Novel Supreme DES with early synchronized antiproliferative drug delivery to inhibit smooth muscle cell proliferation after DES implantation in coronary artery disease: results of the PIONEER III randomized clinical trial

Selected in AHA Journal - Circulation by D. Giacoppo

The PIONEER III trial aims to assess the effectiveness and safety of the biodegradable-polymer sirolimus-eluting Supreme stent compared to durable-polymer everolimus-eluting stent (Xience or Promus), completely releasing the drug by 120 days.

Reviewer

Daniele Giacoppo

@DanieleGiacoppo

Interventional cardiologist / Cardiologist

Catania, Italy

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My Comment

Why this study? – the rationale/objective

New-generation drug-eluting stents (DES) are designed to complete antiproliferative medication release in 3-6 months. However, prolonged drug delivery after implantation may contribute to unfavorable effects such as delayed endothelialization, vessel wall hypersensitivity reactions, and neoatherosclerosis.

By considering that 4-6 weeks is the period of smooth cells proliferative response after DES implantation, the Supreme stent was designed to complete sirolimus elution within this time and promote faster healing and functional endothelium recovery.

The PIONEER III trial aims to assess the effectiveness and safety of the biodegradable-polymer sirolimus-eluting Supreme stent compared to durable-polymer everolimus-eluting stent (Xience or Promus), completely releasing the drug by 120 days.

How was it executed? – the methodology

The PIONEER III trial is a prospective, randomized, single-blind, non-inferiority trial conducted at 74 sites in North America, Europe, and Japan. After treatment of any single non-target lesion located in a different epicardial vessel by regionally approved and commercially available device, patients with chronic coronary syndrome and evidence of ischaemia or non-ST-segment elevation acute coronary syndrome were randomly assigned in a 2:1 ratio to Supreme or Xience/Promus stent implantation for the treatment of the target lesion.

ST-segment elevation myocardial infarction, unprotected left main coronary artery disease, known left ventricular ejection fraction < 30 %, and cardiogenic shock were key exclusion criteria. Patients were treated with dual antiplatelet therapy for at least 6 months in chronic coronary syndromes, and at least 12 months in acute coronary syndromes.

The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, or clinically-driven target lesion revascularization, at 12 months. The patients, site personnel conducting follow-up, clinical events committee independently adjudicating outcomes, and core laboratory performing quantitative coronary angiography analysis were blinded to randomization.

The trial was designed to demonstrate with a margin of 3.58 % the non-inferiority of the Supreme stent compared to the Xience/Promus stent in terms of primary composite endpoint at 12 months. Analyses were primarily conducted according to the intention-to-treat principle. A secondary analysis will be conducted after study completion with the aim of testing superiority of the Supreme stent in the time period from 1 to 5 years in terms of target lesion failure.

What is the main result?

From October 2017 to July 2019, 1, 086 patients (1,304 lesions) were randomly assigned to Supreme stent and 543 patients (677 lesions) to Xience/Promus stent. Baseline and clinical characteristics were balanced between groups with 41.3 % of acute coronary syndrome, 12.0 % of multivessel treatment, and 19.5 % of multiple lesion treatment. Fractional flow reserve and intravascular ultrasound guidance were employed in 7.7 % and 15.1 % of percutaneous coronary interventions, respectively. Lesions were more commonly predilated in the Supreme stent group compared to the Xience/Promus stent group. Lesion success (99.7 % vs. 99.5 %; p = 0.62) and device success (97.3 % vs. 98.9 %; p = 0.07) were not significantly different between Supreme and Xience/Promus groups.

Twelve-month follow-up was complete in 96.9 % of patients in the Supreme stent group and 98.3 % of patients in the Xience/Promus stent group. No significant differences in dual antiplatelet therapy use between groups were observed at 12 months.

The primary endpoint of target lesion failure occurred in 57 patients (5.4 %) assigned to Supreme stent and 27 patients (5.1 %) assigned to Xience/Promus stent (absolute risk difference [ARD] 0.32 %, 95 % confidence interval [CI] - 1.87 % – 2.50 %; p non-inferiority = 0.002). The per-protocol analysis showed consistent results (ARD 0.33 %, 95 % CI - 1.86 % – 2.52 %; p non-inferiority = 0.002). Cardiac death (0.3 % vs. 0.8 %; hazard ratio [HR] 0.37, 9 5% CI 0.08 – 1.67; p = 0.18), target vessel myocardial infarction (3.4 % vs. 4.1 %; HR 0.82, 95 % CI 0.48 – 1.39; p = 0.45), and clinically driven target lesion revascularization (2.3 % vs. 1.0 %; HR 2.42, 95 % CI 0.92 – 6.34 ; p = 0.06) were not significantly different between Supreme and Xience/Promus groups. However, any-type (clinically and non-clinically driven) target lesion revascularization occurred more frequently in the Supreme stent group compared to the Xience/Promus stent group (2.5 % vs. 1.0 %; HR 2.62, 95 % CI 1.01 – 6.83; p = 0.04). Other individual secondary endpoints, including definite/probable stent thrombosis (0.7 % vs. 0.4 %; HR 2.00, 95 % CI 0.42 – 9.42; p = 0.37), were not significantly different between groups. Secondary composite endpoints were also not significantly different between groups. No significant treatment-by-subgroup interaction across major clinical and angiographic subgroups was observed.

Critical reading and the relevance for clinical practice:

The Supreme is the first Chinese-designed and manufactured stent undergoing evaluation for approval in the United States and Japan. The acceptable safety profile of this stent has already emerged from earlier and smaller European and Chinese studies. The PIONEER III trial has confirmed non-inferiority of the Supreme stent compared to the Xience/Promus stent in terms of 12-month target lesion revascularization in a larger cohort of patients. These promising results need to be reassessed at the final 5-year follow-up when possible advantages from short drug elution and complete polymer bioresoption would be more evident.

However, the PIONEER trial has also revealed an increased rate of target lesion revascularization in patients assigned to the Supreme stent compared to the Xience/Promus stent. On the one hand, this result may reveal an insufficient antirestenotic effectiveness of the Supreme stent due to the primary characteristics of a faster antiproliferative drug release compared to other contemporary DES. On the other hand, these results may be an effect of chance, and a larger number of patients is required to draw conclusions in terms of the individual endpoint of target lesion revascularization.

Some considerations should be taken into account when evaluating the results of this trial. First, patients included in the PIONEER III trial mainly show low-complexity coronary artery disease and relatively favourable clinical conditions. Whether trial results can be extended to more complex anatomic and clinical patterns is undefined. Second, the selected non-inferiority margin of 3.58 % against an assumed 6.5 % event rate at 12 months in the control group is large and the prespecified analysis comparing effects between stents from 1 to 5 years will remain affected by low statistical power. Finally, the use of different devices for target and non-target lesions may have introduced significant heterogeneity.