PCSK9 inhibitoRs for Early Passivation of coRonary athEroSclerotic plaqueS in acute coronary syndromes (REPRESS): study protocol for a multicentre randomised controlled trial

Abstract

Introduction

The ‘strike early and strike strong’ lipid-lowering strategy emphasises rapid reduction of low-density lipoprotein cholesterol (LDL-C) in patients with acute coronary syndrome (ACS). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are increasingly used alongside statins to achieve guideline-recommended LDL-C targets after ACS. However, despite substantial LDL-C reductions with early PCSK9i initiation, their effects on non-culprit coronary atherosclerotic plaques remain unclear. This study aims to assess the impact of early intensive LDL-C lowering with PCSK9i added to moderate-intensity statin therapy on optical coherence tomography (OCT)-derived plaque characteristics in non-culprit coronary lesions in patients with ACS.

Methods and analysis

In this prospective, multicentre, open-label trial, 212 patients with ACS will be randomised 1:1 to an early intensified lipid-lowering strategy (PCSK9i added to moderate-intensity statin) or guideline-directed medical therapy for 6 months. Serial OCT imaging of non-culprit coronary arteries with 20–70% stenosis will be performed at baseline and 6 months. The primary endpoint is the absolute change in minimum fibrous cap thickness within a matched target arterial segment from baseline to 6 months. Secondary endpoints include changes in minimum lumen area, maximum lipid arc, presence of macrophage infiltration, LDL-C reduction and achievement of LDL-C targets. The primary endpoint will be analysed using analysis of covariance, adjusting for treatment group, baseline LDL-C stratification (≥1.8 vs <1.8 mmol/L), and baseline minimum FCT. Secondary continuous outcomes will be analysed similarly, while categorical outcomes will be compared using chi-square, Fisher’s exact test or logistic regression, as appropriate.

Ethics and dissemination

Ethics approval was granted by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (2024 Review No 1943). Results will be disseminated via peer-reviewed publications and presentations at academic conferences.

Trial registration number

NCT06791031.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The REPRESS study’s main strength is its enrolment of patients with relatively lower baseline low-density lipoprotein cholesterol (LDL-C) levels (compared with existing proprotein convertase subtilisin/kexin type 9 inhibitor studies) and inclusion of non-culprit vessels with a wider stenosis range (20–70%) in patients with acute coronary syndrome (ACS), which enhances the generalisability of the findings.

• Focusing on the early passivation of non-culprit lesions of ACS and providing early response of atherosclerotic plaque to lipid-lowering treatment for 6 months after discharge.

• Both groups receive moderate-intensity statins, with the control group receiving guideline-directed medical therapy rather than fixed-dose statin monotherapy, better reflecting real-world clinical practice.

• For non-culprit vessels with 50–70% stenosis, functional assessment (eg, fractional flow reserve) is not mandatorily required, taking into account relatively simple execution procedures, but representing a limitation in flow assessment.

• A key limitation of the study is the potential safety risks of early intensive lipid-lowering therapy, which may include increased bleeding and immune effects at very low LDL-C levels.

Introduction

In patients with acute coronary syndrome (ACS), non-culprit lesions tend to be more vulnerable than in those with stable angina pectoris.¹ Because non-culprit plaques are prone to rupture and thrombosis, patients with ACS remain at elevated risk of recurrent cardiovascular events, especially during the first 30 to 90 days after discharge.^{2 3} Indeed, studies have revealed that approximately half of recurrent cardiovascular events occurred during this high-risk period.⁴,⁶ Lipid-lowering therapy (LLT), particularly targeting lowering low-density lipoprotein cholesterol (LDL-C), is pivotal for stabilising atherosclerotic plaques and reducing the risk of cardiovascular events.⁷ Statins are the first-line therapy for lowering LDL-C, reducing levels by approximately 30% with moderate-intensity and 50% with high-intensity therapy. Adding ezetimibe to high-intensity statins can further reduce LDL-C to around 65%.⁸ Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an effective strategy for additional LDL-C lowering: PCSK9 monoclonal antibodies reduce LDL-C by about 60% and decrease cardiovascular events in patients after ACS,^{9 10} while inclisiran, a small interfering RNA targeting hepatic PCSK9, lowers LDL-C by approximately 50%.¹¹ Conventional stepwise escalation of LLT may take up to 3 months to achieve target levels, overlapping with the period of greatest risk for recurrent events. This has led to the proposal of a ‘strike early and strike strong’ (SESS) strategy aimed at rapid LDL-C reduction immediately after ACS.¹² Early initiation of PCSK9i during the acute in-hospital phase of ACS, typically as an adjunct to prior statin therapy, has been demonstrated to be both feasible and well tolerated. This strategy leads to marked LDL-C reductions and higher rates of target attainment within 2–8 weeks post-discharge, with few serious treatment-related adverse events.¹³,¹⁵ Nevertheless, evidence supporting the SESS strategy remains limited.

