Thomas Meinel, MD
Direct oral anticoagulants (DOAC) have proven at least equally effective in the prevention of acute ischemic stroke in patients with atrial fibrillation as compared to the vitamin K antagonists (VKA). They are recommended in stroke prevention for DOAC-eligible atrial fibrillation patients (without moderate-to-severe mitral stenosis or mechanical heart valve) as the oral anticoagulation of choice since their net clinical benefit arises mainly from a reduced risk of intracranial hemorrhage.1,2 Despite a significant reduction of stroke risk,1 recurrent ischemic stroke in patients on DOACs still occurs with an estimated rate of 1-2% per year.3 The randomized controlled trials did not report exact data on the stroke severity in patients on DOACs. Real-world data are conflicting, limited by arbitrary dichotomization of stroke severity scores, and mostly did not look at laboratory assessment of DOAC activity or information on compliance.4–8
In the August 2020 issue of Stroke, Jung et al. used a prospective, multicenter, hospital-based national stroke registry in Korea to evaluate trends of antithrombotic medication use in 6786 stroke patients with atrial fibrillation recruited between 2008 and 2018. The study aim was to explore the association between preceding antithrombotic medication use and initial stroke severity. 4009 patients were candidates for anticoagulation defined by a CHA2DS2-VASc score ≥2 and ATRIA score ≤4 prior to the acute ischemic stroke event. Among those, the overall prevalence of anticoagulation use was 27% and increased from 25% in 2010 to 41% in 2018 (P<0.001). Whereas the percentage of patients on VKA decreased in the recent years, the fraction of patients suffering ischemic stroke on DOACs increased from 4% in 2015 to 25% in 2018. Authors also found that stroke severity was higher in patients who were not on antithrombotics compared to those on antiplatelets or anticoagulants (median NIHSS: 8 versus 7 versus 6, P<0.001). Anticoagulation was also independently associated with mild stroke severity defined as NIHSS ≤5 (adjusted odds ratio, 1.31 [95% CI, 1.15–1.50]). However, there was no difference between antiplatelet agents and anticoagulation in terms of stroke severity.
The strengths of this analysis are a large, national dataset and a comprehensive analysis with use of established scores to identify patients who were candidates for anticoagulation. The main weaknesses apart from bias inherent to observational data are lumping DOAC and VKA together for most analyses and not assessing anticoagulation compliance or activity. It is crucial that clinicians and researchers assess anticoagulation activity to determine compliance and laboratory diagnosis of medication activity for both VKA (INR) and DOAC (specific drug levels). Grouping both populations and associated uncertainty regarding therapeutic activity hamper conclusions regarding their impact on stroke severity and outcome since it is well known that only around half of patients prescribed anticoagulation are within therapeutic range on admission.6,7
Nevertheless, the authors should be complimented for their topical analysis. They provide a clear picture of a changing landscape of anticoagulation use among stroke patients with atrial fibrillation in Korea. The implementation of DOAC resulted in a larger proportion of patients receiving appropriate therapies. Importantly, they show that the frequency of preceding DOAC therapy is on the rise in patients suffering ischemic stroke. Since currently there are no reliable guidelines on how to manage such patients, several questions for clinicians and researchers come to mind: Could intravenous thrombolysis be safely and effectively applied to selected DOAC patients based on compliance or specific drug levels? Should those patients be changed to another DOAC class, or should we consider adding aspirin or even left atrial appendage closure?
Ideally, subgroup analyses of the existing randomized controlled trials (RE-LY, ARISTOTLE, ROCKET) will finally answer the question of whether stroke severity is truly lower in patients on DOACs as compared to VKAs. We as clinicians and researchers should focus on patients suffering ischemic stroke on DOACs since this population is on the rise and a lot of open questions are to be answered.
References:
1. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur. Heart J. 2016;37:2893–2962.
2. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019;140:e125–e151.
3. Almutairi AR, Zhou L, Gellad WF, Lee JK, Slack MK, Martin JR, Lo-Ciganic WH. Effectiveness and Safety of Non–vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation and Venous Thromboembolism: A Systematic Review and Meta-analyses. Clin. Ther. 2017;39:1456-1478.e36.
4. Xian Y, O’Brien EC, Liang L, Xu H, Schwamm LH, Fonarow GC, Bhatt DL, Smith EE, Olson DWM, Maisch L, et al. Association of preceding antithrombotic treatment with acute ischemic stroke severity and in-hospital outcomes among patients with atrial fibrillation. JAMA – J. Am. Med. Assoc. 2017;317:1057–1067.
5. Hellwig S, Grittner U, Audebert H, Endres M, Haeusler KG. Non-Vitamin K-dependent oral anticoagulants have a positive impact on ischaemic stroke severity in patients with atrial fibrillation. Europace. 2018;20:569–574.
6. Sakamoto Y, Okubo S, Nito C, Suda S, Matsumoto N, Abe A, Aoki J, Shimoyama T, Takayama Y, Suzuki K, et al. The relationship between stroke severity and prior direct oral anticoagulant therapy in patients with acute ischaemic stroke and non-valvular atrial fibrillation. Eur. J. Neurol. 2017;24:1399–1406.
7. Auer E, Frey S, Kaesmacher J, Hakim A, Seiffge DJ, Goeldlin M, Arnold M, Fischer U, Jung S, Meinel TR. Stroke severity in patients with preceding direct oral anticoagulant therapy as compared to vitamin K antagonists. J. Neurol. 2019;266:2263–2272.
8. Macha K, Marsch A, Siedler G, Breuer L, Strasser EF, Engelhorn T, Schwab S, Kallmünzer B. Cerebral Ischemia in Patients on Direct Oral Anticoagulants: Plasma Levels Are Associated With Stroke Severity. Stroke. 2019;50:873–879.
