David M Kent1, Jeffrey L Saver2, Scott E Kasner3, Jason Nelson1, John D Carroll4, Gilles Chatellier5, Geneviève Derumeaux6, Anthony J Furlan7, Howard C Herrmann8, Peter Jüni9, Jong S Kim10, Benjamin Koethe1, Pil Hyung Lee11, Benedicte Lefebvre8, Heinrich P Mattle12, Bernhard Meier13, Mark Reisman14, Richard W Smalling15, Lars Soendergaard16, Jae-Kwan Song11, Jean-Louis Mas17, David E Thaler18. 1. Predictive Analytics and Comparative Effectiveness Center, Tufts Medical Center/Tufts University School of Medicine, Boston, Massachusetts. 2. Comprehensive Stroke Center and Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles. 3. Comprehensive Stroke Center, Department of Neurology, University of Pennsylvania Medical Center, Philadelphia. 4. Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora. 5. Centre d'Investigations Cliniques, Unité de Recherche Clinique, Hôpital Européen Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France. 6. Département de Physiologie, Hôpital Henri Mondo, Assistance Publique-Hôpitaux de Paris, Créteil, France. 7. Department of Neurology, Case Western Reserve University, Cleveland, Ohio. 8. Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. 9. Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, University of Toronto, Ontario, Canada. 10. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 11. Department of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 12. Department of Neurology, Bern University Hospital, Bern, Switzerland. 13. Department of Cardiology, Bern University Hospital, Bern, Switzerland. 14. Division of Cardiology, University of Washington Medical Center, Seattle. 15. Division of Cardiology, Department of Medicine, UTHealth/McGovern Medical School, Houston, Texas. 16. Department of Cardiology, University of Copenhagen Hospital Rigshospitalet, Copenhagen, Denmark. 17. GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte-Anne, Département of Neurology, Institut de Psychiatrie et Neurosciences de Paris, Université de Paris, Paris, France. 18. Department of Neurology, Tufts Medical Center/Tufts University School of Medicine, Boston, Massachusetts.
Abstract
Importance: Patent foramen ovale (PFO)-associated strokes comprise approximately 10% of ischemic strokes in adults aged 18 to 60 years. While device closure decreases stroke recurrence risk overall, the best treatment for any individual is often unclear. Objective: To evaluate heterogeneity of treatment effect of PFO closure on stroke recurrence based on previously developed scoring systems. Design, Setting, and Participants: Investigators for the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) Consortium pooled individual patient data from all 6 randomized clinical trials that compared PFO closure plus medical therapy vs medical therapy alone in patients with PFO-associated stroke, and included a total of 3740 participants. The trials were conducted worldwide from 2000 to 2017. Exposures: PFO closure plus medical therapy vs medical therapy alone. Subgroup analyses used the Risk of Paradoxical Embolism (RoPE) Score (a 10-point scoring system in which higher scores reflect younger age and the absence of vascular risk factors) and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System, which combines the RoPE Score with high-risk PFO features (either an atrial septal aneurysm or a large-sized shunt) to classify patients into 3 categories of causal relatedness: unlikely, possible, and probable. Main Outcomes and Measures: Ischemic stroke. Results: Over a median follow-up of 57 months (IQR, 24-64), 121 outcomes occurred in 3740 patients. The annualized incidence of stroke with medical therapy was 1.09% (95% CI, 0.88%-1.36%) and with device closure was 0.47% (95% CI, 0.35%-0.65%) (adjusted hazard ratio [HR], 0.41 [95% CI, 0.28-0.60]). The subgroup analyses showed statistically significant interaction effects. Patients with low vs high RoPE Score had HRs of 0.61 (95% CI, 0.37-1.00) and 0.21 (95% CI, 0.11-0.42), respectively (P for interaction = .02). Patients classified as unlikely, possible, and probable using the PASCAL Classification System had HRs of 1.14 (95% CI, 0.53-2.46), 0.38 (95% CI, 0.22-0.65), and 0.10 (95% CI, 0.03-0.35), respectively (P for interaction = .003). The 2-year absolute risk reduction was -0.7% (95% CI, -4.0% to 2.6%), 2.1% (95% CI, 0.6%-3.6%), and 2.1% (95% CI, 0.9%-3.4%) in the unlikely, possible, and probable PASCAL categories, respectively. Device-associated adverse events were generally higher among patients classified as unlikely; the absolute risk increases in atrial fibrillation beyond day 45 after randomization with a device were 4.41% (95% CI, 1.02% to 7.80%), 1.53% (95% CI, 0.33% to 2.72%), and 0.65% (95% CI, -0.41% to 1.71%) in the unlikely, possible, and probable PASCAL categories, respectively. Conclusions and Relevance: Among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO. Application of this classification system has the potential to guide individualized decision-making.
