Articles

The effects of lowering LDL cholesterol with statin therapy

in people at low risk of vascular disease: meta-analysis of
individual data from 27 randomised trials
Cholesterol Treatment Trialists’ (CTT) Collaborators*

Summary
Background Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of Lancet 2012; 380: 581–90
vascular events remain uncertain. Published Online
May 17, 2012
http://dx.doi.org/10.1016/
Methods This meta-analysis included individual participant data from 22 trials of statin versus control (n=134 537;
S0140-6736(12)60367-5
mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin
See Comment page 541 and 545
(n=39 612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal
*Collaborators are listed at the
myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into end of the report
five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, Correspondence to:
≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol CTT Secretariat, Clinical Trial
reduction was estimated. Service Unit and Epidemiological
Studies Unit (CTSU), Richard Doll
Building, Old Road Campus,
Findings Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, Oxford OX3 7LF, UK
95% CI 0·77–0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous [email protected]
vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at or
least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from National Health and Medical
lowest to highest risk: 0·62 [99% CI 0·47–0·81], 0·69 [99% CI 0·60–0·79], 0·79 [99% CI 0·74–0·85], 0·81 [99% CI Research Council (NHMRC)
0·77–0·86], and 0·79 [99% CI 0·74–0·84]; trend p=0·04), which reflected significant reductions in these two lowest Clinical Trial Centre, Mallett
Street Campus M02, University
risk categories in major coronary events (RR 0·57, 99% CI 0·36–0·89, p=0·0012, and 0·61, 99% CI 0·50–0·74,
of Sydney, NSW 2006, Australia
p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35–0·75, and 0·63, 99% CI 0·51–0·79; both [email protected]
p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10%
(RR per 1·0 mmol/L LDL cholesterol reduction 0·76, 99% CI 0·61–0·95, p=0·0012) was also similar to that seen in
higher risk categories (trend p=0·3). In participants without a history of vascular disease, statins reduced the risks of
vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77–0·95) and all-cause mortality (RR 0·91,
95% CI 0·85–0·97), and the proportional reductions were similar by baseline risk. There was no evidence that
reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction
1·00, 95% CI 0·96–1·04), cancer mortality (RR 0·99, 95% CI 0·93–1·06), or other non-vascular mortality.

Interpretation In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in
LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This
benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not
typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these
guidelines might need to be reconsidered.

Funding British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed
Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.

Introduction yielded further reductions in risk. There was no evidence

The Cholesterol Treatment Trialists’ (CTT) Collaboration that lowering of LDL cholesterol increased the risk of
previously reported meta-analyses of individual data non-vascular death or of cancer, even in participants with
from 170 000 individuals in 21 trials of standard statin baseline LDL cholesterol less than 2 mmol/L (in whom
regimens versus control and five trials of more intensive LDL cholesterol was reduced from about 1·7 mmol/L
versus less intensive regimens.1 That report showed that [65 mg/dL] to 1·3 mmol/L [50 mg/dL]).2
lowering of LDL cholesterol by 1 mmol/L with a standard In those analyses, reduction of LDL cholesterol with a
statin regimen reduced the incidence of major vascular statin in participants with no previous history of
events (defined as non-fatal myocardial infarction or vascular disease reduced the risk of major vascular
coronary death, any stroke, or coronary revascularisation events by about a fifth,1 but there remains uncertainty
procedure) by around a fifth, and that further reductions about whether statin therapy is of overall net benefit
in LDL cholesterol with more intensive statin regimens in primary prevention.3–5 This question is important

www.thelancet.com Vol 380 August 11, 2012 581

 Articles

because, although individuals without previous vascular from both primary prevention trials and low-risk
disease are at lower absolute risk, at least half of all participants in other trials) allows a more complete
vascular events occur among them.6 The availability of assessment of the effects of lowering of LDL cholesterol
individual participant data from each trial within the in low-risk people than was possible in previous meta-
CTT database (allowing the inclusion of information analyses of published data.3,4

Median predicted Estimated 5-year MVE risk Total

5-year MVE risk
<5% ≥5% to <10% ≥10% to <20%* ≥20% to <30% ≥30%
Statin vs control
MEGA† 2·7% 7247 (147) 925 (91) 42 (4) 0 (0) 0 (0) 8214 (242)
JUPITER 4·4% 11 212 (118) 6117 (162) 472 (19) 1 (0) 0 (0) 17 802 (299)
AFCAPS/ TexCAPS 5·2% 2944 (72) 3329 (225) 331 (47) 1 (0) 0 (0) 6605 (344)
ASCOT-LLA 8·1% 1505 (25) 5383 (229) 3168 (245) 234 (22) 15 (3) 10 305 (524)
WOSCOPS 9·2% 34 (0) 3848 (219) 2576 (293) 134 (36) 3 (2) 6595 (550)
GISSI-HF 9·6% 875 (34) 1523 (78) 1789 (171) 357 (52) 30 (11) 4574 (346)
ALERT 10·2% 286 (8) 740 (54) 705 (105) 237 (59) 134 (49) 2102 (275)
CARDS 10·9% 156 (0) 1043 (43) 1524 (144) 109 (16) 6 (1) 2838 (204)
ASPEN 13·6% 108 (0) 648 (13) 980 (99) 517 (90) 157 (48) 2410 (250)
ALLHAT-LLT 14·0% 92 (2) 2331 (144) 5468 (803) 1871 (438) 593 (183) 10 355 (1570)
Post-CABG 17·0% 0 (0) 24 (2) 1022 (128) 279 (44) 26 (5) 1351 (179)
GISSI-P 18·3% 0 (0) 14 (1) 2816 (272) 1268 (140) 173 (26) 4271 (439)
HPS 18·6% 320 (14) 2041 (134) 9424 (1267) 6722 (1488) 2029 (651) 20 536 (3554)
LIPID 22·1% 0 (0) 27 (3) 2946 (484) 5144 (1278) 897 (324) 9014 (2089)
PROSPER 22·4% 0 (0) 108 (13) 2208 (224) 1858 (293) 1630 (396) 5804 (926)
CORONA 23·2% 11 (1) 194 (16) 1463 (144) 2151 (292) 1192 (177) 5011 (630)
CARE 26·1% 0 (0) 0 (0) 362 (58) 2776 (615) 1021 (313) 4159 (986)
ALLIANCE 26·3% 0 (0) 0 (0) 288 (46) 1419 (298) 735 (203) 2442 (547)
LIPS 29·5% 0 (0) 0 (0) 118 (28) 770 (158) 789 (173) 1677 (359)
AURORA 31·7% 0 (0) 61 (8) 546 (85) 676 (136) 1490 (501) 2773 (730)
SSSS 33·1% 0 (0) 0 (0) 139 (13) 1159 (275) 3146 (1063) 4444 (1351)
4D 38·2% 0 (0) 6 (1) 117 (20) 273 (52) 859 (233) 1255 (306)
Subtotal, 22 trials 13·7% 24 790 (421) 28 362 (1436) 38 504 (4699) 27 956 (5782) 14 925 (4362) 134 537 (16 700)
More vs less statin
SEARCH 16·2% ·· ·· 9665 (1969) 2157 (680) 242 (104) 12 064 (2753)
A to Z 17·3% ·· ·· 3097 (307) 1191 (180) 209 (52) 4497 (539)
TNT 21·8% ·· ·· 3507 (520) 5078 (1075) 1416 (458) 10 001 (2053)
IDEAL 24·1% ·· ·· 1754 (326) 5257 (1125) 1877 (593) 8888 (2044)
PROVE-IT 33·8% ·· ·· 27 (3) 1125 (185) 3010 (676) 4162 (864)
Subtotal, five trials 20·8% ·· ·· 18 050 (3125) 14 808 (3245) 6754 (1883) 39 612 (8253)

