Anticoagulation Treatment Response Among Phenotypic ESUS Clusters: Evidence From CASPR
Abstract
ABSTRACT Objective To evaluate treatment effect heterogeneity across phenotypic clusters of patients with cryptogenic embolic stroke using causal inference methods. Methods From a retrospective, multicenter cohort of patients with cryptogenic embolic stroke, we estimated the treatment effect of anticoagulation versus antiplatelet therapy in patients with ESUS in two ways: (1) Partitioning Around Medoids and (2) causal survival forest modeling. We assessed cluster‐level associations with time to primary outcome (recurrent stroke, major bleeding, or death) using Kaplan–Meier survival analysis to assess cluster differences. We then extracted SHapley Additive exPlanations (SHAP) feature importances from the causal forest model to identify candidate effect modifiers from the causal forest. Results Among 1869 patients with ESUS, three phenotypically distinct clusters were extracted with significant differences in event‐free survival across clusters (log‐rank p < 0.0001). There was no significant population‐level benefit of anticoagulation over antiplatelet therapy ( p = 0.23). SHAP feature importance analysis identified several candidate effect modifiers; however, only higher LVEF ( β = −327, 95% CI: −580 to −74, p = 0.011) and cancer history ( β = −226, 95% CI: −441 to −11, p = 0.039) were independent predictors of response to antiplatelet over anticoagulation using best linear projections. Phenotypic cluster assignment did not significantly predict treatment effect heterogeneity. Interpretation Three distinct phenotypic clusters of cryptogenic stroke patients emerged with a differential risk of the composite outcome, but they did not predict responsiveness to anticoagulation. LVEF and cancer history, however, showed differential outcomes across antithrombotic strategies. These findings demonstrate the potential of causal inference methods for identifying effect heterogeneity and individualizing treatment strategies.
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Authors: Elena Badillo Goicoechea, Patrick Ellsworth, James Ernest Siegler, James R. Brorson, Christina M. Lineback, Frank Garrett Conyers, Deborah L.G. Kerrigan, Kelsey Eklund, Shadi R. Yaghi, Farid Khasiyev, Emiliya Melkumova, Collin J. Culbertson, Marissa D’Souza, Dinesh V. Jillella, Patrick A. Glover, Hassan Aboul Nour, Fadi B. Nahab, Mahan Shahrivari, Simona Nedelcu, David S. Liebeskind, Matthew M. Smith, Aaron Rothstein, Anna Bowman, Alicia M. Zha, Narendra Kala, Ahmad Abu Qdais, Sami Al Kasab, Mudassir Farooqui, Diana Rojas-Soto, Yasmin Ninette Aziz, Franziska Herpich, Jean-Philippe Auguste Daniel, Sean L. Thompson, Vivek G. Patel, Thanh N. Nguyen, Siddharth Sehgal, Wenzheng Yu, Wayneho Kam, Russell J. Van Coevering, Oana M. Dumitrascu, Muhammad Alvi, Balaji Krishnaiah, Setareh Salehi Omran, Guillermo Linares, Eesha Singh, Hamid Ali, Mary Penckofer, Jesse M. Thon, Shani Peter, Dalia Chahien, Lucia Chen, Fawad Talat, Mehdi Abbasi, Richa Sharma
Institutions: Brigham and Women's Hospital, University of Pennsylvania, University of California, Los Angeles, University of Chicago, University of Colorado Anschutz, The Ohio State University Wexner Medical Center, The Ohio State University, Brown University, University of Michigan, Emory University, University of Minnesota, University of Houston, Mayo Clinic in Arizona, Duke Medical Center, West Virginia University, Cooper University Hospital, Mayo Clinic, Medical University of South Carolina, Boston Medical Center, Vanderbilt University Medical Center, University of Cincinnati, Trinity Health, The University of Texas Health Science Center at Houston, University of Tennessee Health Science Center, Hospital of the University of Pennsylvania, Augusta University Health, Yale New Haven Hospital, Tufts Medical Center, Dartmouth Psychiatric Research Center, Lahey Hospital and Medical Center, Duke University Hospital, Grady Memorial Hospital, Saint Louis University Hospital, University of Iowa Hospitals and Clinics, Christiana Hospital, Jersey Shore University Medical Center, Sentara Norfolk General Hospital