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1 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: /jama etables 1-12 efigures 1-22 ereferences This supplementary material has been provided by the authors to give readers additional information about their work.

2 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 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 ( ClinicalTrials.gov, Clinical Trial Results ( and major congress proceedings, from database inception until 1 st February 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.

3 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, , , 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, 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 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, Statin AND cholesterol 18, Statin AND LDL 10, Statin AND lipid 22, Ezetimibe AND cholesterol 1, Ezetimibe AND LDL 1,427

4 15 Ezetimibe AND lipid 1, proprotein convertase subtilisin/kexin type 9 AND cholesterol 1, proprotein convertase subtilisin/kexin type 9 AND LDL 1, proprotein convertase subtilisin/kexin type 9 AND lipid 1, Lipid AND hypercholesterolemia 25, LDL AND hypercholesterolemia 13, Statin AND hypercholesterolemia 6, Ezetimibe AND hypercholesterolemia 1, proprotein convertase subtilisin/kexin type 9 AND hypercholesterolemia 854 LDL, low density lipoprotein

5 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 A to Z AFCAPS-TexCAPS ALERT ALLHAT-LLT ALLIANCE ASCOT-LLA ASPEN CARDS CARE FOURIER GISSI-P GREACE HOPE HPS IDEAL IMPROVE-IT JUPITER LIPID LIPS MEGA ODYSSEY LONG TERM OSLER 1&

6 PROSPER PROVE IT-TIMI SEARCH SEAS SHARP SPARCL SPIRE SPIRE The Post CABG Trial TNT WOSCOPS Cohen s Kappa 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.

7 Supplementary Table 3. Cerebrovascular events definitions across studies. Study Cerebrovascular event 4S Any cerebrovascular event A to Z Stroke AFCAPS-TexCAPS Total stroke ALERT Fatal or non-fatal stroke, transient ischaemic attack ALLHAT-LLT Fatal or nonfatal stroke ALLIANCE Stroke ASCOT-LLA Fatal or nonfatal stroke ASPEN Fatal or nonfatal stroke CARDS Stroke CARE Stroke FOURIER Total stroke GISSI-P Fatal or nonfatal stroke GREACE Stroke HOPE Stroke HPS Any stroke IDEAL Fatal or nonfatal stroke IMPROVE-IT Any stroke JUPITER Any stroke LIPID Any stroke LIPS Fatal stroke MEGA Any stroke ODYSSEY LONG TERM Fatal or nonfatal ischemic stroke OSLER 1& Stroke or transient ischemic attack PROSPER Fatal or nonfatal stroke PROVE IT-TIMI Stroke SEARCH Total stroke SEAS Nonhaemorrhagic stroke SHARP Haemorrhagic or nonhaemorrhagic stroke SPARCL Fatal or nonfatal stroke SPIRE Nonfatal stroke SPIRE Nonfatal stroke The Post CABG Trial Stroke TNT Fatal or nonfatal stroke or transient ischemic attack WOSCOPS 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

8 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.

9 Supplementary Table 4. Composite endpoint MACE definitions across studies (where applicable only). Study 4S A to Z AFCAPS- TexCAPS ALERT ALLIANC E ASCOT- LLA ASPEN CARDS CARE FOURIER GISSI-P HOPE HPS IDEAL IMPROVE- IT JUPITER LIPID LIPS MEGA ODYSSEY LONG TERM OSLER 1& PROSPER PROVE IT- TIMI SEARCH 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

10 SEAS SPARCL SPIRE-1& The Post CABG Trial TNT 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 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.

11 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 mg/dL LDL-C Number of patients Setting primary prevention secondary prevention Type of agent statin PCKS9 antibody statin + ezetimibe Risk intermediate/low risk high risk Age <65 yo yo CARDIOVASCULAR MORTALITY Analysis by baseline LDL-C in the more intensive lipid lowering arm mg/dL LDL-C Setting primary prevention secondary prevention Type of agent statin PCKS9 antibody 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 > > >

12 statin + ezetimibe Risk intermediate/low risk high risk Age <65 yo yo Analysis by absolute magnitude of LDL-C reduction mg/dl Setting primary prevention secondary prevention Type of agent statin PCKS9 antibody Risk intermediate/low risk high risk Age <65 yo yo MYOCARDIAL INFARCTION Analysis by baseline LDL-C in the more intensive lipid lowering arm <100 mg/dl LDL-C Type of agent statin Threshold mg/dL LDL-C PCKS9 antibody statin + ezetimibe /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 >0.99 >0.99

