AUGUSTUS Analysis Clarifies Antithrombotic Choice for ACS in AF Patients

Patients with atrial fibrillation (AF) who’ve recently experienced an acute coronary syndrome or undergone PCI are best served by an antithrombotic strategy that includes a P2Y12 inhibitor and a direct oral anticoagulant (DOAC) without aspirin, according to a new four-way analysis of the AUGUSTUS trial.

For these AF patients in need of antiplatelet therapy following ACS and/or PCI, dual therapy with apixaban (Eliquis; Bristol Myers Squibb) and a P2Y12 inhibitor resulted in significantly lower risks of all-cause mortality, major and clinically relevant nonmajor bleeding, and hospitalization for cardiovascular causes when compared with other strategies that included dual therapy with a vitamin K antagonist (VKA) and triple antithrombotic therapy.

“The findings reinforce the idea that a regimen that includes a DOAC plus a P2Y12 inhibitor represents the preferred option for prevention of ischemic events while limiting bleeding events in this high-risk patient population,” write Otavio Berwanger, MD, PhD (George Institute for Global Health UK/Imperial College London, England), and colleagues in a paper published online August 26, 2024, in the Journal of the American College of Cardiology.

Senior investigator Renato Lopes, MD, PhD (Duke Clinical Research Institute, Durham, NC), said the results from this post hoc analysis are reassuring in that they line up with main study findings showing that apixaban without aspirin—dual antithrombotic therapy—is the safest strategy for AF patients with ACS or undergoing PCI as it results in less bleeding.

“Now, [we show] this is the safest and the most efficacious strategy for a composite endpoint that includes cardiovascular hospitalizations, bleeding, and all cause deaths,” he told TCTMD. “These positive results were driven primarily because of less bleeding, but also went in the same direction for cardiovascular hospitalizations. . . . It was good to see the results were aligned with the primary AUGUSTUS result but expanded now for a combination of bleeding and cardiovascular hospitalizations.”

The findings also line up with current guideline recommendations, including a recent decision pathway from the American College of Cardiology (ACC), that relegate triple therapy—DOAC, P2Y12 inhibition, and aspirin—to the periprocedural period, after which point aspirin should be stopped. 

Christopher P. Cannon, MD (Brigham and Women’s Hospital, Boston, MA), who was a co-author on both the ACC decision pathway and an updated North American consensus statement, said the new AUGUSTUS analysis supports current clinical recommendations.

“It makes the case for the so-called default strategy where most patients can be managed with dual therapy when they head home from the hospital,” Cannon told TCTMD, adding that he 100% agrees with those conclusions.

AUGUSTUS

The AUGUSTUS trial, originally published in 2019, was an international study with a 2x2 factorial design of different antithrombotic regimens for patients with AF who had an ACS or underwent PCI. All patients were treated with a P2Y12 inhibitor following the ACS and/or PCI—more than 90% were treated with clopidogrel—and randomized to receive apixaban or VKA and to aspirin or placebo for 6 months. The primary endpoint of the main study focused on bleeding alone and showed that apixaban without aspirin resulted in superior outcomes, along with fewer hospitalizations, without an increased risk of ischemic events.

The new analysis compares the safety and efficacy of the four randomized groups of patients on background P2Y12 inhibition: apixaban and placebo; apixaban and aspirin; VKA and placebo; and VKA plus aspirin.

The primary endpoint of all-cause mortality, major and clinically relevant nonmajor bleeding, and hospitalization for cardiovascular causes at 6 months occurred in 21.9% of patients treated apixaban and placebo, 27.3% of those treated with apixaban and aspirin, 28.0% in those treated with VKA and placebo, and 33.3% of those treated with VKA and aspirin (P < 0.0001).

Major or clinically relevant nonmajor bleeding occurred in 7.8% of those randomized to apixaban plus placebo, 14.6% of those treated with apixaban and aspirin, 12.0% of those treated with VKA and placebo, and 20.0% of those treated with a VKA and aspirin (P < 0.0001). Cardiovascular hospitalization was lowest in those treated with apixaban and placebo (15.3%) and highest in patients treated with a VKA and placebo (19.8%).

Rates of cardiovascular death, stroke, MI, urgent revascularization, and definite or probable stent thrombosis were similar between the four treatment groups.

There was no interaction between treatment group and outcomes by the type of qualifying event. Additionally, the primary endpoint was lowest for patients treated apixaban and placebo in patients with ACS managed medically, ACS managed with PCI, and in patients undergoing elective PCI.

