Richard Jackson, MD
This is a much-needed review on the topic of patent foramen ovale (PFO) closure to help guide physician decision-making in cryptogenic stroke in the young adult. The finding of a PFO in a young or middle-aged ischemic stroke patient is a common clinical dilemma which now has data to guide physician treatment decisions. Three new trials — RESPECT, REDUCE, and CLOSE — in 2017 have added new research into our understanding of the role of PFO in ischemic stroke.
The article begins with a review of the epidemiology of PFO. In the general population, PFOs are present in 20-25% of individuals. In cryptogenic stroke, the prevalence is 50-60%, which translates to a 2.3 fold increased relative risk. The authors theorize through probability theory that PFO is, therefore, causative in the mechanism of stroke in 73% of patients with cryptogenic stroke and incidental in 23% of patients with cryptogenic stroke.
The article then addresses diagnosis. Of particular note is that during the routine stroke work-up, testing with transthoracic echo has a sensitivity of 50-60% while transesophageal echocardiography has a sensitivity of 90%. Importantly, it is stated that “a high grade alternative source of stroke in the work-up greatly lessens the likelihood that a medium grade source like PFO is causative.” In Figure 2, which features the study populations in all 6 trials of PFO closure, patients had an incidence of 11-31% HTN, 14-44% HLD, and 13-29% smoking. This is significant because there is a high grade alternative source in 10-30% of the patient populations of the PFO trials making the medium grade source PFO less likely.
The authors describe five clinical features that increase the likelihood that a PFO is causative: concurrent deep or superficial venous thromboembolism; increased right to left shunt flow, either permanently or transiently; the presence of an atrial septal aneurysm; MRI evidence of embolism (based on infarct topography); and absence of risk factors for atherosclerosis.
The next part of the article addresses the treatment options, which include medical therapy, open closure, and percutaneous devices, both older umbrella-clamshell models and new double-disk models. The new percutaneous options bypass the risks of open surgery. The recent trials showed that there were fewer ischemic events, thrombosis on device, and atrial fibrillation with the double disk devices Amplatzer PFO Occluder (1.4%, 0%, 3.6%) and HELEX Occluder (4.1%, 0.5%, 2.3%) than the umbrella clamshell device (5.9%, 5.0%, 12.3%). In a meta-analysis of the three recent trials, device closure plus antiplatelet reduced the rate of ischemic stroke HR 0.30 compared to medical therapy alone with either antiplatelet or anticoagulation and a difference between the double disk (HR 0.20) compared to the umbrella clamshell devices (HR 0.90) with an event rate of 6.0% over 5 years with medical therapy versus 1.8% with device closure plus long term antiplatelet. The comparison of device closure plus anticoagulation versus anticoagulation alone was underpowered. Effective PFO closure in the trials was reported to be 93-96% with complications 0-1% and a post-procedure risk of atrial fibrillation of 3.2% but only an annual increase risk of atrial fibrillation from 0.39% versus 0.26% per year.
Three groups were identified as having a magnified reduction in recurrent ischemic stroke: atrial septal aneurysm, larger shunt sizes, and index ischemic event not confined to single deep penetrating artery. However, the magnitude of benefit overall is stated to be moderate with a number needed to treat of 24 over 5 years. A lesser number is needed to treat in atrial septal aneurysm (NNT=13) and moderate-substantial shunts (NNT=18) with an annual recurrent ischemic stroke reduction in the medical therapy alone of 1.2%, which is less than other causes of stroke.
The article concludes with valuable recommendations on management and directions for future research. Patients can, therefore, choose between two good options: medical therapy alone with a modest recurrence rate or closure device combined with antiplatelet therapy with a dramatic relative and moderate absolute further reduction in risk. Anticoagulation versus device placement plus medical management, patients older than 60 years of age, and the presence of risk factors other than PFO in the trials require further study and are still hypothesis-generating, but the safety and benefit in a select group of patients is encouraging.