Data are median risk or number of participants (number of first major vascular events). Studies are shown in order of increasing median predicted 5-year MVE risk. The
predicted risk for the trials of more versus less statin is that under the less intensive statin regimen. We imputed missing data for age, sex, treatment for hypertension, lipids,
and blood pressure at baseline for the purpose of predicting 5-year MVE risk and for risk stratification. MEGA=Management of Elevated Cholesterol in the Primary Prevention
Group of Adult Japanese. JUPITER=Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. AFCAPS/TexCAPS=Air Force/Texas Coronary
Atherosclerosis Prevention Study. ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm. WOSCOPS=West of Scotland Coronary Prevention Study.
GISSI-HF=Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca. ALERT=Assessment of Lescol in Renal Transplantation. CARDS=Collaborative
Atorvastatin Diabetes Study. ASPEN=Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus.
ALLHAT-LLT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Post-CABG=Post-Coronary Artery Bypass Graft. GISSI-P=Gruppo Italiano per lo
Studio della Sopravvivenza nell’Infarto Miocardico. HPS=Heart Protection Study. LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease. PROSPER=PROspective
Study of Pravastatin in the Elderly at Risk. CORONA=Controlled Rosuvastatin Multinational Trial in Heart Failure. CARE=Cholesterol And Recurrent Events.
ALLIANCE=Aggressive Lipid-Lowering Initiation Abates New Cardiac Events. LIPS=Lescol Intervention Prevention Study. AURORA=A Study to Evaluate the Use of Rosuvastatin
in Subjects on Regular Hemodialysis: an Assessment of Survival and Cardiovascular Events. SSSS=Scandinavian Simvastatin Survival Study. 4D=Die Deutsche Diabetes Dialyse
Studie. SEARCH=Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine. A to Z=Aggrastat to Zocor. TNT=Treating to New Targets.
IDEAL=Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group. PROVE-IT=Pravastatin or Atorvastatin Evaluation and Infection Therapy.
*For trials of more versus less statin, this category includes 141 participants (48 [4 MVEs] from A to Z and 93 [11 MVEs] from SEARCH) with an estimated 5-year risk of MVE
between 5% and 10%. †Includes 382 patients who were excluded from the original publication.

Table 1: Numbers of participants and number of first major vascular events (MVEs) in each study contributing to vascular disease risk categories

582 www.thelancet.com Vol 380 August 11, 2012

 Articles

Methods both treatment groups of each study were assigned to

Trials one of five baseline categories of 5-year risk of a major
The methods of the CTT collaboration have been vascular event: <5%; ≥5% to <10%; ≥10% to <20%; ≥20%
described in detail elsewhere.1,7,8 In the present analyses, to <30%; or ≥30%. Further details of model development
a trial was eligible if it reported by the end of 2009 and are shown in the appendix pp 15–16.
provided data before June, 2011, and met three criteria: Analyses included all participants who were randomly
(1) it included at least one intervention whose main assigned to treatment groups, irrespective of whether
effect was to lower LDL cholesterol concentration; (2) it they received their allocated treatment (ie, intention-to-
was unconfounded with respect to this intervention (ie, treat). Analyses of the effects on disease rates within each
no other differences in risk factor modification between trial are derived from the logrank (o–e) statistic and its
the treatment groups were intended); and (3) it variance (v) for first events. Meta-analyses were weighted
recruited at least 1000 participants with scheduled by the absolute LDL cholesterol difference in that trial at
treatment duration of at least 2 years. The main 1 year (d mmol/L), and are reported as effects per
outcomes of interest were major vascular events, major 1·0 mmol/L reduction in LDL cholesterol. In a meta-
coronary events (defined as non-fatal myocardial analysis of several trials, the log of the rate ratio (RR) per
infarction or coronary death), stroke (subdivided by 1·0 mmol/L was calculated as S/V with variance 1/V (and
type), coronary revascularisation procedures, cancers, hence, for example, with 95% CI of S/V±1·96/√V), where
and cause-specific mortality. S is the sum over all trials of d(o–e) and V is the sum over
all trials of d²v. For most subgroup analyses, the weight
Statistical analysis for a particular subgroup was the LDL cholesterol
Two different Cox proportional hazards models were difference observed in the whole trial, but analyses by
developed to allow risk to be modelled separately in trials baseline LDL cholesterol concentration used LDL weights
of statin versus control (22 trials; model 1) and in trials specific to a particular subgroup of a particular trial.1 In
of more versus less intensive statin regimens (five trials; trials comparing more versus less intensive statin therapy,
model 2). Both models incorporated terms derived from the relevant baseline lipid values were those achieved on
characteristics measured at the time of randomisation, the less intensive regimen. In three of these trials,9–11
terms that modelled average differences in risk between however, any statin therapy was stopped before random-
trials (as well as within specific periods of time within isation, so we estimated their relevant baseline values by See Online for appendix
each trial), and interaction terms (appendix pp 1–2). On multiplying the values at the randomisation visit (ie, off
the basis of these risk prediction models, participants in statin treatment) by the mean proportional reduction

Number of Observed Observed Median Women (%) Mean age Baseline Diabetes (%) Baseline history of vascular disease (%)
participants annual MVE annual MCE follow-up (SD; years) LDL
rate in those rate in those in survivors cholesterol
allocated allocated (years)* (mmol/L)*
control or control or
less statin less statin
Previous CHD Other vascular† None‡
Statin vs control
<5% 24 790 0·6% 0·2% 4·0 54% 59 (8) 3·43 7% 0% 4% 96%
≥5% to <10% 28 362 1·6% 0·8% 4·3 27% 61 (9) 3·68 18% 2% 11% 87%
≥10% to <20% 38 504 3·4% 1·5% 4·7 29% 64 (9) 3·61 24% 43% 22% 44%
≥20% to <30% 27 956 5·7% 2·6% 5·0 16% 65 (9) 3·72 19% 80% 28% 13%
≥30% 14 925 9·5% 5·1% 4·9 14% 66 (9) 3·92 44% 86% 39% 7%
Subtotal, 22 trials 134 537 3·6% 1·8% 4·8 29% 63 (9) 3·70 21% 39% 20% 52%
More vs less statin§
≥10% to <20%¶ 18 050 3·7% 1·6% 5·9 22% 60 (10) 2·37 4% 100% 1% 0%
≥20% to <30% 14 808 5·9% 2·4% 5·2 17% 62 (9) 2·59 17% 100% 12% 0%
≥30% 6754 10·7% 4·2% 2·4 18% 64 (10) 2·81 35% 100% 35% 0%
Subtotal , five trials 39 612 5·3% 2·2% 5·1 19% 62 (10) 2·53 14% 100% 11% 0%

CHD=coronary heart disease. MCE=major coronary event. *Estimated using standard Kaplan-Meier methods with participants censored at their date of death; median follow-up and baseline LDL cholesterol for
trial subgroups weighted by trial subgroup-specific variances of observed logrank (o–e) for major vascular events. †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. §The estimated 5-year major vascular event risk is with the less intensive statin regimen and observed
MVE and MCE rates are for participants allocated the less intensive statin regimen; in three more versus less statin trials (A to Z, PROVE-IT, and IDEAL) there was no active run-in period before randomisation and
so for the purpose of risk stratification and presentation of results the LDL cholesterol at baseline for the participants in these trials was adjusted for the observed LDL cholesterol reduction from baseline to year 1
in those allocated low intensity statin in the respective trial. ¶Includes 141 participants (48 [4 MVEs] from A to Z and 93 [11 MVEs] from SEARCH) with an estimated 5-year risk of MVE between 5% and 10%.

