Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, which is often fatal or disabling. Prevention of stroke is crucial in AF management, and anticoagulation with non-vitamin K oral anticoagulants (NOACs) is the mainstay of AF management for stroke prevention. Because NOAC prescriptions have been surging worldwide, the development of acute ischemic stroke in patients with AF who receive NOAC treatment is an increasingly important issue in clinical practice. Moreover, these patients show a high risk of recurrence, with more than a 50% higher risk, than do patients with AF and no prior anticoagulation therapy. Careful evaluation is mandatory to determine possible causes of ischemic stroke during NOAC therapy. Differentiation of AF-unrelated stroke and demonstration of combined cardiac disease/systemic coagulopathy are important in these patients and may provide improved results in their treatment. In addition, ensuring appropriate dosing and good adherence to NOAC treatment is important. Cardioembolism, despite sufficient anticoagulation and no other causes, is the most common and challenging complication because switching to anticoagulants or adding antiplatelets to the treatment regimen does not reduce the risk of recurrent stroke, and there are no guidelines for this specific situation. This review article aimed to present the most updated data on the prevalence, causes, and secondary prevention strategies, specifically focusing on non-pharmacological approaches, together with relevant cases of AF in patients who developed ischemic stroke on NOAC therapy.
Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, which is often fatal or disabling. Prevention of stroke is crucial in AF management, and oral anticoagulants (OAC) are mainly used for stroke prevention in patients with AF. Four pivotal randomized controlled trials (RCTs) of non-vitamin K OACs (NOACs)—apixaban, dabigatran, edoxaban, and rivaroxaban—showed non-inferiority to vitamin K antagonists (VKA) in the prevention of stroke/systemic embolism (SE) in patients with AF [
Recently, data on the characteristics of patients with AF who develop ischemic stroke despite NOAC therapy have been accumulating. In addition, significant advances in non-pharmacological approaches to prevent stroke in patients with AF who are ineligible for NOAC treatment have taken place. This review aimed to present the most updated data on the prevalence, causes, and secondary prevention strategies, specifically focusing on nonpharmacological approaches, in patients with AF who developed ischemic stroke while taking NOACs.
For this review, we searched PubMed and ClinicalTrials.gov for relevant references of studies published in English up to July 2022 using the search terms atrial fibrillation, stroke, dabigatran, rivaroxaban, apixaban, edoxaban, NOAC failure, DOAC failure, and left atrial appendage. Additionally, we identified references in relevant articles and reviews. The final reference list was generated on the basis of originality and relevance to this topic.
Recent studies have shown that 20%–36% of ischemic strokes in patients with AF occur while taking VKAs or NOACs: 20.1% in real-world multicenter data of Korea–Japan [
Auer et al. [
Seiffge et al. [
In all aforementioned studies, no significant difference was observed in the risk of hemorrhagic stroke between patients with prior OAC therapy and those with no prior anticoagulation therapy before index stroke.
