Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome : the TICO randomised clinical trial

Selected in JAMA by D. Giacoppo

The outstanding results of the TICO trial have to be interpreted in light of a number of considerations and the generalisability of its results in other contexts requires further analysis.

Reviewer

Daniele Giacoppo

@DanieleGiacoppo

Interventional cardiologist / Cardiologist

Catania, Italy

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My Comment

Why this study? – the rationale/objective

Current guidelines recommend 12 months of dual antiplatelet therapy (DAPT) with aspirin plus a potent P2Y12 receptor inhibitor – ticagrelor or prasugrel – after acute coronary syndrome (ACS), when the individual risk of bleeding is not deemed to be extreme. Technology advances have led to the development of high-biocompatibility drug-eluting stents that in recent years have demonstrated low incidences of device-related adverse events, despite the use of short DAPT regimens. However, randomised clinical trials supporting short DAPT regimens after stenting showed predominant proportions of patients with stable coronary artery disease and unstable angina. Moreover, other recent trials testing different DAPT durations have added further uncertainty by hypothesizing a possible advantage from P2Y12 inhibitor monotherapy in place of aspirin after the short period of DAPT.

Against this background, the TICO trial sought to define whether, in patients with ACS undergoing percutaneous coronary intervention (PCI) with thin-strut bioresorbable-polymer sirolimus-eluting-stent implantation, 3 months of ticagrelor-based DAPT followed by ticagrelor monotherapy reduces the incidence of net adverse clinical events at 12 months compared with standard 12 months of ticagrelor-based DAPT.

How was it executed? – the methodology

The TICO was a multicentre, investigator-initiated, open-label, randomised clinical trial conducted in South Korea. Briefly, patients admitted for ACS who underwent successful PCI with thin-strut bioresorbable-polymer sirolimus-eluting stent implantation were randomly assigned in 1:1 ratio to 3 months of DAPT with aspirin plus ticagrelor followed by ticagrelor monotherapy up to 12 months or 12 months of ticagrelor-based DAPT.

The primary endpoint was a composite of all-cause death, myocardial infarction, definite/probable stent thrombosis, any-type stroke, target vessel revascularisation, or Thrombolysis in Myocardial Infarction (TIMI) major bleeding at 12-month follow-up.

What is the main result?

A total of 3056 patients were randomised from August 2015 to October 2018, 1527 to short ticagrelor-based DAPT followed by ticagrelor monotherapy and 1529 to standard prolonged ticagrelor-based DAPT. The mean age was 61 years, 80% of patients were men, and 27% had diabetes. The distribution of ACS variants across patients showed 30% of unstable angina, 34% of non-ST-segment elevation myocardial infarction (NSTEMI), and 36% of ST-segment elevation myocardial infarction (STEMI). Only 56% of patients underwent PCI by radial access.

At 12 months, the primary net composite endpoint was significantly lower in patients assigned to short DAPT than in those assigned to prolonged DAPT (3.9% vs. 5.9%, HR 0.66, 95% CI 0.48-0.92). The effect was mainly driven by a significant excess in TIMI major bleeding observed in the prolonged DAPT group (1.7% vs. 3.0%, HR 0.56, 95% CI 0.34-0.91). This result did not change after the application of the Bleeding Academic Research Consortium (BARC) definitions (bleeding type 3 or 5: 3.5% vs. 5.5%, HR 0.64, 95% CI 0.45-0.90). The incidence of a composite of major adverse cardiac and cerebrovascular events including death, myocardial infarction, stent thrombosis, stroke, or target vessel revascularisation was not statistically different between short and prolonged DAPT groups (2.3% vs. 3.4%, HR 0.69, 95% CI 0.45-1.06).

