GLOBAL LEADERS Post Hoc: Okay to Drop Aspirin After 1 Month in ACS Patients?

SAN FRANCISCO, CA—Patients with ACS who undergo PCI may do just fine on ticagrelor monotherapy after a month of dual antiplatelet therapy (DAPT), suggests a post hoc analysis of the GLOBAL LEADERS trial, focused on this higher-risk group.

Between 1 and 12 months, ACS patients taking ticagrelor had significantly less BARC type 3 or 5 bleeding (0.8% vs 1.5%) and no increase in all-cause death/new Q-wave MI (1.5% vs 2.0%) compared with those taking ticagrelor plus aspirin, Mariusz Tomaniak, MD (Erasmus Medical Center, Rotterdam, the Netherlands), reported here at TCT 2019.

The results call into question the need for aspirin beyond 1 month, but due to the many limitations that come with a post hoc analysis of a trial that was negative for its primary findings, Tomaniak said this latest batch “should be considered strictly as hypothesis-generating.”

But, he pointed out, the results “correspond very well” with those of the TWILIGHT trial presented at the meeting just hours ahead of this analysis. That trial showed that in high-risk patients who had undergone PCI, ticagrelor (Brilinta; AstraZeneca) monotherapy—following 3 months of ticagrelor plus aspirin—reduced bleeding compared with dual therapy without paying a penalty in terms of ischemic events.

There are some noteworthy differences between the studies in terms of the duration of aspirin therapy, patient populations (STEMIs were excluded from TWILIGHT), and the main bleeding endpoint (BARC type 3 or 5 in GLOBAL LEADERS and BARC type 2, 3, or 5 in TWILIGHT).

Nevertheless, Renato Lopes, MD, PhD (Duke Clinical Research Institute, Durham, NC), one of the moderators of the session at which Tomaniak presented his results, said there were “very similar patterns between this study and TWILIGHT.” He added that the fact that STEMIs were included in GLOBAL LEADERS means that this analysis “kind of adds to what TWILIGHT did, although not randomized. But interesting.”

The analysis was published simultaneously online in JAMA Cardiology.

ACS in the GLOBAL LEADERS Trial

The GLOBAL LEADERS trial enrolled all-comers patients undergoing PCI for either stable coronary disease or ACS. The main results reported last year showed that continuing with ticagrelor alone after 1 month of ticagrelor plus aspirin was not superior to DAPT with aspirin plus either clopidogrel (in stable patients) or ticagrelor (in ACS patients) for 12 months followed by a year of aspirin monotherapy in terms of the primary endpoint of all-cause death or new Q-wave MI at 2 years. A prior post hoc analysis of the trial indicated that ticagrelor monotherapy might be beneficial in patients undergoing complex PCI.

With this new post hoc analysis, the investigators sought to clarify the impact of aspirin in ACS in the context of more potent P2Y12 antagonists like ticagrelor. The study zeroed in on the 7,487 patients with ACS who were included in the trial and risks of bleeding and ischemic events between 1 and 12 months, when patients were taking either ticagrelor alone or ticagrelor plus aspirin.

During that span, the risk of all-cause death/new Q-wave MI was not significantly different between the patients taking ticagrelor alone and those taking ticagrelor plus aspirin (HR 0.73; 95% CI 0.51-1.03), but risk of investigator-reported BARC type 3 or 5 bleeding was reduced with single antiplatelet therapy (HR 0.52; 95% CI 0.33-0.81). That difference was driven mainly by fewer BARC type 3 bleeds.

There were no differences in other efficacy endpoints, including all-cause death, stroke, MI, revascularizations, definite stent thrombosis, and a variety of composite endpoints.

Tomaniak noted several limitations of the analysis, including the post hoc design; the lack of power to detect differences in clinical outcomes between groups; and the use of investigator reporting rather than central adjudication for the secondary outcomes.

“These findings should be interpreted as exploratory and hypothesis-generating; however, they pave the way for further trials evaluating aspirin-free antiplatelet strategies after PCI,” he and his colleagues conclude in their paper.

Take Another Look at Aspirin Monotherapy?

Commenting for TCTMD, David Fischman, MD (Thomas Jefferson University Hospitals, Philadelphia, PA), called the analysis interesting but exploratory, and said more work is needed to sort out the appropriate antiplatelet strategy after PCI.

He said out in practice, there’s some uncertainty about the optimal approach after PCI. “I think in reality, people are confused,” Fischman said, noting that in general, physicians are still opting for 12 months of DAPT after DES implantation. He added that he believes DAPT has a benefit for reducing ischemic events. “But I may be proven wrong now because of some of these studies—TWILIGHT and [this post hoc analysis]—suggesting we can probably shorten the aspirin at no risk of an ischemic event and low bleeding complications.”

For now, though, “I think we have to take these studies and digest them a little bit and then see where we go from here,” he said, advising against being too hasty with changing guidelines. He recommended an individualized approach to choosing antiplatelet therapy after PCI. “You have to put it in context of the actual patient situation, the clinical presentation, what the anatomy is, what was treated,” Fischman said. “Someone who has diffuse disease I think will benefit from a longer-term duration of DAPT.”

At the very least, the information coming out of TWILIGHT and this post hoc analysis “does give us some comfort level for those patients [in whom] you need to reduce it,” he continued. “You look at this and say, ‘Well, it may be okay.’”

Among the work that remains to be done to sort out the best management approach after PCI might be a reevaluation of aspirin monotherapy, Fischman said. Although aspirin did not fare well in older trials in terms of preventing stent thrombosis, both stent technology and deployment methods have improved, he pointed out.

“I think people would be a little afraid, but I think if we’re going to be innovators we have to rethink the strategy and think is it something worth doing,” Fischman said. “Do I think it will get done? Probably not, because who’s going to fund that study? If aspirin comes out to be superior or noninferior, what’s going to happen with these thienopyridines?”