PCSK 9 Inhibitor Added to High-Intensity Statin Therapy to Prevent Cardiovascular Events in Patients With ACS After PCI

Study Overview
=================
Brief Summary
-----------------
The primary objective was to evaluate the effect of PCSK 9 Inhibitor (initiated within 4 h from PCI for the culprit lesion) with high-intensity statin treatment, compared to placebo with high-intensity statin treatment, on cardiovascular events (including cardiovascular death, myocardial infarction, stroke or transit ischemic attack, re-hospitalization due to unstable angina or heart failure, or any ischemia-driven coronary revascularization) in patients with acute coronary syndrome and multiple lesions.

Detailed Description
-----------------
Patients with acute coronary syndrome (ACS) are at high-risk. ACS patients are commonly associated with multiple lesions or multivessel disease. Percutaneous coronary intervention (PCI) is an effective treatment for culprit lesions in ACS. Statin at high-intensity is recommended by current guidelines in order to prevent/slow the progression of non-culprit disease or restenosis. PCSK9 inhibitor serves as the most powerful medication in lowering LDL via promoting the expression of LDL receptors in the liver. However, if the combination of PCSK9 inhibitor with high-intensity statin treatment could significantly reduce the cardiovascular events in patients with ACS who underwent PCI remains unknown.

Official Title
-----------------
PCSK 9 Inhibitor Added to High-Intensity Statin Therapy to Prevent Cardiovascular Events in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study

Conditions
-----------------
Acute Coronary Syndrome, Hyperlipidemias, Percutaneous Coronary Intervention, Cardiovascular Events

