Long-term Ticagrelor Monotherapy May Have an Edge in Complex PCI Patients: GLOBAL LEADERS
This post hoc analysis of what was a negative trial should be considered hypothesis-generating, experts agreed.
PARIS, France—Patients undergoing complex PCI treated with ticagrelor (Brilinta; AstraZeneca) monotherapy following 1 month of dual antiplatelet therapy fared significantly better at 2 years when compared with patients treated with conventional dual antiplatelet therapy, according to a new, post hoc analysis of the GLOBAL LEADERS trial.
That finding is at odds with the main results, reported by TCTMD, showing no significant difference in the primary endpoint—a composite of all-cause mortality or nonfatal new Q-wave MI at 24 months—between the two treatment approaches.
In this new analysis, focused on the most complex patients, dropping aspirin after 1 month and continuing with ticagrelor monotherapy for 23 months was associated with a significant 36% lower relative risk of death and nonfatal new Q-wave MI compared with clopidogrel/ticagrelor for 1 year followed by aspirin alone for 12 months. In contrast, there was no benefit of long-term ticagrelor monotherapy over standard dual antiplatelet therapy in patients who underwent noncomplex PCI.
“Complex PCI favored ticagrelor monotherapy,” said lead investigator Patrick Serruys, MD, PhD (Erasmus Medical Center, Rotterdam, the Netherlands), during a media briefing at EuroPCR 2019. “Why is this important? Patients who undergo complex PCI have a high risk for ischemic events at 2 years compared with the noncomplex PCI group.”
The GLOBAL LEADERS trial 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 to 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.
In the new analysis, Serruys and colleagues investigated the impact of the two treatment strategies in 4,570 patients undergoing complex PCI, which was defined as diffuse multivessel disease, treatment of three or more lesions, interventions requiring three or more stents, bifurcations treated with two or more stents, and total stent lengths exceeding 60 mm. These features are among those included in the 2018 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines for myocardial revascularization that place patients at high risk for ischemic events.
Among the complex patients, there was a significant reduction in the risk of the primary endpoint with ticagrelor monotherapy in the complex PCI group, but not in those undergoing noncomplex PCI. “It’s also pleasant to see that we have P value for interaction—demonstrating the treatment effect—of 0.015,” said Serruys. “The two components [of the primary endpoint], all-cause mortality and new Q-wave MI, also show a 33% and 47% risk reduction with ticagrelor but failed to achieve [significance] for interaction.”
In addition, there was a significant 20% reduction in the relative risk of patient-oriented composite events (POCE)—defined as all-cause mortality, all stroke, all MI, and all revascularization—in the complex patients treated with ticagrelor monotherapy, but no benefit in the noncomplex PCI group (P = 0.017 for interaction). The risk of bleeding with ticagrelor monotherapy was no higher than conventional dual antiplatelet therapy in the complex and noncomplex PCI patients. Net adverse clinical events—defined as POCE plus BARC type 3 or 5 bleeding—also favored ticagrelor monotherapy in the complex patients, but not in the noncomplex patients (P = 0.011 for interaction).
The benefit of long-term ticagrelor monotherapy was greater as the number of high-risk features increased in the complex PCI patients, noted Serruys.
As for how to interpret the positive results of a substudy of complex PCI patients, especially given that the main trial showed no overall treatment benefit with long-term ticagrelor monotherapy, Serruys said he was “happy to see, at least in these complicated patients, it works quite well.” Adherence to ticagrelor monotherapy in the second year of treatment likely impacted the overall trial results, he told TCTMD, noting that adherence was just 78% among patients randomized to ticagrelor monotherapy and 93% among those in the conventional dual antiplatelet arm. Moreover, at 12 months, there was a statistically significant difference between the two treatment arms favoring ticagrelor monotherapy, he added.
Despite these arguments, Andreas Baumbach, MD (Queen Mary University of London and Barts Heart Center, London, England), who moderated the press conference, said he does not believe these latest results are sufficient to alter physician behavior or to change clinical guidelines. “Overall, GLOBAL LEADERS was sadly seen as a negative trial, so it didn’t change clinical practice,” he told TCTMD. “The idea is obviously a great one, but it didn’t work out. In this complex PCI cohort, it worked, but this is hypothesis-generating, although it makes sense to have more powerful prevention in these complex patients.”
Simon Redwood, MBBS (King’s College London, England), agreed, also calling the results interesting but only useful in generating further studies. “The problem is it’s only one stent,” he told TCTMD, referring to the biolimus A9-eluting stent used in the trial, a device not available in the United States. “We need to know if this is applicable to other stents as well.
Peter Jüni, MD (St. Michael’s Hospital, Toronto, Canada), one of the GLOBAL LEADERS investigators, likened negative trials to failed marriages. “In hindsight, you look back and connect the dots, and it makes perfect sense why the marriage failed,” he said. For this subgroup analysis, which wasn’t prespecified, one major question is whether the results showing a benefit of ticagrelor monotherapy in complex PCI is biologically plausible, which he believes it is.
Like Baumbach and Redwood, however, Jüni stressed that these latest findings need to be validated by additional research and physicians should wait before changing their approach to antiplatelet therapy in complex PCI.
Nonetheless, Serruys believes these new findings from GLOBAL LEADERS could gain further support if the TWILIGHT trial is positive. That study, which is expected to be completed later this year, will include approximately 9,000 patients as investigators test 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.
Serruys PW. Effect of ticagrelor monotherapy for 23 months following 1-month DAPT vs. standard DAPT for 12 months followed by 12 months of aspirin monotherapy in patients undergoing complex PCI. Presented at: EuroPCR 2019. May 21, 2019. Paris, France.
- Serruys reports receiving grant/research support and/or consulting fees/honoraria from Abbott, Biosensors, Medtronic, Philips/Volcano, Sinomedical Sciences Technology, SMT, and Xeltis.