revision if necessary. The Writing Committee's revised draft was submitted, reviewed, and finally approved by the Steering Committee.
The update process adheres to the international tool for the assessment of practice guidelines, the Appraisal of Guidelines for Research & Evaluation (AGREE II). The process of guideline development requires the documentation of all literature searches performed for the guideline revision. The search form to be completed by the Writing Committee includes items such as search duration, publication type, key words, search strategy, and database. For this revision, we searched articles from MEDLINE/PubMed and the National Guideline Clearinghouse from July 2007 to May 2014 using the following key words: atrial fibrillation AND stroke OR transient attack AND anticoagulant AND dabigatran OR rivaroxaban OR apixaban OR edoxaban AND warfarin AND stroke. Key words for exclusion included catheter ablation, cardioversion, valve replacement surgery, and left atrial appendage closure. The studies were limited to randomized controlled trials, controlled clinical trials, meta-analyses, and guidelines.
The Writing Committee reviewed all available studies meeting the inclusion and exclusion criteria, and finally retrieved 8 randomized controlled trials, 5 meta-analyses, and 4 subgroup analyses. The Writing Committee additionally reviewed 3 foreign updated guidelines including those of the European Society of Cardiology (2012),
A full version of the updated proposal (in Korean) including detailed evidence is available in the Journal of the Korean Neurological Association.
The most notable change in the current revised guidelines is the recommendation of both NOACs and warfarin. The Ia evidence level for warfarin therapy in patients who suffered an ischemic stroke or transient ischemic attack with nonvalvular persistent or paroxysmal atrial fibrillation was assigned on the basis of the European Atrial Fibrillation Trial (EAFT) of warfarin for secondary stroke prevention
The Ia evidence level and A recommendation grade were assigned based on the EAFT treatment protocol targeting an INR of 2.0-3.0
NOACs are mainly or partly eliminated by renal excretion. Therefore, renal function should be assessed prior to NOAC use. Renal dysfunction criteria for clinical trial enrollment are variable across different NOACs. The RE-LY
There are no validated data to serve as a basis for recommending antithrombotics for patients who had a cardioembolic ischemic stroke or transient ischemic attack despite adequate anticoagulation with warfarin. However, this is a scenario frequently encountered in clinical practice and we therefore provide a recommendation on the basis of expert consensus. For these patients, we recommend considering one of the following: a higher INR target, the addition of antiplatelet therapy, or a switch to dabigatran, rivaroxaban, or apixaban. The assigned evidence level and recommendation grade were IV and C, respectively.
No randomized controlled trials or experimental studies directly tested the efficacy and safety of any antithrombotic therapy for patients with nonvalvular atrial fibrillation who have a history of intracranial bleeding or are at a high risk of intracranial bleeding. However, a reduction of hemorrhagic stroke with dabigatran, rivaroxaban, and apixaban versus warfarin was demonstrated in randomized clinical trials
Although the efficacy of antiplatelet therapy is greatly inferior to that of anticoagulant therapy, a meta-analysis showed that compared with placebo, antiplatelet therapy significantly reduced the risk of stroke.
This study was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065) and the Hallym University Specialization Fund (HRF-S-51).
The authors have no financial conflicts of interest.