Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering - IDEAL
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.
Patients Screened: 9,689
Patients Enrolled: 8,888
Mean Follow Up: Median 4.8 years
Mean Patient Age: Mean 62 years
Age ≤80 years, definite history of myocardial infarction, qualified for statin therapy according to national guidelines at the time of recruitment.
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.
Major coronary event, defined as coronary death, hospitalization for non-fatal acute myocardial infarction or resuscitated cardiac arrest.
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.
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.
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).
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.
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, 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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