Ticagrelor or clopidogrel for patients with chronic coronary syndrome undergoing complex percutaneous coronary intervention?—the verdict has not been delivered yet

Percutaneous coronary intervention (PCI) represents one of the most frequent and rapidly evolving therapeutic interventions in contemporary medicine. The continuing evolution of materials, techniques and pharmaceutical agents, have led to greater intervention success rates, less periprocedural complications and better long-term clinical outcomes.

In patients with chronic coronary syndrome undergoing PCI, dual antiplatelet therapy with clopidogrel and aspirin is the default therapy, while the use of the more potent antiplatelet drugs like ticagrelor and prasugrel, has not been adequately studied, especially in the most demanding, complex procedures. Complex coronary interventions are related to increased rates of periprocedural complications and worse long-term prognosis (1-3).

Periprocedural myocardial injury is a well- known entity caused by different etiologies, like dissection of the treated vessel, side branch occlusion and microvascular obstruction, which jeopardize the distal perfused myocardial territory of the epicardial vessel. Microvascular obstruction includes a series of events, such as thrombus formation, distal embolization of atherosclerotic material, local vasospasm due to vasoconstricting substances (mainly serotonin and endothelin) released from activated platelets, neurohormonal activation, as well as triggering of inflammation process and augmented oxidative stress (4). Platelets activation is increased during PCI, and the complexity of the procedure itself defines the grade of platelet reactivity and the risk of myocardial damage (5,6).

Myocardial injury and myocardial infarction type 4 are associated with adverse cardiovascular events, (7,8) and a more potent platelets inhibition during complex coronary interventions could result in less periprocedural myocardial damage. The definition of complex PCI is not standardized. Technical aspects, such as at least three stents implanted or the treatment of three lesions, total stent length >60 mm, bifurcation with two stents implanted and a chronic total occlusion, have been proposed by the European Society of Cardiology (ESC) and prasugrel or ticagrelor may be considered in patients undergoing elective stenting and complex PCI procedures (9,10). Relevant studies showed no benefit when stronger antiplatelet agents like ticagrelor or prasugrel were used instead of clopidogrel, in chronic coronary syndrome patients treated with PCI (11,12). Interestingly, the investigators of the TWILIGHT study (13) found that in patients undergoing a complex PCI, a monotherapy strategy with ticagrelor after a 3-month period of dual antiplatelet therapy versus a dual antiplatelet regimen of ticagrelor and aspirin was associated with less bleeding complications without adding harm in terms of major adverse cardiovascular events (MACE) over a period of observation of 1 year. In addition, cangrelor, an intravenous strong and fast acting platelet adenosine diphosphate receptor inhibitor, when compared with a loading dose of clopidogrel, reduces PCI related MACE’s occurring within 48 h after the procedure, irrespective of lesion complexity (14).

Recently, the results of the post-hoc analysis of the ALPHEUS trial by Lattuca et al. were published in JACC Cardiovascular Interventions (15). The study questioned the comparative impact of ticagrelor and clopidogrel in patients with chronic coronary syndrome undergoing a complex PCI, in terms of periprocedural myocardial infarction (type 4) and major myocardial injury. This topic is a matter of debate among interventional cardiologists. Whether complex PCI patients should be treated or not with more potent antiplatelet drugs instead of clopidogrel is questionable. The investigators concluded that complex PCI is associated with higher percentages of periprocedural myocardial infarction or major myocardial injury (45.6% vs. 26.6%, P<0.001) and higher adverse events rates (a composite of myocardial infarction, death and stroke) at 48 hours (12.7% vs. 5.1%, P<0.05) and at a 30-day follow-up (13.4% vs. 5.3%, P<0.05). None of those endpoints was reduced with ticagrelor use compared to clopidogrel use. The results of the study are aligned with the conclusions of the main study (ALPHEUS trial) (16).

Nevertheless, after a deep dive into the data presented in this manuscript, several observations can be made. First, as stated by the authors, the patients were randomized to receive a loading dose of ticagrelor or clopidogrel before the start of the procedure. Peak platelets inhibition is obtained after 4 to 6 hours of clopidogrel and after 2 hours of ticagrelor administration. On admission, 391 patients in the complex PCI group were already receiving clopidogrel. Patients already on prasugrel or ticagrelor before the procedure were excluded in the design of the ALPHEUS trial (17). Although a loading dose of ticagrelor (crushed or chewed) was recommended, probably many PCIs in the ticagrelor group were performed before adequate platelet inhibition was achieved. In addition, in the ticagrelor group, atherectomy was used in 22 patients, 18 of whom (81.8%) presented the primary endpoint. Myocardial injury during atherectomy occurs due to phenomena related to platelet hyperreactivity, but also due to extensive distal microembolization from debris, derived from the atherosclerotic material of the plaque, a mechanism that does not depend on the degree of platelets inhibition. It is questionable if patients undergoing PCI with atherectomy should be included in the analysis.

In the complex PCI group, coronary dissection occurred in 41 patients, in the ticagrelor group, compared to 25 patients in the clopidogrel group. In this scenario of an iatrogenic periprocedural complication, myocardial damage observed has nothing to do with the kind of antiplatelet agent used. In addition, post PCI side branch occlusion is not mentioned in the study exclusion criteria (16). In such cases myocardial injury/infarction occurs mainly as a mechanical complication due to the stent placement (due to plaque shift) and has little to do with platelet inhibition. The analysis included patients with chronic kidney disease (CKD) (97 in the complex PCI group) with a creatinine clearance <60 mL/min, a condition that per se can affect troponin kinetics, increasing its values (18). While in the main study the number of patients with CKD was similar between the two groups [89 (9%) for ticagrelor vs. 98 (10%) for clopidogrel], it is not reported if the number of the patients with CKD and complex PCI was analogous.

Myocardial injury, especially after an elective complex PCI, is encountered in everyday’s clinical practice. Whether it can be mitigated by the more potent antiplatelets ticagrelor or prasugrel or not is of particular interest. It is reasonable to expect that potent antiplatelet agents could eliminate microthrombi formation and microvascular injury during complex PCI, by effectively reducing platelet activation. This hypothesis has still to be proven.

The post-hoc analysis of the ALPHEUS trial concluded that ticagrelor is equally effective to clopidogrel in reducing myocardial injury/infarction in complex PCI patients. A randomized controlled study with the same question, with clear inclusion and exclusion criteria (excluding confounding factors other than platelets reactivity which can lead to troponin elevation and myocardial infarction), and a more extended follow-up would surely shed more light on this burning clinical issue.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-57/coif). M.H. reports honoraria for lectures from Astra Zeneca and Sanofi. The other authors have no conflicts of interest to declare.

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