Intervention / Treatment
-----------------
* Drug: Placebo plus high-intensity statin
* Drug: PCSK 9 Inhibitor plus high-intensity statin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, age ≥18 y at screening Patients with ACS who underwent PCI for culprit lesions. ACS defined as: Unstable angina, defined as rest pain lasting for 5-30 minutes or deteriorative exertional angina with either a) transient ST segment depression or elevation, or b) angiography showing a visually estimated diameter stenosis ≥90% or a ruptured plaque or thrombotic lesion Non-ST elevation myocardial infarction (NSTEMI), defined as positive troponin consistent with clinical syndrome and non-ST-segment elevation ST elevation MI (STEMI), defined as positive troponin consistent with clinical syndrome and ST-segment elevation LDL-C ≥70 mg/dL (≥1.8 mmol/L) assessed prior to, or during PCI in patients who have been receiving any stable statin regimen ≥4 wk prior to enrolment; or LDL-C ≥90 mg/dL (≥2.3 mmol/L) in patients who have been on moderate or low intensity statin regimen prior to enrollment; or LDL-C ≥125 mg/dL (≥3.2 mmol/L) in patients who are statin-naïve or have not been on stable statin regimen for ≥4 wk prior to enrollment At least one major native coronary artery (diseased vessels) or lesion meeting the following criteria following the qualifying PCI procedure: Angiographic evidence of <50% diameter stenosis Diseased vessel must not be a bypass (saphenous vein or arterial) graft or a bypassed native vessel Diseased vessel must not have undergone previous PCI prior-to enrollment Hemodynamic stability allowing the repetitive administration of nitroglycerine if necessary Ability to understand the requirements of the study and to provide informed consent Willingness of patient to undergo follow-up procedures and visits Exclusion Criteria: Patients in whom the qualifying index ACS event occurred > 30 days prior to randomization Fasting low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL (< 1.8 mmol/L) if on stable statin treatment for minimal 4 weeks; OR LDL-C <90 mg/dL (<2.3 mmol/L) in patients who have been on moderate or low intensity statin regimen prior to enrollment; OR LDL-C <125 mg/dL (< 3.2 mmol/L) in patients who are statin-naïve or have not been on stable statin regimen for ≥4 wk prior to enrollment Fasting serum triglycerides (TG) >400 mg/dL (>4.52 mmol/L) prior to randomization History of coronary artery bypass surgery Residual diameter stenosis >50% by visual examination after PCI of the culprit lesion TIMI flow <2 after culprit vessel PCI Unstable clinical status (hemodynamic or electrical instability) Uncontrolled hypertension (multiple readings with SBP > 180 mmHg or DBP > 110 mmHg) New York Heart Association (NYHA) class III or IV, or last known left ventricular ejection fraction < 30% Known history of hemorrhagic stroke less than 180 days prior to randomization Uncontrolled cardiac arrhythmia, defined as recurrent and symptomatic ventricular tachycardia or atrial fibrillation with rapid ventricular response not controlled by medications in the past 3 mo prior to screening Severe renal dysfunction, defined by estimated glomerular filtration rate <30 ml/min/1.73m^2 Active liver disease or hepatic dysfunction Known intolerance to rosuvastatin OR known statin intolerance Known allergy to contrast medium, heparin, aspirin, ticagrelor or prasugrel or clopidogrel Patients who previously received PCSK9 inhibitor Patient who received cholesterol ester transfer protein inhibitors in the past 12 mo prior to screening Treatment with systemic steroids or systemic cyclosporine in the past 3 mo Known active infection or major hematologic, metabolic, or endocrine dysfunction in the judgment of the Investigator Planned Non-cardiac surgery within 12 mo Patients who will not be available for study-required visits in the judgment of the Investigator Current enrolment in another investigational device or drug study History of cancer within the past 5 y, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer Estimated life expectancy less than 12 mo Female of childbearing potential (age <50 y and last menstruation within the last 12 mo), who did not undergo tubal ligation, ovariectomy or hysterectomy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are randomly (at a ratio of 1:1) assigned to PCSK9 inhibitor plus high-intensity statin or placebo plus high-intensity statin group, and then the results at 1 year, 2- or 3-year are compared
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo plus high-intensity statin<br>Participants received placebo subcutaneous injections once every 2 weeks (Q2W) plus high-intensity statin treatment (Rosuvastatin, 20 mg, once daily) | Drug: Placebo plus high-intensity statin<br>* Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen, Q2W, and oral administration of rosuvastatin (20 mg, once daily).<br>|
| Active Comparator: PCSK 9 Inhibitor plus high-intensity statin<br>Participants received PCSK 9 Inhibitor Q2W subcutaneous injections | Drug: PCSK 9 Inhibitor plus high-intensity statin<br>* Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen, Q2W, and oral administration of rosuvastatin (20 mg, once daily).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular events | Cardiovascular events defined as the composite of cardiovascular death, myocardial infarction, stroke or transit ischemic attack, re-hospitalization due to unstable angina or heart failure, or any ischemia-driven coronary revascularization. | 12 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular death | It will be adjudicated by an independent external CEC according to protocol defined definition. | 12 months after randomization | 
| All cause death | It is defined as any death from randomization to the last visit. | 12 months after randomization | 
| Myocardial infarction | It will be adjudicated by an independent external CEC. | 12 months after randomization | 
| Stroke or transient ischemic attack (TIA) | stroke or TIA will be adjudicated by an independent external CEC. | 12 months after randomization | 
| Ischemia-driven coronary revascularization | It will be adjudicated by an independent external CEC. | 12 months after randomization | 
| Re-hospitalization due to unstable angina or heart failure | It will be adjudicated by an independent external CEC. | 12 months after randomization | 
| Diagnostic malignant tumor | It will be adjudicated by an independent external CEC. | 12 months after randomization | 
| Clinical relevant bleeding | It will be adjudicated by an independent external CEC. The BARC defined clinical relevant bleeding includes BARC 2-5 | 12 months after randomization | 
| PCSK9 inhibitors or statin intolerance | It will be adjudicated by an independent external CEC. | 12 months after randomization | 
| mFCT | Change in minimal fibrous cap thickness (FCT) | From baseline to week 52 |