Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA)

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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
Authors	Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, et al.
Journal	Lancet
Year/Volume(Issue)/Pages	2003;361(9364):1149-58
Original Article Abstract
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Contents 1 Quick Summary 2 Hypothesis/Objectives 3 Methods/Design 3.1 Inclusion criteria 3.2 Exclusion criteria 3.3 Design 4 Results 4.1 Baseline characteristics 4.2 Primary endpoint results 4.3 Other 5 Limitations

Quick Summary

• This analysis was performed to take a more detailed look at the ASCOT trial, specifically to look for health benefits (primary prevention) seen by reducing cholesterol levels in patients with hypertension that had "average" or "below-average" cholesterol concentrations (<250 mg/dL) and no evidence of coronary heart disease (CHD).
• Researchers found significant risk reductions in major cardiovascular events and procedures in those participants using atorvastatin versus those taking placebo.
• The trial was stopped early due to the statistically significant difference in events between groups.

Hypothesis/Objectives

The primary objective was to compare two regimens, placebo and atorvastatin (both with matched antihypertensive treatment), in long-term (5-year) effects on the combined endpoint of non-fatal myocardial infarction (MI), silent MI, and fatal CHD. Patients enrolled into this study had total cholesterol concentrations below 250 mg/dL (6.5 mmol/L).

Methods/Design

		Y	Randomized?
		Y	Controlled?
		Y	Placebo-controlled?
		Y	Prospective?
		Y	Double-blind?
		*U = not reported

Inclusion criteria

• men and women aged 40 to 79
• untreated hypertension, systolic or diastolic or both (>160/100 mmHg) or treated uncontrolled hypertension (systolic >140 mmHg, diastolic >90 mmHg, or both)
• total cholesterol <250 mg/dL (6.5 mmol/L) not using a statin or fibrate
• 3 of the following risk factors for CVD:
  • left ventricular hypertrophy
  • EKG abnormalities
  • previous stroke or TIA
  • male
  • premature family history of CHD
  • total cholesterol:HDL ratio ≥6
  • type 2 diabetes mellitus
  • peripheral artery disease
  • age 55 years or older
  • microalbuminuria or proteinuria
  • current smoker

Exclusion criteria

• Prior MI
• CHF
• currently treated angina
• CVA within last 3 months
• uncontrolled arrhythmias
• triglycerides >400 mg/dL (4.5 mmol/L)
• biological or hematological abnormality found on routine screening

Design

Subjects meeting inclusion criteria were randomized to either atorvastatin 10 mg daily or placebo. Any other lipid-lowering therapy other than a fibrate or statin, used before inclusion, could be continued during the study. 19,342 patients were randomized to one of the two arms of the trial.

Results

Baseline characteristics

Patients were mainly male (81%) and Caucasian (95%). Baseline BP and lipid levels were not significant between the two groups.

Primary endpoint results

There was a 36% relative risk reduction in the primary endpoint in the atorvastatin group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). The absolute risk reduction of a coronary event was 3.4 per 1,000 patient-years.

Other

There were significant risk reductions in four secondary endpoints: total cardiovascular events including revascularization procedures (p=0.0005), total coronary events (p=0.0005), the primary endpoint excluding silent MI (p=0.0005), and fatal and non-fatal stroke (p=0.0236). All-cause mortality was reduced by 13% in the treatment group; this was not a significant decrease (p=0.1649). Compared to placebo, the mean LDL concentration in the atorvastatin group dropped about 46 mg/dL (1.2 mmol/L). There were no differences between groups in adverse event rates or liver enzyme abnormalities. The lipid-lowering arm of ASCOT was stopped at a median time of 3.3 years (intent of study was 5 years of follow-up) due to statistically significant differences in the primary endpoint.

Limitations

• The absolute risk reduction of a coronary event was 3.4 events reduced per 1,000 patient-years.
• There may not be an indication for putting patients on statins if they have normal cholesterol.
• There is a financial issue with putting lower-risk patients on statins.
• Trial was funded in part by Pfizer, makers of Lipitor (atorvastatin).
• Many of the authors are consultants or have received research monies from pharmaceutical companies that manufacture lipid-lowering medications.
• The definition of "average" total cholesterol being less than 250 mg/dL may be liberal; the American Heart Association's risk levels puts someone having a total cholesterol value above 240 mg/dL as "high risk."