This study is being done to find out if the investigational study treatment, called inclisiran, can help prevent cardiovascular events (such as heart attacks, strokes, and cardiovascular-related deaths) in adults who already have been diagnosed with cardiovascular disease.

Inclisiran is designed to lower LDL-cholesterol (also known as “bad” cholesterol), and will be given as an initial dose, followed by a dose at 3 months and then every 6 months in addition to statin medication. This study will help us understand if a reduction in LDL-cholesterol caused by inclisiran will also reduce important cardiovascular events from occurring.

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Male or female ≥40 years of age at signing of informed consent.

3. Fasting LDL-C ≥1.8 mmol/L (70 mg/dL) at the Screening Visit, measured at the central laboratory.

4. At the Screening Visit, participants must be on a stable (≥4 weeks) and well-tolerated lipid-lowering regimen (including e.g. with or without Ezetimibe) that must include a high-intensity statin therapy with either atorvastatin ≥40 mg QD or rosuvastatin ≥20 mg QD

5. Established CV disease defined as ANY of the following three conditions:

a) MI: Spontaneous MI (either ST-elevation MI or non-ST-elevation MI), which was not the result of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), and which occurred in the period ≥4 weeks prior to the first study visit (Statin Optimization Screening Visit or Screening Visit). Confirmation of MI is a participant history/participant recollection of signs or symptoms consistent with presentation of MI, and at least one of the following: 

*Documentation of cardiac biomarkers that exceed the diagnostic threshold of a local laboratory for MI

*Pathological Q waves on ECG or other ECG changes

*Imaging evidence of loss of viable myocardium or regional wall motion abnormality in a pattern consistent with an infarction or ischemic etiology

*Identification of a coronary thrombus by angiography at the time of presentation with MI

b) Stroke: History of ischemic stroke (an acute episode of focal cerebral, spinal, or visual dysfunction caused by infarction of central nervous system tissue) having occurred in the period ≥4 weeks prior to the first study visit (Statin Optimization Screening Visit or Screening Visit) documented by computerized tomography (CT) scan, Magnetic Resonance Imaging (MRI) or other visualization method. Transient ischemic attack, lacunar infarction or embolic stroke (not of atherosclerotic origin) are not qualifying events.
c) Symptomatic PAD, as evidenced by either intermittent claudication with (ABI) <0.85, prior peripheral arterial revascularization procedure, or, amputation due to atherosclerotic disease. Thromboangiitis obliterans is not a qualifying event.

Exclusion Criteria:

1. Acute coronary syndrome, ischemic stroke, peripheral arterial revascularization procedure or amputation due to atherosclerotic disease <4 weeks prior to the first study visit

2. Planned or expected cardiac, cerebrovascular or peripheral artery surgery or re-vascularization within the 6 months after the first study visit.

3. Heart failure NYHA class III or IV at the Statin Optimization Screening Visit (if applicable), the Screening Visit, or before randomization.

4. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver at the Statin Optimization Screening Visit (if applicable) or Screening Visit.

5. Previous (within 90 days prior to the first study visit i.e. the Statin Optimization Screening Visit or the Screening Visit) treatment with a mAb directed towards PCSK9 (e.g., evolocumab, alirocumab) or planned use post first study visit.

6. Previous exposure to inclisiran or any other non-mAb PCSK9-targeted therapy, either as an investigational or marketed drug within 2 years prior to the first study visit (Statin Optimization Screening Visit or the Screening Visit, whichever comes first).

7. History of hypersensitivity to the study drug or its excipients or to other siRNA drugs.

8. Use of other investigational drugs within 5 half-lives, 30 days or until the expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever is longer, or longer if required by local regulation, prior to the first study visit (Statin Optimization Screening Visit or the Screening Visit, whichever comes first).

9. Severe concomitant non-CV disease that is expected to reduce life expectancy to less than 5 years.

10. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the 3 years prior to the first study visit (defined as either the Statin Optimization Screening Visit or the Screening Visit, whichever comes first).

11. Any surgical or medical condition, which in the opinion of the investigator, may place the participant at higher risk from his/her participation in the study, or is likely to prevent the participant from complying with the requirements of the study or completing the study.

12. Unwillingness or inability (e.g., physical or cognitive) to comply with study procedures (including adherence to study visits, fasting blood draws and compliance with study treatment regimens), and medication administration (injections) and schedule.

13. Pregnant or nursing (lactating) women.

14. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.