Meeting NewsPerspective

ENTRUST-AF PCI: Dual therapy with edoxaban noninferior to triple therapy in AF, PCI

PARIS — In patients with atrial fibrillation who underwent PCI, an antithrombotic strategy of edoxaban plus a P2Y12 inhibitor was noninferior to a vitamin K antagonist-based triple regimen for bleeding, with no significant differences in ischemic events.

The ENTRUST-AF PCI trial evaluated the safety of edoxaban (Savaysa, Daiichi Sankyo) 60 mg in combination with a P2Y12 inhibitor for 12 months compared with a vitamin K antagonist such as warfarin in combination with a P2Y12 inhibitor and aspirin 100 mg. The aspirin duration was for 1 to 12 months.

The results were presented at the European Society of Cardiology Congress and simultaneously published in The Lancet.

Triple therapy is associated with quite high bleeding rates,” Andreas Goette, MD, from the departments of cardiology and intensive care medicine, St. Vincenz-Hospital, Paderborn, Germany, said during a presentation. “So far, in phase 3 clinical trials, edoxaban has been established to be quite safe and effective as an alternative to vitamin K [antagonists] in patients with nonvalvular atrial fibrillation, and so far in the setting of coronary artery stenting we have seen three trials on [non-vitamin K antagonist oral anticoagulant] use. However, the effect of edoxaban in combination with a P2Y12 inhibitor in this setting of PCI is unexplored.”

A total of 1,506 patients were randomly assigned to the dual or triple therapy within 4 hours to 5 days following PCI. Median time from PCI to randomization was 45.1 hours. The dose of edoxaban was reduced from 60 mg to 30 mg if certain factors were present: creatinine clearance 15 to 50 mL/min, body weight of 60 kg or less and/or use of prespecified potent P-glycoprotein inhibitors. The choice of P2Y12 inhibitor was left to the treating physician and was usually clopidogrel, Goette said.

Major or clinically relevant nonmajor bleeding within 12 months, the primary safety endpoint, occurred in 17% of the edoxaban group (annualized event rate, 20.7%) vs. 20% of the triple-therapy group (annualized event rate, 25.6%). The HR was 0.83 (95% CI, 0.65-1.05; P for noninferiority = .001; margin HR = 1.2; P = for superiority = .1154).

The difference in the primary bleeding outcome was mainly attributable to clinically relevant nonmajor bleeding events, according to Goette.

In other findings, fatal bleeding occurred in one patient assigned the edoxaban strategy and seven assigned triple therapy, and intracranial bleeding occurred in four vs. nine patients, respectively. Bleeding rates according to the ISTH, TIMI and BARC definitions were consistent across the antithrombotic strategy groups.

For the primary efficacy outcome, a composite of death from CV causes, stroke, systemic embolic events, MI or definite stent thrombosis, dual and triple therapy yielded similar rates at 12 months (HR = 1.06; 95% CI, 0.71-1.69), according to the researchers.

“Enrollment ... was not large enough to detect small but potentially important differences in the incidence of the main efficacy outcomes,” Goette said during the presentation.

The findings were consistent across various subgroups, Goette said.

In ENTRUST-AF PCI, the median age was 70 years and 26% were women. More than half of patients had an indication for PCI of ACS. Thirteen percent of patients had a previous stroke. At baseline, median CHA2DS2-VASc score was 4 and median HAS-BLED score was 3.

“The edoxaban-based dual therapy regime, as compared to vitamin K [antagonist]-based regime, showed similar effects with respect to the main safety and efficacy outcomes,” Goette said during the presentation. “Of note, all [non-vitamin K antagonist oral anticoagulant] AF/PCI trials show numerically increased rates of myocardial infarction and, in particular, stent thrombosis in patients with early withdrawal of aspirin.”

During a discussion of the trial at ESC Congress, Renato D. Lopes, MD, MHS, PhD, professor of medicine in the division of cardiology at Duke Clinical Research Institute, Duke University Medical Center, said ENTRUST-AF PCI is “an important study in a field that is very challenging.”

Patients with AF undergoing PCI are common in clinical practice. Therefore, Lopes said, the strategy is to “find the antithrombotic sweet spot: in other words, find a combination of drugs at the right dose that can cause the greatest reduction of ischemic events at a minimal cause of bleeding.” While that goal is not easy, he said, the clinical scenario has changed in recent years with the presentation and publication of important trials, including ENTRUST-AF PCI.

“ENTRUST-AF PCI adds to the body of evidence in a field where high-quality evidence is desperately needed,” Lopes said during the discussion. “More details around the timing of aspirin withdrawal are needed so we can better understand those results. I think we can say, for most patients with AF undergoing PCI, after the initial few days from PCI, a novel oral anticoagulant plus P2Y12 inhibitor without aspirin should be the preferred regimen, and VKA plus a P2Y12 inhibitor plus aspirin should generally be avoided.” – by Katie Kalvaitis and Erik Swain

References:

Goette A. Hot Line Session 6. Presented at: European Society of Cardiology Congress; Aug. 31-Sept. 4, 2019; Paris.

