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More Inconclusive Results from PFO-Closure Trials

Summary and Comment |
March 20, 2013

More Inconclusive Results from PFO-Closure Trials

  1. Harlan M. Krumholz, MD, SM

Two new studies fail to provide strong evidence either for or against PFO correction to prevent recurrent cryptogenic stroke.

  1. Harlan M. Krumholz, MD, SM

Patent foramen ovale (PFO) is more prevalent in patients with cryptogenic stroke than in the general population, but can correction of the PFO reduce stroke incidence? Findings from the CLOSURE I trial of the STARFlex PFO-closure device after cryptogenic stroke showed no significant reduction in the rate of recurrent stroke compared with medical therapy (JW Neurol Mar 14 2012). Now, results are available from two randomized trials of another device (the Amplatzer PFO Occluder).

In the manufacturer-funded PC Trial, investigators at 29 European sites assigned 414 patients (mean age, 44) with a neuroradiologically confirmed PFO and cryptogenic stroke, transient ischemic attack (TIA), or peripheral thromboembolism to receive the PFO-closure device or medical treatment. At a mean follow-up of 4 years, the rate of the primary endpoint — a composite of death, nonfatal stroke or TIA, and peripheral embolism — was 3.5% in the closure group and 5.2% in the medical-therapy group (hazard ratio, 0.63; 95% confidence interval, 0.24–1.62; P=0.34).

In the RESPECT trial, sponsored and administered by the manufacturer, investigators at 69 sites in the U.S. and Canada assigned 980 patients (mean age, 46) with a PFO and a history of cryptogenic stroke in the previous 270 days to receive the PFO-closure device or medical treatment. Mean follow-up was 2.6 years. In the intention-to-treat analysis, the rate of the primary endpoint — a composite of recurrent stroke (fatal or nonfatal) and early death (within 45 days after randomization) — was 0.66 per 100 patient-years in the closure group and 1.38 per 100 patient years in the medical-therapy group (HR, 0.49; 95% CI, 0.22–1.11; P=0.08). In a prespecified per-protocol analysis, the rate of the primary endpoint was 0.46 per 100 patient-years in the closure group and 1.30 per 100 patient-years in the medical-therapy group (HR, 0.37; 95% CI, 0.14–0.96; P=0.007).

Comment

The RESPECT trial provides something for everyone. For skeptics of patent foramen ovale closure, the primary intention-to-treat analysis is negative (although there is some suggestion of effect). For enthusiasts, the per-protocol analysis suggests benefit. The PC Trial offers similar uncertainty: The hazard ratio indicates a 37% reduction in risk for the primary endpoint with PFO closure, with a number needed to treat of about 1 in 50; however, the finding is nonsignificant and could have occurred by chance. Is the therapy ineffective, or are these studies underpowered for a meaningful effect? My view is that we need stronger evidence of benefit before recommending to patients that they should undergo this procedure outside of a clinical trial.

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