Supplementary Online Content

Supplementary Online Content Navarese EP, Robinson JG, Kowalewski M, et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA. doi:10.1001/jama.2018.2525 etables 1-12 efigures 1-22 ereferences This supplementary material has been provided by the authors to give readers additional information about their work.

Supplementary Table 1. METHODS and MEDLINE Search Strategy. What is known Evidence has consistently shown that statins reduce total cardiovascular events, and that further low density lipoprotein-cholesterol (LDL-C) lowering by intensifying statin therapy, adding ezetimibe, or adding a proprotein convertase subtilisin/kexin type 9 inhibiting monoclonal antibody (PCSK9 mab) provided incremental additional reduction in cardiovascular risk 1-43. More recent trials have not demonstrated trends in reductions in mortality events. Data Sources and Searches The following databases were searched: Cochrane Central Register of Controlled Trials, MEDLINE, and Embase; TCTMD (www.tctmd.com), ClinicalTrials.gov, Clinical Trial Results (www.clinicaltrialresults.org), and major congress proceedings, from database inception until 1 st February 2018. The following keywords were used: lipidlowering, statin, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody, randomized controlled trial (RCT), and hypercholesterolemia. The results of the MEDLINE electronic search are reported in full in Supplementary Table 1. Citations were screened at title/abstract level and retrieved as full reports if considered relevant. Finally, we verified our search by cross-checking systematic reviews and meta-analyses on lipid lowering strategies. Study Selection The main inclusion criteria were: (1) randomized trials including at least 1,000 patients receiving the allocated pharmacological LDL-C lowering strategy for a minimum of 48 weeks, (2) The included interventions had to be statins and/or nonstatin therapies in combination with a statin; specifically either ezetimibe or PCSK9 inhibitors, (3)The study had to report cardiovascular outcomes of interest. We excluded studies if: (1) the nonstatin intervention did not reduce LDL-C levels primarily through upregulation of LDL receptor expression (i.e., trials of fibrates, niacin, cholesteryl ester transfer protein [CETP] inhibitors were excluded); (2) the study population focused on participants with significant competing risks (i.e., heart failure or end-stage renal disease or 3) headto-head comparisons of different groups of drugs in monotherapy. Data Extraction and Quality Assessment Two investigators (MK and MK) who were not involved in any of the selected trials independently abstracted the data using prespecified forms. Two investigators (MK and MK) then independently appraised the accuracy of the abstractions and resolved any discrepancies by consensus after discussion with a third investigator (EPN). Two unblinded investigators (MK and MK) independently appraised the potential risks of bias of the RCTs using methods described in the Cochrane Collaboration guidelines. Any divergences in the bias assessment were than reported and summarized as Cohen s Kappa (Supplementary Table 2). More intensive therapy was defined as the more potent pharmacological strategy while less intensive therapy corresponded to the control group of the original trial. Mean or median baseline and final LDL-C values were abstracted for both treatment groups. Clinical endpoints included all-cause mortality, cardiovascular mortality, myocardial infarction (MI), cerebrovascular events (Supplementary Table 3), revascularizations (coronary artery bypass grafting, coronary or other arterial percutaneous interventions), and major cardiovascular events (MACE; Supplementary Table 4). Event rates reported in the trial manuscript were abstracted if available; if not reported, then event rates from the 2010 CTT meta-analysis of statin trials were used 1. Data Synthesis and Statistical Analysis Trial level data were analyzed according to the original randomization group for which outcome data were available. The co-primary endpoints were total mortality and cardiovascular mortality. Secondary endpoints included myocardial infarction, cerebrovascular events, revascularizations and MACE. To account for potential differences in study duration and drug exposure, rate ratios (RRs) with 95% CIs derived from an analysis with adjusted models by person-years used as summary statistics, a measure incorporating trial duration.

Absolute risk differences (ARD) between the 2 treatment groups were expressed as incident events per 1000 person years. Random effects meta-regression with baseline LDL-C as covariate was used for the main model, with additional co-variates added in the adjusted analyses. Statistical heterogeneity was assessed using the Cochran Q test and the I 2 statistic 18. Pooled RRs were calculated using a random-effects model. Random effects meta-analyses were performed for prespecified LDL-C subgroups. Stratified analyses were prespecified for commonly used clinical cut-points of mean baseline LDL-C (<100, 100-129, 130-159, and >160 mg/dl were those used in the National Cholesterol Education Program Adult Treatment Panel 3 as LDL-C cutpoints. Prespecified mean difference between final LDL-C levels in the more intensive and less intensive study arms were <35 md/dl, 35-65 mg/dl and >65 mg/dl. Additional stratified sensitivity analyses were based on type of agent used in the treatment groups (statin vs statin+ezetimibe, PCSK9 antibody), treatment in the control group (active vs placebo) and population (primary or secondary). Potential publication bias was examined by constructing a funnel plot in which the SE of the log RR was plotted against the RR. The asymmetry of the plot was estimated both visually and by a linear regression approach 19. By means of random effects meta-regression models we investigated the impact of baseline LDL-C levels on the RR of all investigated endpoints 20. Supplemental multivariable meta-regressions were performed adjusting for covariates in addition to baseline LDL-C: (1) magnitude of LDL-C reduction; (2) baseline risk profile, (2) type of agent, (2) age. Sensitivity analyses testing for potential sources of statistical heterogeneity were defined for study population (primary or secondary, mixed excluded), mean age <65 years or >65 years, type of agent (statin vs PCSK9 Ab/statin, vs ezetimibe/statin), level of risk (low/moderate vs high risk defined as C-reactive protein >2 mg/l, diabetes, kidney disease, or recent MI or acute coronary syndrome, or revascularization). A cumulative meta-analysis to explore the possible impact of the year of study conduction was performed excluding studies conducted prior to year 2000. Additional metaanalyses evaluated trials with a low risk of bias (excluding ALLHAT-LLT, IDEAL, MEGA, GREACE, OSLER1&2), type of treatment in the control group, and the type of agent used in the active treatment group. Sensitivity analyses applying the CTT baseline LDL-C cut-offs to our analysis for each individual endpoint were also conducted. For the summary treatment effect estimate, a 2-tailed P value less than 0.05 was considered statistically significant. To compare treatment effects in subgroups a formal test of interaction was performed; the Bonferroni correction was applied for multiple comparisons. Analyses were done by using Review Manager, version 5.3 (Cochrane Collaboration, Copenhagen, Denmark) and Comprehensive Meta-Analysis Software 2.0 (Biostat, Englewood, NJ). MEDLINE search strategy N Search Records 1 Lipid AND lowering 27,490 2 Lipid AND lowering AND random* 6,226 3 Lipid AND lowering AND random* AND trial 4,941 4 LDL AND lowering 9,493 5 LDL AND lowering AND random* 2,965 6 LDL AND lowering AND random* AND trial 2,520 7 Cholesterol AND lowering 18,828 8 Cholesterol AND lowering AND random* 4,717 9 Cholesterol AND lowering AND random* AND trial 3,776 10 Statin AND cholesterol 18,045 11 Statin AND LDL 10,278 12 Statin AND lipid 22,353 13 Ezetimibe AND cholesterol 1,991 14 Ezetimibe AND LDL 1,427

15 Ezetimibe AND lipid 1,989 16 proprotein convertase subtilisin/kexin type 9 AND cholesterol 1,365 17 proprotein convertase subtilisin/kexin type 9 AND LDL 1,378 18 proprotein convertase subtilisin/kexin type 9 AND lipid 1,261 19 Lipid AND hypercholesterolemia 25,351 20 LDL AND hypercholesterolemia 13,106 21 Statin AND hypercholesterolemia 6,999 22 Ezetimibe AND hypercholesterolemia 1,001 23 proprotein convertase subtilisin/kexin type 9 AND hypercholesterolemia 854 LDL, low density lipoprotein

Supplementary Table 2. Listing of potential sources of bias. Study Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data Selective reporting Other bias 4S 1994 7 A to Z 2004 21 AFCAPS-TexCAPS 1998 22 ALERT 2003 23 ALLHAT-LLT 2002 24 ALLIANCE 2004 29 ASCOT-LLA 2003 31 ASPEN 2006 28 CARDS 2004 27 CARE 1996 30 FOURIER 2017 3 GISSI-P 2000 25 GREACE 2002 26 HOPE-3 2016 32 HPS 2002 43 IDEAL 2005 11 IMPROVE-IT 2015 2 JUPITER 2008 9 LIPID 1998 8 LIPS 2002 33 MEGA 2006 34 ODYSSEY LONG TERM 2015 4 OSLER 1&2 2015 5