Beyond early lipid reduction, there is increasing interest in the effects of PCSK9i on coronary atherosclerotic plaques, particularly as assessed by high-resolution intravascular imaging such as optical coherence tomography (OCT). OCT is an invasive intracoronary imaging modality that uses back-scattered infrared light to characterise plaque morphology—including fibrous, calcified and lipid-rich plaques, thin-cap fibroatheroma and thrombus—and to quantify fibrous cap thickness (FCT).^{16 17} Serial OCT imaging enables assessment of coronary plaque progression or regression in response to medical therapy. The HUYGENS (High-Resolution Assess-ment of Coronary Plaques in a Global EvolocumabRandomized Study)¹⁸ and PACMAN-AMI (Effects of the PCSK9 AntibodyAlirocumab on Coronary Atherosclerosis in Patients WithAcute Myocardial Infarction)¹⁹ trials demonstrated that adding evolocumab or alirocumab to statin therapy resulted in favourable plaque modifications over 1 year, including increased FCT and reduced lipid arc and macrophage infiltration. Nevertheless, early dynamics of atherosclerotic plaque changes under intensive LLT remain insufficiently characterised in the post-statin era, underscoring the need for further investigation.²⁰ Accordingly, the present study aims to evaluate the effects of early intensive LLT, incorporating PCSK9i in addition to moderate-intensity statin therapy, on coronary plaque stabilisation in patients with ACS at 6 months post-discharge.

Methods and analysis

Study design

The PCSK9 inhibitoRs for Early Passivation of coRonary athEroSclerotic plaqueS in patients with acute coronary syndromes (REPRESS) is an investigator-initiated, prospective, multicentre, open-label, randomised controlled trial, which evaluates the effects of early intensive LLT with PCSK9i initially added to moderate-intensity statins on non-culprit coronary atherosclerotic plaques by serial OCT imaging in patients with ACS undergoing percutaneous coronary intervention (PCI). A total of 212 patients will be randomised 1:1 to receive either the ‘PCSK9i early’ intensified therapy group (early addition of PCSK9i to moderate-intensity statin) or the guideline-directed medical therapy (GDMT) group for 6 months. Study visits are scheduled at months 1, 3, 6 and 12, with OCT imaging performed at baseline and repeated at 6 months (figure 1). This study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines,²¹ with the trial registration dataset items provided in online supplemental material 1).

Figure 1. REPRESS study design and treatment programme. ACC, American College of Cardiology; ACS, acute coronary syndrome (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina); AHA, American Heart Association; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors; REPRESS, The PCSK9 inhibitoRs for Early Passivation of coRonary athEroSclerotic plaqueS in patients with acute coronary syndromes .

Study setting

This multicentre study will be conducted across approximately five institutions in various provinces of China, including West China Hospital of Sichuan University, the Second Affiliated Hospital of Army Medical University, Chengdu Third People’s Hospital, the Affiliated Hospital of Zunyi Medical University and Yan'an Hospital Affiliated with Kunming Medical University. Each centre will be required to have experience in routine primary angioplasty for acute myocardial infarction (MI) (with past experience of at least 500 PCI procedures per year in the last 3 years and the main operator is qualified for interventional therapy and has independently completed at least 200 PCI cases per year) and to have a 24 hours on-call angioplasty team available. The main operator still needs to be skilled to OCT examination and image interpretation. Each centre competes for inclusion, with a maximum enrolment of 120 cases per centre.