Vranckx P, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)31872-0.

Disclosures: The study was funded by Daiichi Sankyo. Goette reports he receives honoraria from AstraZeneca, Bayer, Berlin Chemie, Biotronik, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Boston Scientific, Cordis, Daiichi Sankyo, Medtronic and Omeicos. Please see the study for the other authors’ relevant financial disclosures. Lopes reports he receives research contracts from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer and Sanofi and is a consultant/owner/stockholder for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola and Sanofi.

Editor’s note: This article was updated on Sept. 7, 2019, with additional context and discussion of the trial.

PARIS — In patients with atrial fibrillation who underwent PCI, an antithrombotic strategy of edoxaban plus a P2Y12 inhibitor was noninferior to a vitamin K antagonist-based triple regimen for bleeding, with no significant differences in ischemic events.

The ENTRUST-AF PCI trial evaluated the safety of edoxaban (Savaysa, Daiichi Sankyo) 60 mg in combination with a P2Y12 inhibitor for 12 months compared with a vitamin K antagonist such as warfarin in combination with a P2Y12 inhibitor and aspirin 100 mg. The aspirin duration was for 1 to 12 months.

The results were presented at the European Society of Cardiology Congress and simultaneously published in The Lancet.

Triple therapy is associated with quite high bleeding rates,” Andreas Goette, MD, from the departments of cardiology and intensive care medicine, St. Vincenz-Hospital, Paderborn, Germany, said during a presentation. “So far, in phase 3 clinical trials, edoxaban has been established to be quite safe and effective as an alternative to vitamin K [antagonists] in patients with nonvalvular atrial fibrillation, and so far in the setting of coronary artery stenting we have seen three trials on [non-vitamin K antagonist oral anticoagulant] use. However, the effect of edoxaban in combination with a P2Y12 inhibitor in this setting of PCI is unexplored.”

A total of 1,506 patients were randomly assigned to the dual or triple therapy within 4 hours to 5 days following PCI. Median time from PCI to randomization was 45.1 hours. The dose of edoxaban was reduced from 60 mg to 30 mg if certain factors were present: creatinine clearance 15 to 50 mL/min, body weight of 60 kg or less and/or use of prespecified potent P-glycoprotein inhibitors. The choice of P2Y12 inhibitor was left to the treating physician and was usually clopidogrel, Goette said.

Major or clinically relevant nonmajor bleeding within 12 months, the primary safety endpoint, occurred in 17% of the edoxaban group (annualized event rate, 20.7%) vs. 20% of the triple-therapy group (annualized event rate, 25.6%). The HR was 0.83 (95% CI, 0.65-1.05; P for noninferiority = .001; margin HR = 1.2; P = for superiority = .1154).

The difference in the primary bleeding outcome was mainly attributable to clinically relevant nonmajor bleeding events, according to Goette.

In other findings, fatal bleeding occurred in one patient assigned the edoxaban strategy and seven assigned triple therapy, and intracranial bleeding occurred in four vs. nine patients, respectively. Bleeding rates according to the ISTH, TIMI and BARC definitions were consistent across the antithrombotic strategy groups.

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For the primary efficacy outcome, a composite of death from CV causes, stroke, systemic embolic events, MI or definite stent thrombosis, dual and triple therapy yielded similar rates at 12 months (HR = 1.06; 95% CI, 0.71-1.69), according to the researchers.

“Enrollment ... was not large enough to detect small but potentially important differences in the incidence of the main efficacy outcomes,” Goette said during the presentation.

The findings were consistent across various subgroups, Goette said.

In ENTRUST-AF PCI, the median age was 70 years and 26% were women. More than half of patients had an indication for PCI of ACS. Thirteen percent of patients had a previous stroke. At baseline, median CHA2DS2-VASc score was 4 and median HAS-BLED score was 3.

“The edoxaban-based dual therapy regime, as compared to vitamin K [antagonist]-based regime, showed similar effects with respect to the main safety and efficacy outcomes,” Goette said during the presentation. “Of note, all [non-vitamin K antagonist oral anticoagulant] AF/PCI trials show numerically increased rates of myocardial infarction and, in particular, stent thrombosis in patients with early withdrawal of aspirin.”

During a discussion of the trial at ESC Congress, Renato D. Lopes, MD, MHS, PhD, professor of medicine in the division of cardiology at Duke Clinical Research Institute, Duke University Medical Center, said ENTRUST-AF PCI is “an important study in a field that is very challenging.”

Patients with AF undergoing PCI are common in clinical practice. Therefore, Lopes said, the strategy is to “find the antithrombotic sweet spot: in other words, find a combination of drugs at the right dose that can cause the greatest reduction of ischemic events at a minimal cause of bleeding.” While that goal is not easy, he said, the clinical scenario has changed in recent years with the presentation and publication of important trials, including ENTRUST-AF PCI.

