CTT (Cholesterol Treatment Trialists' Collaboration)

170,000 patients in various trials (second cycle)

First cycle

Second cycle

Publications

Funders

Objectives

The Cholesterol Treatment Trialists' (CTT) Collaboration was established in 1994 after it was identified that no single ongoing trial would have sufficient statistical power to address some key uncertainties about the effects of lowering cholesterol. It was recognised that, while the individual trials might be large enough to demonstrate effects on the aggregate of all coronary events, they might well over- or underestimate any effects on coronary death or on other specific vascular or non-vascular outcomes, especially when particular subgroups of participants were considered. Hence, it was planned to conduct periodic meta-analyses of individual participant data on mortality and morbidity from all relevant large-scale randomised trials of lipid-modifying treatments whose first results would appear subsequently (see published protocol1).

First Cycle

Results

The first cycle of analyses included 14 randomised trials of statin therapy, and involved over 8000 deaths, 14,000 major vascular events, and 5000 cancers among 90,056 participants2. The mean duration of treatment in these trials was about 5 years, and the overall average difference in LDL cholesterol at 1 year was 1·09 mmol/l. All analyses were weighted by the absolute difference in LDL cholesterol in each trial after 1 year of treatment. Overall, there was a 12% reduction in all-cause mortality per mmol/l LDL cholesterol reduction, attributable mainly to a proportional reduction of about one fifth in CHD deaths per mmol/l lower LDL cholesterol (figure). Among the non-vascular causes of death, there was no evidence that lowering LDL cholesterol with a statin adversely influenced the risk of death from cancer, respiratory disease, trauma, or other/unknown causes.

There was a significant trend towards greater proportional reductions in major vascular events being associated with greater LDL cholesterol reductions in the different trials (figure), but no heterogeneity among the results of the individual trials after adjusting for achieved differences in LDL cholesterol. Overall, there was a one fifth proportional reduction in the incidence of major vascular events per mmol/l LDL cholesterol reduction, reflecting similar proportional reductions of about one fifth in major coronary events, coronary revascularisation procedures, and strokes (figure). The one fifth reduction in stroke was mainly attributable to a reduction in ischaemic stroke, whilst there was no evidence of an adverse effect on haemorrhagic stroke (relative risk [RR] 1.05 [99% CI 0.78-1.41]; p=NS).

Given the large numbers of major vascular events, the effects of lowering LDL cholesterol with a statin could be examined particularly reliably in various different circumstances (e.g. sex, age, treated for hypertension, history of diabetes, LDL cholesterol).

The incidence of major vascular events was reduced by about one fifth per mmol/l LDL cholesterol reduction in each pre-specified subgroup, and was statistically significant in each of these subgroups considered separately (figure, figure cont.). There were also significant reductions in the incidence of major vascular events in a number of other subgroups of interest (including people with pre-treatment LDL cholesterol ≤2·6 mmol/l, diabetic individuals without pre-existing vascular disease, women and people aged over 75 years).

There was a significant 10% proportional reduction in major vascular events during the first year after randomisation, which was followed by highly significant annual reductions of around one-quarter during each subsequent year (figure).

There was no evidence that lowering LDL cholesterol with statin therapy increased the risk of developing cancer, nor was there any evidence of an excess incidence of cancer emerging with increasing duration of treatment (figure). Moreover, when cancer was analysed by site, there were no apparent excesses for any particular site-specific cancer (figure).

Benefits of statin therapy among patients with diabetes mellitus

The CTT collaboration explored the effects of statin therapy in more detail among the 18,686 individuals with diabetes (1466 type 1 and 17,220 type 2) included within the 14 trials3. During mean follow up of 4.3 years, 3247 of these diabetic individuals had major vascular events. Among them, there was a 9% proportional reduction in all-cause mortality per mmol/l reduction in LDL cholesterol, which was similar to the 13% reduction among those without diabetes (figure). This reflected a significant reduction in vascular mortality, but no apparent effect on non-vascular mortality (or on cancer incidence). There was a one fifth proportional reduction in major vascular events per mmol/l reduction in LDL cholesterol among people with diabetes, which again was similar to the effect observed in those without diabetes (figure). Among diabetic participants there were also separately significant reductions of about one fifth in myocardial infarction or coronary death, in coronary revascularisation, and in stroke. The reduction in major vascular events was similar among diabetic participants with pre-existing vascular disease and those with no such history (figure). Among diabetic individuals, there was no evidence that the relative effects of statin therapy differed by diabetes type (type 1 or 2), gender, age, systolic or diastolic blood pressure, smoking, body mass index, renal function, predicted annual risk of a major vascular event, (figure, figure cont.) or the baseline lipid profile (figure). The effects on major vascular events started to emerge within the first year, but were greater in subsequent years (figure). Consequently, these new analyses suggest that statin therapy should be considered routinely in all people with diabetes, unless there are particular reasons not to do so (e.g. pregnancy or a low absolute risk of vascular disease in a young adult with type I diabetes).

Publications

Main publications from trials included in the first cycle

  • AFCAPS/TEXCAPS (AirForce/Texas Coronary Atherosclerosis Prevention Study)

  • ALERT (Assessment of Lescol in Transplantation)

  • ALLHAT-LLT (Antihypertensive Lipid Lowering Heart Attack Trial)

  • ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial)

  • CARDS (Collaborative Atorvastatin Diabetes Study)

  • CARE (Cholesterol and Recurrent Events Study)

  • GISSI Prevention (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico):

  • HPS (Heart Protection Study)

  • LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease)

  • LIPS (Lescol Intervention Prevention Study)

  • Post-CABG (Post-Coronary Artery Bypass Graft study)

  • PROSPER (Prospective Study of Pravastatin in the Elderly at Risk)

  • 4S (Scandinavian Simvastatin Survival Study)

  • WOSCOPS (West of Scotland Coronary Prevention Study)

Second Cycle

The main purpose of the second cycle was to assess the effects of additional reductions in LDL cholesterol among patients receiving a standard statin regimen, but the meta-analyses of trials comparing statin versus control have also been updated.

