More GLOBAL LEADERS: No Benefit of Ticagrelor Monotherapy in New Analyses

SAN DIEGO, CA—New data from the GLOBAL LEADERS trial, a study that failed to demonstrate a benefit of ticagrelor monotherapy over conventional dual antiplatelet therapy, show that treatment with the more potent antiplatelet agent is not associated with an improvement in patient-oriented clinical outcomes. Nor is it associated with an improvement in net adverse cardiovascular and cerebrovascular events.

However, in a lone bright spot, Pascal Vranckx, MD, PhD (Hartcentrum Hasselt, Belgium), presented clinical outcomes data in patients with ACS and stable coronary artery disease and showed there was a reduction in BARC 3 or 5 bleeding at 2 years in patients with acute coronary syndromes treated with ticagrelor alone (RR 0.73; 95% 0.54-0.98). The reduction in bleeding with ticagrelor monotherapy in the ACS group was statistically significant in the first year (RR 0.64; 95% 0.46-0.90).

No such benefit was seen in the stable patients. Instead, the Kaplan-Meier major bleeding curves were “twisted around, such that the aspirin and clopidogrel are doing better than the ticagrelor,” said Vranckx. 

Overall, the GLOBALS LEADERS analysis showed there was no significant interaction by indication in terms of the all-cause mortality endpoint, or any clinical endpoints, with neither stable nor ACS patients benefiting from ticagrelor monotherapy.

Vranckx, who presented the data during a session devoted to GLOBAL LEADERS and other pharmacotherapy trials at TCT 2018, cautiously suggested that based on the safety, “ticagrelor as a single antiplatelet therapy in the first year after drug-eluting stent implantation in patients with acute coronary syndromes seems promising.” Given the trend toward higher rates of BARC 3 or 5 in patients with stable coronary artery disease, ticagrelor should not be used alone or in combination with another antiplatelet agent in this patient population, said Vranckx.

Neil Kleiman, MD (Houston Methodist Hospital, Texas), who chaired the morning session along with Dominick Angiolillo, MD (University of Florida, Gainesville), isn’t entirely certain what to make of the reduction in bleeding with ticagrelor monotherapy in patients with ACS. “To me it’s perplexing,” he told TCTMD. “To understand this, we need multivariable analyses. Maybe the ACS patients were older, had more comorbidities, or a lower body weight? Maybe they were on other drugs that predisposed them to bleeding. I don’t know those answers, but it is nice to see these types of things pop out [in the study]. It’s hypothesis-generating and needs to be explored in a big way.”

Patient-Oriented Clinical Outcomes

GLOBAL LEADERS included patients undergoing PCI with a biolimus A9-eluting stent (BioMatrix, Biosensors International) for ACS or stable coronary disease. In the trial, patients 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.

Presented last month at the European Society of Cardiology Congress, the study was designed with the hypothesis that ticagrelor might be a better foundation as a single drug for long-term antiplatelet therapy. Patrick Serruys, MD, PhD (Imperial College London, England), one of the principal investigators, said the goal was to avoid the higher risk of bleeding potentially associated with the addition of aspirin while maintaining potent antiplatelet therapy with ticagrelor.

The trial, however, failed to show any clinical advantage of ticagrelor monotherapy over conventional dual antiplatelet therapy. Treatment with ticagrelor monotherapy failed to lower the risk of all-cause mortality or new Q-wave MI at 2 years. There also was no reduction in BARC 3 or 5 major bleeding. Based on the results, several experts told TCTMD the trial was definitive and dual antiplatelet therapy should remain the default standard of care for patients undergoing PCI. 

Serruys presented new GLOBAL LEADERS data today TCT 2018, including the patient-oriented clinical endpoint that included all-cause mortality, any MI, any stroke, and any coronary revascularization. The net adverse cardiovascular and cerebrovascular events (NACCE) endpoint included the patient-oriented clinical endpoint plus BARC 3 or 5 major bleeding.

At 2 years, the patient-oriented clinical endpoint occurred in 13.16% of patients in the ticagrelor arm and 14.16% of patients in the reference treatment group, a nonsignificant difference. The rate of NACCE occurred in 14.35% of patients in the ticagrelor arm and 15.49% of patients in the reference group, a difference that trended toward benefit for ticagrelor but was not statistically significant (P = 0.057). Landmark analyses suggested there was no benefit with respect to the patient-oriented clinical event endpoint or NACCE in the first or second years of treatment.

Negative Study Viewed Positively by Some

Despite the negative results, some physicians still view GLOBAL LEADERS as a positive study, citing the lower rate of adherence with ticagrelor in the second year as one potential reason why the trial failed to show a benefit with ticagrelor monotherapy.

“In my mind, when I look at these data, I don’t make the conclusion that this is a negative study even though it missed its primary endpoint,” said Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY). “I think we as clinicians always want to know if it’s safe to take away aspirin and give a potent therapy and let that potent therapy do its job. And really, we care about that first year where those patients would remain compliant on that therapy.”

For his part, Kleiman pointed out there is a point in time where the PCI-treated patient transitions from unstable—fresh stent, disrupted tissue, and activated platelets, he said—to stable coronary artery disease. “We’ve never been sure when that is,” said Kleiman. “Maybe that occurs around 1 year, and I think that’s important because now we have to ask ourselves what are the new antithrombotic agents that have been studied stable coronary artery disease. These are lower-dose ticagrelor and low-dose rivaroxaban.”

Kleiman noted that the expected risk reduction in GLOBAL LEADERS was based on the PLATO trial, a study in ACS patients, but more than half of patients in GLOBAL LEADERS had stable coronary artery disease. Based on this modeling, the expected event reduction might have been too optimistic, said Kleiman. As for whether aspirin can or should be dropped following PCI, Kleiman cut right to the chase.

“Aspirin is basically free,” he said. “Unless things have changed this morning, ticagrelor is not. How much better than aspirin does ticagrelor have to be?” To TCTMD, Kleiman said the question of dual antiplatelet therapy versus antiplatelet monotherapy has been discussed for nearly two decades, and yet nobody can really say which single antiplatelet agent should be used.