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CTT 2010


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E?cacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials
Cholesterol Treatment Trialists’ (CTT) Collaboration*

Summary
Lancet 2010; 376: 1670–81 Published Online November 9, 2010 DOI:10.1016/S01406736(10)61350-5 See Comment page 1622 See Articles page 1658 *Collaborators are listed at the end of the paper Correspondence to: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK ctt@ctsu.ox.ac.uk or National Health and Medical Research Council (NHMRC) Clinical Trial Centre, Mallett Street Campus M02, University of Sydney, NSW 2006, Australia ctt@ctc.usyd.edu.au

Background Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and e?cacy of more intensive lowering of LDL cholesterol with statin therapy. Methods We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years’ treatment duration of more versus less intensive statin regimens (?ve trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. Findings In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly signi?cant 15% (95% CI 11–18; p<0·0001) further reduction in major vascular events, consisting of separately signi?cant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7–19; p<0·0001), in coronary revascularisation of 19% (95% CI 15–24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5–26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76–0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87–0·93; p<0·0001), largely re?ecting signi?cant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74–0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81–0·98; p=0·002), with no signi?cant e?ect on deaths due to stroke (RR 0·96, 95% CI 0·84–1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81–1·18; p=0·8). No signi?cant e?ects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92–1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96–1·04; p=0·9), even at low LDL cholesterol concentrations. Interpretation Further reductions in LDL cholesterol safely produce de?nite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a ?fth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2–3 mmol/L would reduce risk by about 40–50%. Funding UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

Introduction
The Cholesterol Treatment Trialists’ (CTT) Collaboration previously reported a meta-analysis1 of individual data from 90 000 individuals in 14 randomised trials2–15 of statin therapy versus control. Allocation to the statin regimens in those trials resulted in a weighted mean di?erence of about 1·0 mmol/L in LDL cholesterol and a proportional reduction of about a ?fth in major vascular events (de?ned as coronary death, non-fatal myocardial infarction, coronary revascularisation, or stroke). Observational studies show that there is a continuous positive relation between coronary disease risk and blood cholesterol
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concentrations,16–18 so larger reductions in LDL cholesterol might well produce larger reductions in risk. This hypothesis is indirectly supported by the positive association identi?ed in the previous meta-analysis between the absolute reduction in LDL cholesterol in a trial and the proportional reduction in major vascular events in that trial.1 Standard statin regimens (eg, 20–40 mg simvastatin daily) typically reduce LDL cholesterol concentrations by about a third, but regimens involving higher doses or newer, more potent statins (eg, 40–80 mg atorvastatin or 10–20 mg rosuvastatin daily) can halve LDL cholesterol.19–22
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To determine whether larger reductions in LDL cholesterol safely produce further reductions in major vascular events, several trials have compared more intensive versus standard statin regimens.23–27 Although their results tend to suggest further bene?t,28 only two had signi?cant results for their primary outcome.24,26 The present meta-analysis of individual data from all of these trials assesses the e?ects of more intensive statin therapy more reliably than before. Several recent trials of statin therapy in patients with renal failure29,30 or chronic heart failure31,32 have not shown clear evidence of bene?t, and in our meta-analysis we also investigate those ?ndings. Moreover, we address the question of whether lowering of LDL cholesterol to very low concentrations might have adverse consequences.18,33–35

Methods
Study eligibility and outcomes
The CTT protocol was agreed before the ?rst trial results were available.36 In this second cycle of analyses, we aimed to include all eligible trials reported by the end of 2009. Trials were eligible for inclusion if: the main e?ect of the intervention was to lower LDL cholesterol; no other di?erences in risk factor modi?cation were intended; and at least 1000 participants were to be recruited with at least 2 years’ scheduled treatment duration. Prespeci?ed outcomes were cause-speci?c mortality, major coronary event (coronary death or non-fatal myocardial infarction), coronary revascularisation (angioplasty or bypass grafting), stroke (subdivided by type), and new cancer diagnosis (subdivided by site).36 As in the ?rst cycle of meta-analyses,1 a major vascular event was de?ned as the ?rst occurrence of any major coronary event, coronary revascularisation, or stroke. In trials in patients with acute coronary syndrome,23,24 many of the revascularisation procedures had been planned before trial entry and happened soon afterwards, so the masked treatment allocation could not a?ect them. Consequently, only procedures resulting from recurrent ischaemia23 or occurring more than 30 days after randomisation24 (depending on the trial) were included. For the present analyses, cardiac deaths were subdivided into those probably or de?nitely due to coronary disease and those that might not have been (eg, sudden deaths or deaths attributed to arrhythmia, heart failure, or unspeci?ed cardiac causes). As a result, the 14 trials that were included in the previous report1 now involve slightly fewer major coronary and major vascular events than they did before.

in that trial at 1 year (d mmol/L),36 and are reported as e?ects per 1·0 mmol/L reduction in LDL cholesterol. In a meta-analysis of several trials, the log of the rate ratio per mmol/L (log RR) is calculated as S/V with variance 1/V (and hence with 95% CI of S/V±1·96/√V), where S is the sum over all trials of d (o–e) and V is the sum over all trials of d?v. (For unweighted analyses, d is omitted from these formulae.) For most subgroup analyses, the weight for a particular subgroup was the LDL cholesterol di?erence observed in the whole trial, but analyses by baseline LDL cholesterol concentration used trial- and subgroupspeci?c LDL weights. In trials comparing more versus less intensive statin therapy, the relevant baseline lipid values would be those achieved on the less intensive regimen. In three of these trials,23–25 however, any statin therapy was stopped before randomisation, so their relevant baseline values had to be estimated by multiplying the values at the randomisation visit (ie, o? statin treatment) by the mean proportional reduction observed at 1 year among those allocated the less intensive regimen. Proportional risk reductions in di?erent subgroups were compared by standard χ? tests for heterogeneity or, where appropriate, trend. To help to allow for multiple subdivisions, only summary rate ratios have 95% CIs; all other rate ratios have 99% CIs. Analyses were done with SAS version 9.1 (SAS Institute, Cary) and R version 2.11.1 (www.R-project.org).

Role of the funding sources
The funding sources had no involvement in study design, data collection, analysis, interpretation, report writing or publication. The writing committee had full access to all data and accepts full responsibility for the content of this report.

Results
For the meta-analyses of more versus less intensive statin therapy, individual participant data were available from all ?ve eligible trials: two23,24 in 8659 patients with acute coronary syndrome and three in 30 953 patients with stable coronary disease25–27 (table; webappendix pp 1 and 2). Overall, among the 39 612 participants in these ?ve trials, the weighted mean baseline LDL cholesterol concentration was estimated to be 2·53 mmol/L, the weighted mean di?erence at one year was 0·51 mmol/L, and the weighted median follow-up duration among survivors was 5·1 years (2·1 years for patients with acute coronary syndrome and 5·8 years for those with stable disease). The previous CTT meta-analysis of statin therapy versus control involved 14 trials in 90 056 participants.1 For this second cycle, individual participant data were available from seven more trials29–31,37–40 of statin versus control among 39 470 participants: two in primary prevention,37,38 two in haemodialysis patients,29,30 and one each in patients with coronary disease,39 diabetes,40 and heart failure31 (table; webappendix pp 1 and 2). Overall, among the 129 526 participants in these 21 trials, the weighted mean

See Online for webappendix

Statistical analysis
Analyses were to include all randomised patients irrespective of whether they received their allocated treatment (intention to treat). The primary meta-analyses were of the e?ects on disease event rates in each trial calculated as the logrank (o–e) and its variance (v) for ?rst events weighted by the absolute LDL cholesterol di?erence
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Number of patients

Treatment comparison (mg per day)

Baseline Median follow–up LDL-C in survivors (mmol/L) (years)*

Women (%) LDL-C di?erence at 1 year (mmol/L)

Diabetes (%)

Prior CHD (%)

Other vascular No prior disease (%)? vascular disease (%)?

