Research in context
Evidence before this study
We searched PubMed and ISI Web of Science with the terms ((“All-comer patients” OR, “all-comers”) AND “percutaneous coronary intervention”) OR ((ticagrelor OR clopidogrel OR antiplatelet OR aspirin) AND “secondary prevention”)) for reports published in English before July 1, 2018, of all-comers percutaneous coronary intervention trials and comparative effectiveness studies in which an established antiplatelet strategy was compared with a ticagrelor-based strategy (appendix). We did not find any randomised long-term outcome trials comparing standard dual antiplatelet therapy with an experimental ticagrelor regimen or any other potent P2Y12 receptor antagonist without aspirin in patients after implantation of a drug-eluting stent. We identified four randomised large outcome trials of ticagrelor alone or in combination with aspirin across a wide range of cardiovascular indications, with follow-up ranging from 90 days to 3 years. In PLATO, clopidogrel plus aspirin was compared with ticagrelor plus aspirin in 18 624 patients with acute coronary syndromes, with or without ST-segment elevation. The primary endpoint, a composite of death from cardiovascular causes or cerebrovascular causes or any death without another known cause, occurred significantly less often in the ticagrelor group than in the clopidogrel group (9·8% vs 11·7% at 12 months; hazard ratio [HR] 0·84 [95% CI 0·77–0·92]; p<0·001). The overall risk of major bleeding did not differ significantly between groups, but bleeding associated with non-coronary artery bypass grafting was significantly more common in the ticagrelor group than in the clopidogrel group at 12 months (4·5% vs 3·8%; p=0·03). In PEGASUS-TIMI 54, two doses of ticagrelor (60 mg and 90 mg) were compared with aspirin in 21 162 high-risk patients (eg, patients with diabetes, renal disease, multivessel disease, or recurrent myocardial infarction) who had a myocardial infarction at least 1 year before the trial. Compared with placebo, both doses of ticagrelor were associated with at least a 15% decrease in the frequency of the primary endpoint of death from cardiovascular causes, myocardial infarction, or stroke (p=0·008 for the 90 mg dose and p=0·004 for the 60 mg dose). However, ticagrelor treatment also increased the frequency of clinically significant bleeding complications by a factor of 2·3–2·7 (p<0·001 for each dose vs placebo). In EUCLID, a trial of 13 885 patients with symptomatic peripheral artery disease, ticagrelor monotherapy was not superior to clopidogrel monotherapy for the reduction of cardiovascular events—a composite of cardiovascular death, myocardial infarction, or ischaemic stroke (10·8% vs 10·6%; HR 1·02 [95% CI 0·92–1·13]; p=0·65). Major bleeding occurred at a similar frequency in both groups (HR 1·10 [95% CI 0·84–1·43]; p=0·49). In the SOCRATES trial of 13 199 patients with a non-severe ischaemic stroke or high-risk transient ischaemic attack who had not received intravenous or intra-arterial thrombolysis and were not judged to have had a cardioembolic stroke, ticagrelor was not superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. Again, the frequency of major bleeding occurred was similar in the two treatment groups (HR 0·83 [95% CI 0·52–1·44]). Other trials investigating an aspirin-free strategy in patients not on oral anticoagulants include GEMINI-ACS-1 and COMPASS, in which aspirin was replaced with a direct factor Xa inhibitor rather than a potent P2Y12 inhibitor.
Added value of this study
To our knowledge, GLOBAL LEADERS is the largest trial so far of 1 month of dual antiplatelet therapy with aspirin and ticagrelor followed by ticagrelor monotherapy versus a standard dual antiplatelet regimen after implantation of a drug-eluting stent. The sole use of ticagrelor, a P2Y12 receptor antagonist, as an antiplatelet regimen rather than aspirin after cessation of dual anti-platelet therapy was a unique aspect of the study. GLOBAL LEADERS is the only randomised trial so far in which randomisation was done at percutaneous coronary intervention and in which two antiplatelet strategies were compared, with up to 2 years of follow-up.
Implications of all the available evidence
Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone was not superior to 1 year of standard dual antiplatelet therapy followed by aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction at 2 years after percutaneous coronary intervention. The frequency of major bleeding according to the Bleeding Academic Research Consortium criteria was similar between groups. Overall, our data do not support a change to standard clinical practice.