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Introduction: In the intention-to-treat (ITT) analysis of the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial, a trend favoring PFO closure in the primary analytic period (median follow-up 2.1y) was statistically significant with longer follow-up (median 5.9y).Hypotheses: Populations with less clinical trial noise [Per Protocol (PP), As Treated (AT), Device in Place (DIP)] will show > benefit, consistent with a genuine treatment effect of closure. Analysis of strokes without known mechanisms (per ASCOD) or occurring while patients are less subject to non-PFO stroke mechanisms (<60y) will show heightened treatment effect.Methods: RESPECT was a prospective, multicenter, RCT comparing patients assigned 1:1 to PFO closure (Amplatzer PFO Occluder) or to medical management (MM) alone. Data were collected through May 2016.Results: We enrolled 980 patients who were followed for a median of 5.9y (IQR 4.2-8.0, range 0-11). All primary endpoint events were nonfatal ischemic strokes. The efficacy outcome in the ITT population significantly favored device closure over MM alone (HR: 0.55, 95% CI: 0.305 to 0.999, log-rank p=0.046) and was equal (PP) or magnified in the other populations analyzed by treatment actually received. It was also greater if events were excluded when they occurred after patients reached 60y or had a known (non-PFO) mechanism (Table).Conclusions: The final data from RESPECT, after long-term follow-up, show that the benefit of PFO closure seen in the ITT population is magnified in populations that account for treatment crossover and that include the age range in which recurrent ischemic strokes are predominantly cryptogenic. These secondary analyses reinforce the main trial finding that PFO closure with the Amplatzer PFO Occluder is superior to medical therapy alone in preventing recurrent ischemic stroke.