By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCES: Makkar RR, et al, Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015 Oct 5. [Epub ahead of print].
Holmes DR, Mack MJ. Uncertainty and possible subclinical valve leaflet thrombosis. N Eng J Med 2015 Oct 5. [Epub ahead of print].
Laschinger JD, et al. Reduced leaflet motion in bioprosthetic aortic valves — The FDA perspective. N Eng J Med 2015 Oct 5. [Epub ahead of print].
Is more information always better? That is one question for cardiologists and regulatory agencies alike since the recent publication of the above report. Transcatheter aortic valve replacement (TAVR) is currently available in the United States with two commercially available bioprostheses: the Edwards Sapien series of bovine balloon-expandable valves and the CoreValve line of self-expanding porcine valves. The PORTICO IDE trial is an ongoing prospective, clinical trial examining the safety and efficacy of another valve — the investigational Portico device — for TAVR. As part of this trial, a prespecified subgroup underwent post-implant CT scans to examine the valve frame. These scans demonstrated the unanticipated finding of reduced leaflet motion in several patients. A detailed analysis of all CT and imaging data ensued, leading also to the formation of two separate registries to evaluate bioprosthetic leaflet function after transcatheter or surgical aortic valve replacement: the Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and Its Treatment with Anticoagulation (RESOLVE) registry and the Subclinical Aortic Valve Bioprosthesis Thrombosis Assessed with Four-Dimensional Computed Tomography (SAVORY) registry.
The findings thus far are striking. Of the 55 patients in the PORTICO IDE trial with complete contrast CT data, 22 showed reduced aortic leaflet motion. The mix included 16 of 37 with Portico valves, 6 of 14 with Sapien XT valves, and none of the four Corevalve patients. All patients with reduced leaflet motion had hypodense opacities at the base of the corresponding leaflets. The 10 patients from this group of 22 who also underwent transesophageal echo had concordant findings, with echogenic masses on the aortic aspect of the leaflets preventing normal motion.
None of the eight patients who received therapeutic warfarin were found to have reduced leaflet motion, as opposed to more than half of patients on no anticoagulation or antiplatelet agents alone. Moreover, all 11 of the patients who were subsequently placed on therapeutic warfarin recovered normal leaflet motion on follow-up CT, while this was true of only one of 10 patients who did not receive warfarin but had follow-up imaging.
Among the registry patients, the numbers were lower but still significant. Reduced leaflet motion occurred in 17 of 132 patients studied, including 15 of 105 with transcatheter valves and two of 27 with surgical valves. As in the PORTICO patients, none of the 13 patients who happened to be on therapeutic anticoagulation with warfarin had subsequent leaflet motion abnormalities.
The authors concluded that abnormal leaflet motion is reliably detected in a significant proportion of both surgical and transcatheter bioprosthetic aortic valves by volume-rendered CT scans. This phenomenon appears to be effectively prevented and treated by warfarin but not by antiplatelet drugs. These observations, in concert with the imaging findings on the leaflets themselves, suggest a thrombotic cause.
One important term in the title of this work is “subclinical.” Both transcatheter and surgical aortic bioprostheses are routinely followed by transthoracic echocardiogram, which fails to detect the noted phenomenon in most cases. Despite the finding of often-severe restriction of leaflet motion, the mean gradients measured across these valves were not significantly different than those from unaffected valves. Clinically evident bioprosthetic valve thrombosis remains rare with currently available valves and periprocedural care, occurring in less than 1% of cases.
The potential link of subclinical valve thrombosis to stroke is tenuous at best, as the number of events in the combined studies was quite small. However, this clearly deserves more study.
Overall, the clinical data on these valves have not changed — for the most part they remain both effective and safe. The study paper itself, as well as two accompanying editorials, calls for more data to answer a host of questions brought up by these findings. Although it is clearly premature to change practice, I would be surprised if there were not a move to expand the use of warfarin in TAVR patients, at least in patients with higher risk profiles. Ultimately, the meaning and appropriate response to these findings will be answered by further rigorous study.