More versus less statin PROVE–IT A to Z TNT IDEAL SEARCH Subtotal (5 trials) Statin versus control SSSS WOSCOPS CARE Post–CABG AFCAPS/TexCAPS LIPID GISSI–P LIPS HPS PROSPER ALLHAT–LLT ASCOT–LLA ALERT CARDS ALLIANCE** 4D** ASPEN** MEGA**?? JUPITER** GISSI–HF** AURORA** Subtotal (21 trials) Total (26 trials) 4444 6595 4159 1351 6605 9014 4271 1677 20 536 5804 10 355 10 305 2102 2838 2442 1255 2410 8214 17 802 4574 2773 129 526 169 138 S20–40 vs placebo P40 vs placebo P40 vs placebo L40–80 vs L2·5–5 L20–40 vs placebo P40 vs placebo F80 vs placebo S40 vs placebo P40 vs placebo P40 vs usual care A10 vs placebo F40 vs placebo A10 vs placebo A20 vs placebo A10 vs placebo R20 vs placebo R10 vs placebo R10 vs placebo NA NA 5·4 4·8 5·0 4·3 5·2 6·0 3·9 5·4 3·3 4·9 3·3 5·5 4·1 4·0 4·0 2·0 4·2 4·6 4·8|| 4·9|| 4·88 4·96 3·58 4·02 3·89 3·88 3·92 3·42 3·38 3·79 3·76 3·44 4·14 3·03 3·80 3·25 2·93 4·05 2·70 3·06 2·58 3·70|| NA –1·77 –1·07 –1·03 –1·07 –0·94 –1·03 –0·35 –0·92 –1·29 –1·04 –0·54 –1·07 –0·84 –1·14 –1·16 –0·89 –0·99 –0·67 –1·09 –0·92 –0·99 –1·07|| NA 827 (19%) 0 576 (14%) 102 (8%) 997 (15%) 1516 (17%) 587 (14%) 271 (16%) 5082 (25%) 3000 (52%) 5051 (49%) 1942 (19%) 715 (34%) 909 (32%) 434 (18%) 578 (46%) 811 (34%) 5547 (68%) 6801 (38%) 1032 (23%) 1050 (38%) 37 828 (29%) 45 495 (27%)
24

4162 4497 10 001 8888 12 064 39 612

A80 vs P40 S40 then S80 vs placebo then S20 A80 vs A10 A40–80 vs S20–40 S80 vs S20 NA

2·1 2·0 5·0 4·8 7·0 5·1||

2·62§ 2·09§ 2·52 2·64§ 2·50 2·53||

–0·65 –0·30 –0·62 –0·55 –0·39 –0·51||

911 (22%) 1100 (24%) 1902 (19%) 1702 (19%) 2052 (17%) 7667 (19%)

734 (18%) 1059 (24%) 1501 (15%) 1069 (12%) 1267 (11%) 5630 (14%) 202 (5%) 76 (1%) 586 (14%) 116 (9%) 155 (2%) 782 (9%) 582 (14%) 202 (12%) 5963 (29%) 623 (11%) 3638 (35%) 2527 (25%) 396 (19%) 2838 (100%) 540 (22%) 1255 (100%) 2410 (100%) 1686 (21%) 76 (<1%) 1196 (26%) 731 (26%) 26 580 (21%) 32 210 (19%)

4162 (100%) 4497 (100%) 10 001 (100%) 8888 (100%) 12 064 (100%) 39 612 (100%) 4444 (100%) 338 (5%) 4159 (100%) 1351 (100%) 10 (<1%) 9014 (100%) 4271 (100%) 1677 (100%) 13 386 (65%) 1881 (32%) 1188 (11%) 15 (<1%) 400 (19%) 9 (<1%) 2442 (100%) 630 (50%) 578 (24%) 42 (<1%) 0 1797 (39%) 659 (24%) 48 291 (37%) 87 903 (52%)

328 (8%) 479 (11%) 1537 (15%) 971 (11%) 1062 (9%) 4377 (11%) 126 (3%) 193 (3%) 0 37 (3%) 9 (<1%) 905 (10%) 179 (4%) 142 (8%) 8865 (43%) 1026 (18%) 1788 (17%) 1435 (14%) 241 (11%) 97 (3%) 162 (7%) 666 (53%) 302 (13%) 53 (<1%) 0 4574 (100%) 743 (27%) 21 543 (17%) 25 920 (15%)
23

0 0 0 0 0 0 0 6096 (92%) 0 0 6586 (>99%) 0 0 0 3161 (15%) 3254 (56%) 8037 (78%) 8860 (86%) 1702 (81%) 2738 (96%) 0 344 (27%) 1663 (69%) 8119 (99%) 17 802 (100%) 0 1663 (60%) 70 025 (54%) 70 025 (41%)

P20 vs no treatment 2·0

A10–80 vs usual care 4·7

P10–20 vs usual care 5·0

LDL-C=LDL-cholesterol. CHD=coronary heart disease. PROVE-IT=Pravastatin or Atorvastatin Evaluation and Infection Therapy. A=atorvastatin. P=pravastatin. A to Z=Aggrastat to Zocor. S=simvastatin. TNT=Treating to New Targets.26 IDEAL=Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group.25 SEARCH=Study of the E?ectiveness of Additional Reductions in Cholesterol and Homocysteine.27 SSSS=Scandinavian Simvastatin Survival Study.2 WOSCOPS=West of Scotland Coronary Prevention Study.3 CARE=Cholesterol And Recurrent Events.4 Post-CABG=Post-Coronary Artery Bypass Graft.5 L=lovastatin. AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study.6 LIPID=Long–term Intervention with Pravastatin in Ischaemic Disease.7 GISSI–P=Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico.8 LIPS=Lescol Intervention Prevention Study.9 F=?uvastatin. HPS=Heart Protection Study.10 PROSPER=PROspective Study of Pravastatin in the Elderly at Risk.11 ALLHATLLT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.12 ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm.13 ALERT=Assessment of Lescol in Renal Transplantation.14 CARDS=Collaborative Atorvastatin Diabetes Study.15 ALLIANCE=Aggressive Lipid-Lowering Initiation Abates New Cardiac Events.39 4D=Die Deutsche Diabetes Dialyse Studie.29 ASPEN=Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus.40 MEGA=Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study Group.37 JUPITER=Justi?cation for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study group.38 R=rosuvastatin. GISSI-HF=Gruppo Italiano per lo Studio della Sopravvivenza nell’Insu?cienza cardiac.31 AURORA=A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events.30 *Estimated with standard Kaplan-Meier methods, with patients censored at their date of death. ?History of intracerebral bleed, transient ischaemic attack, ischaemic stroke, unknown stroke, peripheral artery disease, or heart failure (if known). ?No known history of CHD or other vascular disease. §These three trials did not have active run–in periods; the values shown are the estimated on-treatment LDL cholesterol levels in the standard statin group. ||Median follow– up, baseline LDL-C, and LDL-C di?erence at 1 year weighted by trial–speci?c variances of observed logrank (o–e) for major vascular events. **Additional statin versus control trials included in this second cycle of analyses. ??Includes 382 randomised patients who were excluded from the original publication.37

