Trial population

Participants were enrolled across 630 investigational sites located in North America, South America, Europe, Middle East, South Africa, Australia, and New Zealand. Patients were eligible if they were at least 45 years of age, recently hospitalized for an acute coronary syndrome within the previous 1–3 months, clinically stable, treated with guidelines-based management of LDL-cholesterol at a minimum to a target level <2.6 mmol/L, and confirmed in a central laboratory to have the AA genotype at variant rs1967309 in the ADCY9 gene in DNA derived from whole blood using the validated cobas® genotype system (Roche Molecular Systems) and a real-time polymerase chain reaction test. Genetic testing results were available to the clinical research site within 2–4 days of the blood draw.

Patients were excluded if they had New York Heart Association Class III or IV heart failure, coronary artery bypass graft surgery between the index event and the randomization, clinically apparent liver disease, a history of malignancy (except for curatively treated basal cell or squamous cell carcinoma of the skin) during the 1 year prior to screening, current or recent alcohol or drug abuse, and/or a life expectancy shorter than 3 years; serum triglyceride level above 5.65 mmol/L, glycated haemoglobin above 10%, serum creatinine above 195 μmol/L, transaminase level higher than three times the upper limit of normal, and/or haemoglobin lower than 10 g/dL; or were pregnant, breastfeeding, or of childbearing potential if not using contraception. Further details regarding eligibility criteria are provided in the Supplementary material online, Tables S2 and S3.

Written informed consent was obtained from all patients before enrolment. Blinded randomization was centralized and performed electronically through an automated IWRS. Allocation sequence was computer generated in a 1:1 ratio using a global randomization code and was stratified as described above. Eligible patients were randomized by research nurses through the IWRS system that provided the bottle number to give to patients. The patient randomization numbers were allocated sequentially in the order in which the participants were enrolled.

All staff involved, including study investigators and nurses, and patients were blinded to the treatment received. All randomized patients received instructions on a heart healthy diet; were counselled on appropriate lifestyle modifications such as weight control, physical activity, and smoking cessation; received contemporary evidence-based medical care; and were to complete all planned revascularization procedures prior to randomization. Clinical evaluations occurred at 1 and 6 months following randomization, and visits thereafter took place every 6 months for efficacy and safety assessments until completion of the trial.