The individual secondary endpoints of all-cause death (1.1% vs. 1.5%, HR 0.70, 95% CI 0.37-1.32), acute myocardial infarction (0.4% vs. 0.7%, HR 0.55, 95% CI 0.20-1.48), definite/probable stent thrombosis (0.4% vs. 0.3%, HR 1.51, 95% CI 0.43-5.33), any-type stroke (0.5% vs. 0.7%, HR 0.73, 95% CI 0.29-1.81), and target vessel revascularisation (0.5% vs. 0.7%, HR 0.80, 95% CI 0.32-2.03) were not significantly different between short and prolonged DAPT groups. Prespecified subgroup analyses with respect to the primary net composite endpoint did not reveal treatment-by-subgroup interaction for age (< 65 year or ≥ 65 years), gender, body mass index, diabetes, chronic kidney disease, ACS variant, and total stent length (<30 mm or ≥30 mm); while a significant treatment-by-subgroup interaction (p=0.04) was observed according to number of diseased main epicardial vessel, with no significant difference between antithrombotic regimens in patients with multivessel disease (5.2% vs. 6.0%, HR 0.86, 95% CI 0.58-1.30) and enhanced benefit from short DAPT in patients with single-vessel disease (2.4% vs. 5.7%, HR 0.41, 95% CI 0.23-0.73).

Critical reading and the relevance for clinical practice

The TICO trial showed that in patients undergoing successful PCI with new-generation drug-eluting stent, 3 months of ticagrelor-based DAPT followed by ticagrelor monotherapy may not only be similarly effective to standard 12 months of ticagrelor-based DAPT in terms of major cardiac and cerebrovascular adverse events prevention but also safer due to a significant reduction in major bleeding incidence. Of note, the individual review of major ischemic endpoints did not arise concerns and an exploratory subgroup analysis showed that regardless of the type of ACS (unstable angina/NSTEMI vs. STEMI), the net benefit of short DAPT followed by ticagrelor monotherapy remains superior to prolonged DAPT.

In the TICO trial, differences between regimens are mainly related to major bleeding. Previous studies have highlighted that major bleeding after PCI has significant prognostic impact due to the strong association with survival. In the TICO trial, however, the incidence of death was not significantly different between groups likely as a consequence of the relatively low proportion of patients with high bleeding risk.

The outstanding results of the TICO trial have to be interpreted in light of a number of considerations.

First, the trial is clearly underpowered as a result of the unrealistic assumptions used for sample size calculation. Indeed, the expected 18% incidence at 12 months of the net primary composite endpoint in the control group did not largely meet the observed incidence of 5.9% and the anticipated 25% relative reduction needed to demonstrate the superiority of short DAPT would have required a total sample size more than double the number of patients enrolled.

Second, although results were reasonable and consistent, the limited incidence of individual major ischemic endpoints does not permit to draw definitive conclusions in terms of safety. Statistically-powered analyses with respect to major target lesion-related endpoints would be required, though difficult to accomplish.

Third, randomisation was performed within index hospitalisation, mainly after PCI (95%). Although an immediate randomisation study design has the advantage of avoiding artificial populations as in trials with treatment assignment in uneventful patients when DAPT had to be interrupted (e.g. TWILIGHT and DAPT trials), influences of superimposed factors unrelated to DAPT and potentially related to index myocardial revascularisation might not be fully excluded. However, landmark analysis at 3 months showed the same incidence of primary net composite endpoint in the two groups before aspirin interruption (2.5% vs. 2.5%, HR 1.00, 95% CI 0.64-1.57) and quite comparable incidences of individual endpoints. Fourth, the number of treated lesions per patient (1.24 ± 0.51), the number of stents implanted per patient (1.37 ± 0.66), the total stent length per patient (35 ± 21 mm), and the proportion of lesions involving a bifurcation (15%) in the TICO trial generally define a low-to-moderate complexity coronary artery disease setting. Whether short DAPT after stenting for ACS can be safely employed in more complex coronary artery disease patterns is highly uncertain. With respect to this aspect of the matter, the significant treatment-by-subgroup interaction for single- vs. multivessel disease should be cautiously taken into account because adjustment for multiple statistical testing in subgroup analyses was not performed. Fifth, the effect of ticagrelor monotherapy compared with standard single antiplatelet therapy with aspirin is unknown due to the absence of direct comparison trials.

Finally, the present trial included only patients enrolled in South Korea. Previous studies have indicated that Asian ethnicity can be associated with significantly different ischemic risk, bleeding propensity, and drug metabolism compared with White ethnicity.

For these reasons, the generalisability of the results of the TICO trial in other contexts requires further analysis.