13 Setting primary prevention secondary prevention Type of agent statin PCKS9 antibody statin + ezetimibe Risk intermediate/low risk high risk Age <65 yo yo REVASCULARIZATION Analysis by baseline LDL-C in the more intensive lipid lowering arm <100 mg/dl LDL-C Type of agent statin mg/dL LDL-C PCKS9 antibody statin + ezetimibe Setting primary prevention secondary prevention Type of agent statin PCKS9 antibody statin + ezetimibe /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] > >0.99

14 Risk intermediate/low risk high risk Age <65 yo yo Analysis by absolute magnitude of LDL-C reduction <35 mg/dl Setting primary prevention secondary prevention Type of agent statin statin+ezetimibe Risk intermediate/low risk high risk Age <65 yo yo 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 mg/dL LDL-C PCKS9 antibody statin + ezetimibe Setting primary prevention /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] [0.73, 0.90] 0.83 [0.76, 0.90] [0.48, 0.74] 0.82 [0.72, 0.92] [0.80, 0.94] 0.84 [0.78, 0.90] > [0.75, 1.05] 0.68 [0.48, 0.96] > [0.80, 0.92] 0.85 [0.79, 0.92] > [0.76, 0.97] 0.88 [0.73, 1.05] 0.90 [0.78, 1.02] > [0.89, 0.99] 0.72 [0.61, 0.85] 0.15

15 secondary prevention Type of agent statin PCKS9 antibody statin + ezetimibe Risk intermediate/low risk high risk Age <65 yo yo Analysis by absolute magnitude of LDL-C reduction >65 mg/dl Setting primary prevention secondary prevention Type of agent statin PCKS9 antibody statin + ezetimibe Risk intermediate/low risk high risk Age <65 yo yo 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]

16 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 , ( ) < S and WOSCOPS excluded , ( ) < Year 2000 excluded , ( ) CV mortality Original meta-analysis , ( ) < S and WOSCOPS excluded , ( ) <0.001 < Year 2000 excluded , ( ) <0.001 MI Original meta-analysis , ( ) < S and WOSCOPS excluded , ( ) <0.001 < Year 2000 excluded , ( ) <0.001 Cerebrovascular events Original meta-analysis , ( ) < S and WOSCOPS excluded , ( ) <0.001 < Year 2000 excluded , ( ) <0.001 Revascularization Original meta-analysis , ( ) < S and WOSCOPS excluded , ( ) <0.001 < Year 2000 excluded , ( ) <0.001 MACE Original meta-analysis , ( ) < S and WOSCOPS excluded , ( ) <0.001 < Year 2000 excluded , ( ) < S (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

