Background: The optimal strategy of secondary stroke prevention in patients with patent foramen ovale (PFO) is controversial. This study was performed to evaluate the efficacy and safety of the device closure (DC) versus the medical therapy (MT) in patients with cryptogenic stroke or transient ischemic attack (TIA) and PFO. Summary: Randomized controlled trials with active and control groups receiving the DC plus MT and MT alone in patients with history of cryptogenic stroke/TIA and diagnosis of PFO were systematically searched. The main efficacy outcome was stroke recurrence. Subgroup-analyses were performed according to age, shunt size, and presence of atrial septal aneurysm (ASA). Safety endpoints included any serious adverse event (SAE), atrial fibrillation (AF), and major bleeding complications. Risk ratios (RRs) and hazard ratios (HRs) with 95% CIs were estimated. Five trials were included, involving 3,440 participants (DC = 1,829, MT = 1,611). There was a protective effect of closure in the risk of recurrent stroke (RR 0.43 [0.21–0.90]; p = 0.024; HR = 0.39 [0.19–0.83]; p = 0.014). The benefit of PFO closure was significant in patients with PFO associated with substantial right-to-left shunt or ASA. There were no differences in the risks of SAEs and major bleedings between the groups. The rate of new-onset AF was higher in the DC than in the MT arm (RR 4.46 [2.35–8.41]; p < 0.001). Successful device implantation and effective PFO closure were achieved in 96 and 91% of the patients respectively. Key Messages: In selected adult patients with PFO and history of cryptogenic stroke, the DC plus MT is more effective to prevent stroke recurrence and is associated with an increased risk of new-onset AF compared to the MT alone.

Keywords:
Cryptogenic stroke, Patent foramen ovale, Meta-analysis
1.
Feigin VL, Norrving B, Mensah GA: Global burden of stroke. Circ Res 2017; 120: 439–448.
2.
Lattanzi S, Silvestrini M, Provinciali L: Elevated blood pressure in the acute phase of stroke and the role of Angiotensin receptor blockers. Int J Hypertens 2013; 2013: 941783.
3.
Saver JL: Clinical practice. Cryptogenic stroke. N Engl J Med 2016: 374: 2065–2074.
4.
Lattanzi S, Cagnetti C, Pulcini A, et al: The P-wave terminal force in embolic strokes of undetermined source. J Neurol Sci 2017; 375: 175–178.
5.
Hagen PT, Scholz DG, Edwards WD: Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59: 17–20.
6.
Homma S, Sacco RL: Patent foramen ovale and stroke. Circulation 2005; 112: 1063–1072.
7.
Lechat P, Mas JL, Lascault G, et al: Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318: 1148–1152.
8.
Alsheikh-Ali AA, Thaler DE, Kent DM: Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 2009; 40: 2349–2355.
9.
Overell JR, Bone I, Lees KR: Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55: 1172–1179.
10.
Cabanes L, Mas JL, Cohen A, et al: Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993; 24: 1865–1873.
11.
Maron BA, Shekar PS, Goldhaber SZ: Paradoxical embolism. Circulation 2010; 122: 1968–1972.
12.
Berthet K, Lavergne T, Cohen A, et al: Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke 2000; 31: 398–403.
13.
Silver MD, Dorsey JS: Aneurysms of the septum primum in adults. Arch Pathol Lab Med 1978; 102: 62–65.
14.
Schneider B, Hanrath P, Vogel P, Meinertz T: Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebrovascular events. J Am Coll Cardiol 1990; 16: 1000–1009.
15.
Di Tullio MR, Homma S: Patent foramen ovale and stroke: what should be done? Curr Opin Hematol 2009; 16: 391–396.
16.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6:e1000097.
17.
Higgins JP, Green S: Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. http://handbook-5–1.cochrane.org/(accessedDecember2017).
18.
Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.
19.
Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558.
20.
Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M: How should we lower blood pressure after cerebral hemorrhage? A systematic review and meta-analysis. Cerebrovasc Dis 2017; 43: 207–213.
21.
Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M: Brivaracetam add-on for refractory focal epilepsy: a systematic review and meta-analysis. Neurology 2016; 86: 1344–1352.
22.
Lattanzi S, Cagnetti C, Danni M, Provinciali L, Silvestrini M: Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol 2017; 264: 1697–1704.
23.
Lattanzi S, Grillo E, Brigo F, Silvestrini M: Efficacy and safety of perampanel in Parkinson's disease. A systematic review with meta-analysis. J Neurol 2017, DOI: 10.1007/s00415–017–8681-y.
24.
Landzberg MJ, Khairy P: Indications for the closure of patent foramen ovale. Heart 2004; 90: 219–224.
25.
Steiner MM, Di Tullio MR, Rundek T, et al: Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 1998; 29: 944–948.
26.
The Effect of Device Closure of Patent Foramen Ovale in Elderly Patients with Cryptogenic Stoke/TCI (CryptoCard). https://clinicaltrials.gov/ct2/NCT01018355
27.
Device Closure versus Medical Therapy for Cryptogenic Stroke Patients with High-Risk Patent Foramen Ovale (DEFENSE-PFO). https://clinicaltrials.gov/ct2/NCT01550588
28.
Furlan AJ, Reisman M, Massaro J, et al; CLOSURE I Investigators: Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366: 991–999.
29.
Meier B, Kalesan B, Mattle HP, et al; PC Trial Investigators: Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368: 1083–1091.
30.
Saver JL, Carroll JD, Thaler DE, et al; RESPECT Investigators: Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017; 377: 1022–1032.
31.
Mas JL, Derumeaux G, Guillon B, et al; CLOSE Investigators: Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017; 377: 1011–1021.
32.
Søndergaard L, Kasner SE, Rhodes JF, et al; Gore REDUCE Clinical Study Investigators: Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017; 377: 1033–1042.
33.
Alsheikh-Ali AA, Thaler DE, Kent DM: Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 2009; 40: 2349–2355.
34.
Kent DM, Ruthazer R, Weimar C, et al: An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81: 619–625.
35.
Mekaj YH, Mekaj AY, Duci SB, Miftari EI: New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 2015; 11: 967–977.
36.
Kearon C, Akl EA, Ornelas J, et al: Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149: 315–352.
37.
Stortecky S, da Costa BR, Mattle HP, et al: Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network meta-analysis. Eur Heart J 2015; 36: 120–128.
38.
Rengifo-Moreno P, Palacios IF, Junpaparp P, Witzke CF, Morris DL, Romero-Corral A: Patent foramen ovale transcatheter closure vs. medical therapy on recurrent vascular events: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J 2013; 34: 3342–3352.
39.
Li J, Liu J, Liu M, et al: Closure versus medical therapy for preventing recurrent stroke in patients with patent foramen ovale and a history of cryptogenic stroke or transient ischemic attack. Cochrane Database Syst Rev 2015; 9: CD009938.
40.
Messé SR, Gronseth G, Kent DM, et al: Practice advisory: recurrent stroke with patent foramen ovale (update of practice parameter): report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology. Neurology 2016; 87: 815–821.
41.
Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease: Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45: 2160–2236.
42.
European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee: Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457–507.
43.
Carroll JD, Saver JL, Thaler DE, et al; RESPECT Investigators: Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013; 368: 1092–1100.
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2018
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