Transcript ideal - Clinical Trial Results

IDEAL Trial
Incremental Decrease in Clinical Endpoints Through
Aggressive Lipid Lowering (IDEAL) Trial
Presented at
The American Heart Association
Scientific Session 2005
Presented by Dr. Terje Pedersen
IDEAL Trial: Background
• 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.
• In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI22) study of patients recently hospitalized with acute coronary syndromes, aggressive
lipid lowering with 80 mg per day of atorvastatin provided more protection from death
and cardiovascular events than 40 mg per day of pravastatin.
• The Treating to New Targets (TNT) study demonstrated that aggressive lipid
lowering with 80 mg per day of atorvastatin provided greater protection from major
cardiovascular events than low-dose atorvastatin in stable CHD patients.
• On the other hand, the Aggrastat to Zocor (A to Z) trial showed that treatment with
high-dose simvastatin failed to show a significant reduction in the primary composite
endpoint of cardiovascular death, MI readmission for ACS or stroke.
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Presented at AHA 2005
IDEAL Trial: Study Design
8,888 patients ≤80 years with definite history of myocardial infarction and qualified for
stain therapy at time of recruitment
Pts. on statin therapy at baseline: simvastatin (50%), atorvastatin (11%), pravastatin (10%); baseline LDL 121.5 mg/dL;
total cholesterol 196 mg/dL; median time from last MI 21 mos in atorvastatin group, 22 mos in simvastatin group
19% female, mean age 62 yrs, fasting blood samples were obtained at baseline, 12 weeks, 24 weeks, 1 year and each
year thereafter, mean follow-up median of 4.8 years
Randomized
High-dose atorvastatin
Standard-dose simvastatin
80 mg/day
If LDL was <40 mg/dL at 24 wks
dose could be reduced to 40 mg/day
20 mg/day
If cholesterol >190 mg/dL at 24 wks
dose could be increased to 40 mg/day
n=4,439
n=4,449
Primary Endpoint: Composite of major coronary event, defined as coronary death,
hospitalization for non-fatal acute MI or resuscitated cardiac arrest.
Secondary Endpoint: Major cardiovascular events, anyCHD event, hospitalization with a
primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events
and all-cause mortality.
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Presented at AHA 2005
IDEAL Trial: Primary Endpoint
Primary Composite of major coronary event * (%)
p = 0.07
12
10.4
9.3
• The primary composite
endpoint of major
coronary event occurred
in 9.3% of the
atorvastatin group and
10.4% of the simvastatin
group.
%
9
6
3
0
Atorvastatin
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Simvastatin
* Major coronary event defined as coronary
death, hospitalization for non-fatal acute MI
or resuscitated cardiac arrest.
Presented at AHA 2005
IDEAL Trial: Primary Endpoint cont.
• Among the components of the primary endpoint, there was no difference
in CHD death or cardiac arrest with resuscitation, but nonfatal MI occurred
less frequently in the atorvastatin group.
p=0.02
8
7.2
6.0
%
6
4
p=0.90
3.9
4.0
p=NS
2
0.2
0.2
0
CHD death
Cardiac arrest with
resuscitation
Atorvastatin
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Nonfatal MI
Simvastatin
Presented at AHA 2005
IDEAL Trial: Secondary Endpoints
Major cardiovascular events and any
cardiovascular event (%)
p<0.001
32
30.8
26.5
24
• Major cardiovascular
events, defined as any
primary event plus
stroke, occurred less
often in the atorvastatin
group.
%
p=0.02
16
12.0
13.7
8
0
Major CV events
Atorvastatin
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Any CV event
•Any cardiovascular
event, defined as major
CV event plus
hospitalization for CHF
and peripheral artery
disease, also occurred
less often in the
atorvastatin group.
Simvastatin
Presented at AHA 2005
IDEAL Trial: Serious Adverse Events
Serious adverse events and adverse event resulting
in permanent study drug discontinuation (%)
p=0.42
48%
47.4
46.5
40%
%
32%
24%
p<0.001
16%
9.6
8%
4.2
• There was no difference in
the frequency of serious
adverse events, but
adverse event resulting in
permanent drug
discontinuation was more
frequent in the atorvastatin
group.
• Liver enzyme elevation
occurred more frequently in
the atorvastatin group as
did myalgia.
0%
SAE
Atorvastatin
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SAE drug discontinuation
Simvastatin
Presented at AHA 2005
IDEAL Trial: Serious Adverse Events cont.
Liver enzyme elevation and myalgia (%)
2.2%
p<0.001
2%
p<0.001
%
ALT >3x upper
limit of normal
1%
1.1%
0.97%
•Liver enzyme
elevation
occurred more
frequently in the
atorvastatin
group as did
myalgia.
0.11%
0%
Liver Enzyme Elevation
Atorvastatin
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Myalgia
Simvastatin
Presented at AHA 2005
IDEAL Trial: Summary
• Among patients with a previous myocardial infarction, treatment with
high-dose atorvastatin was associated with a directional but nonsignificant reduction in the primary composite endpoint of major
coronary events compared with standard dose simvastatin at five year
follow-up.
• The present trial further extends the evaluation of aggressive lipidlowering to the setting of post-myocardial infarction patients.
• While there was a reduction in the secondary endpoint of recurrent
MI, 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.
www. Clinical trial results.org
Presented at AHA 2005