Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 - PROVE IT/TIMI 22—Lipid Lowering Results

Description:

The goal of the PROVE IT/TIMI 22 trial was to evaluate the efficacy of standard lipid lowering with pravastatin compared with aggressive lipid lowering using atorvastatin in patients hospitalized for an acute coronary syndrome (ACS).

Hypothesis:

Standard lipid lowering with pravastatin will be noninferior to aggressive lipid-lowering therapy using atorvastatin for the composite of all-cause mortality, myocardial infarction (MI), documented unstable angina requiring rehospitalization, revascularization, and stroke in patients hospitalized for an ACS.

Study Design

Patients Enrolled: 4,162
Mean Follow Up: Mean two years
Mean Patient Age: Mean age 58 years
Female: 22

Patient Populations:

Age ≥18 years; hospitalized for an ACS (ST elevation MI, non-ST elevation MI, or high-risk unstable angina) in the prior 10 days; stable condition at time of enrollment; total cholesterol ≤240 mg/dl if not on lipid-lowering therapy or ≤200 mg/dl if on lipid-lowering therapy; and LDL 200-240

Exclusions:

Coexisting condition that shortened expected survival to <2 years or use of any statin at a dose of 80 mg/day at time of index event

Primary Endpoints:

Composite of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke during follow-up

Secondary Endpoints:

Death from coronary heart disease, nonfatal MI, or revascularization (if performed at least 30 days after randomization), death from coronary heart disease or nonfatal MI, and the individual components of the primary endpoint

Drug/Procedures Used:

Patients were randomized in a double-blind, 2 x 2 factorial, parallel-group design to either standard lipid lowering with pravastatin (40 mg/day; n=2,063) or aggressive lipid lowering using atorvastatin (80 mg/day; n=2,099). Patients were then randomized to either the antibiotic gatifloxacin or placebo. Patients were followed for a minimum of 18 months, with a mean duration of 24 months.

Concomitant Medications:

Standard medical and interventional treatment for ACSs, including aspirin (75-325 mg/day) and clopidogrel or warfarin. Treatment with a nonstudy lipid-lowering medication was not allowed.

Principal Findings:

Median time from index event to enrollment in the study was seven days, with 69% of patients having undergone percutaneous coronary intervention (PCI) for the treatment of the index event prior to randomization. The index event was unstable angina in 29% of patients, non-ST segment elevation MI in 36% of patients, and ST elevation MI in 34% of patients. Approximately 25% of patients were on statin therapy at randomization.

Median low-density lipoprotein (LDL) cholesterol level was reduced from 106 mg/dl at baseline in each group to 95 mg/dl in the standard-dose pravastatin group and 62 mg/dl in the high-dose atorvastatin group (p<0.001 for difference in change during follow-up between treatment groups). Median C-reactive protein was reduced from 12.3 mg/l at baseline to 2.1 mg/l in the pravastatin arm and 1.3 mg/l in the atorvastatin arm (p<0.001).

The primary composite endpoint of all-cause mortality, MI, documented unstable angina requiring rehospitalization, revascularization, and stroke at two years occurred in 26.3% in the pravastatin group and 22.4% in the atorvastatin group per Kaplan-Meier estimates (16% relative reduction; p=0.005). The prespecified hypothesis for equivalence was not met, but the criteria for superiority of the more intensive regimen was achieved.

Mortality occurred in 3.2% of patients in the pravastatin arm and 2.2% of patients in the atorvastatin arm (28% risk reduction, p=0.07). The composite of death from coronary heart disease, MI, or revascularization was higher in the pravastatin arm (22.3% vs. 19.7%, 14% risk reduction, p=0.0004), as was unstable angina requiring rehospitalization (5.1% vs. 3.8%, 29% risk reduction). There was no difference in stroke (1.0% each). Alanine aminotransferase levels ≥3 times the upper limit of normal were higher in the atorvastatin arm (3.3% vs. 1.1%, p<0.001).

Interpretation:

Among patients hospitalized for an ACS, use of an aggressive lipid-lowering strategy was associated with a reduction in the primary composite endpoint of all-cause mortality, MI, documented unstable angina requiring rehospitalization, revascularization, and stroke at two-year follow-up compared with standard lipid-lowering strategy.

Prior studies have demonstrated clinical improvements associated with standard dose statin compared with placebo, but the present study is the first large-scale trial to demonstrate an added clinical benefit of a more intensive lipid-lowering therapy in post-ACS patients beyond the current guidelines of LDL <100 mg/dl. Given the different doses used in the treatment arms, it is unclear if the benefit is fully derived from the additional reduction in LDL or if it is due to potential nonlipid differences between the statins.

Additional trials comparing differing doses of an individual statin would help to clarify whether the clinical benefit was due to the dose of the statin or differences between the statins. The benefit of such an aggressive approach to lipid lowering among patients with chronic coronary artery disease is not addressed by this study.

References:

Presented by Dr. Christopher P. Cannon at the American College of Cardiology Annual Scientific Session, March 2004.

Cannon CP, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease, Chronic Angina

Keywords: Coronary Artery Disease, Kaplan-Meier Estimate, Follow-Up Studies, Angina, Stable, Vitamins, Research Personnel, Uncertainty, Stroke, Myocardial Infarction, Acute Coronary Syndrome, Plaque, Atherosclerotic, Cholesterol, LDL, Risk Reduction Behavior, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Heptanoic Acids, Simvastatin, Fluoroquinolones, Percutaneous Coronary Intervention, Pyrroles, Trinitrotoluene, C-Reactive Protein, Pravastatin


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