PROSPER 2002 35 PROVE IT-TIMI 22 2004 12 SEARCH 2010 36 SEAS 2008 37 SHARP 2011 38 SPARCL 2006 39 SPIRE-1 2017 40 SPIRE-2 2017 40 The Post CABG Trial 1997 41 TNT 2005 10 WOSCOPS 1995 42 Cohen s Kappa 0.90 0.86 0.86 0.94 0.86 0.90 0.76 high risk of bias; unclear risk of bias; low risk of bias 4S (SSSS), Scandinavian Simvastatin Survival Study; A to Z, Aggrastat to Zocor; AFCAPS-TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALERT, Assessment of LEscol in Renal Transplantation Study; ALLHAT LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; ASCOT- LLA, Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus; CARDS, Collaborative Atorvastatin Diabetes Study; CARE, Cholesterol And Recurrent Events; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; GISSI-P, Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico; GREACE, The GREek Atorvastatin and Coronary-heart-disease Evaluation Study; HOPE-3, Heart Outcomes Prevention Evaluation; HPS, Heart Protection Study; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study group; LIPID, Long term Intervention with Pravastatin in Ischaemic Disease; LIPS, Lescol Intervention Prevention Study; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study Group; ODYSSEY LONG TERM, Long-term Safety and Tolerability of Ali-rocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy; OSLER 1&2, Open-Label Study of Long- Term Evaluation against LDL Cholesterol Phase 1 & Phase 2; PROSPER, PROspective Study of Pravastatin in the Elderly at Risk; PROVE IT-TIMI 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy; SEARCH, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SEAS, Simvastatin and Ezetimibe in Aortic Stenosis; SHARP, Study of Heart and Renal Protection; SPARCL, The Stroke Prevention by Aggressive Reduction in Cholesterol Levels; SPIRE-1&2, Studies of PCSK9 Inhibition and the Reduction of Vascular Events 1&2; The Post CABG, Post-Coronary Artery Bypass Graft; TNT, Treating to New Targets; WOSCOPS, West of Scotland Coronary Prevention Study.

Supplementary Table 3. Cerebrovascular events definitions across studies. Study Cerebrovascular event 4S 1994 7 Any cerebrovascular event A to Z 2004 21 Stroke AFCAPS-TexCAPS 1998 22 Total stroke ALERT 2003 23 Fatal or non-fatal stroke, transient ischaemic attack ALLHAT-LLT 2002 24 Fatal or nonfatal stroke ALLIANCE 2004 29 Stroke ASCOT-LLA 2003 31 Fatal or nonfatal stroke ASPEN 2006 28 Fatal or nonfatal stroke CARDS 2004 27 Stroke CARE 1996 30 Stroke FOURIER 2017 3 Total stroke GISSI-P 2000 25 Fatal or nonfatal stroke GREACE 2002 26 Stroke HOPE-3 2016 32 Stroke HPS 2002 43 Any stroke IDEAL 2005 11 Fatal or nonfatal stroke IMPROVE-IT 2015 2 Any stroke JUPITER 2008 9 Any stroke LIPID 1998 8 Any stroke LIPS 2002 33 Fatal stroke MEGA 2006 34 Any stroke ODYSSEY LONG TERM 2015 4 Fatal or nonfatal ischemic stroke OSLER 1&2 2015 5 Stroke or transient ischemic attack PROSPER 2002 35 Fatal or nonfatal stroke PROVE IT-TIMI 22 2004 12 Stroke SEARCH 2010 36 Total stroke SEAS 2008 37 Nonhaemorrhagic stroke SHARP 2011 38 Haemorrhagic or nonhaemorrhagic stroke SPARCL 2006 39 Fatal or nonfatal stroke SPIRE-1 2017 40 Nonfatal stroke SPIRE-2 2017 40 Nonfatal stroke The Post CABG Trial 1997 41 Stroke TNT 2005 10 Fatal or nonfatal stroke or transient ischemic attack WOSCOPS 1995 42 Fatal or nonfatal stroke 4S (SSSS), Scandinavian Simvastatin Survival Study; A to Z, Aggrastat to Zocor; AFCAPS-TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALERT, Assessment of LEscol in Renal Transplantation Study; ALLHAT LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus; CARDS, Collaborative Atorvastatin Diabetes Study; CARE, Cholesterol And Recurrent Events; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; GISSI-P, Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico; GREACE, The GREek Atorvastatin and Coronary-heart-disease Evaluation Study; HOPE-3, Heart Outcomes Prevention Evaluation; HPS, Heart Protection Study; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study group; LIPID, Long term Intervention with Pravastatin in Ischaemic Disease; LIPS, Lescol Intervention Prevention Study; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study Group; ODYSSEY LONG TERM, Long-term Safety and Tolerability of Ali-rocumab in High Cardiovascular

Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy; OSLER 1&2, Open-Label Study of Long-Term Evaluation against LDL Cholesterol Phase 1 & Phase 2; PROSPER, PROspective Study of Pravastatin in the Elderly at Risk; PROVE IT-TIMI 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy; SEARCH, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SEAS, Simvastatin and Ezetimibe in Aortic Stenosis; SHARP, Study of Heart and Renal Protection; SPARCL, The Stroke Prevention by Aggressive Reduction in Cholesterol Levels; SPIRE-1&2, Studies of PCSK9 Inhibition and the Reduction of Vascular Events 1&2; The Post CABG, Post- Coronary Artery Bypass Graft; TNT, Treating to New Targets; WOSCOPS, West of Scotland Coronary Prevention Study.

Supplementary Table 4. Composite endpoint MACE definitions across studies (where applicable only). Study 4S 1994 7 A to Z 2004 21 AFCAPS- TexCAPS 1998 22 ALERT 2003 23 ALLIANC E 2004 29 ASCOT- LLA 2003 31 ASPEN 2006 28 CARDS 2004 27 CARE 1996 30 FOURIER 2017 3 GISSI-P 2000 25 HOPE-3 2016 32 HPS 2002 43 IDEAL 2005 11 IMPROVE- IT 2015 2 JUPITER 2008 9 LIPID 1998 8 LIPS 2002 33 MEGA 2006 34 ODYSSEY LONG TERM 2015 4 OSLER 1&2 2015 5 PROSPER 2002 35 PROVE IT- TIMI 22 2004 12 SEARCH 2010 36 MACE Secondary endpoint: coronary death, nonfatal definite or probable MI, silent MI, or resuscitated cardiac arrest Primary endpoint: cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke Primary end point: fatal or nonfatal MI, unstable angina, or sudden cardiac death major adverse cardiac event, defined as cardiac death, non-fatal MI verified by hospital records, or coronary revascularization procedure, including coronary-artery bypass graft or percutaneous coronary intervention Primary endpoint: cardiac death, non-fatal MI, resuscitated cardiac arrest, cardiac revascularization, and unstable angina requiring hospitalization Secondary endpoint: total cardiovascular events and procedures Primary endpoint: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization Primary endpoint: acute coronary heart disease events, coronary revascularization, or stroke. Primary endpoint: Death from CHD or nonfatal MI Primary endpoint: cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization the cumulative rate of total mortality, non-fatal MI, and stroke First co-primary outcome: death from cardiovascular causes, nonfatal MI, or nonfatal stroke Any major vascular event: coronary death, nonfatal MI, stroke, revascularization MACE: CHD death, nonfatal MI, cardiac arrest with resuscitation and stroke Primary end point: death from cardiovascular causes, major coronary event, or nonfatal stroke Primary end point: myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes Death due to CHD or nonfatal MI MACE: cardiac death, nonfatal myocardial infarction, or re-intervention procedure coronary heart disease Post hoc: death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, and unstable angina requiring hospitalization Post hoc: death, major coronary events, and major cerebrovascular events Primary endpoint: death from CHD or nonfatal MI or fatal or non-fatal stroke Primary end point: death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke Primary endpoint: coronary death, myocardial infarction, stroke, or arterial revascularization

SEAS 2008 37 SPARCL 2006 39 SPIRE-1&2 2017 40 The Post CABG Trial 1997 41 TNT 2005 10 Primary end point: death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, CABG, PCI, and non-hemorrhagic stroke. MACE: death from cardiac causes, nonfatal MI, resuscitation after cardiac arrest, nonfatal or fatal stroke Nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death All-cause mortality, nonfatal MI, stroke, revascularization Primary endpoint: death from CHD, nonfatal non procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke WOSCOPS 1995 42 Nonfatal MI or death from CHD 4S (SSSS), Scandinavian Simvastatin Survival Study; A to Z, Aggrastat to Zocor; AFCAPS-TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALERT, Assessment of LEscol in Renal Transplantation Study; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus; CARDS, Collaborative Atorvastatin Diabetes Study; CARE, Cholesterol And Recurrent Events; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; GISSI-P, Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico; HOPE-3, Heart Outcomes Prevention Evaluation; HPS, Heart Protection Study; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study group; LIPID, Long term Intervention with Pravastatin in Ischaemic Disease; LIPS, Lescol Intervention Prevention Study; MACE = major adverse cardiovascular events; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study Group; ODYSSEY LONG TERM, Long-term Safety and Tolerability of Ali-rocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy; OSLER 1&2, Open- Label Study of Long-Term Evaluation against LDL Cholesterol Phase 1 & Phase 2; PROSPER, PROspective Study of Pravastatin in the Elderly at Risk; PROVE IT-TIMI 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy; SEARCH, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SEAS, Simvastatin and Ezetimibe in Aortic Stenosis; SHARP, Study of Heart and Renal Protection; SPARCL, The Stroke Prevention by Aggressive Reduction in Cholesterol Levels; SPIRE-1&2, Studies of PCSK9 Inhibition and the Reduction of Vascular Events 1&2; The Post CABG, Post-Coronary Artery Bypass Graft; TNT, Treating to New Targets; WOSCOPS, West of Scotland Coronary Prevention Study.

