Mona Al Banna, MB BCh, Msc(Res)
Messé SR, Erus G, Bilello M, Davatzikos C, Andersen G, Iversen HK, Roine RO, Sjöstrand C, Rhodes JF, Søndergaard L, Kasner SE, and on behalf of the Gore REDUCE Study Investigators. Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial. Stroke. 2021;52:3419–3426.
Patent foramen ovale (PFO) is found in one quarter of the population. However, in cryptogenic strokes, PFOs have been found in approximately one half of patients. (1) The association is even stronger in younger patients with a stroke, as a four-fold greater incidence of PFO has been detected compared to a stroke-free age- and sex-matched control group. (2) The pathophysiology of PFO-related stroke involves the paradoxical embolism of a clot from the venous circulation to the arterial circulation through a right-to-left shunt. Therefore, PFO closure to eradicate the right-to-left shunt has been proposed as an intervention to reduce PFO-related stroke. Percutaneous PFO closure devices have been in use for many years. However, up until recently, clinical trials did not show significantly lower rates of recurrent stroke with PFO closure compared to standard medical therapy alone. (3-5) A sub-group analysis of the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial showed significant reduction of stroke recurrence in patients with larger sized PFOs and atrial septal aneurysm. (6) The latest randomized controlled trials investigating the benefit of PFO closure utilized stricter inclusion criteria, in which patients were only eligible for closure if they had PFOs with an associated large interatrial shunt or atrial septal aneurysm, cortical stroke, and were <60 years old. (7-9) These trials concluded that the rate of recurrent stroke was significantly lower with closure, with one stroke avoided at 2 years for every 24 treated patients. (7)However, due to feasibility, these trials used an open label design where the patients and the treating clinicals were aware of the treatment assignment, increasing the risk of bias.
The REDUCE study was the only trial that required all patients to undergo magnetic resonance imaging (MRI) at baseline and after a clinical neurological event or at 2 years of follow-up. This study analysis evaluated the change in volume, number and location of infarcts from baseline to follow-up MRI as an objective measure. A total of 664 patients who met study criteria were enrolled in the study. They were randomized to closure plus antiplatelet therapy vs antiplatelet therapy alone. A blinded MRI lab reviewed all brain MRIs for evidence of new ischemic stroke by comparing FLAIR and DWI sequences between the initial and follow-up MRI.
The authors found that new clinical stroke or silent MRI infarct occurred in 18/383 (4.7%) of PFO-closure patients and in 19/177 (10.7%) of medically treated patients (relative risk [RR], 0.44 [95% CI, 0.24–0.81], P=0.02). This shows a significant reduction in total infarcts in the PFO-closure group. Clinical strokes were reported in 5 (1.3%) patients assigned to closure and 12 (6.8%) of medically treated patients (RR, 0.19 [95% CI, 0.07–0.54], P=0.001). Silent brain infarcts occurred in 13/383 (3.4%) of PFO-closure patients versus 7/177 (4.0%) of medically treated patients, (RR, 0.86 [95% CI, 0.35–2.11], P=0.81). There was no association between shunt size and total volume of or new ischemic infarct. The total and discrete lesion volumes, infarct distribution and number of lesions did not differ between the treatment arms. This is in contrast to the RESPECT trial, which reported that there was a trend towards fewer large infarcts in patients who underwent closure compared with patients who were treated medically.
This study shows that in patients with PFO-closure compared to those treated with antiplatelet therapy alone, there was a significant reduction in recurrent clinical strokes but no difference in the number of patients with silent subclinical infarcts. The explanation for this discrepancy between clinical strokes and subclinical infarcts is not clear. One thought it that small infarcts on MRI are not uncommon cardiac procedures due to small embolization. Thus, some patients who underwent PFO closure may have had small subclinical periprocedural infarcts. In contrast, patients who did not undergo closure could have slowly accumulated these lesions over time due to their right-to-left shunt. This study adds further support in favor of PFO-closure by showing a reduction in clinical infarcts and through utilizing MRI follow-up imaging as an objective measures that should be used in open-label stroke prevention trials to minimize bias.
1. Sanchez CE, Lee JA, Eubank G, Yakubov SJ. Cryptogenic stroke in patients with patent foramen ovale. JCOM. 2010;17(7).
2. Windecker S, Wahl A, Chatterjee T, Garachemani A, Eberli FR, Seiler C, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long-term risk of recurrent thromboembolic events. Circulation. 2000;101(8):893-8.
3. Meier B. Patent foramen ovale and closure technique with the amplatzer occluder. Scientifica. 2014;2014.
4. Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. New England Journal of Medicine. 2012;366(11):991-9.
5. Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D, Dudek D, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. New England Journal of Medicine. 2013;368(12):1083-91.
6. Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. New England Journal of Medicine. 2013;368(12):1092-100.
7. Mas J-L, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. New England Journal of Medicine. 2017;377(11):1011-21.
8. Søndergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. New England Journal of Medicine. 2017;377(11):1033-42.
9. Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. New England Journal of Medicine. 2017;377(11):1022-32.