Table: Baseline characteristics and eligibility criteria of participating trials

baseline LDL cholesterol concentration was 3·70 mmol/L, the weighted mean di?erence at 1 year was 1·07 mmol/L, and the weighted median follow-up duration in survivors was 4·8 years. Individual participant data were unavailable from three eligible trials involving 11 342 patients: CORONA,32 SPARCL,33 and GREACE.41
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First major vascular events were recorded in the ?ve trials of more versus less intensive statin therapy in 3837 (4·5% per annum) of 19 829 participants allocated more intensive versus 4416 (5·3% per annum) of 19 783 allocated less intensive therapy (?gure 1), corresponding to a highly signi?cant further
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proportional risk reduction of 15% (95% CI 11–18; p<0·0001) associated with the mean 0·51 mmol/L further LDL cholesterol reduction. In comparisons between these ?ve trials, larger absolute reductions in LDL cholesterol were associated with larger proportional risk reductions (trend p=0·0004), but there was little residual variation after adjustment for LDL cholesterol di?erences (trend p=0·05). Overall, the weighted average further reduction in ?rst major vascular events was 28% (95% CI 22–34; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol (?gure 1), with separately
LDL-C reduction (mmol/L) Events (% per annum)

signi?cant reductions in each of the major components of this composite outcome (?gure 2). In the updated meta-analysis of 21 trials of statin versus control, 7136 (2·8% per annum) of 64 744 participants allocated statin therapy had ?rst major vascular events versus 8934 (3·6% per annum) of 64 782 allocated control (?gure 1), corresponding to a highly signi?cant 22% (95% CI 19–24; p<0·0001) risk reduction with a 1·07 mmol/L LDL cholesterol reduction. In comparisons between these 21 trials, larger absolute reductions in LDL cholesterol were
Unweighted RR (CI) RR (CI) per 1 mmol/L reduction in LDL-C

Statin/more More vs less statin PROVE?IT TNT IDEAL SEARCH A to Z Subtotal (5 trials) Statin vs control SSSS HPS ALLIANCE CARDS JUPITER ASCOT?LLA Post-CABG WOSCOPS PROSPER CARE LIPID ASPEN AURORA AFCAPS/TexCAPS LIPS GISSI?HF 4D ALERT MEGA ALLHAT?LLT GISSI?P Subtotal (21 trials)

Control/less

0·65 0·62 0·55 0·39 0·30 0·51

406 (11·3%) 889 (4·0%) 938 (5·2%) 1347 (3·6%) 257 (7·2%) 3837/19 829 (4·5%) 555 (5·4%) 1511 (3·1%) 254 (5·4%) 81 (1·5%) 105 (0·5%) 217 (1·3%) 79 (3·0%) 232 (1·5%) 431 (4·9%) 433 (4·8%) 936 (4·1%) 114 (2·7%) 362 (8·1%) 143 (0·8%) 164 (6·9%) 172 (2·2%) 144 (9·0%) 135 (2·7%) 102 (0·5%) 758 (3·3%) 208 (5·4%) 7136/64 744 (2·8%) 10 973/84 573 (3·2%)

458 (13·1%) 1164 (5·4%) 1106 (6·3%) 1406 (3·8%) 282 (8·1%) 4416/19 783 (5·3%) 796 (8·2%) 2043 (4·3%) 293 (6·4%) 123 (2·4%) 194 (1·0%) 307 (1·9%) 100 (3·8%) 318 (2·1%) 495 (5·6%) 553 (6·3%) 1153 (5·2%) 136 (3·3%) 368 (8·3%) 201 (1·2%) 195 (9·0%) 174 (2·2%) 162 (10·1%) 140 (2·7%) 140 (0·7%) 812 (3·5%) 231 (6·1%) 8934/64 782 (3·6%) 13 350/84 565 (4·0%)

Trend: χ21=12·4 (p=0·0004)

Trend: χ21=3·7 (p=0·05)

0·85 (0·82?0·89) p<0·0001

0·72 (0·66?0·78) p<0·0001

1·77 1·29 1·16 1·14 1·09 1·07 1·07 1·07 1·04 1·03 1·03 0·99 0·99 0·94 0·92 0·92 0·89 0·84 0·67 0·54 0·35 1·07

Trend: χ21=32·3 (p<0·0001)

Trend: χ21=0·6 (p=0·4)

0·78 (0·76?0·81) p<0·0001

0·79 (0·77?0·81) p<0·0001 0·78 (0·76?0·80) p<0·0001

Overall (26 trials)

Heterogeneity between statin vs control and more vs less: ? before taking account of LDL di?erences: χ21=10·7 (p=0·001) ? after taking account of LDL di?erences: χ21=4·5 (p=0·03) 99% or 95% CI 0·5 0·75 Statin/more better 1 1·25 Control/less better 1·5 0·5 0·75 Statin/more better 1 1·25 Control/less better 1·5

Figure 1: E?ects on any major vascular event in each study In the left panel, unweighted rate ratios (RRs) for each trial of the comparison of ?rst event rates between randomly allocated treatment groups are plotted along with 99% CIs. Trials are ordered according to the absolute reduction in LDL cholesterol (LDL-C) at 1 year within each type of trial comparison (more vs less statin and statin vs control). In the right panel, rate ratios are weighted per 1·0 mmol/L LDL cholesterol di?erence at 1 year. Subtotals and totals with 95% CIs are shown by open diamonds.

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associated with larger proportional reductions in risk (trend p<0·0001), but no signi?cant residual variation remained after adjustment for LDL cholesterol di?erences (trend p=0·4). Overall, the weighted average reduction in major vascular events was 21% (95% CI 19–23; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol (?gures 1 and 2). After di?erences in the absolute reductions in LDL cholesterol were accounted for, the proportional reduction in the incidence of major vascular events per mmol/L was slightly larger (heterogeneity p=0·03; ?gure 1) in the trials of more versus less intensive therapy than in those of statin versus control. Taking all 26 trials together, the risk reduction was 22% (95% CI

20–24; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol at 1 year, with a signi?cant 12% reduction during the ?rst year after randomisation (p<0·0001) and highly signi?cant reductions of about a quarter during each subsequent year (all p<0·0001; webappendix p 3). First major coronary events were recorded in the ?ve trials of more versus less intensive statin therapy in 1725 (1·9% per annum) participants allocated more intensive versus 1973 (2·2% per annum) allocated less intensive therapy (?gure 2). This highly signi?cant further risk reduction of 13% (95% CI 7–19; p<0·0001) represented a signi?cant reduction in non-fatal myocardial infarction of 15% (99% CI 6–24; p<0·0001) and a non-signi?cant reduction in coronary death of 7% (p=0·2). The

Events (% per annum) Statin/more Control/less

Unweighted RR (CI)

RR (CI) per 1 mmol/L reduction in LDL-C

More vs less statin (?ve trials: 0·51 mmol/L LDL di?erence) Non-fatal MI 1175 (1·3%) 1380 (1·5%) CHD death 645 (0·7%) 694 (0·7%) Any major coronary event 1725 (1·9%) 1973 (2·2%) CABG PTCA Unspeci?ed Any coronary revascularisation Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke Five trials: any major vascular event 637 (0·7%) 1166 (1·3%) 447 (0·5%) 2250 (2·6%) 440 (0·5%) 69 (0·1%) 63 (0·1%) 572 (0·6%) 3837 (4·5%) 731 (0·9%) 1508 (1·8%) 502 (0·6%) 2741 (3·2%) 526 (0·6%) 57 (0·1%) 80 (0·1%) 663 (0·7%) 4416 (5·3%)

0·85 (0·76?0·94) 0·93 (0·81?1·07) 0·87 (0·81?0·93) p<0·0001 0·86 (0·75?0·99) 0·76 (0·69?0·84) 0·87 (0·74?1·03) 0·81 (0·76?0·85) p<0·0001 0·84 (0·71?0·99) 1·21 (0·76?1·91) 0·79 (0·51?1·21) 0·86 (0·77?0·96) p=0·009 0·85 (0·82?0·89) p<0·0001 0·71 (0·66?0·76) 0·78 (0·71?0·86) 0·73 (0·70?0·77) p<0·0001 0·71 (0·63?0·80) 0·76 (0·66?0·87) 0·77 (0·71?0·83) 0·75 (0·72?0·79) p<0·0001 0·80 (0·72?0·89) 1·15 (0·87?1·51) 0·88 (0·76?1·02) 0·85 (0·80?0·91) p<0·0001 0·78 (0·76?0·81) p<0·0001