Eligibility criteria

Patients undergoing clinically indicated PCI for ACS—including ST-elevation or non-ST-elevation MI or high-risk unstable angina (defined as worsening angina with ischaemic ST-T changes in ≥2 contiguous electrocardiographic leads or cardiac troponin elevation ≤2 times the upper limit of normal according to each centre’s laboratory reference range)—will be screened for clinical and anatomical eligibility, as summarised in Box 1. In brief, patients with ACS who have successfully undergone PCI of culprit lesions are eligible if they possess a target segment in a non-culprit artery with angiographically estimated diameter stenosis of 20–70%. Exclusion criteria include severe hepatic insufficiency (Child-Pugh class C) and severe renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m²), history of statin intolerance or prior use of PCSK9i.

Box 1. Inclusion and exclusion criteria.

Inclusion criteria

• Male or female, age ≥18 years at screening.

• Acute coronary syndrome who underwent PCI of the culprit lesions.

• Non-culprit vessel (target vessel) meets the following criteria after culprit vessel. PCI:

  • Target vessel diameter >2.5 mm, suitable for OCT examination.

  • Target vessel with angiographically estimated stenosis (diameter stenosis 20–70%).

  • Target vessel must be native coronary arteries, vessel segment without previous PCI.

  • Target vessel cannot be a venous or arterial bridge vessel.

• Ability to cooperate with the requirements of the study and to offer written informed consent.

• Willingness to complete follow-up visits and examinations as required by the schedule.

• Life expectancy >1 year.

Exclusion criteria

• Left main disease of non-culprit artery, defined as ≥50% reduction in lumen diameter of the left main coronary artery via angiographic visual estimation.

• Thrombotic target lesion, severe calcification or tortuosity lesions unfavourable for OCT examination.

• Coronary artery anatomy that prevents complete imaging of the segment of interest (including at least 5 mm of both edges of the stenosis).

• True bifurcation lesions requiring stenting.

• TIMI flow <2 of the culprit-related arteries after PCI.

• Unstable clinical status (cardiogenic shock, haemodynamic or electrical instability).

• Advanced heart failure (New York cardiac class III-IV).

• Ischaemic stroke within the past 6 months or cerebral haemorrhage at any time in the past.

• Severe valvular disease or valvular disease that may require surgery or percutaneous valve replacement.

• Diffuse coronary artery lesions or the presence of ≥1 untreated non-culprit lesion (non-culprit flow-restricting lesion planned for near-term, phase II PCI).

• Target vessel with coronary artery bypass grafting or PCI.

• Planned major surgery requiring interruption of dual-antiplatelet therapy.

• Statin intolerance and patients unsuitable for statin therapy with alanine aminotransferase greater than three times the upper limit of normal or creatine kinase greater than three times the upper limit of normal (not attributed to an acute MI) or greater.

• Familial hypercholesterolaemia.

• Prior (within 180 days prior to the first study visit) exposure to PCSK9i, either as an experimental or marketed drug.

• Female subjects of childbearing potential, defined as all female subjects who are physiologically capable of becoming pregnant, unless such female subjects are using an effective method of contraception during the trial.

• Women who are pregnant or breastfeeding or intend to become pregnant.

• Comorbidities with malignancies, active infections or major haematologic, metabolic or endocrine disorders are judged unsuitable by the investigator.

• Severe hepatic insufficiency (Child-Pugh class C).

• Severe renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m²).

• Current enrolment in another investigational device or drug study.

• Poor adherence and inability to complete the expected follow-up.

Recruitment and randomisation

The initial assessment and interview will be conducted within several hours after PCI. Patients meeting all inclusion criteria, without any exclusion criteria, and who provide written informed consent (online supplemental material 2) will be randomised 1:1 via an interactive web-based system to either the ‘PCSK9i early’ group (early initiation of PCSK9i with a moderate-intensity statin) or the GDMT group. Randomisation will be stratified by baseline LDL-C level (≥1.8 mmol/L or <1.8 mmol/L) and performed prior to hospital discharge.

