Reduced Leaflet Motion in Bioprosthetic Aortic Valves Not Uncommon But Remedied by Anticoagulation
Some degree of leaflet motion irregularity is “not uncommon” in patients receiving bioprosthetic aortic valves, according to paper published online October 5, 2015, ahead of print in the New England Journal of Medicine. While the condition appears to resolve after patients begin taking anticoagulants, its full clinical implications are still unknown.
Investigators led by Raj R. Makkar, MD, of Cedars-Sinai Heart Institute (Los Angeles, CA), looked into the phenomenon after it was observed last year in 2 patients—one who had a stroke after TAVR and one asymptomatic—taking part in the PORTICO US Investigational Device Exemption (IDE) trial.
Dr. Makkar and colleagues analyzed 4-D CT scans from 55 patients enrolled in the trial, which compared the Portico valve (St. Jude Medical) with commercially available transcatheter valves, and 132 patients who took part in 1 of 2 single-center registries, SAVORY and RESOLVE, which included patients with surgical aortic valves.
CT scans were obtained at 30 days after TAVR in the trial patients and at a median of 87 days in registry patients. Transthoracic echocardiography was performed at baseline and at the time of CT; transesophageal echo was performed in a subgroup of trial and SAVORY patients.
Leaflet motion that was not normal was defined as:
- Mildly reduced: < 50% decrease
- Moderately reduced: 50-70% decrease
- Severely reduced: > 70% decrease
- Immobile: lack of motion of at least 1 leaflet
All Cases Resolved
Reduced leaflet motion was seen in 40% of trial patients (22 of 55)—affecting 43% of those treated with Portico or Sapien XT valves (Edwards LifeSciences) and none of those receiving the CoreValve device (Medtronic)—and in 13% of the pooled registry cohort (17 of 132). Among the trial patients, 68% of cases involved 1 leaflet, 27% involved 2 leaflets and 5% involved 3 affected leaflets (1 immobile and 2 with severe reduction in motion). The registry cases included 2 patients with surgical aortic valves.
Interestingly, trial patients who had reduced leaflet motion and those who did not had similar measures of mean aortic valve gradient at discharge, 30 days, and 6 months. To further elucidate this concept, the researchers conducted a benchtop experiment in which they forced closure of 1 or more leaflets. The result: only a minor increase in the transvalvular gradient.
Patients given therapeutic anticoagulation with warfarin at the time of the index CT following TAVR had a lower prevalence of reduced leaflet motion compared with those who received either no or subtherapeutic levels of anticoagulation (P = .007). In both the trial and the registry participants, reduced leaflet motion also was less likely with anticoagulation compared with dual antiplatelet therapy (P = .01 and P = .04, respectively). Use of anticoagulants was at physician discretion and was based on “bleeding risk and the uncertain clinical significance of the finding,” the paper notes.
Anticoagulation resulted in resumption of normal leaflet motion, whereas patients who did not receive the therapy continued to show abnormal motion.
When clinical outcomes including death, MI, and stroke or TIA were compared, there were no differences between trial patients with or without reduced leaflet motion. However, within the pooled SAVORY and RESOLVE cohorts, those with reduced leaflet motion had a greater rate of stroke or TIA than did patients with normal leaflet motion (18% vs 1%; P = .007), although the total number of events was small (2 strokes in trial patients and 1 stroke and 3 TIAs in registry patients). Furthermore, all strokes occurred within 1 day after TAVR and before 4D CT.
Is Thrombosis to Blame?
After the first 2 cases of reduced leaflet motion were observed, St. Jude Medical announced in 2014 that it would temporarily “pause” implanting the Portico valve worldwide. By June 2015, however, the FDA granted approval for the IDE trial to resume, noting that no evidence was found of an excess rate of adverse clinical events associated with the leaflet motion observation.
According to Dr. Makkar and colleagues, “reduced leaflet motion… could be associated with subclinical leaflet thrombosis.”
However, that theory is based primarily on imaging characteristics and the fact that the problem resolved with anticoagulation, they acknowledge. Still, if borne out in larger studies, it may suggest “that thrombus formation is the primary event leading to reduced leaflet motion rather than reduced leaflet motion leading to the formation of an overlying thrombus,” the study authors note.
While symptomatic thrombosis occurring with TAVR is rare, they add, “the fact that reduced leaflet motion was found fairly frequently in 3 small cohorts suggests that the phenomenon is not uncommon.” They also hypothesize that the strokes occurring within 1 day were related to the procedural aspects of TAVR rather than to leaflet thrombosis.
In an editorial accompanying the study, David Holmes, MD, of the Mayo Clinic (Rochester, MN), and Michael Mack, MD, of Baylor Scott and White Health (Plano, TX), write that while the study “is very small and underpowered for definitive conclusions,” it raises questions that require further inquiry:
- What is the true incidence of reduced leaflet motion?
- Is its occurrence specific to TAVR?
- What are the clinical implications in terms of stroke and TIA?
- Are there adverse outcomes associated with anticoagulation in these patients?
“This is where moving from a finding to an action becomes very complicated,” Ted Feldman, MD, of NorthShore University HealthSystem (Evanston, Illinois), told TCTMD in a telephone interview.
“We haven’t established that [reduction in leaflet motion] is related to any early clinical problem. We haven’t established that it’s related to valve durability, and most importantly, even though we have a pretty clear suggestion that antithrombotic therapy will make this go away, we don’t know if it comes back later,” he observed. “Importantly, if we put everyone on 3 or 6 months of anticoagulants, are we going to create more hemorrhagic strokes trying to prevent the thromboembolic ones, if indeed thromboembolic strokes are related to the leaflet problem?”
In addition to the thrombosis theory, the impact of procedural risk factors should be explored, Dr. Feldman noted. Postdilatation during TAVR, for example, might change the leaflet enough to raise the risk of motion issues. However, since the finding was observed in surgical valves where postdilatation is not used, there is also a possibility that reduced motion is related to the inherent variability in the tissue of biologic valves, he added. Patient-related factors, too, may play a role.
Another unknown, Dr. Feldman said, is whether the leaflet issue now needs to be investigated in mitral valves as well.
In another accompanying editorial, representatives from the FDA led by John C. Laschinger, MD, of the Center for Devices and Radiological Health (Silver Spring, MD), say “the available clinical evidence supports the conclusion that these valves remain safe and effective and that findings to date concerning reduced leaflet motion have not changed the overall favorable benefit-risk balance for these valves when they are used for their approved indications.”
The agency is also asking clinicians who suspect or have a problem with a bioprosthetic aortic valve to file a report through MedWatch, and to follow reporting procedures established by their facilities.
Note: Study co-author Martin Leon, MD, is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.
Makkar RR, Fontana, G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med. 2015;Epub ahead of print.
Holmes DR, Mack MJ. Uncertainty and possible subclinical valve leaflet thrombosis. N Engl J Med. 2015;Epub ahead of print.
Laschinger JC, Wu C, Ibrahim NG, Shuren JE. Reduced leaflet motion in bioprosthetic aortic valves — the FDA perspective. N Engl J Med. 2015;Epub ahead of print.
- The study was funded by St. Jude Medical and Cedars-Sinai Heart Institute.
- Makkar reports grant support, personal fees and other support from Saint Jude Medical; grant support and personal fees from Edwards Lifesciences; grant support from Medtronic; and other support from Entourage.
- Mack reports support from Edwards Lifesciences.
- Holmes and Laschinger report no relevant conflicts of interest.
- Feldman reports receiving consulting fees and grants from Abbott Vascular, Boston Scientific, and Edwards Lifesciences.