Anticoagulant Considered After Bioprosthetic Valve Surgery

CHICAGO — Edoxaban, a direct oral anticoagulant, appeared to be as effective as or more effective than warfarin in preventing thromboembolism — such as stroke, systemic embolism, or intracardiac thrombus — in patients who had undergone bioprosthetic valve replacement surgery, the Japanese ENBALV trial showed.

However, the event rate was so low that definitive conclusions could not be reached.

The frequency of bleeding was numerically higher in the edoxaban group, but no fatal bleeding or intracranial hemorrhage was seen in the edoxaban group, whereas one fatal intracranial hemorrhage occurred in the warfarin group.

“The ENBALV trial provides the first large-scale evidence on the use of direct oral anticoagulants in low-risk patients early after bioprosthetic valve surgery,” said lead investigator Chisato Izumi, MD, from the National Cerebral and Cardiovascular Center in Osaka, Japan.

“Our results suggest that edoxaban could be an alternative to warfarin for patients early after bioprosthetic valve surgery, which could offer more flexibility and convenience,” she said during her presentation of the ENBALV results at the American Heart Association (AHA) Scientific Sessions 2024.

Patients who receive a mechanical heart valve require lifelong anticoagulant therapy to prevent thrombus formation on the valve, she explained. Current guidelines recommend anticoagulant therapy with vitamin K antagonists, such as warfarin, for just 3-6 months after bioprosthetic valve replacement, even for patients in sinus rhythm.

But warfarin has several disadvantages, including a narrow therapeutic range, the need for frequent monitoring with blood tests, and interactions with various drugs and food. In contrast, the new direct oral anticoagulants can be used at a constant dose, do not require frequent monitoring with blood tests, work quickly, and have a low risk for interaction with other drugs and food.

If the new anticoagulants are available for patients who have undergone bioprosthetic valve replacement, it could simplify the care process and reduce the burden on patients and medical staff, Izumi pointed out.

The ENBALV study evaluated whether edoxaban could be used as an alternative to warfarin shortly after bioprosthetic valve surgery.

The 410 eligible study participants (20% of whom had atrial fibrillation) were randomly allocated to either edoxaban or warfarin for 12 weeks. Primary and secondary outcome measures were assessed 12 weeks after surgery.

The primary outcome — a composite of stroke and systemic embolism — occurred in one patient (0.5%) in the edoxaban group and three patients (1.5%) in the warfarin group.

Intracardiac thrombus did not occur in any of the patients in the edoxaban group but occurred in 1% of patients in the warfarin group.

Major bleeding occurred in eight patients in the edoxaban group (although there was no fatal bleeding or intracranial hemorrhage) and two patients in the warfarin group (including one fatal intracranial hemorrhage).

However, there were more instances of gastrointestinal bleeding in the edoxaban group than in the warfarin group (2.1% vs 0.0%).

Improved Stratification of Patients Needed

Many patients opt for a bioprosthetic valve over a mechanical valve because they do not want to be on long-term warfarin therapy, Manesh Patel, MD, from the Duke University School of Medicine in Durham, North Carolina, explained during an AHA press conference.

Antithrombotic therapy for patients with bioprosthetic valves has some level of supporting data, but most of the evidence is in patients who have concomitant atrial fibrillation. In the ARISTOTLE and RIVER trials, the anticoagulants apixaban and rivaroxaban, respectively, seemed just as good as, if not better than, warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation and a bioprosthetic valve.

In contrast, in the RE-ALIGN trial, dabigatran was less effective than warfarin for thrombotic prevention in patients with mechanical valves and was associated with more bleeding.

The ENBALV study moves the field forward, as most of the study participants did not have underlying atrial fibrillation, Patel pointed out.

“We’ve seen from observational data that these patients do have a stroke risk from clots in the bioprosthetic valve, and our guidelines do recommend some short-term antithrombotic therapy for these patients, usually warfarin,” he explained.

Although the ENBALV study suggests a lower thrombosis rate with edoxaban than with warfarin, there were very few events. “In 410 patients, we see just four events. So that makes me think that this is a population that’s at risk, but they may be at a low risk,” he added.

There was a bleeding risk with both edoxaban and warfarin, Patel reported, and a fatal intracranial hemorrhage in the warfarin group.

“On the basis of these data, I guess edoxaban can be considered for this indication. I think it’s the first trial showing us that it can be considered for this indication in patients without atrial fibrillation,” he said.

“But the limitations are that the population is so low risk [that] we need to improve the stratification of patients undergoing valvular surgery, specifically those who are undergoing bioprosthetic valvular surgery without known atrial fibrillation, to assess who is at risk for stroke and systemic embolism in that short-term period,” he added.

Although this trial shows the feasibility of using “a direct oral anticoagulant in this population, I think we have to target patients with high-risk features who are going to undergo bioprosthetic valve surgery,” Patel said.

A major limitation of the study is that the time in the therapeutic range in the warfarin group was just 19%, said Philippe Gabriel Steg, MD, from Hôpital Bichat in Paris, France, who served as discussant for the trial at the main late-breaking science presentation.

And he highlighted the very low event rate in the trial, noting that the ” absence of evidence is not evidence of absence, ” he said.

“With just four primary outcome events in total,” Steg added, “we cannot conclude that edoxaban was comparable to warfarin in ENBALV.”