Impact of long-term ticagrelor monotherapy following 1-month dual antiplatelet therapy in patients who underwent complex percutaneous coronary intervention: insights from the Global Leaders trial

Selected in the European Heart Journal by J. Bil , D. Milasinovic

GLOBAL LEADERS was a randomized, open-label, superiority trial in patients who underwent PCI with a biolimus A9-eluting stent for stable CAD or ACS...

Reviewers

Jacek Bil

Interventional cardiologist / Cardiologist

Centre of Postgraduate Medical Education - Warsaw, Poland

Dejan Milasinovic

@MilasinD18

Interventional cardiologist / Cardiologist

Clinical Centre of Serbia - Belgrade, Serbia

Our Comment

This joint review is part of the PCRonline GLOBAL Journal Club Initiative by selected members of the EAPCI/PCR Journal Club and PCR NextGen, and is based on the underlying idea of “Bringing peers together, exchanging ideas, towards a common standard of care”.

Why this study – the rationale/objective?

In this secondary analysis of the GLOBAL-LEADERS trial, the authors evaluated the impact of 23-month ticagrelor monotherapy after 1-month DAPT vs. a reference regimen of 12-month aspirin monotherapy after the first 12 months of DAPT (aspirin + ticagrelor for ACS and clopidogrel for stable CAD), on clinical outcomes of patients treated with complex percutaneous coronary intervention (PCI).

How was it executed – the methodology?

GLOBAL LEADERS was a randomized, open-label, superiority trial in patients who underwent PCI with a biolimus A9-eluting stent for stable CAD or ACS. 

• Complex PCI was defined as: multivessel PCI, ≥ 3 stents implanted, ≥ 3 lesions treated, bifurcation PCI with ≥2 stents, or total stent length >60 mm.
• The primary endpoint was defined as all-cause death or new Q-wave myocardial infarction (MI) at 2 years. 
• The patient-oriented composite endpoint (POCE) was defined as all-cause death, any stroke, any MI, or any revascularization and the net adverse clinical endpoints (NACE) were defined as POCE or Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding.

What is the main result?

The Global Leaders trial randomized a total of 15,991 patients, of whom 15,450 patients were included in the present analysis. Among these patients, 4,570 underwent complex PCI.

• The risk of the primary endpoint was numerically higher but statistically non-significant in the complex PCI group (4.47% vs. 3.94%, P = 0.124).
• Complex PCI was associated with a significantly increased risk of POCE (15.62% vs. 12.41%, P < 0.001). 
• The risk of BARC Type 3 or 5 bleeding was also higher in the complex PCI group at 2 years (2.49% vs. 1.96%, P = 0.034), leading to a significantly increased risk of NACE (17.05% vs. 13.61%, P < 0.001). 
• In patients with complex PCI, ticagrelor monotherapy significantly reduced risks of the primary endpoint [HR: 0.64, 95% CI: 0.48–0.85] and POCE (HR: 0.80, 95% CI: 0.69-0.93), but not in those with non-complex PCI (Pinteraction = 0.015 and 0.017, respectively). The risk of BARC Type 3 or 5 bleeding was similar (HR: 0.97, 95% CI: 0.67–1.40). 
• In stable CAD patients with complex PCI, ticagrelor monotherapy did not significantly reduce ischemic events, whereas the risk of BARC Type 3 or 5 bleeding was numerically higher. 
• In contrast, in ACS patients with complex PCI, ticagrelor monotherapy was associated with a significant risk reduction in the primary endpoint (3.07% vs. 5.85%, P = 0.002, Pinteraction = 0.003) and POCE (12.80% vs. 16.46%, P = 0.008, Pinteraction = 0.009).

Critical reading and the relevance for clinical practice

The present analysis highlights that patients undergoing complex PCI are under an increased risk of both ischemic and bleeding events at 2 years as compared with the non-complex PCI group. Compared with a 12-month DAPT followed by aspirin monotherapy, ticagrelor monotherapy (after the initial 1 month of aspirin and ticagrelor), significantly reduced ischemic events without a significant increase in major bleeding in patients with complex PCI.

This being said, 3 accompanying findings should be noted. First, most of the observed benefit was confined to patients with ACS. Second, the positive effects of ticagrelor monotherapy were mostly evident in the first year following the PCI, during which patients in the comparator arm were treated with a DAPT regimen. Third, the benefit of ticagrelor monotherapy increased with the degree of PCI complexity. 

The here presented analysis, adds to the growing evidence investigating the option of antiplatelet monotherapy in PCI-treated patients. Recently, STOPDAPT-2 trial (n=3009) results were published, in which 1-month DAPT followed by aspirin discontinuation and continued clopidogrel monotherapy, vs. 12 months of DAPT was assessed.

Similarly, the SMART-CHOICE trial randomized 2993 patients receiving current-generation DES to either 3 months DAPT (after which aspirin was discontinued and patients remained on P2Y monotherapy) vs. 12 months DAPT. There were no significant differences in ischemic events in both studies. Moreover, at TCT 2019 the results of the TWILIGHT study are expected to be presented. This study was designed to enroll 9,000 high-risk patients with successful PCI, who, after all being treated with aspirin + ticagrelor for 3 months and if event-free, would be randomized to either ticagrelor alone or aspirin + ticagrelor for 12 months. 

In summary, although there seems to be an increasing pool of data suggesting safety of discontinuing aspirin 1–3 months after PCI with DES, the findings of this post-hoc analysis of the GLOBAL LEADERS trial may draw additional attention to the issue of PCI complexity when deciding on antiplatelet strategies.