Not All Valves With Leaflet Thickening Develop Mobility Problems, Repeat 4D CT Shows in SAVORY

CHICAGO, IL— In a study of the natural history of leaflet thrombosis and abnormal motion in aortic bioprosthetic valves, approximately one-third of patients developed some degree of subclinical leaflet thickening, with roughly the same prevalence observed between patients undergoing transcatheter aortic valve replacement and surgery.

However, leaflet thickening that resulted in a restriction of mobility was seen more frequently in patients treated with a transcatheter valve than in patients who had been treated surgically.

Presenting 4D computed tomography data from 105 patients in the SAVORY registry at TVT 2016, Lars Sondergaard, MD (Rigshospitalet, Copenhagen, Denmark), said the results suggest that leaflet thickening can occur without affecting the mobility of the valve and that progression toward impaired mobility—defined as a reduction in leaflet excursion of more than 50%—is a “further gradation of severity.”

Despite the data, Sondergaard said there is still a lot to learn, noting that the relationship between the subclinical CT findings and long-term valve performance, durability, and clinical outcomes is unknown.

Of note, CT substudies have been included as part of the recently launched, randomized controlled trials testing TAVR versus surgery in low-risk patient populations. The PARTNER 3 trial will include a 400-patient substudy in an attempt to provide clarity on leaflet mobility and thrombosis among patients treated with Sapien 3 (Edwards Lifesciences). Similarly, the Medtronic low-risk study testing the Evolut R device will also include a 400-patient CT substudy.

Last October, the issue of restricted leaflet motion gained a lot of attention when Raj Makkar, MD (Cedars Sinai Medical Center, Los Angeles, CA), and colleagues published data in the New England Journal of Medicine showing reduced leaflet motion in patients from the Portico Resheathable Transcatheter Aortic Valve System US investigational device exemption (PORTICO-IDE) study, as well as in a pooled cohort of patients from the RESOLVE and SAVORY single-center registries. The pooled RESOLVE/SAVORY data revealed a higher incidence of stroke or transient ischemic attack in those with reduced leaflet motion when compared with those with normal leaflet function (18% vs 1%; P = 0.007).

Analysis of SAVORY

The latest study is an expanded analysis of patients in the SAVORY cohort with longer follow-up. Compared with the previous SAVORY data, individuals in this latest analysis underwent two 4D-CT scans, first at a median 89 days after implantation and again at a median of 253 days after the procedure. Of the 105 patients studied, 75 underwent TAVR with a range of different devices, including CoreValve/Evolut R (Medtronic), Portico (St. Jude Medical), Lotus (Boston Scientific), and Sapien 3 and 30 patients were treated with surgery.

There was no change in medication between the baseline and follow-up CT scans. Use of oral anticoagulation varied, ranging from 7% to nearly 50% in patients treated with the different valve types. Approximately one-quarter of the patients also had atrial fibrillation.  

In total, 30.1% of patients treated with TAVR had leaflet thickening, which researchers labeled hypoattenuating leaflet thickening (HALT), compared with 28.2% of patients treated surgically, a nonsignificant difference. They did not observe any significant differences in the prevalence of HALT between the valve brands. The prevalence of leaflet thickening affecting motion—referred to as hypoattenuation affecting motion (HAM)—was 19.0% among patients treated with TAVR and 3.9% among the surgical patients, a difference that trended toward statistical significance (P = 0.08). Similarly, there was no difference in the prevalence of impaired mobility between the different valve types.

Regarding clinical outcomes, there were two transient ischemic attacks in two patients with HALT.

Sondergaard said the prevalence of HALT and HAM is a “dynamic process.” For example, in the group of patients not taking oral anticoagulants, leaflet thickening developed in the period from the baseline CT scan to the follow-up scan in 11 patients but resolved in five patients during the same period. In the analysis of patients taking oral anticoagulants, leaflet thickening also resolved in two patients (and developed in none of those who had normal leaflets at baseline).

Similar temporal dynamics were observed in patients with leaflet thickening affecting motion. Sondergaard noted that all patients with restricted leaflet mobility have HALT, which was defined as leaflet thickening involving the periphery and base and extending to varying degrees to the edges of the leaflet, but he stressed that not every patient with HALT progresses to impaired motion.

Regarding the role of oral anticoagulation, freedom from leaflet thickening at follow-up was significantly better among patients treated with warfarin when compared with patients treated only with antiplatelet therapy. In contrast, use of the novel oral anticoagulants, a category that includes drugs such as dabigatran (Pradaxa, Boeringer-Ingelheim) and the factor Xa inhibitors rivaroxaban (Xarelto, Bayer/Johnson & Johnson), apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), and others, was not associated with freedom from leaflet thickening compared with antiplatelet therapy.

Speaking during the “TAVR 2016 Highlights and Controversies” session, Sondergaard said he doesn’t know why the warfarin appeared to provide protection from leaflet thickening but the novel oral anticoagulants did not. While without a mechanism to explain the difference—which was also observed in other studies—Sondergaard said the data do appear to suggest there is a “big difference” between the drug classes. 

Jonathon Leipsic, MD (St. Paul’s Hospital, Vancouver, Canada), agreed with Sondergaard, saying the data consistently show that impaired leaflet mobility is less likely to occur in warfarin-treated patients and that anticoagulation with warfarin is more likely to result in the resumption of normal leaflet function. Leipsic added, though, that the results do not mean all patients should be treated with oral anticoagulation to prevent potential leaflet thickening and impaired leaflet mobility.

Sondergaard agreed. “I don’t think there’s any indication to put a patient on oral anticoagulation unless they have a classic indication, such as atrial fibrillation,” he said. “I also don’t think we need to be putting all these patients into a CT scanner to look for these findings. First of all, it’s a dynamic finding—it might be normal today and tomorrow a positive finding. And we don’t know the meaning of it. We don’t know the impact on durability or on the risk of stroke long term.”

More Longitudinal Follow-Up Needed

Speaking with TCTMD, Leipsic, who was not involved in the present analysis but was part of the earliest European imaging studies identifying leaflet thrombosis, said the CT substudies that are part of the newly launched low-risk trials will provide important information, such as the prevalence of subclinical thrombosis, whether leaflet thickening and restricted mobility is associated with symptoms, and whether or not the CT-identified findings resolve on their own or require treatment. Like Sondergaard, Leipsic said it is unclear whether the formation of leaflet thrombosis is a marker of early structural valve deterioration.   

“I think we’re going need longitudinal follow-up to really understand if [leaflet thickening] goes away, is that patient still at risk? If it doesn’t go away, are they at risk of early structural valve degeneration? I don’t think it’s going to be a risk for stroke,” Leipsic said. “We’d see the stroke signal earlier. We have enough outcomes data to suggest it doesn’t drive stroke, but it may be a marker of patients who are at an increased risk of early degeneration.”