Supplementary Table 5. Sources of statistical heterogeneity in subgroup analyses. Subgroup Number of studies ALL-CAUSE MORTALITY Analysis by baseline LDL-C in the more intensive lipid lowering arm 100-129mg/dL LDL-C Number of patients Setting primary prevention 6 49493 secondary prevention 4 19888 Type of agent statin 7 53305 PCKS9 antibody 2 6806 statin + ezetimibe 1 9270 Risk intermediate/low risk 2 17170 high risk 8 52211 Age <65 yo. 8 38874 65 yo. 2 30507 CARDIOVASCULAR MORTALITY Analysis by baseline LDL-C in the more intensive lipid lowering arm 100-129mg/dL LDL-C Setting primary prevention 6 49493 secondary prevention 4 19888 Type of agent statin 7 53305 PCKS9 antibody 2 6806 NO. OF PATIENTS WITH EVENT/ TOTAL NO. (%) MORE INTENSIVE LESS INTENSIVE LDL-C LOWERING LDL-C LOWERING 1809/25528 (7.09%) 524/10356 (5.06%) 1179/26705 (4.41%) 12/4529 (0.26%) 1142/4650 (24.56%) 338/9337 (3.62%) 1995/26547 (7.51%) 1801/20622 (8.73%) 532/15262 (3.49%) 502/25528 (1.97%) 333/10356 (3.22%) 629/26705 (2.36%) 8/4529 (0.18%) 1875/23965 (7.82%) 580/9532 (6.08%) 1324/26600 (4.98%) 16/2277 (0.70%) 1115/4620 (24.13%) 363/7833 (4.63%) 2092/25664 (8.15%) 1851/18252 (10.14%) 604/15245 (3.96%) 589/23965 (2.46%) 363/9532 (3.81%) 758/26600 (2.85%) 10/2277 (0.44%) Rate Ratio [CIs 95%] 0.91 [0.80, 1.03] 0.80 [0.63, 1.02] 0.88 [0.80, 0.96] 0.38 [0.18, 0.80] 1.02 [0.94, 1.11] 0.68 [0.27, 1.72] 0.87 [0.77, 0.99] 0.87 [0.76, 1.00] 0.87 [0.75, 1.01] 0.90 [0.81, 1.00] 0.82 [0.61, 1.10] 0.91 [0.83, 0.99] 0.41 [0.16, 1.05] Interaction p-value >0.99 0.02 >0.99 0.99 >0.99 0.56

statin + ezetimibe 1 9270 Risk intermediate/low risk 2 17170 high risk 8 52211 Age <65 yo. 8 38874 65 yo. 2 30507 Analysis by absolute magnitude of LDL-C reduction 35-65 mg/dl Setting primary prevention 8 56785 secondary prevention 8 91739 Type of agent statin 13 93522 PCKS9 antibody 3 55002 Risk intermediate/low risk 2 13200 high risk 14 146071 Age <65 yo. 13 104382 65 yo. 3 44142 MYOCARDIAL INFARCTION Analysis by baseline LDL-C in the more intensive lipid lowering arm <100 mg/dl LDL-C Type of agent statin 2 22065 Threshold 100-129mg/dL LDL-C PCKS9 antibody 2 44381 statin + ezetimibe 1 18144 361/4650 (7.76%) 158/9337 (1.69%) 840/26547 (2.65%) 761/20622 (3.69%) 74/15262 (0.48%) 294/28410 (1.03%) 1559/45886 (3.40%) 1700/46792 (3.63%) 316/27504 (1.15%) 67/6606 (1.01%) 1901/73066 (2.60%) 1058/52235 (2.03%) 958/22061 (4.34%) 802/11026 (7.27%) 566/22192 (2.55%) 977/9067 (10.78%) 388/4620 (8.40%) 174/7833 (2.22%) 778/25664 (3.03%) 828/18252 (4.54%) 204/15245 (1.34%) 648/28375 (1.56%) 1837/45853 (4.01%) 2181/46730 (4.67%) 304/27498 (1.11%) 98/6594 (1.49%) 2273/73005 (3.11%) 1269/52147 (2.43%) 1216/22081 (5.51%) 964/11039 (8.73%) 727/22189 (3.28%) 1118/9077 (12.32%) 0.92 [0.80, 1.07] 0.89 [0.72, 1.11] 0.88 [0.78, 1.00] 0.89 [0.78, 1.01] 0.88 [0.72, 1.07] 0.77 [0.67, 0.87] 0.87 [0.78, 0.98] 0.80 [0.75, 0.85] 1.04 [0.89, 1.22] 0.68 [0.50, 0.93] 0.84 [0.78, 0.90] 0.83 [0.74, 0.92] 0.83 [0.76, 0.90] 0.83 [0.76, 0.91] 0.88 [0.59, 1.33] 0.87 [0.80, 0.95] >0.99 >0.99 >0.99 0.003 >0.99 >0.99 >0.99

Setting primary prevention 6 49493 secondary prevention 4 19888 Type of agent statin 7 53305 PCKS9 antibody 2 6806 statin + ezetimibe 1 9270 Risk intermediate/low risk 2 17170 high risk 8 52211 Age <65 yo. 8 38874 65 yo. 2 30507 REVASCULARIZATION Analysis by baseline LDL-C in the more intensive lipid lowering arm <100 mg/dl LDL-C Type of agent statin 2 22065 100-129mg/dL LDL-C PCKS9 antibody 2 44381 statin + ezetimibe 1 18144 Setting primary prevention 6 49493 secondary prevention 4 19888 Type of agent statin 7 53305 PCKS9 antibody 2 6806 statin + ezetimibe 1 9270 380/25528 (1.49%) 571/10356 (5.51%) 715/26705 (2.68%) 23/4529 (0.51%) 213/4650 (4.58%) 54/9337 (0.58%) 897/26547 (3.38%) 875/20622 (4.24%) 76/15262 (0.50%) 1237/11026 (11.22%) 786/22192 (3.54%) 1871/9067 (20.64%) 537/25528 (2.10%) 1088/10356 (10.51%) 1278/26705 (4.79%) 63/4529 (1.39%) 284/4650 (6.11%) 499/23965 (2.08%) 647/9532 (6.79%) 893/26600 (3.36%) 23/2277 (1.01%) 230/4620 (4.98%) 74/7833 (0.94%) 1072/25664 (4.18%) 1009/18252 (5.53%) 137/15245 (0.90%) 1514/11039 (13.72%) 998/22189 (4.50%) 1962/9077 (21.62%) 705/23965 (2.94%) 1279/9532 (13.42%) 1591/26600 (5.98%) 41/2277 (1.80%) 352/4620 (7.62%) 0.67 [0.52, 0.87] 0.85 [0.71, 1.01] 0.75 [0.63, 0.89] 0.53 [0.24, 1.16] 0.92 [0.76, 1.11] 0.67 [0.47, 0.96] 0.76 [0.64, 0.90] 0.82 [0.72, 0.94] 0.55 [0.39, 0.78] 0.83 [0.66, 1.04] 0.79 [0.72, 0.86] 0.95 [0.90, 1.02] 0.71 [0.58, 0.87] 0.83 [0.76, 0.91] 0.79 [0.70, 0.90] 0.70 [0.31, 1.57] 0.80 [0.69, 0.94] 0.27 0.60 >0.99 0.12 0.01 0.30 >0.99

