People with diabetes are at high risk for heart disease and stroke. Since elevated lipid levels are associated with cardiovascular vascular disease, keeping blood cholesterol close to the recommended target numbers can lower the risk. The American Diabetes Association has recommended using statins (a class of drug used to lower cholesterol levels) for patients with type 2 diabetes. The Collaborative Atorvastatin Diabetes Study (CARDS) is the first randomized controlled trial that assessed the effectiveness and safety of using atorvastatin in patients with type 2 diabetes with no prior history of cardiovascular disease. Atorvastin is sold by Pfizer (under the trade name Lipitor) and is a member of the drug class statins. We present a summary of the CARDS, which, being a landmark trial, is also an excellent example to illustrate characteristics of a randomized controlled experiment.
The needs for aggressive lipid treatment are urgent since diabetic patients have a two to four times increased risk for heart disease and stroke. For a middle aged person with diabetes, the chance of having a heart attack is as high as someone without diabetes who has already had one heart attack. People with diabetes who have already had one heart attack have an even greater risk of having a second one. In addition, people with diabetes have a greater risk of dying after a heart attack. However, there was insufficient clinical data supporting the effectiveness and safety of lipid lowering therapy of statins for the primary prevention of cardiovascular disease in diabetic patients.
To determine the effectiveness and safety of using a statin (10-mg atorvastatin) for the primary prevention of cardiovascular disease in diabetic patients.
Design, Settings, and Subjects
The CARDS, a collaboration between Pfizer, University College London, Diabetes UK and the UK Department of Health, was a prospective and placebo-controlled double-blind trial conducted in in 132 centers in the UK and Ireland.
The CARDS is a completely randomized experimental design. This experiment has a single factor (atorvastatin) and two levels (10-mg atorvastatin and placebo). A total of 2,383 subjects were randomized to either 10-mg atorvastatin (1428 subjects) or placebo (1410 subjects). Figure 1 is an outline of this experimental design.
The subjects were enrolled with the following criteria:
- Patients aged 40 to 75 with type 2 diabetes.
- No prior history of heart disease.
- With average or below average levels of cholesterol (LDL and triglycerides).
- Having at least one of the following additional risk factors: hypertension, retinopathy, albuminuria, current smoking.
Main Outcome Measures
The main outcome measures (called the primary endpoints) were: coronary revascularization procedures (e.g. by-pass surgery), and stroke, acute coronary heart disease events, which include CHD death, myocardial infarction (heart attack), unstable angina (chest pain requiring hospitalization), resusitated cardiac arrest. The secondary outcome measures (secondary endpoints) were all-cause mortality, acute coronary events, lipid and lipoproteins levels.
The atorvastatin group experienced a 37% reduction in the primary endpoints as compared to the placebo group. Assessed separately, the acute coronary events were reduced by 36% and coronary revascularization procedures by 31% and the risk of stroke by 48% in the atorvastatin group as compared to placebo. The all-cause mortality was 27% lower for atorvastatin patients than for the patients on placebo. The atorvastatin patients experienced the same magnitude of benefit regardless of their baseline LDL-cholesterol or triglyceride levels. The patients treated with atorvastatin had, on average, a 40% reduction in LDL-cholesterol.
There was no significant difference in the frequency of adverse events between the atorvastatin group and the placebo group.
The CARDS was terminated in June 2003, nearly two years earlier than expected, because of the significant benefits experienced by the patients treated with atorvastatin. The median follow-up time was 3.9 years.
The investigators in the study concluded that the cholesterol lowering therapy using atorvastatin (Lipitor) has the effect of significantly and dramatically reducing the occurences of acute cardiovascular events as well as reducing the risk of stroke and overall mortality in type 2 diabetic patients. The benefits were so great that the trial had to be terminated early. In addition to being effective, the atorvastatin therapy had also been shown to be highly safe.
- Colhoun H., et al, Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, The Lancet, 2004, 364 (9435), 685-696. Abstract.
- Owen O. G., The collaborative atorvastatin diabetes study: preliminary results, Int J Clin Pract, 2005, 59 (1), 121-123. Abstract.