Patent foramen ovale in older patients with cryptogenic stroke or transient ischaemic attack
Authors: David Thaler
Journal: The Lancet Neurology (2018)

A cryptogenic stroke is one that has eluded an explanation despite complete investigation aimed at uncovering a cause. Since 2003, six randomised trials have collected a large amount of data showing the benefit of patent foramen ovale (PFO) closure compared with standard medical therapy in young patients (aged 18–60 years) with cryptogenic stroke. However, new questions have now emerged concerning the best treatment for people older than 60 years. Traditionally, PFO-related stroke has been considered a disease of younger people, and excluded from the differential diagnosis in elderly patients. But this exclusion confuses incidence with prevalence estimates. In fact, factors that predispose people to paradoxical embolism (immobility, venous thrombosis, and hypercoagulability) increase with age, and it is probable that the incidence of PFO-related stroke also increases. However, among patients with stroke, older people will have a lower prevalence of PFO-related strokes because of competing stroke mechanisms, such as lacunar disease, large artery atherosclerosis, and cardiogenic embolism. However, notwithstanding these coexisting mechanisms, older patients with PFO-related stroke might also benefit from PFO-specific therapy. It has been argued that diagnostic tests to establish the cause of stroke are only indicated if a new, active treatment decision is needed to change the management of a patient. But a physician's responsibility includes making accurate diagnoses, irrespective of what ends up on a prescription pad. An accurate diagnosis of PFO-related stroke informs recurrence risk (which is relatively low1Kent DM Ruthhazer R Weimar C et al.An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke.Neurology. 2013; 81: 619-625Crossref PubMed Scopus (378) Google Scholar) and guides investigations and treatment later, if stroke recurs. The Risk of Paradoxical Embolism score can help to distinguish pathogenic from incidental PFOs. This score is applicable to older populations because it was derived from patients of all ages.2Larsson SC Åkesson A Wolk A Healthy diet and lifestyle and risk of stroke in a prospective cohort of women.Neurology. 2014; 83: 1-6Crossref Scopus (66) Google Scholar Over the past year, the research interest in PFO has shifted away from debating the efficacy of closure and towards optimising patient selection. In The Lancet Neurology, Sara Mazzucco and colleagues3Mazzucco S Li L Binney L Rothwell PM Prevalence of patent foramen ovale in cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysis.Lancet Neurol. 2018; (published online June 7.)http://dx.doi.org/10.1016/S1474-4422(18)30198-4Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar contribute to this shift by showing that screening for a right-to-left shunt (RLS) using contrast-enhanced transcranial Doppler (bubble-TCD) was feasible in 91% of a series of patients aged over 60 years with transient ischaemic attack or non-disabling stroke. Not surprisingly, the results are consistent with those seen in younger patients—the prevalence of PFO is significantly higher in patients with cryptogenic stroke than in patients with stroke of known cause. The authors highlight the importance of distinguishing large from small PFOs. In principle, this distinction might be relevant for identifying pathogenic PFOs, for predicting stroke recurrence, or for selecting those patients that are more likely to benefit from closure. However, evidence on these issues is not clear. In the largest study of PFO size and relation to the index stroke,4Wessler BS Thaler DE Ruthazer R et al.Transesophageal echocardiography in cryptogenic stroke and patent foramen ovale: analysis of putative high-risk features from the risk of paradoxical embolism database.Circ Cardiovasc Imaging. 2014; 7: 125-131Crossref PubMed Scopus (48) Google Scholar PFO size was not correlated with its likelihood of pathogenicity. Confusingly, stroke recurrence might be increased by more than 3 times in patients with small PFOs compared to that in patients with large ones.2Larsson SC Åkesson A Wolk A Healthy diet and lifestyle and risk of stroke in a prospective cohort of women.Neurology. 2014; 83: 1-6Crossref Scopus (66) Google Scholar Similarly, the effect of PFO closure has not been shown to be different for subgroups of patients with particular PFO characteristics, such as a large RLS or the coexistence of an atrial septal aneurysm. Based on first principles, patients in different subgroups might be expected to respond differently to PFO closure, but the data from randomised controlled trials are equivocal. Evidence from one trial5Saver JL Carroll JD Thaler DE et al.Long-term outcomes of patent foramen ovale closure or medical therapy after stroke.N Engl J Med. 2017; 377: 1022-1032Crossref PubMed Scopus (573) Google Scholar suggested heterogeneity but a second trial6Meier B Kalesan B Mattle HP et al.Percutaneous closure of patent foramen ovale in cryptogenic embolism.N Engl J Med. 2013; 368: 1083-1091Crossref PubMed Scopus (685) Google Scholar seemingly did not. A third trial7Søndergaard L Kasner SE Rhodes JF et al.Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke.N Engl J Med. 2017; 377: 1033-1042Crossref PubMed Scopus (601) Google Scholar did not suggest heterogeneity, although some researchers have pointed to the forest plots published in the trial as supporting it, overlooking the non-significant pinteraction values. The significant point estimate seen in people with large RLS was almost identical to those with small RLS (which was not significant due to a wider CI).7Søndergaard L Kasner SE Rhodes JF et al.Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke.N Engl J Med. 2017; 377: 1033-1042Crossref PubMed Scopus (601) Google Scholar Provocatively, the results for men compared with women in this trial show the same relationship (ie, a significant point estimate was seen in men, but not in women), but it would not be realistic to only treat men.7Søndergaard L Kasner SE Rhodes JF et al.Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke.N Engl J Med. 2017; 377: 1033-1042Crossref PubMed Scopus (601) Google Scholar Therefore, reliance on the relevance of PFO characteristics for determining who should undergo closure is not yet evidence-based. Mazzucco and colleagues3Mazzucco S Li L Binney L Rothwell PM Prevalence of patent foramen ovale in cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysis.Lancet Neurol. 2018; (published online June 7.)http://dx.doi.org/10.1016/S1474-4422(18)30198-4Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar have shown that PFO is easily identifiable with bubble-TCD and overrepresented in older patients with cryptogenic stroke, which implicates PFO as a cause of stroke, even in patients older than 60 years. Treatment options for this population should be investigated. Having made a diagnosis of PFO-related stroke in an otherwise healthy 70-year-old, should clinicians change their management strategy and consider closure? DT reports personal fees from Abbott Laboratories for serving on a steering committee. Prevalence of patent foramen ovale in cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysisBubble-TCD was feasible in most older patients with transient ischaemic attack or non-disabling stroke, the association of RLS with cryptogenic events remained at older ages, and the population burden of PFO-associated events is substantial. Randomised trials of PFO closure at older ages are required and should be feasible. Full-Text PDF Open Access