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Oral anticoagulants vs antiplatelets in cryptogenic stroke with potential cardiac emboli: Meta-analysis

Open AccessPublished:August 18, 2021DOI:https://doi.org/10.1016/j.ejim.2021.08.002

      Learning points

      • Oral anticoagulants compared with antiplatelet therapies may be associated with a reduced recurrent ischemic stroke risk in patients with cryptogenic stroke and potential cardiac emboli.
      • The benefits of oral anticoagulants are homogenous across patent foramen ovale, moderate-severe left atrial enlargement, and heart failure with reduced ejection fraction.
      • Oral anticoagulants compared with antiplatelet therapies may be associated with a non-significant increased risk major bleeding in patients with cryptogenic stroke and potential cardiac emboli.
      • Oral anticoagulants might be a viable non-procedural alternative in patients with cryptogenic stroke and potential cardiac emboli.

      Abstract

      Background

      The best antithrombotic strategy for cryptogenic stroke with potential cardiac emboli is not known. The objective of this study was to conduct a meta-analysis to evaluate the efficacy and safety of oral anticoagulants (OACs) vs. antiplatelet therapies in these patients

      Methods

      Pubmed, EMBASE, CENTRAL and clinicaltrials.gov were searched from January 1980 to April 2021 to identify trials comparing OACs versus antiplatelet therapies in patients with cryptogenic stroke and potential cardiac emboli (patent foramen ovale, moderate-severe left atrial enlargement, heart failure with reduced ejection fraction). Relative risk (RR) with 95% confidence (CI) was used as a measure of the effect of OACs versus antiplatelet therapies on recurrent ischemic stroke and major bleeding. We computed a random-effect estimate based on the Mantel-Haenszel method for a given outcome.

      Results

      We identified 6 studies derived from 5 trials with 2282 patients. Pooled results from 6 studies showed that compared with antiplatelet therapies, OACs were associated with a lower risk of recurrent ischemic stroke (RR 0.61, 95% CI 0.41 to 0.91, P=0.02). Only 3 studies of cryptogenic stroke with patent foramen ovale reported a major bleeding endpoint and pooled results from random-effects model showed that OACs compared with antiplatelet therapies were associated with a non-significantly increased risk of major bleeding (RR 1.61, 95% CI 0.76 to 3.40, P=0.21).

      Conclusions

      OACs compared with antiplatelet therapies were associated with a reduced recurrent ischemic stroke risk and OACs might be a viable non-procedural alternative in patients with cryptogenic stroke and potential cardiac emboli.

      Keywords

      1. Introduction

      Cryptogenic strokes are cerebral infarcts for which no probable underlying pathophysiologic cause is identified after adequate diagnostic evaluation [
      • Saver JL.
      Clinical practice. Cryptogenic stroke.
      ]. However, it's been shown that some strokes classified as cryptogenic are actually caused by cardioembolism from medium-grade cardiac sources, such as paradoxical embolism related to presence of a patent foramen ovale (PFO) [
      • Saver JL.
      Clinical practice. Cryptogenic stroke.
      ]. A meta-analysis of randomized controlled trials suggests that device closure plus medical therapy, compared with medical therapy alone, reduces the risk of recurrent ischemic stroke among patients with cryptogenic strokes [
      • Saver JL
      • Mattle HP
      • Thaler D.
      Patent foramen ovale closure versus medical therapy for cryptogenic ischemic stroke: a topical review.
      ], supporting a causal role for PFO and paradoxical embolism in the genesis of embolic stroke in some cryptogenic stroke patients [
      • Hankey GJ.
      Drugs, devices, and procedual therapies.
      ].
      Left atrial diameter has a graded and independent association with ischemic stroke in women [
      • Bouzas-Mosquera A
      • Broullon FJ
      • Alvarez-Garcia N
      • Mendez E
      • Peteiro J
      • Gandara-Sambade T
      • et al.
      Left atrial size and risk for all-cause mortality and ischemic stroke.
      ], and among stroke patients without atrial fibrillation (AF), moderate-severe left atrial enlargement (LAE) vs. normal left atrial size trends towards higher risk of recurrent cardioembolic or cryptogenic stroke [
      • Yaghi S
      • Moon YP
      • Mora-McLaughlin C
      • Willey JZ
      • Cheung K
      • Di Tullio MR
      • et al.
      Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study.
      ]. Heart failure with reduced ejection fraction (HFrEF) and normal sinus rhythm is likely a prothrombotic state with a higher plasma viscosity, soluble P-selectin, von Willebrand factor and fibrinogen [
      • Gibbs CR
      • Blann AD
      • Watson RD
      • Lip GY.
      Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy.
      ], and ranks second as a cause of cardiogenic stroke after AF [
      • Pullicino P
      • Thompson JL
      • Mohr JP
      • Sacco RL
      • Freudenberger R
      • Levin B
      • et al.
      Oral anticoagulation in patients with cardiomyopathy or heart failure in sinus rhythm.
      ].
      While antithrombotic therapy is a cornerstone for secondary stroke prevention, administration of a given antithrombotic agent depends on the underlying pathophysiologic mechanism of the index stroke. In this study, we hypothesized that in cryptogenic stroke with potential cardiac emboli, oral anticoagulants (OACs) would be superior to antiplatelet therapies for secondary stroke prevention. We therefore conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of OACs compared with antiplatelet therapies in cryptogenic stroke patients with potential cardiac emboli.

