If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
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.
]. 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) [
]. 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 [
], 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 [
]. 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 [
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.
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 [
The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
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 [
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 [
]. 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) [
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical 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 [
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
] only reported recurrent stroke as an endpoint. Recurrent ischemic stroke risk between OACs and antiplatelet therapy was assessed in 4 studies with PFO [
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
Heart failure with ejection fraction ≤35%, sinus rhythm and prior ischemic stroke
128 patients assigned to warfarin (with a target INR 2 to 3.5)
120 patients assigned to aspirin325 mg once daily
NA
NA
3.5
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.
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.
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) [
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical 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).
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
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 [
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) [
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
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) [
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
]. 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).
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 [
], 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 [
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
]. 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 [
]. This finding aligns with evidence suggesting warfarin compared with aspirin was associated with lower risk of stroke in patients with HFrEF and sinus rhythm [
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 [
Association of intracranial hemorrhage risk with non-vitamin k antagonist oral anticoagulant use vs aspirin use: a systematic review and meta-analysis.
], 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 [
]. 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 [
]. 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 [
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 [
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
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.
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.
The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial.
Association of intracranial hemorrhage risk with non-vitamin k antagonist oral anticoagulant use vs aspirin use: a systematic review and meta-analysis.
00268-5&id=gr1.jpg){kind=link}
00268-5&id=gr2.jpg){kind=link}
00268-5&id=gr3.jpg){kind=link}
00268-5&id=gr4.jpg){kind=link}