Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial

Selected in the Lancet by A. N. Calik

The ALPHEUS study sought to investigate whether more potent and rapid platelet inhibition properties of ticagrelor could reduce periprocedural atherothrombotic complications in chronic coronary syndrome patients undergoing high-risk PCI.

Reviewer

Ali Nazmi Calik

@ANazmiCalik

Interventional cardiologist / Cardiologist

Istanbul, Türkiye

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My Comment

Why this study? – the rationale/objective

Percutaneous coronary intervention (PCI) related myocardial injury is a frequent clinical issue diagnosed with the aid of high sensitive biomarkers, and several reports highlighted that such periprocedural complications are closely associated with major cardiac adverse events in the future.
Ticagrelor, a potent P2Y12 inhibitor, provides better outcomes in acute coronary syndrome (ACS) patients when compared to clopidogrel given its higher level of platelet inhibition and faster onset of action. 

The ALPHEUS study sought to investigate whether more potent and rapid platelet inhibition properties of ticagrelor could reduce periprocedural atherothrombotic complications in chronic coronary syndrome (CCS) patients undergoing high-risk PCI.

How was it executed? – the methodology

This international, multicenter, randomized, controlled, and open-label trial included a total of 1910 stable coronary patients undergoing elective PCI with at least one high-risk feature. (High-risk PCI criteria are listed in Table 1). Once the coronary anatomy is known, eligible patients were randomly assigned (1:1) to either ticagrelor or clopidogrel before PCI. 
While ticagrelor group were loaded 180 mg ticagrelor before PCI and maintained 90 mg twice for 30 days, the clopidogrel group received 300-600 mg loading dose and 75 mg daily thereafter for 30 days.

Table 1. High-risk PCI criteria

The primary endpoint of the study was PCI-related myocardial infarction (MI) (type 4a or 4b) or major myocardial injury within 48 h of the procedure. The secondary endpoints included:

• PCI-related MI (type 4a or 4b) or any type of myocardial injury (minor or major),
• Type 1, 4, 5 MI according to the third universal definition of MI,
• Death from any cause or all MIs, 
• Death from any cause, MI or major myocardial injury, urgent revascularization, recurrent ischemia requiring catheterization.

As regards to safety outcomes, whereas Bleeding Academic Research Consortium (BARC) major bleeding (BARC 3 or 5) was defined as the primary safety endpoint, secondary safety endpoints consisted of minor or nuisance bleeding (BARC 1 or 2) and any type of bleeding (BARC 1 to 5).  

Cardiac troponin levels were measured at baseline, 6 and 24 hours after PCI or at discharge, and peak levels were noted for outcome assessment. Clinical outcomes were evaluated at 48 hours and 30 days. 

What is the main result?

After exclusion, 941 patients in the ticagrelor group (n=956 assigned, n=15 excluded) and 942 patients in the clopidogrel group (n=954 assigned, n=12 excluded) were included in the intention-to-treat analysis. Among those (n=1883), 1736 (93%) patients had negative baseline troponin levels, and 1246 (66%) patients had at least three high-risk features for PCI, with no differences between the groups.

The primary outcome including PCI-related MI (type 4a or 4b) or major myocardial injury at 48 h occurred in 35.5% of those treated with ticagrelor and 36.2 % in the clopidogrel group (p=0.75). The rates of each component of the primary outcome were similar in both treatment arms.

The main secondary outcome, defined as PCI-related MI (type 4a or 4b) and any type of myocardial injury was observed in 78 % of the ticagrelor group and 77 % of the clopidogrel group (p=0.67). 

Concerning safety endpoints, major bleeding (BARC 3 to 5), or nuisance or minor bleeding (BARC 1 or 2), or any type of bleeding (BARC 1 to 5) occurred in similar numbers at 48 h. However, the rate of nuisance or minor bleeding was higher in the ticagrelor group (0.007) at 30 days, as well as dyspnea. 

Critical reading and the relevance for clinical practice:

Even though a more robust P2Y12 inhibition was observed with ticagrelor compared to clopidogrel in the pharmacodynamic substudy of ALPHEUS trial (Bio-ALPHEUS), this superiority did not translate into a reduction of PCI-related MI or myocardial injury within 48 hours of high-risk PCI in CCS patients. Whereas ticagrelor therapy did not provide any benefits over clopidogrel for ischemic and bleeding outcomes, an increased tendency towards minor or nuisance bleeding was noted in the ticagrelor group at 30 days. 

In short, the results of ALPHEUS study are in line with the recommendations of current guidelines and support the use of clopidogrel as the standard antiplatelet therapy in stable coronary patients undergoing elective-PCI.