Why didn’t the US Food and Drug Administration (FDA) require a panel review before approving the CoreValve transcatheter aortic valve replacement (TAVR) system (Medtronic, Inc., Minneapolis, MN)?

I think there are two reasons. The first is that recently, the FDA has been working with study sponsors in a very collaborative manner to address questions that the FDA may have about the premarket submission by ongoing correspondence and interactions with the study sponsor, facilitated by a modular submission process to the FDA. That increased communication between the study sponsor and the FDA has benefitted all parties. Rather than waiting for an isolated PMA to be submitted, with questions generated and responses going back and forth for several months, from the first contact with the FDA, there are ongoing discussions about the clinical trial design and the ultimate PMA submission. I feel that a lot of credit goes to the FDA for its efforts to enhance communications with study sponsors in order to shorten the time during which these devices are approved.

Second, I believe that the data presented in the Extreme Risk patients treated with CoreValve were very compelling. With our initial IDE submission in fall 2010, we understood that the CoreValve program was 3 years behind the Sapien program (Edwards Lifesciences, Irvine, CA), and there was loss of any clinical equipoise for a randomized trial of CoreValve with medical therapy in patients not suitable for surgery. Understanding the dismal prognosis of patients in PARTNER B who were managed with medical therapy, we needed a rigorously defined objective performance goal for all-cause mortality and major stroke in medically treated patients with which to compare the results of CoreValve. We understood that it would be critical to precisely characterize the clinical characteristics of the Extreme Risk patients, using not only the Society of Thoracic Surgery Predicted Risk of Mortality, but also to provide a detailed description of their comorbidities, disabilities, and frailty. This was ultimately important because we were able to provide evidence to the FDA that these patients truly represented a population that was not suitable for surgical aortic valve replacement. Our performance goal of 43% for all-cause mortality and major stroke in medically treated patients was very conservative—we set a very high bar for the CoreValve clinical trial. Remember that for the patients in the medical therapy arm of PARTNER B, this value was approximately 50.7%. I believe that CoreValve Extreme Risk Trial results were very compelling with respect to the primary endpoint of all-cause mortality and major stroke of 25.5%, a highly significant reduction compared to the conservative performance goal. I think that these strong results provided the FDA with a reasonable assurance of safety and efficacy in this intended population.

How will this approval affect patients and practice, now that there are two valves available for treatment?

I think the significance of the CoreValve approval is that there are now more treatment options for patients who may have been unsuitable for the currently available commercial device. We know that more patients can currently be treated with the transfemoral approach using the CoreValve device. We also know that there is a broader range of annular diameters available with the CoreValve device than what was available with the Sapien device. Additionally, there are subtle distinctions when selecting which device to use in selected patients relating to the geometry of the aortovalvular complex, as well as in the presence of calcification. Therefore, clinicians will now be better able to select the right valve for the right patient.

This approval is for extreme-risk patients only. What percent of those requiring TAVR fall into this category?

Our Heart Team is challenged with determining in which patients the benefits of surgical aortic valve replacement exceed its risks, primarily based on the input of our heart surgeons. Put another way, our Heart Team must decide in which patients surgical aortic valve replacement does more harm than good. Because these are relatively subjective statements, many factors go into this determination by the Heart Team. It was initially estimated that 40% to 50% of patients are denied surgical aortic valve replacement because of comorbidities, and I suspect that this number is about right in our clinical practice. We have also found that some patients are not suitable for any valve replacement procedure, because their life expectancy is limited by comorbidities rather than aortic stenosis. The lines are sometimes blurred between high-risk and extreme-risk patients, but we do our best with our heart surgeons to categorize patients into the appropriate risk group.

What are the plans to expand the CoreValve’s indication to treat lower-risk patients?

Based on the results of the Extreme Risk CoreValve study, it would certainly be reasonable to compare the CoreValve TAVR with surgical aortic valve replacement in those patients who are believed to be at increased risk for surgery. We will be presenting these trial results at the American College of Cardiology’s Late-Breaking Clinical Trials session in Washington, DC at the end of March. We also are recruiting patients who are more intermediate risk in the SURTAVI trial. While it is sometimes difficult to define intermediate risk, I would suggest that these patients are those in whom the Heart Team estimates a 3% to 15% 30-day surgical mortality rate with surgical. I also feel that it will be important to use randomized trials to address this important expansion into lower-risk patients.

Jeffrey J. Popma, MD, is Director, Interventional Cardiology Clinical Services, Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Professor of Medicine, Harvard Medical School. He has disclosed that he receives grant/ research funding from Medtronic, Inc. Dr. Popma may be reached at (617) 632-9210; jpopma@bidmc.harvard.edu.