      2. Methods

      This study was a systematic review and meta-analysis of randomized clinical trials and did not need institutional review board or ethics committee approval. This study was performed in accordance with the recommendations of the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) statement [
      • Hutton B
      • Salanti G
      • Caldwell DM
      • Chaimani A
      • Schmid CH
      • Cameron C
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ].

      2.1 Data sources and searches

      We searched Pubmed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and the clinical trial registry maintained at clinicaltrials.gov covering the period of January 1 1980 to April 30 2021, utilizing these terms: warfarin or coumadin or vitamin K antagonist or novel oral anticoagulants or non-vitamin K antagonist oral anticoagulants or direct oral anticoagulants or Factor Xa Inhibitors or thrombin inhibitor or dabigatran or rivaroxaban or apixaban or edoxaban and antiplatelet or aspirin or acetylsalicylic acid or ASA or clopidogrel or dipyridamole or ticlopidine or cilostazol and strokes or cerebrovascular accident or CVA or cerebrovascular apoplexy or brain vascular accident or cerebrovascular stroke or apoplexy or cerebral stroke or acute cerebrovascular accident or cerebrovascular disorder or intracranial vascular disease or cerebrovascular disease or brain vascular disorder or cerebrovascular occlusion or cerebrovascular insufficiency and cryptogenic or patent foramen ovale or heart failure or reduced ejection fraction or atrial enlargement. We restricted our search to human and clinical trials. There were no language restrictions. We reviewed the Introduction and Discussion sections of retrieved clinical trial publications, as well as relevant review articles, to identify additional studies. One investigator (WYH) abstracted the data and another investigator (ML) reviewed the abstracted data. Any discrepant judgments were resolved by joint discussion.

      2.2 Study selection

      Criteria for inclusion of a study were as follows: (1) the study design was a randomized controlled trial; and (2) all or an identifiable subset of participants had a history of cryptogenic stroke with potential cardiac emboli (PFO, moderate or severe LAE, or HFrEF). We included cryptogenic stroke with PFO irrespective of grade and presence of atrial septal aneurysm/defect, with moderate or severe LAE defined as left atrial diameter > 4.6 cm, and with HFrEF defined as heart failure with left ventricular ejection fraction 35% or less. (3) the study included a comparison of an OAC (warfarin, dabigatran, rivaroxaban, apixaban or edoxaban) with antiplatelet therapy; (4) recurrent ischemic stroke was reported as an endpoint; (5) total participants and the number with recurrent ischemic stroke were reported separately in each group; and (6) treatment duration was for at least 6 months.
      Although the concept of cryptogenic stroke includes both a lack of a clear source and the presence of more than one source of ischemic stroke, we excluded patients with either AF or extracranial or intracranial arterial stenosis≧50% and therefore we actually explored OACs vs antiplatelet therapies in patients with embolic stroke of undetermined source (ESUS) who had potential cardiac emboli. Additional exclusion criteria were if participants had (1) blood coagulation disorder; (2) an antiplatelet agent was used in an active arm; or (3) an OAC was used in a control arm.

