Edoxaban matches VKA post-TAVI, at a cost: ENVISAGE-TAVI AF

The NOAC* edoxaban was noninferior to VKA** for the primary composite outcome of net adverse clinical events (NACE) after a successful TAVI*** in patients with atrial fibrillation (AF), but this comes at the cost of higher major bleeding rates, according to the ENVISAGE-TAVI AF^# trial — thus leaving the question on the optimal antithrombotic strategies in AF after TAVI unanswered.

The primary efficacy outcome of NACE — comprising a composite of all-cause death, ischaemic stroke, myocardial infarction, valve thrombosis, systemic embolism, or major bleeding — occurred at a rate of 17.3 per 100 person-years in edoxaban-treated patients and 16.5 per 100 person-years in those on warfarin, which met the criteria for noninferiority between the two groups (hazard ratio [HR], 1.05; p=0.01 for noninferiority). [N Engl J Med 2021;doi:10.1056/NEJMoa2111016]

The rates of ischaemic stroke and all-cause mortality were both numerically lower with edoxaban than with VKA.  

However, the risk of ISTH^{# #}-defined major bleeding was 40 percent higher in the edoxaban group compared with the warfarin group (rates, 9.7 vs 7.0 per 100 person-years; HR, 1.40; p=0.93 for noninferiority). The difference was mainly driven by the higher rates of gastrointestinal (GI) bleeding in the edoxaban group (5.4 vs 2.7 per 100 person-years; HR, 2.03, 95 percent confidence interval [CI], 1.28–3.22), including one that was fatal.

Intracranial haemorrhage and fatal bleeding events were rare and occurred at similar rates in both groups.

Nonetheless, edoxaban appeared to have better balanced risk to benefit profile — with similar rates of NACE and major bleeding — in a subset of patients who met the criteria for using a reduced dose (halved from 60 mg to 30 mg) and those without concomitant oral antiplatelet therapy.

“Based on secondary analyses, it seems that lowering the edoxaban dosage when indicated and avoiding patients on mandatory antiplatelet therapy is reasonable safety advice from a clinical point of view. We will be conducting a detailed analysis on specific types of bleeding in the near future,” said Dr George Dangas from the Icahn School of Medicine at Mount Sinai, New York, New York, US, who presented the findings during the ESC 2021 Congress.

Impact on practice?

While NOACs have been shown to be beneficial over warfarin in the general population of AF patients, these studies excluded patients undergoing TAVI, in whom the data on NOACs have been limited.

Based on findings from the recent ATLANTIS trial presented in ACC.21 Meeting, another NOAC apixaban was not superior to standard care with respect to a composite clinical outcome but there was no increase in bleeding either.  

Invited reviewer Dr Jean-Philippe Collet of Pitié-Salpêtrière Hospital in Paris, France, who was also the principle investigator of ATLANTIS, pointed out the many differences in patient characteristics between the two trials, including concomitant antiplatelet therapy, NOAC dose adjustment, and discontinuation of the study drug which were more frequent in ENVISAGE-TAVI AF.

Participants in the multicentre, prospective, open-label ENVISAGE-TAVI AF trial were 1,426 patients (mean age 82.1 years, 47.5 percent women) who were indicated for oral anticoagulation due to prevalent or incident AF following a successful TAVR. They were randomized to edoxaban 60 mg/day or standard VKA, with or without antiplatelet therapy based on physician’s discretion.

“Whether it is time to update the guidelines is unsure,” he said, in view of the increased bleeding risk with edoxaban. “The transition of NOACs to practice is tricky because whether NOACs are all the same after TAVI seems unlikely. Clearly, NOAC safety depends on concomitant use of antiplatelet therapy and dosing.”

Echoing the same sentiment, panel discussant Dr Alec Vahanian from Universite ́ de Paris, France, said the many questions raised “have to be answered before moving to a guideline recommendation,” and suggested that pooling the data might shed more light into the matter.  

*NOAC: Novel oral anticoagulant
**VKA: Vitamin K antagonist
***TAVI: Transcatheter aortic valve implantation
^#ENVISAGE-TAVI AF: Edoxaban versus standard of care and their effects on clinical outcomes in patients having undergone transcatheter aortic valve implantation – atrial fibrillation
^##ISTH: International Society on Thrombosis and Haemostasis