“ENTRUST-AF PCI adds to the body of evidence in a field where high-quality evidence is desperately needed,” Lopes said during the discussion. “More details around the timing of aspirin withdrawal are needed so we can better understand those results. I think we can say, for most patients with AF undergoing PCI, after the initial few days from PCI, a novel oral anticoagulant plus P2Y12 inhibitor without aspirin should be the preferred regimen, and VKA plus a P2Y12 inhibitor plus aspirin should generally be avoided.” – by Katie Kalvaitis and Erik Swain

References:

Goette A. Hot Line Session 6. Presented at: European Society of Cardiology Congress; Aug. 31-Sept. 4, 2019; Paris.

Vranckx P, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)31872-0.

Disclosures: The study was funded by Daiichi Sankyo. Goette reports he receives honoraria from AstraZeneca, Bayer, Berlin Chemie, Biotronik, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Boston Scientific, Cordis, Daiichi Sankyo, Medtronic and Omeicos. Please see the study for the other authors’ relevant financial disclosures. Lopes reports he receives research contracts from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer and Sanofi and is a consultant/owner/stockholder for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola and Sanofi.

Editor’s note: This article was updated on Sept. 7, 2019, with additional context and discussion of the trial.

    Perspective
    Grant Reed

    Grant Reed

    ENTRUST-AF PCI is the first randomized controlled trial to evaluate the safety and efficacy of dual antithrombotic therapy with the non-vitamin K antagonist oral anticoagulant edoxaban plus a P2Y12 inhibitor vs. triple antithrombotic therapy with a vitamin K antagonist (eg, warfarin) plus a P2Y12 inhibitor plus low-dose aspirin in patients with AF after coronary stenting. 

    The trial is important as it showed that the dual therapy strategy with edoxaban was safe with regard to ischemic events in 1-year follow-up. Surprisingly, there was not less bleeding seen with dual compared to triple therapy, but there was a trend. One explanation for this is that more patients on vitamin K antagonists were subtherapeutic, with international normalized ratio < 2 initially. Supporting this, in a landmark analysis of events after 14 days in which most patients were at goal INR, there was significantly less bleeding with dual therapy than with triple therapy.

    The results from ENTRUST-AF PCI continue to reinforce the findings from WOEST and recent trials in this space, including PIONEER-AF PCI, RE-DUAL and AUGUSTUS. The take-home message is that in patients with AF and recent PCI, it is likely safe to drop aspirin after a short course, and use dual therapy with clopidogrel and a non-vitamin K antagonist oral anticoagulant instead.

    Although edoxaban is a recent addition to the U.S. market, this trial should provide reassurance to providers that using edoxaban for AF is at least as safe as warfarin after coronary stenting.

    However, the results from this trial might steer patients toward the other non-vitamin K antagonist oral anticoagulants if choosing to start an agent for dual therapy after PCI. While all of the trials with non-vitamin K antagonist oral anticoagulants showed equivalent ischemic events with dual compared to triple therapy, rivaroxaban (Xarelto, Janssen/Bayer) caused less bleeding in PIONEER-AF PCI, dabigatran (Pradaxa, Boehringer Ingelheim) caused less bleeding in RE-DUAL PCI, and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) caused less bleeding in AUGUSTUS.

    That said, it is not possible to draw conclusions between trials as the patients studied were slightly different, and a direct comparison of other non-vitamin K antagonist oral anticoagulants is needed to demonstrate which agent is really the safest.

    One important trend seen across these trials is that in patients who stopped aspirin very early, there was a trend toward increased stent thrombosis. While the long-term strategy of dropping aspirin appears safe, there is concern that some of these trials may have been underpowered for ischemic events, and the ideal timing of stopping aspirin has yet to be defined. It is possible that certain subgroups of patients at higher ischemic risk may benefit from a slightly longer course of aspirin (1 to 4 weeks). These patients at higher ischemic risk may include patients after ACS, bifurcation PCI or patients with other risk factors for stent thrombosis.

    It is also important to recognize that nearly all patients in ENTRUST-AF PCI were on clopidogrel and not prasugrel (Effient, Daiichi Sankyo/Eli Lilly) or ticagrelor (Brilinta, AstraZeneca), which are more potent P2Y12 inhibitors and associated with higher bleeding risks.

    We now have a strong body of evidence, including four randomized controlled trials and meta-analyses, which supports that dual therapy is safe from an ischemic standpoint and reduces bleeding compared with triple therapy for patients with AF after PCI. Guidelines should be updated to reflect this.

    A personalized treatment approach is key. Cardiologists should avoid falling into a one-size-fits-all approach to this problem. It is important to tailor each patient’s antithrombotic regimen to their individual risks of bleeding and recurrent ischemic events after PCI.

    • Grant Reed, MD, MSc, FACC
    • Interventional Cardiologist, Invasive and Interventional Cardiology Section
      Robert and Suzanne Tomsich Department of Cardiovascular Medicine
      Sydell and Arnold Miller Family Heart & Vascular Institute
      Cleveland Clinic

    Disclosures: Reed reports no relevant financial disclosures.

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