0·71 (0·58?0·87) 0·85 (0·63?1·15) 0·74 (0·65?0·85) p<0·0001 0·72 (0·55?0·95) 0·60 (0·50?0·71) 0·78 (0·58?1·04) 0·66 (0·60?0·73) p<0·0001 0·69 (0·50?0·95) 1·39 (0·57?3·39) 0·63 (0·24?1·66) 0·74 (0·59?0·92) p=0·007 0·72 (0·66?0·78) p<0·0001 0·74 (0·69?0·78) 0·80 (0·73?0·86) 0·76 (0·73?0·79) p<0·0001 0·76 (0·69?0·83) 0·78 (0·69?0·89) 0·76 (0·70?0·83) 0·76 (0·73?0·80) p<0·0001 0·80 (0·73?0·88) 1·10 (0·86?1·42) 0·88 (0·76?1·02) 0·85 (0·80?0·90) p<0·0001 0·79 (0·77?0·81) p<0·0001 0·78 (0·76?0·80) p<0·0001

Statin vs control (21 trials: 1·07 mmol/L LDL di?erence) Non-fatal MI 2310 (0·9%) CHD death 1242 (0·5%) Any major coronary event 3380 (1·3%) CABG PTCA Unspeci?ed Any coronary revascularisation Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke 816 (0·3%) 601 (0·2%) 1686 (0·6%) 3103 (1·2%) 987 (0·4%) 188 (0·1%) 555 (0·2%) 1730 (0·7%)

3213 (1·2%) 1587 (0·6%) 4539 (1·7%) 1126 (0·4%) 775 (0·3%) 2165 (0·8%) 4066 (1·6%) 1225 (0·5%) 163 (0·1%) 629 (0·2%) 2017 (0·8%)

21 trials: any major vascular event

7136 (2·8%)

8934 (3·6%)

All 26 trials: any major vascular event 99% or 95% CI

10 973 (3·2%)

13 350 (4·0%)

0·5

0·75 Statin/more better

1

1·25 Control/less better

1·5

0·5

0·75 Statin/more better

1

1·25 Control/less better

1·5

Figure 2: E?ects on each type of major vascular event In the left panel, unweighted rate ratios (RRs) are plotted for each comparison of ?rst event rates between randomly allocated treatment groups. In the right panel, RRs are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) di?erence at 1 year. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds denoting 95% CIs. MI=myocardial infarction. CHD=coronary heart disease. CABG=coronary artery bypass graft. PTCA=percutaneous transluminal coronary angioplasty.

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proportional reduction in the incidence of major coronary events per 1·0 mmol/L LDL cholesterol reduction was similar (heterogeneity p=0·8; ?gure 2; webappendix p 4) in the trials of more versus less intensive therapy (26% reduction, 95% CI 15–35) and in those of statin versus control (24%, 95% CI 21–27). Taking all 26 trials together, the risk reduction was 24% (95% CI 22–27; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol, with highly signi?cant reductions in non-fatal myocardial infarction of 27% (95% CI 23–30; p<0·0001; webappendix p 5) and in coronary death of 20% (95% CI 15–25; p<0·0001; webappendix p 6). First coronary revascularisation procedures were recorded in the ?ve trials of more versus less intensive statin therapy in 2250 (2·6% per annum) participants allocated more intensive versus 2741 (3·2% per annum) allocated less intensive therapy (?gure 2). This highly signi?cant further risk reduction of 19% (95% CI 15–24; p<0·0001) represented signi?cant reductions in coronary artery surgery of 14% (99% CI 1–25; p=0·005) and in coronary angioplasty of 24% (99% CI 16–31; p<0·0001). The proportional reduction in the incidence of coronary revascularisation per 1·0 mmol/L reduction in LDL cholesterol was signi?cantly larger (heterogeneity p=0·01; ?gure 2; webappendix p 7) in the trials of more versus less intensive therapy (34% reduction, 95% CI 27–40) than in those of statin versus control (24%, 95% CI 20–27). This signi?cant heterogeneity re?ected a larger e?ect on coronary angioplasty and accounted for the observed di?erence between these groups of trials in the proportional reduction in major vascular events. Taking all 26 trials together, the risk reduction was 25% (95% CI 22–28; p<0·0001; webappendix p 7) per 1·0 mmol/L reduction in LDL cholesterol, with similar reductions in coronary artery surgery (25%, 99% CI 18–31) and in coronary angioplasty (28%, 99% CI 20–35). First strokes of any type were recorded in the ?ve trials of more versus less intensive statin therapy in 572 (0·6% per annum) participants allocated more intensive versus 663 (0·7% per annum) allocated less intensive therapy (?gure 2). This signi?cant further risk reduction of 14% (95% CI 4–23; p=0·009) represented a 16% (99% CI 1–29) reduction in the risk of ischaemic stroke (440 vs 526; risk ratio [RR] 0·84, 99% CI 0·71–0·99; p=0·005) and a non-signi?cant excess of haemorrhagic stroke (69 vs 57; RR 1·21, 99% CI 0·76–1·91; p=0·3). The proportional reduction in the incidence of stroke per 1·0 mmol/L LDL cholesterol reduction was nonsigni?cantly larger (heterogeneity p=0·2; ?gure 2; webappendix p 8) in the trials of more versus less intensive statin therapy (26% reduction, 95% CI 8–41) than in those of statin versus control (15% reduction, 95% CI 10–20). Taking all 26 trials together, the risk reduction was 16% (95% CI 11–21; p<0·0001; webappendix p 8) per 1·0 mmol/L LDL cholesterol reduction, with a highly signi?cant reduction in ischaemic stroke (1427 vs 1751; RR 0·79, 95% CI
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0·74–0·85; p<0·0001; webappendix p 9) and a nonsigni?cant excess of haemorrhagic stroke (257 vs 220; RR 1·12, 95% CI 0·93–1·35; p=0·2; webappendix p 10). The outcome of ?rst stroke after randomisation was available from 24 of the 26 trials, with 728 (15%) of 4948 ?rst strokes classi?ed as fatal and a further 256 stroke deaths reported (253 after non-fatal ?rst strokes and three in a trial9 without stroke incidence data). Overall, there was no signi?cant e?ect on mortality from
Events (% per annum) Statin/more Control/less 0·79 (0·76?0·82) 0·81 (0·71?0·92) 0·75 (0·69?0·82) RR (CI) per 1 mmol/L reduction in LDL-C Heterogeneity/ trend test

Previous vascular disease 8395 (4·5%) 10 123 (5·6%) CHD 802 (3·7%) 674 (3·1%) Non-CHD vascular 1904 (1·4%) 2425 (1·8%) None Diabetes 145 (4·5%) 192 (6·0%) Type 1 diabetes 2494 (4·2%) 2920 (5·1%) Type 2 diabetes 8272 (3·2%) 10 163 (4·0%) No diabetes Sex 8712 (3·5%) 10 725 (4·4%) Male 2261 (2·5%) 2625 (2·9%) Female Age (years) 6056 (2·9%) 7455 (3·6%) ≤65 4032 (3·7%) 4908 (4·6%) >65 to ≤75 885 (4·8%) 987 (5·4%) >75 Treated hypertension 6176 (3·7%) 7350 (4·5%) Yes 4543 (2·7%) 5707 (3·5%) No Systolic blood pressure (mm Hg) 5470 (3·2%) 6500 (3·8%) <140 3145 (3·0%) 4049 (3·9%) ≥140 to <160 2067 (3·6%) 2473 (4·5%) ≥160 Diastolic blood pressure (mm Hg) 4558 (3·5%) 5306 (4·2%) <80 3670 (3·0%) 4587 (3·8%) ≥80 to <90 2452 (3·0%) 3128 (3·9%) ≥90 Body-mass index (kg/m2) 3030 (3·0%) <25 5033 (3·3%) ≥25 to <30 2732 (3·3%) ≥30 HDL cholesterol (mmol/L) 5032 (4·0%) ≤1·0 3656 (3·1%) >1·0 to ≤ 1·3 2199 (2·4%) >1·3 3688 (3·7%) 6125 (4·1%) 3331 (4·1%) 6165 (5·0%) 4452 (3·9%) 2633 (2·9%)