      2.3 Data abstraction

      We abstracted data about baseline characteristics including age, sex, duration of follow-up, study populations, patient number, and antithrombotic agents from each group. We also abstracted data on recurrent ischemic stroke and major bleeding by antithrombotic type (OACs vs. antiplatelet agents) from each study.

      2.4 Quality assessment

      The risk of bias (e.g. sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other issues) of included studies was assessed using the Cochrane risk of bias tool [
      • Higgins JPT.
      Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated march 2011].
      ].

      2.5 Statistical analysis

      Data were analyzed according to the intention-to-treat principle. The primary endpoint was recurrent ischemic stroke and the secondary endpoint was major bleeding. Definition of the primary endpoint (i.e. recurrent ischemic stroke) was the first event of ischemic stroke after index ischemic stroke. If recurrent ischemic stroke was not reported, recurrent stroke would be used as the primary endpoint. Risk ratios (RRs) with 95% confidence intervals (CIs) were used to quantify the association of OACs vs antiplatelet therapies with recurrent ischemic stroke and major bleeding. We computed a random-effect estimate based on the Mantel-Haenszel method when 2 or more trials provided data for a given outcome. Sensitivity tests with comparing NOACs vs aspirin and warfarin vs aspirin for recurrent ischemic stroke and major bleeding, respectively, were also conducted. Heterogeneity was assessed by P value of chi-square statistics and I2, which describes the percentage of variability in the estimates that is due to heterogeneity rather than chance. We considered study-level estimates to be heterogeneous if I2 statistic was greater than 50%. For all analyses, two-sided P < 0.05 was considered statistically significant. Publication bias was assessed by funnel plots when there were at least 10 studies were included in the meta-analysis [
      • Higgins JPT.
      Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated march 2011].
      ]. The Cochrane Collaboration's Review Manager Software Package (RevMan 5.3) was used for this meta-analysis.

      3. Results

      We identified 62 full articles for detailed assessment, of which 56 were excluded for not meeting inclusion criteria, and the final analysis included 6 studies derived from 5 randomized controlled trials (Fig. 1) [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ,
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ,
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ] Overall, 2282 cryptogenic ischemic stroke patients with potential cardiac emboli had a total of 108 recurrent ischemic stroke events. The Table 1 shows the patient characteristics of the included studies. Five studies [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ,
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ] reported recurrent ischemic stroke as an endpoint whereas one study [
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ] only reported recurrent stroke as an endpoint. Recurrent ischemic stroke risk between OACs and antiplatelet therapy was assessed in 4 studies with PFO [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ,
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ], 1 study with moderate or severe LAE [
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ], and 1 study with HFrEF [
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ]. For an OAC arm, warfarin was used in 2 studies [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ], non-vitamin K antagonist oral anticoagulants (NOACs) were used 3 studies [
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ], and warfarin or NOACs were used in 1 study [
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ]. For an antiplatelet therapy arm, aspirin was used in 5 studies [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ,
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ] and aspirin, clopidogrel, or aspirin plus dipyridamole, or aspirin plus clopidogrel were used in 1 study [
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ]. Follow-up duration ranged from 0.9 to 5.3 years.
      Table 1Characteristics of included studies.
      Study acronym, publication yearPopulation characteristicsOral anticoagulant groupAntiplatelet groupMean age (years)Woman (%)Study duration, years
      CLOSE, 2017
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      Ischemic stroke with no identifiable cause other than a PFO with an associated atrial septal aneurysm or large interatrial shunt187 patients assigned to warfarin (with a target INR of 2 to 3) or NOAC174 patients assigned to antiplatelet therapy, including aspirin, clopidogrel, or aspirin plus dipyridamole44435.3
      NAVIGATE ESUS, 2018
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ESUS with PFO259 patients assigned to rivaroxaban 15mg once daily275 patients assigned to aspirin 100mg once daily65360.9
      PICSS, 2002
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      Cryptogenic stroke with PFO42 patients assigned towarfarin (with a target INR 1.4 to 2.8)56 patients assigned to aspirin 325mg once daily58412
      RE-SPECT ESUS, 202112ESUS with PFO319 patients assigned to dabigatran 150mg or 110mg twice daily361 patients assigned to aspirin 100mg once dailyNANA1.6
      NAVIGATE ESUS, 2019
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ESUS with left atrial diameter > 4.6 cm187 patients assigned to rivaroxaban 15mg once daily174 patients assigned to aspirin 100mg once dailyNANA0.9
      WARCEF, 2014
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      Heart failure with ejection fraction ≤35%, sinus rhythm and prior ischemic stroke128 patients assigned to warfarin (with a target INR 2 to 3.5)120 patients assigned to aspirin325 mg once dailyNANA3.5
      Trial names: CLOSE, Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence; NAVIGATE ESUS, New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source; PICSS, PFO in Cryptogenic Stroke Study; RE-SPECT ESUS, Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source; LA, Left atrial; WARCEF, the Warfarin versus aspirin in reduced cardiac ejection fraction.
      ESUS, Embolic Stroke of Undetermined Source; INR, International normalized ratio; NA: not available; NOAC, Non–vitamin K antagonist oral anticoagulant; PFO, Patent foramen ovale.
      The Cochrane risk of bias assessment for the included studies is summarized in Fig. 2 and no major risk of bias was found in the included studies.
      Fig 2
      Fig. 2Risk of bias
      Legends: Risk of bias of included studies.
      Fig 3
      Fig. 3recurrent ischemic stroke
      Legends: Relative risk with 95% confidence interval of recurrent ischemic stroke in oral anticoagulants vs antiplatelet therapy in cryptogenic stroke patients with potential cardiac emboli. OACs, oral anticoagulants.

