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

• 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

• 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

  • Slides: view^* or download

• 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

  • Slides: view^* or download

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 CTT Steering Committee, which includes principal investigators from all of the contributing trials, meets regularly each year at the American Heart Association Scientific Sessions. At the Steering Committee meeting in November 2006, it was agreed to proceed with a second cycle of data collection to allow the following analyses:

Extended comparisons of statin versus control: The first cycle included 14 trials comparing a statin versus a control regimen. In the second cycle, it is proposed to extend these analyses, and the potentially eligible trials for this comparison are: GREACE (Greek Atorvastatin and Coronary-heart-disease Evaluation)⁴; ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events)⁵; 4D (Die Deutsche Diabetes Dialyze)⁶; MEGA (Management of Elevated cholesterol in the primary prevention group of Adult Japanese)⁷; SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)⁸; and ASPEN (Atorvastatin Study for Prevention of coronary heart disease Endpoints in non-insulin dependent diabetes mellitus)⁹. This will increase the number of outcomes available for analysis (e.g. major vascular events will increase from 14,300 to around 17,000) and, in particular, will increase the statistical precision of analyses within certain subgroups.

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, it did not demonstrate directly that more intensive LDL -lowering regimens produce larger reductions in such events as compared to less intensive regimens. Four trials examining this hypothesis have already been published: two were conducted among patients with a recent acute coronary syndrome (PROVE-IT [Pravastatin or Atorvastatin Evaluation and Infection Therapy]¹⁰ and A to Z¹¹), whilst the other two were performed in people with a prior MI ( TNT [Treating to New Targets]¹² and IDEAL [Incremental Decrease in Endpoints Through Aggressive Lipid Lowering]¹³). A further trial (SEARCH [Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine] is due to report in late 2008. Analyses of the effects of more intensive reductions in LDL cholesterol with statin therapy will involve a total of about 40,000 patients and 6600 major vascular events. Such large numbers should allow the CTT collaboration to provide reliable evidence about both the efficacy and safety of more intensive therapy.

Comparisons of fibrate versus control: The third set of analyses that are planned for the second cycle involve direct randomised comparisons of a fibrate versus a control regimen. Four trials are potentially eligible involving, around 20,000 patients, in which there were around 2,600 major vascular events. Since the benefits of fibrates are postulated to result from changes to the lipid profile other than lowering LDL cholesterol^{14 15}, these meta-analyses (unlike those for statins) will not be weighted by LDL cholesterol reduction. Instead we plan to investigate the relevance of weighting by other measures (such as differences in the HDL : LDL cholesterol ratio at 1 year).

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. 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.
5. 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.
6. 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.
7. 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.
8. Amarenco P, Bogousslavsky J, Callahan A, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006; 355: 549-59.
9. 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 noninsulin-dependent diabetes mellitus ( ASPEN ). Diabetes Care 2006; 29: 1478-85.
10. 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.
11. 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.
12. 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.
13. 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.
14. Fruchart JC, Brewer HB Jr, Leitersdorf E, Fibrate Consensus Group. Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Am J Cardiol.1998; 81(7): 912-7.
15. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98(19): 2088-93.

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