CARDS

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Colhoun HM, 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.
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Clinical Question

In patients with type 2 diabetes without hypercholestrolemia, does atorvastatin reduce the risk of cardiovascular events, as compared to placebo?

Bottom Line

In patients with type 2 diabetes without hypercholestrolemia, atorvastatin is safe and effectively reduced the risk of cardiovascular events, as compared to placebo.

Major Points

Type 2 diabetes (T2DM) significantly increases the risk of cardiovascular disease (CVD).[1] Previous studies have shown that lipid lowering with statin therapy reduces the risk of subsequent CV events in diabetic patients with established CVD.[2][3] However, more evidence supporting the benefits of lipid lowering for primary prevention of CVD in T2DM was required.

The Collaborative AtoRvastatin Diabetes Study (CARDS) randomized 2,383 patients to receive atorvastatin 10 mg daily or placebo. The aim was to assess the safety and efficacy of atorvastatin in primary prevention of CVD in patients with T2DM.

The trial was terminated 2 year earlier than planned after meeting the prespecified efficacy endpoints. After 3.9 years of follow-up, atorvastatin reduced the risk of the primary outcome (ACS, coronary revascularisation, or stroke) by 37% (95% CI -52 to -17; P=0·001) with a strong trend towards reduction of all-cause mortality risk (HR 0.73; 95% CI 0.52-1.01; P=0·059). Safety outcomes of atorvastatin were comparable to the placebo group.

The CARDS trial and subgroup analyses of diabetic patients in the ALLHAT-LLT, HPS and ASCOT-LLA trials were included in a meta-analysis (18,686 diabetic patients, mean follow-up 4.3 years).[4][5][6] LDL-C lowering by 1 mmol/L reduces the risk of major vascular events by 21% (RR 0·79; 99% CI 0·72-0·86; P<0·0001) and that of all-cause mortality by 9% (RR 0·91; 99% CI 0·82-1.01; P=0.02).[7]

Guidelines

ADA Standards of Medical Care in Diabetes (2016, adapted)[8]

  • For diabetic patients aged <40 years with additional CVD risk factors, consider moderate- or high-intensity statin and lifestyle therapy. (Level of evidence: C)
  • For diabetic patients aged 40-75 years without additional CVD risk factors, consider moderate-intensity statin and lifestyle therapy. (Level of evidence: A)
  • For diabetic patients aged 40-75 years with additional CVD risk factors, consider high-intensity statin and lifestyle therapy. (Level of evidence: B)
  • For diabetic patients aged >75 years without additional CVD risk factors, consider moderate-intensity statin and lifestyle therapy. (Level of evidence: B)
  • For diabetic patients aged >75 years with additional CVD risk factors, consider moderate- or high-intensity statin and lifestyle therapy. (Level of evidence: B)

ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (2013, adapted)[9]

  • For diabetic patients aged 40-75 with LDL-C of 70-189 mg/dL, moderate-intensity statin therapy should be initiated or continued. (Class I, Level of Evidence: A)
  • For diabetic patients aged 40-75 with LDL-C of 70-189 mg/dL and a ≥7.5% estimated 10-year ASCVD risk, high-intensity statin therapy is reasonable unless contraindicated. (Class IIa, Level of Evidence: B)
  • For diabetic patients aged <40 or >75, or with LDL-C < 70 mg/dL, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy (Class IIa, Level of Evidence: C)

Design

  • Double-blind, randomized, placebo-controlled, multicenter study
  • N=2,383
    • Atorvastatin 10 mg daily: 1,428
    • Placebo: 1,410
  • Setting: 132 centres in the UK and Ireland
  • Enrollment: 1997-2001
  • Mean follow-up: 3.9 years; the trial was terminated 2 years earlier than planned after meeting the prespecified early stopping rule for efficacy
  • Analysis: intention to treat
  • Primary outcome: acute coronary syndrome (ACS), coronary revascularisation, or stroke

Population

Inclusion Criteria

Described elsewhere[10]

  • Aged 40-75 years
  • T2DM diagnosed ≥ 6 months prior to study according to the 1985 WHO criteria
  • One of the following comorbidities: hypertension, retinopathy, microalbuminuria or macroalbuminuria
  • Fasting LDL-C ≤ 4.14 mmol/l (160 mg/dl); fasting triglycerides ≤ 6.78 mmol/l (600 mg/dl)

Exclusion Criteria

  • Previous MI, unstable angina, coronary artery surgery, stroke, severe peripheral vascular disease requiring surgery
  • On treatment for significant arrhythmias or heart failure (NYHA class III or IV)
  • Serum creatinine > 150 μmol/L
  • HbA1c>12%
  • T1DM, secondary causes of diabetes
  • Active liver disease, AST or ALT ≥ 1.5× the upper limit of normal (ULN)
  • CK ≥ 3 × ULN
  • Severe renal dysfunction or nephrotic syndrome
  • BMI > 35 kg/m2
  • Alcohol dependence
  • Hypersensitivity to HMG-CoA reductase inhibitors
  • Compliance rate < 80% during the placebo baseline phase
  • Uncontrolled hypertension (systolic BP > 200 mm Hg and/or diastolic BP > 110 mm Hg)
  • Other serious comorbidities
  • Participation in another ongoing clinical study

Baseline Characteristics

From the atorvastatin group:

