All international guidelines suggest dual antiplatelet treatment (DAPT) with aspirin plus a P2Y12 receptor inhibitor for 12 months after an acute coronary syndrome for patients undergoing PCI, towards reducing myocardial infarction and stent thrombosis. However, there are few evidence regarding reduced duration of DAPT and especially whether P2Y12 receptor inhibitor monotherapy could reduce major bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE)
ULTIMATE-DAPT, recently presented at the annual American Congress of Cardiology (ACC) 2024 congress, is a novel, recently-published double-blind randomized controlled trial, comparing ticagrelor monotherapy versus dual antiplatelet treatment with aspirin and ticagrelor, from month 1 to month 12 in patients undergoing percutaneous coronary intervention (PCI) in an acute coronary syndrome (ACS) setting.
The primary superiority endpoint of the trial was clinically relevant bleeding, while the primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischemic stroke, definite stent thrombosis, or clinically driven target vessel revascularization). Clinically relevant bleeding was reported in 35 patients (2.1%) in the ticagrelor plus placebo group and in 78 patients (4.6%) in the ticagrelor plus aspirin group (HR 0.45 [95% CI 0.30-0.66]; p<0.0001), while MACCE was reported in 61 patients (3.6%) in the ticagrelor plus placebo group and in 63 patients (3.7%) in the ticagrelor plus aspirin group (absolute difference –0.1%, p(non-inferiority) <0.0001).
The driven hypothesis led to the design and successful assessment of ULTIMATE-DAPT that most of antithrombotic protection is derived from P2Y12 receptor inhibition, while aspirin addition mainly contributes to the increased hemorrhagic complications, in patients with ACS treated with drug-eluting stents implantation. The significant reduced rates of major bleeding events in ticagrelor monotherapy arm were consistent with previous studies’ results, evaluating aspirin omitting ACS. Furthermore, ULTIMATE-DAPT seem to extend the results of TICO trial in a blinded setting, that in a recent individual patient data meta-analysis of TICO and T-PASS trials, ticagrelor monotherapy was associated with statistically significant reduced incidence of major bleeding events (2.4% vs. 4.5%; adjusted HR 0.54; 95% CI 0.40–0.72; p < .001), without a concomitant increase in thrombotic events.
The study comes with several limitations, including that the majority of the trial centers were located in Asia, there was no assessment of earlier than one month discontinuation of aspirin, while there were minor bleedings included in the clinically-relevant bleedings primary endpoint. However, other parameters not specifically addressed by the investigators were the context of multivessel disease, as mainly the patients treated in this trial had single-vessel disease treated with one stent. It is known that increased stent number and total length are predictors of thrombotic events, thus future trials should aim to include more complex lesions and multivessel disease, in order to identify any differences in ischemic outcomes. Finally, despite this trial was an analysis of an intravascular ultrasound (IVUS)-based study, there was no extensive reporting of association of intravascular imaging parameters of stent expansion and apposition, i.e. PCI optimization, with ischemic or bleeding events. This pitfall of the study needs to be further explored in future analyses.
The additive use of aspiring to a P2Y12 inhibitors, as also shown by pre-clinical trials, is limited in the context of PCI. The aforementioned trial adds to a number of evidence currently available towards safety and efficacy of shortening DAPT to 1 month, followed by a strong P2Y12 inhibitor, in terms of both ischemic and bleeding complications, in the era of contemporary PCI. However, it should be kept in mind that advancements in the current PCI practice, including bioresorbable scaffolds, new stent platforms and technologies, intravascular imaging and drug coated balloons (DCBs) could limit PCI-associated thrombotic risk in the immediate post-intervention period, thus further reducing the need for extended DAPT. PCI optimization, especially in the context of high bleeding risk, is desirable and future trials, specifically designed to address the duration of antiplatelets under such technologies and techniques, should provide more clear evidence regarding the shortened DAPT period and its indications.
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