Risk intermediate/low risk 2 17170 high risk 8 52211 Age <65 yo. 8 38874 65 yo. 2 30507 Analysis by absolute magnitude of LDL-C reduction <35 mg/dl Setting primary prevention 5 42572 secondary prevention 8 64469 Type of agent statin 11 79627 statin+ezetimibe 2 27414 Risk intermediate/low risk 1 12705 high risk 12 94336 Age <65 yo. 10 79710 65 yo. 3 27331 MAJOR ADVERSE CARDIOVASCULAR EVENTS Analysis by baseline LDL-C in the more intensive lipid lowering arm <100 mg/dl LDL-C Type of agent statin 2 22065 100-129mg/dL LDL-C PCKS9 antibody 2 44381 statin + ezetimibe 1 18144 Setting primary prevention 6 49493 71/9337 (0.76%) 1554/26547 (5.85%) 1498/20622 (7.26%) 127/15262 (0.83%) 769/21258 (3.62%) 4501/32251 (13.96%) 3115/39792 (7.83%) 2155/13717 (15.71%) 56/6361 (0.88%) 5214/47148 (11.06%) 4755/39840 (11.94%) 515/13669 (3.77%) 1911/11026 (17.33%) 1517/22192 (6.84%) 2572/9067 (28.37%) 1180/25528 (4.62%) 99/7833 (1.26%) 1885/25664 (7.34%) 1771/18252 (9.70%) 213/15245 (1.40%) 933/21314 (4.38%) 5130/32218 (15.92%) 3749/39835 (9.41%) 2314/13697 (16.89%) 82/6344 (1.29%) 5981/47188 (12.67%) 5463/39870 (13.70%) 600/13662 (4.39%) 2101/11039 (19.03%) 1736/22189 (7.82%) 2742/9077 (30.21%) 1511/23965 (6.31%) 0.61 [0.42, 0.88] 0.45 0.81 [0.73, 0.90] 0.83 [0.76, 0.90] 0.018 0.60 [0.48, 0.74] 0.82 [0.72, 0.92] 0.69 0.87 [0.80, 0.94] 0.84 [0.78, 0.90] >0.99 0.89 [0.75, 1.05] 0.68 [0.48, 0.96] >0.99 0.86 [0.80, 0.92] 0.85 [0.79, 0.92] >0.99 0.86 [0.76, 0.97] 0.88 [0.73, 1.05] 0.90 [0.78, 1.02] >0.99 0.94 [0.89, 0.99] 0.72 [0.61, 0.85] 0.15

secondary prevention 4 19888 Type of agent statin 7 53305 PCKS9 antibody 2 6806 statin + ezetimibe 1 9270 Risk intermediate/low risk 2 17170 high risk 8 52211 Age <65 yo. 8 38874 65 yo. 2 30507 Analysis by absolute magnitude of LDL-C reduction >65 mg/dl Setting primary prevention 2 6338 secondary prevention 2 6785 Type of agent statin 1 4444 PCKS9 antibody 2 6806 statin + ezetimibe 1 1873 Risk intermediate/low risk 2 6338 high risk 2 8385 Age <65 yo. 3 12850 65 yo. 1 1873 LDL-C, low-density lipoprotein cholesterol; NA, not available. 1339/10356 (12.93%) 1938/26705 (7.26%) 55/4529 (1.21%) 526/4650 (11.31%) 263/9337 (2.82%) 2256/26547 (8.50%) 2142/20622 (10.39%) 377/15262 (2.47%) 361/3920 (9.21%) 380/3774 (10.07%) 353/2221 (15.89%) 55/4529 (1.21%) 333/944 (35.28%) 361/3920 (9.21%) 380/3774 (10.07%) 408/6750 (6.04%) 333/944 (35.28%) 1520/9532 (15.95%) 2356/26600 (8.86%) 56/2277 (2.46%) 619/4620 (13.40%) 334/7833 (4.26%) 2697/25664 (10.51%) 2476/18252 (13.57%) 555/15245 (3.64%) 385/2418 (15.92%) 528/3011 (17.54%) 502/2223 (22.58%) 56/2277 (2.46%) 355/929 (38.21%) 385/2418 (15.92%) 528/3011 (17.54%) 558/4500 (12.40%) 355/929 (38.21%) 0.86 [0.79, 0.93] 0.79 [0.71, 0.89] 0.49 [0.34, 0.72] 0.84 [0.75, 0.95] 0.64 [0.40, 1.03] 0.79 [0.71, 0.88] 0.83 [0.76, 0.90] 0.66 [0.49, 0.90] 0.69 [0.35, 1.33] 0.69 [0.59, 0.80] 0.70 [0.61, 0.81] 0.49 [0.34, 0.72] 0.92 [0.79, 1.07] 0.69 [0.35, 1.33] 0.69 [0.59, 0.80] 0.62 [0.48, 0.80] 0.92 [0.79, 1.07] 0.12 0.99 0.54 0.03 0.008 0.06 0.06

Supplementary Table 6. Cumulative meta-analysis accounting for year of the study publication Studies Patients Rate Ratio (95% CIs) Random effects model p-value All cause mortality Original meta-analysis 34 270,288 0.918 (0.878-0.959) <0.001 4S and WOSCOPS excluded 32 259,249 0.932 (0.893-0.972) 0.001 < Year 2000 excluded 28 238,120 0.944 (0.905-0.984) 0.007 CV mortality Original meta-analysis 34 270,288 0.863 (0.808-0.911) <0.001 4S and WOSCOPS excluded 32 259,249 0.881 (0.819-0.922) <0.001 < Year 2000 excluded 28 238,120 0.890 (0.839-0.942) <0.001 MI Original meta-analysis 34 270,288 0.758 (0.716-0.803) <0.001 4S and WOSCOPS excluded 32 259,249 0.766 (0.721-0.813) <0.001 < Year 2000 excluded 28 238,120 0.770 (0.721-0.823) <0.001 Cerebrovascular events Original meta-analysis 34 270,288 0.823 (0.780-0.868) <0.001 4S and WOSCOPS excluded 32 259,249 0.827 (0.783-0.873) <0.001 < Year 2000 excluded 28 238,120 0.829 (0.780-0.881) <0.001 Revascularization Original meta-analysis 34 270,288 0.784 (0.743-0.827) <0.001 4S and WOSCOPS excluded 32 259,249 0.794 (0.752-0.837) <0.001 < Year 2000 excluded 28 238,120 0.799 (0.752-0.848) <0.001 MACE Original meta-analysis 32 258,333 0.815 (0.781-0.851) <0.001 4S and WOSCOPS excluded 30 247,294 0.824 (0.790-0.860) <0.001 < Year 2000 excluded 26 226,165 0.835 (0.798-0.873) <0.001 4S (SSSS), Scandinavian Simvastatin Survival Study; CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular event; MI, myocardial infarction; WOSCOPS, West of Scotland Coronary Prevention Study