  • Demographics: age 61.5±8.3 years; 68% males; 95% white race
  • Qualifying event specifics:
    • Duration of diabetes: 7.9±6.36 years
    • Oral hypoglycemic treatment: 65%; HbA1c 7.87±1.42%
    • Retinopathy 30%
    • Microalbuminuria 15%, macroalbuminuria: 2%, median urinary albumin:creatinine: 1.15 (0.63-2.78); plasma creatinine: 102±14.7 μmol/L
  • PMH: Hypertension 84%; Active smoker 22%; ex-smoker 44%
  • BMI: 28.7±3.61 kg/m2
  • BP: systolic 144±15.9 mm Hg; diastolic 83±8.5 mm Hg
  • LDL-C: 3.04±0.72 mmol/L; total cholesterol 5·36±0·83 mmol/L; HDL-C 1·39±0·32 mmol/L; median triglyceride 1.7 (1.2-2.4) mmol/L

Interventions

  • Patients were randomized to receive placebo or atorvastatin 10 mg daily in a triple-blind manner
  • Patient's were considered to be compliant if they had taken ≥80% of the study drug
  • The study drug was discontinued if liver transaminases increase to ≥3 × ULN or CK increase to ≥10 × ULN

Outcomes

comparisons are atorvastatin vs. placebo

Primary Outcome

ACS, coronary revascularization, or stroke
1.54 vs. 2.46 per 100 person-yrs (relative risk reduction 37%; 95% CI -52 to -17; P=0·001)
5.9% vs. 9% (HR 0.63; 95% CI 0.48-0.83; P=0·001)
ACS
3.6% vs. 5.5% (HR 0.64; 95% CI 0.45-0.91; P=0·001)
Coronary revascularization
1.7% vs. 2.4% (HR 0.69; 95% CI 0.41-1.16; P=0·001)
Stroke
1.5% vs. 2.8% (HR 0.52; 95% CI 0.31-0.89; P=0·001)

Secondary Outcomes

Any acute CVD event
9.4% vs. 13.4% (HR 0.68; 95% CI 0.55-0.85; P=0·001)
All-cause mortality
4.3% vs. 5.8% (HR 0.73; 95% CI 0.52-1.01; P=0·059)

Additional Outcomes

LDL-C at 4-years follow up
2.11±0.7 mmol/L vs. 3.12±0.8 mmol/L (treatment effect -40%; 95% CI -41 to -39; P<0.0001)

Total cholesterol at 4-years follow up

4.12±0.84 mmol/L vs. 5.28±0.91 mmol/L (treatment effect -26%; 95% CI -27 to -26; P<0.0001)
HDL-C at 4-years follow up
1.26±0.3 mmol/L vs. 1.23±0.3 mmol/L (treatment effect 1%; 95% CI 0.7-2; P=0.0002)
Non-HDL-C at 4-years follow up
2.86±0.82 mmol/L vs. 4.05±0.9 mmol/L (treatment effect -36%; 95% CI -37 to -35; P<0.0001)
Triglyceride at 4-years follow up
1.61±0.93 mmol/L vs. 1.9±1.1 mmol/L (treatment effect -19%; 95% CI -20 to -17; P<0.0001)

Apo-A1 at 4-years follow up

1320±230 mg/L vs. 1310±230 mg/L (treatment effect -0.1%; 95% CI -0.9 to 0.7; P=0.8)

Apo-B at 4-years follow up

800±190 mg/L vs. 1050±210 mg/L (treatment effect -23%; 95% CI -24 to -22; P<0.0001)

HbA1c at 4-years follow up

8.3% vs. 8.1% (P not given)

Subgroup analysis

No heterogeneity in the efficacy of atorvastatin across major subgroups, including age, sex, BP, retinopathy, albuminuria, smoking status, cholesterol levels or HbA1c.

Adverse Events

serious adverse events
1.1% vs. 1.1% (P=NS)
discontinuation due to treatment-related adverse effects
9% vs. 10% (P=NS)
  • Elevation in ALT of ≥ 3 × ULN
    • 1% vs. 1% (P not given)
  • Elevation in AST of ≥ 3 × ULN
    • 0.4% vs. 0.3% (P not given)
  • Elevation in CK of ≥ 10 × ULN
    • 0.1% vs. 0.7% (P not given)
    • 1 case of myopathy was seen in the atorvastatin group another in the placebo group
    • Myalgia was noted in 61 patients in the atorvastatin group and 72 in the placebo group
mortality
  • from non-CV events
2.5% vs. 3.2% (P not given)
  • from cancer
20 patients vs. 30 patients (p=0·14)

Criticisms

  • The trial patients were carefully selected. For example, results may not be generalized to elderly or young patients, patients with CKD, very high LDL-C and/or triglyceride levels.[11]

Funding

  • UK Department of Health, Diabetes UK, and Pfizer

Further Reading

  1. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16(2):434–44.
  2. Pyŏrälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20(4):614–20.
  3. Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 1998;98(23):2513–9.
  4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288(23):2998–3007.
  5. Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005–16.
  6. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149–58.
  7. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. 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.
  8. American Diabetes Association. 8. Cardiovascular Disease and Risk Management. Diabetes Care. 2015 Jan;38 Suppl:S49-57. doi: 10.2337/dc15-S011
  9. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014;63(25_PA):2889-2934. doi:10.1016/j.jacc.2013.11.002.
  10. Colhoun, H. M., Thomason, M. J., Mackness, M. I., Maton, S. M., Betteridge, D. J., Durrington, P. N., Hitman, G. A., Neil, H. A. W., Fuller, J. H. and the CARDS Investigators (2002), Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with Type 2 diabetes. Diabetic Medicine, 19: 201–211. doi: 10.1046/j.1464-5491.2002.00643.x
  11. Garg A. Statins for all patients with type 2 diabetes: not so soon. Lancet. 2004;364(9435):641–2.