Ticagrelor Monotherapy After Multivessel PCI? Latest Slice From GLOBAL LEADERS Says . . . Maybe

Discontinuing aspirin after 1 month of dual antiplatelet therapy (DAPT) with ticagrelor may be an effective and safe treatment strategy after multivessel PCI for ACS or stable coronary artery disease, according to a post hoc substudy of the GLOBAL LEADERS trial. The researchers suggest that the results should be considered “hypothesis-generating.”

This is not the first post hoc analysis to look for a silver lining in the otherwise negative large randomized trial—just last month the researchers reported that ticagrelor (Brilinta; AstraZeneca) monotherapy might be the way to treat high-risk patients with ACS. Another analysis, zeroing in on patient-oriented clinical outcomes, showed no difference in patient-focused hard endpoints or net adverse cardiovascular and cerebrovascular events with ticagrelor alone over 2 years, but did suggest a reduction in BARC type 3 or 5 bleeding among ACS patients.

Taking a slightly different approach, the recently published TWILIGHT trial showed that in patients at high risk for bleeding or an ischemic event after PCI, dropping aspirin after 3 months of DAPT with ticagrelor reduced BARC type 2, 3, or 5 bleeding versus continued dual therapy and did not involve paying a penalty in terms of ischemic events.

“[This] has been a difficult year for aspirin. There is no doubt about that,” co-author Patrick Serruys, MD, PhD (Erasmus University Medical Center, Rotterdam, the Netherlands), told TCTMD this week. “Many people are questioning the value of aspirin these days.”

Serruys along with lead investigator Kuniaki Takahashi, MD (University of Amsterdam, the Netherlands), and colleagues describe their results in a paper published in the October 22, 2019, issue of the Journal of the American College of Cardiology.

Medicine is never finished. Patrick Serruys

For David Fischman, MD (Jefferson University Hospitals, Philadelphia, PA), who was not involved in the study, the findings raise “more questions” about DAPT duration after PCI. “As an interventionalist, I’m approached all the time by the referring docs . . . because they're confused when they get out there and they see the studies,” he said, adding that changes in stent technology also bring a layer of complexity.

That said, some reassurances can be found in these data for physicians tailoring care. “It gives you some comfort in that individual patient where you need to consider stopping [aspirin]—the patient who may have had a bleeding episode or some kind of event [where] you feel obligated to stop the blood thinner but you’re worried about stent thrombosis,” Fischman said. “But for everybody with multivessel CAD to follow this strategy, I think we’re too early. We're not there yet. Even with TWILIGHT, . . . I don’t think we’re there yet.”

Multivessel PCI Details

Among the 15,845 patients in the main GLOBAL LEADERS population, those who had multivessel PCI (n = 3,576) reported higher rates of both ischemic and bleeding events at 2 years compared with those who underwent single-vessel PCI.

Patients with multivessel disease seemed to do better in terms of the primary endpoint—a composite of all-cause mortality or nonfatal Q-wave MI—when aspirin was dropped after 1 month versus continued DAPT (3.06% vs 4.85%; HR 0.62; 95% CI 0.44-0.88; P for interaction = 0.031). This difference was mainly driven by a 37% reduction in the risk of all-cause death within the study arm (P for interaction = 0.048). Interestingly, the risk of BARC 3 or 5 bleeding was similar between the pharmacotherapy regimens (2.47% vs 2.68%; HR 0.92; 95% CI 0.61-1.39; P for interaction = 0.754).

A 1-year landmark analysis showed that the risk of the primary endpoint was similar for multivessel PCI patients who received either treatment strategy, “suggesting that the benefit of the experimental antiplatelet strategy was mainly obtained during the first year of the treatment,” the authors write. Also, there were no differences in outcomes in sensitivity analyses that addressed the inclusion or exclusion of patients undergoing left main stem PCI.

In patients with stable CAD who underwent multivessel PCI, there were no significant differences between the treatment strategies, but those who received ticagrelor monotherapy saw a numerically lower risk of the primary endpoint and a numerically higher risk of BARC 3 or 5 bleeding. In contrast, ACS patients with multivessel PCI saw a lower risk of the primary endpoint and a numerically lower rate of BARC 3 or 5 bleeding with ticagrelor monotherapy compared with continued DAPT.

Outcomes Following Multivessel PCI by Disease Presentation

“These findings should be interpreted as hypothesis-generating and need to be replicated in future dedicated randomized trials,” the authors write.

‘Sub-sub-group’ Caution

In an editorial accompanying the study, Jean-Philippe Collet, MD, PhD (Hôpital Pitié-Salpêtrière, Paris, France), and colleagues note that this latest GLOBAL LEADERS analysis has several limitations. “First, because of the lack of prespecification, low event rates, and lack of control for multiple comparisons, unexpected findings derived from subgroups of trials are often the play of chance, false positive, or false negative,” they say.

Also, since GLOBAL LEADERS was negative for its primary endpoint and there were no observed differences between patients who received single-vessel and multivessel PCI, “the given explanation to account for the decrease in ischemic outcomes in the experimental arm is a lower bleeding rate,” they add. “However, no difference in major bleeding was demonstrated between the intervention and the control group except within the ‘sub-sub-group’ of patients admitted with both multivessel disease and acute coronary syndrome. Considering these methodological limitations, the present results should be considered as hypothesis-generating, and more research is needed to explore the biological and clinical plausibility of these observations.”

Until now, aspirin has remained “the cornerstone of secondary prevention after PCI,” Collet et al conclude. “But for how long?”

“I don’t think we’ll ever get the definitive answer,” Fischman said. “You have to take [all the data] into perspective and use it to individualize your care of each patient.”

“Medicine is never finished,” Serruys said. “I've done a lot of trials in my life and every time that you go to a trial, you raise more questions. It's an endless process. I think as long as we go in the right direction, it's good.”