Background

Comparisons of more versus less intensive regimens: The first cycle indicated that there was an approximately linear relationship between the absolute reductions in LDL cholesterol and the proportional reductions in major vascular events. However, a direct test of the hypothesis that further reductions in LDL-cholesterol would provide additional reduction in risk requires randomised trials of a more intensive versus less intensive LDL-lowering regimen. To date, five large trials have examined this hypothesis: two have been conducted among patients with a recent acute coronary syndrome (PROVE-IT [Pravastatin or Atorvastatin Evaluation and Infection Therapy]5 and A to Z6) and three among patients with a prior MI (TNT [Treating to New Targets]7, IDEAL [Incremental Decrease inEndpoints Through Aggressive Lipid Lowering]8 and SEARCH [Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine]9) (figure).

Extended comparisons of statin versus control: The first cycle included 14 trials comparing a statin versus a control regimen. In this updated analysis the additional trials are: ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events)10; 4D (Die Deutsche Diabetes Dialyze)11; ASPEN (Atorvastatin Study for Prevention of coronary heart disease Endpoints in non-insulin dependent diabetes mellitus)12; MEGA (Management of Elevated cholesterol in the primary prevention group of Adult Japanese)13; JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)14; GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca)15 and AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events)16 (figure).

Results

The second cycle of analyses included 26 randomised trials of statin therapy: 5 trials were of more vs. less statin therapy (39,612 patients, median follow up 5.1 years) and 21 trials were of statin vs. control (129,526 patients, median follow up 4.8 years). Taken together, these trials involved 15,969 deaths, 24,323 major vascular events, and 10,124 cancers among 169,138 participants4. The average difference in LDL cholesterol at 1 year among the statin vs. control trials was 1.07 mmol/L, whilst 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. Analyses were done both before and after weighting for the absolute difference in LDL cholesterol in each trial after 1 year of treatment.

Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11–18; p<0·0001) further reduction in major vascular events (figure), consisting of separately significant 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) (figure). Overall the weighted average further reduction in major vascular events was 28% (22-34; p<0.0001) per mmol/L reduction in LDL-cholesterol (figure) with separately significant reductions in each of the major components of this composite outcome (figure).

The results of the updated meta-analysis of the 21 statin vs. control trials were similar to those observed in the first cycle: there was a highly significant 21% (95% CI 19-23;p<0.0001) reduction per mmol/L LDL cholesterol reduction. The proportional reductions per mmol/L LDL cholesterol reduction were separately significant for coronary death or non-fatal myocardial infarction (24%, 95% CI 21–27;p<0·0001), coronary revascularisation (24%, 95% CI 20–27; p<0·0001), and ischaemic stroke (20%, 95% CI 14–26; p<0·0001) (figure).

When both types of trial were combined, similar proportional reductions in major vascular events per mmol/L LDL cholesterol reduction were found in all types of patient studied (figure, figure cont.) (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 (figure).

Across all 26 trials, all-cause mortality was reduced by 10% per mmol/L LDL reduction (RR 0·90, 95% CI 0·87–0·93; p<0·0001), largely reflecting significant 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 significant effect 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) (figure). No significant effects 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) (figure), even at low LDL cholesterol concentrations.

Publication

Main publications from additional trials in the second cycle

  • A to Z (Aggrastat to Zocor)

  • IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering)

  • PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy)

  • SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine)

  • TNT (Treating to New Targets)

  • ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events)

  • ASPEN (Atorvastatin Study for Prevention of Coronary Heart Disease Endpointsin Non-Insulin-Dependent Diabetes Mellitus)

  • AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events)

  • 4D (Die Deutsche Dialyse Studie)

  • GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca)

  • JUPITER (Justification for the Use of Statins in Prevention: an InterventionTrial Evaluating Rosuvastatin)

  • MEGA (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese)

References

  1. Cholesterol Treatment Trialists' (CTT) Collaborators. Protocol for a prospective collaborative overview of all current and planned randomized trials of cholesterol treatment regimens. Am J Cardiol 1995; 75(16):1130-4.
  2. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R, Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366(9493):1267-78.
  3. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Baigent C, Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371(9607): 117–25.
  4. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R, Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376: 1670–81.
  5. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495-504.
  6. de Lemos JA, Blazing MA, Wiviott SD et al . Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292: 1307-16.
  7. La Rosa JC, Grundy SM, Waters DD, et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. N Engl J Med 2005; 352:1425-1435.
  8. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005; 294: 2437-45.
  9. Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010; 376: 1658–69.
  10. Koren M, Hunninghake D, ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: The ALLIANCE study. J Am Coll Cardiol 2004; 44: 1772-79.
  11. Wanner C, Krane V, März W, et al. for the German Diabetes and Dialysis Study Group. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238-48.
  12. Knopp RH, d'Emden M, Smilde JG, et al. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006; 29: 1478-85.
  13. Nakamura H, Arakawa K, Itakura H, et al. for the MEGA Study Group. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006; 368: 1155-63.
  14. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008;359:2195-207.
  15. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231–39.
  16. Fellström, BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis. N Engl J Med 2009;360:1395-407.

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For further information please contact: CTT@ctsu.ox.ac.uk