χ22=2·28 (p=0·3)

0·77 (0·58?1·01) χ2 =0·41 0·80 (0·74?0·86) 2 (p=0·8) 0·78 (0·75?0·81) 0·77 (0·74?0·80) χ21=4·13 0·83 (0·76?0·90) (p=0·04) 0·78 (0·75?0·82) 0·78 (0·74?0·83) 0·84 (0·73?0·97) χ21=0·70 (p=0·4)

2 0·80 (0·76?0·84) χ 1=2·67 0·76 (0·72?0·80) (p=0·1)

0·80 (0·77?0·85) 0·75 (0·70?0·80) 0·79 (0·73?0·85) 0·81 (0·76?0·85) 0·77 (0·73?0·82) 0·77 (0·72?0·82)

χ21=1·19 (p=0·3)

χ21=2·01 (p=0·2)

0·79 (0·74?0·84) 2 χ 1=0·10 0·78 (0·74?0·82) (p=0·8) 0·78 (0·73?0·84) 0·78 (0·75?0·82) 2 χ 1=0·15 0·77 (0·73?0·82) (p=0·7) 0·80 (0·74?0·87) 0·78 (0·73?0·84) 0·78 (0·75?0·82) χ21=0·02 (p=0·9)

Smoking status 2268 (3·6%) 2896 (4·7%) Current smokers 8703 (3·1%) 10 452 (3·9%) Non?smokers Estimated GFR (mL/min per 1·73m2) 2712 (4·1%) 3354 (5·1%) <60 6161 (3·2%) 7540 (4·0%) ≥60 to <90 1315 (2·5%) 1571 (3·0%) ≥90 10 973 (3·2%) 13 350 (4·0%) Total 99% or

0·77 (0·72?0·83) 2 0·78 (0·75?0·82) χ 1=0·02 0·77 (0·69?0·85) (p=0·9) 0·78 (0·76?0·80)

0·5
95% CI

0·75
Statin/more better

1

1·25
Control/less better

Figure 3: E?ects on major vascular events per 1·0 mmol/L reduction in LDL cholesterol, by baseline prognostic factors Rate ratios (RRs) are plotted for each comparison of ?rst event rates between treatment groups, and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) di?erence at 1 year. Missing data are not plotted. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs. CHD=coronary heart disease. GFR=glomerular ?ltration rate.

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stroke (483 statin/more statin vs 501 control/less statin; RR 0·96, 95% CI 0·84–1·09; p=0·5), on mortality from ?rst stroke (369 vs 359), or on mortality from ?rst ischaemic (136 vs 124) or ?rst haemorrhagic (94 vs 75) stroke. Likewise, there was no signi?cant e?ect on the incidence of ?rst non-fatal haemorrhagic stroke (163 vs 145; RR 1·05, 99% CI 0·77–1·43; p=0·7). There was, however, a highly signi?cant reduction in ?rst nonfatal ischaemic stroke (1291 vs 1627), corresponding to a 23% (99% CI 15–30; p<0·0001) reduction per 1·0 mmol/L reduction in LDL cholesterol. First major vascular events were reduced by about a ?fth per 1·0 mmol/L LDL cholesterol reduction in each subgroup examined in the ?ve trials of more versus less intensive statin therapy (webappendix p 11), in the 21 trials of statin versus control (webappendix p 12), and in all 26 trials combined (?gure 3), even though the annual event rates in control groups di?ered substantially according to participants’ medical history and other characteristics. In particular, there was a highly signi?cant proportional risk reduction of 25% (99% CI 18–31; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol in participants with no previous history of vascular disease, as well as signi?cant reductions of 17% (99% CI 10–24; p<0·0001) among women and of 16% (99% CI 3–27; p=0·002) in people older than 75 years at entry (?gure 3).
Events (% per annum) Statin/more Control/less 0·71 (0·52?0·98) 0·77 (0·64?0·94) 0·81 (0·67?0·97) χ2=2·04 1 0·61 (0·46?0·81) (p=0·2) 0·64 (0·47?0·86) 0·72 (0·66?0·78) 0·87 (0·60?1·28) 0·77 (0·62?0·97) 0·76 (0·67?0·86) χ21=0·80 0·77 (0·71?0·84) (p=0·4) 0·80 (0·77?0·84) 0·79 (0·77?0·81) 0·78 (0·61?0·99) 0·77 (0·67?0·89) 2 0·77 (0·70?0·85) χ 1=1·08 0·76 (0·70?0·82) (p=0·3) 0·80 (0·76?0·83) 0·78 (0·76?0·80) RR (CI) per 1 mmol/L reduction in LDL-C Trend test

More vs less statin <2 mmol/L 704 (4·6%) 795 (5·2%) ≥2 to <2·5 mmol/L 1189 (4·2%) 1317 (4·8%) ≥2·5 to <3·0 mmol/L 1065 (4·5%) 1203 (5·0%) ≥3 to <3·5 mmol/L 517 (4·5%) 633 (5·8%) ≥3·5 mmol/L 398 (7·8%) 303 (5·7%) Total 3837 (4·5%) 4416 (5·3%) Statin vs control <2 mmol/L 206 (2·9%) 217 (3·2%) ≥2 to <2·5 mmol/L 339 (2·4%) 412 (2·9%) ≥2·5 to <3·0 mmol/L 801 (2·5%) 1022 (3·2%) ≥3 to <3·5 mmol/L 1490 (2·9%) 1821 (3·6%) ≥3·5 mmol/L 4205 (2·9%) 5338 (3·7%) Total 7136 (2·8%) 8934 (3·6%) All trials combined <2 mmol/L 910 (4·1%) 1012 (4·6%) ≥2 to <2·5 mmol/L 1528 (3·6%) 1729 (4·2%) ≥2·5 to <3·0 mmol/L 1866 (3·3%) 2225 (4·0%) ≥3 to <3·5 mmol/L 2007 (3·2%) 2454 (4·0%) ≥3·5 mmol/L 4508 (3·0%) 5736 (3·9%) Total 10 973 (3·2%) 13 350 (4·0%) 99% or 95% CI 0·45 0·75 Statin/more better 1

1·3 Control/less better

Figure 4: E?ects on major vascular events per 1·0 mmol/L reduction in LDL cholesterol, by baseline LDL cholesterol concentration on the less intensive or control regimen Rate ratios (RRs) are plotted for each comparison of ?rst event rates between treatment groups, and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) di?erence at 1 year. Analyses were done with trial-speci?c and subgroupspeci?c LDL weights for each baseline LDL cholesterol category. Missing data are not plotted. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs.