Although carotid intervention is the mainstay treatment for symptomatic carotid stenosis, not all recurrent stroke in patients with carotid stenosis are due to a carotid origin. Likewise, AF is not always an etiology of stroke in patients with AF and ischemic stroke. A sub-analysis of a prospective, open-label, multicenter, post-marketing surveillance study in South Korea of 651 patients with stroke and AF treated with apixaban showed that patients with cerebral atherosclerotic lesions had a higher rate of major events than did those without (4.6% vs. 1.7%,
We compared morphometric and volumetric parameters of the left atrial appendage (LAA) on multidetector cardiac computed tomography (CT) between patients with AF-related and unrelated strokes [
Non-adherence to prescribed NOACs could be a cause of stroke while taking NOACs. A large US commercial insurance database of 64,661 patients with AF showed that adherence to OAC therapy is poor and modestly improved with NOACs [
The use of lower doses than those recommended in drug data sheets is not uncommon, especially in Asian populations [
Drug interactions could be another pharmacokinetic cause of NOAC failure [
Combined cardiac or systemic illness should be suspected in patients with AF after treatment failure with NOAC. Valvular AF is defined as AF related to rheumatic valvular disease or prosthetic heart valve. The pivotal NOAC trials included a substantial number of patients with valvular heart diseases. The sub-studies of pivotal trials compared the effects of NOACs and VKA in patients with AF and valvular heart disease and supported the use of NOACs in patients with AF and valvular heart disease, excluding only those with prosthetic valve disease or hemodynamically significant mitral stenosis [
Coagulopathy may coexist in patients with AF. Among the causes of coagulopathy, malignancy and antiphospholipid antibody syndrome (APS) have been reported to be associated with NOAC failure [
This is the most common and challenging entity in the selection of optimal pharmacological and non-pharmacological strategies to prevent recurrent ischemic stroke. Polymeris et al. [
High CHA2DS2-VASc scores and the presence of individual components of the scoring system (e.g., heart failure and prior stroke) were associated with the occurrence of ischemic stroke in patients with AF on NOACs. The RENo study investigators compared the characteristics of 713 patients with AF who had a stroke during NOAC therapy with those of 700 patients with AF who did not have a stroke during NOAC therapy to investigate the pathogenesis and risk factors for a stroke occurring during NOAC therapy for stroke prevention [
In addition to the CHA2DS2-VASc score, impaired renal function was associated with NOAC failure. Patients with AF often show decreased estimated glomerular filtration rates (eGFR), and chronic kidney disease (CKD) could be a predictor of LAA thrombus in patients taking NOACs. Budnik et al. [
Left atrial (LA) and LAA features are associated with the occurrence of ischemic stroke/TIA and the presence of an LA/LAA thrombus in patients taking NOACs. Yaghi and IAC study investigators showed that severe LA enlargement was more prevalent in patients with prior anticoagulant use than in those with no anticoagulant use prior to index stroke (43.9% vs. 34.9%,
Fastner et al. [
Several case series have shown successful resolution of LAA thrombi with dabigatran, a factor IIa inhibitor that had been refractory to rivaroxaban, a factor Xa inhibitor [
Several observational studies have investigated whether changes in OACs are associated with a reduced risk of stroke recurrence in patients receiving anticoagulation therapy before the stroke. Seiffge et al. [
In summary, to our knowledge, no evidence indicates that the addition of antiplatelet agents to OACs or supratherapeutic INR improves outcomes in secondary stroke prevention. In addition, no study has prospectively evaluated the efficacy of the change in OAC therapy (either from NOAC to VKA or from one NOAC to another NOAC), and further RCT studies are needed for patients with cardioembolic stroke, despite sufficient anticoagulation.
Genetic variability could cause susceptibility to recurrent stroke in patients with AF and OAC use.
More than 90% of atrial thrombi in patients with non-rheumatic AF originate in the LAA [
In 2001, Sievert et al. [
Considering the procedural aspects, pre- and post-procedural imaging between 1 and 6 months with either cardiac CT angiography or TEE are recommended to rule out pre-existing LAA thrombus and detect device-related thrombus (DRT) and peri-device leak, respectively [
The following issues need to be addressed by future randomized studies. First, effectiveness and safety of catheter-based LAAO compared with NOACs should be evaluated in patients with NOAC failure. Antithrombotic therapy after LAAO has never been evaluated in RCTs. Thus, current guidelines recommend that LAAO may be considered for stroke prevention in patients with AF who have contraindications for long-term OAC and high bleeding risk under chronic OAC (Class IIb) [
