ENTRUST-AF PCI Supports Safety of Dual Therapy With Edoxaban

Marlene Busko

September 19, 2019

PARIS — Dual therapy with the novel oral anticoagulant (NOAC) edoxaban (Savaysa, Daiichi Sankyo) and a P2Y12 inhibitor was noninferior to triple therapy with a vitamin K antagonist, a P2Y12 inhibitor, and aspirin to prevent major bleeding after successful stenting in patients with atrial fibrillation (AF).

The P2Y12 inhibitor was clopidogrel (Plavix, Sanofi) in 93% of the patients, and rarely ticagrelor (Brilinta/Brilique, AstraZeneca) or prasugrel (Effient, Lilly/Daiichi Sankyo).  

Andreas Goette

Andreas Goette, MD, professor and head, Department of Cardiology and Intensive Care Medicine, St. Vincenz Hospital, Paderborn, Germany, presented results from the Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI) trial during a press briefing and a hotline session here at the European Society of Cardiology Congress 2019. The results were published online September 3 in the Lancet.

In addition, the researchers performed a meta-analysis of this trial plus three other trials of the three other NOACs, which showed that NOAC-based dual antithrombotic therapy was safe and as effective as vitamin K-agonist–based triple antithrombotic therapy.

Now it remains for investigators to determine the optimal time for stopping aspirin and to shed more light on the infrequent complication of stent thrombosis, observers say.

Bleeding Reduced With Dual Therapy in Four NOAC Trials

About 15% of patients with AF might require stent placement to treat obstructive coronary artery disease, Goette said.

And patients with AF undergoing PCI "need oral anticoagulation to prevent cardioembolic events and antiplatelet therapy to prevent coronary events," Davide Capodanno, MD, PhD, AOU Policlinico-Vittorio Emanuele, Catania, Italy, and Dominick J. Angiolillo, MD, PhD, University of Florida College of Medicine, Jacksonville, explain in an accompanying editorial.

"In this context," they write, "three trials of rivaroxaban (PIONEER-AF PCI), dabigatran (
RE-DUAL PCI), and apixaban (AUGUSTUS) showed that combining a non-vitamin K antagonist oral anticoagulant (NOAC) and a P2Y12 inhibitor, a strategy known as dual antithrombotic therapy (DAT), reduces bleeding compared with triple antithrombotic therapy (TAT) consisting of a vitamin K antagonist (VKA), a P2Y12 inhibitor, and aspirin."

Now the results of ENTRUST AF-PCI complete the full spectrum of trials of NOACs in such patients, Capodanno and Angiolillo write, so on the basis of these findings, "as far as we are aware, few would argue against DAT as the safest regimen."

"The question remains," they continue, "about whether DAT is equally protective with respect to coronary events," because none of the individual trials was powered for infrequent events, such as stent thrombosis, and "the optimal timing of abandoning aspirin," is still unclear.

"Use of DAT does not imply abandoning aspirin in the peri-PCI period," they caution, "and a weaning period should be considered as was done in the aforementioned trials (i.e., between discharge up to 2 weeks)."

According to the editorialists, "for patients at higher thrombotic potential, such as those undergoing complex PCI or with an acute coronary syndrome, prolonging the duration of aspirin or considering more potent P2Y12 inhibition can be envisaged on the basis of careful weighing of bleeding and ischemic risk at the individual level."

When to Drop Aspirin

Goette told theheart.org | Medscape Cardiology that "the meta-analysis is very important because it shows that the dual therapy with regard to bleeding reduced events in comparison to triple therapy."

"But the reason we use all these therapeutic approaches is to prevent stroke and stent thrombosis," he said, "and not really to prevent bleeding — bleeding is just a side effect — and there was a clear trend toward an increment in stent thrombi, which we want to prevent."

So, he noted, "we think dual therapy in the long run for safety is the best way to go; however, in the very early phase, it might be necessary to protect the stent by in addition giving aspirin in all patients."

During the hotline session, discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, North Carolina, said that ENTRUST AF-PCI "adds to the body of evidence in a field where high-quality evidence is desperately needed."

"In 2019, with around 12,000 patients from randomized studies, I think we can say that for most patients with ACS undergoing PCI, after the initial few days from PCI, using a NOAC with a P2Y12 inhibitor without aspirin (in other words, drop the aspirin) should be the preferred regimen," Lopes said, and a vitamin K antagonist plus a P2Y12 inhibitor plus aspirin "should generally be avoided."

