GLOBAL LEADERS: Ticagrelor Monotherapy Fails to Beat Conventional DAPT After PCI

MUNICH, Germany—Dropping aspirin after 1 month and continuing monotherapy with ticagrelor is no better than standard dual antiplatelet therapy (aspirin plus ticagrelor or clopidogrel) among patients undergoing PCI for ACS or stable coronary artery disease, according to the results of the GLOBAL LEADERS study.

Presenting the results today at a late-breaking clinical trials session at the European Society of Cardiology (ESC) Congress 2018, Patrick Serruys, MD, PhD (Erasmus Medical Center, Rotterdam, the Netherlands), said ticagrelor (Brilinta, AstraZeneca) is a potent and consistent antiplatelet agent and the hypothesis had been that it might be a better agent as monotherapy for long-term use compared with aspirin.

“We tried to avoid the higher risk of bleeding potentially associated with adding aspirin, even low-dose aspirin, to ticagrelor,” said Serruys. “And we tried to maintain the clinical benefit of potent platelet inhibition after PCI beyond the initial period of high stent thrombosis risk in the first 30 days. At the time, we believed the trial might pave the way for ticagrelor as a single foundation therapy.”

Stephan Windecker, MD (University of Bern, Switzerland), one of the study investigators, said the results were disappointing.

“Whenever you have a study that isn’t positive, there is a level of disappointment,” he told TCTMD. “I would nevertheless say that the study just missed the target. If you look at the hazard ratio and the P value, if we had included more patients, we would have met the target. One of the constraints was sample size. We included 16,000 patients and had we enough funding we would have included up to 20,000 patients. That’s one explanation why we failed to have a positive study.”

For Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), GLOBAL LEADERS, a pragmatic trial with a complex design, tested a sound hypothesis, but its negative results were quite clear.

“The trial provided a pretty definitive answer. It might not have been the one the investigators were hoping for, but is nonetheless informative,” Bhatt told TCTMD. “We shouldn’t change our standard of care. Dual antiplatelet therapy for a period of at least several months after stenting—and at least a year after an ACS—remains the standard of care. Though it’s an appealing concept to drop aspirin and continue ticagrelor, it’s not superior to what we’re doing right now.”

ACS and Stable CAD Patients    

The GLOBAL LEADERS trial, which is published simultaneously in the Lancet, was an open-label, superiority trial conducted at 130 sites in 18 countries. Patients undergoing PCI with a biolimus A9-eluting stent (BioMatrix, Biosensors International) for ACS or stable coronary disease were randomized to 75-100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month followed by ticagrelor monotherapy for 23 months or to dual antiplatelet therapy with either 75 mg clopidogrel (for stable coronary artery disease) or 90 mg ticagrelor twice daily (for ACS) for 12 months followed by aspirin monotherapy for 12 months.

Among the 15,968 participants randomized into the trial, the primary endpoint—a composite of all-cause mortality or nonfatal Q-wave MI—occurred in 3.81% of participants treated with aspirin for 1 month followed by ticagrelor alone for 23 months and 4.37% of patients randomized to standard dual antiplatelet therapy with clopidogrel/ticagrelor for 12 months followed by aspirin monotherapy for 12 months (P = 0.073).

In assessing an expanded endpoint that included all-cause mortality, new Q-wave MI, definite stent thrombosis, or investigator-reported BARC 3 or 5 major bleeding, there was no difference between the two treatment arms. All-cause mortality did not differ between groups. Additionally, there was no difference in the treatment effect for the primary endpoint across the prespecified subgroups of ACS and stable coronary artery disease.

In terms of safety, BARC 3 or 5 major bleeding occurred in 2.04% of patients treated with aspirin for 1 month and extended ticagrelor and 2.12% of patients treated with conventional dual antiplatelet therapy (P = 0.77).

Did Adherence Affect the Results?

Adherence in the second year of treatment was just 78% among patients randomized to ticagrelor monotherapy, while 93% treated with aspirin in the conventional dual antiplatelet arm were adherent to treatment. For Serruys, GLOBAL LEADERS suggests that stopping aspirin after 1 month and continuing with ticagrelor monotherapy is “feasible and safe,” as well as potentially efficacious.

“In the second year, the lack of adherence to the experimental strategy may have compromised the assessment of superiority,” said Serruys. Had the trial been stopped at 1 year, GLOBAL LEADERS would have been a highly positive trial, he added.

Adnan Kastrati, MD (Deutsches Herzzentrum, Munich, Germany), who discussed the trial during the late-breaking trial session, pointed out there isn’t much that can be done about nonadherence given that its largely caused by the patients feeling uncomfortable on the drug. The reduction in drug adherence in the second year of GLOBAL LEADERS is “unlikely to have driven a reduction in the treatment effect of ticagrelor during this period,” said Kastrati.

In his presentation, though, Kastrati pooled several studies together—PLATO, PEGASUS, and GLOBAL LEADERS, among others—and suggested there is no increased risk of bleeding with ticagrelor, although there was large heterogeneity among the trials. Pooling trials of patients with coronary artery disease also hinted at a reduction of all-cause mortality with ticagrelor, which may be driven by a reduction in MI.

Freek Verheugt, MD (Hartcentrum OLVG, Amsterdam, the Netherlands), who was not involved in the study, said the GLOBAL LEADERS trial disappointed from a statistical perspective, “but my personal feeling is that ticagrelor can be used.”

Speaking with TCTMD, he said that if he designed the trial, he would have stopped aspirin after PCI—and started ticagrelor monotherapy immediately—and performed a 1-year study to minimize the risks of bleeding. When aspirin was stopped immediately in PIONEER-AF and WOEST, there was a significant benefit in terms of bleeding, said Verheugt.

Serruys, for his part, wasn’t sold on the explanation, noting that landmark analyses suggested no signal of increased bleeding with 1-month aspirin and extended ticagrelor monotherapy in the first year. Windecker told TCTMD they had considered stopping aspirin after the procedure, but the data safety and monitoring board recommended at least 1 month of aspirin with ticagrelor to reduce the risk of stent thrombosis.

TWILIGHT to Address Similar Question

Bhatt, who wrote an editorial accompanying the study, said optimal antiplatelet therapy after PCI remains far from a settled question. “It still might be the case that a more potent antiplatelet monotherapy, such as with ticagrelor, is the way to go after a period of initial dual antiplatelet therapy,” he told TCTMD. “That strategy is being tested in the ongoing TWILIGHT trial.”

In TWILIGHT, which is being led by Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), and will include approximately 9,000 patients, investigators are testing a strategy of ticagrelor monotherapy versus dual antiplatelet therapy with aspirin and ticagrelor. Patients will be switched to ticagrelor monotherapy after completing a 3-month course of ticagrelor and aspirin.

“Unless TWILIGHT comes out positive, I certainly wouldn’t adopt the strategy of ticagrelor monotherapy,” said Bhatt. “And on a practical level—this is point I made in the editorial—ticagrelor is more expensive than aspirin, it’s twice per day, adherence is lower, and side effects, such as dyspnea, are higher. Even though there are some intriguing signals in GLOBAL LEADERS, and some trends that are interesting and biologically plausible, I wouldn’t act on it.”

Like Bhatt, many in the ESC audience remained unconvinced by the new data, with a postpresentation poll showing that the majority will not be changing their current clinical practice based on the study results.