      3.1 Recurrent ischemic stroke

      Of cryptogenic stroke patients with potential cardiac emboli, pooled results from 6 studies showed that OACs compared with antiplatelet therapies were associated with a lower risk of recurrent ischemic stroke (RR 0.61, 95% CI 0.41 to 0.91, P = 0.02) [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ,
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ,
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ] There was mild heterogeneity among subgroups of potential cardiac emboli (PFO: RR 0.69, 95% CI 0.43 to 1.11 vs left atrial diameter > 4.6cm: RR 0.25, 95% CI 0.07 to 0.89 vs HFrEF: RR 0.63, 95% CI 0.26 to 1.48; subgroup differences P=0.34, I2=6.6%) (Figurer 3).
      Since 2 studies [
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ] included in this meta-analysis presented different potential cardiac emboli subgroups, with PFO and moderate/severe LAE, respectively, from the same trial, it is conceivable that overlapping patient populations existed in 2 studies. We therefore conducted additional analyses to address this issue. When only subgroup of PFO [
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ] from NAVIGATE ESUS trial was used to be pooled with other trials, OACs compared with antiplatelet therapies were associated with a trend of lower risk of recurrent ischemic stroke (RR 0.68, 95% CI 0.45 to 1.02, P = 0.06) (Supplemental Fig. 1) [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ,
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ]. When only subgroup of moderate/severe LAE [
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ] from NAVIGATE ESUS trial was used to be pooled with other trials, OACs compared with antiplatelet therapies were associated with a lower risk of recurrent ischemic stroke (RR 0.58, 95% CI 0.34 to 0.97, P = 0.04) (Supplemental Fig. 2) [
      • Homma S
      • Sacco RL
      • Di Tullio MR
      • Sciacca RR
      • Mohr JP
      • PFOiCSS Investigators
      Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale in cryptogenic stroke study.
      ,
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ,
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ,
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ].

      3.2 Major bleeding

      The safety outcome was major bleeding according to International Society on Thrombosis and Hemostasis (ISTH) Criteria in 2 PFO studies [
      • Diener HC
      • Chutinet A
      • Easton JD
      • Granger CB
      • Kleine E
      • Marquardt L
      • et al.
      Dabigatran or aspirin after embolic stroke of undetermined source in patients with patent foramen ovale: Results from RE-SPECT ESUS.
      ,
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ] and major or fatal hemorrhagic complications in another PFO study [
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ]. Pooled results from these 3 studies showed that OACs compared with antiplatelet therapies were associated with a non-significantly increased risk of major bleeding (RR 1.61, 95% CI 0.76 to 3.40, P=0.21) (Fig. 4).
      Fig 4
      Fig. 4Major bleeding
      Legends: Relative risk with 95% confidence interval of major bleeding in oral anticoagulants vs antiplatelet therapy in cryptogenic stroke patients with potential cardiac emboli. OACs, oral anticoagulants.
      Since only 6 studies were included in the current meta-analysis, publication bias was not assessed by the funnel plots.