17 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/ / / /22189 <100 mg/dl [0.94, 1.05] (12.26%) (12.34%) (2.30%) (2.18%) 1.05 [0.93, 1.19] mg/dl / / / / [0.69, 1.05] (5.86%) (6.52%) (6.71%) (7.62%) 0.89 [0.77, 1.02] mg/dl /676 35/ / / [0.57, 1.47] (4.73%) (5.19%) (7.83%) (8.64%) 0.91 [0.86, 0.96] 160 mg/dl / /6316 NA %) (6.82%) 0.72 [0.62, 0.84] Total / / / / [0.92, 1.03] (10.18%) (10.46%) (6.22%) (6.92%) 0.90 [0.86, 0.95] absolute 2979/ / / /24672 <35 mg/dl [0.91, 1.03] magnitude of (10.31%) (10.58%) (9.85%) (10.03%) 0.98 [0.92, 1.03] LDL-C reduction 32/676 35/ / / mg/dl [0.57, 1.47] (4.73%) (5.19%) (5.29%) (5.90%) 0.90 [0.85, 0.96] >65 mg/dl / /6229 NA (3.79%) (6.61%) 0.70 [0.52, 0.95] Total / / / / [0.92, 1.03] (10.18%) (10.46%) (6.22%) (6.92%) 0.90 [0.86, 0.95] baseline LDL-C 1228/ / / /22189 <100 mg/dl [0.88, 1.06] (6.11%) (6.29%) (1.30%) (1.22%) 1.06 [0.91, 1.25] mg/dl / / / / [0.70, 1.11] (3.74%) (4.07%) (1.97%) (2.41%) 0.89 [0.80, 1.00] mg/dl /676 20/ / / [0.60, 2.01] (3.25%) (2.96%) (3.90%) (4.74%) 0.82 [0.78, 0.87] 160 mg/dl / /6316 NA (3.26%) (5.03%) 0.65 [0.54, 0.77] Total / / / / [0.89, 1.03] (5.34%) (5.56%) (2.81%) (3.46%) 0.83 [0.78, 0.88] absolute 1557/ / / /24672 <35 mg/dl [0.87, 1.03] magnitude of (5.39%) (5.62%) (3.88%) (4.22%) 0.92 [0.84, 1.00] LDL-C reduction 22/676 20/ / / mg/dl [0.60, 2.01] (3.25%) (2.96%) (2.49%) (3.07%) 0.83 [0.77, 0.89] >65 mg/dl / /6229 NA (2.48%) (4.99%) 0.66 [0.56, 0.79] Total / / / / [0.89, 1.03] (5.34%) (5.56%) (2.81%) (3.46%) 0.83 [0.78, 0.88] baseline LDL-C 1779/ / / /22189 <100 mg/dl [0.80, 0.91] (8.85%) (10.35%) (2.55%) (3.28%) 0.88 [0.59, 1.33] mg/dl / / / / [0.78, 0.99] (6.33%) (7.19%) (1.45%) (2.09%) 0.64 [0.50, 0.83] mg/dl /676 40/ / / [0.56, 1.38] (5.18%) (5.93%) (5.02%) (6.70%) 0.74 [0.68, 0.79] 160 mg/dl / /6316 NA (7.01%) (10.66%) 0.64 [0.53, 0.78] Total / / / / [0.82, 0.91] (8.02%) (9.31%) (3.72%) (5.12%) 0.72 [0.67, 0.77] absolute 2336/ / / /24672 <35 mg/dl [0.81, 0.91] magnitude of (8.08%) (9.39%) (3.25%) (3.91%) 0.77 [0.66, 0.91] LDL-C reduction 35/676 40/ / / mg/dl [0.56, 1.38] (5.18%) (5.93%) (3.84%) (5.24%) 0.72 [0.67, 0.78] >65 mg/dl / /6229 NA (4.06%) (8.48%) 0.58 [0.46, 0.74] Total / / / / [0.82, 0.91] (8.02%) (9.31%) (3.72%) (5.12%) 0.72 [0.67, 0.77] baseline LDL-C <100 mg/dl / / [0.78, 0.94] / / [0.50, 1.01] Cardiovascular mortality Myocardial infarction

18 Cerebrovascular (3.72%) (4.34%) (1.02%) (1.34%) events 200/ / / / mg/dl [0.72, 1.05] (2.27%) (2.63%) (1.28%) (1.86%) mg/dl /676 15/ / / [0.53, 2.15] (2.37%) (2.22%) (3.17%) (3.77%) 160 mg/dl / /6316 NA (1.83%) (2.58%) Total / / / / [0.79, 0.94] (3.26%) (3.79%) (2.16%) (2.73%) absolute 947/ / / /24672 <35 mg/dl [0.79, 0.94] magnitude of (3.28%) (3.83%) (2.41%) (2.83%) LDL-C reduction 16/676 15/ / / mg/dl [0.53, 2.15] (2.37%) (2.22%) (2.17%) (2.72%) >65 mg/dl / /6229 NA (1.37%) (2.41%) Total / / / / [0.79, 0.94] (3.26%) (3.79%) (2.16%) (2.73%) Revascularization baseline LDL-C 3108/ / / /22189 <100 mg/dl [0.74, 1.02] (15.47%) (17.28%) (3.54%) (4.50%) mg/dl / / / / [0.75, 0.92] (11.81%) (14.35%) (2.16%) (2.95%) mg/dl /676 62/ / / [0.48, 1.04] (6.51%) (9.19%) (6.11%) (7.74%) 160 mg/dl / /6316 NA (5.14%) (8.04%) Total / / / / [0.77, 0.94] (14.18%) (16.23%) (4.52%) (5.93%) absolute 4148/ / / /24672 <35 mg/dl [0.78, 0.95] magnitude of (14.35%) (16.39%) (4.56%) (5.40%) LDL-C reduction 44/676 62/ / / mg/dl [0.48, 1.04] (6.51%) (9.19%) (4.46%) (5.82%) >65 mg/dl / /6229 NA (4.87%) (9.41%) Total / / / / [0.77, 0.94] (14.18%) (16.23%) (4.52%) (5.93%) MACE baseline LDL-C 4483/ / / /22189 <100 mg/dl [0.84, 0.99] (22.31%) (24.08%) (6.84%) (7.82%) mg/dl / / / / [0.81, 0.94] (14.90%) (17.09%) (4.46%) (6.21%) mg/dl / / / / [0.62, 1.10] (12.57%) (15.26%) (11.59%) (14.41%) 160 mg/dl / /5516 NA (9.54%) (13.60%) Total / / / / [0.85, 0.94] (19.88%) (21.80%) (8.52%) (10.82%) absolute 5795/ / / /19487 <35 mg/dl [0.85, 0.95] magnitude of (20.05%) (21.96%) (7.21%) (8.59%) LDL-C reduction 85/ / / / mg/dl [0.62, 1.10] (12.57%) (15.26%) (8.74%) (10.96%) >65 mg/dl / /5429 NA (9.63%) (16.82%) Total / / / / [0.85, 0.94] (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]