Supplementary Table 7. Sensitivity analysis stratified for the type of treatment in the control group All-cause mortality ACTIVE NO. OF PATIENTS WITH EVENT/ TOTAL NO. (%) PLACEBO NO. OF PATIENTS WITH EVENT/ TOTAL NO. (%) OUTCOME ANALYSIS SUBGROUP RATE RATIO RATE RATIO STUDIES PATIENTS STUDIES PATIENTS [95% CI] [95% CI] MORE INTENSIVE LESS INTENSIVE MORE INTENSIVE LESS INTENSIVE LDL-C LOWERING LDL-C LOWERING LDL-C LOWERING LDL-C LOWERING baseline LDL-C 2463/20093 2483/20116 510/22192 484/22189 <100 mg/dl 3 40209 0.99 [0.94, 1.05] 2 44381 (12.26%) (12.34%) (2.30%) (2.18%) 1.05 [0.93, 1.19] 100-129 mg/dl 3 17547 516/8803 570/8744 1817/27081 1885/24753 0.85 [0.69, 1.05] 7 51834 (5.86%) (6.52%) (6.71%) (7.62%) 0.89 [0.77, 1.02] 130-159 mg/dl 1 1351 32/676 35/675 4002/51131 4423/51196 0.91 [0.57, 1.47] 15 102327 (4.73%) (5.19%) (7.83%) (8.64%) 0.91 [0.86, 0.96] 160 mg/dl 0 0 311/6323 431/6316 NA 3 12639 4.92%) (6.82%) 0.72 [0.62, 0.84] Total 7 59107 3011/29572 3088/29535 6640/106727 7223/104454 0.97 [0.92, 1.03] 27 211181 (10.18%) (10.46%) (6.22%) (6.92%) 0.90 [0.86, 0.95] absolute 2979/28896 3053/28860 2425/24613 2475/24672 <35 mg/dl 6 57756 0.97 [0.91, 1.03] 7 49285 magnitude of (10.31%) (10.58%) (9.85%) (10.03%) 0.98 [0.92, 1.03] LDL-C reduction 32/676 35/675 3893/73620 4336/73553 35-65 mg/dl 1 1351 0.91 [0.57, 1.47] 15 147173 (4.73%) (5.19%) (5.29%) (5.90%) 0.90 [0.85, 0.96] >65 mg/dl 0 0 322/8494 412/6229 NA 5 14723 (3.79%) (6.61%) 0.70 [0.52, 0.95] Total 7 59107 3011/29572 3088/29535 6640/106727 7223/104454 0.97 [0.92, 1.03] 27 211181 (10.18%) (10.46%) (6.22%) (6.92%) 0.90 [0.86, 0.95] baseline LDL-C 1228/20093 1265/20116 288/22192 270/22189 <100 mg/dl 3 40209 0.97 [0.88, 1.06] 2 44381 (6.11%) (6.29%) (1.30%) (1.22%) 1.06 [0.91, 1.25] 100-129 mg/dl 3 17547 329/8803 356/8744 533/27081 596/24753 0.88 [0.70, 1.11] 7 51834 (3.74%) (4.07%) (1.97%) (2.41%) 0.89 [0.80, 1.00] 130-159 mg/dl 1 1351 22/676 20/675 1996/51131 2428/51196 1.10 [0.60, 2.01] 15 102327 (3.25%) (2.96%) (3.90%) (4.74%) 0.82 [0.78, 0.87] 160 mg/dl 0 0 206/6323 318/6316 NA 3 12639 (3.26%) (5.03%) 0.65 [0.54, 0.77] Total 7 59107 1579/29572 1641/29535 2996/106727 3612/104454 0.96 [0.89, 1.03] 27 211181 (5.34%) (5.56%) (2.81%) (3.46%) 0.83 [0.78, 0.88] absolute 1557/28896 1621/28860 954/24613 1040/24672 <35 mg/dl 6 57756 0.95 [0.87, 1.03] 7 49285 magnitude of (5.39%) (5.62%) (3.88%) (4.22%) 0.92 [0.84, 1.00] LDL-C reduction 22/676 20/675 1831/73620 2261/73553 35-65 mg/dl 1 1351 1.10 [0.60, 2.01] 15 147173 (3.25%) (2.96%) (2.49%) (3.07%) 0.83 [0.77, 0.89] >65 mg/dl 0 0 211/8494 311/6229 NA 5 14723 (2.48%) (4.99%) 0.66 [0.56, 0.79] Total 7 59107 1579/29572 1641/29535 2996/106727 3612/104454 0.96 [0.89, 1.03] 27 211181 (5.34%) (5.56%) (2.81%) (3.46%) 0.83 [0.78, 0.88] baseline LDL-C 1779/20093 2082/20116 566/22192 727/22189 <100 mg/dl 3 40209 0.86 [0.80, 0.91] 2 44381 (8.85%) (10.35%) (2.55%) (3.28%) 0.88 [0.59, 1.33] 100-129 mg/dl 3 17547 557/8803 629/8744 394/27081 517/24753 0.88 [0.78, 0.99] 7 51834 (6.33%) (7.19%) (1.45%) (2.09%) 0.64 [0.50, 0.83] 130-159 mg/dl 1 1351 35/676 40/675 2569/51131 3430/51196 0.87 [0.56, 1.38] 15 102327 (5.18%) (5.93%) (5.02%) (6.70%) 0.74 [0.68, 0.79] 160 mg/dl 0 0 443/6323 673/6316 NA 3 12639 (7.01%) (10.66%) 0.64 [0.53, 0.78] Total 7 59107 2371/29572 2751/29535 3972/106727 5347/104454 0.86 [0.82, 0.91] 27 211181 (8.02%) (9.31%) (3.72%) (5.12%) 0.72 [0.67, 0.77] absolute 2336/28896 2711/28860 801/24613 964/24672 <35 mg/dl 6 57756 0.86 [0.81, 0.91] 7 49285 magnitude of (8.08%) (9.39%) (3.25%) (3.91%) 0.77 [0.66, 0.91] LDL-C reduction 35/676 40/675 2826/73620 3855/73553 35-65 mg/dl 1 1351 0.87 [0.56, 1.38] 15 147173 (5.18%) (5.93%) (3.84%) (5.24%) 0.72 [0.67, 0.78] >65 mg/dl 0 0 345/8494 528/6229 NA 5 14723 (4.06%) (8.48%) 0.58 [0.46, 0.74] Total 7 59107 2371/29572 2751/29535 3972/106727 5347/104454 0.86 [0.82, 0.91] 27 211181 (8.02%) (9.31%) (3.72%) (5.12%) 0.72 [0.67, 0.77] baseline LDL-C <100 mg/dl 3 40209 747/20093 874/20116 0.86 [0.78, 0.94] 2 44381 226/22192 298/22189 0.71 [0.50, 1.01] Cardiovascular mortality Myocardial infarction

Cerebrovascular (3.72%) (4.34%) (1.02%) (1.34%) events 200/8803 230/8744 347/27081 460/24753 100-129 mg/dl 3 17547 0.87 [0.72, 1.05] 7 51834 (2.27%) (2.63%) (1.28%) (1.86%) 130-159 mg/dl 1 1351 16/676 15/675 1619/51131 1930/51196 1.07 [0.53, 2.15] 15 102327 (2.37%) (2.22%) (3.17%) (3.77%) 160 mg/dl 0 0 116/6323 163/6316 NA 3 12639 (1.83%) (2.58%) Total 7 59107 963/29572 1119/29535 2308/106727 2851/104454 0.86 [0.79, 0.94] 27 211181 (3.26%) (3.79%) (2.16%) (2.73%) absolute 947/28896 1104/28860 594/24613 699/24672 <35 mg/dl 6 57756 0.86 [0.79, 0.94] 7 49285 magnitude of (3.28%) (3.83%) (2.41%) (2.83%) LDL-C reduction 16/676 15/675 1598/73620 2002/73553 35-65 mg/dl 1 1351 1.07 [0.53, 2.15] 15 147173 (2.37%) (2.22%) (2.17%) (2.72%) >65 mg/dl 0 0 116/8494 150/6229 NA 5 14723 (1.37%) (2.41%) Total 7 59107 963/29572 1119/29535 2308/106727 2851/104454 0.86 [0.79, 0.94] 27 211181 (3.26%) (3.79%) (2.16%) (2.73%) Revascularization baseline LDL-C 3108/20093 3476/20116 786/22192 998/22189 <100 mg/dl 3 40209 0.87 [0.74, 1.02] 2 44381 (15.47%) (17.28%) (3.54%) (4.50%) 100-129 mg/dl 3 17547 1040/8803 1255/8744 585/27081 729/24753 0.83 [0.75, 0.92] 7 51834 (11.81%) (14.35%) (2.16%) (2.95%) 130-159 mg/dl 1 1351 44/676 62/675 3124/51131 3963/51196 0.71 [0.48, 1.04] 15 102327 (6.51%) (9.19%) (6.11%) (7.74%) 160 mg/dl 0 0 325/6323 508/6316 NA 3 12639 (5.14%) (8.04%) Total 7 59107 4192/29572 4793/29535 4820/106727 6198/104454 0.85 [0.77, 0.94] 27 211181 (14.18%) (16.23%) (4.52%) (5.93%) absolute 4148/28896 4731/28860 1122/24613 1332/24672 <35 mg/dl 6 57756 0.86 [0.78, 0.95] 7 49285 magnitude of (14.35%) (16.39%) (4.56%) (5.40%) LDL-C reduction 44/676 62/675 3284/73620 4280/73553 35-65 mg/dl 1 1351 0.71 [0.48, 1.04] 15 147173 (6.51%) (9.19%) (4.46%) (5.82%) >65 mg/dl 0 0 414/8494 586/6229 NA 5 14723 (4.87%) (9.41%) Total 7 59107 4192/29572 4793/29535 4820/106727 6198/104454 0.85 [0.77, 0.94] 27 211181 (14.18%) (16.23%) (4.52%) (5.93%) MACE baseline LDL-C 4483/20093 4843/20116 1517/22192 1736/22189 <100 mg/dl 3 40209 0.91 [0.84, 0.99] 2 44381 (22.31%) (24.08%) (6.84%) (7.82%) 100-129 mg/dl 3 17547 1312/8803 1494/8744 1207/27081 1537/24753 0.87 [0.81, 0.94] 7 51834 (14.90%) (17.09%) (4.46%) (6.21%) 130-159 mg/dl 1 1351 85/676 103/675 5329/45961 6628/46011 0.82 [0.62, 1.10] 14 91972 (12.57%) (15.26%) (11.59%) (14.41%) 160 mg/dl 0 0 527/5523 750/5516 NA 2 11039 (9.54%) (13.60%) Total 7 59107 5880/29572 6440/29535 8580/100757 10651/98469 0.90 [0.85, 0.94] 25 199226 (19.88%) (21.80%) (8.52%) (10.82%) absolute 5795/28896 6337/28860 1402/19443 1673/19487 <35 mg/dl 6 57756 0.90 [0.85, 0.95] 6 38930 magnitude of (20.05%) (21.96%) (7.21%) (8.59%) LDL-C reduction 85/676 103/675 6437/73620 8065/73553 35-65 mg/dl 1 1351 0.82 [0.62, 1.10] 15 147173 (12.57%) (15.26%) (8.74%) (10.96%) >65 mg/dl 0 0 741/7694 913/5429 NA 4 13123 (9.63%) (16.82%) Total 7 59107 5880/29572 6440/29535 8580/100757 10651/98469 0.90 [0.85, 0.94] 25 199226 (19.88%) (21.80%) (8.52%) (10.82%) CI, confidence interval, LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular event; NA, not available 0.70 [0.56, 0.88] 0.85 [0.79, 0.91] 0.71 [0.55, 0.93] 0.81 [0.75, 0.87] 0.85 [0.76, 0.95] 0.80 [0.72, 0.87] 0.73 [0.47, 1.15] 0.81 [0.75, 0.87] 0.79 [0.72, 0.86] 0.74 [0.61, 0.89] 0.78 [0.74, 0.83] 0.64 [0.56, 0.74] 0.76 [0.72, 0.80] 0.84 [0.78, 0.91] 0.76 [0.71, 0.80] 0.65 [0.54, 0.78] 0.76 [0.72, 0.80] 0.90 [0.78, 1.02] 0.71 [0.60, 0.83] 0.80 [0.77, 0.83] 0.70 [0.63, 0.79] 0.79 [0.76, 0.83] 0.84 [0.78, 0.90] 0.79 [0.74, 0.83] 0.70 [0.54, 0.90] 0.79 [0.76, 0.83]