Interventions

Patients randomised to the ‘PCSK9i early’ intensified therapy group will receive initial treatment with a PCSK9 inhibitor—either evolocumab 140 mg, administered subcutaneously every 2 weeks with the initial dose given during hospitalisation and subsequent doses self-administered at home—or inclisiran sodium 300 mg (equivalent to 284 mg inclisiran), administered by healthcare professionals at baseline and again at the 3 month study visit. All patients will receive moderate-intensity statin, including atorvastatin 20 mg or rosuvastatin 10 mg daily. The intervention will be initiated during hospitalisation for the index ACS event, within 24 hours of randomisation, irrespective of baseline LDL-C levels or prior statin use. Patients in the GDMT group will receive GDMT, consisting of stepwise lipid-lowering strategies in accordance with the 2025 American College of Cardiology/American Heart Association guidelines for ACS, Chinese Lipid Management Guidelines (2023) and Expert Consensus on Clinical Pathways for Lipid Management in Chinese Patients with ACS.²²,²⁴ In general, a stepwise approach to LDL-C management is recommended, starting with moderate-intensity statin therapy (eg, atorvastatin 20 mg daily or rosuvastatin 10 mg daily) for patients who have not previously received statins. If target LDL-C levels are not achieved after 4–6 weeks of statin therapy, a cholesterol absorption inhibitor, such as ezetimibe 10 mg daily, should be added. If LDL-C goals remain unmet after an additional 4–6 weeks, a PCSK9 inhibitor may be introduced. The dosing and administration of these agents are consistent with those used in the intervention group. Early initiation of PCSK9i in extremely high-risk patients with elevated baseline LDL-C levels who are unlikely to achieve target levels with statin therapy combined with a cholesterol absorption inhibitor (Class IIa recommendation in Chinese Lipid Management Guidelines) is not encouraged. The specific risk stratification and LDL-C management strategies are provided in online supplemental material 3.

Acquisition and analysis of OCT imaging

In patients with ACS and multivessel disease following intervention of the culprit lesion, non-culprit vessels will be assessed. Non-culprit lesions with 20–70% stenosis on angiography are further evaluated using OCT with the FD-OCT ILUMIEN system (Abbott, USA). Contrast volume and infusion rate will be tailored to vessel diameter to optimise image quality. The region of interest will be scanned at a pullback speed of 18 mm/s over a 54 mm segment, with OCT pullback recorded concurrently with fluoroscopy for angiographic correlation. Additional runs will be performed if image quality is inadequate, and multiple target lesions will be imaged separately when feasible for OCT. OCT images and corresponding angiograms will be analysed offline by trained specialists in an OCT core laboratory, blinded to the patient’s treatment allocation and imaging timepoint (baseline or follow-up). Image evaluation follows tissue characterisation criteria described in previous OCT consensus publications.^{25 26} Cross-sectional OCT images are obtained at 0.2 mm intervals, and each frame is systematically classified as normal vessel, fibrous plaque, fibrocalcific plaque or vulnerable plaque.

Imaging will be performed in a non-culprit coronary artery with an angiographically estimated diameter stenosis of 20–70%, considered unlikely to require revascularisation during the study period. In patients with multiple stenotic vessels and/or multiple plaques, the plaque with the thinnest FCT will be selected, and the arterial segment containing that plaque will be designated as the target segment. All imaging parameters will be assessed within the same matched arterial segment, including minimum FCT, minimum lumen area (MLA), maximum lipid arc and presence of macrophage infiltration. Baseline and follow-up OCT images will be aligned using anatomical landmarks, including calcifications and side branches, and the OCT system will be calibrated prior to analysis. A plaque will be defined as ‘vulnerable’ if it exhibits an FCT <75 µm in combination with at least two of the following features: lipid arc>180°, MLA<3.5 mm² or macrophage infiltration.²⁷

Study visits and procedures

Study visits, procedures and assessments are scheduled at baseline and at 1, 3, 6 and 12 months after randomisation. The schedule of study visits and planned assessments, including OCT imaging, laboratory tests, electrocardiography, echocardiography, medication adherence and safety monitoring, is summarised in table 1. This schedule ensures standardised data collection and patient monitoring throughout the study.