Baseline LDL cholesterol concentrations were substantially higher in the trials of statin versus control (3·70 mmol/L on no statin) than in those of more versus less intensive therapy (2·53 mmol/L on the less intensive regimen), so the latter group provides most of the information about the e?ects of reducing LDL cholesterol concentrations that were already low (eg, less than 2·5 mmol/L; ?gure 4). In these trials of more versus less statin, the RR per 1·0 mmol/L further reduction in LDL cholesterol did not depend on the baseline LDL cholesterol concentration (trend p=0·2; ?gure 4), with signi?cant reductions of 23% (99% CI 6–36; p=0·0005) in participants who had LDL cholesterol of 2·0–2·5 mmol/L reduced further and of 29% (99% CI 2–48; p=0·007) in those who had LDL cholesterol lower than 2·0 mmol/L (mean 1·71 mmol/L) reduced further. Indeed, even among those reaching 1·8 mmol/L (70 mg/dL) or lower with a standard statin regimen, further reduction yielded de?nite bene?t (RR 0·63, 99% CI 0·41–0·95; p=0·004; not shown separately in ?gure 4). Some have suggested that HDL cholesterol concentrations might not be inversely associated with vascular disease risk when LDL cholesterol is reduced intensively42 (which would imply that the risk reduction with statin therapy is smaller in people with higher HDL cholesterol). But, this hypothesis was not supported by comparisons of the major vascular event risks in baseline HDL cholesterol subgroups (?gure 3; webappendix pp 11 and 12). In particular, after adjustment for other risk factors, the risk ratio for upper versus lower tertiles of HDL cholesterol in participants allocated more intensive statin therapy (RR 0·81, 95% CI 0·74–0·89) was similar to that in those allocated less intensive therapy (RR 0·84, 95% CI 0·77–0·92). Death was recorded for 3593 participants in the ?ve trials of more versus less intensive statin therapy and for 12 376 in the 21 trials of statin versus control, yielding a total of 15 969 deaths in all 26 trials. Overall, 9014 (56%) of these deaths were attributed to vascular causes (4168 coronary, 3049 other cardiac, 984 stroke, 813 other vascular), 5937 (37%) were attributed to non-vascular causes (3579 cancer, 461 respiratory, 254 trauma, and 1643 other), and 1018 (6%) had unknown causes (webappendix p 2). For each of these categories of death, the proportional reductions in risk per 1·0 mmol/L LDL cholesterol reduction did not di?er between the two types of trial comparison (all heterogeneity p values >0·1). Taking all 26 trials together, there was a proportional reduction in allcause mortality of 10% (95% CI 7–13; p<0·0001; ?gure 5) per 1·0 mmol/L reduction in LDL cholesterol, which consisted of a highly signi?cant reduction in vascular mortality of 14% (95% CI 10–18; p<0·0001) and a marginally signi?cant reduction in mortality from unknown causes of 13% (95% CI 1–24; p=0·04), with no apparent e?ect on non-vascular mortality (RR 0·97, 95% CI 0·92–1·03; p=0·3). The reduction in vascular mortality was chie?y attributable to signi?cant reductions in deaths due to
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coronary disease of 20% (99% CI 13–26; p<0·0001) and other cardiac causes of 11% (99% CI 2–19; p=0·002) per 1·0 mmol/L, with no apparent e?ects on deaths due to stroke (RR 0·96, 95% CI 0·84–1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81–1·18; p=0·8). With respect to non-vascular mortality, there were no apparent e?ects on deaths from cancer (RR 0·99, 99% CI 0·91–1·09), respiratory disease (RR 0·88, 99% CI 0·70–1·11), trauma (RR 0·98, 99% CI 0·70–1·38), or all other non-vascular causes (RR 0·96, 99% CI 0·83–1·10). There was no indication that reduction of LDL cholesterol in individuals with lower baseline concentrations increased non-vascular mortality (trend p=0·2). First cancers after randomisation were recorded in 2938 participants in the ?ve trials of more versus less intensive statin therapy and in 7186 participants in the 21 trials of statin versus control, yielding a total of 10 124 ?rst cancers in all 26 trials (excluding cancers known to be recurrences of primary tumours diagnosed before randomisation, and non-melanoma skin cancers since they were not recorded routinely). In the ?ve trials of more versus less intensive statin therapy, reduction of LDL cholesterol to a mean of about 2 mmol/L had no signi?cant e?ect on the incidence of cancer at all sites combined (RR 1·02 per 1·0 mmol/L LDL cholesterol reduction, 95% CI 0·89–1·18; p=0·8) or at any particular site (?gure 6 and webappendix p 13). Similarly, there was no signi?cant e?ect in the 21 trials of statin versus control and, taking all 26 trials together, there was no evidence of an excess of cancer at all sites combined (RR 1·00 per 1·0 mmol/L LDL reduction, 95% CI 0·96–1·04; p=0·9) or at any particular site. There was also no indication that reduction of LDL cholesterol in individuals with lower baseline concentrations increased cancer incidence (indeed, if anything, the opposite pattern was observed; trend p=0·1). Only cases of myopathy that had progressed to rhabdomyolysis were sought from the individual trials. Overall, the observed excess of rhabdomyolysis was 4 (SE 2) per 10 000 in the ?ve trials of more versus less intensive statin therapy (14 vs six cases) compared with 1 (SE 1) per 10 000 in the 21 trials of standard statin regimens versus control (14 vs nine cases). All of the excess (ten vs no cases) with more intensive therapy occurred in the two trials of 80 mg versus 20 mg simvastatin daily; these two trials have also reported de?nite excesses in the incidence of myopathy with 80 mg simvastatin daily.23,27

Events (% per annum) Statin/more Vascular causes of death CHD Other cardiac All cardiac Ischaemic stroke Haemorrhagic stroke Unknown stroke Stroke Other vascular Any vascular 1887 (0·5%) 1446 (0·4%) 3333 (0·9%) 153 (0·0%) 102 (0·0%) 228 (0·1%) 483 (0·1%) 404 (0·1%) 4220 (1·2%) Control/less 2281 (0·6%) 1603 (0·4%) 3884 (1·1%) 139 (0·0%) 89 (0·0%) 273 (0·1%) 501 (0·1%) 409 (0·1%) 4794 (1·3%)

RR (CI) per 1 mmol/L reduction in LDL-C

0·80 (0·74?0·87) 0·89 (0·81?0·98) 0·84 (0·80?0·88) 1·04 (0·77?1·41) 1·12 (0·77?1·62) 0·85 (0·66?1·08) 0·96 (0·84?1·09) 0·98 (0·81?1·18) 0·86 (0·82?0·90)

Non-vascular causes of death 1781 (0·5%) Cancer 224 (0·1%) Respiratory 127 (0·0%) Trauma 811 (0·2%) Other non-vascular 2943 (0·8%) Any non-vascular Unknown Any death 99% or 479 (0·1%) 7642 (2·1%)

1798 (0·5%) 237 (0·1%) 127 (0·0%) 832 (0·2%) 2994 (0·8%) 539 (0·1%) 8327 (2·3%)

0·99 (0·91?1·09) 0·88 (0·70?1·11) 0·98 (0·70?1·38) 0·96 (0·83?1·10) 0·97 (0·92?1·03) 0·87 (0·73?1·03) 0·90 (0·87?0·93)

0·5
95% CI

0·75
Statin/more better

1

1·25
Control/less better

1·5

Figure 5: E?ects on cause-speci?c mortality per 1·0 mmol/L reduction in LDL cholesterol Rate ratios (RRs) are plotted for each comparison of ?rst event rates between treatment groups and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) di?erence at 1 year. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs. CHD=coronary heart disease.