Supplementary Table 8. Sensitivity analysis stratified for agent used in the active treatment group. OUTCOME ANALYSIS SUBGROUP All-cause mortality Cardiovascular mortality Myocardial infarction Cerebrovascular events baseline LDL-C absolute magnitude of LDL-C reduction baseline LDL-C absolute magnitude of LDL-C reduction baseline LDL-C absolute magnitude of LDL-C reduction baseline LDL-C STUDIES PATIENTS <100 mg/dl 2 22065 100-129 mg/dl 130-159 mg/dl 7 53305 14 91184 160 mg/dl 3 12639 Total 26 179193 <35 mg/dl 11 79627 35-65 mg/dl 13 93522 >65 mg/dl 2 6044 Total 26 179193 <100 mg/dl 2 22065 100-129 mg/dl 130-159 mg/dl 7 53305 14 91184 160 mg/dl 3 12639 Total 26 179193 <35 mg/dl 11 79627 35-65 mg/dl 13 93522 >65 mg/dl 2 6044 Total 26 179193 <100 mg/dl 2 22065 100-129 mg/dl 130-159 mg/dl 7 53305 14 91184 160 mg/dl 3 12639 Total 26 179193 <35 mg/dl 11 79627 35-65 mg/dl 13 93522 >65 mg/dl 2 6044 Total 26 179193 <100 mg/dl 2 22065 100-129 mg/dl 130-159 mg/dl 7 53305 14 91184 160 mg/dl 3 12639 Total 26 179193 STATIN STATIN+EZETIMIBE PCSK9 ANTIBODY NO. OF PATIENTS WITH EVENT/ NO. OF PATIENTS WITH EVENT/ NO. OF PATIENTS WITH EVENT/ TOTAL NO. (%) TOTAL NO. (%) TOTAL NO. (%) RATE RATIO RATE RATIO STUDIES PATIENTS [95% CI] [95% CI] STUDIES PATIENTS MORE INTENSIVE LDL-C LOWERING 1248/11026 (11.32%) 1179/26705 (4.41%) 3875/45551 (8.51%) 311/6323 (4.92%) 6613/89605 (7.38%) 3047/39792 (7.66%) 3361/46792 (7.18%) 205/3021 (6.79%) 6613/89605 (7.38%) 691/11026 (6.27%) 466/26705 (1.74%) 1943/45551 (4.27%) 206/6323 (3.26%) 3306/89605 (3.69%) 1613/39792 (4.05%) 1537/46792 (3.28%) 156/3021 (5.16%) 3306/89605 (3.69%) 802/11026 (7.27%) 715/26705 (2.68%) 2488/45551 (5.46%) 443/6323 (7.01%) 4448/89605 (4.96%) 1947/39792 (4.89%) 2201/46792 (4.70%) 300/3021 (9.93%) 4448/89605 (4.96%) 451/11026 (4.09%) 358/26705 (1.34%) 1576/45551 (3.46%) 116/6323 (1.83%) 2501/89605 (2.79%) LESS INTENSIVE LDL-C LOWERING 1252/11039 (11.34%) 1324/26600 (4.98%) 4299/45633 (9.42%) 431/6316 (6.82%) 7306/89588 (8.16%) 3182/39835 (7.99%) 3828/46730 (8.19%) 296/3023 (9.79%) 7306/89588 (8.16%) 727/11039 (6.59%) 554/26600 (2.08%) 2358/45633 (5.17%) 318/6316 (5.03%) 3957/89588 (4.42%) 1735/39835 (4.36%) 2181/46730 (4.23%) 245/3023 (8.10%) 3957/89588 (4.42%) 964/11039 (8.73%) 893/26600 (3.36%) 3312/45633 (7.26%) 673/6316 (10.66%) 5842/89588 (6.52%) 2327/39835 (5.84%) 3046/46730 (6.52%) 469/3023 (15.51%) 5842/89588 (6.52%) 529/11039 (4.79%) 470/26600 (1.77%) 1877/45633 (4.11%) 163/6316 (2.58%) 3039/89588 (3.39%) 1.00 [0.92, 1.08] 0.88 [0.80, 0.96] 0.91 [0.86, 0.96] 0.72 [0.62, 0.84] 0.90 [0.85, 0.94] 0.95 [0.91, 1.01] 0.88 [0.83, 0.93] 0.69 [0.58, 0.83] 0.90 [0.85, 0.94] 0.92 [0.77, 1.11] 0.91 [0.83, 1.00] 0.82 [0.78, 0.88] 0.65 [0.54, 0.77] 0.83 [0.78, 0.88] 0.93 [0.87, 0.99] 0.80 [0.75, 0.85] 0.64 [0.52, 0.78] 0.83 [0.78, 0.88] 0.83 [0.76, 0.91] 0.75 [0.63, 0.89] 0.74 [0.68, 0.80] 0.64 [0.53, 0.78] 0.74 [0.70, 0.79] 0.83 [0.77, 0.89] 0.71 [0.66, 0.76] 0.56 [0.35, 0.88] 0.74 [0.70, 0.79] 0.85 [0.73, 0.99] 0.75 [0.63, 0.88] 0.85 [0.79, 0.91] 0.71 [0.55, 0.93] 0.83 [0.78, 0.88] 1 18144 1 9270 1 1873 0 0 3 29287 2 27414 0 0 1 1873 3 29287 1 18144 1 9270 1 1873 MORE INTENSIVE LDL-C LOWERING 1215/9067 (13.40%) 1142/4650 (24.56%) 105/944 (11.12%) 2462/14661 (16.79%) 2357/13717 (17.18%) 105/944 (11.12%) 2462/14661 (16.79%) 537/9067 (5.92%) 361/4650 (7.76%) 47/944 (4.98%) 0 0 3 29287 2 27414 0 0 1 1873 3 29287 1 18144 1 9270 1 1873 0 0 3 29287 2 27414 0 0 1 1873 3 29287 1 18144 1 9270 1 1873 0 0 3 29287 945/14661 (6.45%) 898/13717 (6.55%) 47/944 (4.98%) 945/14661 (6.45%) 977/9067 (10.78%) 213/4650 (4.58%) 22/944 (2.33%) 1212/14661 (8.27%) 1190/13717 (8.68%) 22/944 (2.33%) 1212/14661 (8.27%) 296/9067 (3.26%) 176/4650 (3.78%) 33/944 (3.50%) 505/14661 (3.44%) LESS INTENSIVE LDL-C LOWERING 1231/9077 (13.56%) 1115/4620 (24.13%) 100/929 (10.76%) 2446/14626 (16.72%) 2346/13697 (17.13%) 100/929 (10.76%) 2446/14626 (16.72%) 538/9077 (5.93%) 388/4620 (8.40%) 56/929 (6.03%) 982/14626 (6.71%) 926/13697 (6.76%) 56/929 (6.03%) 982/14626 (6.71%) 1118/9077 (12.32%) 230/4620 (4.98%) 36/929 (3.88%) 1384/14626 (9.46%) 1348/13697 (9.84%) 36/929 (3.88%) 1384/14626 (9.46%) 345/9077 (3.80%) 211/4620 (4.57%) 29/929 (3.12%) 585/14626 (4.00%) 0.99 [0.91, 1.07] 1.02 [0.94, 1.11] 1.03 [0.79, 1.36] 2 44381 2 6806 1 10621 NA 0 0 1.00 [0.95, 1.06] 1.00 [0.95, 1.06] 5 61808 0 0 NA 3 55002 1.03 [0.79, 1.36] 1.00 [0.95, 1.06] 1.00 [0.89, 1.13] 0.92 [0.80, 1.07] 0.83 [0.56, 1.22] 2 6806 5 61808 2 44381 2 6806 1 10621 NA 0 0 0.96 [0.88, 1.05] 0.97 [0.88, 1.06] 5 61808 0 0 NA 3 55002 0.83 [0.56, 1.22] 0.96 [0.88, 1.05] 0.87 [0.80, 0.95] 0.92 [0.76, 1.11] 0.60 [0.35, 1.02] 2 6806 5 61808 2 44381 2 6806 1 10621 NA 0 0 0.87 [0.80, 0.96] 0.88 [0.82, 0.95] 5 61808 MORE INTENSIVE LDL-C LOWERING 510/22192 (2.30%) 12/4529 (0.26%) 54/5312 (1.02%) 576/32033 (1.80%) 564/27504 (2.05%) 12/4529 (0.26%) 576/32033 (1.80%) 288/22192 (1.30%) 8/4529 (0.18%) 28/5312 (0.53%) 324/32033 (1.01%) 316/27504 (1.15%) 8/4529 (0.18%) 324/32033 (1.01%) 566/22192 (2.55%) 23/4529 (0.51%) 94/5312 (1.77%) 683/32033 (2.13%) 0 0 NA 3 55002 0.60 [0.35, 1.02] 0.87 [0.80, 0.96] 0.86 [0.74, 1.00] 0.83 [0.68, 1.01] 1.12 [0.68, 1.84] 2 6806 5 61808 2 44381 2 6806 1 10621 NA 0 0 0.86 [0.76, 0.97] 5 61808 660/27504 (2.40%) 23/4529 (0.51%) 683/32033 (2.13%) 226/22192 (1.02%) 13/4529 (0.29%) 26/5312 (0.49%) 265/32033 (0.83%) LESS INTENSIVE LDL-C LOWERING 484/22189 (2.18%) 16/2277 (0.70%) 59/5309 (1.11%) 559/29775 (1.88%) 543/27498 (1.97%) 16/2277 (0.70%) 559/29775 (1.88%) 270/22189 (1.22%) 10/2277 (0.44%) 34/5309 (0.64%) 314/29775 (1.05%) 304/27498 (1.11%) 10/2277 (0.44%) 314/29775 (1.05%) 727/22189 (3.28%) 23/2277 (1.01%) 122/5309 (2.30%) 872/29775 (2.93%) 849/27498 (3.09%) 23/2277 (1.01%) 872/29775 (2.93%) 298/22189 (1.34%) 9/2277 (0.40%) 39/5309 (0.73%) 346/29775 (1.16%) RATE RATIO [95% CI] 1.05 [0.93, 1.19] 0.38 [0.18, 0.80] 0.91 [0.63, 1.32] NA 0.94 [0.73, 1.20] NA 1.04 [0.92, 1.17] 0.38 [0.18, 0.80] 0.94 [0.73, 1.20] 1.06 [0.91, 1.25] 0.41 [0.16, 1.05] 0.91 [0.63, 1.32] NA 1.00 [0.82, 1.21] NA 1.04 [0.90, 1.20] 0.41 [0.16, 1.05] 1.00 [0.82, 1.21] 0.88 [0.59, 1.33] 0.53 [0.24, 1.16] 0.77 [0.59, 1.01] NA 0.79 [0.62, 1.00] NA 0.84 [0.66, 1.06] 0.53 [0.24, 1.16] 0.79 [0.62, 1.00] 0.71 [0.50, 1.01] 0.77 [0.10, 5.86] 0.67 [0.41, 1.09] NA 0.69 [0.50, 0.94]

