Extended ticagrelor monotherapy after PCI not superior to standard DAPT
Extending ticagrelor therapy to 2 years with aspirin given for only 1 month after percutaneous coronary intervention (PCI) is not superior to standard treatment, according to results of the GLOBAL LEADERS trial reported at the European Society of Cardiology (ESC) Congress 2018.
In the open-label superiority trial, 15,991 patients scheduled to undergo PCI with a drug-eluting stent for stable coronary artery disease (SCAD) or acute coronary syndromes (ACS) were randomized in a 1:1 ratio to receive an experimental regimen of aspirin (75–100 mg/day) plus ticagrelor (90 mg BID) for 1 month followed by ticagrelor monotherapy for 23 months, or standard dual antiplatelet therapy (DAPT) with aspirin (75–100 mg/day) plus ticagrelor (90 mg BID; for ACS patients) or clopidogrel (75 mg/day; for SCAD patients) for 12 months followed by aspirin monotherapy for 12 months. [Lancet 2018, doi: 10.1016/S0140-6736(18)31858-0]
The primary outcome of all-cause mortality or nonfatal new Q-wave MI at 2 years occurred in 3.81 percent of patients in the experimental arm vs 4.37 percent of patients in the reference arm. The 13 percent reduction with the experimental regimen (risk ratio [RR], 0.87; 95 percent confidence interval [CI], 0.75 to 1.01; p=0.73) did not reach statistical significance, although a significant reduction in this endpoint was seen with the experimental regimen at 1 year (1.95 percent vs 2.47 percent; RR, 0.79; 95 percent CI, 0.64 to 0.98; p=0.028).
“There was no evidence for a difference in treatment effects for the primary endpoint across the prespecified subgroups of patients stratified by indication [ACS or SCAD], age [> or ≤75 years], diabetes mellitus, renal failure, peripheral vascular disease, treatment of left main coronary artery lesion, and geographic area,” reported investigator Professor Patrick Serruys of the Erasmus University, Rotterdam, the Netherlands. “However, the RR for patients above 75 years of age and those from Western Europe was 0.75 and 0.83, respectively, with a 95 percent CI just below 1 [0.58 to 0.99 and 0.69 to 0.99, respectively].”
In terms of safety, grade 3 or 5 bleeding (based on the Bleeding Academic Research Consortium [BARC] criteria) occurred in 1.47 percent of patients in the experimental arm vs 1.7 percent of those in the reference arm at 1 year (RR, 0.86; 95 percent CI, 0.67 to 1.11; p=0.243). At 2 years, the rate was 2.04 percent vs 2.12 percent (RR, 0.97; 95 percent CI, 0.78 to 1.20; p=0.77).
Importantly, adherence to the experimental regimen showed a continuous decrease throughout the trial, dropping from 98 percent at discharge to 82 percent at 1 year and 78 percent at 2 years. In contrast, adherence to the reference regimen was 97 percent at discharge, 89 percent at 1 year, and 93 percent at 2 years.
“Lack of adherence to the experimental regimen in the second year of follow-up might have compromised the assessment of superiority,” Serruys noted. “Further per-protocol analysis will be performed to adjust for the difference in treatment adherence between the two arms.”
“Drug nonherence is difficult to prevent because it is mostly related to patients feeling uncomfortable with the drug. However, the small further reduction in drug adherence during the second year of the trial is unlikely to have driven the reduction in treatment effect of ticagrelor during this period,” said discussant Dr Adnan Kastrati of the German Centre for Cardiovascular Research, Munich, Germany. “The most appropriate interpretation in this regard is that the trial results were achieved despite inferior drug adherence in the experimental arm.”“Although GLOBAL LEADERS is a formally negative trial, it may have a positive impact on the overall value of ticagrelor therapy in patients with CAD undergoing PCI,” he continued. “Questions now to be answered are whether 1 month of aspirin is absolutely needed after PCI in patients who are on ticagrelor, whether all patients need the same 90 mg dose of ticagrelor after PCI, and whether all patients should be treated with ticagrelor beyond 1 year after PCI.”