Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial

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The aim of the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial was to determine whether intensive low-density lipoprotein (LDL)–cholesterol lowering to a level of approximately 70 mg/dL (1.8 mmol/L) with atorvastatin 80 mg/day was more efficacious than standard LDL cholesterol lowering to 100 mg/dL (2.6 mmol/L) with pravastatin 40 mg/day in reducing the incidence of cardiovascular events in patients with acute coronary syndrome (ACS). In total, 4,162 men and women aged >18 years, who had been hospitalized for an ACS within the preceding 10 days, were randomized to receive either pravastatin 40 mg/day or atorvastatin 80 mg/day. The median LDL cholesterol levels achieved during follow-up were 95 mg/dL (2.5 mmol/L) in the pravastatin group and 62 mg/dL (1.6 mmol/L) in the atorvastatin group (P <0.001). Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/day) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/day). At 2 years, a relative risk reduction of 16% (95% confidence interval, 5%–26%; P = 0.005) in the primary end point rate (death, myocardial infarction, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy. The benefit of intensive treatment was apparent as early as 30 days and was consistent over time. The PROVE IT–TIMI 22 data indicate that patients recently hospitalized for an ACS benefit from early and continued lowering of LDL cholesterol to levels substantially below current guideline recommendations.

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The relation between low-density lipoprotein cholesterol levels and coronary heart disease risk

To date, the following 3 theoretical models have been proposed to explain the relation between LDL cholesterol levels and the risk of CHD: the linear model, the curvilinear model, and the threshold model (Figure 1).12 Until recently there has been some dispute over which model is most accurate and, therefore, whether intensive LDL cholesterol lowering should be favored over less intensive LDL cholesterol lowering, which has proven effectiveness.

The linear model suggests that the reduction in

Effects of robust low-density lipoprotein cholesterol lowering on atherosclerosis

There also appears to be a consensus developing supporting the view that intensive versus standard LDL cholesterol–lowering therapy produces a superior effect on measurements of atherosclerotic progression at clinically important sites. In the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study,16 carotid intima media thickness (CIMT) decreased by 0.031 mm (95% confidence interval [CI], −0.007 mm to −0.055 mm; P = 0.0017) after treatment with atorvastatin 80 mg/day for 2

Intensive statin treatment in patients with acute coronary syndrome

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial19 was specifically designed to assess the clinical benefits of intensive statin therapy (such as prevention of unstable angina [UA], MI, or coronary death) in patients with acute coronary syndrome (ACS). A total of 3,086 adults aged ≥18 years with UA or non–Q-wave acute MI were randomized to receive treatment with either atorvastatin 80 mg/day or placebo within 24 to 96 hours after admission. The primary end

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial was designed to establish whether intensive LDL cholesterol lowering to approximately 70 mg/dL (1.8 mmol/L) would achieve a greater reduction in incidence of cardiovascular events than standard LDL cholesterol lowering to an average of 100 mg/dL (2.6 mmol/L) in patients with ACS.21 Based on data from the CARE trial, it was hypothesized that aggressive statin therapy

The Aggrastat to Zocor trial conflict

Together, the MIRACL and PROVE IT–TIMI 22 studies provide evidence that in patients with ACS, lowering LDL cholesterol levels below those recommended by current guidelines provides greater benefit in terms of reductions in cardiovascular events than does more moderate lowering of LDL cholesterol levels. In the Aggrastat to Zocor (A to Z) trial—a large randomized, double-blind, controlled trial—an intensive statin regimen (simvastatin 40 mg/day for 1 month and then 80 mg/day thereafter [n =

Future studies

On the basis of the results from PROVE IT–TIMI 22, the recent update of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines now suggest that in patients with ACS, an LDL cholesterol goal of <70 mg/dL (<1.8 mmol/L) can be considered.29 However, in other patient populations, such as those with stable coronary artery disease, the effects of aggressive lipid lowering beyond current guideline recommendations also appear to be beneficial. The results from

Summary

Data from PROVE IT–TIMI 22 provided solid evidence in patients with ACS regarding the benefits of intensive lipid-lowering therapy to reduce levels of LDL cholesterol below those previously recommended in national and international guidelines. Thus, it is now recognized that patients with ACS can be considered for treatment to LDL cholesterol goals of <70 mg/dL (<1.8 mmol/L). Treatment to this new goal has the potential to further reduce cardiovascular morbidity and mortality in this patient

References (31)

  • J. Shepherd et al.

    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

    N Engl J Med.

    (1995)
  • J.R. Downs et al.

    Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levelsresults of AFCAPS/TexCAPS [Air Force/Texas Coronary Atherosclerosis Prevention Study]

    JAMA.

    (1998)

  • MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individualsa randomised placebo-controlled trial

    Lancet.

    (2002)

  • Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

    N Engl J Med.

    (1998)
  • J. Genest et al.

    Recommendations for the management of dyslipidemia and the prevention of cardiovascular diseasesummary of the 2003 update

    CMAJ.

    (2003)

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