New Findings on Bioprosthetic Valve Thrombosis Have Implications for Surveillance, Research

Only a month after a study in the New England Journal of Medicine grabbed headlines by documenting reduced leaflet motion—a possible sign of subclinical valve thrombosis—in various bioprosthetic valves, new data from the Mayo Clinic on symptomatic surgical patients support the idea that valve thrombosis is not as uncommon as once thought.

Bioprosthetic valve thrombosis (BPVT) “can occur several years after implantation” but much earlier than degeneration, stress Sorin V. Pislaru, MD, PhD, and colleagues. The good news, they say, is that cases—once diagnosed—respond well to vitamin K antagonist (VKA) therapy.

The findings are being published in the December 1, 2015, issue of the Journal of the American College of Cardiology.

Raj R. Makkar, MD, of Cedars-Sinai Heart Institute (Los Angeles, CA), lead author of the NEJM paper, told TCTMD in a telephone interview: “Clearly we’ve underappreciated the importance of leaflet thrombosis on structural valve failure, and in a subset of patients this may be the mechanism.”

No prospective RCTs have tested the value of anticoagulation in patients with bioprosthetic valves, and studies on both surgical and transcatheter valves would be important, he noted.

Makkar said awareness of these issues is growing in the TAVR field. “I think people are serious and people are interested. Everybody wants to understand what this actually means,” he commented. “We all went out and told people not to overreact …, because the worst thing you can do is give anticoagulants to old and frail patients when we really don’t understand the significance of this.”

Predictors May Enable Better Diagnosis

Focusing their attention on 397 consecutive cases of explanted bioprostheses that occurred at the Mayo Clinic (Rochester, MN) between 1997 and 2013, investigators led by Pislaru found 46 instances of BPVT (11.6%) in a mix of aortic, mitral, tricuspid, and pulmonary locations. Nearly two-thirds of cases occurred beyond 1 year after the initial valve implantation. Median valve longevity was 24 months for affected devices, whereas explanted valves without BVPT had a median longevity of 108 months (P < .001). There also were 92 cases of structural valve failure (2.3%).

Independent predictors of BPVT were: greater than 50% increase in mean echo-Doppler gradient from baseline within 5 years (OR 12.7), paroxysmal A-fib (OR 5.19), subtherapeutic international normalized ratio (INR; OR 7.37), increased cusp thickness (OR 12.2), and abnormal cusp mobility (OR 6.94).

“Based on our proposed risk model, diagnosis of BPVT can be made with > 70% sensitivity and > 90% specificity in patients with 3 of 5 independent risk factors,” the researchers note. Structural valve failure, they add, “was more commonly associated with calcified cusps, reduced leaflet mobility, and significant regurgitation.”

According to Pislaru and colleagues, “It is crucial to consider the diagnosis of BPVT before referring for reoperation because VKA therapy may reverse the [valve] dysfunction.”

Isaac George, MD, of Columbia University Medical Center (New York, NY), pointed out that the study population—consisting of symptomatic patients whose valves were evaluated by echocardiography—differs from that addressed by Makkar et al in the recent NEJM paper. Those patients, he emphasized to TCTMD in an email, “were asymptomatic, were found by 4-D CT scanning, and had transcatheter valves.”

What this retrospective study cannot reveal is “how many surgical patients that are asymptomatic have valve thrombosis,” he added.

“Overall, the incidence of valve thrombosis in this group appears to be low, when [calculated] based on the total number of valve replacements performed (~1%),” George explained. “This is in sharp contrast to the transcatheter valve population, in which the incidence may be much higher.”

In an email with TCTMD, Pislaru said that, given the current findings and the NEJM paper, “we believe that bioprosthetic thrombosis after TAVR is underestimated. It is highly speculative to put a number, but one would guess the incidence is more than the 0.6% reported in a recent multicenter registry study, but probably less than the 13-40% reported by Makkar.”

Importantly, imaging technologies such as CT, MRI, and echo “cannot make a tissue diagnosis, but rather give a ‘probable cause,’” he stressed. “The diagnosis of [valve thrombosis] can be firmly established only by pathology; a surrogate positive diagnosis is provided by successful resolution of abnormal findings with anticoagulant therapy.”

Specific Advice for Patient Management

Based on their findings, Pislaru et al make 5 recommendations for practice:

• Patients with bioprosthetic valves who need VKA for any reason should have INR maintained between 2.0 and 3.0.
• Patients with paroxysmal A-fib who receive bioprosthetic valves should be on VKA therapy unless contraindicated.
• Patients who present with valve dysfunction, particularly within 5 years, should be evaluated for BVPT using the 5-item risk model.
• Patients who have clinical and/or echocardiographic BPVT but no contraindications to VKA therapy should go on a trial regimen rather than being referred for additional intervention.
• Echo surveillance of valves should be done within 12 months of VKA cessation in high-risk patients.

George countered that echo “will likely be an inadequate screening tool for patients without significant symptoms or less than severe elevations in valve gradients.

For now, 4-D CT appears to be the main and best way to screen for valve thrombosis, as echocardiography has been associated with lower sensitivity in our center’s experience,” he continued. “Further imaging research will clarify the utility of CT scanning as the primary modality for screening, while serial follow-up will likely be with echocardiography.”

Thrombosis a Step Along the Continuum?

In an accompanying editorial, William J. Stewart, of the Cleveland Clinic Foundation (Cleveland, OH), suggests that BPVT and valve failure “represent the same disease process at different points in time.”

Early detection and VKA therapy may spare patients later surgery, he agrees, concluding that the paper “incites us to search more diligently for BPVT, obtain baseline ‘fingerprint’ echocardiographic studies, perform yearly echocardiographic studies even in the early post-operative period, and lower the threshold for prophylactic and therapeutic anticoagulation in patients with [bioprosthetic valves].”

Looking ahead, Pislaru called for “multicenter, prospective evaluation of the incidence of bioprosthetic thrombosis after TAVR. Considering the huge volumes (over 200,000 procedures already performed worldwide), this is a critical issue of utmost urgency.

“A study using systematically echocardiography (TTE/TEE) and CT will allow better understanding of the limitations in each imaging technique, and would lay the foundations for optimal follow-up surveillance strategies in the future,” he advised.

Additionally, Pislaru suggested that current guidelines—which currently recommend yearly evaluation post-TAVR and surveillance after 5 years post-surgery—“should be amended to include systematic surveillance of all bioprosthetic valves with the first 2-3 years post-implantation.”