Report Highlights Risks of Bioprosthetic Aortic Valves: Reduced Leaflet Motion Observed by CT

October 06, 2015

LOS ANGELES, CA — A new analysis of clinical and registry data suggests a troubling finding with the implantation of bioprosthetic aortic valves, either with surgery or via the catheter-based procedure[1].

For patients in the Portico Resheathable Transcatheter Aortic Valve System US investigational device exemption (PORTICO-IDE) study, computed tomography (CT) screening revealed reduced leaflet motion in 40% of individuals—22 of 55 patients—who underwent transcatheter aortic-valve replacement (TAVR). The findings were confirmed with follow-up transesophageal echocardiography (TEE).

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.

Publishing their findings October 5, 2015 in the New England Journal of Medicine, the investigators, led by Dr Raj Makkar (Cedars-Sinai Heart Institute, Los Angeles, CA), who is also a principal investigator of PORTICO-IDE, say the reduced leaflet motion observed appears to be "hemodynamically subclinical" at the time of detection, with patients having normal aortic-valve gradients on echocardiography. While detected on four-dimensional (4D)-volume-rendered CT and TEE, the problem was not detected on transthoracic echocardiography.

In terms of clinical events, the investigators observed no significant between-group difference in the PORTICO-IDE study, but the pooled RESOLVE/SAVORY-cohort data revealed a higher incidence of stroke or transient ischemic attack (TIA) in those with reduced leaflet motion when compared with those with normal leaflet function (18% vs 1%; P=0.007).

As part of the analysis of PORTICO-IDE, RESOLVE, and SAVORY, the researchers did document a lower prevalence of reduced leaflet motion in patients receiving therapeutic anticoagulation with warfarin after TAVR. In PORTICO, among those treated with warfarin (international normalized ratio >2.0) at the time of the index CT scan, there were no reported cases of reduced leaflet motion. In contrast, for those not treated with warfarin or those receiving a subtherapeutic dose, reduced leaflet motion was observed in 21 of 41 patients. For those treated with dual antiplatelet therapy (DAPT), 11 of 20 patients had reduced leaflet motion.

For patients who underwent a follow-up CT scan, normal leaflet function recovered in all 11 patients who started or continued to receive oral anticoagulation while abnormal leaflet motion remained in nine of 10 patients who did not receive therapeutic warfarin.

Overall, the researchers say the results suggest reduced leaflet motion could be associated with subclinical leaflet thrombosis. However, they say this is not yet confirmed. "The interpretation of reduced leaflet motion as thrombosis is based only on the imaging characteristics and its resolution with anticoagulation," write Makkar and colleagues.

The FDA Responds to the Issue

In a perspective from the US Food and Drug Administration (FDA)[2], Drs John Laschinger, Changfu Wu, Nicole Ibrahim, and Jeffrey Shuren, all from the Centers for Devices and Radiological Health, state that after careful review of the available data, they still believe the "benefits of using these devices for the currently approved indications continue to outweigh the risks."

Right now, the subclinical finding of reduced leaflet motion is an "early signal of unknown clinical significance," states the FDA. They add they are closely monitoring the situation and are working with physicians and device manufacturers to determine exactly what this finding means clinically. They are mindful, however, of any potential effect on safety, effectiveness, and the risk/benefit profile of bioprosthetic valves, particularly the potential for increased risk of late neurologic events and MI, as well as unexpected heart failure and death.

The FDA points out that the finding of reduced leaflet motion with the Portico valve is not entirely new. As reported by heartwire from Medscape in 2014, St Jude Medical temporarily halted the PORTICO-IDE study because of an unexpected finding of reduced leaflet motion in a subgroup of patients who underwent CT scanning 30 days postimplant.

The FDA also issued a notification to physicians through MedWatch, its safety information and adverse-event reporting program. In terms of recommendations, it states that patients with a bioprosthetic aortic valve might require additional diagnostic testing, such as with 3D or 4D CT or TEE. It also urges the prompt reporting of adverse events to the FDA to help it better identify and understand the risks of reduced leaflet motion.

In an editorial[3], Dr David Holmes (Mayo Clinical, Rochester, MN) and Dr Michael Mack (Baylor Scott and White Health, Plano, TX) write that more information is urgently needed and list more than a dozen questions that highlight what is not yet known. For example, the editorialists ask what the true incidence of reduced leaflet motion is. Is it specific to TAVR, or does it occur as frequently with surgery? Also critical, is the reduced leaflet motion caused by thrombus on the leaflets, and if it is, is this related to stent structure or deployment strategies?

They also question whether the issue needs to be resolved before the FDA expands approval of TAVR into lower-risk patients.

In the US, the Transcatheter Valve Therapy Registry, created by the Society of Thoracic Surgeons and American College of Cardiology, has enrolled approximately 35,000 patients treated with commercially approved devices at 376 centers. In Europe, more than 200,000 procedures have been performed. At present, the Portico transcatheter valve is not approved by the FDA but received CE Mark approval for European use in 2012. CoreValve and Sapien XT are both approved in the US and Europe.

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. Disclosures for the coauthors are listed on the journal website. Laschinger et al have no relevant financial relationships. Holmes has no relevant financial relationships. Mack reports support from Edwards Lifesciences as a member of the executive committee of the PARTNER trial.

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