19 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 mg/dl mg/dl mg/dl Total <35 mg/dl mg/dl >65 mg/dl Total <100 mg/dl mg/dl mg/dl mg/dl Total <35 mg/dl mg/dl >65 mg/dl Total <100 mg/dl mg/dl mg/dl mg/dl Total <35 mg/dl mg/dl >65 mg/dl Total <100 mg/dl mg/dl mg/dl mg/dl Total 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] 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%) /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] NA [0.95, 1.06] 1.00 [0.95, 1.06] NA [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] NA [0.88, 1.05] 0.97 [0.88, 1.06] NA [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] NA [0.80, 0.96] 0.88 [0.82, 0.95] 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 [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] NA [0.76, 0.97] /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]

20 absolute 1069/ / /13717 <35 mg/dl magnitude of (2.69%) (3.13%) [0.79, 0.93] (3.44%) LDL-C reduction 1362/ / mg/dl (2.91%) (3.60%) [0.73, 0.91] >65 mg/dl / / / (2.32%) (3.70%) [0.46, 0.84] (3.50%) Total / / / (2.79%) (3.39%) [0.78, 0.88] (3.44%) Revascularization baseline LDL-C 1237/ / /9067 <100 mg/dl (11.22%) (13.72%) [0.66, 1.04] (20.64%) / / / mg/dl (4.79%) (5.98%) [0.70, 0.90] (6.11%) / / / mg/dl (6.70%) (8.47%) [0.74, 0.84] (8.16%) 160 mg/dl / / (5.14%) (8.04%) [0.56, 0.74] Total / / / (6.57%) (8.35%) [0.73, 0.82] (15.22%) absolute 3115/ / /13717 <35 mg/dl magnitude of (7.83%) (9.41%) [0.78, 0.90] (15.71%) LDL-C reduction 2502/ / mg/dl (5.35%) (7.07%) [0.69, 0.79] >65 mg/dl / / / (9.07%) (14.16%) [0.51, 0.78] (8.16%) Total / / / (6.57%) (8.35%) [0.73, 0.82] (15.22%) MACE baseline LDL-C 1911/ / /9067 <100 mg/dl (17.33%) (19.03%) [0.73, 1.05] (28.37%) / / / mg/dl (7.26%) (8.86%) [0.71, 0.89] (11.31%) / / / mg/dl (12.14%) (15.21%) [0.77, 0.83] (35.28%) 160 mg/dl / / (9.54%) (13.60%) [0.63, 0.79] Total / / / (11.09%) (13.59%) [0.76, 0.84] (23.40%) absolute 4099/ / /13717 <35 mg/dl magnitude of (11.84%) (13.42%) [0.82, 0.91] (22.59%) LDL-C reduction 4826/ / mg/dl (10.31%) (13.28%) [0.73, 0.81] >65 mg/dl / / / (15.89%) (22.58%) [0.61, 0.81] (35.28%) Total / / / (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 [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] NA [0.67, 1.00] 0.89 [0.75, 1.05] NA [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] NA [0.86, 0.97] 0.90 [0.82, 1.00] NA [0.79, 1.07] 0.91 [0.86, 0.97] /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]

21 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 mg/dl mg/dl mg/dl Total <35 mg/dl mg/dl >65 mg/dl Total <100 mg/dl mg/dl mg/dl mg/dl Total <35 mg/dl mg/dl >65 mg/dl Total <100 mg/dl mg/dl mg/dl mg/dl Total <35 mg/dl mg/dl >65 mg/dl Total 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 [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] NA [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] NA [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] 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]