FDA Advisory Panel Split on Medtronic’s Symplicity Spyral Renal Denervation

August 23, 2023—A Circulatory System Devices Panel met to consider the premarket approval application for the Medtronic Symplicity Spyral renal denervation (RDN) system and advise the FDA regarding approval and optimization of any potential postapproval study.

After a day of deliberation, the panel was unanimous in its support of the device’s safety, voting 13-0 in favor. On whether the platform is effective, seven panelists voted in favor and six voted against. Regarding whether the benefits of the device and procedure outweigh the risks, the panel voted six in favor and six against, with one abstaining; given the tie on the final question, the chairperson, Dr. Richard Lange, cast a deciding vote and was against the motion, with the final tally of six in favor, seven against, and one abstaining.

On the previous day, the advisory panel weighed the evidence for ReCor Medical’s Paradise ultrasound RDN platform and voted largely in favor on each question (with a few differences in the voting members across the 2 days), despite deliberation over the strength of the evidence as to efficacy and durability of effect.

Clinical investigators and representatives from Medtronic presented the designs and findings of the family of trials evaluating the Symplicity Spyral platform. These studies include the Global SYMPLICITY Registry, the SPYRAL HTN-OFF MED randomized trial, and the SPYRAL HTN-ON MED randomized trial, as well as a patient preference study. Medtronic’s Symplicity Spyral system comprises a catheter-based approach to RDN using radiofrequency energy.

Although safety was confirmed in each study and the primary efficacy endpoint was met in the HTN-OFF trial, the efficacy endpoint was not met in the HTN-ON trial, where a numeric advantage in the treatment arm did not reach statistical significance and multiple factors seemed to confound clear evaluation by the panel. Several hypotheses were discussed as to what led to this result, in particular relating to changes in medication use in the sham arm. Presenters and panelists raised the point that the HTN-ON sham arm’s success might attenuate the efficacy signal in the treatment arm, but several panel members remained concerned at the inability to clearly resolve the confounding aspects. Some factors, such as those related to the increased medication use in the sham arm, were described as possibly owing to challenges of the trial taking place during the COVID-19 pandemic, although there was no consensus on this point.

Other points of discussion included how missing data were imputed, and, echoing the panel’s sentiments the day before, whether the study populations were truly shown to have uncontrolled or treatment-resistant hypertension despite being on medications. As was the case when the panel evaluated ReCor’s data and proposed labeling, the members did not agree with the proposed labeling as worded, leaving the FDA to consider and possibly revise this language in any approved device.

Still, multiple panelists pointed to data indicating Symplicity Sypral is a potentially effective treatment for some patients, with interest in clearly identifying which populations might be most likely to benefit.

“The Symplicity Blood Pressure Procedure has the potential to fill a significant unmet need in hypertension care, and we know patients are looking for options in addition to medication and lifestyle modifications to manage their blood pressure,” said David Kandzari, MD, in a statement provided by Medtronic. Dr. Kandzari is Chief, Piedmont Heart Institute and Cardiovascular Services and lead principal investigator of the SPYRAL HTN-ON MED clinical trial. “The totality of evidence demonstrated that there is a benefit with the Spyral RDN catheter, and there is no question about the safety of the procedure.”

“We appreciate the robust conversation that occurred prior to the vote,” said Medtronic's Jason Weidman, Senior Vice President and President of the Coronary and Renal Denervation business, in the company's statement. “We will continue to collaborate with the FDA on bringing a new option to the millions of people living with high blood pressure.”

If the FDA approves the Symplicity Spyral application, a postapproval study (PAS) would be initiated as part of the Breakthrough Device regulatory pathway through which both Medtronic’s and ReCor Medical’s RDN platforms are separately being evaluated. A proposed design of Medtronic’s PAS, called AFFIRM, was presented, outlining a plan to continue to study safety by recording incidence of major adverse events, and effectiveness via change in office systolic blood pressure, home blood pressure, and 24-hr ambulatory systolic blood pressure, as well as procedural characteristics, BP medication burden, proportion requiring repeat denervation, and time in target range. Prespecified subgroup analyses would also be conducted. As was the case in the ReCor session, the panel was asked to weigh the potential design and goals, and members shared various ideas to resolve challenges related to population sizes and design feasibility.

On both days, the sponsors, FDA, and panelists acknowledged the challenges in studying and managing patients with treatment-resistant hypertension, as well as the clear clinical and public health need to reduce resultant cardiovascular events. In the public forum, patients treated with RDN again described their desire to be on fewer medications and the increased quality of life they associate with reduction of side effects.

“There is clear patient need for alternative treatment options for the management of resistant hypertension,” commented Eric A. Secemsky, MD, to Cardiac Interventions Today. Dr. Secemsky is Director of Vascular Intervention at Beth Israel Deaconess Medical Center; Section Head, Interventional Cardiology and Vascular Research; Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology; and Assistant Professor of Medicine at Harvard Medical School in Boston, Massachusetts. “The totality of evidence has demonstrated that there is a benefit with the Spyral RDN catheter, and there is no question about the safety of the procedure. It is disappointing that the full evidence landscape was not enough to convince the majority of the panel. It is worth noting that the overwhelming sentiment of the panelists was that there was a likely benefit of this procedure, and hopefully this will be considered when the FDA deliberates approval.”