Ticagrelor monotherapy after acute coronary syndrome: lessons from the ULTIMATE-DAPT trial

Dual antiplatelet therapy (DAPT) for 12 months is the current standard of care in patients with acute coronary syndrome (ACS), regardless of stent implantation, and is endorsed by the 2023 European guidelines with a Class I recommendation (Level of Evidence: A) [1]. Potent P2Y12 receptor inhibitors, ticagrelor or prasugrel, should be combined with aspirin, in preference of clopidogrel, given the evidence of superior anti-ischemic protection in this setting [1]. However, the benefit of 12-month DAPT with potent P2Y12 receptor inhibitors is offset by an increased risk of major bleeding, which adversely affects short- and long-term prognosis [2–5]. Therefore, alternative antithrombotic strategies to standard DAPT have been investigated over the past decades to achieve a more favorable balance between ischemic and bleeding risk after ACS [1,6,7]. In particular, several randomized trials have examined the safety and efficacy of an alternative strategy based on aspirin discontinuation after a short course of DAPT and continuation of long-term P2Y12 inhibitor monotherapy after coronary revascularization, including patients with ACS [8–11]. In the Single Versus Dual Antiplatelet Therapy (Sidney)-2 meta-analysis [12], patient-level data from more than 24,000 participants in six randomized controlled trials were pooled to examine the treatment effect of P2Y12 inhibitor monotherapy after 1–3 months of DAPT compared with standard DAPT. This study showed that P2Y12 inhibitor monotherapy was associated with a significant 50% lower risk of major bleeding (Bleeding Academic Research Consortium [BARC] type 3 or 5) and a similar risk of fatal and ischemic events compared with DAPT [12]. The benefit of early P2Y12 inhibitor monotherapy was observed regardless of the complexity of the percutaneous coronary intervention (PCI), which is reassuring given the large proportion of patients with severe coronary artery disease undergoing complex interventions in contemporary practice [13,14]. A more recent appraisal of available randomized evidence also suggests that the treatment effect of the P2Y12 inhibitor monotherapy after PCI depends on the type of the P2Y12 inhibitor [15,16]. In the Sidney-3 patient-level meta-analysis, ticagrelor monotherapy reduced the risk of major bleeding compared with standard DAPT while preserving effective anti-ischemic benefits. On the other hand, clopidogrel monotherapy was similarly associated with reduced bleeding but was not non-inferior to DAPT for all-cause death, myocardial infarction or stroke. The difference in ischemic outcomes between the two monotherapy regimens is at least partly explained by the more consistent antiplatelet effect of ticagrelor compared with clopidogrel, as the latter is known to exhibit interindividual variability in pharmacodynamic response [17]. This aspect is more relevant in patients with ACS, as shown by the results of randomized trials and meta-analyses [18,19]. The available data on prasugrel monotherapy after PCI are limited. In the STOPDAPT-3 trial, an aspirin-free strategy with low-dose prasugrel (3.75 mg daily) was not superior for major bleeding and noninferior for cardiovascular events within 1 month after PCI compared with DAPT [20]. However, low-dose prasugrel monotherapy was also associated with a signal of possible harm for an excess of coronary events, raising concerns about its use in practice [20]. Taken together, current evidence indicates that ticagrelor monotherapy after a short DAPT is an attractive strategy to achieve effective cardiovascular protection with minimal bleeding. In this context, the recently published data from the ULTIMATE-DAPT trial [21] lend further support to this concept.

The ULTIMATE-DAPT is a multicenter, randomized, double-blind, placebo-controlled trial that compared ticagrelor from 1 month after drug-eluting coronary stent implantation for ACS with a standard DAPT strategy of ticagrelor plus aspirin for an additional 11 months [21]. This trial was part of a broader study program that included another randomized trial, the IVUS-ACS [22]. According to the research protocol, 3505 patients with ACS were randomized (1:1) to receive intravascular ultrasound-guided PCI or angiography-guided PCI at the time of the index procedure [23]. This first randomization formed the IVUS-ACS trial cohort. At 1 month after PCI, 3400 (97%) patients were event-free and were further randomized to receive ticagrelor 90 mg twice daily plus placebo or ticagrelor 90 mg twice daily plus aspirin 100 mg once daily for an additional 11 months. This second randomization formed the ULTIMATE-DAPT trial cohort.

The ULTIMATE-DAPT was designed to assess the superiority of ticagrelor monotherapy versus DAPT for clinically relevant bleeding (defined as BARC 2, 3 or 5 bleeding) and the noninferiority of the experimental strategy versus the control strategy for major adverse cardiovascular or cerebrovascular events (MACCE, a composite of cardiac death, myocardial infarction, ischemic stroke, definite stent thrombosis and clinically driven target vessel revascularization) between 1 and 12 months after PCI for ACS. MACCE were analyzed using the Fine–Gray model to account for the competing risk of noncardiac death [21].

The trial was conducted at 58 centers, with 52 in China. The study population consisted of 3400 ACS patients, of whom 1376 (40%) presented with unstable angina, 1076 (32%) with non-ST-segment elevation myocardial infarction and 948 (28%) with ST-segment elevation myocardial infarction. Major exclusion criteria included a history of high bleeding risk conditions, such as recent stroke, previous intracranial hemorrhage, chronic oral anticoagulation, thrombocytopenia and liver cirrhosis. The median age of the trial cohort was 63 years, and approximately 75% of patients were male. In addition, around a third of patients had a history of diabetes, nearly 10% had a previous PCI, and a small proportion of patients (less than 8%) had chronic kidney disease. The median duration of DAPT was 28 days (interquartile range: 25–33) in the ticagrelor monotherapy group and 365 days (interquartile range: 365–365) in the standard DAPT group.

Between 1 and 12 months after PCI, the primary superiority end point of BARC 2, 3 or 5 bleeding occurred significantly less often with ticagrelor monotherapy than with standard DAPT (2.1 vs 4.6%; HR: 0.45; 95% CI: 0.30–0.66; p < 0.0001) with a number needed-to-treat of 48; the rate of major bleeding (BARC 3 or 5 bleeding) was also reduced with ticagrelor monotherapy (0.7 vs 1.7%; HR: 0.39; 95% CI: 0.19–0.79; p = 0.0087) with a number needed-to-treat of 100. The co-primary noninferiority end point of MACCE occurred in 61 (3.6%) patients receiving ticagrelor plus placebo and in 63 (3.7%) patients receiving ticagrelor plus aspirin (HR: 0.98; 95% CI: 0.69–1.39; p < 0.0001 for noninferiority; p = 0.89 for superiority). The incidence of net clinical adverse events, a key secondary end point, was also lower in the ticagrelor monotherapy group than in the standard DAPT group (5.7 vs 8.2%; HR: 0.68; 95% CI: 0.53–0.88; p = 0.0066).

The ULTIMATE-DAPT trial is another step toward a paradigm shift in the antithrombotic management of patients with ACS [21]. These results, in concert with previous randomized trials and patient-level meta-analyses [12,15,24], warrant an update of current guidelines [1] and a change in daily practice to treat the majority of ACS patients undergoing PCI with current-generation drug-eluting stents with a short DAPT (1–3 months) followed by conversion to single antiplatelet therapy with a potent P2Y12 inhibitor, with the strongest evidence to date supporting ticagrelor.

Author contributions

Conceptualization: F Gragnano, P Calabrò. Writing – original draft: F Gragnano, V De Sio. Writing – review & editing: A Cesaro, P Calabrò.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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No writing assistance was utilized in the production of this manuscript.