Discussion
The previous CTT meta-analysis of individual participant data from randomised trials showed that lowering of LDL cholesterol by about 1 mmol/L with standard statin regimens safely reduced the 5-year incidence of major coronary events, revascularisations, and ischaemic strokes by about a ?fth.1 Several trials have since directly compared more intensive versus standard statin regimens.23–27 This updated meta-analysis has shown that
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additional reductions in LDL cholesterol (down to about 1–2 mmol/L) with more intensive therapy further reduce the incidence of these major vascular events, that the relation between absolute LDL cholesterol reductions and proportional risk reductions is consistent between the trials of more versus less intensive statin therapy and those of standard statin regimens versus control, and that these further reductions in vascular risk can be achieved safely even in individuals with low LDL cholesterol concentrations. Only two24,26 of the ?ve trials that assessed the e?ects of reducing LDL cholesterol more intensively23–27 produced separately signi?cant results. But, adjustment for the absolute reduction in LDL cholesterol indicates that the results of these ?ve trials are compatible with one another. Overall, a further reduction in LDL cholesterol of about 0·5 mmol/L was achieved, which reduced the residual risk of major vascular events by about a sixth, with separately signi?cant reductions in coronary death or non-fatal myocardial infarction (p<0·0001), in coronary revascularisation procedures (p<0·0001), and in ischaemic stroke (p=0·005). Moreover, the proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol was similar to that observed in the updated meta-analysis of trials of statin versus control. The previous meta-analysis of statin versus control involved comparatively few major vascular events in participants with low LDL cholesterol before treatment,1 whereas the present meta-analyses provide
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Events (% per annum) Statin/more More vs less statin Gastrointestinal Genitourinary Respiratory Female breast Haematological Melanoma Other/unknown Any Statin vs control Gastrointestinal Genitourinary Respiratory Female breast Haematological Melanoma Other/unknown Any All trials combined Gastrointestinal Genitourinary Respiratory Female breast Haematological Melanoma Other/unknown Any 99% or 95% CI 288 (0·3%) 480 (0·5%) 231 (0·3%) 73 (0·4%) 95 (0·1%) 56 (0·1%) 243 (0·3%) 1466 (1·6%) Control/less 322 (0·4%) 496 (0·5%) 219 (0·2%) 54 (0·3%) 82 (0·1%) 42 (0·0%) 257 (0·3%) 1472 (1·6%)

RR (CI) per 1 mmol/L reduction in LDL-C

0·79 (0·52?1·20) 1·00 (0·72?1·38) 1·15 (0·70?1·90) 1·60 (0·66?3·87) 1·34 (0·61?2·98) 1·84 (0·64?5·29) 0·96 (0·63?1·46) 1·02 (0·89?1·18)

878 (0·3%) 1116 (0·4%) 582 (0·2%) 194 (0·3%) 210 (0·1%) 103 (0·0%) 511 (0·2%) 3594 (1·4%)

872 (0·3%) 1149 (0·4%) 595 (0·2%) 187 (0·2%) 209 (0·1%) 100 (0·0%) 480 (0·2%) 3592 (1·4%)

0·99 (0·88?1·11) 0·96 (0·87?1·06) 0·99 (0·86?1·14) 1·04 (0·80?1·34) 1·02 (0·81?1·28) 1·09 (0·78?1·51) 1·05 (0·89?1·25) 1·00 (0·95?1·04)

1166 (0·3%) 1596 (0·5%) 813 (0·2%) 267 (0·3%) 305 (0·1%) 159 (0·0%) 754 (0·2%) 5060 (1·4%)

1194 (0·3%) 1645 (0·5%) 814 (0·2%) 241 (0·3%) 291 (0·1%) 142 (0·0%) 737 (0·2%) 5064 (1·4%)

0·97 (0·87?1·09) 0·97 (0·88?1·06) 1·00 (0·88?1·15) 1·07 (0·84?1·38) 1·04 (0·84?1·30) 1·14 (0·83–1·56) 1·04 (0·89?1·21) 1·00 (0·96?1·04)

0·5

0·75

1

1·25

1·6

Statin/more better

Control/less better

Figure 6: E?ects on site-speci?c cancer incidence per 1·0 mmol/L reduction in LDL cholesterol Rate ratios (RRs) are plotted for each comparison of ?rst event rates between treatment groups and are weighted per 1·0 mmol/L LDL cholesterol (LDL-C) di?erence at 1 year. RRs are shown with horizontal lines denoting 99% CIs or with open diamonds showing 95% CIs. Analyses are of ?rst cancers, subdivided by site: gastrointestinal (International Classi?cation of Disease codes version 9 140–159); genitourinary (179–189); respiratory (160–163,165); female breast (174); haematological (200–208); melanoma (172); other/unknown site (other cancers with codes 140–172, 174–209, plus deaths with codes 173, 210–239).

good evidence of bene?t, with no evidence of any hazard, even when LDL cholesterol concentrations lower than 2 mmol/L are reduced further. Overall, there was a 22% proportional reduction in the risk of major vascular events for each 1 mmol/L reduction in LDL cholesterol, which implies that, at least within the range of LDL cholesterol studied to date, a 2 mmol/L reduction would reduce the risk by about 40% (since the combination of risk ratios of 0·78×0·78 yields a risk ratio of about 0·6), and a 3 mmol/L reduction could reduce the risk by about 50%. In the combined meta-analysis of trials of more versus less intensive statin therapy and of statin therapy versus control, coronary mortality was reduced by about a ?fth per 1·0 mmol/L LDL cholesterol reduction, but the reduction in cardiac deaths that were not attributed to coronary disease was only about half as large. This ?nding may re?ect a relative lack of bene?t from lowering of LDL cholesterol on cardiac deaths that are mediated by non1678

