Experts Debate Risk of Thrombosis With Bioprosthetic Valves

October 19, 2015

SAN FRANCISCO, CA – In the end, there wasn't a lot new to say except to stress the findings were subclinical and should be studied further. That was the consensus of a press conference hosted by an expert panel addressing the potential risks of reduced leaflet function and subclinical thrombosis following the implantation of bioprosthetic aortic valves here at TCT 2015.

Importantly, the panel stressed that the finding of reduced leaflet mobility on imaging and subclinical thrombosis should not invoke the kind of fears generated by, for example, late stent thrombosis with drug-eluting stents.

"This is not late stent thrombosis," said Dr Jeffrey Popma (Beth Israel Deaconess Medical Center, Boston, MA). "Late stent thrombosis was a clinical presentation, with blood clot on the stent that was associated with myocardial infarction. This is not. This is an imaging observation of uncertain clinical significance at this point that needs to be studied and evaluated further."

The concern surfaced 2 weeks ago when Dr Raj Makkar (Cedars-Sinai Heart Institute, Los Angeles, CA) and colleagues published a report showing reduced leaflet function in 22 of 55 patients who underwent transcatheter aortic-valve replacement (TAVR) and were later screened with four-dimensional computed tomography (4D-CT). More importantly, pooled data from two registries revealed a higher incidence of stroke or transient ischemic attack (TIA) in those with reduced leaflet motion compared with those with normal leaflet function.

I don't think patients in any shape or form should feel as if they're at risk.

As reported by heart wire from Medscape, the investigators identified 40% of the CT-screened patients with reduced leaflet function in the Portico Resheathable Transcatheter Aortic Valve System US investigational device exemption (PORTICO-IDE) study. In PORTICO-IDE, reduced leaflet motion was observed in 16 of 37 patients who received the Portico valve (St Jude Medical) and six of 14 patients who received the Sapien XT valve (Edwards Lifesciences). Four patients in the trial received CoreValve (Medtronic), but abnormalities were not detected in this group.

Also, in data pooled from the RESOLVE and SAVORY cohorts—each a single-center registry of patients with newly implanted aortic valves—CT data revealed reduced leaflet motion in 17 of 132 patients, including 15 patients who underwent TAVR and two of 27 valves implanted surgically.

Following the release of the potentially concerning findings, TCT 2015 hosted a press conference with Makkar and other TAVR experts to address the clinical significance of the findings. Makkar explained that the issue emerged following 4D-CT in a TAVR patient who had a stroke immediately following the procedure. In doing so, the researchers noticed two leaflets on the valve were not moving.

"It's not unanticipated to have a stroke after a TAVR procedure," said Makkar. "That is when most strokes do occur, but it set off further investigation in terms of people looking at CT scans that were done. We actually found a number of patients who had leaflets that were not moving very well."

Speaking during the press conference, Popma said they fielded calls from patients following the report published October 5, 2015 in the New England Journal of Medicine. Despite their concerns, Popma said no late safety signals have emerged with TAVR in the two landmark clinical trials testing different devices. At present, there are data out to 5 years in patients who underwent TAVR in PARTNER and nearly 3 years for patients in the CoreValve study, yet there has been no signal of valve deterioration.

"I think we really need to make sure we take a broader view of what we're looking at," said Popma. "We're looking at an imaging finding. The other surrogates of structural valve deterioration—increasing aortic gradients, worsening aortic regurgitation, or perhaps worsening heart failure—in both data sets, now with thousands of patients, we really haven't seen that so far. I think what we're doing is refining our understanding, but I don't think patients in any shape or form should feel as if they're at risk or need to have anything done differently."

Dr Jeffrey Popma

Dr Susheel Kodali (Columbia University Medical Center, New York, NY), who was not involved in the analysis but who moderated the special TAVR press conference debating the results, added that in the US alone, there are approximately 20,000 patient-years of data from the CoreValve and PARTNER trials, but so far no late signal of stroke has emerged. "We have the seen a hazard of bleeding, which nearly triples mortality," he said.

