January 26, 2016
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Spotlight on Bioprosthetic Aortic Valves

Reduced leaflet motion in some bioprosthetic aortic valves prompts further investigation, additional clinical imaging.

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In the past 5 years, a continuum of good news about aortic valve replacement has emerged, particularly for transcatheter aortic valve replacement. But in recent months, the spotlight has been focused on bioprosthetic aortic valves after concerns were raised about reduced leaflet motion in some valves.

The FDA in October 2015 issued a notification about the issue, and recommended additional clinical imaging using 3D/4D CT or transesophageal echocardiogram when clinically indicated. The notification came in the wake of observations of reduced leaflet motion in valves used for TAVR and surgical AVR at several centers. Evidence from the imaging studies suggests that thrombus deposits on the leaflets may cause restricted motion, according to the agency statement.

The safety alert and publication of a study detailing the findings published in The New England Journal of Medicine led to a discussion and dedicated press conference at Transcatheter Cardiovascular Therapeutics Annual Scientific Symposium. There, Raj R. Makkar, MD, lead researcher for the NEJM study, and other leading experts discussed the recent imaging observations and the need for more investigation.

Reduced Leaflet Motion ‘Easily Detected’

For the NEJM study, Makkar and colleagues analyzed data on 55 patients in the PORTICO Investigational Device Exemption trial who underwent TAVR with the Portico valve (St. Jude Medical) compared with other transcatheter valves and 132 patients in the RESOLVE and SAVORY registries who underwent TAVR or surgical AVR. The PORTICO IDE study was stopped in September 2014 after reports of reduced leaflet motion surfaced, but was resumed in June 2015 after an analysis found no excess rates of clinical events related to the issue.

“A finding of reduced aortic valve leaflet motion on CT in a patient who had a stroke after TAVR and similar findings in an asymptomatic patient at one clinical site led to closer scrutiny of this observation,” the researchers wrote in the study background. “Additional CT review by the core laboratory revealed that this finding was not isolated, which prompted a more extensive investigation that involved analysis of all available CT and echocardiographic data.” Thereafter, two physician-initiated registries — RESOLVE and SAVORY — were established to evaluate leaflet function after TAVR or surgical AVR.

CT scans revealed reduced leaflet motion in 40% of patients in the PORTICO IDE trial (43% with Portico valve; 43% with Sapien XT valve [Edwards Lifesciences]; 0% with CoreValve [Medtronic]) and 13% of patients in the pooled RESOLVE and SAVORY registries. The finding of reduced leaflet motion was detected across multiple bioprosthesis types, including transcatheter and surgical, according to the results.

However, the incidence of reduced leaflet motion was lower among patients who were treated with warfarin compared with those treated with dual antiplatelet therapy (PORTICO IDE: 0% and 55%, respectively; P = .01; RESOLVE and SAVORY: 0% and 29%, respectively; P = .04).

“Reduced aortic valve leaflet motion ... was easily detected noninvasively by [4D], volume-rendered CT,” Makkar, director of interventional cardiology and the cardiac catheterization laboratory at Cedars-Sinai Medical Center, and colleagues wrote.

Twenty-one patients in the PORTICO IDE trial and the pooled registries had follow-up CT, 11 of whom had started or continued therapeutic anticoagulation. Restored leaflet motion was observed in all of the patients receiving anticoagulation compared with just one of 10 patients not receiving anticoagulation (P < .001).

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Among patients in the PORTICO IDE trial, stroke or transient ischemic attack occurred in two of 22 patients with reduced leaflet motion and 0 of 33 patients with normal leaflet motion (P =.16). In the pooled registries, stroke or TIA occurred in three of 17 patients with reduced leaflet motion and one of 115 patients with normal leaflet motion (P = .007).