Table 1. Schedule of study visits and procedures.

Study procedures	Visit 1 (baseline)	Visit 2 (month 1)	Visit 3 (month 3)	Visit 4 (month 6)	Visit 5 (month 12)
	In-hospital	Clinical visit	Clinical visit	In-hospital	Phone call
Patient informed consent	X
Review of inclusion/exclusion criteria	X
Demographic data	X
Medical history	X
Physical examination	X
Dietary counselling	X	X	X	X
Randomisation	X
PCSK9i injection training	X
Review of concomitant medications	X	X	X	X
Laboratory Testing (local testing at study site):
Haematology (haematocrit, haemoglobin, WBC count, platelet count)	X	X	X	X
Blood chemistry (ALT, AST, blood glucose, sodium, potassium, creatinine, CK)	X	X	X	X
Lipid profile (TC, LDL-C, HDL-C, TG, ApoB, Lp(a), VLDL-C)	X	X	X	X
Inflammatory and immune markers (hs-CRP, TNF-α, IL-6, T, B and NK cell counts)	X			X
ECG, electrocardiography	X			X
OCT intracoronary imaging	X			X
Assessment of LDL-C target achievement (<1.4 mmol/L)	X	X	X	X
Medication adherence (assessed by PDC)	X	X	X	X
PCSK9i administration	X	X	X	X
Safety assessment (AE/SAE recording)	X	X	X	X	X

AE, adverse event; ALT, alanine aminotransferase; ApoB, apolipoprotein B; AST, aspartate aminotransferase; B cells, B lymphocytes; T cells, T lymphocytes; CK, creatine kinase; ECG, electrocardiography; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); NK cells, natural killer cells; OCT, optical coherence tomography; PCSK9i, proprotein convertase subtilisin/kexin type nine inhibitors; PDC, proportion of days (PDC=days covered/observation period); SAE, serious adverse event; TC, total cholesterol; TG, triglycerides; TNF-α, tumour necrosis factor alpha; VLDL-C, very low-density lipoprotein cholesterol; WBC, white blood cell.

Study endpoints

The primary endpoint is the absolute change in minimum FCT within a matched target arterial segment, as assessed by OCT from baseline to 6 months. Secondary endpoints include the percent change in minimum FCT, the absolute change in mean minimum FCT, and absolute changes in MLA and maximum lipid arc within the same matched arterial segment, as measured by OCT. Additional secondary measures comprise the presence of macrophage infiltration in target vessels at 6 months, the proportion of patients with OCT-identified vulnerable plaques (defined as FCT<75 µm plus at least two of three features: lipid arc>180°, MLA<3.5 mm² and macrophage infiltration),²⁷ the change in lipid-related biomarkers (total cholesterol, apolipoprotein B, lipoprotein(a), triglycerides, very LDL-C, LDL-C and high-density lipoprotein cholesterol) from baseline to 3 and 6 months, the proportion of patients achieving predefined LDL-C targets (<1.4 mmol/L) at 3 and 6 months, and adherence to lipid-lowering therapy (statin, cholesterol absorption inhibitor and PCSK9i) during the study period.

The exploratory endpoint is defined as the incidence of major adverse cardiovascular events (MACEs) at 6 and 12 months, comprising a composite of cardiac death, non-fatal MI, non-fatal stroke and ischaemia-driven revascularisation (online supplemental material 3) for detailed definitions). Safety assessments focus on the potential risks of intensive lipid-lowering therapy, including bleeding events and immunological effects associated with very low LDL-C levels. Accordingly, bleeding events will be monitored throughout follow-up, while high-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-alpha and the absolute counts of T, B and natural killer cells will be measured at baseline and 6 months.

