In November 2015, the US Food and Drug Administration (FDA) granted the first Investigational Device Exemption (IDE) to evaluate the safety and effectiveness of transcatheter aortic valve replacement (TAVR) in subjects with severe aortic stenosis who are at low risk for surgical mortality. This first IDE for patients with low risk for mortality is an important landmark in the development of the TAVR procedure and its implementation for patients with severe aortic stenosis in the United States. The approval of TAVR in the United States was always based on data driven from adequately powered clinical trials. This investigator-sponsored IDE is for the Low Risk TAVR (LRT) study and listed on clinicaltrials.gov as NCT02628899. The LRT study, which is limited to 200 patients at up to 4 sites, is actually a feasibility registry utilizing valves approved for marketing in the United States for patients at extreme and high risk of surgical mortality. These valves are the balloon-expandable Edwards SAPIEN 3® (Edwards Lifesciences, Irvine, CA) and the self-expanding CoreValve® Evolut® R (Medtronic, Minneapolis, MN).

The main objectives of the LRT study are to look at the safety aspects of TAVR for the first time in a low-risk population and to investigate the incidence of the latest reported phenomenon of leaflet thrombosis between 30 and 60 days post TAVR. The study conduct adheres to the principles of the Heart Team, which will determine eligibility of patients to participate in the study based on the inclusion/exclusion criteria and agreement that TAVR is a reasonable therapeutic option for this patient population. The main inclusion criteria are stable symptomatic patients with aortic stenosis who are 65 years of age and older. The Heart Team must agree that the patient is low risk, quantified by an estimated risk of ≤ 3% by the calculated Society of Thoracic Surgeons (STS) score for operative mortality at 30 days, and agree that surgical aortic valve replacement (SAVR) would be an appropriate therapy if offered. The main exclusion criteria are concomitant disease of another heart valve or the aorta that requires either transcatheter or surgical intervention, renal failure, low ejection fraction, and bicuspid aortic valve. By design, this is a registry, and the newly acquired data from the study will be compared with historical control data from SAVR patients at each of the 4 sites in a patient-to-patient match.

Following the initiation of this investigator-sponsored IDE, there will be 2 pivotal studies for both approved commercial devices, the SAPIEN 3 and Evolut R, that will require randomization to SAVR. These pivotal studies will have similar inclusion/exclusion criteria to the LRT study and will also extensively examine the incidence of leaflet thrombosis for both strategies, SAVR and TAVR. These studies will be powered for noninferiority of TAVR versus SAVR for efficacy and safety endpoints, similar to the design of the intermediate-risk studies, Placement of AoRTic TraNscathetER Valves (PARTNER II) and the Safety and Efficacy Study of the Medtronic CoreValve® System in the Treatment of Severe, Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI).

An interesting addition to the TAVR investigation, which is part of the LRT study, is the imaging for leaflet thrombosis. This add-on was prompted by the recent recognized phenomenon of subclinical leaflet thrombosis, which was first described in October 2015 in 22 of 55 patients undergoing 4-dimensional computed tomography angiography post TAVR . Although an interesting finding, this observation was mainly on the Portico™ valve (St. Jude Medical, Minneapolis, MN). The sample size of the study was small, and the study did not include the second-generation valves. The LRT study will determine the incidence of leaflet thrombosis on 200 patients with both second-generation valves, SAPIEN 3 and Evolut R, and will be able to detect whether this phenomenon is associated with any clinical sequelae. The study will observe the outcome of treatment of such leaflet thrombosis if it is detected by the noninvasive imaging. The pivotal trials to follow will also investigate the incidence of leaflet thrombosis in the SAVR group and will address the question of whether leaflet thrombosis is a phenomenon related only to TAVR or a class effect for valve replacement irrespective to the method of implantation with TAVR or SAVR.

Although this is a desired investigation, there are several anticipated challenges to the studies in the low-risk population. Currently, SAVR is the standard of care in this younger and low-risk population presenting with severe aortic stenosis and has reported outstanding results. TAVR in the low-risk population has to perform better when compared to the high- and intermediate-risk patients to equate to the results of SAVR. This should include lower rates of vascular complications, transfusions, pacemakers, paravalvular leak, and stroke. The second challenge is to compare the durability of TAVR versus SAVR: How long should these patients be followed and what would be sufficient follow-up time to grant approval for marketing? So far, there have been no signs of early failure of the valves used in TAVR when compared to SAVR, but because of the nature of the other morbidities of these patients, the data on durability is sparse. Based on the high-risk randomized trials and the anticipated results of the intermediate-risk trials, the durability of TAVR is similar to SAVR with respect to the functioning of the valve at 2 and 5 years . Therefore, it would make sense to grant approval based on a similar time frame of follow-up, between 12 and 24 months after enrollment. However, by lowering the eligibility age to 65 and with a life expectancy of more than 10 years, the durability of the valve becomes a critical question when compared to the surgical and percutaneous options. Patients who will be enrolled in the pivotal low-risk trials should be followed for their lifetime or at least to the lifetime of the implanted valve with an endpoint of valve failure that will require valve replacement or a valve-in-valve procedure. Finally, with the sliding of the STS score in patients undergoing commercial TAVR, as reported by the Transcatheter Valve Therapy registry , and the anticipation of the approval of expanded labeling of TAVR to the intermediate-risk patients, the enrollment into a randomized trial may encounter some difficulties because patients usually do not like to be randomized to surgery if they have a less-invasive alternative. However, randomization for the low-risk TAVR prior to approval is imperative to addressing the durability question. One option to help with sampling size with respect to durability is to amend the intermediate-risk protocols to include lifetime follow-up of this population. This will enable us to find out earlier if there are differences in valve durability between SAVR and TAVR.

The prior investigational data on TAVR for the low-risk population is limited to the Nordic Aortic Valve Intervention (NOTION) investigator study from Denmark and Sweden, which was basically an all-comers TAVR versus SAVR study that included patients with low STS scores of 2.9 for TAVR and 3.1 for SAVR . The study was small and did not find differences for the composite of any death, myocardial infarction, and stroke between the two modalities at 12 months. LRT is the first dedicated feasibility study to investigate TAVR for the low-risk population, and with the approval of the FDA for upcoming pivotal trials, the United States will lead the TAVR field to the next frontier of low-risk patients for TAVR. If partnered with the industry, the LRT trial can finish enrollment by the third quarter of 2016 and report the results of 30-day safety endpoints and leaflet thrombosis data by the end of 2016. This data will be valuable to better understand the leaflet thrombosis phenomenon, incidence, and implication. The results from the LRT study may assist in sampling for future studies for the low-risk indication of TAVR.

This year is going to be another important milestone for the TAVR field. The publication of the PARTNER II study that will reveal the results of TAVR for the intermediate-risk cohort, the anticipated approval of the intermediate-risk indication for marketing in the United States, and the initiation of the TAVR studies for the low-risk population will make 2016 an exciting time for patients with severe aortic stenosis.