Biomarker May Predict Late Bleeding Events After TAVR

Patrice Wendling

October 26, 2018

A new study highlighting the unholy alliance between late bleeding complications and mortality after transcatheter aortic valve replacement (TAVR) suggests that a prolonged adenosine diphosphate closure time (CT-ADP) might predict these noxious complications.

After following 372 patients who underwent TAVR for a median 13.6 months, French researchers found that the risk for major late bleeding complications (MLBCs) was 2.5-fold higher when postprocedure CT-ADP was longer than 180 seconds than when it was shorter (27.4% vs 11.5%; P < .001).

On multivariate analyses, independent predictors of MLBCs were a CT-ADP longer than180 s (hazard ratio [HR], 3.08; 95% CI, 1.62 - 5.81) and significant paravalvular leak (PVL) 1 month after TAVR (HR, 6.31; 95% CI, 3.43 - 11.60).

MLBCs were mainly gastrointestinal and were associated with significantly higher all-cause and cardiovascular mortality, Marion Kibler, MD, University of Strasbourg, France, and colleagues report in the Journal of the American College of Cardiology .

"It has been known for years that PVL increases mortality and we proved, with this evidence, that part of this is related to bleeding," said coauthor, Eric Van Belle, MD, PhD, CHU Lille, Institute Coeur-Poumon, France. "Bleeding is part of the missing link between PVL and mortality, and this is related to the persistence of a severe hemostasis disorder in those patients with PVL."

In patients with aortic stenosis, increased shear stress is associated with a loss of high-molecular-weight (HMW) multimers of von Willebrand factor — a key driver of the gastrointestinal bleeding in AS known as Heyde's syndrome. HMW-multimer defects are corrected minutes after TAVR, except in cases complicated by significant PVL, where shear stress and turbulent flow persist and thus increase the risk of late bleeding complications, he explained.

The researchers honed in on CT-ADP because it is highly sensitive to HMW-multimer defects, which are not routinely measured in clinical practice. The results reinforce another recent study by the group, in which a CT-ADP threshold longer than 180 s measured on a bedside assay identifies PVL during the procedure and at 30 days.

For the current study, the team enrolled 372 patients at moderate to high surgical risk who underwent TAVR at a single center in France from November 2012 to December 2013 or from June 2015 to June 2017.

All patients received aspirin (75 mg to 160 mg) and clopidogrel (loading dose, 300 mg; maintenance dosem 75 mg/day) before the procedure, with ongoing double antiplatelet therapy for 3 months after TAVR.

During follow-up, seven life-threatening and 35 major bleeding events occurred with 50 deaths, translating into a MLBC cumulative incidence rate of 11.3% at 1 year and 15.4% at 2 years.

GI bleeding was the most common event, at 42.8% (nine cases of confirmed or suspected Heyde's syndrome), followed by genitourinary (14.3%), chronic anemia secondary to iron-deficiency anemia or myelofibrosis (11.9%), and neurologic bleeding, epistaxis, muscular bleeding, or trauma (7.1%).

"In most of the current studies, the weight of gastrointestinal and mucosal bleeding is not carefully collected," Van Belle said. "Our current questionnaires focus on obvious bleeding at vascular access or genitourinary bleeding. This is something we need to keep in mind, and we need to rethink how to document bleedings in this population. If you don't look for it, you can miss it."

At 30 days, moderate/severe PVL was present at 30 days in 7.4% of patients with CT-ADP of 180 s or less and in 53.9% with CT-ADP longer than 180 s.

When the cohort was stratified into four groups on the basis of 30-day PVL and postprocedure CT-ADP longer than 180 s, the 1-year rate of major/life-threatening bleeding was lowest in patients without PVL and CT-ADP elevation, at 5.2%, compared with a high of 34.0% in those with significant PVL (VARC 2-defined) and CT-ADP longer than 180 s.

MLBCs were associated with increased overall mortality (HR, 5.66; 95% CI, 3.10 - 10.31 and cardiac mortality (HR, 11.62; 95% CI, 4.59 - 29.37). The associations were statistically significant; however, CT-ADP longer than 180 s had no impact on death, cardiac death, or heart failure hospitalization.

Commenting for theheart.org | Medscape Cardiology, Roxana Mehran, MD, Ichan School of Medicine at Mount Sinai, New York City, said, "With 372 patients, it's very, very hard to be definitive about anything," but she added that one of the oldest things taught in medical school is to look for AV malformations in the GI tract because of their association with aortic stenosis.

"I think they continue to show this important interplay, but we need to further elucidate this because the idea of a paravalvular leak with shear stress and continued platelet dysfunction is something that makes a very interesting clinical scenario or hypothesis, and this relationship is one that continues to be seen," she said.

In an accompanying editorial, Mehran and colleagues observe that there was a high degree of collinearity between PVL and prolonged CT-ADP, but "the correlation was not perfect," with 41 of 89 patients having prolonged CT-ADP but no moderate/severe PVL, and 21 of 69 patients having moderate/severe PVL but no prolonged CT-ADP.

This could be partly explained by concomitant medical conditions and other drugs influencing CT-ADP, but the 30-day rate of moderate/severe PVL was "relatively high compared with those observed with new-generation TAVR devices," they note.

"The rates of PVL are probably higher than what we would find today, but still we need to keep in mind that in real life, the rates of PVL are likely to be higher than what is reported in the most reported, very clean studies," said Van Belle. "Just to give you some information, the most recent French registry data suggest the rate of significant PVL is around 8% to 9%."

Thus, real-time, bedside assessment of CT-ADP could be a useful tool to screen for patients at high-risk of late bleeding and to guide de-escalation of antithrombotic therapy in patients with PVL or CT-ADP longer than 180 s after TAVR, he said. The optimal dual antiplatelet therapy after TAVR remains unclear, with Van Belle calling out the recent early termination of the GALILEO trial because of an excess of death, thromboembolic events, and bleeding with post-TAVR rivaroxaban (Xarelto, Bayer/Janssen).

The editorialists observe that "the increasing concern regarding clinical and subclinical valve thrombosis after TAVR further underscores the need for high-quality data on antithrombotic regimens after TAVR."

Ultimately, Mehran said, the study observations highlight the need to find new approaches to prevent PVL in the first place.

"I think it kind of brings us back to the importance of this paravalvular leak and that, if we are going to treat aortic stenosis, we are going to need to get the best possible results without leaving shear stress behind."

The study was supported by Groupe pour l'Enseignement, la Recherche cardiologique en Alsace. Kibler and Van Belle report no relevant conflicts of interest. Mehran reports numerous relationships with pharmaceutical and device companies, as well as receiving consulting fees from Medscape.

J Am Coll Cardiol. 2018;72:2139-2148 and 2149-2151. Abstract, Editorial

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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