Edoxaban Noninferior to Warfarin After Valve Surgery?

April 07, 2020

The first randomized trial comparing a direct oral anticoagulant (DOAC) with warfarin after surgical bioprosthetic valve replacement has suggested noninferiority of edoxaban (Savaysa, Daiichi Sankyo) to the vitamin K antagonist.

However, the study was small, and outside commentators called for more data regarding this question as well as whether anticoagulation is needed at all in this population.

The ENAVLE trial was presented last week by Geu-Ru Hong, MD, Yonsei University College of Medicine, Seoul, Korea, at the "virtual" American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).

For the open-label study, 220 patients who had undergone successful surgical bioprosthetic valve implantation or valve repair to the mitral valve, aortic valve, or both were randomly assigned to receive either edoxaban (60 mg orally once daily or 30 mg once daily for those patients whose creatinine clearance was 30–50 mL/min or whose body weight was ≥60 kg) or warfarin (dose adjustment to maintain the INR between 2.0 and 3.0) during a treatment period of 3 months.

The primary efficacy outcome was a composite of death, clinical thromboembolic events (stroke, myocardial infarction [MI], symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, or systemic embolism), and asymptomatic intracardiac thrombosis (subclinical leaflet thrombosis or thrombus within the cardiac cavities detected by CT scan or echocardiography).

This occurred in none of the patients in the edoxaban group and in four patients (3.67%) in the warfarin group. Among those four patients, one had MI and three had asymptomatic intracardiac thrombus (P for noninferiority, <.001).

The primary safety outcome, major bleeding, as determined using ISTH criteria, occurred in three patients (2.75%) in the edoxaban group (two gastrontestinal [GI] bleeds and one pericardial bleed) in one patient (0.92%) in the warfarin group (intracranial hemorrhage) (P for noninferiority, .013).

The net clinical outcome, therefore, occurred in three patients (2.75%) in the edoxaban group vs five patients in the warfarin group (4.59%), which Hong said was within the trial's noninferiority margin of 8%.

During the discussion, Daniel H. Steinberg, MD, Medical University of South Carolina, Charleston, congratulated Hong on completing a randomized trial "in this area where there is little real data to help guide therapy following valve replacement."

Steinberg said the use of anticoagulation after valve repair/replacement was "an issue we all struggle with," inasmuch as the guidelines were not clear. Noting that in some centers, there is a question of whether to give anticoagulation at all for these patients, he asked whether the ENAVLE investigators considered having a study arm in which no anticoagulation was given.

Hong replied that he believed anticoagulation in the early postoperative period was important for those patients who are at a low risk of bleeding, and that in Korea, it was standard to treat these patients with anticoagulation (usually warfarin) for 3 months. "Sometimes we treat for 6 months if we see subclinical thrombosis on the bioprosthetic valve on echo," he said.

Steinberg also questioned whether a 3% bleeding risk with edoxaban would be acceptable.

Hing responded that there was a small increase in risk for GI bleeding but that this could be reduced with GI protection. He also noted that in the study, the only intracerebral hemorrhage that occurred was in the warfarin group.

The chair of the session at which the study was presented, Martin Leon, MD, Columbia University Medical Center, New York City, said that this was an "important study that leads us in a different direction," but he queried some of the statistics underlying the trial.

"The assumed event rate of 11.7% in the warfarin group was pretty high, and you selected a broad noninferiority margin of 8%. There was an unequal expectation (4.3%) in the experimental arm, which allowed a small sample size," he noted.

"If we're going to change the guideline recommendation and begin using a DOAC after valve replacement, we need more data. We need a larger number of patients to be assured of safety and to be at least somewhat confident that there is an efficacy benefit relative to no therapy, which is generally the standard in the US," Leon commented.

The ENAVLE study was funded by a research grant from Daiichi Sankyo. Hong has disclosed no relevant financial relationships.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC): Abstract 20-LB-20547-ACC. Presented March 30, 2020.

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