Sample size determination

The sample size estimation for this study is based on the primary effectiveness endpoint. According to the primary endpoint of the HUYGENS study,¹⁸ the FCT of target lesions was 100.6±40.6 µm in the evolocumab group, compared with 81.7±35.4 µm in the placebo group. Based on these data, and assuming a more conservative treatment effect than observed in HUYGENS, the minimum FCT at 6 months was assumed to be 81.7±35.4 µm in the GDMT group and 99.7±40.6 µm in the early PCSK9i-intensified therapy group. The latter value was derived from the evolocumab arm of the HUYGENS study,¹⁸ resulting in an anticipated between-group difference of approximately 18 µm. Using PASS 2023 software with a two-sample Z-test allowing for unequal variances, and assuming a two-sided α of 0.05 and 90% power, the required sample size was estimated to be approximately 95 participants per group (190 participants in total). Allowing for a 10% dropout rate, the final target sample size was set at approximately 212 participants, with 106 participants in each group.

Data collection and management

Data will be collected at baseline, and at 1, 3 and 6 months during on-site follow-up, as well as at 12 months via telephone follow-up. Trained researchers will record patient information on standardised case report forms, which will be entered into an internet-based electronic data capture (EDC) system and verified against source documents. Collected variables include demographics, medical history, laboratory results, and procedural and lesion-specific characteristics (eg, access route, culprit vessel, lesion length, stenosis severity, lumen diameters, post-procedural outcomes and OCT-derived intracoronary imaging outcomes) and adverse events. Patients who withdraw will not be replaced, although follow-up data will be obtained whenever possible. Data quality will be ensured through standardised researcher training, double-checking of entries, predefined EDC validation rules and secure data storage to maintain confidentiality.

Blinding

The study follows a single-blind design. Investigators responsible for data management and analysis will remain blinded to treatment allocation, while participants will be instructed not to reveal their assigned group during the study.

Statistical analysis

All primary analyses will be conducted in the intention-to-treat population, defined as all randomised participants irrespective of the treatment received. Continuous variables will be summarised as mean±SD or median (IQR), as appropriate, and categorical variables as counts and percentages. Comparisons between treatment groups will use Student’s t-test or Wilcoxon rank-sum test for continuous variables, and chi-square or Fisher’s exact test for categorical variables, as appropriate. The primary endpoint, defined as the absolute change in minimum FCT of the target segment, will be analysed using analysis of covariance (ANCOVA), including treatment group, the stratification factor at randomisation (baseline LDL-C≥1.8 vs <1.8 mmol/L), and baseline minimum FCT as covariates. Secondary continuous endpoints will be analysed using ANCOVA with adjustment for corresponding baseline values, while secondary categorical endpoints will be compared using χ² or Fisher’s exact test, or logistic regression, as appropriate. The exploratory endpoint will be assessed using Kaplan-Meier survival curves and log-rank tests, with HRs and 95% CIs estimated via Cox proportional hazards models. Safety assessments will include comparisons of bleeding events and biomarker changes between groups. Pre-specified subgroup analyses for the primary endpoint will evaluate potential treatment-by-subgroup interactions across the following clinically relevant variables: ACS subtype (ST-elevation MI, non–ST-elevation MI or high-risk unstable angina); diabetes status (yes vs no); lesion length (> 10 mm vs ≤10 mm); vessel diameter (>3 mm vs ≤3 mm); baseline LDL-C level (≥1.8 mmol/L vs <1.8 mmol/L); class of PCSK9i (evolocumab vs inclisiran); stenosis severity (20–50% vs 50–70%); and use of stable statin therapy for ≥4 weeks (yes vs no). A two-sided p-value of less than 0.05 will be considered statistically significant. All analyses will be conducted using SPSS version 26.0.

Data monitoring

A comprehensive safety monitoring plan is established. All adverse events will be systematically documented, managed and followed to resolution or stabilisation. Serious adverse events and unexpected events will be reported without delay to the ethics committee and regulatory authorities. The principal investigator periodically reviews cumulative safety data, and an independent Data Safety Monitoring Board oversees aggregated safety and efficacy outcomes. Investigator meetings will be convened as required to evaluate the risk-benefit balance and to determine the appropriateness of study continuation.

Study timelines

Enrolment of the first patient is planned in January 2026. The recruitment is anticipated to last for 12 to 18 months with 1 year follow-up. All analysis is expected to be completed by January 2029.

Patient and public involvement statement

None.