Importance: Patent foramen ovale (PFO)-associated strokes comprise approximately 10% of ischemic strokes in adults aged 18 to 60 years. While device closure decreases stroke recurrence risk overall, the best treatment for any individual is often unclear. Objective: To evaluate heterogeneity of treatment effect of PFO closure on stroke recurrence based on previously developed scoring systems. Design, Setting, and Participants: Investigators for the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) Consortium pooled individual patient data from all 6 randomized clinical trials that compared PFO closure plus medical therapy vs medical therapy alone in patients with PFO-associated stroke, and included a total of 3740 participants. The trials were conducted worldwide from 2000 to 2017. Exposures: PFO closure plus medical therapy vs medical therapy alone. Subgroup analyses used the Risk of Paradoxical Embolism (RoPE) Score (a 10-point scoring system in which higher scores reflect younger age and the absence of vascular risk factors) and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System, which combines the RoPE Score with high-risk PFO features (either an atrial septal aneurysm or a large-sized shunt) to classify patients into 3 categories of causal relatedness: unlikely, possible, and probable. Main Outcomes and Measures: Ischemic stroke. Results: Over a median follow-up of 57 months (IQR, 24-64), 121 outcomes occurred in 3740 patients. The annualized incidence of stroke with medical therapy was 1.09% (95% CI, 0.88%-1.36%) and with device closure was 0.47% (95% CI, 0.35%-0.65%) (adjusted hazard ratio [HR], 0.41 [95% CI, 0.28-0.60]). The subgroup analyses showed statistically significant interaction effects. Patients with low vs high RoPE Score had HRs of 0.61 (95% CI, 0.37-1.00) and 0.21 (95% CI, 0.11-0.42), respectively (P for interaction = .02). Patients classified as unlikely, possible, and probable using the PASCAL Classification System had HRs of 1.14 (95% CI, 0.53-2.46), 0.38 (95% CI, 0.22-0.65), and 0.10 (95% CI, 0.03-0.35), respectively (P for interaction = .003). The 2-year absolute risk reduction was -0.7% (95% CI, -4.0% to 2.6%), 2.1% (95% CI, 0.6%-3.6%), and 2.1% (95% CI, 0.9%-3.4%) in the unlikely, possible, and probable PASCAL categories, respectively. Device-associated adverse events were generally higher among patients classified as unlikely; the absolute risk increases in atrial fibrillation beyond day 45 after randomization with a device were 4.41% (95% CI, 1.02% to 7.80%), 1.53% (95% CI, 0.33% to 2.72%), and 0.65% (95% CI, -0.41% to 1.71%) in the unlikely, possible, and probable PASCAL categories, respectively. Conclusions and Relevance: Among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO. Application of this classification system has the potential to guide individualized decision-making.
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Authors: David M Kent; Jessica K Paulus; David van Klaveren; Ralph D'Agostino; Steve Goodman; Rodney Hayward; John P A Ioannidis; Bray Patrick-Lake; Sally Morton; Michael Pencina; Gowri Raman; Joseph S Ross; Harry P Selker; Ravi Varadhan; Andrew Vickers; John B Wong; Ewout W Steyerberg Journal: Ann Intern Med Date: 2019-11-12 Impact factor: 25.391
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