Anticoagulation versus Antiplatelets Across Subgroups of Embolic Stroke of Undetermined Source: A Meta-Analysis of Seven Randomized Controlled Trials
Abstract Body: Background: The term embolic stroke of undetermined source (ESUS) encompasses a substantial but heterogeneous population of patients with ischemic stroke, underscoring the importance of identifying personalized treatment strategies. In subgroups of patients randomized in ESUS trials, we evaluated the effectiveness of anticoagulation compared to antiplatelet therapy in secondary ischemic stroke prevention.
Methods: A study-level meta-analysis was conducted of randomized controlled trials of patients with ESUS, comparing anticoagulation to antiplatelet therapy. The primary efficacy outcome was recurrent ischemic stroke and safety outcomes were major bleeding and death. Subgroups assessed were age, sex, presence of patent foramen ovale (PFO), left atrial enlargement (LAE), and atrial cardiopathy. Pooled relative risks (RRs) were meta-analyzed. Cochrane Risk of Bias Tool 2.0 (RoB 2) was used for risk of bias assessment.
Results: A total of seven randomized controlled trials involving 14,804 patients were analyzed, with 7,406 patients treated with anticoagulation, and 7,398 treated with antiplatelet therapy. Compared with antiplatelet therapy, anticoagulation was associated with a similar rate of recurrent ischemic stroke (RR 0.91, 95% CI 0.80-1.05; I2 = 0%). In ESUS with PFO, anticoagulation was associated with significantly lower risk of ischemic stroke (RR 0.59, 95% CI 0.35-0.98; I2 = 0%). Heterogeneity was present in those with LAE: antiplatelet therapy was superior in trials allowing cardiac monitoring after randomization (RR 6.65, 95% CI 1.26-35.08; I2 = 0%), but anticoagulation was superior in trials prohibiting cardiac monitoring after randomization (RR 0.25 95% CI 0.07-0.89). Subgroups based on age, sex, or presence of atrial cardiopathy did not benefit from anticoagulation over antiplatelet therapy.
Conclusions: In this meta-analysis, an empiric anticoagulation approach is not beneficial for patients with ESUS. This finding highlights the importance of an individualized treatment strategy. Such a strategy should include prolonged cardiac monitoring for atrial fibrillation, particularly in patients with moderate to severe LAE. Anticoagulation treatment showed promise in patients with medically treated PFO. Other subgroups did not benefit from anticoagulation therapy. Large prospective studies within ESUS subgroups are needed to validate our findings.
Ghannam, Malik
( University of Iowa
, North Liberty
, Iowa
, United States
)
Elkind, Mitchell
( American Heart Association
, New York
, New York
, United States
)
Tirschwell, David
( HARBORVIEW MEDICAL CENTER
, Seattle
, Washington
, United States
)
Poli, Sven
( UNIVERSITY HOSPITAL TUEBINGEN
, Tuebingen
, Germany
)
Kamel, Hooman
( Weill Cornell Medicine
, New York
, New York
, United States
)
Yaghi, Shadi
( Brown University
, Providence
, Rhode Island
, United States
)
Al-qudah, Abdullah
( University of Pittsburgh Medical Center
, Pittsburgh
, Pennsylvania
, United States
)
Alshaer, Qasem
( University of Iowa
, Iowa City
, Iowa
, United States
)
Kronmal, Richard
( University of Washington
, Seattle
, Washington
, United States
)
Ntaios, George
( University of Thessaly
, Larissa
, Greece
)
Longstreth, W
( Harborview Medical Center
, Seattle
, Washington
, United States
)
Furie, Karen
( Department of Neurology
, Providence
, Rhode Island
, United States
)
Saver, Jeffrey
( GEFFEN SCHOOL OF MEDICINE AT UCLA
, Los Angeles
, California
, United States
)
Kasner, Scott
( UNIVERSITY OF PENN
, Philadelphia
, Pennsylvania
, United States
)
Author Disclosures:
Malik Ghannam:DO NOT have relevant financial relationships
| Mitchell Elkind:DO have relevant financial relationships
;
Research Funding (PI or named investigator):Roche:Past (completed)
; Employee:American Heart Association:Active (exists now)
; Speaker:Atria Academy of Science and Medicine:Past (completed)
; Research Funding (PI or named investigator):BMS-Pfizer Alliance for Eliquis:Past (completed)
| David Tirschwell:DO have relevant financial relationships
;
Consultant:AbbVie:Past (completed)
; Research Funding (PI or named investigator):Abbott:Active (exists now)
| Sven Poli:DO have relevant financial relationships
;
Research Funding (PI or named investigator):BMS/Pfizer:Past (completed)
; Consultant:Boehringer-Ingelheim:Past (completed)
; Speaker:AstraZeneca:Past (completed)
; Speaker:Alexion:Past (completed)
; Consultant:Werfen:Past (completed)
; Consultant:Daiichi Sankyo:Past (completed)
; Consultant:AstraZeneca:Past (completed)
; Consultant:Alexion:Past (completed)
; Research Funding (PI or named investigator):Werfen:Active (exists now)
; Research Funding (PI or named investigator):Helena Laboratories:Active (exists now)
; Research Funding (PI or named investigator):German Federal Ministry of Education and Research:Active (exists now)
; Research Funding (PI or named investigator):German Federal Joint Committee Innovation Fund:Past (completed)
; Research Funding (PI or named investigator):European Union:Past (completed)
; Research Funding (PI or named investigator):Daiichi Sankyo:Past (completed)
; Research Funding (PI or named investigator):Boehringer Ingelheim:Active (exists now)
| Hooman Kamel:DO have relevant financial relationships
;
Other (please indicate in the box next to the company name):Financial disclosures for Hooman Kamel: a PI role in the ARCADIA trial, which received in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; a Deputy Editor role for JAMA Neurology; clinical trial steering/executive committee roles for the STROKE-AF (Medtronic), LIBREXIA-AF (Janssen), and LAAOS-4 (Boston Scientific) trials; consulting or endpoint adjudication committee roles for AbbVie, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and household ownership interests in TETMedical, Spectrum Plastics Group, and Ascential Technologies.:Active (exists now)
| Shadi Yaghi:DO NOT have relevant financial relationships
| Abdullah Al-Qudah:DO NOT have relevant financial relationships
| Qasem Alshaer:DO NOT have relevant financial relationships
| Richard Kronmal:DO NOT have relevant financial relationships
| George Ntaios:DO NOT have relevant financial relationships
| W Longstreth:DO NOT have relevant financial relationships
| Karen Furie:DO have relevant financial relationships
;
Consultant:Janssen/BMS:Active (exists now)
| Jeffrey Saver:DO have relevant financial relationships
;
Consultant:Abbott:Active (exists now)
; Individual Stocks/Stock Options:Viz.ai:Active (exists now)
; Individual Stocks/Stock Options:Let's Get Proof:Active (exists now)
; Individual Stocks/Stock Options:Neuronics:Active (exists now)
; Consultant:Genentech:Expected (by end of conference)
; Consultant:Roche:Active (exists now)
; Consultant:Novo Nordisc:Active (exists now)
; Consultant:AstraZeneca:Active (exists now)
; Consultant:BrainQ:Active (exists now)
; Consultant:Medtronic:Active (exists now)
| Scott Kasner:DO have relevant financial relationships
;
Researcher:WL Gore:Active (exists now)
; Consultant:Bristol-Myers Squibb:Active (exists now)
; Researcher:DiaMedica:Active (exists now)
; Researcher:Bayer:Active (exists now)
; Royalties/Patent Beneficiary:UpToDate:Active (exists now)