Discussion

The REPRESS trial will evaluate the effects of early initiation of PCSK9i on coronary atherosclerotic plaques, using prospective, serial OCT imaging of non-culprit arteries in patients with ACS undergoing PCI. Plaques in non-culprit lesions have been consistently linked to plaque vulnerability and rupture in pathological studies, as well as to subsequent cardiac events in prospective clinical studies.^{27 28} Considering the prognostic role of these high-risk features, the REPRESS trial is designed to evaluate the mechanistic impacts of early intensive LDL-C lowering on coronary atherosclerotic plaque stabilisation, focusing on plaque composition and microstructural characteristics, in light of the evidence supporting the substantial LDL-C lowering efficacy of PCSK9i.

The SESS lowering-lipid strategy

The 2023 European Society of Cardiology guidelines for ACS recommend a stepwise intensification of LLT, with high-intensity statins as the first-line therapy for all patients.²⁹ Trials in the statin era demonstrated that early intensive LLT provided superior protection against mortality and MACEs compared with standard regimens.^{30 31} However, real-world practice shows suboptimal implementation, with low LDL-C target attainment and substantial residual risk, especially post-ACS.^{32 33} In China, control rates are even lower (25.5% in high-risk and 6.8% in very high-risk atherosclerotic cardiovascular disease (ASCVD)), mainly due to poor adherence and high-dose statin intolerance.³⁴,³⁶ To address this gap, recent studies have evaluated the early use of PCSK9i.³⁷ In the EVACS (Evolocumab in Acute Coronary Syndrome) study,¹³ initiating evolocumab within 24 hours of ACS enabled nearly 90% of patients to reach LDL-C levels below 55 mg/dL at 1 month, compared with 11% of those receiving statin therapy alone. Similarly, in the EVOPACS (EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes) trial,¹⁴ early administration of 420 mg evolocumab in combination with high-intensity statin therapy lowered LDL-C by 40.7%, with 95.7% of patients achieving the 55 mg/dL target at 8 weeks. The VICTORION-INITIATE trial further demonstrated that an ‘inclisiran first’ approach achieved significantly higher LDL-C goal attainment than standard care (<70 mg/dL: 81.8% vs 22.2%; <55 mg/dL: 71.6% vs 8.9%).³⁸ Based on these findings, the proposed SESS strategy emphasises early intensive LLT after ACS to accelerate achievement of guideline-recommended LDL-C targets and potentially reduce residual cardiovascular risk.¹² However, the SESS strategy still requires additional evidence to support its widespread implementation.

Atherosclerotic plaque response to early intensive LLT

Favourable plaque alterations with early intensive LLT have been consistently reported. In the YELLOW II trial, high-intensity rosuvastatin therapy significantly increased minimal FCT within 8–12 weeks.³⁹ Consistent results have also been reported with high-intensity atorvastatin regimens within 6 months.⁴⁰ The Japanese OCT study demonstrated that adding evolocumab to statins reduced plaque vulnerability as early as 1 month, with further improvement at 3 months.⁴¹ Consistently, the HUYGENS¹⁸ and PACMAN-AMI trial¹⁹ showed that PCSK9i combined with high-intensity or maximally tolerated statins provided incremental stabilisation and morphological benefits at 1 year in patients with ACS. Extending beyond 1 year, the GLAGOV (Global Assessment ofPlaque Regression With a PCSK9 Antibody as Measured byIntravascular Ultrasound) study revealed that patients receiving evolocumab achieved significantly greater plaque volume reduction over 1.5 years compared with placebo plus intensive statin therapy.⁴² Collectively, this evidence suggests that early intensive LLT rapidly enhances FCT within weeks, promotes compositional and volumetric improvements over months and sustains regression with prolonged treatment, particularly when combined with PCSK9i. However, plaque responses evolve dynamically, and because most studies rely on baseline and single follow-up imaging, it remains unclear whether all favourable changes occur simultaneously at any point after LLT initiation. Moreover, evidence regarding the short-term incremental benefit of initiating PCSK9i within the first 6 months in patients with ACS remains limited.²⁰ To address this knowledge gap, the REPRESS trial aims to characterise plaque changes over the short term associated with early intensified LLT using PCSK9i.

