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, B Mihaylova, J Emberson, L Blackwell, A Keech, J Simes, E H Barnes, M Voysey, A Gray, R Collins, C Baigent, J de Lemos, E Braunwald, M Blazing, S Murphy, J R Downs, A Gotto, M Clearfield, H Holdaas, D Gordon, B Davis, M Koren, B Dahlof, N Poulter, P Sever, R H Knopp, B Fellström, H Holdaas, A Jardine, R Schmieder, F Zannad, U Goldbourt, E Kaplinsky, H M Colhoun, D J Betteridge, P N Durrington, G A Hitman, J Fuller, A Neil, C Wanner, V Krane, F Sacks, L Moyé, M Pfeffer, C M Hawkins, E Braunwald, J Kjekshus, H Wedel, J Wikstrand, P Barter, A Keech, L Tavazzi, A Maggioni, R Marchioli, G Tognoni, M G Franzosi, A Maggioni, H Bloomfield, S Robins, R Collins, J Armitage, A Keech, S Parish, R Peto, P Sleight, T R Pedersen, P M Ridker, R Holman, T Meade, J Simes, A Keech, S MacMahon, I Marschner, A Tonkin, J Shaw, P W Serruys, H Nakamura, G Knatterud, C Furberg, R Byington, P Macfarlane, S Cobbe, I Ford, M Murphy, G J Blauw, C Packard, J Shepherd, J Kjekshus, T Pedersen, L Wilhelmsen, E Braunwald, C Cannon, S Murphy, R Collins, J Armitage, L Bowman, S Parish, R Peto, P Sleight, C Baigent, M Landray, R Collins, J La Rosa, J Rossouw, J Probstfield, J Shepherd, S Cobbe, P Macfarlane, I Ford, M Flather, J Kastelein, C Newman, C Shear, J Tobert, J Varigos, H White, S Yusuf, M Mellies, M McGovern, J Barclay, R Belder, Y Mitchel, T Musliner, J-C Ansquer, M Llewellyn, M Bortolini, G Brandrup-Wognsen, B Bryzinski, G Olsson, J Pears, D DeMicco, C Baigent, E H Barnes, A Baxter, 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, Cholesterol Treatment Trialists' (CTT) Collaborators, B Mihaylova, J Emberson, L Blackwell, A Keech, J Simes, E H Barnes, M Voysey, A Gray, R Collins, C Baigent, J de Lemos, E Braunwald, M Blazing, S Murphy, J R Downs, A Gotto, M Clearfield, H Holdaas, D Gordon, B Davis, M Koren, B Dahlof, N Poulter, P Sever, R H Knopp, B Fellström, H Holdaas, A Jardine, R Schmieder, F Zannad, U Goldbourt, E Kaplinsky, H M Colhoun, D J Betteridge, P N Durrington, G A Hitman, J Fuller, A Neil, C Wanner, V Krane, F Sacks, L Moyé, M Pfeffer, C M Hawkins, E Braunwald, J Kjekshus, H Wedel, J Wikstrand, P Barter, A Keech, L Tavazzi, A Maggioni, R Marchioli, G Tognoni, M G Franzosi, A Maggioni, H Bloomfield, S Robins, R Collins, J Armitage, A Keech, S Parish, R Peto, P Sleight, T R Pedersen, P M Ridker, R Holman, T Meade, J Simes, A Keech, S MacMahon, I Marschner, A Tonkin, J Shaw, P W Serruys, H Nakamura, G Knatterud, C Furberg, R Byington, P Macfarlane, S Cobbe, I Ford, M Murphy, G J Blauw, C Packard, J Shepherd, J Kjekshus, T Pedersen, L Wilhelmsen, E Braunwald, C Cannon, S Murphy, R Collins, J Armitage, L Bowman, S Parish, R Peto, P Sleight, C Baigent, M Landray, R Collins, J La Rosa, J Rossouw, J Probstfield, J Shepherd, S Cobbe, P Macfarlane, I Ford, M Flather, J Kastelein, C Newman, C Shear, J Tobert, J Varigos, H White, S Yusuf, M Mellies, M McGovern, J Barclay, R Belder, Y Mitchel, T Musliner, J-C Ansquer, M Llewellyn, M Bortolini, G Brandrup-Wognsen, B Bryzinski, G Olsson, J Pears, D DeMicco, C Baigent, E H Barnes, A Baxter, 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

Abstract

Background: Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.

Methods: This meta-analysis included individual participant data from 22 trials of statin versus control (n=134,537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39,612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated.

Findings: Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77-0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from 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 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 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, 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 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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Effects on major coronary events, strokes, coronary revascularisation procedures, and major vascular events per 1·0 mmol/L reduction in LDL cholesterol at different levels of risk MVE=major vascular event. RR=rate ratio. CI=confidence interval.
Figure 2
Figure 2
Effects on major vascular events per 1·0 mmol/L reduction in LDL cholesterol at different levels of risk, by history of vascular disease MVE=major vascular event. RR=rate ratio. CI=confidence interval.
Figure 3
Figure 3
Effects on vascular and non-vascular deaths per 1·0 mmol/L reduction in LDL cholesterol at different levels of risk, by history of vascular disease 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 unknown cause among participants without vascular disease and 309 (statin/more statin) versus 338 (control/less statin) deaths of unknown cause among participants with vascular disease.
Figure 4
Figure 4
Effects on cancer incidence and cancer mortality per 1·0 mmol/L reduction in LDL cholesterol at different levels of risk MVE=major vascular event. RR=rate ratio. CI=confidence interval.
Figure 5
Figure 5
Predicted 5-year benefits of LDL cholesterol reductions with statin treatment at different levels of risk (A) Major vascular events and (B) vascular deaths. Lifetable estimates using major vascular event risk or vascular death risk in the respective risk categories and overall treatment effects per 1·0 mmol/L reduction in LDL cholesterol with statin.

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