Standalone or concomitant surgical LAAO during cardiac surgery has been performed for decades. To avoid the invasiveness of conventional cardiac surgery, minimally invasive LAAO, including totally thoracoscopic or da Vinci robotic cardiac surgery systems, has been performed. Currently, three methods are available to occlude the LAA: internal obliteration, epicardial resection with a stapler, and epicardial occlusion with clip devices (
Endocardial suture obliteration of the LAA is an invasive procedure that requires the use of cardiopulmonary bypass, with an associated risk of bleeding and injury to the adjacent structures around the mitral annulus, such as the circumflex coronary artery. In addition, it is incomplete in 10%–30% of patients [
In a landmark study in 2008, different surgical techniques were used to evaluate surgical LAAO from 1993 to 2004 [
Because of the low success rate of LAA exclusion using sutures, LAA resection using staplers or occlusion using a clip system is being adopted. The AtriClip device (AtriCure, Inc., Mason, OH, USA) is the first approved device for surgical LAA exclusion and has been deployed in more than 300,000 patients worldwide. This is a self-closing implantable clip made of two parallel titanium bars, connected with nitinol hinges and covered in a braided polyester lining. The clip may be repositioned if the initial placement is inadequate. After deployment, it produces a constant compression pressure, ensuring the complete exclusion of the LAA. This retrospective analysis assessed the long-term LAA efficacy of the AtriClip device applied via a totally thoracoscopic approach with chest CT [
A recent meta-analysis of the AtriClip system found that complete closure was 97.8%, and there were no periprocedural device-related adverse events in 922 patients [
Although more data on surgical LAAO are emerging, evidence from RCTs on LAAO remains scarce. The LAAOS III study (Left Atrial Appendage Occlusion Study III) randomized 4,811 patients who either underwent or did not undergo surgical LAAC at the time of cardiac surgery for another indication [
Although anticoagulation with NOACs is the mainstay of AF management to prevent stroke, caution is required in patients with AF at high risk of stroke who have been under-represented or not studied in the RCTs of NOACs for stroke prevention. Development of acute ischemic stroke in patients with AF while receiving NOAC treatment is becoming an increasingly important issue in clinical practice. This is due to an increase in the number of patients with preceding NOAC therapy and a high risk of recurrence (>50% higher risk than in patients with AF and no prior anticoagulation therapy). Careful evaluation is mandatory to determine the possible causes of ischemic stroke during NOAC therapy (
The results of the aforementioned studies showed that switching anticoagulation therapeutics does not reduce the risk of recurrent stroke in high-risk patients, including patients with renal impairment and older patients with multiple risk factors, and, more importantly, those who develop stroke on NOAC therapy. Novel pharmacological approaches, such as factor XIa inhibitors, and non-pharmacological interventional treatments, either percutaneous or surgical LAAO, are warranted in patients with AF and stroke despite sufficient NOAC use. Most recent guidelines recommend that LAAO may be considered for stroke prevention in patients with AF and contraindications for long-term anticoagulant treatment (e.g., intracranial bleeding without a reversible cause) and that surgical occlusion or exclusion of the LAA may be considered for stroke prevention in patients with AF undergoing cardiac surgery [
This study was supported by the National Research Foundation of Korea grant (no. 2022R1A2C209148111).
The authors have no financial conflicts of interest.
Conceptualization: OYB. Study design: OYB. Methodology: all authors. Data collection: all authors. Investigation: all authors. Writing—original draft: all authors. Writing—review & editing: all authors. Funding acquisition: OYB. Approval of final manuscript: all authors.
Competing mechanism: high-resonance magnetic resonance imaging (MRI) findings of a 69-year-old man with atrial fibrillation on anticoagulated with edoxaban. (A) He experienced transient right hemiparesis. He was taking edoxaban with good adherence. Magnetic resonance (MR) angiogram shows focal stenosis on the distal M1 segment. No acute infarct is observed on diffusion-weighted imaging and MR perfusion showed perfusion delay on the left middle cerebral artery hemisphere. High resonance MRI shows intraplaque hemorrhage on T1-weighted images (arrow) and eccentric wall thickening and enhancement on contrast-enhanced T1-weighted images (arrowhead) suggesting unstable intracranial plaque. The echocardiogram showed no cardiac thrombi and left atrial enlargement was not prominent. Clopidogrel and a high-dose statin were added to edoxaban. (B) A follow-up high-resolution MRI at 6 months of treatment. Plaque enhancement disappears (arrowhead). TOF-MRA, time-of-flight magnetic resonance angiography.