Table 2: Baseline characteristics of participants, by predicted 5-year risk of a major vascular event (MVE)

www.thelancet.com Vol 380 August 11, 2012 583

 Articles

5-year MVE risk Events (% per annum) RR (CI) per 1·0 mmol/L reduction Trend test
Results
at baseline in LDL cholesterol Individual participant data were available from 27 trials
Statin/more Control/less in 174 149 participants. 22 trials compared a standard
Major coronary event statin regimen versus control (134 537 participants; mean
<5% 50 (0·11) 88 (0·19) 0·57 (0·36–0·89) baseline LDL cholesterol 3·70 [SD 0·7] mmol/L; mean
≥5% to <10% 276 (0·50) 435 (0·79) 0·61 (0·50–0·74) difference at 1 year 1·08 mmol/L; median follow-up
≥10% to <20% 1644 (1·29) 1973 (1·57) 0·77 (0·69–0·85) χ21=5·66 duration in survivors 4·8 years)12–33 and five trials assessed
≥20% to <30% 1789 (1·93) 2282 (2·49) 0·77 (0·71–0·83) (p=0·02) a more intensive versus a less intensive statin regimen
≥30% 1471 (3·73) 1887 (4·86) 0·78 (0·72–0·84) (39 612 participants; mean baseline LDL cholesterol
Overall 5230 (1·45) 6665 (1·87) 0·76 (0·73–0·79) 2·53 [SD 0·6] mmol/L; mean difference at 1 year
p<0·0001
0·51 mmol/L; median follow-up duration in survivors
Any stroke 5·1 years).9–11,34,35 Individual participant data were unavail-
<5% 71 (0·16) 90 (0·20) 0·74 (0·46–1·19) able from only two eligible trials in 6331 higher-risk
≥5% to <10% 190 (0·34) 240 (0·43) 0·77 (0·60–0·98) patients with pre-existing vascular disease (SPARCL36
≥10% to <20% 797 (0·62) 907 (0·71) 0·86 (0·75–0·98) χ21=1·03 and GREACE37).
≥20% to <30% 781 (0·84) 900 (0·97) 0·86 (0·75–0·97) (p=0·3)
The baseline prognostic factors that were strong
≥30% 571 (1·45) 661 (1·68) 0·86 (0·75–0·99)
predictors of major vascular event risk (ie, at the 1%
Overall 2410 (0·67) 2798 (0·78) 0·85 (0·80–0·89)
p<0·0001 significance level) were broadly similar in the trials of
statin versus control and the trials of more versus less
Coronary revascularisation intensive statin regimens (appendix pp 1–2). Predicted
<5% 73 (0·16) 135 (0·30) 0·52 (0·35–0·75)
risk compared well with observed risk for each trial, as
≥5% to <10% 224 (0·40) 342 (0·62) 0·63 (0·51–0·79)
well as within each 5-year risk group (appendix p 3).
≥10% to <20% 1706 (1·36) 2061 (1·67) 0·75 (0·67–0·83) χ21=4·93
(p=0·03)
When trials were ordered by their median 5-year
≥20% to <30% 2206 (2·46) 2717 (3·08) 0·79 (0·73–0·86)
≥30% 1260 (3·28) 1655 (4·40) 0·76 (0·69–0·83)
predicted risk of a major vascular event, the five trials
Overall 5469 (1·55) 6910 (1·98) 0·76 (0·73–0·79) with the lowest median predicted risks (all <10%) were
p<0·0001 primary prevention trials (table 1).13,15,22,29,31 By contrast,
almost all participants with predicted 5-year risk of 20%
Major vascular event
<5% 167 (0·38) 254 (0·56) 0·62 (0·47–0·81)
or higher were recruited into trials in patients with a
≥5% to <10% 604 (1·10) 847 (1·57) 0·69 (0·60–0·79)
definite history of vascular disease.12,14,16–19,25,28 The
≥10% to <20% 3614 (2·96) 4195 (3·50) 0·79 (0·74–0·85) χ21=4·29 predicted 5-year risk of a major vascular event was also
≥20% to <30% 4108 (4·74) 4919 (5·80) 0·81 (0·77–0·86) (p=0·04) 20% or higher in most dialysis patients.26,30 In two trials
≥30% 2787 (7·64) 3458 (9·82) 0·79 (0·74–0·84) in patients with heart failure,32,33 there was a high risk of
Overall 11 280 (3·27) 13 673 (4·04) 0·79 (0·77–0·81) sudden death, but such deaths were categorised
p<0·0001 differently, with a much smaller proportion of such
99% limits 95% limits 0·50 0·75 1 1·25 1·50 deaths thought to be due to coronary occlusion in the
Statin/more better Control/less better GISSI-HF trial33 than in CORONA;32 this difference is
Figure 1: Effects on major coronary events, strokes, coronary revascularisation procedures, and major the main reason why the predicted 5-year risk of major
vascular events per 1·0 mmol/L reduction in LDL cholesterol at different levels of risk vascular events was more than twice as high in CORONA
MVE=major vascular event. RR=rate ratio. CI=confidence interval. (23%) as in GISSI-HF (10%).
Among the 22 trials of statin versus control, the
observed at 1 year in participants allocated the less observed annual major vascular event rate ranged from
intensive regimen.1 Proportional risk reductions in 0·6% in the lowest predicted risk category to 9·5% in the
different subgroups were compared by standard χ² tests highest risk category, whereas in trials of more versus
for heterogeneity or, where appropriate, trend. To allow less intensive statin therapy (which were undertaken
for multiple testing by subdivisions, only overall summary solely in patients with previous coronary disease) the
rate ratios have 95% CIs; all other rate ratios have observed annual event rate varied between 3·7% and
99% CIs. Analyses used SAS version 9.1 (SAS Institute, 10·7% across the categories studied (table 2). In both sets
Cary, NC, USA), Stata version 11.2 (StataCorp, TX, USA), of trials, the achieved reduction in LDL cholesterol at
For more on R see and R version 2.11.1. 1 year with statin therapy or more intensive statin therapy
www.R-project.org was greater in people with higher predicted 5-year risk of
Role of the funding sources major vascular events (appendix p 4).
The funding sources had no involvement in the study Among all 27 trials, statins reduced the risk of major
design, data collection, analysis and interpretation, the vascular events by 21% per 1·0 mmol/L LDL cholesterol
writing of the report, or the decision to submit for reduction (RR 0·79, 95% CI 0·77–0·81, p<0·0001), with
publication. The writing committee had full access to all separately significant proportional reductions in each
data and accepts full responsibility for the content of risk group (figure 1). In particular, there were significant
this report. reductions in major vascular event risk in each of the two

584 www.thelancet.com Vol 380 August 11, 2012

 Articles

lowest risk categories (RR per 1·0 mmol/L LDL 5-year MVE Events (% per annum) RR (CI) per 1·0 mmol/L reduction Trend test
cholesterol reduction 0·62, 99% CI 0·47–0·81, for 5-year risk at in LDL cholesterol
predicted risk <5%, and 0·69, 99% CI 0·60–0·79, for baseline