occlusive mechanisms. For example, in the GISSI-HF31 trial of rosuvastatin versus placebo in patients with heart failure (which was included in this meta-analysis), as well as in the similar CORONA32 trial (which was not), most cardiac deaths were non-occlusive and there were no signi?cant reductions in cardiac mortality. Nor were there signi?cant reductions in cardiac mortality in the two statin trials among patients with renal disease,29,30 in which only about half of cardiac deaths were de?nitely due to coronary disease. By contrast, since most of the cardiac deaths that were coded as non-coronary in this meta-analysis occurred in patients with pre-existing coronary disease, some are likely to have been due to coronary occlusion (and, hence, reduced by statin therapy). These ?ndings suggest that the absolute reduction in cardiac mortality produced by lowering of LDL cholesterol with statin therapy in a given population depends chie?y on the absolute risk of death due to coronary occlusion. There was no signi?cant evidence in the meta-analysis of trials of more versus less intensive therapy that further lowering of LDL cholesterol (weighted mean of 2·5 mmol/L reduced to 2·0 mmol/L) produced any adverse e?ects, even in participants with baseline LDL cholesterol lower than 2·0 mmol/L. In one of those trials, the mean LDL cholesterol was reduced from 2·5 mmol/L to 1·9 mmol/L, and there was a non-signi?cant excess of death from non-vascular or unknown causes (158 on 80 mg atorvastatin vs 127 on 10 mg atorvastatin daily; p=0·06).25 But, that adverse trend was not supported by larger numbers of such deaths (590 [4·0%] vs 612 [4·1%]; RR 0·96, 95% CI 0·86–1·08; p=0·5) in the four other trials, or by an excess of any particular type of non-vascular mortality. Nor were there any adverse e?ects on cancer incidence in the meta-analyses of more versus less intensive therapy or of statin versus control. If lowering of LDL cholesterol with statin therapy was carcinogenic then it might be expected to increase the incidence of cancer at some particular site, and previous reports from individual trials had raised such concerns about breast4 and gastrointestinal cancers;11 there was, however, no evidence in our analyses of an increase in cancer at these or any other sites. Previous observational studies have generated the hypothesis that low cholesterol concentrations might be associated with an increased risk of intracerebral haemorrhage.18,43,44 The present meta-analyses, which included nearly 500 con?rmed haemorrhagic strokes, showed that lowering of LDL cholesterol with statin therapy was associated with a non-signi?cant excess (257 vs 220; p=0·2: webappendix p 10). In the SPARCL trial33 of atorvastatin versus placebo in patients with previous cerebrovascular disease (which was not available for this meta-analysis), there was a signi?cant 20% proportional reduction in major vascular events (RR 0·80, 95% CI 0·69–0·92; p=0·002). This result included a signi?cant reduction in ischaemic stroke (218 vs 274;
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p=0·008), but a signi?cant excess of haemorrhagic stroke (55 vs 33; p=0·02). In the two other trials of statin versus control that were not available for the meta-analysis, there were 15 versus nine haemorrhagic strokes in CORONA,32 but the numbers were not available for GREACE.41 If the published data for haemorrhagic stroke from SPARCL and CORONA were combined with the present meta-analysis then the rate ratio would be 1·21 (95% CI 1·05–1·41) per 1·0 mmol/L LDL cholesterol reduction. Although this result is signi?cant (p=0·01), the absolute size of the potential hazard would be about 50 times smaller (perhaps a few extra haemorrhagic strokes annually per 10 000 treated) than the de?nite absolute bene?ts (a few hundred occlusive events avoided annually per 10 000 treated) for patients who are at high risk of occlusive vascular events. In these meta-analyses, the size of the proportional reduction in major vascular events is directly proportional to the absolute LDL reduction that is achieved, with further bene?t from more intensive statin therapy, even if LDL cholesterol is already lower than 2·0 mmol/L. Each 1 mmol/L LDL cholesterol reduction reduces the risk of occlusive vascular events by about a ?fth, irrespective of baseline cholesterol concentration, which implies that a 2–3 mmol/L reduction would reduce risk by about 40–50%. These ?ndings suggest that the primary goal for patients at high risk of occlusive vascular events should be to achieve the largest LDL cholesterol reduction possible without materially increasing myopathy risk. Current therapeutic guidelines tend to emphasise the need to reach a particular LDL cholesterol target—for example, US National Cholesterol Education Program guidelines suggest that the objective in high-risk patients should generally be to reduce LDL cholesterol to below 100 mg/dL (2·6 mmol/L) or, optionally, for very high risk patients, to below 70 mg/dL (1·8 mmol/L).45 By contrast, our results suggest that lowering of LDL cholesterol further in high-risk patients who achieve such targets would produce additional bene?ts, without an increased risk of cancer or non-vascular mortality. Guidelines have proposed that high doses of generic statins (eg, 80 mg simvastatin daily) be used to achieve these bene?ts,46 but such regimens may be associated with higher risk of myopathy.27 Instead, these bene?ts may be achieved more safely with newer, more potent statins (eg, 80 mg atorvastatin or 20 mg rosuvastatin daily) and, potentially, by combination of standard doses of generic statins (eg, 40 mg simvastatin or pravastatin daily) with other LDLcholesterol-lowering therapies.47–49
Contributors All of the members of the writing committee contributed to collection and analysis of the data, and to the preparation of the report. All collaborators had an opportunity to contribute to the interpretation of the results and to drafting of the report. Con?icts of interest Most of the trials in this report were supported by research grants from the pharmaceutical industry. Some members of the writing committee have received reimbursement of costs to participate in scienti?c meetings from

the pharmaceutical industry. AK and JS have also received honoraria from Solvay for lectures related to these studies. Acknowledgments This collaboration is coordinated jointly by the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) at the University of Oxford, UK, and the National Health and Medical Research Council Clinical Trials Centre (CTC) at the University of Sydney, Australia. This work is supported at the CTSU by the UK Medical Research Council, British Heart Foundation, and, previously, the European Community Biomed Programme, and at the CTC by the Australian National Health and Medical Research Council and National Heart Foundation. Current membership of the CTT Collaboration Writing Committee: C Baigent, L Blackwell, J Emberson, L E Holland, C Reith, N Bhala, R Peto, E H Barnes, A Keech, J Simes, R Collins. Collaborating trialists: A to Z trial (phase Z) J de Lemos, E Braunwald, M Blazing, S Murphy; AFCAPS/TEXCAPS (AirForce/Texas Coronary Atherosclerosis Prevention Study) J R Downs, A Gotto, M Clear?eld; ALERT (Assessment of Lescol in Transplantation) H Holdaas; ALLHAT (Antihypertensive Lipid Lowering Heart Attack Trial) D Gordon, B Davis; ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) M Koren; ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) B Dahlof, N Poulter, P Sever; ASPEN (Atorvastatin Study for the prevention of coronary heart disease endpoints in noninsulin dependent diabetes mellitus) RH Knopp (deceased); AURORA ( A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events) B Fellstr?m, H Holdaas, A Jardine, R Schmieder, F Zannad; BIP (Beza?brate Infarction Prevention Study) U Goldbourt, E Kaplinsky; CARDS (Collaborative Atorvastatin Diabetes Study) H M Colhoun, D J Betteridge, P N Durrington, G A Hitman, J Fuller, A Neil; 4D (Die Deutsche Diabetes Dialyse study) C Wanner, V Krane; CARE (Cholesterol And Recurrent Events Study) F Sacks, L Moyé, M Pfe?er; C M Hawkins, E Braunwald; FIELD (Feno?brate Intervention and Event Lowering in Diabetes) P Barter, A Keech; GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico)–Heart Failure L Tavazzi, A Maggioni; GISSI–Prevention R Marchioli, G Tognoni, M G Franzosi, A Maggioni; HIT (Veteran Administration Low HDL Intervention Trial) H Bloom?eld, S Robins; HPS (Heart Protection Study) R Collins, J Armitage, A Keech, S Parish, R Peto, P Sleight; IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid-lowering) T R Pedersen; JUPITER (Justi?cation for the Use of Statins in Prevention: an International Trial Evaluating Rosuvastatin) P M Ridker; LDS (Lipids in Diabetes Study) R Holman; LEADER (Lower Extremity Arterial Disease Event Reduction trial) T Meade; LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) J Simes, A Keech, S MacMahon, I Marschner, A Tonkin, J Shaw; LIPS (Lescol Intervention Prevention Study) P W Serruys; MEGA (Management of Elevated cholesterol in the primary prevention Group of Adult japanese) H Nakamura; Post-CABG (Post- Coronary Artery Bypass Graft Study) G Knatterud; PPP (Pravastatin Pooling Project) C Furberg, R Byington; PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) P Macfarlane, S Cobbe, I Ford, M Murphy, G J Blauw, C Packard, J Shepherd; 4S (Scandinavian Simvastatin Survival Study) J Kjekshus, T Pedersen, L Wilhelmsen; PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) E Braunwald, C Cannon, S Murphy; SEARCH (Study of E?ectiveness of Additional Reductions in Cholesterol and Homocysteine) R Collins, J Armitage, L Bowman, S Parish, R Peto, P Sleight; SHARP (Study of Heart and Renal Protection) C Baigent, A Baxter, R Collins, M Landray; TNT (Testing New Targets) J La Rosa; WHI (Women’s Health Initiative) J Rossouw, J Probst?eld; WOSCOPS (West of Scotland Coronary Prevention Study) J Shepherd, S Cobbe, P Macfarlane, I Ford. Other members: M Flather, J Kastelein, C Newman, C Shear, J Tobert, J Varigos, H White, S Yusuf. Observers: Bristol-Myers Squibb M Mellies, M McGovern, J Barclay, R Belder; Merck Y Mitchel, T Musliner; Laboratoires Fournier J-C Ansquer; Bayer M Llewellyn; Novartis Pharma M Bortolini; AstraZeneca G Brandrup-Wognsen, B Bryzinski, G Olsson, J Pears; P?zer D DeMicco. CTT secretariat: A Baxter, C Baigent, E H Barnes, N Bhala, L Blackwell, G Buck, R Collins, J Emberson, W G Herrington, L E Holland, P M Kearney, A Keech, A Kirby, D A Lewis, I Marschner, C Pollicino, C Reith, J Simes, T Sourjina.

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