absolute 1069/39792 1247/39835 0.86 472/13717 <35 mg/dl 11 79627 2 27414 magnitude of (2.69%) (3.13%) [0.79, 0.93] (3.44%) LDL-C reduction 1362/46792 1680/46730 0.82 35-65 mg/dl 13 93522 0 0 (2.91%) (3.60%) [0.73, 0.91] >65 mg/dl 2 6044 70/3021 112/3023 0.63 33/944 1 1873 (2.32%) (3.70%) [0.46, 0.84] (3.50%) Total 26 179193 2501/89605 3039/89588 0.83 505/14661 3 29287 (2.79%) (3.39%) [0.78, 0.88] (3.44%) Revascularization baseline LDL-C 1237/11026 1514/11039 0.83 1871/9067 <100 mg/dl 2 22065 1 18144 (11.22%) (13.72%) [0.66, 1.04] (20.64%) 100-129 1278/26705 1591/26600 0.79 284/4650 7 53305 1 9270 mg/dl (4.79%) (5.98%) [0.70, 0.90] (6.11%) 130-159 3051/45551 3866/45633 0.79 77/944 14 91184 1 1873 mg/dl (6.70%) (8.47%) [0.74, 0.84] (8.16%) 160 mg/dl 3 12639 325/6323 508/6316 0.64 0 0 (5.14%) (8.04%) [0.56, 0.74] Total 26 179193 5891/89605 7479/89588 0.78 2232/14661 3 29287 (6.57%) (8.35%) [0.73, 0.82] (15.22%) absolute 3115/39792 3749/39835 0.84 2155/13717 <35 mg/dl 11 79627 2 27414 magnitude of (7.83%) (9.41%) [0.78, 0.90] (15.71%) LDL-C reduction 2502/46792 3302/46730 0.74 35-65 mg/dl 13 93522 0 0 (5.35%) (7.07%) [0.69, 0.79] >65 mg/dl 2 6044 274/3021 428/3023 0.63 77/944 1 1873 (9.07%) (14.16%) [0.51, 0.78] (8.16%) Total 26 179193 5891/89605 7479/89588 0.78 2232/14661 3 29287 (6.57%) (8.35%) [0.73, 0.82] (15.22%) MACE baseline LDL-C 1911/11026 2101/11039 0.88 2572/9067 <100 mg/dl 2 22065 1 18144 (17.33%) (19.03%) [0.73, 1.05] (28.37%) 100-129 1938/26705 2356/26600 0.79 526/4650 7 53305 1 9270 mg/dl (7.26%) (8.86%) [0.71, 0.89] (11.31%) 130-159 4902/40381 6152/40448 0.80 333/944 13 80829 1 1873 mg/dl (12.14%) (15.21%) [0.77, 0.83] (35.28%) 160 mg/dl 2 11039 527/5523 750/5516 0.70 0 0 (9.54%) (13.60%) [0.63, 0.79] Total 24 167239 9278/83635 11359/83603 0.80 3431/14661 3 29287 (11.09%) (13.59%) [0.76, 0.84] (23.40%) absolute 4099/34622 4649/34650 0.87 3098/13717 <35 mg/dl 10 69272 2 27414 magnitude of (11.84%) (13.42%) [0.82, 0.91] (22.59%) LDL-C reduction 4826/46792 6208/46730 0.77 35-65 mg/dl 13 93522 0 0 (10.31%) (13.28%) [0.73, 0.81] >65 mg/dl 1 4444 353/2221 502/2223 0.70 333/944 1 1873 (15.89%) (22.58%) [0.61, 0.81] (35.28%) Total 24 167238 9278/83635 11359/83603 0.80 3431/14661 3 29287 (11.09%) (13.59%) [0.76, 0.84] (23.40%) CI, confidence interval, LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular event; NA, not available; PCSK9, proprotein convertase subtilisin/kexin type 9 556/13697 (4.06%) 29/929 (3.12%) 585/14626 (4.00%) 1962/9077 (21.62%) 352/4620 (7.62%) 117/929 (12.59%) 2431/14626 (16.62%) 2314/13697 (16.89%) 117/929 (12.59%) 2431/14626 (16.62%) 2742/9077 (30.21%) 619/4620 (13.40%) 355/929 (38.21%) 3716/14626 (25.41%) 3361/13697 (24.54%) 355/929 (38.21%) 3716/14626 (25.41%) 0.85 [0.75, 0.96] 0 0 NA 3 55002 1.12 [0.68, 1.84] 0.86 [0.76, 0.97] 0.95 [0.90, 1.02] 0.80 [0.69, 0.94] 0.65 [0.49, 0.86] 2 6806 5 61808 2 44381 2 6806 1 10621 NA 0 0 0.82 [0.67, 1.00] 0.89 [0.75, 1.05] 5 61808 0 0 NA 3 55002 0.65 [0.49, 0.86] 0.82 [0.67, 1.00] 0.94 [0.89, 0.99] 0.84 [0.75, 0.95] 0.92 [0.79, 1.07] 2 6806 5 61808 2 44381 2 6806 1 10621 NA 0 0 0.91 [0.86, 0.97] 0.90 [0.82, 1.00] 5 61808 0 0 NA 3 55002 0.92 [0.79, 1.07] 0.91 [0.86, 0.97] 2 6806 5 61808 252/27504 (0.92%) 13/4529 (0.29%) 265/32033 (0.83%) 786/22192 (3.54%) 63/4529 (1.39%) 40/5312 (0.75%) 889/32033 (2.78%) 826/27504 (3.00%) 63/4529 (1.39%) 889/32033 (2.78%) 1517/22192 (6.84%) 55/4529 (1.21%) 179/5312 (3.37%) 1751/32033 (5.47%) 1696/27504 (6.17%) 55/4529 (1.21%) 1751/32033 (5.47%) 337/27498 (1.23%) 9/2277 (0.40%) 346/29775 (1.16%) 998/22189 (4.50%) 41/2277 (1.80%) 42/5309 (0.79%) 1081/29775 (3.63%) 1040/27498 (3.78%) 41/2277 (1.80%) 1081/29775 (3.63%) 1736/22189 (7.82%) 56/2277 (2.46%) 224/5309 (4.22%) 2016/29775 (6.77%) 1960/27498 (7.13%) 56/2277 (2.46%) 2016/29775 (6.77%) NA 0.74 [0.63, 0.89] 0.77 [0.10, 5.86] 0.69 [0.50, 0.94] 0.79 [0.72, 0.86] 0.70 [0.31, 1.57] 0.95 [0.62, 1.47] NA 0.80 [0.70, 0.91] NA 0.79 [0.72, 0.87] 0.70 [0.31, 1.57] 0.80 [0.70, 0.91] 0.90 [0.78, 1.02] 0.49 [0.34, 0.72] 0.80 [0.66, 0.97] NA 0.80 [0.68, 0.95] NA 0.87 [0.80, 0.95] 0.49 [0.34, 0.72] 0.80 [0.68, 0.95]