5-year predicted risk ≥5% to <10%; both p<0·0001; Statin/more Control/less

figure 1). These results were qualitatively similar after Participants without vascular disease
exclusion of five trials12,15,22,24,31 that ended early on the <5% 148 (0·35) 229 (0·53) 0·61 (0·45–0·81)
advice of their data monitoring committees (data not ≥5% to <10% 487 (1·02) 716 (1·53) 0·66 (0·57–0·77)
≥10% to <20% 854 (2·52) 1003 (2·98) 0·82 (0·72–0·93) χ21=9·10
shown). The proportional reductions in major vascular
≥20% to <30% 294 (4·40) 351 (5·28) 0·81 (0·65–1·01) (p=0·003)
events per 1·0 mmol/L LDL cholesterol reduction in the
≥30% 121 (7·29) 126 (8·16) 0·83 (0·58–1·18)
two lowest risk categories seemed to be at least as large
Subtotal 1904 (1·44) 2425 (1·84) 0·75 (0·70–0·80)
as for other participants (figure 1), even after further p<0·0001
stratification by age and sex (appendix p 6) or by baseline
Participants with vascular disease
LDL cholesterol (appendix p 7).
<5% 19 (0·87) 25 (1·18) 0·73 (0·33–1·61)
The reductions in risk of major vascular events among 0·84 (0·62–1·14)
≥5% to <10% 117 (1·56) 131 (1·80)
the two categories of participant at lowest risk reflected ≥10% to <20% 2760 (3·13) 3192 (3·71) 0·78 (0·72–0·85) χ21=0·01
reductions in major coronary events (RR per 1·0 mmol/L ≥20% to <30% 3814 (4·77) 4568 (5·85) 0·81 (0·76–0·86) (p=0·9)
LDL cholesterol reduction 0·57, 99% CI 0·36–0·89, ≥30% 2666 (7·66) 3332 (9·90) 0·79 (0·74–0·84)
p=0·0012, and 0·61, 99% CI 0·50–0·74, p<0·0001), Subtotal 9376 (4·41) 11 248 (5·43) 0·80 (0·77–0·82)
mainly non-fatal myocardial infarction, and in coronary p<0·0001

revascularisations (RR 0·52, 99% CI 0·35–0·75, and All participants

0·63, 99% CI 0·51–0·79; both p<0·0001), that were at <5% 167 (0·38) 254 (0·56) 0·62 (0·47–0·81)
least as large as those seen in higher risk participants ≥5% to <10% 604 (1·10) 847 (1·57) 0·69 (0·60–0·79)
(trend p=0·02 for major coronary events and p=0·03 for ≥10% to <20% 3614 (2·96) 4195 (3·50) 0·79 (0·74–0·85) χ21=4·29
coronary revascularisations; figure 1, appendix p 8). The ≥20% to <30% 4108 (4·74) 4919 (5·80) 0·81 (0·77–0·86) (p=0·04)
reduction in stroke risk per 1·0 mmol/L LDL cholesterol ≥30% 2787 (7·64) 3458 (9·82) 0·79 (0·74–0·84)
reduction (RR 0·85, 95% CI 0·80–0·89) was similar at all Overall 11 280 (3·27) 13 673 (4·04) 0·79 (0·77–0·81)
Heterogeneity between participants without p<0·0001
levels of baseline major vascular event risk (trend p=0·3;
and with vascular disease: χ21=2·74 (p=0·10)
figure 1). In particular, the reduction in stroke risk in
99% limits 95% limits 0·50 0·75 1 1·25 1·50
those with predicted 5-year major vascular event risk
Statin/more better Control/less better
lower than 10% (ie, the two lowest risk groups combined;
RR 0·76, 99% CI 0·61–0·95; p=0·0012) was similar to Figure 2: Effects on major vascular events per 1·0 mmol/L reduction in LDL cholesterol at different levels of
that seen in higher risk categories. The proportional risk, by history of vascular disease
MVE=major vascular event. RR=rate ratio. CI=confidence interval.
reductions in ischaemic stroke (RR per 1·0 mmol/L LDL
cholesterol reduction 0·79, 95% CI 0·74–0·85) and in
strokes of unknown cause (RR 0·87, 95% CI 0·79–0·97) predicted risk ≥5% to <10%). The LDL-weighted
were similar irrespective of baseline major vascular event proportional reduction in major coronary events in par-
risk, and there was no evidence that the RR for ticipants with no history of vascular disease was also at
haemorrhagic stroke (1·15, 95% CI 0·97–1·38) varied by least as large in the two lowest risk groups as in those at
baseline risk (appendix p 9). Separate analyses of major higher risk (appendix p 12).
vascular events and its components in the trials that In all participants, there was a proportional reduction
tested statin versus control and the trials that tested more in vascular mortality of 12% per 1·0 mmol/L LDL
versus less intensive statin regimens are shown in the cholesterol reduction (RR 0·88, 95% CI 0·84–0·91;
appendix pp 10–11. figure 3), which was chiefly attributable to reductions in
For participants with previous vascular disease, the coronary deaths of 20% (RR 0·80, 95% CI 0·76–0·85)
proportional reductions in major vascular event risk and in other cardiac deaths of 8% (RR 0·92, 95% CI
were broadly similar irrespective of predicted risk of 0·87–0·98; appendix p 13). There were too few deaths
these events (figure 2). In participants with no history of among the lower risk participants to allow reliable direct
vascular disease, the proportional reduction in major assessment of the effects of statin therapy (appendix
vascular events was at least as large in the two lowest risk p 13). However, the LDL-weighted proportional reduc-
groups (RR per 1·0 mmol/L LDL reduction 0·61, 99% CI tions seemed similar in each risk category both for the
0·45–0·81, and 0·66, 99% CI 0·57–0·77) as in those at aggregate of all vascular deaths (trend p=0·7; figure 3)
higher risk. Further exclusion from these lowest risk and for each specific cause of vascular death (all trend
groups of participants with diabetes or chronic kidney p=NS; appendix p 13), and there was no significant trend
disease had little effect on the proportional reductions in towards an increase in non-vascular mortality in those at
major vascular events (RR per 1·0 mmol/L LDL lower risk (trend p=0·9; figure 3). In participants with
cholesterol reduction 0·63, 99% CI 0·46–0·85, for 5-year no history of vascular disease, reduction of LDL
predicted risk <5%; 0·64, 99% CI 0·54–0·76, for 5-year cholesterol with statin therapy reduced the risk of

