Recurrence Risk in Patients with Cryptogenic Stroke, Patent Foramen Ovale, and Thrombophilia: A Systematic Review and Meta-AnalysisFunding None.
29 April 2019
13 June 2019
04 August 2019 (eFirst)
Objective A patent foramen ovale (PFO) is frequently associated with cryptogenic stroke in the young. Endovascular closure is superior to antithrombotic treatment in prevention of recurrence, but in the presence of a concomitant thrombophilia, the best preventive strategy is unknown. This review investigates if thrombophilia increases the risk of recurrence in patients with cryptogenic stroke and PFO and attempts to evaluate the best antithrombotic strategy after PFO closure in these patients.
Methods Medline, Embase, and Web of Science were searched until April 2018. Study quality was assessed by the National Heart, Lung and Blood Institute Quality assessment tool. Odds ratio (OR) and hazard ratio for recurrence were pooled in a random effect model stratified by secondary preventive strategy.
Results Eleven studies were included. Inherited or acquired thrombophilia was associated with an increased risk of recurrence (OR = 2.41, 95% confidence interval [CI]: 1.44–4.06). Looking only at patients treated with PFO closure, the risk of recurrence just lost significance (OR = 2.07, 95% CI: 0.95–4.48). The antithrombotic treatment after PFO closure was heterogeneous and recurrent events occurred in patients with both inherited and acquired thrombophilia treated by antiplatelet as well as anticoagulant therapy.
Conclusion Thrombophilia is associated with an increased risk of recurrence in patients with PFO and cryptogenic stroke, which may persist after PFO closure. This suggests a need for antithrombotic therapy after PFO closure. Study heterogeneity precludes strong conclusions on antithrombotic treatment, but life-long antiplatelet therapy to patients without preexisting indication for anticoagulant therapy seems reasonable.
- 1 Béjot Y, Bailly H, Durier J, Giroud M. Epidemiology of stroke in Europe and trends for the 21st century. Presse Med 2016; 45 (12 Pt 2): e391-e398
- 2 Lozano R, Naghavi M, Foreman K. , et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380 (9859): 2095-2128
- 3 Hart RG, Diener HC, Coutts SB. , et al; Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13 (04) 429-438
- 4 Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007; 357 (22) 2262-2268
- 5 Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55 (08) 1172-1179
- 6 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 (11) 1022-1032
- 7 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 (11) 1033-1042
- 8 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 (11) 1011-1021
- 9 Shah R, Nayyar M, Jovin IS. , et al. Device closure versus medical therapy alone for patent foramen ovale in patients with cryptogenic stroke: a systematic review and meta-analysis. Ann Intern Med 2018; 168 (05) 335-342
- 10 Lee PH, Song JK, Kim JS. , et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO trial. J Am Coll Cardiol 2018; 71 (20) 2335-2342
- 11 Pezzini A, Grassi M, Zotto ED. , et al. Do common prothrombotic mutations influence the risk of cerebral ischaemia in patients with patent foramen ovale? Systematic review and meta-analysis. Thromb Haemost 2009; 101 (05) 813-817
- 12 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 (07) e1000097
- 13 Study quality assessment tools: National Heart, Lung, and Blood Institute, U.S. Department of Health & Human Services. Available at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools . Accessed September 5, 2018
- 14 Higgins JG. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available at: www.handbook.cochrane.org . Accessed November 14, 2018
- 15 Lim ST, Murphy SJX, Smith DR. , et al. Clinical outcomes and a high prevalence of abnormalities on comprehensive arterial and venous thrombophilia screening in TIA or ischaemic stroke patients with a patent foramen ovale, an inter-atrial septal aneurysm or both. J Neurol Sci 2017; 377: 227-233
- 16 Ford MA, Reeder GS, Lennon RJ. , et al. Percutaneous device closure of patent foramen ovale in patients with presumed cryptogenic stroke or transient ischemic attack: the Mayo Clinic experience. JACC Cardiovasc Interv 2009; 2 (05) 404-411
- 17 Rajamani K, Chaturvedi S, Jin Z. , et al; PICSS-APASS Investigators. Patent foramen ovale, cardiac valve thickening, and antiphospholipid antibodies as risk factors for subsequent vascular events: the PICSS-APASS study. Stroke 2009; 40 (07) 2337-2342
- 18 Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. , eds. Introduction to Meta-Analysis. West Sussex, United Kingdom: John Wiley & Sons, Ltd.; 2009
- 19 Dodge SM, Hassell K, Anderson CA, Keller J, Groves B, Carroll JD. Antiphospholipid antibodies are common in patients referred for percutaneous patent foramen ovale closure. Catheter Cardiovasc Interv 2004; 61 (01) 123-127
- 20 Donti A, Giardini A, Salomone L, Formigari R, Picchio FM. Transcatheter patent foramen ovale closure using the Premere PFO occlusion system. Catheter Cardiovasc Interv 2006; 68 (05) 736-740
- 21 Giardini A, Donti A, Formigari R. , et al. Comparison of results of percutaneous closure of patent foramen ovale for paradoxical embolism in patients with versus without thrombophilia. Am J Cardiol 2004; 94 (08) 1012-1016
- 22 Inglessis I, Elmariah S, Rengifo-Moreno PA. , et al. Long-term experience and outcomes with transcatheter closure of patent foramen ovale. JACC Cardiovasc Interv 2013; 6 (11) 1176-1183
- 23 Kefer J, Sluysmans T, Hermans C. , et al. Percutaneous transcatheter closure of interatrial septal defect in adults: procedural outcome and long-term results. Catheter Cardiovasc Interv 2012; 79 (02) 322-330
- 24 Musto C, Cifarelli A, Fiorilli R. , et al. Comparison between the new Gore septal and Amplatzer devices for transcatheter closure of patent foramen ovale. Short- and mid-term clinical and echocardiographic outcomes. Circ J 2013; 77 (12) 2922-2927
- 25 Rigatelli G, Dell'Avvocata F, Giordan M. , et al. Safety and long-term results of patent foramen ovale transcatheter closure in patients with thrombophilia. Minerva Cardioangiol 2009; 57 (03) 285-289
- 26 Giardini A, Donti A, Formigari R. , et al. Spontaneous large right-to-left shunt and migraine headache with aura are risk factors for recurrent stroke in patients with a patent foramen ovale. Int J Cardiol 2007; 120 (03) 357-362
- 27 Pezzini A, Grassi M, Lodigiani C. , et al; Italian Project on Stroke in Young Adults (IPSYS) Investigators. Predictors of long-term recurrent vascular events after ischemic stroke at young age: the Italian Project on Stroke in Young Adults. Circulation 2014; 129 (16) 1668-1676
- 28 Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 2018; 378 (21) 2010-2021
- 29 Kasner SE, Swaminathan B, Lavados P. , et al; NAVIGATE ESUS Investigators. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol 2018; 17 (12) 1053-1060
- 30 Hart RG, Sharma M, Mundl H. , et al; NAVIGATE ESUS Investigators. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 378 (23) 2191-2201