Elsevier

The Lancet

Volume 392, Issue 10151, 15–21 September 2018, Pages 940-949
The Lancet

Articles
Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial

https://doi.org/10.1016/S0140-6736(18)31858-0Get rights and content

Summary

Background

We hypothesised that ticagrelor, in combination with aspirin for 1 month, followed by ticagrelor alone, improves outcomes after percutaneous coronary intervention compared with standard antiplatelet regimens.

Methods

GLOBAL LEADERS was a randomised, open-label superiority trial at 130 sites in 18 countries. Patients undergoing percutaneous coronary intervention with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes were randomly assigned (1:1) to 75–100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy, or standard dual antiplatelet therapy with 75–100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable coronary artery disease) or 90 mg ticagrelor twice daily (for patients with acute coronary syndromes) for 12 months, followed by aspirin monotherapy for 12 months. Randomisation was concealed, stratified by centre and clinical presentation (stable coronary artery disease vs acute coronary syndrome), and blocked, with randomly varied block sizes of two and four. The primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction as assessed by a core lab in a blinded manner. The key secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01813435, and is closed to new participants, with follow-up completed.

Findings

Between July 1, 2013, and Nov 9, 2015, 15 968 participants were randomly assigned, 7980 to the experimental group and 7988 to the control group. At 2 years, 304 (3·81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4·37%) participants in the control group (rate ratio 0·87 [95% CI 0·75–1·01]; p=0·073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p=0·93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2·04% vs 2·12%; rate ratio 0·97 [95% CI 0·78–1·20]; p=0·77).

Interpretation

Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction 2 years after percutaneous coronary intervention.

Funding

AstraZeneca, Biosensors, and The Medicines Company.

Introduction

Dual antiplatelet therapy reduces the risk of stent-related and spontaneous recurrent ischaemic events among patients with acute coronary syndromes or stable coronary artery disease undergoing percutaneous coronary intervention.1, 2, 3, 4 However, dual antiplatelet therapy increases the risk of bleeding, which could offset the anticipated benefits of a reduction in ischaemic events.1, 2, 3, 5 An abbreviated dual antiplatelet therapy regimen followed by P2Y12-receptor-antagonist monotherapy could favourably affect the balance between bleeding risks and ischaemic benefits.6

Ticagrelor is a reversible and direct-acting oral antagonist of the P2Y12 receptor that provides faster, greater, and more consistent platelet inhibition than clopidogrel.7 In the PLATO trial, treatment with ticagrelor as compared with clopidogrel (both given in combination with aspirin) significantly reduced the rate of major adverse cardiac events and all-cause mortality.7 It has been suggested by Mahaffey and colleagues8 that a daily aspirin dose of 150 mg or higher could attenuate the therapeutic effect of ticagrelor. We hypothesised that the use of ticagrelor without concomitant aspirin could preserve ischaemic protection while potentially avoiding bleeding complications.

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.

The GLOBAL LEADERS trial was designed to compare the benefits and risks of 2 years of treatment with 90 mg ticagrelor twice daily (in combination with aspirin for the first month) with conventional 1-year dual antiplatelet therapy followed by aspirin alone in patients undergoing percutaneous coronary intervention with uniform use of an intravenous direct thrombin inhibitor and biodegradable polymer biolimus-eluting stents.9

Section snippets

Study design and participants

GLOBAL LEADERS was an open-label, randomised superiority trial done at 130 sites in 18 countries, the design of which was described previously (appendix).9 The study population consisted of patients scheduled to undergo percutaneous coronary intervention for stable coronary artery disease or acute coronary syndromes who required dual antiplatelet therapy, unless oral anticoagulation was indicated.9 The full inclusion and exclusion criteria are in the appendix. The trial was approved by the

Results

Between July 1, 2013, and Nov 9, 2015, we recruited and randomly assigned 15 991 participants, but 23 patients subsequently withdrew consent and requested deletion of their data from the database. Thus, 15 968 patients remained, 7980 in the experimental group and 7988 in the control group (figure 1). 7782 patients (97·5%) in the experimental group and 7767 (97·2%) in the control group received the allocated treatment regimen. Baseline clinical and procedural characteristics were well matched

Discussion

In our multicentre randomised trial, ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to standard 1-year dual antiplatelet therapy followed by aspirin monotherapy in terms of the composite endpoint of all-cause mortality or new Q-wave myocardial infarction after percutaneous coronary intervention. When the components of the primary endpoint were individually analysed, they did not differ significantly between groups. Rates of

Data sharing

GLOBAL LEADERS trial is an investigator-initiated trial. Multiple substudies are predefined. Internal investigators, who actively participated in the study, and who provide a methodologically sound study proposal will be granted priority access to the study data for 60 months. After 60 months, this option might be extended to external investigators not affiliated to the trial, whose proposed use of the data has been approved by an independent review committee identified by the steering

References (29)

  • D Capodanno et al.

    Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention

    Nat Rev Cardiol

    (2018)
  • M Valgimigli et al.

    Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial

    Circulation

    (2012)
  • G Gargiulo et al.

    A critical appraisal of aspirin in secondary prevention: is less more?

    Circulation

    (2016)
  • L Wallentin et al.

    Ticagrelor versus clopidogrel in patients with acute coronary syndromes

    N Engl J Med

    (2009)
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