Ticagrelor Alone After PCI: A Strategy Gaining Momentum

April 02, 2019

NEW ORLEANS — Further data supporting the approach of giving only a short period of dual antiplatelet therapy after stenting then continuing long-term on a P2Y12 inhibitor alone has come from a new subgroup analysis of the GLOBAL LEADERS trial.

In the main analysis of GLOBAL LEADERS, presented and published last August, ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months narrowly missed showing superiority to standard 1-year dual antiplatelet therapy followed by 1 year of aspirin monotherapy in terms of the primary end point of all-cause mortality or new Q-wave myocardial infarction at 2 years. Major bleeding was similar between the two groups.

The current analysis, known as GLASSY (GLOBAL LEADERS Adjudication SubStudY), was a prespecified substudy of the main trial involving 7585 patients (about half of those in the main trial) in whom all ischemic and bleeding events were adjudicated.

The main result of GLASSY shows noninferiority of the ticagrelor monotherapy approach to standard treatment for the composite ischemic end point of death, myocardial infarction, stroke, and urgent target vessel revascularization at 2 years. Bleeding rates were identical in the two groups.

"So the study opens a new paradigm of treatment: a very short duration of dual antiplatelet therapy followed by discontinuation of aspirin but continuation with ticagrelor," lead author Marco Valgimigli, MD, University of Bern, Switzerland, told theheart.org | Medscape Cardiology.

Valgimigli presented the GLASSY data at the recent American College of Cardiology 68th Annual Scientific Session (ACC.19).

He explained that all clinical end points in the GLOBAL LEADERS study were investigator reported without central adjudication.

"The GLASSY substudy was therefore designed to prospectively implement an independent central adjudication process of both reported events and potential unreported event triggers to further assess the impact of this novel experimental treatment in a large stratified sample of patients included in the GLOBAL LEADERS trial," he reported.

The coprimary efficacy end point in GLASSY was a composite of death, myocardial infarction, stroke, and urgent target vessel revascularisation at 2 years. The coprimary safety end point was BARC 3 or 5 bleeding.

"We prespecified to test first the noninferiority of the coprimary efficacy end point and, if met, the superiority of the experimental versus control treatment and independently the superiority of the experimental treatment on the safety end point," Valgimigli noted.

Results showed that ticagrelor alone after 1 month of dual antiplatelet therapy was noninferior to dual antiplatelet therapy for 1 year followed by aspirin alone.

At 2 years, the primary efficacy end point had occurred in 7.1% of the ticagrelor monotherapy group and in 8.4% in the dual antiplatelet/aspirin monotherapy group (RR, 0.85; 95% CI, 0.72 - 0.99; P noninferiority < .001).

However, the experimental regimen failed to show superiority at the prespecified level of 0.025 (P = .0465).

Valgimigli explained that although the P value was nominally significant (less than 5%), they set the significance level at 2.5% because they had two primary end points.

BARC 3 or 5 bleeding events were identical in the two study groups (2.5% vs 2.5%; RR, 1.00; 95% CI, 0.75 - 1.33; P = .99).

Results at 1 year (basically a comparison of ticagrelor monotherapy and dual antiplatelet therapy) showed very similar rates of MI and stent thrombosis in the two groups, Valgimigli reported.

"There was no signal that aspirin removal was exposing patients to higher ischemic risks."

"But when looking into the second year of follow-up (i.e., comparing ticagrelor monotherapy with aspirin monotherapy), we saw that ticagrelor reduced the risks of MI by more than 40%, stent thrombosis by more than 80%, and also the composite of cardiovascular death or MI," he noted.

Valgimigli commented: "GLASSY is the first and the biggest study today based on adjudicated end points showing that aspirin can be safely discontinued as early as 1 month after PCI. There is no penalty to pay for ischemic events, compared to standard 1-year dual antiplatelet therapy, and long term, we have data suggesting that having ticagrelor on board is more protective for ischemic events than aspirin, without increasing the bleeding risk."

Noting that ticagrelor is licensed only for ACS patients, he suggested this new treatment paradigm is more applicable to ACS patients than to those with stable heart disease undergoing stenting.

"This is an interesting analysis that adjudicates events after the completion and initial reporting of the GLOBAL LEADERS trial results," said Deepak Bhatt, MD, Brigham and Women's Hospital, Boston. "Adjudication can add precision to the ascertainment of clinical end points and thereby allow detection of an efficacy or safety signal that would otherwise be missed. When done in a blinded fashion, it should produce an unbiased assessment of a drug's effect."

"This analysis provides some further signals (beyond the main trial results) that ticagrelor monotherapy (that is, dropping aspirin after a month) might be a viable strategy," he told theheart.org | Medscape Cardiology.

These results are also consistent with two other clinical trials from Asia (STOPDAPT2 and SMARTCHOICE) presented at ACC.19, which showed promising results with P2Y12 inhibitor monotherapy after 1 or 3 months of dual antiplatelet therapy after stenting.

An American trial, TWILIGHT, is now underway to investigate this approach.

"I think the results of the ongoing TWILIGHT trial should help to determine if this strategy of dropping aspirin after an initial short period of dual antiplatelet therapy is the way to go or not," Bhatt said.

GLOBAL LEADERS/GLASSY was an investigator-initiated trial sponsored by the European Clinical Research Institute, which received funding from Biosensors International, AstraZeneca, and the Medicines Company. Valgimigli reports personal fees from Astrazeneca and Biosensors.

American College of Cardiology (ACC) 68th Annual Scientific Session: Session 408. Presented March 17, 2019.

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