FDA Releases Briefing Documents for Advisory Panel on the Edwards Sapien Transcatheter Aortic Valve Implant Reply

The FDA has posted the briefing documents for the much-anticipated meeting on Wednesday of the Circulatory Systems Devices Panel for the Edwards Sapien transcatheter heart valve system in patients with severe aortic stenosis who are not eligible for surgical valve replacement, as studied in the PARTNER B trial. Overall the FDA documents suggest that the committee will likely recommend approval of the device. The document raises no major unexpected concerns about the pivotal PARTNER B trial, and states that the “trial met the pre-specified criteria for study success, as defined by the primary safety and effectiveness endpoint of all-cause mortality throughout the duration of the study, demonstrating superiority of the SAPIEN THV as compared to the Control group.”

Much of the discussion will likely focus on the questions surrounding the rate of strokes in PARTNER B (see the FDA text below) and the details of a post-approval study and risk mitigation strategy. Edwards has proposed a post-approval study of an anticoagulation/antiplatelet regimen to help reduce the risk of stroke.

Some of the discussion will revolve around the definition of “inoperable” used in PARTNER B and the use of “standard” therapy in these patients. The FDA points out that there is a wide variety of treatments used for patients with inoperable aortic disease and that “there is no ‘standard’ therapy for this patient cohort as evidenced by the various treatments received.”

Here is the text of the FDA’s discussion question regarding neurological adverse events:

As shown in the tables below, there was a significant increase in the neurological event risk in the SAPIEN arm compared to Control, noting that the majority of Controls had BAV, in both the acute periprocedural period and the longer-term follow-up phase of the PARTNER trial. The breakdown of neurological events by type (stroke, transient ischemic attack, intracranial hemorrhage) is also presented. These events may actually have been under-reported, since the identification of stroke in the current study depended on recognition of symptoms by the cardiovascular team, rather than rigorous neurological evaluations. While interpretation of the increased late event rate is complicated because of the higher mortality rate in the Control group, neurological adverse events remain an important safety consideration for this device and impact the overall risk-benefit profile of the SAPIEN THV.


Q3a. Please comment on the clinical significance of the neurological adverse event risk observed in patients treated with the SAPIEN THV.
The cause of neurological injury with transcatheter valve implantation is multifactorial. One important consideration is management of coagulation and platelet aggregation. The PARTNER trial did not require patients to be on a protocolized anticoagulation or antiplatelet regimen. In light of this, as well as the increased neurological event risk discussed above, the sponsor has proposed a protocolized anticoagulation/antiplatelet regimen to be used in the proposed post-approval study.

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