Recurrent cardioembolism despite sufficient anticoagulation: a 76-year-old woman experienced recurrent stroke despite sufficient anticoagulation. (A) Warfarin was switched to rivaroxaban owing to poor international normalized ratio control. She was a
Percutaneous left atrial appendage (LAA) occluder devices: (A) PLAATO, (B) WATCHMAN, and (C) Amplatzer. Echocardiographic views of the devices: (D) WATCHMAN and (E) Amplatzer. LA, left atrium; white arrow, LAA; white triangle, LAA occluder device.
Epicardial left atrial appendage (LAA) exclusion: resection and occlusion. (A) Epicardial resection using a stapler. LAA is resected using a stapling device. A suture line at the base of LAA demonstrates no residual stump. (B) Epicardial occlusion with clip devices. LAA is occluded using a white-color clip device at the base of LAA. LAA is left unresected.
Relative reduction of ischemic stroke with surgical left atrial appendage occlusion, compared with the predicted rate. Relative ischemic stroke reduction compared with the predicted rate. (A) Overall patients. (B) Patients other than those with CHA2DS2-VASc score 0. Adapted from Kim et al.
Possible causes of ischemic stroke during NOAC treatment
Ischemic stroke during NOAC therapy in patients with non-valvular AF (20%–36%) [ |
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Competing mechanism (AF-unrelated stroke) | Inappropriate low dose of NOACs | Cardioembolism despite sufficient anticoagulation | |
Proportion | 24% Among prior NOAC user [ |
32% Among prior NOAC user [ |
44% Of prior NOAC users [ |
16.4% Had atherosclerotic stenosis >50%. [ |
13.3% Recurred with off-label reduced doseof a NOAC. [ |
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25.8% Had non-cardioembolic stroke. [ |
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30.8% Recurred as non-cardioembolic stroke. [ |
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Examples | Atherosclerotic or lacunar stroke (Figure 1) | Poor adherence | LA enlargement (Figure 2) |
Other causes, such as hidden cancer or valvular heart disease | Off-label low dose | ||
Drug interactions | |||
Workup | Brain MRI for infarct pattern and vascular stenosis | Medication history for NOAC adherence and concomitant medications | Cardiac imaging (CCTA) |
Coagulopathy, such as D-dimer and antiphospholipid antibodies | Coagulation test, e.g., aPTT and PT | Echocardiographic LA dysfunction measure | |
Therapeutic strategies | Use antiplatelet and statins as appropriate | Education for adherence and drug interaction | Interventional LAA closure |
Switch to LMWH in cancer coagulopathy or VKA for Valvular heart disease or antiphospholipid syndrome | Standard dosing of NOACs | LAA surgical resection | |
Avoid enzyme inducers |
NOAC, non-vitamin K oral anticoagulant; AF, atrial fibrillation; LA, left atrium; MRI, magnetic resonance imaging; aPTT, activated partial thromboplastin time; PT, prothrombin time; CCTA, coronary computed tomography angiography; LMWH, low-molecular-weight heparin; VKA, vitamin K antagonist; LAA, left atrial appendage.
