Subclinical Changes in Valve Hemodynamics Observed in TAVR Patients

A new study evaluating valve hemodynamics over time has revealed a mild but significant increase in transvalvular gradient among patients undergoing TAVR, with an overall mean progression of 0.30 mm Hg per year.

In an analysis of 1,521 patients included as part of a multicenter registry, the incidence of subclinical valve hemodynamic deterioration—defined as at least a 10-mm Hg increase in mean gradient between discharge after TAVR and the last follow-up—was documented in 4.5% of patients. Incidence in the first year was 2.8%.

To TCTMD, senior investigator Josep Rodés-Cabau, MD, of Laval University (Quebec City, Canada), said that while data to date with TAVR have been very reassuring, there have been recent reports showing increases in transvalvular gradient over time and 4-dimensional CT data highlighting “hemodynamically subclinical” reduced leaflet function. The purpose of this analysis was not to examine clinically relevant structural changes in the valve, but rather to study changes at the “echocardiographic and subclinical” level, Rodés-Cabau said. “The idea was to look at consecutive patients with serial echos and to see how the valve is working over time.”

The overall mean annualized rate of transvalvular gradient progression during follow-up was “quite minimal,” Rodés-Cabau told TCTMD. The increase was driven by 68 patients within the registry who experienced changes in valve hemodynamics. Among the patients who met the definition of valve hemodynamic deterioration, 47 patients had mean gradients ≥ 20 mm Hg and 8 patients had gradients ≥ 40 mm Hg at follow-up.

Regarding the clinical significance of the findings, Rodés-Cabau said it is uncertain what impact the progression in transvalvular mean gradient will have on valve structure over time. At present, there is no documentation that the change in transvalvular gradient impacts the structure of the valve long term. “If your gradient goes from 8 to 25 [mm Hg], meaning something is going on in the valve, and then after 5 years the valve is completely destroyed, then we have shown we need to prevent this problem,” he said.

Right now, data showing there is a relationship between subclinical changes in valve hemodynamics and structural failure are not there, he said.

Commenting on the results for TCTMD, Ron Waksman, MD, of MedStar Heart and Vascular Institute (Washington, DC), said the relatively low rate of valve hemodynamic deterioration observed in the analysis is reassuring but also noted that the results do suggest TAVR patients should continue to be monitored. As the technology is used in lower-risk and younger patients with longer life expectancies, physicians will need to check for any subclinical changes in valve hemodynamics, he said. Until now, the high- and extreme-risk patients tested in the landmark TAVR trials simply didn’t live long enough, but intermediate- and lower-risk patients should be monitored for at least 5 years, with the lowest-risk patients likely monitored for the rest of their lives, said Waksman.

The study was published in the February 16, 2016, issue of the Journal of the American College of Cardiology.

Anticoagulation Issue Emerges Again

In the analysis, which included patients from 10 clinical centers who underwent an echocardiogram at discharge and at a minimum of 6 to 12 months after TAVR (mean 20 months), there was a near equal distribution of patients who received the Sapien and Sapien XT (Edwards Lifesciences) and CoreValve (Medtronic) devices.

Patients not prescribed oral anticoagulation at discharge, those who underwent a valve-in-valve procedure, those who received a 23-mm bioprosthetic valve, and those with a greater body mass index were all significantly more likely to experience valve hemodynamic deterioration in the first year.

In November 2015, the study that first identified reduced leaflet motion among TAVR patients also showed that the problem was not observed among those treated with warfarin (international normalized ratio > 2.0) at the time of the index CT scan. A pooled analysis of data from PORTICO-IDE and 2 single-center registry studies also showed a lower prevalence of reduced leaflet motion in patients receiving therapeutic anticoagulation with warfarin after TAVR.

The issue of anticoagulation in TAVR is a “hot topic,” explained Rodés-Cabau, and there is a need for large-scale, prospective studies to determine if a specific antithrombotic regimen after TAVR can reduce the risk of valve hemodynamic deterioration. In the present analysis, patients taking an oral anticoagulant were doing so because of a diagnosis of atrial fibrillation and not to reduce the risk of thrombosis related to the valve. At present, researchers and clinicians can only speculate that anticoagulation might play a role in reducing the potential risks.

“I think it’s an issue that’s worth being evaluated,” said Rodés-Cabau. “The type of patients that we are treating [with TAVR] are at high risk for bleeding complications. I don’t have the certainty in that implementing anticoagulation treatment for everybody the benefits will surpass the potential risks.” As the use of TAVR expands into younger and lower-risk patients, including those with lower bleeding risks, it’s possible that such patients might benefit from short-term anticoagulation, he said. Hazarding a guess, Rodés-Cabau said he “suspects” anticoagulation could have an effect on valve hemodynamics, but it needs to be tested.

For Waksman, both studies—the analysis by Makkar et al that identified reduced leaflet motion and the present one—provide evidence that warfarin could be beneficial in certain patients who undergo TAVR. If reduced leaflet function is observed with imaging, he suggests physicians could prescribe warfarin to “dissolve the clot and restore full leaflet functionality.”

Unanswered Questions Need Answering, Pronto

Michael Mack, MD, of Baylor Scott & White Health (Plano, TX), Pamela Douglas, MD, of Duke University (Durham, NC), and David Holmes, MD, of the Mayo Clinic (Rochester, MN), call for “expeditious answers” to a dozen key points they raise in an accompanying editorial. Although the field has a wealth of evidence from randomized trials and commercial experience—including 5-year data that has failed to turn up any signs of early structural valve deterioration or valve thrombosis—the past 2 years have exposed concerns about subclinical valve thrombosis and hemodynamic deterioration.

“It has become clear that the harder one looks, the more one finds,” write the editorialists.

A critical issue that needs to be resolved is the relationship observed between the leaflet abnormalities seen on 4D-CT and hemodynamic changes on TEE with clinical outcomes. The editorialists call for all patients undergoing TAVR to be monitored for incremental increases in the transvalvular mean gradient with transthoracic echocardiography (TTE).

They note that trials are currently investigating the role of anticoagulation and antiplatelet therapies after TAVR, including GALILEO and CLOE. In the meantime, “if an interval increase in transvalvular mean gradient is detected, there should be consideration of anticoagulation, on the basis of a clinical evaluation of risk versus benefit in that individual patient,” write Mack, Douglas, and Holmes. Physicians should also be vigilant in patients with valve hemodynamic deterioration who have a clinical event, they say, adding these patients should undergo 4D-CT scanning or TEE as well as more routine TTE.

“TAVR has undeniably benefited thousands of patients with severe aortic stenosis,” note the editorialists. “However, as with any new therapy, adverse events and limitations—many unanticipated—may gradually become known as usage and experience expand.”

---

Sources: 
1. Del Trigo M, Muñoz-Garcia AJ, Wijeysundera HC, et al. Incidence, timing, and predictors of valve hemodynamic deterioration after transcatheter aortic valve replacement: multicenter registry. J Am Coll Cardiol. 2016;67:644-655.  
2. Mack MJ, Douglas PS, Holmes DR. Shedding more light on valve thrombosis after transcatheter aortic valve replacement [editorial]. J Am Coll Cardiol. 2016;67:656-658.

Related Stories:

• Reduced Leaflet Motion in Bioprosthetic Aortic Valves Not Uncommon But Remedied by Anticoagulation
• New Findings on Bioprosthetic Valve Thrombosis Have Implications for Surveillance, Research