www.thelancet.com Vol 380 August 11, 2012 585

 Articles

vascular mortality (RR per 1·0 mmol/L reduction 0·85,

5-year MVE Events (% per annum) RR (CI) per 1·0 mmol/L reduction Trend test 95% CI 0·77–0·95, p=0·004; figure 3) and, since there
risk at in LDL cholesterol
baseline was no increase in the risk of non-vascular causes of
Statin/more Control/less death (RR 0·97, 95% CI 0·88–1·07; figure 3), reduced
Any vascular death the risk of all-cause mortality (RR 0·91, 95% CI
Participants without vascular disease 0·85–0·97, p=0·007; appendix p 14). These mortality
<5% 31 (0·07) 40 (0·09) 0·80 (0·43–1·47) benefits remained even after further exclusion of
≥5% to <10% 117 (0·24) 153 (0·32) 0·75 (0·55–1·04) participants with diabetes or chronic kidney disease at
χ21=1·46
≥10% to <20% 307 (0·87) 342 (0·96) 0·84 (0·67–1·05) baseline (vascular death, RR 0·80, 95% CI 0·67–0·95;
(p=0·2)
≥20% to <30% 164 (2·32) 168 (2·34) 0·97 (0·72–1·32) any death, 0·87, 95% CI 0·78–0·95). There was no
≥30% 93 (5·21) 98 (5·84) 0·88 (0·59–1·33) evidence of an increase in cancer incidence (RR per
Subtotal 712 (0·53) 801 (0·59) 0·85 (0·77–0·95) 1·0 mmol/L LDL reduction 1·00, 95% CI 0·96–1·04) or
p=0·004
of cancer death (RR 0·99, 95% CI 0·93–1·06) at any level
Participants with vascular disease of major vascular event risk (figure 4).
<5% 48 (2·16) 52 (2·40) 0·93 (0·53–1·62)
≥5% to <10% 193 (2·52) 177 (2·35) 1·07 (0·81–1·41)
χ21=1·49
Discussion
≥10% to <20% 1166 (1·24) 1249 (1·34) 0·89 (0·79–1·00)
(p=0·2)
The most recent CTT meta-analysis of individual
≥20% to <30% 1432 (1·61) 1665 (1·89) 0·87 (0·80–0·95) participant data from randomised trials showed that
≥30% 1247 (3·14) 1435 (3·60) 0·87 (0·79–0·95) lowering of LDL cholesterol with standard statin
Subtotal 4086 (1·76) 4578 (1·98) 0·88 (0·84–0·92)
p<0·0001
regimens safely reduced the 5-year incidence of major
coronary events, coronary revascularisations, and
All participants ischaemic strokes by about one fifth per 1·0 mmol/L
<5% 79 (0·18) 92 (0·20) 0·87 (0·58–1·31)
reduction in LDL cholesterol, and that additional
≥5% to <10% 310 (0·55) 330 (0·59) 0·92 (0·74–1·13)
χ21=0·18 reductions in LDL cholesterol obtained with more
≥10% to <20% 1473 (1·14) 1591 (1·23) 0·88 (0·79–0·97)
(p=0·7) intensive statin regimens further reduced the incidence
≥20% to <30% 1596 (1·67) 1833 (1·92) 0·88 (0·81–0·96)
≥30% 1340 (3·23) 1533 (3·69) 0·87 (0·80–0·95)
of these major vascular events.1 The present results show
Overall 4798 (1·30) 5379 (1·47) 0·88 (0·84–0·91)
that reduction of LDL cholesterol with statin therapy
Heterogeneity between participants without p<0·0001 significantly reduced the risk of major vascular events in
and with vascular disease: χ21=0·28 (p=0·6) individuals with 5-year risk lower than 10% (in whom
Non-vascular death
the mean risks were 2·6% for major coronary events
Participants without vascular disease plus 3% for other major vascular events), even in those
<5% 98 (0·23) 87 (0·20) 1·13 (0·76–1·69) with no previous history of vascular disease, diabetes, or
≥5% to <10% 205 (0·42) 238 (0·49) 0·87 (0·67–1·11) chronic kidney disease (panel).
χ21=0·47
≥10% to <20% 352 (0·99) 377 (1·06) 0·94 (0·76–1·15) The estimated absolute reduction in major vascular
(p=0·5)
≥20% to <30% 169 (2·39) 148 (2·07) 1·13 (0·81–1·57) events in participants with 5-year risk of these events
≥30% 79 (4·43) 71 (4·23) 1·07 (0·68–1·69) lower than 10% was around 11 per 1000 over 5 years for
Subtotal 903 (0·67) 921 (0·68) 0·97 (0·88–1·07) each 1·0 mmol/L reduction in LDL cholesterol (4·1%
p=0·60
statin or more intensive statin regimen vs 5·2% control
Participants with vascular disease or less intensive regimen). Modern statin regimens,
<5% 18 (0·81) 14 (0·65) 1·38 (0·53–3·63) however, can often reduce LDL cholesterol by more than
≥5% to <10% 65 (0·85) 71 (0·94) 0·92 (0·61–1·41) 1 mmol/L,38,39 which would yield even larger absolute
χ21=0·04
≥10% to <20% 702 (0·74) 727 (0·78) 0·95 (0·81–1·11)
(p=0·8)
reductions in major vascular events. The avoidance of
≥20% to <30% 794 (0·90) 793 (0·90) 0·98 (0·86–1·12) life-threatening or potentially disabling events in
≥30% 602 (1·52) 634 (1·59) 0·95 (0·82–1·09) apparently healthy low-risk people might be deemed
Subtotal 2181 (0·94) 2239 (0·97) 0·96 (0·90–1·02)
p=0·18
worthwhile provided that they are not accompanied by
any definite hazard that is of comparable severity.
All participants Although there was no evidence of any increased risk of
<5% 116 (0·26) 101 (0·22) 1·16 (0·80–1·68) death from non-vascular causes or of cancer in those at
≥5% to <10% 270 (0·48) 309 (0·55) 0·88 (0·71–1·09)
χ21=0·02 low risk (which is consistent with previous detailed
≥10% to <20% 1054 (0·81) 1104 (0·86) 0·94 (0·83–1·07)
(p=0·9) analyses of the effect of statins on cancer2), several known
≥20% to <30% 963 (1·01) 941 (0·99) 1·00 (0·89–1·13)
≥30% 681 (1·64) 705 (1·70) 0·96 (0·83–1·10)
Overall 3084 (0·84) 3160 (0·86) 0·96 (0·92–1·01) Figure 3: Effects on vascular and non-vascular deaths per 1·0 mmol/L reduction
Heterogeneity between participants without p=0·16 in LDL cholesterol at different levels of risk, by history of vascular disease
and with vascular disease: χ21=0·07 (p=0·8) MVE=major vascular event. RR=rate ratio. CI=confidence interval. There were a
further 179 (statin/more statin) versus 210 (control/less statin) deaths of
99% limits 95% limits 0·50 0·75 1 1·25 1·50 unknown cause among participants without vascular disease and 309 (statin/
Statin/more better Control/less better more statin) versus 338 (control/less statin) deaths of unknown cause among
participants with vascular disease.

586 www.thelancet.com Vol 380 August 11, 2012

 Articles

or potential hazards of statin therapy need to be 5-year MVE risk Events (% per annum) RR (CI) per 1·0 mmol/L reduction Trend test
considered when estimating the net effects of statin at baseline in LDL cholesterol
therapy in people at lowest risk. Statin/more Control/less
First, statin therapy is associated with a small increased Cancer incidence
risk of myopathy (excess incidence of about 0·5 per 1000 <5% 324 (0·73) 315 (0·70) 1·05 (0·85–1·31)
over 5 years) and, more rarely, of rhabdomyolysis (excess ≥5% to <10% 605 (1·10) 663 (1·21) 0·91 (0·78–1·05)
incidence of about 0·1 per 1000 over 5 years).38 The risks ≥10% to <20% 1804 (1·42) 1827 (1·45) 1·00 (0·91–1·10) χ21=0·83
of myopathy are dose-related but, with the exception of ≥20% to <30% 1667 (1·79) 1628 (1·76) 1·02 (0·93–1·12) (p=0·4)
simvastatin 80 mg daily (or lower doses in Asian ≥30% 821 (2·04) 777 (1·92) 1·02 (0·90–1·16)
populations), intensive statin regimens have not been Overall 5221 (1·45) 5210 (1·45) 1·00 (0·96–1·04)
p=0·99
shown to result in substantial myopathy risks.38 Second, Cancer death
the most recent CTT report raised the possibility that <5% 64 (0·14) 57 (0·13) 1·14 (0·69–1·89)
statin therapy might increase the risk of haemorrhagic ≥5% to <10% 171 (0·30) 186 (0·33) 0·93 (0·71–1·23)
stroke.1 The present analyses suggest that the annual ≥10% to <20% 697 (0·54) 718 (0·56) 1·00 (0·86–1·16) χ21=0·01
excess risk of haemorrhagic strokes per 1·0 mmol/L LDL ≥20% to <30% 609 (0·64) 584 (0·61) 1·02 (0·88–1·19) (p=0·9)
cholesterol reduction might be of the order of 0·5 per ≥30% 293 (0·71) 304 (0·73) 0·97 (0·80–1·19)

