Letter to the editor in response to Prof. Audebert and Nolte

Dear Editor,

The PFO writing group appreciates the thoughtful feedback provided by Professors Nolte and Audebert on the ESO guideline for the diagnosis and management of patent foramen ovale (PFO) after stroke. ¹

Specifically, they highlighted that the guideline does not provide recommendations on the timing of PFO closure. They noted that other ESO guidelines on secondary prevention and carotid stenosis advocate for the early use of antiplatelets after ischemic stroke and early endarterectomy for carotid artery stenosis, respectively.

In response, the PFO guideline included an analysis of the DEFENSE-PFO, CLOSURE I, CLOSE, and GORE REDUCE RCTs, where patients were included if their index stroke occurred within 6 months before the intervention. Specific timings varied, with enrollment in the RESPECT trial at a mean time of 2.6–3.3 months post-stroke, GORE REDUCE around 3.4 months, CLOSE at approximately 3.1 months, and PC Trial at about 4.3 months following the index stroke. Based on these data, the working group provided the following expert consensus: “Given the lack of evidence for the timing of PFO closure, the panel suggests considering PFO closure within 6 months post-index stroke, based on randomized studies. However, as secondary prevention procedures are time-dependent, PFO closure should be performed as soon as possible based on each patient’s clinical scenario, including stroke lesion size and risk profile.” (Vote: 9/9 experts agree). ¹

Professors Nolte and Audebert advised that early PFO closure could hinder thorough diagnostic evaluations and reduce the chances of identifying alternative stroke mechanisms, as current evidence suggests a low risk of early stroke recurrence in PFO-associated stroke patients, supporting a wait until comprehensive diagnostics are completed. The working group agrees that unnecessary overtreatment should be avoided in a relatively low-risk population. Therefore, the working group adopted the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System based on an individual patient data meta-analysis (IPDMA) of available RCTs. ² This system integrates information on (1) features that increase the likelihood of PFO-stroke mechanisms (high-risk PFO physiological and structural features like large shunt or ASA) and (2) absence of features that increase the likelihood of non-PFO stroke mechanisms (older age, vascular risk factors, and stroke topography features), as quantified by the RoPE score. The IPDMA showed a 60% relative risk reduction of recurrent stroke with PFO closure in these patients, although the absolute risk reduction was slight (2-year ARR: 1.7%).

Moreover, as we referred to international guidelines, the PFO working group did not include a comprehensive diagnostic protocol for patients with cryptogenic stroke to exclude other rare etiologies beyond a PFO. ³ The 2022 ESO screening guideline already addressed the detection of subclinical AF in patients with PFO and cryptogenic stroke. ⁴ Finally, 6 months is a reasonable time to complete the etiological workup of an ischaemic stroke.

In conclusion, while we appreciate the need for careful patient evaluation, we advocate for a balanced approach that does not unduly delay potentially beneficial interventions like PFO closure.