Abstract: We included three RCTs involving a total of 2303 participants: 1150 participants were randomized to receive TDC and 1153 participants were randomized to receive medical therapy. Overall, the risk of bias was regarded as high. The mean follow-up period of all three included trials was less than five years. Baseline characteristics (age, sex, and vascular risk factors) were similar across trials. Intention-to-treat analyses did not show a statistically significant risk reduction in the composite endpoint of recurrent stroke or TIA in the TDC group when compared with medical therapy (RR 0.73, 95% CI 0.45 to 1.17). A time-to-event analysis combining the results of two RCTs also failed to show a significant risk reduction with TDC (HR 0.69, 95% CI 0.43 to 1.13). When assessing stroke prevention alone, TDC still did not show a statistically significant benefit (RR 0.61, 95% CI 0.29 to 1.27) (HR 0.55, 95% CI 0.26 to 1.18). In a sensitivity analysis including the two studies using the Amplatzer PFO occluder, TDC showed a possible protective effect on recurrent stroke compared with medical therapy (HR 0.38, 95% CI 0.14 to 1.02); however, it did not reach statistical significance. Safety analysis found that the overall risks for all-cause mortality and adverse events were similar in both the TDC and medical therapy groups. However, TDC increased the risk of new-onset atrial fibrillation (RR 3.50, 95% CI 1.47 to 8.35) and may be associated with the type of device used. The combined data from recent RCTs have shown no statistically significant differences between TDC and medical therapy in the prevention of recurrent ischemic stroke. TDC closure was associated with an increased risk of atrial fibrillation but not with serious adverse events.

Plain-language summary: The evidence is current to July 2014. We included in our analysis three multicenter randomized trials involving a total of 2303 participants. All three trials recruited participants aged 60 years or younger with a cryptogenic stroke or minor stroke and had a PFO diagnosed by specialist heart scan. 1150 participants were randomized to the TDC group where the procedure was performed with the Amplatzer device in two studies, and with the STARFlex device in one study. The mean follow-up period of all three included trials was less than five years. Two studies were sponsored by St Jude Medical and one study was sponsored by NMT Medical. We found that, when compared with medical therapy, TDC failed to show any significant benefit in reducing the risk of recurrent stroke or similar events. However, there was a possible protective effect on recurrent strokes in those participants for whom an Amplatzer device was used compared with medical therapy. We did not find evidence that TDC increased the rate of serious adverse events overall. However, TDC increased the risk of new-onset atrial fibrillation (where there is a problem with the rate or rhythm of the heartbeat) and may be associated with the type of device used. We performed this systematic review of three randomized trials to compare both the safety and efficacy of TDC with medical therapy on recurrent cerebrovascular events in people with cryptogenic stroke and PFO following theCochrane Handbook for Systematic Reviews of Interventions.The major problem in terms of risk of bias is the high dropout rate compared with event rate in these three trials and different dropout rates between groups. Meanwhile, we lack individual-level data for analysis. Although there is a suggestion of potential benefit with the Amplatzer device closure in preventing recurrent stroke, our findings still need to be confirmed in further studies.