However, "more details around timing of aspirin withdrawal is needed," he too said.

ESC spokesperson Kurt Huber, MD, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, succinctly summarized to theheart.org | Medscape Cardiology that the ENTRUST-AF-PCI showed that there is now a fourth NOAC that can be used in this indication, patients with AF who undergo PCI, which is important.

The four studies show us that "all four NOACs work and are better and are safer than vitamin K antagonists," Huber said, and "second, we may need aspirin at least for 2 up to 4 weeks after the intervention, especially in high-ischemic-risk patients."

ESC spokesperson Tom Quinn, professor of cardiovascular nursing, Kingston College, London, told theheart.org | Medscape Cardiology that "in past years, if you had a patient coming for PCI who was on a vitamin K antagonist, warfarin for example, and you needed to switch to a different agent or other anticlotting medicines, the risk of bleeding was considerable, and it was a real dilemma for the clinician."

Now this trial and the three other NOAC trials suggest "there is a way to get equivalent benefit, a noninferiority finding, for patients with lower bleeding risk."

Phase 3b Trial

From February 2017 to May 2018, ENTRUST-AF PCI enrolled and randomized 1506 adults who had AF requiring oral anticoagulation and who had undergone successful PCI for stable coronary artery disease or acute coronary syndrome from 186 sites in 18 countries in Asia and Europe.

Soon after PCI (median, 45.1 hours), the patients were randomly assigned to receive dual therapy (edoxaban plus a P2Y12 inhibitor for 12 months) or triple therapy (a vitamin K antagonist plus a P2Y12 inhibitor for 12 months plus aspirin 100 mg once daily for 1 to 12 months).

The site investigators had to prespecify the choice of P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and length of aspirin treatment for each patient, where aspirin duration was based on CHA₂DS₂-VASc and HAS-BLED scores and whether the patient had acute coronary syndrome or stable CAD.

Edoxaban was given at the stroke prevention dose of 60 mg/day — but it could be reduced to 30 mg/day if the patient had moderate or severe renal impairment (creatine clearance ≤15–50 mL/min), low bodyweight (≤60 kg), or was concurrently taking a potent P-glycoprotein inhibitor (cyclosporine, dronedarone, erythromycin, or ketoconazole).

At baseline, the patients had a mean age of 69 years and a quarter were female.

Their mean CHA₂DS₂-VASc and HAS-BLED scores were 4.0 and 3.0, respectively. About half (52%) had acute coronary syndrome and the other half had stable CAD.

Among patients in the triple-therapy group, the median time in therapeutic range (INR, 2.0 - 2.0) was 63%, and the median duration of triple therapy was 66 days.

At 12 months, the primary end point of a composite of major or clinically relevant nonmajor (CRNM) bleeding occurred in 128 of 751 patients (17%) in the double-therapy group without aspirin and in 152 of 755 patients (20%) in the triple-therapy group with aspirin (hazard ratio [HR], 0.83; 95% CI, 0.65 - 1.05; P =.001 for noninferiority; and HR, 1.20; P = .1154 for superiority).

The secondary end points of a composite of cardiovascular death, stroke, myocardial infarction, definite stent thrombosis, and systemic embolic events, as well as its individual components, did not differ significantly between the two groups (7% in the edoxaban group vs 6% in the group that received a vitamin K antagonist; HR, 1.06; 95% CI, 0.71 - 1.69).

The study was funded by Daiichi Sankyo. Goette has received honoraria and speaker fees from AstraZeneca, Bayer Health Care, Berlin-Chemie, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Medtronic, Novartis, and Omeicos. Goette's research has been supported by Josef-Freitag-Stiftung and Deutsche Herzstiftung outside the submitted work. Coauthor Marco Valgimigli, MD, reports grants and personal fees from Abbott, Alvimedica, Amgen, Bayer, Bristol-Myers Squibb, Coreflow, Daiichi Sankyo, Vifor, Idorsia, Terumo, and iVascular outside the submitted work; and grants and personal fees from AstraZeneca and Medicure outside the submitted work.

Lancet. Published online September 3, 2019. Article, Editorial

European Society of Cardiology (ESC) Congress 2019. Presented September 3, 2019.

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