Popma agreed about the safety of the devices, noting that physicians are continuing to watch for late stroke events in the CoreValve and PARTNER studies. "The 5-year [PARTNER] data are overwhelmingly similar," said Popma. "We don't seen anything different compared with surgery."

Results Are Preliminary, Inconclusive

In their journal article, Makkar and colleagues did report a signal of harm with regard to reduced leaflet function, with 18% of patients with reduced leaflet function in a pooled analysis of the RESOLVE and SAVORY registries having a stroke/TIA vs 1% among patients with normal leaflet function. Regarding the clinical findings, though, the jury is still out, stressed Makkar.

"There was a signal, but the findings related to the neurologic events are preliminary and inconclusive," he said. "We clearly believe more investigation needs to be done in terms of understanding the impact of these interesting imaging findings."

The panel was united in their belief that the studies should not propel physicians to start treating all TAVR patients with oral anticoagulation. Instead, any changes in practice should be based on clinical-trial data and not data from CT findings.

"Decisions on how we treat patients are made on properly conducted clinical trials with hard outcomes," said Makkar. "We should not make the leap from these imaging findings and conclude that all patients receiving a transcatheter aortic valve should be on blood-thinning medications, which are a risk themselves."

The question of oral anticoagulation following TAVR is currently being studied in the GALILEO study. Led by Dr George Dangas (Icahn School of Medicine at Mount Sinai, New York, NY) and Dr Stephan Windecker (Bern University Hospital, Switzerland), GALILEO will include 1500 patients treated with rivaroxaban 10 mg plus aspirin 75 to 100 mg vs clopidogrel 75 mg and aspirin for the prevention of cardiovascular events, including stroke.

As reported last week, Makkar reiterated during TCT 2015 that he thinks the reduced leaflet function is believed to be caused by thrombosis. Even though there is no histologic or pathologic evidence of thrombosis, the fact that thrombosis was not detected in patients taking anticoagulants and that thrombosis resolved following the commencement of anticoagulation suggests the finding was related to a blood clot.

The findings related to the neurologic events are preliminary and inconclusive.

Makkar said that as TAVR matures and moves into lower-risk patients, it would be justified to study different anticoagulation strategies and regimens. To heartwire, he noted that the US and European clinical guidelines recommend the use of antiplatelet medication following TAVR, but there is no recommendation for anticoagulation. In their analysis, dual antiplatelet therapy was not associated with a lowered risk of stroke/TIA.

Kodali emphasized that the research does not show a temporal or causal relationship between the imaging findings and stroke. In addition, the difference in neurologic events between groups was driven by a difference in TIA, an end point that is very difficult to adjudicate, especially in an older patient population.

During the press conference, Dr Jonathon Leipsic (St Paul's Hospital, Vancouver, BC) said, "CT provides insight into findings that would otherwise be occult." He points out that although technological advances with 4D-CT might provide early evidence of valve degeneration and lead to improvements in the technology, there is also a risk of "sensationalism" with the imaging results. "If we take a step back and look at this, it's an opportunity for the field to improve on already excellent clinical outcomes," said Leipsic.

Makkar reports grant support, personal fees. and other support from St Jude Medical during the conduct of the study; grant support from Medtronic, grant support and personal fees from Edwards Lifesciences, and other support from Entourage, outside the submitted work. Popma has served as advisor/consultant for Abbott Laboratories and Boston Scientific and as a speaker/members of a speaker's bureau for Abbott Laboratories, Boston Scientific, Covidien, Cook Medical, Direct Flow Medical, and Medtronic. Kodali reports grant/research support from Edwards, Medtronic, Boston Scientific, and Claret Medical; equity in Thubrikar Aortic Valve; and honoraria from St Jude Medical and Claret Medical. Leipsic reports being a member of the GE Company speaker's bureau and a consultant for Edwards Lifesciences, HeartFlow, and Circle Cardiovascular Imaging.


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