Gore releases statement in response to safety of GORE HELEX Septal Occluder for PFO closure in cryptogenic stroke patients

W. L. Gore & Associates (Gore) today released the following statement from the Gore REDUCE Clinical Study Principal Investigators on behalf of the Gore REDUCE Clinical Study Steering Committee in response to the recent CLOSURE I results presentation. The Gore REDUCE Clinical Study is a prospective, randomized, multi-center, multi-national trial designed to demonstrate safety and effectiveness of the GORE® HELEX Septal Occluder for PFO closure in patients with history of cryptogenic stroke or imaging-confirmed Transient Ischemic Attack (TIA). The unique study includes up to fifty investigational sites in the US and Europe.

"On November 15, 2010 at the American Heart Association (AHA) annual meeting in Chicago, Anthony Furlan, MD presented the results of CLOSURE I, a prospective, multi-center, randomized controlled trial of PFO closure with the STARFLEX^® Device (NMT Medical, Inc) versus best medical therapy for the prevention of recurrent stroke and/or transient ischemic attack (TIA) in patients with cryptogenic stroke / TIA and PFO. The results of the study, as presented, showed no statistically significant difference between device closure and best medical therapy. In a discussant presentation, Pierre Amarenco, MD concluded that PFO closure is not needed for the majority of patients with stroke and PFO and should not be performed in routine practice. However, he noted that many patients with stroke and PFO have alternative (non-PFO) causes for their strokes, and argued that this may have diluted a true causal effect of PFO in the CLOSURE I study. Dr. Amarenco left open the possibility that PFO closure may still be considered in patients with truly cryptogenic stroke.

This presentation and the recommendations discussed would appear to refute the innovative device approach to the prevention of recurrent cryptogenic stroke in patients with PFO. However, there are several key issues that we believe should limit the impact of the CLOSURE I results on the ongoing Gore REDUCE Clinical Study. These issues are mostly related to device and patient selection:

• CLOSURE I included patients with clinically-defined (not imaging-confirmed) TIAs. Recent studies have shown that MRI-negative TIAs are associated with an extremely low risk of subsequent stroke. Inclusion of such patients likely resulted in an underestimation of stroke event rates in both arms of the trial as compared to a population with strokes confirmed by imaging.
• The majority of the stroke endpoint events during follow-up appeared to have a determinable origin, suggesting that these patients likely had alternative explanations for their index stroke. Stroke due to atherosclerosis or small vessel disease would not be affected by PFO closure, and therefore would bias the results toward underestimating a potential treatment effect for PFO closure (i.e., bias towards the null).
• Nearly half of the stroke endpoint events in the PFO closure arm appeared to be directly related to the device itself, and about a quarter of these occurred in the first 30 days after implantation. Alternative devices (like the GORE HELEX Septal Occluder) may offer substantial advantages and fewer complications, thereby increasing the differences between device and medical therapy.
• Although device-related complications were considered insignificant, the incidence of new atrial fibrillation (5.7%) and device thrombus (four cases and two cases lead to a subsequent stroke) appear to be associated with recurrent events and more frequent when compared to the GORE HELEX Septal Occluder reports.
• Medical therapy differed between PFO closure and control arm, thereby introducing a confounding effect on the study endpoints.

We, the Gore REDUCE Clinical Study Principal Investigators, conclude that improved patient selection focused on truly cryptogenic strokes (rather than other causes of stroke or TIA) and use of a device with a low complication rate is needed to determine whether PFO closure is superior to best medical therapy.

The Gore REDUCE Clinical Study addresses the CLOSURE I limitations by design:

• All TIAs must be confirmed by neuroimaging studies, which will prevent the inclusion of spurious neurological events that are not vascular in origin.
• Eligibility criteria are more stringent and better exclude patients with non-cryptogenic strokes, such as the exclusion of lacunar strokes and exclusion of patients with a substantial burden of vascular risk factors.
• Both test and control arms for the study have the same medical therapy and sites are directed to apply a uniform medical therapy regimen for both test and control subjects.
• The clinical literature for the GORE HELEX Septal Occluder supports a low rate of device related atrial fibrillation and a nearly non-existent incidence of device thrombus formation.

With additional PFO trials still underway, much remains to be determined regarding the best course of therapy for cryptogenic stroke patients with PFO. Taking into consideration the Gore REDUCE Clinical Study design and the noted shortcomings of the CLOSURE I study, the Gore REDUCE Clinical Study Steering Committee has concluded that the best course of action is to continue the study without significant changes. Additionally, in June, the FDA also recommended that the Gore REDUCE Clinical Study continue as original planned. At this point in time there is no compelling reason to alter the current clinical study. It remains imperative, as it has since the beginning of the trial, that we recruit patients with truly cryptogenic stroke (and PFO) to get a definitive answer to these essential questions."