1000 people treated over 5 years (appendix p 9), although Overall 1834 (0·50) 1849 (0·50) 0·99 (0·93–1·06)
p=0·86
it might be higher in populations in which haemorrhagic
99% limits 95% limits 0·50 0·75 1 1·25 1·50
stroke accounts for a higher proportion of strokes (eg,
Statin/more better Control/less better
Asian populations40). But, since statin therapy produced a
clear reduction in overall stroke that was independent of Figure 4: Effects on cancer incidence and cancer mortality per 1·0 mmol/L reduction in LDL cholesterol at
predicted risk, such an increase in haemorrhagic stroke different levels of risk
MVE=major vascular event. RR=rate ratio. CI=confidence interval.
risk would typically be outweighed by the reduction in
the risk of ischaemic stroke (as well as the reduction in
other occlusive vascular events and deaths) even in Panel: Research in context
individuals whose 5-year risk of major vascular events is
lower than 5%. Third, recent meta-analyses have Systematic review
suggested that statin therapy might be associated with a Lowering of LDL cholesterol with a statin reduces the risk of
proportional increase in the diagnosis of diabetes myocardial infarction, coronary death, ischaemic stroke, and
mellitus of about 10%41 and that more intensive statin coronary revascularisation by about one fifth per 1 mmol/L
therapy produces a bigger increase.42 The observed LDL cholesterol reduction in a wide range of people.1
incidence of diabetes recorded in the primary prevention However, tabular meta-analyses of people at low risk of these
trials was about 5% over 5 years, so the absolute excess events, studied predominantly in primary prevention trials,
was about 0·1% per year.41 If new diagnoses of diabetes have concluded that statin therapy might not result in
were associated with an immediate doubling in worthwhile net benefit in this group.3,4
cardiovascular risk43 in individuals with 5-year risk of Interpretation
major vascular events lower than 10%, then the expected Individual participant data in the Cholesterol Treatment
effect would be only about 0·2 fewer events avoided per Trialists’ Collaboration of 27 trials involving
1000 individuals treated over 5 years. Such an effect is 175 000 participants showed that statin therapy reduces the
more than 50-times smaller than the absolute benefit risk of major vascular events (non-fatal myocardial
observed with statin therapy in such individuals (about infarction, coronary death, coronary revascularisation, or
11 fewer major vascular events per 1000 treated over stroke) in people with 5-year risk of such an event lower than
5 years per 1·0 mmol/L reduction in LDL cholesterol; see 10% (and, separately, in those at 5-year risk <5%), and in
figure 5 for absolute benefits corresponding to particular these people each 1·0 mmol/L reduction in LDL cholesterol
reductions in LDL cholesterol in individuals at different produces 11 fewer major vascular events per 1000 treated
levels of major vascular event risk). Moreover, long-term over 5 years, a benefit that greatly exceeds any known
follow-up of statin trials has shown that the absolute hazards of statin therapy.
reductions in major vascular events increase while the
statin treatment is continued1 and that these benefits
persist for at least 5 years after the treatment has stopped, The observed event rates shown in the figures for
with no evidence of any adverse effects emerging with each risk category can be readily compared with risk
extended follow-up.44–47 These findings would suggest thresholds used in treatment guidelines. For example,
that any long-term effects of any small excesses in under present guidelines, including those of the Adult
haemorrhagic strokes and in diagnoses of diabetes are Treatment Panel III,48,49 the Fourth Joint Task Force of
not associated with long-term effects on major vascular the European Society of Cardiology,50 the Task Force for
events that are sufficiently large to outweigh the the management of dyslipidaemias of the European
persistent benefits of statin therapy. Society of Cardiology and the European Atherosclerosis

www.thelancet.com Vol 380 August 11, 2012 587

 Articles

A Observed Observed Broad eligibility under

MCE vascular current guidelines
event rate death rate
(% per (% per
160 142 annum)* annum)*
ATP-III† ESC task NICE§
140 119 force‡
CTT risk category
Major vascular events avoided per 1000

120 93
100 <5% 0·2 0·1 × × ×
100 84 ≥5% to <10% 0·8 0·3 × × ×
61
≥10% to <20% 1·6 1·0 3 3 3
66
80 ≥20% to <30% 3·2 2·3 3 3 3
45 68
57 ≥30% 5·6 5·8 3 3 3
60 45
31 CTT=Cholesterol Treatment Trialists’. MCE=major coronary event. *Among
40 control-allocated participants without a history of vascular disease. †The Adult
≥30% Treatment Panel III (ATP III) of the National Cholesterol Education p rogram in the
15 21 27 31 ≥20% to <30% 5-year USA. ‡The Fourth Joint Task Force of the European Society of Cardiology (ESC)
20 risk of and Other Societies on Cardiovascular Disease Prevention in Clinical Practice and
≥10% to <20% major the ESC/EAS Guidelines for the management of dyslipidaemias. §The National
6 8 vascular
0 10 ≥5% to <10% Institute for Health and Clinical Excellence (NICE) in the National Health Service in
1 12 event England and Wales.
1·5 <5%
2
2·5 Table 3: Eligibility of CTT participants without a history of vascular
disease for statin therapy under existing major guidelines, by estimated
B 5-year major vascular event risk

vascular events in patients at lower risk also depend on

50 46
the cost effectiveness of such a strategy, which in turn
45
depends on the local availability and cost of therapy.
38
Generic statin interventions, if effective, are likely to be
40
30
cost-effective in individuals at annual vascular disease
Vascular deaths avoided per 1000

35
risk down to at least about 1%.53–55 The present report
shows that statins are indeed both effective and safe for
30 20
25 people with 5-year risk of major vascular events lower
25
21 than 10% and, therefore, suggests that these guidelines
16
might need to be reconsidered.
20 11
17
14 Contributors
11 The writing committee accepts full responsibility for the content of
15 8
this paper. All of the members contributed to collection and analysis of
≥30%
10 the data and to the preparation of the report. All collaborators had an
7 ≥20% to <30% 5-year opportunity to contribute to the interpretation of the results and to
4 5 8
5 risk of
≥10% to <20% drafting of the report.
major
1·2 vascular
0 1·7 ≥5% to <10% Current membership of the CTT Collaboration
2·2 event
1 2·7 Writing committee: B Mihaylova, J Emberson, L Blackwell, A Keech,
1·5 <5%
2 J Simes, E H Barnes, M Voysey, A Gray, R Collins, C Baigent.
2·5 Collaborating trialists: A to Z trial (phase Z) J de Lemos, E Braunwald,
LDL cholesterol reduction (mmol/L)
M Blazing, S Murphy; AFCAPS/TEXCAPS (AirForce/Texas Coronary
with statin treatment
Atherosclerosis Prevention Study) J R Downs, A Gotto, M Clearfield;
Figure 5: Predicted 5-year benefits of LDL cholesterol reductions with statin treatment at different levels of risk ALERT (Assessment of Lescol in Transplantation) H Holdaas; ALLHAT
(A) Major vascular events and (B) vascular deaths. Lifetable estimates using major vascular event risk or vascular (Antihypertensive Lipid Lowering Heart Attack Trial) D Gordon, B Davis;
death risk in the respective risk categories and overall treatment effects per 1·0 mmol/L reduction in LDL ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac
cholesterol with statin. 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 Non-Insulin Dependent
Society,51 and the UK National Institute of Clinical Diabetes Mellitus) R H Knopp (deceased); AURORA (A study to evaluate
Excellence,52 people with 5-year risk of major vascular the Use of Rosuvastatin in subjects On Regular haemodialysis: an
Assessment of survival and cardiovascular events) B Fellström, H Holdaas,
events lower than 10% (ie, the lowest two categories of A Jardine, R Schmieder, F Zannad; BIP (Bezafibrate Infarction
risk in these analyses) would typically not be judged Prevention Study) U Goldbourt, E Kaplinsky; CARDS (Collaborative
suitable for statin treatment (table 3, appendix p 5). Atorvastatin Diabetes Study) H M Colhoun, D J Betteridge,
P N Durrington, G A Hitman, J Fuller, A Neil; 4D (Die Deutsche
Judgments about the appropriateness of widespread
Diabetes Dialyse Studie) C Wanner, V Krane; CARE (Cholesterol And
prescription of statins for the primary prevention of

