What Is the Best Anticoagulant Therapy in Acute-Phase Ischemic Stroke With Nonvalvular Atrial Fibrillation?
Article ID: CJ-21-1002
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Article ID: CJ-21-1002
Although anticoagulant agents are usually used to prevent cardioembolic stroke, evidence remains insufficient regarding the timing of initiating anticoagulant therapy and how best to use anticoagulants in the acute phase. Before the advent of direct oral anticoagulants (DOACs), warfarin, a vitamin K antagonist, and unfractionated heparin were the only anticoagulant agents that could be used for acute cardioembolic stroke in Japan. However, the efficacy of unfractionated or low-molecular weight heparin in acute ischemic stroke has not been confirmed.1–4 In addition, warfarin is known to exert an initial tendency toward hypercoagulation via the mechanism of suppressing the production of not only coagulation factors, but also anticoagulants such as protein S and protein C as vitamin K antagonists.5 As a result, temporary bridging therapy with unfractionated heparin is usually implemented (Figure A).
Anticoagulant therapy in the acute phase of ischemic stroke with nonvalvular atrial fibrillation. Is bridging therapy with low-dose heparin and oral anticoagulant [warfarin (A) or direct oral anticoagulants (DOACs; B)] beneficial? Considering previous studies, bridging therapy with low-dose heparin seems to offer no benefit. As a new treatment strategy, optimal timing as well as the efficacy and safety of direct initiation of DOACs (C) should be investigated.
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The Recurrent Embolism Lessened by rivaroxaban, an Anti-Xa agent, of Early Dosing for acute ischemic stroke and transient ischemic attack (TIA) with atrial fibrillation (RELAXED) study6,7 demonstrated that, for the prevention of stroke recurrence in acute ischemic stroke patients with nonvalvular atrial fibrillation (NVAF), rivaroxaban can be feasibly initiated within 14 days of onset. Rivaroxaban started within 3 days of onset may also be feasible for patients with a small or medium-sized infarction or with mild severity. Another Japanese observational study showed that DOACs were being started relatively early in the acute phase of ischemic stroke with NVAF.8 Blood concentrations of DOACs rise quickly after internal use, and the effect is expressed quickly. Moreover, the frequency of major bleeding (particularly intracranial hemorrhage) is known to be reduced in patients treated with DOACs as compared with warfarin for stroke prevention.9 With regard to DOACs as antithrombotic therapy in the acute phase of ischemic stroke, a meta-analysis of several observational studies revealed that DOACs were also superior to warfarin for composite outcomes of ischemic stroke, intracranial hemorrhage, and death.10
In this issue of the Journal, Tokunaga et al11 report a post-hoc analysis of the RELAXED study and reveal that the composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin (Figure B) than in patients who started directly on rivaroxaban (Figure C) after ischemic stroke or TIA. In particular, the frequency of bleeding events was very low even in the group with bridging therapy, and ischemic events were relatively more frequent in the group with bridging therapy. A post-hoc analysis of the Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation (RAF) and RAF-NOAC studies also demonstrated that bridging therapy with low-molecular-weight heparin before starting DOACs was associated with ischemic events in patients with acute ischemic stroke and NVAF.12 On the other hand, another study showed that the use of unfractionated heparin with activated partial thromboplastin time adjusted 2–2.5 times in acute-phase ischemic stroke significantly increased symptomatic intracranial hemorrhage, but improved short-term functional outcomes.13 As the authors describe in their discussion, low-dose heparin was used only for a short period in the group with bridging therapy, and the effectiveness of this as an anticoagulant therapy was questionable in the RELAXED study.
What is the best anticoagulant therapy in the acute phase of ischemic stroke with NVAF (Figure)? Considering previous research results as mentioned above, no benefit seems to result from bridging therapy with low-dose heparin before DOAC initiation, although the efficacy and safety of DOACs in the acute phase have yet to be fully verified.14 The timing of DOAC initiation will probably need to be determined according to the presence or absence of large vessel occlusion, the extent of ischemia, neurological severity and so on. Anticoagulant therapy that can be started after the evaluation of such clinical factors should be initiated at a dose proven to be effective, such as the recommended doses of DOACs. Of course, under-dosing with DOACs should be avoided, because under-dosed DOACs, as with low-dose heparin in bridging therapy, do not reduce the risk of major bleeding and can increase the risks of ischemic events and death.15 When DOACs should be started in the acute phase of ischemic stroke is a future problem to be solved. To address these issues, several randomized controlled trials examining the early initiation of DOACs in patients with acute ischemic stroke and NVAF are currently underway.
S.F. received personal lecture fees unrelated to the current work, from Nippon Boehringer Ingelheim, Bayer Yakuhin, Pfizer Japan, Daiichi Sankyo, Bristol-Myers Squibb, Otsuka Pharmaceutical, and Takeda Pharmaceutical.
None.