Current ongoing clinical trials
Study names (Clinicaltrials. gov; unique identifier) | Design (No. of participants) | Subjects | Study arms | Primary outcomes | |
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Non-interventional | |||||
NOACISP Long Term (NCT03826927) | Observational (n=1,000) | Patients with AF and recent stroke/TIA/ICH with/without prior OAC therapy | NOAC vs. VKA | Change in anticoagulation treatment (2 years) | |
MAFIC study (NCT04508855) | Observational (n=240) | Patients with cancer and AF receiving NOACs and antineoplastic therapy | Continue NOACs vs. switch to LMWH | Major bleeding and clinically relevant bleeding (6 months) | |
LEAVE Safe With DOACs (NCT04068727) | RCT (n=561) | New prescription of NOAC or new episode of thromboembolic/bleeding event during NOAC use | Education by clinical pharmacists for drug adherence vs. no additional guidance | Number of NOAC-related clinically important medication errors (90 days) | |
MAS study (NCT03803579) | Observational laboratory (n=4,000) | Patients with NVAF | Blood sampling at 15–20 days after enrollment | Measurement of plasma concentration of NOACs and their correlation with the occurrence of stroke, SE, major bleeding, and death | |
DOAC-REAL (NCT05378035) | Observational laboratory (n=427) | Patients with NVAF who require 48 h interruption of NOACs for elective medical procedures | Blood sampling for NOAC levels and pharmacogenomic studies | Measurement of NOAC pharmacokinetic profiles during 48 h interruption period and occurrence of stroke/SE/bleeding | |
Catheter-based LAAO devices | |||||
ASAP-TOO (NCT02928497) | RCT (n=481) | Patients with NVAF who are deemed not suitable for OAC therapy | WATCHMAN vs. single antiplatelet therapy or no therapy | 7-Day combined rate of death, ischemic stroke, SE, complications requiring major cardiovascular or endovascular intervention | |
STROKECLOSE (NCT02830152) | RCT (n=750) | Patients with NVAF with intracerebral hemorrhage within 6 months | Amulet vs. medical therapy | Composite endpoint of stroke, SE, life-threatening or major bleeding, and all-cause mortality (5 years) | |
CLOSURE-AF (NCT03463317) | RCT (n=1,512) | Patients with NVAF with a high risk of bleeding or contraindication for OAC therapy | CE-marking approved LAA closure devices vs. medical therapy | Composite of stroke, SE, major bleeding, and cardiovascular and unexplained death (2 years) | |
Occlusion-AF (NCT03642509) | RCT (n=750) | Patients with NVAF who are eligible for NOAC therapy | Amulet and WATCHMAN vs. NOAC | Composite endpoint of stroke, SE, major bleeding, and all-cause mortality (5 years) | |
CHAMPION-AF (NCT04394546) | RCT (n=3,000) | Patients with NVAF who are eligible for OAC therapy | WATCHMAN FLX vs. NOAC | The occurrence of stroke, cardiovascular death, and SE (3 years) | |
CATALYST (NCT04226547) | RCT (n=2,650) | Patients with NVAF who are eligible for NOAC therapy | Amulet vs. NOAC | Composite of ischemic stroke, SE, and cardiovascular mortality (2 years) |
NOACISP Long Term, New Oral Anticoagulants (NOAC) in Stroke Patients; MAFIC study, Management of Atrial Fibrillation in Patients With Cancer; LEAVE Safe With DOACs, Leveraging Evidence-based Practices for Ambulatory VTE and Other Patients to be Safe With Direct Oral Anticoagulants; MAS study, Baseline Concentration of Direct Oral Anticoagulant and Incidence of Adverse Event Measure And See; DOAC-REAL, Direct Oral Anticoagulant Levels in Chinese Patients With Atrial Fibrillation - A Real-World Pharmacokinetic Study; ASAP-TOO, Assessment of the WATCHMAN™ Device in Patients Unsuitable for Oral Anticoagulation; STROKECLOSE, Prevention of Stroke by Left Atrial Appendage Closure in Atrial Fibrillation Patients After Intracerebral Hemorrhage; CLOSURE-AF, Left Atrial Appendage CLOSURE in Patients With Atrial Fibrillation Compared to Medical Therapy; Occlusion-AF, Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation; CHAMPION-AF, WATCHMAN FLX Versus NOAC for Embolic ProtectION in in the Management of Patients With Non-Valvular Atrial Fibrillation; CATALYST, Clinical Trial of Atrial Fibrillation Patients Comparing Left Atrial Appendage Occlusion Therapy to Non-vitamin K Antagonist Oral Anticoagulants; AF, atrial fibrillation; TIA, transient ischemic attack; ICH, intracerebral hemorrhage; OAC, oral anticoagulation; NOAC, non-vitamin K oral anticoagulant; VKA, vitamin K antagonist; LMWH, low molecular weight heparin; DOAC, direct oral anticoagulants; RCT, randomized controlled trial; NVAF, non-valvular atrial fibrillation; SE, systemic embolism; LAAO, left atrial appendage occlusion; CE, Conformité Européene; LAA, left atrial appendage.