The clinical value of the REPRESS trial

While PCSK9i-based LLT has proven effective in intermediate non-culprit lesions, most prior studies have been limited to lesions<50% stenosis, patients with elevated baseline LDL-C, or those on high-intensity statins, and data on short-term benefits within the first 6 months after ACS remain scarce.¹⁸,²⁰ Whether these benefits extend to patients with different clinical profiles or across lesions of varying severity remains uncertain. Exploring such variation may provide insights into disease progression and the broader applicability of PCSK9i. The REPRESS trial is designed to address existing gaps by evaluating the impact of early initiation of PCSK9i on coronary atherosclerosis in patient populations that have been underrepresented in prior studies. Specifically, it focuses on the first 6 months after ACS in patients with 20–70% stenosis in non-culprit vessels, lower baseline LDL-C levels and those not receiving high-intensity statin therapy, and compares this approach with the standard GDMT strategy. In the ‘PCSK9i early’ group, patients with LDL-C <1.8 mmol/L will continue PCSK9i to assess its additional plaque-modifying effects. Consistent with updated Chinese guidelines recommending moderate-intensity statins for ASCVD patients,^{43 44} PCSK9i will be added to moderate-intensity therapy to examine the OCT-derived plaque characteristics in non-culprit arteries, reflecting real-world clinical practice. The control group will receive GDMT rather than fixed-dose statin monotherapy (as used in the HUYGENS and PACMAN-AMI trials), which may fail to reach LDL-C targets and influence cardiovascular outcomes. REPRESS aims to generate clinically relevant evidence to guide optimal lipid-lowering strategies in patients with post-ACS, particularly in China, while also elucidating the early mechanistic effects of the SESS strategy on coronary plaques using advanced OCT imaging within a rational study design.

Limitations

This study has several limitations. First, for non-culprit vessels with approximately 70% stenosis, ischaemia is assessed based on clinical symptoms and ECG by experienced clinicians, while functional evaluations such as fractional flow reserve are not routinely performed. Second, early intensive LLT may raise safety concerns, particularly when very low LDL-C levels are achieved. Meta-analyses have reported a small but statistically significant increase in haemorrhagic stroke risk (relative risk~1.16),⁴⁵ and pooled observational data suggest a numerical increase in overall bleeding events, especially among patients receiving concomitant antithrombotic therapy or with cerebrovascular vulnerability.⁴⁶ Potential effects on immune function at very low LDL-C levels have been theoretically hypothesised based on cholesterol’s role in innate immunity⁴⁷; however, large randomised trials of PCSK9i have not demonstrated an excess of serious infections or immune-related adverse events.^{48 49} Bleeding events and immune-related laboratory parameters will be closely monitored throughout follow-up to ensure participant safety. Third, repeat OCT imaging at 6 months is not part of routine clinical care and is performed for research purposes. Although OCT is an invasive procedure, prior studies have shown that serial imaging can be conducted with a low incidence of complications when performed by experienced operators. In this study, OCT is limited to non-culprit vessels and will follow standardised protocols to minimise procedural risk. Fourth, a limitation of this study is the inclusion of multiple PCSK9i, including evolocumab and inclisiran, as no head-to-head randomised controlled trials have directly compared these agents. Prespecified subgroup analyses will be conducted to explore potential differences in treatment effects. Fifth, the relatively short follow-up may limit the assessment of long-term cardiovascular outcomes and the detection of late adverse effects of early intensive LLT.

Ethics and dissemination

This study will be conducted in accordance with the study protocol, the Declaration of Helsinki, and relevant national and regulatory requirements. Ethical approval has been obtained from the Biomedical Research Ethics Committee of West China Hospital of Sichuan University, which serves as the primary and coordinating centre for this multicentre trial (Review No 1943, 2024). Ethics approval from all other participating centres will be obtained prior to participant recruitment at each site and is anticipated to be completed by June 2026. All participants will provide written informed consent before enrolment. The study will adhere to ethical standards ensuring participant safety, voluntary and informed participation, and strict confidentiality and anonymity in data reporting. Results will be presented following the CONSORT 2010 Statement and disseminated through peer-reviewed publications and presentations at national and international scientific meetings.