To TCTMD, Lopes explained AUGUSTUS was not powered to look at the outcomes from the four groups that made up the 2x2 factorial, randomized, controlled trial, but that there was clinical interest in seeing the results. “Looking at individual [groups] is something that is inevitable because everybody wants to see what the best combination would be,” he said.

Host of Trials, Consensus Documents

In the last several years, there have been a raft of trials comparing dual versus triple therapy for patients with AF undergoing PCI. These include WOEST, PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI. In the dual-therapy arm, aspirin is relegated to the periprocedural period, with the duration of use ranging from 4 hours to 7 days.

Dharam Kumbhani, MD (UT Southwestern Medical Center, Dallas, TX), the lead author of the ACC decision pathway, said this new analysis helps quantify the relative risks and benefits of the four treatment strategies in AUGUSTUS. 

“When you look at the other trials, there have been two moving targets,” he said. “It was a DOAC-based dual antithrombotic regimen versus VKA-based triple therapy. It was a little bit unfair, the comparison. AUGUSTUS is the only one that I think is truly able to dissociate the two questions—do you use triple therapy or do you use double therapy? And if you use double therapy, which [oral anticoagulant] is better?”

AUGUSTUS shows that the best strategy from a bleeding and cardiovascular hospitalization standpoint is apixaban plus a P2Y12 inhibitor, said Kumbhani.  

The ACC decision pathway for anticoagulant and antiplatelet therapy for patients with AF undergoing PCI states that low-dose aspirin is recommended for the duration of the hospitalization and should be stopped prior to or upon discharge in most patients. Although the default antithrombotic approach should be a DOAC plus a single antiplatelet agent (clopidogrel is preferred over prasugrel and ticagrelor), the ACC pathway does concede that continued aspirin use for 30 days after PCI might be an option in select patients with a high thrombotic risk coupled with a low risk of bleeding.

Regarding the use of oral anticoagulation, the ACC experts recommend a DOAC over VKA, stating that if a patient with AF is currently treated with VKA, the preferred option would be to switch them to a DOAC, if possible.  

In 2021, an updated North American consensus statement—one that incorporated information from AUGUSTUS and ENTRUST-AF PCI—also continued to recommend dual therapy with an oral anticoagulant and P2Y12 inhibitor for up to 12 months in AF patients undergoing PCI. Triple therapy with aspirin should be relegated to the periprocedural period and stopped on discharged, although it could be continued for up to 1 month in patients at high ischemic/thrombotic risk who were at low risk of bleeding.

When to Drop Aspirin?

The use of aspirin during the “periprocedural” period remains a bit of an open question, said Kumbhani, noting that aspirin duration differed in the multiple trials, including for 7 days in AUGUSTUS.

“It’s a little bit all over the map,” he said, adding that most clinicians will stop aspirin at discharge or continue its use for a week. With high-risk coronary interventions, including left main PCI, triple therapy with aspirin might be continued for a month. Beyond 30 days, though, there is no further ischemic benefit from aspirin but only an increased risk of bleeding, said Kumbhani.  

Lopes explained that aspirin was used for a median of 6 to 7 days before it was stopped (if randomized to no aspirin), which is a reflection of the median time of hospitalization in the international trial. Based on AUGUSTUS, their message is to use aspirin for a few days, and if there are no major issues during hospitalization, to stop it at discharge. They previously published an analysis showing that from randomization to 30 days, aspirin caused more bleeding but was associated with fewer ischemic events. Beyond 30 days, bleeding was increased without any benefit on ischemic side

“If you have a patient that has an extremely high risk of recurrence of ischemic events, a high risk of stent thrombosis, or they had a PCI that was very complex, with multiple risk factors and multiple lesions that are associated with the risk of stent thrombosis, but their bleeding risk is not that high, it’s fine to go a little bit longer with aspirin,” said Lopes. “At 30 days, you definitely need to stop because it only adds harm and doesn’t have any benefit.”

Cannon said they use the same approach in their practice.

“We do risk stratify patients,” he said. “If somebody comes in with ACS and has four stents put in, and they’re not 80 years old, and they also have atrial fibrillation or an indication for anticoagulation, then those are people where we’d do triple therapy and watch carefully for bleeding. For most patients, though, we just get rid of the aspirin at the time of discharge, and I think that’s become the standard where people don’t even think about it anymore.”

Apixaban is favored slightly as the DOAC of choice given its overall safety and efficacy, but clinicians typically will select the drug that is covered by the patient’s insurance, said Cannon.