Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering - IDEAL

Description:

The goal of the trial was to evaluate treatment with high dose atorvastatin compared with treatment with simvastatin on the risk of cardiovascular disease among patients with a previous myocardial infarction.

Study Design

Study Design:

Patients Screened: 9,689
Patients Enrolled: 8,888
Mean Follow Up: Median 4.8 years
Mean Patient Age: Mean 62 years
Female: 19

Patient Populations:

Age ≤80 years, definite history of myocardial infarction, qualified for statin therapy according to national guidelines at the time of recruitment.

Exclusions:

Known contraindications to statin therapy, previous intolerance to statins in low or high doses, liver enzymes >two times the upper limit of normal, pregnancy or breast-feeding, nephrotic syndrome, uncontrolled diabetes mellitus, uncontrolled hypothyreoidism, plasma triglycerides >600 mg/dL, congestive heart failure, hemodynamically important valvular heart disease, gastrointestinal conditions affecting absorption of drugs, treatment with other drugs that seriously affected the pharmacokinetics of statins, and other lipid-lowering drugs.

Primary Endpoints:

Major coronary event, defined as coronary death, hospitalization for non-fatal acute myocardial infarction or resuscitated cardiac arrest.

Secondary Endpoints:

Major cardiovascular events (any primary event plus stroke), any CHD event (any primary event, any coronary revascularization procedure, or hospitalization for unstable angina), hospitalization with a primary diagnosis of congestive heart failure, peripheral arterial disease, any cardiovascular events (any of the former) and all-cause mortality.

Drug/Procedures Used:

Patients were randomized to high-dose atorvastatin (80 mg/day; n=4,439) or standard-dose simvastatin (20 mg/day; n=4,449). Patients were followed for a median of 4.8 years. Fasting blood samples were obtained at baseline, 12 weeks, 24 weeks, 1 year, and each year thereafter. Laboratory measures were performed at a central laboratory. If total cholesterol was greater than 190 mg/dL at 24 weeks, the dose of simvastatin could be increased to 40 mg/day. If LDL was less than 40 mg/dL, the dose of atorvastatin could be reduced to 40 mg/day.

Principal Findings:

A large majority of patients were on statin therapy at baseline, including simvastatin (50%), atorvastatin (11%), and pravastatin (10%). Baseline LDL was 121.5 mg/dL, and total cholesterol was 196 mg/dL. Median time from last MI was 21 months in the atorvastatin group and 22 months in the simvastatin group. Simvastatin dose was increased to 40 mg/day following the 24 week visit in 21% of patients.

At one year, the reduction in LDL was greater in the atorvastatin group by 22.9 mg/dL, to 79.1 mg/dL in the atorvastatin group and 102.0 mg/dL in the simvastatin group. Likewise, the reduction in total cholesterol was greater in the atorvastatin group by -28.7 mg/dL, to 147.4 mg/dL in the atorvastatin group and 175.9 mg/dL in the simvastatin group.

The primary composite endpoint of major coronary event occurred in 9.3% of the atorvastatin group and 10.4% of the simvastatin group (hazard ratio [HR] 0.89, p=0.07). Among the components of the composite, there was no difference in CHD death (3.9% vs 4.0%, p=0.90) or cardiac arrest with resuscitation (0.2% each), but nonfatal MI occurred less frequently in the atorvastatin group (6.0% vs 7.2%, p=0.02). Major cardiovascular events, defined as any primary event plus stroke, occurred less often in the atorvastatin group (12.0% vs 13.7%, HR 0.87, p=0.02). Any cardiovascular event, defined as major CV event plus hospitalization for CHF and peripheral artery disease, also occurred less often in the atorvastatin group (26.5% vs 30.8%, HR 0.84, p<0.001).

There was no difference in the frequency of serious adverse events (46.5% for atorvastatin vs 47.4% for simvastatin, p=0.42), but adverse event resulting in permanent study drug discontinuation was more frequent in the atorvastatin group (9.6% vs 4.2%, p<0.001). Liver enzyme elevation occurred more frequently in the atorvastatin group (ALT >3x upper limit of normal 0.97% vs 0.11%, p<0.001), as did myalgia (2.2% vs 1.1%, p<0.001).

Interpretation:

Among patients with a previous myocardial infarction, treatment with high-dose atorvastatin was associated with a directional but non-significant reduction in the primary composite endpoint of major coronary events compared with standard dose simvastatin at five year follow-up.

Several recent studies have evaluated a regimen of high-dose statin compared with a lower-dose, usual care statin regimen in the setting of stable or unstable acute coronary syndromes, including TNT, PROVE-IT TIMI 22, and A to Z. The present trial further extends these findings to the setting of post-myocardial infarction patients. While the primary endpoint did not reach statistical significance, other endpoints such as MI were lower in the high-dose atorvastatin group. These findings were observed despite a high rate of statin use at entry into the study. While there were some efficacy improvements, adverse events and liver enzyme elevations were more frequent in the high-dose atorvastatin group, highlighting the need for careful monitoring of patients on this regimen.

References:

Pedersen TR, et al. High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction. JAMA. 2005;294:2437-2445.

Presented by Dr. Terje Pedersen at the American Heart Association Scientific Session, Dallas, Texas, November 2005.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Dyslipidemia, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Myocardial Infarction, Stroke, Acute Coronary Syndrome, Resuscitation, Follow-Up Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peripheral Arterial Disease, Heptanoic Acids, Heart Arrest, Simvastatin, Pyrroles, Cholesterol, Trinitrotoluene, Pravastatin, Myalgia


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