Ticagrelor Monotherapy Noninferior to DAPT After PCI in Adjudicated-Events Analysis: GLASSY

NEW ORLEANS, LA—Using an independent clinical endpoint committee (CEC) to adjudicate event rates in the GLOBAL LEADERS trial, investigators have found that ticagrelor monotherapy after 1 month of dual antiplatelet therapy (DAPT) was noninferior to conventional DAPT therapy for the prevention of all-cause death, nonfatal MI, nonfatal stroke, or urgent target-vessel revascularization at 2 years in this large, provocative trial.

In GLASSY, a prespecified substudy of GLOBAL LEADERS that depended on CEC-adjudicated events rather than the investigator-reported events used in the main trial, the ticagrelor monotherapy strategy was also noninferior to standard DAPT for major bleeding, but failed to demonstrate superiority—a hoped-for benefit of dropping aspirin in these high-risk patients.

As previously reported by TCTMD, the GLOBAL LEADERS trial enrolled nearly 16,000 patients from 130 sites worldwide and concluded that dropping aspirin after 1 month and continuing with ticagrelor alone was no better than standard DAPT (aspirin plus ticagrelor or clopidogrel) among patients undergoing PCI for ACS or stable coronary artery disease.

Presenting the GLASSY findings last week in a featured clinical research session at the American College of Cardiology (ACC) 2019 Scientific Session, Marco Valgimigli, MD, PhD (Swiss Cardiovascular Center Bern, Switzerland), explained that by adding an independent central adjudication process for both reported events and potential unreported events, this “trial in trial” would be able to more accurately assess the effect of ticagrelor monotherapy in this patient group.

“Our results provide new evidence that discontinuation of aspirin while continuing ticagrelor alone does not expose patients to higher ischemic risk as compared to the standard DAPT for 1 year, and actually may reduce the rates of MI and stent thrombosis as compared to aspirin alone,” he said.

Looking Through GLASSY

For the study, researchers took 7,585 patients from the 20 top enrolling sites in GLOBAL LEADERS and conducted a thorough adjudication of all investigator-reported events as well as “endpoint triggers”—typically additional events picked up by the core lab or from electronic case reports. Importantly, Valgimigli noted that treatment effects were consistent with respect to the primary efficacy and key safety endpoints of GLOBAL LEADERS for GLASSY versus non-GLASSY patients.

In GLASSY, the ticagrelor monotherapy strategy reduced the CEC-adjudicated, primary composite efficacy endpoint of all-cause death, MI, stroke, and urgent TVR compared with conventional DAPT (7.14% vs 8.41%; RR 0.85; 95% CI 0.72-0.99; P < 0.001 for noninferiority). At 2 years, ticagrelor monotherapy did not affect the individual rates of death, cardiac death, cardiac death or MI, MI, stroke, or definite stent thrombosis compared with standard DAPT, but it did reduce the risk of urgent TVR (1.87% vs 2.72%; RR 0.69; 95% CI 0.51-0.93).

A landmark analysis across a range of endpoints showed no signal that dropping aspirin after 30 days exposed patients to a higher ischemic risk within 1 year, Valgimigli reported. After 1 year, there were indications that patients in the experimental arm benefited more in terms of MI (P for interaction = 0.062) and definite stent thrombosis (P for interaction = 0.007).

The ticagrelor monotherapy strategy failed to demonstrate a reduction in the primary safety endpoint (BARC 3 or 5 bleeding), which was observed in 2.46% of patients in both treatment cohorts. Digging into these data, Valgimigli and colleagues saw a trend toward an excess of bleeding complications within the first 30 days associated with the experimental treatment, but this was flipped after 1 month (P for interaction = 0.043). There was no difference observed in bleeding between the ticagrelor monotherapy and conventional groups in a landmark analysis at 1 year.

DAPT and Adjudication

In a panel discussion following the presentation, Eric Peterson, MD (Duke University School of Medicine, Durham, NC), congratulated the investigators for “taking on two of the toughest issues in cardiology,” namely dual antiplatelet therapy and adverse-event adjudication within clinical trials. “This study actually mixes both of those issues up in a very interesting fashion,” he said.

Peterson noted that the GLASSY researchers found a somewhat different result than what was seen in GLOBAL LEADERS, “despite the fact that you were looking at only about half the patients.” He asked: “Was it the sites that you engaged, the patients you engaged, or the method of adjudication?”

“It's an interplay of multiple factors,” Valgimigli replied. “[First], by selecting these 20 sites, we slightly enriched the population with ischemic risk.” Compared with GLOBAL LEADERS patients not selected for this substudy, GLASSY patients had more peripheral vascular disease, were more often smokers, and had more unstable CAD. As to how event adjudication would affect the outcomes, “we are still in a preliminary stage to be able to answer that question properly, but we did analyze the results with respect to adjudicated versus investigator-reported endpoints [using a] time frame from 0 to 2 years. What I can say is that if you look at the treatment effect, this is pretty much consistent across the board.”

But there are two important exceptions that might help explain why GLASSY found success where GLOBAL LEADERS did not. “One is MI and the other one is bleeding. For MI, what we have seen that investigators tend to over-report MI as compared to the CEC-adjudicated events and that has resulted in a slight dilution of treatment effect. On the other side for BARC 2 bleeding, the investigators tended to downgrade, down-report the event rate,” Valgimigli noted.

As for the GLASSY analysis itself, Peterson told TCTMD he thought it was “reasonable,” especially given that it was prespecified. “There were a lot of things they hoped to find in the study—superiority on the bleeding, at least noninferiority on the initial part and maybe that they would get superiority overall because they would start to win in the second half of the study, but they didn't find that.”

At this time, the GLASSY results should not change practice, Peterson said. “The decision of 1 month versus 1 year seems to be a little bit of a dealer's choice still based on these studies,” he said, noting that the big remaining question for him is whether there were any differences between the adjudicated and nonadjudicated events in the study. Valgimigli confirmed those results are forthcoming.

“This will be a paper that we'll really need to read more closely once it comes out in press,” Peterson said.