      3.3 Sensitivity tests

      NOACs compared with aspirin were associated with a non-significantly lower risk of recurrent ischemic stroke (RR 0.61, 95% CI 0.29 to 1.27, P=0.19) whereas warfarin compared with aspirin were associated with a lower risk of recurrent ischemic stroke (RR 0.50, 95% CI 0.26 to 0.96, P=0.04) (Supplemental Fig. 3). NOACs compared with aspirin were associated with a non-significantly increased risk of major bleeding (RR 1.22, 95% CI 0.40 to 3.73, P=0.73) whereas warfarin compared with aspirin were associated with a non-significantly increased risk of major bleeding (RR 2.33, 95% CI 0.74 to 7.28, P=0.15) (Supplemental Fig. 4).

      4. Discussion

      In this meta-analysis, comprising 6 studies that enrolled 2282 cryptogenic ischemic stroke patients with potential cardiac emboli, we found that OACs compared with antiplatelet therapies, were significantly associated with a 39% risk reduction of recurrent ischemic stroke, along with a non-significant rise in major bleeding risk. Still, we cannot exclude the possibility that these pooled results were biased due to confounding from the different characteristics of enrolled patients (i.e. PFO, left atrial diameter > 4.6cm, and HFrEF). Therefore, these observational data should only be seen as a suggestive rather than a definitive evidence-based guide for clinical practice.
      We observed that OACs trended towards being a better secondary stroke prevention strategy than antiplatelet therapies in cryptogenic stroke patients with PFO. Prior randomized clinical trials show that closure of PFO plus antiplatelet therapy is superior to antiplatelet therapy alone [
      • Mas JL
      • Derumeaux G
      • Guillon B
      • Massardier E
      • Hosseini H
      • Mechtouff L
      • et al.
      Patent foramen ovale closure or anticoagulation vs. Antiplatelets after stroke.
      ,
      • Sondergaard L
      • Kasner SE
      • Rhodes JF
      • Andersen G
      • Iversen HK
      • Nielsen-Kudsk JE
      • et al.
      Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke.
      ,
      • Saver JL
      • Carroll JD
      • Thaler DE
      • Smalling RW
      • MacDonald LA
      • Marks DS
      • et al.
      Long-term outcomes of patent foramen ovale closure or medical therapy after stroke.
      ], but not OACs alone [
      • Saver JL
      • Carroll JD
      • Thaler DE
      • Smalling RW
      • MacDonald LA
      • Marks DS
      • et al.
      Long-term outcomes of patent foramen ovale closure or medical therapy after stroke.
      ], for secondary stroke prevention, which implies that OACs could probably be used in these patients, if medical therapy alone is being considered.
      Underlying atrial cardiopathy, such as moderate-severe LAE, may cause left atrial thromboembolism in the absence of recognized AF, and OACs might be more capable than antiplatelet therapies to prevent future stroke with such an underlying mechanism [
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ,
      • Kamel H
      • O'Neal WT
      • Okin PM
      • Loehr LR
      • Alonso A
      • Soliman EZ
      Electrocardiographic left atrial abnormality and stroke subtype in the atherosclerosis risk in communities study.
      ]. Subgroup analysis of a trial of patients with HFrEF and sinus rhythm who had a history of prior stroke showed that recurrent ischemic stroke events were numerical lower, although not achieving statistical significance, among patients taking warfarin than aspirin [
      • Pullicino PM
      • Qian M
      • Sacco RL
      • Freudenberger R
      • Graham S
      • Teerlink JR
      • et al.
      Recurrent stroke in the warfarin versus aspirin in reduced cardiac ejection fraction (WARCEF) trial.
      ]. This finding aligns with evidence suggesting warfarin compared with aspirin was associated with lower risk of stroke in patients with HFrEF and sinus rhythm [
      • Lee M
      • Saver JL
      • Hong KS
      • Wu HC
      • Ovbiagele B.
      Risk-benefit profile of warfarin versus aspirin in patients with heart failure and sinus rhythm: a meta-analysis.
      ]. Furthermore, both moderate-severe LAE and HFrEF are associated with higher risk of new incident or unrecognized AF [
      • Perlepe K
