Trial Tentatively Backs DOACs After TAVR

In a departure from other transcatheter aortic valve replacement (TAVR, or TAVI) trials, direct oral anticoagulant (DOAC, or NOAC) therapy seemed to safely prevent subclinical leaflet thrombosis in ACASA-TAVI — but not convincingly enough to change practice.

Among people randomized to DOAC monotherapy, the incidence of hypoattenuated leaflet thickening at 12 months (HALT; detected on cardiac CT scan) was 16.2%, a significant reduction from the 28.6% of peers getting aspirin or another antiplatelet instead (RR 0.55, 95% CI 0.37-0.82, P=0.004 for superiority). Moreover, where there was HALT, the degree of leaflet involvement was at least numerically higher in the antiplatelet group compared with the DOAC group, according to Øyvind Lie, MD, PhD, MSc, of Oslo University Hospital, Rikshospitalet in Norway.

As for safety, the DOAC approach had reassuring results regarding combined VARC-3 bleeding events, thromboembolic events, and all-cause death at 12 months (7.5% vs 10.6%, P<0.001 for noninferiority). This safety analysis relied on lower-than-expected event numbers in a 360-person trial, however, so it is not to be taken as definitive, the authors acknowledged.

“Anticoagulation monotherapy can be beneficial after TAVI in selected patients. The results can inform future antithrombotic treatment strategies after TAVI, and we will report the clinical outcomes later,” Lie told the audience at the European Society of Cardiology (ESC) Congress in Munich, Germany. ACASA-TAVI was also simultaneously published in JAMA.

Antithrombotic strategies are of great interest in TAVR as clinicians seek a perfect balance of reduced valve thrombosis without unacceptable bleeding side effects.

However, with major trials previously finding no benefit and even harm with DOAC use after TAVR (e.g., GALILEO, ATLANTIS), patients have been left by default with single antiplatelet therapy (SAPT) such as aspirin. Additionally, many remain skeptical that HALT, a common finding of clotting on imaging, actually affects long-term valve durability and clinical outcomes in the first place.

As such, the most recent clinical guidelines strongly discourage anticoagulation in patients without an independent indication.

The NOTION-4 trial, presented in tandem with ACASA-TAVI at ESC and published separately in the Journal of the American College of Cardiology, cast more doubt on DOACs being a viable clot-preventing strategy after TAVR.

In this trial of 352 people randomized to lifelong SAPT or 3 months of upfront DOAC therapy and SAPT thereafter, the initial 3-month course of DOAC reduced HALT during active treatment before the benefit disappeared 9 months after patients stopped DOACs and got on lifelong SAPT. What’s more, the combined risk of all-cause mortality, stroke, or major/life-threatening bleeding at 12 months was 2.3% in the SAPT group versus 8.2% with short-term DOACs in NOTION-4.

“Together, these findings support the current guidelines recommendation against routine use of DOAC after TAVI in patients without any other indication for oral anticoagulant therapy,” said study author Troels Hojsgaard Jørgensen, MD, PhD, of Rigshospitalet, Copenhagen University Hospital in Denmark.

With ACASA-TAVI and NOTION-4 now reported, the DOAC-TAVR literature as a whole is still “overall non-conclusive,” commented ESC session discussant Stephan Windecker, MD, of Bern University Hospital, Inselspital in Switzerland.

“DOAC effectively reduces HALT, but it is not durable, has not been conclusively shown to improve clinical outcomes, and routine screening for HALT is not recommended. What should we do in clinical practice after ACASA and NOTION-4? I would say that single antiplatelet therapy remains the default strategy as recommended in the guidelines, but that we need to pay attention to optimize TAVR implantation to reduce the risk of HALT,” Windecker concluded.

ACASA-TAVI was a prospective, open-label randomized trial conducted at three high-volume Norwegian centers. Participants were people age 65-80 years who had successful TAVR for severe aortic valve stenosis. Exclusion criteria included those having a conventional indication for anticoagulation or antiplatelet therapy or a contraindication against either.

Out of nearly 2,000 people screened for entry, 360 were randomized 1:1 to either DOAC or aspirin monotherapy for 12 months (mean age 74.5 years, 37% women).

The choice of DOAC was a shared decision between the patient and treating physician. Standard DOAC doses were apixaban (Eliquis) 5 mg twice daily, edoxaban (Savaysa) 60 mg once daily, and rivaroxaban (Xarelto) 20 mg once daily. Reduced doses were allowed.

For the controls, aspirin 75 mg was the default. Those who were intolerant to aspirin or who used clopidogrel (Plavix) prior to study inclusion could be treated with clopidogrel in ACASA-TAVI.

Ultimately, in the DOAC group, 51% received apixaban, 41% received edoxaban, and 8% received rivaroxaban. Eleven participants in the control group took clopidogrel.

Study authors noted that a substantial number of treatment deviations, interruptions, and crossovers occurred.

“We had lower than anticipated rates of the primary endpoints and a relatively young and low-risk population in Norway, which might not necessarily be applicable to octogenarians and higher-risk populations,” Lie cautioned.

And while a blinded core laboratory cardiac CT analysis was employed for ACASA-TAVI, the trial’s open-label design may have influenced participant behavior, the researchers also acknowledged.