Descartes.

Study characteristics
Methods	Type of RCT: 2:1 parallel‐group, double‐blind RCT with stratified randomisation Settings: outpatient care Duration: 52 weeks Start and stop dates: January 2012 and November 2013
Participants	Number of participants: 905 (901 with baseline data) Number lost to follow‐up: 134 Women: 471 (52%) Mean age (SD), years: 56 (11) History of CVD: 136 (15%) Participants with FH: NA Participants with fasting LDL‐C ≥ 75 mg/dL and fasting TG 400 mg/dL
Interventions	Background therapy: SOC, which consisted of diet only, daily atorvastatin 10 mg, 80 mg, or 80 mg + ezetimibe 10 mg Randomised therapy: evolocumab every 4 weeks vs placebo Evolocumab dose: 48 weeks of 420 mg each 4 weeks. 2‐week equivalent dose of 210 mg
Outcomes	CVD, all‐cause mortality
Notes	All lipid analyses performed by Medpace Reference Laboratories (MRL). Laboratories maintained Part III certification according to the CDC Lipid Standardization Program throughout the study. LDL‐C and very low‐density lipoprotein cholesterol measured after preparative ultracentrifugation (β‐quantification). Calculated LDL‐C using Friedewald formula. TGs and cholesterol measured with enzymatic colorimetric tests (Olympus AU2700 or AU5400 Analyzer, Olympus, Center Valley, PA) with calibration directly traceable to CDC reference procedures. ApoB‐containing lipoproteins precipitated with dextran sulphate, and HDL‐C was measured in the supernatant. ApoA1 and ApoB were measured with rate immunonephelometry (Dade Behring BNII nephelometer, Siemens Healthcare Diagnostics, Deerfield, IL), and Lp(a) was measured by immuno turbidimetry (Denka Seiken Co. Ltd. Lp(a) assay from Polymedco, Cortlandt Manor, NY, on the Olympus Analyzer). NCT01516879 Parent trial of OSLER‐2 Funded by Amgen
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation performed centrally using an interactive voice‐response system.
Allocation concealment (selection bias)	Low risk	Randomisation performed centrally using an interactive system.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Although paper and appendix described the study as double‐blind, it was unclear how this was maintained and who was blinded. Lack of blinding will likely cause a change in adherence or participant choices regarding SOC/lifestyle (or both), which may influence outcomes.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Although paper and appendix described the study as double‐blind, it was unclear how this was maintained and who was blinded. However, any lack of blinding of participants and personnel seems unlikely to bias LDL‐C assessment, which was performed in independent laboratories. Outcomes such as adverse events may be biased owing to detection bias.
Incomplete outcome data (attrition bias) All outcomes	High risk	4 participants were randomised but were not included in the ITT (small number, good). However, at 2 weeks of follow‐up, the number of available participants had decreased by about 15% (number of missing measurements 44 (14.57%) in comparison arm, and 90 (15.03%) in intervention arm). In some cases, missing participants were likely due to different enrolment times, limiting follow‐up; however, reported numbers of discontinued participants were similarly high: 73 in the evolocumab arm and 28 in the placebo arm. Missing LDL‐C data were imputed using linear‐mixed models, including baseline measurements. Other missing lipid measurements were imputed using a last observation carried forward approach and were analysed by ANCOVA.
Selective reporting (reporting bias)	Low risk	Reported most endpoints.
Other bias	Low risk	No concerns outside the assessed risk of bias domains.