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The primary Objective of IDEAL

LDL-C

Simvastatin 20-40 mg/d Atorvastatin 80 mg/d

risk CHD

In stable CHD patients

IDEAL: The Incremental Decrease in End Points through Aggressive Lipid Lowering CHD: coronary heart disease.

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• Reduction in the primary endpoint was not statistically significant.

• Reduction in the secondary endpoint was statistically significant in favor of atorvastatin.

• No statistically significant differences were seen in all-cause mortality, cardiovascular mortality, or noncardiovascular mortality between the 2

treatment groups .

Results of the IDEAL Study :

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Methods

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Study design

• Multicenter.• Prospective.• Randomized.• Open-label.• Blinded end-point classification trial

(PROBE design)

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March 1999- March 2001

9,689 screened 416 246 unwilling to participate 14 lost to follow-up 125 other

8888 randomized

4449 Simvastatin 20 mg/d 4439 atorvastatin 80 mg/d

Men + women aged 80 years or younger

with a history of a definite MI.

and qualified for statin therapy .

801 excluded

• Contraindications.• Previous intolerance to low/high doses.• Liver enzyme levels >2 times the normal.• Pregnancy or breastfeeding.• Nephrotic syndrome.• Uncontrolled D.M.• Uncontrolled hypothyroidism.• Plasma TG > 600 mg/dL(6.8 mmol/L).• CHF.• GIT conditions affecting absorption of

drugs.• Hemodynamically VHD.• Treatment with other drugs that seriously

.affect the pharmacokinetics of statins.• Treatment with other lipid lowering drugs

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Follow-up

Patients were followed up at the centers after : 12 and 24 weeks and every 6 months thereafter.

• If, at 24 wks, plasma total cholesterol level was > 190mg/dl ( 5 mmol/L)The dose of Simvastatin may be to 40 mg / d

• If the atorvastatin group experience adverse effects :The dose may to 40 mg/d

•LDL-C decreased to less than 39 mg/dL (1.0 mmol/L), an investigator would be notified and could consider reducing the statin dose.

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Study outcomes

Primary clinical outcome : was time to first occurrence of a major coronary eventmajor coronary event,

defined as :• Coronary death.

• Hospitalization for nonfatal acute MI , or cardiac arrest

with resuscitation.

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Cont’.Secondary clinical outcomes : (1) Major cardiovascular events :• Any primary event + stroke.

(2) Any CHD event :• Any primary event.• Any coronary revascularization procedure.• Hospitalization for unstable angina.

(3) Any cardiovascular events :• Hospitalization with a primary diagnosis of CHF and PAD, defined as

new clinical diagnosis or hospitalization for such disease.• All cause mortality.

CFH: congestive heart failure .PAD: peripheral arterial disease.

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Results

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250 (6 %)

40 mg/d

900 (21%)

40 mg/d

At 24 weeks of follow-up

Simvastatin Atorvastatin

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587 (13%)

40 mg/d

1034 (23%)

40 mg/d

At the end

Simvastatin Atorvastatin

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Most patients who stopped taking study drug switched to a different statin

At the end

Simvastatin7 %

Atorvastatin14%

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Simvastatin Atorvastatin

During treatment (LDL-C level)

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Comments

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1. Insufficient difference in levels of LDL-C between the groups since the observed difference was slightly smaller than projected.

2. The follow-up duration was only a median of 4.8 years even though the study protocol anticipated the prespecified number of primary end points to be reached after a median of 5.5 years.

3. The effect of simvastatin on HDL-C would attenuate the difference produced by the improved effect of atorvastatin on LDL-C.

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Design and Adherence

1. The IDEAL study was carried out with the PROBE design and, thus, did not have the advantages of a double-blind trial.2. The end-point classification was conducted

by a blinded clinical end-points committee with the idea of minimizing bias.

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3. The open-label design with prescription of study medication had the advantage of being more like a “real-world” setting, but the possibility of bias for some of the physician-initiated end points, such as coronary revascularization and hospitalization for unstable angina, cannot be excluded.

4. The fact that most patients had to pay part of the cost of the study drug apparently did not affect prescription rates, because the cost for the patients of the 2 study drugs was identical.

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Comparison With Other Trials

A recent prospective meta-analysis of 14 cholesterol-lowering statin trials with more than 90 000 patients found a 23% proportional reduction in the incidence of major coronary events and a 21% proportional reduction in the incidence of major cardiovascular events per 1 mmol/L of LDL-C reduction.

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Conclusion

When comparing standard and intensive LDL-C–lowering therapies in patients with previous myocardial infarction, there was no statistically significant reduction in the primary end point of major coronary events, but there was reduced risk of other composite secondary end points and nonfatal acute myocardial infarction.

There were no differences in cardiovascular and all-cause mortality. The results indicate that patients with myocardial infarction may benefit from intensive lowering of LDL-C without increase in noncardiovascular mortality or other serious adverse reactions.

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Criticism

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Pharmacokinetics Effect on lipids

Atorvastatin Simvastatin

First-Pass Hepatic Extraction (%) 40-70 50-80

Systemic Bioavailability (%) 14 < 5

Known Metabolizing Enzymes CYP3A4 CYP3A4

Active Metabolites Yes Yes

Protein Binding (%) 98 95

Half-life (hours) 13-16 3

Renal Excretion (%) < 2 13

LDL-C - 39-60 % * - 24-47% **

HDL + 5-9% + 8-12

TGL -19-52% - 10-36%

* Dose 10-80 mg / day **Dose 10 -80 mg / day

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