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CLINICAL RESEARCH: LIPID-LOWERING THERAPY

Baseline Low-Density Lipoprotein Cholesterol Is an Important Predictor of the Benefit of Intensive Lipid-Lowering Therapy

A PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) Analysis

TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Manuscript received April 4, 2008; revised manuscript received May 12, 2008, accepted May 12, 2008.

^_* Reprint requests and correspondence: Dr. Robert P. Giugliano, TIMI Study Office, 350 Longwood Avenue, 1st Floor Offices, Boston, Massachusetts 02115 (Email: rgiugliano{at}partners.org).

Objectives: This study sought to determine whether the benefit of intensive lipid-lowering therapy (LLT) is dependent on baseline low-density lipoprotein cholesterol (LDL-C).

Background: Aggressive LDL-C reduction with statins improves cardiovascular outcomes in acute and chronic coronary heart disease (CHD). The importance of baseline LDL-C is unclear.

Methods: We compared 2-year composites of death, myocardial infarction (MI), unstable angina, revascularization >30 days, and stroke (primary end point), and CHD death, MI, and revascularization >30 days (secondary end point) in 2,986 statin-naïve patients with recent acute coronary syndrome (ACS) randomized to atorvastatin 80 mg versus pravastatin 40 mg in the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) study stratified by quartiles of baseline LDL-C. Multivariable models assessed whether the treatment benefit was dependent on baseline LDL-C.

Results: A significant reduction in the hazards of the primary (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.47 to 0.85, p = 0.002) and secondary (HR: 0.57, 95% CI: 0.42 to 0.79, p = 0.001) end points occurred in patients within the highest quartile (>132 mg/dl) of baseline LDL-C treated with atorvastatin 80 mg. The benefit of intensive therapy progressively declined as baseline LDL-C decreased. The lowest quartile (LDL-C 92 mg/dl) experienced similar rates of the primary (HR: 0.93, 95% CI: 0.69 to 1.25, p = 0.63) and secondary (HR: 0.98, 95% CI: 0.71 to 1.35, p = 0.89) end points. Adjusted interaction tests between treatment and highest versus lowest baseline LDL-C quartile were significant for the primary and secondary end points (p = 0.03 and p = 0.007, respectively). Analyzing baseline LDL-C as a continuous variable, atorvastatin 80 mg was associated with improved outcomes provided the baseline LDL-C was >66 mg/dl.

Conclusions: A progressive reduction in the benefit of intensive LLT with atorvastatin 80 mg over pravastatin 40 mg occurred in statin-naïve ACS patients as baseline LDL-C declined. (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 [PROVE IT–TIMI 22]; NCT00382460)

Key Words: LDL-C • lipid-lowering therapy • atorvastatin • pravastatin • outcomes

Abbreviations and Acronyms   ACS = acute coronary syndromes   CABG = coronary artery bypass graft   CHD = coronary heart disease   CI = confidence interval   HDL-C = high-density lipoprotein cholesterol   HR = hazard ratio   LDL-C = low-density lipoprotein cholesterol   MI = myocardial infarction   NCEP = National Cholesterol Education Program   PCI = percutaneous coronary intervention

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