Rebuttal: “A critical appraisal of a meta‐analysis comparing transcatheter closure of PFO versus medical therapy”

For the past two decades, transcatheter closure of patent foramen ovale (PFO) for the prevention of recurrent neurological events after a cryptogenic ischemic stroke has been subject of a never-ending debate in the medical community. Therefore, we receive the letter by Drs. Pandit and Hakim with great interest, and we are happy to clarify some points. First of all, it was confirmed by the three recently available randomized controlled trials (RCTs), that patients with ischemic cerebrovascular events and PFO, whether percutaneously closed or not, have a low incidence of recurrent neurological events. This fact, in addition to the relatively small number of patients enrolled in each of the RCTs, is the most likely explanation of the negative results of each RCT individually, as pointed out in our meta-analysis [1]. When performing a meta-analysis of studies with rare events, the Cochrane Handbook for Systematic Reviews of Interventions, in its last version (section 16.9.5), states that the Mantel–Haenszel odds ratio is among the best performing statistical methods for low event risks [2]. In this setting, the handbook specifically recommends to avoid the inverse-variance methods, which was the method encouraged by Drs. Pandit and Hakim. They had also suggested the outcomes of our metaanalysis should have been reported in hazard ratios rather than odds ratios, as used in a similar metaanalysis more recently published [3]. This would have been correct if a time-to-event outcome was used in our publication. However, given that not all the outcomes of interest were part of the primary end point of the respective RCTs, we decided to use the total number of events (raw data reported in the trials), rather than risk estimates or a time-to-event outcome, for our analysis. In regards to the RESPECT trial events, we respectfully recommend the authors of the above letter to the editor, to carefully review the RESPECT original publication, including the supplement material [4]. Their primary end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. As correctly pointed out by Drs. Pandit and Hakim, there were 25 primary end-point events, 9 in the closure group and 16 in the medical therapy group, all of which were nonfatal ischemic strokes [4]. However, they erroneously stated in their letter that “: : :the RESPECT trial clearly reports no events of transient ischemic attacks (TIA): : :”. Although the actual count is not given in the main manuscript, it is clearly stated in the RESPECT trial, in the last sentence of the paragraph subtitled Secondary End Points (page 1096), that “there was no significant difference between the two groups in the incidence of transient ischemic attack. ” The number of TIA events in the RESPECT trial is, however, easily found in their supplementary appendix, specifically in Table S5, in which six TIA events are reported for the closure group and five TIA events for the medical therapy group. This information is critical for the meta-analysis and if excluded, may overestimate the benefit of the percutaneous PFO closure. In fact, the meta-analysis by Rengifo-Moreno et al. does not include the TIA events in the RESPECT trial in their table describing outcomes for each trial, and it is not completely clear whether these events were included or not in their statistical analysis [3]. Three recent meta-analyses with different statistical methodologies have been published within the last two months [1,3,5]. Despite the slightly different numeric results, all three meta-analyses showed some benefit from PFO transcatheter closure versus medical therapy for the prevention of recurrent cerebrovascular events, and therefore, this therapeutic option should be still considered for such patients.