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. 2021 Dec 14;326(22):2277-2286.
doi: 10.1001/jama.2021.20956.

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

David M Kent  1 , Jeffrey L Saver  2 , Scott E Kasner  3 , Jason Nelson  1 , John D Carroll  4 , Gilles Chatellier  5 , Geneviève Derumeaux  6 , Anthony J Furlan  7 , Howard C Herrmann  8 , Peter Jüni  9 , Jong S Kim  10 , Benjamin Koethe  1 , Pil Hyung Lee  11 , Benedicte Lefebvre  8 , Heinrich P Mattle  12 , Bernhard Meier  13 , Mark Reisman  14 , Richard W Smalling  15 , Lars Soendergaard  16 , Jae-Kwan Song  11 , Jean-Louis Mas  17 , David E Thaler  18
Affiliations

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

David M Kent et al. JAMA. .

Erratum in

  • Data Plotted Incorrectly in Figure 2.
    [No authors listed] [No authors listed] JAMA. 2022 Jan 25;327(4):394. doi: 10.1001/jama.2021.24545. JAMA. 2022. PMID: 35076685 Free PMC article. No abstract available.

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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Curve of Recurrent Ischemic Stroke
Median time to the primary outcome of recurrent ischemic stroke was 13.7 months (IQR, 4.8-29.7; n = 121).
Figure 2.
Figure 2.. Recurrent Ischemic Stroke Heterogeneity of Treatment Effect (HTE) Analyses for RoPE and PASCAL
The hazard ratios account for age, sex, prior myocardial infarction, diabetes, hypertension, hyperlipidemia, prior stroke or transient ischemic attack, smoking status, index event (stroke vs transient ischemic attack), atrial septal aneurysm on transesophageal echocardiography (definition in eAppendix 5 and eTables 3 and 4 in the Supplement), patent foramen ovale shunt size (large vs small, definition in eAppendix 5 and eTables 3 and 4 in the Supplement), and superficial infarction on neuroimaging (present vs absent). Two-year absolute risk reductions calculated as differences in Kaplan-Meier event rates at 2 years. Median time to the primary outcome of recurrent ischemic stroke was 13.7 months (IQR, 4.8-29.7; n = 121). RoPE indicates Risk of Paradoxical Embolism (definition provided in Table 1); PASCAL, PFO-Associated Stroke Causal Likelihood.
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Comment in

References

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