      • Sirimarco G
      • Strambo D
      • Eskandari A
      • Karagkiozi E
      • Vemmou A
      • et al.
      Left atrial diameter thresholds and new incident atrial fibrillation in embolic stroke of undetermined source.
      ,
      • Wang TJ
      • Larson MG
      • Levy D
      • Vasan RS
      • Leip EP
      • Wolf PA
      • et al.
      Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study.
      ], for which an OAC is indicated.
      The risk of major bleeding possessed by each individual NOAC is important when that NOAC to be considered in a clinical scenario other than treatment of patients with AF. Meta-analysis of randomized clinical trials [
      • Lopez-Lopez JA
      • Sterne JAC
      • Thom HHZ
      • Higgins JPT
      • Hingorani AD
      • Okoli GN
      • et al.
      Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis.
      ,
      • Huang WY
      • Singer DE
      • Wu YL
      • Chiang CE
      • Weng HH
      • Lee M
      • et al.
      Association of intracranial hemorrhage risk with non-vitamin k antagonist oral anticoagulant use vs aspirin use: a systematic review and meta-analysis.
      ], as well as results from a US nationwide claims database [
      • Fralick M
      • Colacci M
      • Schneeweiss S
      • Huybrechts KF
      • Lin KJ
      • Gagne JJ.
      Effectiveness and safety of apixaban compared with rivaroxaban for patients with atrial fibrillation in routine practice: a cohort study.
      ] and a study regarding drug levels within the expected range [
      • Lin SY
      • Kuo CH
      • Yeh SJ
      • Tsai LK
      • Liu YB
      • Huang CF
      • et al.
      Real-world rivaroxaban and apixaban levels in asian patients with atrial fibrillation.
      ], suggest that apixaban may be safer than rivaroxaban. Two ongoing trials are assessing the benefit of apixaban in cryptogenic stroke patients with atrial or other cardiac dysfunction [
      • Geisler T
      • Poli S
      • Meisner C
      • Schreieck J
      • Zuern CS
      • Nagele T
      • et al.
      Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): rationale and study design.
      ,
      • Kamel H
      • Jr. Longstreth WT
      • Tirschwell DL
      • Kronmal RA
      • Broderick JP
      • Palesch YY
      • et al.
      The atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke randomized trial: rationale and methods.
      ].
      Recent trials have shown that prolonged cardiac monitoring for AF can result in increased detection of AF [
      • Sanna T
      • Diener HC
      • Passman RS
      • Di Lazzaro V
      • Bernstein RA
      • Morillo CA
      • et al.
      Cryptogenic stroke and underlying atrial fibrillation.
      ,
      • Gladstone DJ
      • Spring M
      • Dorian P
      • Panzov V
      • Thorpe KE
      • Hall J
      • et al.
      Atrial fibrillation in patients with cryptogenic stroke.
      ] and following treatment, lower risk of recurrent stroke [
      • Tsivgoulis G
      • Katsanos AH
      • Grory BM
      • Kohrmann M
      • Ricci BA
      • Tsioufis K
      • et al.
      Prolonged cardiac rhythm monitoring and secondary stroke prevention in patients with cryptogenic cerebral ischemia.
      ]. Given the absence of prolonged cardiac monitoring in all included studies, and the combination of multiple different pathologies into “potential cardiac emboli” in this meta-analysis, if a significant portion of patients in any group had undetected AF, this could significantly affect the findings of this study. However, prolonged electrocardiogram monitoring is relatively expensive and inconvenient, thereby limiting its widespread use in clinical practice, and therefore identifying potential cardiac emboli in patients with cryptogenic stroke, may still help guide the choice of an optimal antithrombotic drug to reduce the risk of recurrent ischemic stroke.
      Two completed large ESUS trials did not show NOACs compared with aspirin significantly reduced a risk of recurrent ischemic stroke [
      • Hart RG
      • Sharma M
      • Mundl H
      • Kasner SE
      • Bangdiwala SI
      • Berkowitz SD
      • et al.
      Rivaroxaban for stroke prevention after embolic stroke of undetermined source.
      ,
      • Diener HC