A recent study published in the European Heart Journal of 156 patients who underwent TAVR with the Sapien 3 valve (Edwards Lifesciences) found that 10.3% (95% CI, 5.5-15) had hypo-attenuated leaflet thickening, with no significant differences between those on single antiplatelet therapy (13.3%; 95% CI, 3.4-23.3) or those on dual antiplatelet therapy (9%; 95% CI, 3.7-14.3; P = .42). The researchers found that the condition was not associated with any clinical symptoms and, among those who had follow-up CTA, it was resolved with full anticoagulation.

Bioprosthetic Valves ‘Reasonably Safe’

In the FDA notification, the agency stated that the questions raised are important, but the data are limited and the causes, incidence, and short- and long-term risks of reduced valve leaflet motion are not clear.

“At this time, [the] FDA believes that bioprosthetic aortic valves remain reasonably safe and effective when used according to their approved indications. This view is supported by the favorable benefit/risk profile observed in [surgical] AVR devices in the 30 years they have been on the market and in TAVR devices in the 8 years they have been in use,” the agency wrote.

The agency will work with the American College of Cardiology, the Society of Thoracic Surgeons and device manufacturers to design clinical studies to fully evaluate reduced valve leaflet motion for all types of bioprosthetic aortic valves. In the meantime, if reduced leaflet motion is found, treatment options should be discussed with the patient’s heart team, according to the statement.

Putting the Findings into Context

Raj R. Makkar

During the TCT press conference, Makkar said “more investigation needs to be done in terms of understanding the impact of these interesting imaging findings.”

“Clinical decisions and how we treat patients are made [based] on properly conducted clinical trials with hard outcomes. Images can guide [clinical decisions]. In this particular case, we would like to learn from this imaging finding and do further research. But we should not take a leap from this imaging finding and make the conclusion that everybody getting [TAVR] should be on a blood-thinning medication,” Makkar said.

Jonathon A. Leipsic, MD, FRCPC, FSCCT, Canada Research Chair in Advanced Cardiac Imaging and vice chairman of radiology at University of British Columbia, said he and his colleagues have observed similar findings. “It has been consistently shown across multiple studies ... that CT provides insight into findings that would otherwise be occult with transthoracic echo imaging. CT is providing us an opportunity potentially to understand ... early signals for mechanisms of valve degeneration down the road.”

Leipsic and others cautioned against sensationalization of the NEJM findings, however.

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“The study did not show a temporal or causal relationship between the imaging findings and stroke. That has to be emphasized,” Susheel Kodali, MD, co-director of the Heart Valve Center at the Center for Interventional Vascular Therapy at Columbia University in New York, said during TCT 2015. “It is an important study, but it is a small study.”

Nonetheless, patients have expressed concern over the findings, the experts said.

Makkar said it is crucial to reassure patients that there is no evidence yet that reduced leaflet motion causes clinical harm, and that everyone who needs AVR still must get it.

“Patients don’t need to worry. They are lifesaving devices. The last thing that should happen is patients panic and don’t get their serious valve issues fixed,” Makkar said. “We have an opportunity to do more research and further optimize.”

If anticoagulation turns out to be a solution to the issue, the results of the ongoing GALILEO trial may shed some light on the optimal strategy. The study, which is planned to enroll 1,520 patients undergoing TAVR and to be completed in 2018, is comparing death, thrombotic events and bleeding events in patients assigned rivaroxaban (Xarelto, Janssen Pharmaceuticals) plus aspirin vs. those assigned clopidogrel plus aspirin after TAVR. — by Erik Swain and Katie Kalvaitis

Disclosures: Kodali reports consulting for Claret Medical and Edwards Lifesciences and equity interest in Thubrikar Aortic Valve. Leipsic reports consulting for Edwards Lifesciences and HeartFlow and receiving grants from Edwards Lifesciences, Neovasc and Tendyne. Makkar reports receiving grant support, personal fees and other support from St. Jude Medical; grant support from Medtronic; grant support and personal fees from Edwards Lifesciences; and other support from Entourage Inc.