A Narrative and Critical Review of Randomized-Controlled Clinical Trials on Patent Foramen Ovale Closure for Reducing the Risk of Stroke Recurrence

Well then do the research that determines what the objective factors are that would lead to PFO closing. PROTOCOLS, not this wishy-washy crapola. 

A Narrative and Critical Review of Randomized-Controlled Clinical Trials on Patent Foramen Ovale Closure for Reducing the Risk of Stroke Recurrence

Apostolos Safouris^1*, Odysseas Kargiotis¹, Klearchos Psychogios^1,2, Pericles Kalyvas³, Ignatios Ikonomidis⁴, Maria Drakopoulou⁵, Konstantinos Toutouzas⁶ and Georgios Tsivgoulis^2,7

• ¹Stroke Unit, Metropolitan Hospital, Pireus, Greece
• ²Second Department of Neurology, School of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
• ³Cardiology Department, Metropolitan Hospital, Pireus, Greece
• ⁴Department of Echocardiography and Laboratory of Preventive Cardiology, Second Cardiology Department, Attikon Hospital, National and Kapodistrian University of Athens, Athens, Greece
• ⁵First Department of Cardiology, Athens School of Medicine, Hippokration Hospital, Athens, Greece
• ⁶First Department of Cardiology, Medical School of Athens University, Hippokration Hospital, Athens, Greece
• ⁷Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, United States

Patent foramen ovale (PFO) is a common cardiac anatomic variant that has been increasingly found in young (<60 years) cryptogenic stroke patients. Despite initial neutral randomized-controlled clinical trials (RCTs), there have been four recent RCTs providing consistent data in favor of the efficacy and safety of PFO closure compared to medical therapy for secondary stroke prevention. However, taking into consideration the high prevalence of PFO, the low risk of stroke recurrence under medical treatment and the uncommon yet severe adverse events of the intervention, patient selection is crucial for attaining meaningful clinical benefits. Thorough workup to exclude alternative causes of stroke and identification of high-risk PFOs through clinical, neuroimaging and echocardiographic criteria are essential. Cost effectiveness of the procedure cannot be proven for the time being, since there are no robust data on clinical outcome after PFO-associated stroke but only limited anecdotal data suggesting low risk for long-term disability.

Introduction

Foramen ovale is a component of the fetal cardiovascular circulation that during postnatal life closes in ≈70% of subjects, whereas in the remaining 30%, remains patent as a tunnel and converts into a “flap-like” valve that may open every time the right atrial pressure overcomes the left one. Patent foramen ovale (PFO) is therefore a normal variant of the atrial septum rather than a congenital heart defect. PFO has been associated with cryptogenic ischemic stroke especially in younger patients (<60 years) after several seminal epidemiological studies in the 90's have shown a statistically significant association (1–4). Estimates on prevalence vary considerably depending on the population and the diagnostic method used (5). PFO is detected on transesophageal echocardiography in 1 out of 4–5 individuals whereas among younger patients with cryptogenic ischemic stroke, PFOs is present in more than 50% of cases. Transthoracic echocardiography bubble study is commonly used for the diagnosis of PFO in patients with cryptogenic stroke. Transcranial Doppler (TCD) is a bedside, non-invasive investigation of the cerebral blood flow that has also been evaluated as a potential screening tool for the detection of a right-to-left shunt (RLS) (6). TCD showed greater sensitivity and overall diagnostic accuracy but lower specificity compared to transthoracic echocardiography for the detection of PFO in cryptogenic stroke patients in a meta-analysis of prospective observational studies (7). Transesophageal echocardiography (TEE) bubble study is currently considered the gold standard for PFO investigation. A meta-analysis of prospective studies determined that TEE bubble study has a sensitivity of 89% and specificity of 91% when compared to confirmation by autopsy, surgery, and/or right heart catheterization. False negative and false positive results may occur due to technical limitations including patient intolerance for the probe, inadequate Valsalva maneuver during sedation and operator experience (8, 9). TCD is more sensitive (sensitivity: 95–98%) compared with TEE (sensitivity: 80–100%) but carries a lower specificity, diagnosing not PFO per se but only RLS; it also fails to provide any information about other potential cardiac and aortic embolic sources (10, 11).

PFO width ranges widely in adults from 1 to 19 mm (mean 4.9 mm). Depending on its size, which may be echocardiographically evaluated by measuring the maximum opening between septum primum and septum secundum in the left atrium, PFO can be classified as large ≥4 mm, medium 2–3.9 mm and small <2 mm. Certain PFO characteristics as described by TEE may increase the association with cryptogenic stroke (Table 1).