      • Sacco RL
      • Easton JD
      • Granger CB
      • Bernstein RA
      • Uchiyama S
      • et al.
      Dabigatran for prevention of stroke after embolic stroke of undetermined source.
      ]. The current definition of ESUS includes patients with aortic arch atherosclerosis, mild carotid stenosis and branch atheromatous disease and NOACs compared with antiplatelet therapies were not associated with a lower risk of recurrent ischemic stroke among these patients [
      • Ntaios G
      • Pearce LA
      • Meseguer E
      • Endres M
      • Amarenco P
      • Ozturk S
      • et al.
      Aortic arch atherosclerosis in patients with embolic stroke of undetermined source: an exploratory analysis of the NAVIGATE ESUS trial.
      ,
      • Ntaios G
      • Swaminathan B
      • Berkowitz SD
      • Gagliardi RJ
      • Lang W
      • Siegler JE
      • et al.
      Efficacy and safety of rivaroxaban versus aspirin in embolic stroke of undetermined source and carotid atherosclerosis.
      ,
      • Uchiyama S
      • Toyoda K
      • Kitagawa K
      • Okada Y
      • Ameriso S
      • Mundl H
      • et al.
      Branch atheromatous disease diagnosed as embolic stroke of undetermined source: A sub-analysis of NAVIGATE ESUS.
      ].
      Our study has several limitations. Most included studies were derived from subgroups of trials. Pooling data from post hoc subgroups of randomized controlled trials is prone to chance findings and can only be hypothesis generating. Since the overall result was pooled from different “potential cardiac emboli”, we undertook a random rather than fixed effects meta-analysis. Also, the confidence intervals of results were wide, suggesting insufficient precision. Therefore, our results should only be seen as suggestive, and not definitive, pending further work in this area. Second, since the current meta-analysis included 6 studies derived from 5 trials, it is conceivable that overlapping patient populations existed in 2 studies [
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ] derived from the same trial. However, we were unable to clarify the overlapping patient populations because these 2 studies [
      • Kasner SE
      • Swaminathan B
      • Lavados P
      • Sharma M
      • Muir K
      • Veltkamp R
      • et al.
      Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
      ,
      • Healey JS
      • Gladstone DJ
      • Swaminathan B
      • Eckstein J
      • Mundl H
      • Epstein AE
      • et al.
      Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
      ] did not provide relevant information. Third, the safety analysis has major limitations due to the limited number of patients in the analysis of bleeding complications. Fourth, follow-up duration ranged from 0.9 to 5.3 years among studies. Five years seems an adequate period to observe stroke recurrences (and bleeding complications), a period of less than one year seems insufficient. The insufficient length of follow-up in some studies may constitute an element of heterogeneity and a further limitation of the meta-analysis.
      In conclusion, OACs compared with antiplatelet therapies were associated with a lower risk of recurrent ischemic stroke in patients with cryptogenic stroke and potential cardiac emboli, and therefore might be a viable therapeutic alternative for these patients, especially those OACs with comparable major bleeding risks to antiplatelet therapies. Results from dedicated randomized controlled trials in these patients, specifically comparing a NOAC to an antiplatelet medication are warranted.

      Sources of funding

      This work was supported by Ministry of Science and Technology, Taiwan, grant number: MOST 108-2314-B-182-017- MOST 109-2314-B-182-033 -, MOST 110-2314-B-182-036 -MY2 and Chang Gung Memorial Hospital, Taiwan, grant number: CORPG6G0191,CORPG6G0192,CORPG6G0193, CMRPG6H0441. The sponsors played no role in the study design, data collection and analysis, or decision to submit the article for publication.

      Declaration of Competing Interest

      The authors have no conflicts of interest.

      Acknowledgements

      None.

      Appendix. Supplementary materials

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