588 www.thelancet.com Vol 380 August 11, 2012

 Articles

Recurrent Events Study) F Sacks, L Moyé, M Pfeffer; C M Hawkins, 2 Cholesterol Treatment Trialists’ (CTT) Collaboration. Lack of effect
E Braunwald; CORONA (Rosuvastatin in Older Patients with Systolic of lowering LDL cholesterol on cancer: meta-analysis of individual
Heart Failure) J Kjekshus, H Wedel, J Wikstrand; FIELD (Fenofibrate data from 175,000 people in 27 randomised trials of statin therapy.
Intervention and Event Lowering in Diabetes) P Barter, A Keech; GISSI PLoS One 2012; 7: e29849.
(Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto 3 Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mortality
miocardico)–Heart Failure L Tavazzi, A Maggioni; GISSI–Prevention in high-risk primary prevention: a meta-analysis of 11 randomized
R Marchioli, G Tognoni, M G Franzosi, A Maggioni; HIT (Veteran controlled trials involving 65,229 participants. Arch Intern Med 2010;
170: 1024–31.
Administration Low HDL Intervention Trial) H Bloomfield, S Robins;
HPS (Heart Protection Study) R Collins, J Armitage, A Keech, S Parish, 4 Taylor F, Ward K, Moore TH, et al. Statins for the primary
prevention of cardiovascular disease. Cochrane Database Syst Rev
R Peto, P Sleight; IDEAL (Incremental Decrease in Endpoints through
2011; 1: CD004816.
Aggressive Lipid-lowering) T R Pedersen; JUPITER (Justification for the
5 Redberg RF, Katz M, Grady D. Editor’s Note—to make the case—
Use of Statins in Prevention: an Intervention Trial Evaluating
evidence is required: comment on “Making the case for selective
Rosuvastatin) P M Ridker; LDS (Lipids in Diabetes Study) R Holman; use of statins in the primary prevention setting”. Arch Intern Med
LEADER (Lower Extremity Arterial Disease Event Reduction trial) 2011; 171: 1594.
T Meade; LIPID (Long-term Intervention with Pravastatin in Ischaemic 6 Kerr AJ, Broad J, Wells S, Riddell T, Jackson R. Should the first
Disease) J Simes, A Keech, S MacMahon, I Marschner, A Tonkin, priority in cardiovascular risk management be those with prior
J Shaw; LIPS (Lescol Intervention Prevention Study) P W Serruys; MEGA cardiovascular disease? Heart 2009; 95: 125–29.
(Management of Elevated cholesterol in the primary prevention Group of 7 Cholesterol Treatment Trialists’ (CTT) Collaboration. Protocol for a
Adult Japanese) H Nakamura; Post-CABG (Post- Coronary Artery Bypass prospective collaborative overview of all current and planned
Graft Study) G Knatterud; PPP (Pravastatin Pooling Project) C Furberg, randomized trials of cholesterol treatment regimens. Am J Cardiol
R Byington; PROSPER (Prospective Study of Pravastatin in the Elderly at 1995; 75: 1130–34.
Risk) P Macfarlane, S Cobbe, I Ford, M Murphy, G J Blauw, C Packard, 8 Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and
J Shepherd; 4S (Scandinavian Simvastatin Survival Study) J Kjekshus, safety of cholesterol-lowering treatment: prospective meta-analysis
T Pedersen, L Wilhelmsen; PROVE-IT (Pravastatin or Atorvastatin of data from 90 056 participants in 14 randomised trials of statins.
Evaluation and Infection Therapy) E Braunwald, C Cannon, S Murphy; Lancet 2005; 366: 1267–78.
SEARCH (Study of Effectiveness of Additional Reductions in Cholesterol 9 de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a
and Homocysteine) R Collins, J Armitage, L Bowman, S Parish, R Peto, delayed conservative simvastatin strategy in patients with acute
P Sleight; SHARP (Study of Heart and Renal Protection) C Baigent, coronary syndromes: phase Z of the A to Z Trial. JAMA 2004;
M Landray, R Collins; TNT (Treating to New Targets) J La Rosa; WHI 292: 1307–16.
(Women’s Health Initiative) J Rossouw, J Probstfield; WOSCOPS (West 10 Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus
of Scotland Coronary Prevention Study) J Shepherd, S Cobbe, moderate lipid lowering with statins after acute coronary
syndromes. N Engl J Med 2004; 350: 1495–504.
P Macfarlane, I Ford.
Other members: M Flather, J Kastelein, C Newman, C Shear, J Tobert, 11 Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose
atorvastatin vs usual-dose simvastatin for secondary prevention
J Varigos, H White, S Yusuf.
after myocardial infarction: the IDEAL study: a randomized
Observers: Bristol-Myers Squibb M Mellies, M McGovern, J Barclay, controlled trial. JAMA 2005; 294: 2437–45.
R Belder; Merck Y Mitchel, T Musliner; Laboratoires Fournier
12 Scandinavian Simvastatin Survival Study Group. Randomised trial
J-C Ansquer; Bayer M Llewellyn; Novartis Pharma M Bortolini; of cholesterol lowering in 4444 patients with coronary heart disease:
AstraZeneca G Brandrup-Wognsen, B Bryzinski, G Olsson, J Pears; the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;
Pfizer D DeMicco. 344: 1383–89.
CTT secretariat: C Baigent, E H Barnes, A Baxter, N Bhala, L Blackwell, 13 Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart
G Buck, R Collins, J Emberson, W G Herrington, L E Holland, disease with pravastatin in men with hypercholesterolemia. West of
P M Kearney, A Keech, A Kirby, D A Lewis, I Marschner, C Pollicino, Scotland Coronary Prevention Study Group. N Engl J Med 1995;
C Reith, J Simes, T Sourjina. 333: 1301–07.
Conflicts of interest 14 The Post Coronary Artery Bypass Graft Trial Investigators. The
effect of aggressive lowering of low-density lipoprotein cholesterol
Most of the trials in this report were supported by research grants from
levels and low-dose anticoagulation on obstructive changes in
the pharmaceutical industry. Some members of the writing committee saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;
have received reimbursement of costs to participate in scientific 336: 153–62.
meetings from the pharmaceutical industry. AK and JS have also 15 Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute
received honoraria from Solvay for lectures related to these studies. coronary events with lovastatin in men and women with average
Acknowledgments cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas
Coronary Atherosclerosis Prevention Study. JAMA 1998;
The Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU)
279: 1615–22.
in the UK and the National Health and Medical Research Council
16 The Long-Term Intervention with Pravastatin in Ischaemic
Clinical Trials Centre (CTC) in Australia coordinate this collaboration
Disease Study Group. Prevention of cardiovascular events and
jointly. The present meta-analysis work is supported at the Health
death with pravastatin in patients with coronary heart disease and
Economics Research Centre, University of Oxford (writing committee a broad range of initial cholesterol levels. N Engl J Med 1998;
members B Mihaylova, A Gray) by a British Heart Foundation research 339: 1349–57.
grant (Grant No PG/08/063/25397), and at the CTSU (writing 17 GISSI Prevenzione Investigators. Results of the low-dose (20 mg)
committee members J Emberson, L Blackwell, R Collins, C Baigent) by pravastatin GISSI Prevenzione trial in 4271 patients with recent
the UK Medical Research Council, British Heart Foundation, Cancer myocardial infarction: do stopped trials contribute to overall
Research UK and, previously, the European Community Biomed knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per
Programme. The CTC is supported by a programme grant from the lo Studio della Sopravvivenza nell’Infarto Miocardico). Ital Heart J
Australian National Health and Medical Research Council, and a grant 2000; 1: 810–20.
from the National Heart Foundation, Australia. JE acknowledges 18 Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention
support from the BHF Centre of Research Excellence, Oxford, UK of cardiac events following successful first percutaneous coronary
(RE/08/04). intervention: a randomized controlled trial. JAMA 2002;
287: 3215–22.
References 19 Heart Protection Study Collaborative Group. MRC/BHF Heart
1 Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and Protection Study of cholesterol lowering with simvastatin in
safety of more intensive lowering of LDL cholesterol: a 20 536 high-risk individuals: a randomised placebo-controlled trial.
meta-analysis of data from 170 000 participants in 26 randomised Lancet 2002; 360: 7–22.
trials. Lancet 2010; 376: 1670–81.

