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Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke

Educational Objective
To learn whether there is heterogeneity of treatment effect of patent foramen ovale (PFO) closure on ischemic stroke recurrence among patients with otherwise cryptogenic ischemic stroke and PFO.
1 Credit CME
Key Points

Question  Which patients with patent foramen ovale (PFO)–associated stroke might benefit from PFO closure?

Findings  In this individual participant data meta-analysis that included 6 randomized clinical trials with 3740 patients with otherwise cryptogenic stroke and PFO, PFO closure plus medical therapy, compared with medical therapy alone, was associated with varying risk reduction for recurrent stroke among subgroups with different probabilities that the stroke was causally related to the PFO. For patients classified as unlikely (ie, with vascular risk factors and without high-risk PFO features), the hazard ratio (HR) was 1.14 but was not statistically significant; for those classified as possible or probable, the HRs were 0.38 and 0.10, respectively, both statistically significant.

Meaning  Application of a multivariable causal classification system to randomized trial results distinguished subgroups who may benefit from PFO closure from those unlikely to receive benefit.

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.

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Article Information

Corresponding Author: David M. Kent, MD, MS, Predictive Analytics and Comparative Effectiveness Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington St, PO Box 63, Boston, MA 02111 (dkent1@tuftsmedicalcenter.org).

Accepted for Publication: November 3, 2021.

Correction: This article was corrected January 25, 2022, to fix incorrectly plotted data in Figure 2A.

Author Contributions: Dr Kent had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kent, Saver, Kasner, Carroll, Chatellier, Herrmann, Meier, Sondergaard, Song, Thaler.

Acquisition, analysis, or interpretation of data: Kent, Saver, Kasner, Nelson, Carroll, Derumeaux, Furlan, Herrmann, Jüni, Kim, Koethe, Lee, Lefebvre, Mattle, Meier, Reisman, Smalling, Mas, Thaler.

Drafting of the manuscript: Kent, Nelson, Koethe, Song.

Critical revision of the manuscript for important intellectual content: Kent, Saver, Kasner, Nelson, Carroll, Chatellier, Derumeaux, Furlan, Herrmann, Jüni, Kim, Lee, Lefebvre, Mattle, Meier, Reisman, Smalling, Sondergaard, Mas, Thaler.

Statistical analysis: Kent, Saver, Nelson, Chatellier, Jüni, Koethe.

Obtained funding: Kent, Mas, Thaler.

Administrative, technical, or material support: Kent, Saver, Chatellier, Derumeaux, Furlan, Herrmann, Lefebvre, Reisman.

Supervision: Kent, Kim, Meier, Song.

Conflict of Interest Disclosures: Dr Kent reported receiving grants from the Patient-Centered Outcomes Research Institute (PCORI; RS-SCOPE-2019-001 and PARC.OCSO.2018.01.25) and WL Gore during the conduct of the study and speaker honorarium from the Canadian Stroke Consortium outside the submitted work. Dr Saver is an employee of the Regents of the University of California. Neither the Regents of the University of California nor Dr Saver received any direct support for work on the current study. For topics broadly related to this study, the Regents of the University of California received payments on the basis of clinical trial contracts for the number of patients enrolled in multicenter clinical trials from Abbott and Boehringer Ingelheim; Dr Saver served as an unpaid site investigator under these contracts. Dr Saver has received contracted hourly payments and travel reimbursement for service as a scientific consultant advising on rigorous trial design and conduct to Abbott and Boehringer Ingelheim. Dr Kasner reported receiving grants from WL Gore and Associates (principal investigator [PI] of REDUCE Trial), Medtronic, Bristol Myers Squibb, and Janssen; personal fees from Bristol Myers Squibb (national lead investigator for AXIOMATIC Trial); consulting fees from Medtronic, Bristol Meyers Squibb, AbbVie, and AstraZeneca; and royalties from UpToDate and Elsevier. Dr Carroll was a member of the steering committee for the RESPECT Trial sponsored by Abbott; a local site investigator for the REDUCE Trial sponsored by Gore; a local site investigator in the TRILUMINATE, COAPT, EVEREST 2, SUMMIT, and EXPAND clinical trials; on the steering committee for the AMULET IDE project; and as chair of the data and safety monitoring board for the TENDYNE EFS project, all associated with Abbott. Dr Carroll was also a consultant for Holistick. Dr Furlan was PI of CLOSURE NMT Boston. Dr Herrmann reported receiving grants and personal fees from WL Gore Inc, grants from Abbott, and consultant fees and equity from Holistick Medical during the conduct of the study. Outside of this work, Dr Herrmann has received institutional research funding from Bayer, Boston Scientific, Edwards Lifesciences, Highlife Medical, Medtronic, and Shockwave; consultant fees from Edwards Lifesciences, Medtronic, and Shockwave; and equity in Microinterventional Devices. Dr Jüni reported serving as an unpaid member of the steering group of trials funded by Abbott Vascular, AstraZeneca, Biotronik, Biosensors, St Jude Medical, Terumo, and The Medicines Company; receiving research grants to the institution from AstraZeneca, Appili Therapeutics, Biotronik, Biosensors International, Eli Lilly, and The Medicines Company; and receiving honoraria to the institution for participation in advisory boards and/or consulting from Amgen, Ava, and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. Mr Koethe reported receiving grants from PCORI during the conduct of the study. Dr Mattle reported receiving grants from Abbott for the PC and PRIMA Trials during the conduct of the study and personal fees from Servier, Bayer, Medtronic, and Cerenovus outside the submitted work. Dr Meier was a co-PI for the PC and PRIMA Trials and received personal fees from Abbott during the conduct of the study. Dr Smalling was a member of the steering committee for the RESPECT Trial, sponsored by Abbott, St Jude Medical, and AGA Medical; has served as a consultant and proctor for PFO closure (Abbott); and is on the steering committee for the PFO-PAS registry for Abbott. Dr Thaler reported receiving personal fees from Abbott for serving as a steering committee member of the RESPECT and AMULET Trials during the conduct of the study. No other disclosures were reported.

Funding/Support: Research reported in this publication was funded in part through 2 PCORI awards (RS-SCOPE-2019-001 and PARC.OCSO.2018.01.25).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The statements in this publication are solely the responsibility of the authors and do not necessarily represent the views of PCORI, its board of governors, or its methodology committee.

Data Sharing Statement: The datasets used and/or analyzed during the current study were pooled based on data use agreements with each of the 6 original study data owners, to whom requests for data usage should be addressed.

Additional Contributions: We thank Rebecca E. H. Maunder, BSc, from the PACE Center (Tufts Medical Center) for her help with manuscript preparation, who was partially supported through the PCORI grant. We also thank Abbott US and WL Gore (who received no compensation) for facilitating data access.

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