A Meta-analysis of Patent Foramen Ovale Closure Trials

We considered the outcome of recurrent stroke as our primary outcome (as opposed to also including transient ischemic attacks), given its more standardized definition and its long-term clinical import. We additionally explored composite outcomes in sensitivity analyses, and apart from the intentionto-treat analysis, we also synthesized the per-protocol results of the trials to appreciate the effects of crossovers and dropouts. For the statistical synthesis, we considered the generally accepted random effects model, 7 which accounts for possible between-trial treatment-effect heterogeneity. In sensitivity analysis excluding the CLOSURE-I trial, we also explored a (less conservative) fixed effects model for the 2 RCTs using the same device, appropriate only under a strong assumption of a single true effect of closure using the Amplatzer device. First, we examined the absolute event rates of recurrent stroke, incidence rates with their 95% exact Poisson confidence intervals (95% CIs) in device and medical groups separately (Figure 1). By random effects meta-analysis, the summary incidence rate of stroke was relatively low in both groups; in the device groups, it was 0.76 (95% CI, 0.30–1.96) per 100 person-years versus 1.30 (95% CI, 0.94–1.81) per 100 person-years in medical groups. Statistically significant heterogeneity of incidence rates in the device groups (I 2 for heterogeneity=78%; P=0.01) may reflect between-trial differences in study design. Important differences may have included variation in the stringency of patient selection, medical therapy received on either arm, the presence of true, device-specific effects of closure, or differences in outcome ascertainment methods (which were, for example, much more assiduous in RESPECT than in the PC trial). In fact, a concerning signal for differential referral for outcome adjudication in the device group was noted in the PC trial, 5 which may, in part, contribute to the exceedingly low incidence rate in this trial. Next, we conducted a series of meta-analyses for the treatment effects estimated as hazard ratios. In our primary results for the outcome of stroke, closure showed a nonsignificant 45% reduction in risk with all 3 RCTs combined (summary hazard ratio, 0.55 [95% CI, 0.26–1.18]; Figure 2). The results for the outcome of stroke were also nonsignificant when the 2 Amplatzer device trials were combined without the CLOSURE-I trial included, or when the per-protocol results were synthesized (Table). Yet the absence of significance is not universally the case across all analyses. Importantly, for the composite primary outcome for which each RCT was powered (nonidentically defined across studies), a borderline statistically significant effect was found for the intentionto-treat analysis only (summary hazard ratio, 0.67 [95% CI, 0.44–1.00]). The treatment effect was larger still and more statistically significant when the 2 Amplatzer device trials (RESPECT and PC trial) were synthesized with a fixed effects model (summary hazard ratio, 0.41 [95% CI, 0.19–0.88]), although a random effects model is probably more appropriate given differences in the design and conduct of these trials. No significant effects were found for the composite of stroke or transient ischemic attack. We further explored sources of potential treatment-effect heterogeneity with subgroup meta-analyses based on available data from RCTs for their primary outcomes (Figure 3).