Supplementary Table 9. Sensitivity analysis stratified for the type of population. OUTCOME ANALYSIS SUBGROUP All-cause mortality Cardiovascular mortality Myocardial infarction baseline LDL-C absolute magnitude of LDL-C reduction baseline LDL-C absolute magnitude of LDL-C reduction baseline LDL-C absolute magnitude of LDL-C reduction STUDIES PATIENTS <100 mg/dl 0 0 100-129 mg/dl 6 49493 130-159 mg/dl 8 49607 160 mg/dl 1 6595 Total 15 105695 <35 mg/dl 5 42572 35-65 mg/dl 8 56785 >65 mg/dl 2 6338 Total 15 105695 <100 mg/dl 0 0 100-129 mg/dl 6 49493 130-159 mg/dl 8 49607 160 mg/dl 1 6595 Total 15 105695 <35 mg/dl 5 42572 35-65 mg/dl 8 56785 >65 mg/dl 2 6338 Total 15 105695 <100 mg/dl 0 0 100-129 mg/dl 6 49493 130-159 mg/dl 8 49607 160 mg/dl 1 6595 Total 15 105695 <35 mg/dl 5 42572 35-65 mg/dl 8 56785 >65 mg/dl 2 6338 Total 15 105695 PRIMARY PREVENTION NO. OF PATIENTS WITH EVENT/ TOTAL NO. (%) MORE INTENSIVE LDL-C LOWERING 1809/25528 (7.09%) 1713/24758 (6.92%) 106/3302 (3.21%) 3628/53588 (6.77%) 2232/21258 (10.50%) 1287/28410 (4.53%) 109/3920 (2.78%) 3628/53588 (6.77%) 502/25528 (1.97%) 652/24758 (2.63%) 50/3302 (1.51%) 1204/53588 (2.25%) 859/21258 (4.04%) 294/28410 (1.03%) 51/3920 (1.30%) 1204/53588 (2.25%) 380/25528 (1.49%) 957/24758 (3.87%) 143/3302 (4.33%) 1480/53588 (2.76%) 704/21258 (3.31%) 745/28410 (2.62%) 31/3920 (0.79%) 1480/53588 (2.76%) LESS INTENSIVE LDL-C LOWERING 1875/23965 (7.82%) 1764/24849 (7.10%) 135/3293 (4.10%) 3774/52107 (7.24%) 2260/21314 (10.60%) 1408/28375 (4.96%) 106/2418 (4.38%) 3774/52107 (7.24%) 589/23965 (2.46%) 755/24849 (3.04%) 73/3293 (2.22%) 1417/52107 (2.72%) 914/21314 (4.29%) 648/28375 (1.56%) 59/2418 (2.44%) 1417/52107 (2.72%) 499/23965 (2.08%) 1243/24849 (5.00%) 204/3293 (6.19%) 1946/52107 (3.73%) 819/21314 (3.84%) 1086/28375 (3.83%) 41/2418 (1.70%) 1946/52107 (3.73%) RATE RATIO [95% CI] STUDIES PATIENTS NA 5 84590 0.91 [0.80, 1.03] 0.97 [0.91, 1.04] 0.78 [0.61, 1.01] 0.94 [0.89, 1.00] 0.98 [0.92, 1.05] 0.91 [0.83, 1.00] 0.70 [0.24, 2.01] 0.94 [0.89, 1.00] 4 19888 8 54071 2 6044 19 164593 8 64469 8 91739 3 8385 19 164593 NA 5 84590 0.90 [0.81, 1.00] 0.87 [0.78, 0.96] 0.68 [0.48, 0.98] 0.87 [0.81, 0.94] 0.94 [0.85, 1.03] 0.77 [0.67, 0.87] 0.81 [0.56, 1.19] 0.87 [0.81, 0.94] 4 19888 8 54071 2 6044 19 164593 8 64469 8 91739 3 8385 19 164593 NA 5 84590 0.67 [0.52, 0.87] 0.70 [0.60, 0.82] 0.70 [0.56, 0.87] 0.70 [0.62, 0.78] 0.82 [0.71, 0.96] 0.65 [0.56, 0.75] 0.65 [0.40, 1.05] 0.70 [0.62, 0.78] 4 19888 8 54071 2 6044 19 164593 8 64469 8 91739 3 8385 19 164593 SECONDARY PREVENTION NO. OF PATIENTS WITH EVENT/ TOTAL NO. (%) MORE INTENSIVE LDL-C LOWERING 2973/42285 (7,03%) 524/10356 (5,06%) 2321/27049 (8,58%) 205/3021 (6,79%) 6023/82711 (7,28%) 3172/32251 (9,84%) 2638/45886 (5,75%) 213/4574 (4,66%) 6023/82711 (7,28%) 1516/42285 (3,59%) 333/10356 (3,22%) 1366/27049 (5,05%) 156/3021 (5,16%) 3371/82711 (4,08%) 1652/32251 (5,12%) 1559/45886 (3,40%) 160/4574 (3,50%) 3371/82711 (4,08%) 2345/42285 (5,55%) 571/10356 (5,51%) 1647/27049 (6,09%) 300/3021 (9,93%) 4863/82711 (5,88%) 2433/32251 (7,54%) 2116/45886 (4,61%) 314/4574 (6,86%) 4863/82711 (5,88%) LESS INTENSIVE LDL-C LOWERING 2967/42305 (7,01%) 580/9532 (6,08%) 2694/27022 (9,97%) 296/3023 (9,79%) 6537/81882 (7,98%) 3268/32218 (10,14%) 2963/45853 (6,46%) 306/3811 (8,03%) 6537/81882 (7,98%) 1535/42305 (3,63%) 363/9532 (3,81%) 1693/27022 (6,27%) 245/3023 (8,10%) 3836/81882 (4,68%) 1747/32218 (5,42%) 1837/45853 (4,01%) 252/3811 (6,61%) 3836/81882 (4,68%) 2809/42305 (6,64%) 647/9532 (6,79%) 2227/27022 (8,24%) 469/3023 (15,51%) 6152/81882 (7,51%) 2856/32218 (8,86%) 2809/45853 (6,13%) 487/3811 (12,78%) 6152/81882 (7,51%) RATE RATIO [95% CI] 1.00 [0.95, 1.06] 0.80 [0.63, 1.02] 0.86 [0.81, 0.91] 0.69 [0.58, 0.83] 0.90 [0.84, 0.96] 0.97 [0.92, 1.02] 0.90 [0.82, 0.99] 0.68 [0.57, 0.81] 0.90 [0.84, 0.96] 0.99 [0.92, 1.06] 0.82 [0.61, 1.10] 0.81 [0.75, 0.87] 0.64 [0.52, 0.78] 0.86 [0.79, 0.93] 0.92 [0.85, 1.01] 0.87 [0.78, 0.98] 0.62 [0.49, 0.77] 0.86 [0.79, 0.93] 0.84 [0.76, 0.92] 0.85 [0.71, 1.01] 0.74 [0.69, 0.79] 0.56 [0.35, 0.88] 0.78 [0.73, 0.84] 0.85 [0.79, 0.90] 0.76 [0.71, 0.81] 0.52 [0.35, 0.77] 0.78 [0.73, 0.84]