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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

Summary 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.

1 Webtable 1: Cox proportional hazard models predicting the risk of a first major vascular event in participants allocated to control (model 1) or less statin (model 2) Webtable 3: Mean difference in plasma lipid concentrations at 1 year in participants at different levels of risk  In trials where the LDL-C at 1 year was missing (or >10mmol/L) the baseline value was assigned. In some studies, only a subsample of participants were selected for 1 year blood samples: HPS (~4% of trial participants); SEARCH (~3% of participants). In other studies, no samples at 1 year were taken and so other blood samples were used: In A to Z and PROVE-IT, blood samples taken at 8 months were used; in ALLHAT samples taken at 2 years (from a random sample of 10% of participants randomised to pravastatin and 5% of participants randomised to usual care) were used. In ALLIANCE, lipid differences at 1 year in the usual care group were interpolated from those at baseline and final follow-up because the 1 year bloods were assayed in different laboratories depending on treatment allocation. 3. The National Institute for Health and Clinical Excellence (NICE) in the National Health Service (NHS) in England and Wales recommends lipid modification drug therapy for individuals without known cardiovascular disease (CVD) who have 20% or greater 10-year risk of developing CVD (defined as myocardial infarction, CHD death, angina, stroke or transient ischemia). As no total CVD endpoint was available in CTT data, an approximate estimation of risk was carried out to allow interpretation. Total CVD was evaluated by multiplying observed vascular death rates within the risk categories by a factor of 3 to 4 (as indicated by the SCORE data). The total estimated 10-year CVD risk among those allocated to control intervention in the two lowest risk categories in CTT was less than 20% and therefore these participants are ineligible for statin intervention under NICE guidelines. Webfigure 5: 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 in the 22 statin vs control trials Webfigure 6: 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 in the 5 trials of more vs less statin

Statistical appendix
Estimating the five year risk of major vascular event among the 174,149 participants in 27 randomised trials of statin therapy The 5Ͳyear risk of a major vascular event (first nonͲfatal myocardial infarction, coronary death, stroke or coronary revascularisation procedure) was estimated using separate Cox proportional hazards models for the 67,000 patients allocated the control regimen in the 22 trials of statin versus control (model 1) and the 20,000 patients allocated the less intensive statin regimen in the 5 trials of more versus less statin (model 2). The results from these two regression models were then applied to all patients (including those in the active treatment arms), as described below.
For patient i in study j with allocated treatment k (where k=0 corresponds to the control/less statin treatment and k=1 corresponds to the statin/more statin treatment), the hazard function in the control/less statin g ou regression r p was modelled by the equation: where h 0 (t) is the baseline hazard function, ɲ is an overall intercept term, ɴ j represents the effect of study j relative to the Heart Protection Study for model 1 or the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine for model 2 (see Webtable 1, terms C), ࢽ represents a vector of log hazard ratios corresponding to the patient's set of baseline characteristics x ij0 (centred around study means ഥ Ǥ where appropriate: see Webtable 1, terms A), represents a vector of log hazard ratios corresponding to interactions w ij0 between various baseline characteristics (see Webtable 1, terms B), and represents a vector of log hazard ratios corresponding to trialͲspecific time dependent effects z j (t) (defined for initial sixͲmonthly time periods: see Webtable 1, terms D).
For each of the two regression models, the baseline characteristics x ij and interactions w ij were selected using backward elimination, with factors remaining in the model if they were statistically significant at the 1% level (age and sex were to be included in both models irrespective of statistical significance). The baseline characteristics included in the final models are shown in Webtable 1. The trialͲspecific time dependent effects z j (t) were defined for initial sixͲmonthly time periods and a backwards elimination strategy with statistical significance at 1% was employed to select the effects remaining in the models.
The Cox models provide estimates of log hazard ratios, but provide no direct estimate of the baseline hazard ݄ ሺ‫ݐ‬ሻ. However, an estimate of the cumulative hazard function ‫ܪ‬ ሺ‫ݐ‬ሻ can be recovered by estimation of baseline hazard contributions at failure times using the Kalbfleisch and Prentice method and, from that, an estimate of the baseline cumulative survival S 0 (t) = exp(ͲH 0 (t)) can be made.