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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 2  |  Page : 525-526

Acute ischemic stroke on apixaban: What next?

Charleston Area Medical Center, West Virginia University, Charleston, West Virginia, Akron Neurology Inc, Akron, Ohio, USA

Date of Web Publication15-Mar-2018

Correspondence Address:
Dr. Konark Malhotra
Department of Neurology, Charleston Area Medical Center, West Virginia University, Charleston, West Virginia - 25301
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.227300

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How to cite this article:
Malhotra K, Ramanathan SR. Acute ischemic stroke on apixaban: What next?. Neurol India 2018;66:525-6

How to cite this URL:
Malhotra K, Ramanathan SR. Acute ischemic stroke on apixaban: What next?. Neurol India [serial online] 2018 [cited 2020 Oct 22];66:525-6. Available from:


Cardioembolic strokes are associated with poor clinical outcomes and add to the stroke-related morbidity and mortality. Various novel oral anticoagulants have been approved for treatment of nonvalvular atrial fibrillation (NVAF), with apixaban being a preferred choice due to its superior efficacy and comparable bleeding rates to that of aspirin. However, a therapeutic dilemma exists for patients with recurrent strokes while on apixaban therapy. We share our opinion and suggestions for cases where a diagnostic dilemma exists.

Acute ischemic stroke (AIS) is the leading cause of morbidity with a high recurrence rate.[1] Cardioembolic stroke secondary to NVAF is usually associated with worse clinical outcomes. Atrial fibrillation is associated with a 4.5% annual risk of stroke, whereas anticoagulants tend to reduce this risk to 1.4% per year.[2] For decades, vitamin K antagonists (VKA) especially warfarin, have been the preferred treatment options for secondary stroke prevention in patients with atrial fibrillation. Warfarin has a superior efficacy compared to aspirin; however, its use is limited due to a narrow therapeutic window, multiple food and drug interactions, and frequent coagulation monitoring and dosage adjustments. Recently, non-VKA oral anticoagulants (NOACs) including three Factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) and one direct thrombin inhibitor (dabigatran) were approved for secondary stroke prevention in NVAF patients.

Anticoagulation in AIS poses a hemorrhage risk; however, various algorithms have been proposed that guide the anticoagulation therapy in AIS based on the age and size of infarct core.[3] However, NOACs have been associated with reduced major or minor hemorrhagic rates compared to warfarin. Indications for anticoagulation in stroke patients apart from NVAF include arterial dissection, unstable intra- or extra-cranial vessel thrombus, cardiac thrombus, or paradoxical embolism from venous thrombosis. Based on the recent landmark trials, apixaban has emerged as the preferred anticoagulant in clinical practice for the secondary prevention of stroke in NVAF patients. However, instances occur where NVAF patients on apixaban therapy present with stroke recurrence, suggesting a treatment failure. Clinicians often face these perplexing situations that result in therapeutic dilemmas for future anticoagulation options. At this juncture, clinicians are posed with the theranostic question of whether or not this correlates with a treatment failure?

Superiority of apixaban

Various individual trials have compared warfarin with different NOACs, including dabigatran, xarelto, and edoxaban, and demonstrated their noninferior efficacy compared to warfarin in secondary stroke prevention for NVAF patients. Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)[4] demonstrated the superior efficacy of apixaban over warfarin, whereas Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES)[5] trial demonstrated comparable bleeding rates when apixaban is compared to aspirin.

Stroke mechanism based on neuroimaging

Neuroimaging in stroke is an important component in the assessment of stroke mechanisms. Imaging patterns in AIS tend to differentiate various stroke mechanisms and support clinicians in therapeutic decision-making. Cardioembolic stroke usually has a predilection for multiple cortical arterial territories, whereas cervical atheroembolic phenomenon demonstrates distal borderzone ischemia. Lacunar stroke in deep subcortical and posterior circulation areas demonstrates atherothrombotic phenomenon involving small perforating branches. Differentiation of various stroke mechanisms from cardioembolic etiologies such as NVAF, determines the utilization of various antithrombotic options during clinical decision-making. Antiplatelet and anticholesterol therapy with lifestyle modifications has been pivotal in atheroembolic and lacunar infarction; however, anticoagulation is essential in reducing stroke recurrence in NVAF patients. It is prudent to thoroughly assess stroke mechanisms via the neuroimaging patterns prior to adjudication of an anticoagulation option such as apixaban as a treatment failure.

Significance of medication compliance and metabolism

Apixaban is a reversible inhibitor of Factor Xa activity and a substrate of CYP3A4 and P-gp. Given its rapid onset of action with a peak effect of 3–4 hours and rapid clearance with a half-life of 10–14 hours, coagulation monitoring is not routinely performed. Due to the lack of drug monitoring, the compliance of a drug cannot be followed and confirmed. Patients need to pay due consideration to the dosing and frequency of administration of the drug because a couple of missed doses could predispose to a prothrombotic state. Similarly, drug interactions need to be monitored as the concomitant use of CYP3A4 and P-gp reduces the bioavailability of apixaban and increases the thromboembolic risk.

Future aspects

Recent advent of NOACs has rendered a plethora of anticoagulant options in the clinical practice. However, more data is needed to establish the safety, therapeutic efficacy, and reversal of hemorrhagic complications. A head-to-head comparative, randomized clinical trial among individual NOACs for NVAF patients would establish the superiority and preference of various medications in clinical practice. Coagulation monitoring assays with modified chromogenic anti-Xa profiling for Factor Xa inhibitors would be prudent for compliance and dose adjustments in the future. Similarly, reversal agents for hemorrhagic complications secondary to NOAC would solve dilemmas during emergent scenarios. After the approval of idarucizumab for reversing the effects of dabigatran, reversal agents for Factor Xa inhibitors, such as andexanet alfa, are currently being investigated.[6]

Our approach and recommendations

From our clinical practice, we would like to provide our recommendations for cases with recurrence of AIS on apixaban [Table 1]. Continuous monitoring of drug compliance and identification of triggers that lead to medication discontinuation remains pivotal. Identification of imaging patterns remains important in differentiating various stroke mechanisms. Given the established superiority of apixaban over warfarin, we suggest the continuation of apixaban for patients with stroke recurrence and recommend the exclusion of other potential etiologies prior to considering its lack of effect as a treatment failure.
Table 1: Recommendations for stroke recurrence on apixaban

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Conflicts of interest

There are no conflicts of interest.

  References Top

Malhotra K, Liebeskind DS. Imaging in endovascular stroke trials. J Neuroimaging 2015;25:517-27.  Back to cited text no. 1
Barnes GD, Kaatz S, Winfield J, Gu X, Haymart B, Kline-Rogers E,et al. Warfarin use in atrial fibrillation patients at low risk for stroke: Analysis of the michigan anticoagulation quality improvement initiative (maqi(2)). J Thromb Thrombolysis 2014;37:171-6.  Back to cited text no. 2
Malhotra K, Khunger M, Liebeskind DS. Non-vitamin K oral anticoagulants in stroke patients: Practical issues. J Stroke 2017;19:104-6.  Back to cited text no. 3
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M,et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.  Back to cited text no. 4
Flaker GC, Eikelboom JW, Shestakovska O, Connolly SJ, Kaatz S, Budaj A,et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: The apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (averroes) trial. Stroke 2012;43:3291-7.  Back to cited text no. 5
Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL,et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373:2413-24.  Back to cited text no. 6


  [Table 1]


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