www.thelancet.com Vol 380 August 11, 2012 589

 Articles

20 Shepherd J, Blauw GJ, Murphy MB, et al, on behalf of the 38 Armitage J. The safety of statins in clinical practice. Lancet 2007;
PROSPER study group. Pravastatin in elderly individuals at risk of 370: 1781–90.
vascular disease (PROSPER): a randomised controlled trial. Lancet 39 Davidson MH, Robinson JG. Safety of aggressive lipid management.
2002; 360: 1623–30. J Am Coll Cardiol 2007; 49: 1753–62.
21 The Allhat Officers and Coordinators for the ALLHAT Collaborative 40 Cheung BMY, Lam KSL. Is intensive LDL-cholesterol lowering
Research Group. Major outcomes in moderately beneficial and safe? Lancet 2010; 376: 1622–24.
hypercholesterolemic, hypertensive patients randomized to 41 Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident
pravastatin vs usual care: the Antihypertensive and Lipid-Lowering diabetes: a collaborative meta-analysis of randomised statin trials.
Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; Lancet 2010; 375: 735–42.
288: 2998–3007.
42 Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with
22 Sever PS, Dahlöf B, Poulter NR, et al, for the ASCOT investigators. intensive-dose compared with moderate-dose statin therapy: a
Prevention of coronary and stroke events with atorvastatin in meta-analysis. JAMA 2011; 305: 2556–64.
hypertensive patients who have average or lower-than-average
43 The Emerging Risk Factors Collaboration. Diabetes mellitus,
cholesterol concentrations, in the Anglo-Scandinavian Cardiac
fasting blood glucose concentration, and risk of vascular disease: a
Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre
collaborative meta-analysis of 102 prospective studies. Lancet 2010;
randomised controlled trial. Lancet 2003; 361: 1149–58.
375: 2215–22.
23 Holdaas H, Fellström B, Jardine AG, et al, on behalf of the
44 Strandberg TE, Pyorala K, Cook TJ, et al, for the 4S Group. Mortality
Assessment of LEscol in Renal Transplantation (ALERT) Study
and incidence of cancer during 10-year follow-up of the
Investigators. Effect of fluvastatin on cardiac outcomes in renal
Scandinavian Simvastatin Survival Study (4S). Lancet 2004;
transplant recipients: a multicentre, randomised, placebo-controlled
364: 771–77.
trial. Lancet 2003; 361: 2024–31.
45 LIPID Study Group. Long-term effectiveness and safety of
24 Colhoun HM, Betteridge DJ, Durrington PN, et al, on behalf of the
pravastatin in 9014 patients with coronary heart disease and average
CARDS investigators. Primary prevention of cardiovascular disease
cholesterol concentrations: the LIPID trial follow-up. Lancet 2002;
with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin
359: 1379–87.
Diabetes Study (CARDS): multicentre randomised
placebo-controlled trial. Lancet 2004; 364: 685–96. 46 Ford I, Murray H, Packard CJ, et al. Long-term follow-up of the
West of Scotland Coronary Prevention Study. N Engl J Med 2007;
25 Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on
357: 1477–86.
coronary events after myocardial infarction in patients with average
cholesterol levels. Cholesterol and Recurrent Events Trial 47 Heart Protection Study Collaborative Group. Effects on 11 year
investigators. N Engl J Med 1996; 335: 1001–09. mortality and morbidity of lowering LDL cholesterol with
simvastatin for about 5 years in 20 536 high-risk individuals. Lancet
26 Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with
2011; 378: 2013–20.
type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med
2005; 353: 238–48. 48 Grundy SM, Cleeman JI, Merz CNB, et al. Implications of Recent
Clinical Trials for the National Cholesterol Education Program
27 Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety
Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227–39.
of atorvastatin in the prevention of cardiovascular end points in
subjects with type 2 diabetes: the Atorvastatin Study for Prevention 49 Expert Panel on Detection Evaluation and Treatment of High Blood
of Coronary Heart Disease Endpoints in non-insulin-dependent Cholesterol in Adults. Executive Summary of the Third Report of
diabetes mellitus (ASPEN). Diabetes Care 2006; 29: 1478–85. the National Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation, and Treatment of High Blood Cholesterol
28 Koren MJ, Hunninghake DB, on behalf of the AI. Clinical outcomes
in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–97.
in managed-care patients with coronary heart disease treated
aggressively in lipid-lowering disease management clinics: the 50 Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on
ALLIANCE study. J Am Coll Cardiol 2004; 44: 1772–79. cardiovascular disease prevention in clinical practice: full text.
Fourth Joint Task Force of the European Society of Cardiology and
29 Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of
other societies on cardiovascular disease prevention in clinical
cardiovascular disease with pravastatin in Japan (MEGA Study): a
practice (constituted by representatives of nine societies and by
prospective randomised controlled trial. Lancet 2006; 368: 1155–63.
invited experts). Eur J Cardiovasc Prev Rehabil 2007;
30 Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and 14 (suppl 2): 1–113.
cardiovascular events in patients undergoing hemodialysis.
51 Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for
N Engl J Med 2009; 360: 1395–407.
the management of dyslipidaemias: the Task Force for the
31 Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent management of dyslipidaemias of the European Society of
vascular events in men and women with elevated C-reactive protein. Cardiology (ESC) and the European Atherosclerosis Society (EAS).
N Engl J Med 2008; 359: 2195–207. Eur Heart J 2011; 32: 1769–818.
32 Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients 52 Cooper A, Nherera L, Calvert N, et al. Clinical guidelines and
with systolic heart failure. N Engl J Med 2007; 357: 2248–61. evidence review for lipid modification: cardiovascular risk
33 Gissi-HF investigators. Effect of rosuvastatin in patients with assessment and the primary and secondary prevention of
chronic heart failure (the GISSI-HF trial): a randomised, double- cardiovascular disease. London: National Collaborating Centre for
blind, placebo-controlled trial. Lancet 2008; 372: 1231–39. Primary Care and Royal College of General Practitioners, 2008.
34 LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering 53 Heart Protection Study Collaborative Group. Lifetime cost
with atorvastatin in patients with stable coronary disease. effectiveness of simvastatin in a range of risk groups and age
N Engl J Med 2005; 352: 1425–35. groups derived from a randomised trial of 20,536 people. BMJ
35 Study of the Effectiveness of Additional Reductions in Cholesterol 2006; 333: 1145–48.
and Homocysteine (SEARCH) Collaborative Group. Intensive 54 Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K,
lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin Goldman L. Cost-effectiveness of statin therapy for primary
daily in 12 064 survivors of myocardial infarction: a double-blind prevention in a low-cost statin era. Circulation 2011; 124: 146–53.
randomised trial. Lancet 2010; 376: 1658–69. 55 Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact
36 Amarenco P, Bogousslavsky J, Callahan A III, et al. High-dose and cost-effectiveness of primary prevention strategies for
atorvastatin after stroke or transient ischemic attack. N Engl J Med lipid-lowering. Ann Intern Med 2009; 150: 243–54.
2006; 355: 549–59.
37 Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with
atorvastatin to the National Cholesterol Educational Program goal
versus ‘usual’ care in secondary coronary heart disease prevention.
The GREek Atorvastatin and Coronary-heart-disease Evaluation
(GREACE) study. Curr Med Res Opin 2002; 18: 220–28.

590 www.thelancet.com Vol 380 August 11, 2012