The IDEAL Cholesterol

Incremental Decrease in Clinical Endpoints Through Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) TrialAggressive Lipid Lowering (IDEAL) Trial

Incremental Decrease in Clinical Endpoints Through Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) TrialAggressive Lipid Lowering (IDEAL) Trial

IDEAL TrialIDEAL TrialIDEAL TrialIDEAL Trial

Presented atPresented atThe American Heart AssociationThe American Heart Association

Scientific Session 2005Scientific Session 2005

Presented by Dr. Terje PedersenPresented by Dr. Terje Pedersen

www. Clinical trial results.org

IDEAL Trial: BackgroundIDEAL Trial: BackgroundIDEAL Trial: BackgroundIDEAL Trial: Background

• Several recent studies have evaluated a regimen of high-dose statin compared with 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 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.coronary syndromes, including TNT, PROVE-IT TIMI-22 and A to Z.

• In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI-In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI-22) study of patients recently hospitalized with acute coronary syndromes, aggressive 22) study of patients recently hospitalized with acute coronary syndromes, aggressive lipid lowering with 80 mg per day of atorvastatin provided more protection from death lipid lowering with 80 mg per day of atorvastatin provided more protection from death and cardiovascular events than 40 mg per day of pravastatin.and cardiovascular events than 40 mg per day of pravastatin.

• The Treating to New Targets (TNT) study demonstrated that aggressive lipid The Treating to New Targets (TNT) study demonstrated that aggressive lipid lowering with 80 mg per day of atorvastatin provided greater protection from major lowering with 80 mg per day of atorvastatin provided greater protection from major cardiovascular events than low-dose atorvastatin in stable CHD patients.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 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 high-dose simvastatin failed to show a significant reduction in the primary composite endpoint of cardiovascular death, MI readmission for ACS or stroke.endpoint of cardiovascular death, MI readmission for ACS or stroke.

Presented at AHA 2005Presented at AHA 2005


High-dose atorvastatinHigh-dose atorvastatin80 mg/day80 mg/day

If LDL was <40 mg/dL at 24 wks If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/daydose could be reduced to 40 mg/day

n=4,439n=4,439

High-dose atorvastatinHigh-dose atorvastatin80 mg/day80 mg/day

If LDL was <40 mg/dL at 24 wks If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/daydose could be reduced to 40 mg/day

n=4,439n=4,439

Primary Endpoint:Primary Endpoint: Composite of major coronary event, defined as coronary death, Composite of major coronary event, defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest.hospitalization for non-fatal acute MI or resuscitated cardiac arrest.

Secondary Endpoint:Secondary Endpoint: Major cardiovascular events, anyCHD event, hospitalization with a Major cardiovascular events, anyCHD event, hospitalization with a primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events and all-cause mortality.and all-cause mortality.

Primary Endpoint:Primary Endpoint: Composite of major coronary event, defined as coronary death, Composite of major coronary event, defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest.hospitalization for non-fatal acute MI or resuscitated cardiac arrest.

Secondary Endpoint:Secondary Endpoint: Major cardiovascular events, anyCHD event, hospitalization with a Major cardiovascular events, anyCHD event, hospitalization with a primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events and all-cause mortality.and all-cause mortality.

IDEAL Trial: Study DesignIDEAL Trial: Study DesignIDEAL Trial: Study DesignIDEAL Trial: Study Design


Standard-dose simvastatinStandard-dose simvastatin20 mg/day20 mg/day

If cholesterol >190 mg/dL at 24 wks If cholesterol >190 mg/dL at 24 wks dose could be increased to 40 mg/daydose could be increased to 40 mg/day

n=4,449n=4,449

Standard-dose simvastatinStandard-dose simvastatin20 mg/day20 mg/day

If cholesterol >190 mg/dL at 24 wks If cholesterol >190 mg/dL at 24 wks dose could be increased to 40 mg/daydose could be increased to 40 mg/day

n=4,449n=4,449

8,888 patients 8,888 patients ≤80 years ≤80 years with definite history of myocardial infarction and qualified for with definite history of myocardial infarction and qualified for

stain therapy at time of recruitmentstain therapy at time of recruitment Pts. on statin therapy at baseline: simvastatin (50%), atorvastatin (11%), pravastatin (10%); baseline LDL 121.5 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 mg/dL; total cholesterol 196 mg/dL; median time from last MI 21 mos in atorvastatin group, 22 mos in simvastatin group group

19% female, mean age 62 yrs, fasting blood samples were obtained at baseline, 12 weeks, 24 weeks, 1 year and each 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 yearsyear thereafter, mean follow-up median of 4.8 years

RandomizedRandomized

8,888 patients 8,888 patients ≤80 years ≤80 years with definite history of myocardial infarction and qualified for with definite history of myocardial infarction and qualified for

stain therapy at time of recruitmentstain therapy at time of recruitment Pts. on statin therapy at baseline: simvastatin (50%), atorvastatin (11%), pravastatin (10%); baseline LDL 121.5 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 mg/dL; total cholesterol 196 mg/dL; median time from last MI 21 mos in atorvastatin group, 22 mos in simvastatin group group

19% female, mean age 62 yrs, fasting blood samples were obtained at baseline, 12 weeks, 24 weeks, 1 year and each 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 yearsyear thereafter, mean follow-up median of 4.8 years

RandomizedRandomized


IDEAL Trial: Primary EndpointIDEAL Trial: Primary EndpointIDEAL Trial: Primary EndpointIDEAL Trial: Primary Endpoint

9.310.4

0

3

6

9

12

Atorvastatin Simvastatin

9.310.4

0

3

6

9

12


• The primary composite The primary composite endpoint of major endpoint of major coronary event occurred coronary event occurred in 9.3% of the in 9.3% of the atorvastatin group and atorvastatin group and 10.4% of the simvastatin 10.4% of the simvastatin group.group.

Primary Composite of major coronary event * (%)Primary Composite of major coronary event * (%)p = 0.07p = 0.07


%%

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


IDEAL Trial: Primary Endpoint cont.IDEAL Trial: Primary Endpoint cont.IDEAL Trial: Primary Endpoint cont.IDEAL Trial: Primary Endpoint cont.%%


3.9

0.2

6.0

4.0

0.2

7.2

0

2

4

6

8

CHD death Cardiac arrest withresuscitation

Nonfatal MI


3.9

0.2

6.0

4.0

0.2

7.2

0

2

4

6

8

CHD death Cardiac arrest withresuscitation

Nonfatal MI


p=NSp=NS

p=0.02p=0.02

p=0.90p=0.90

• Among the components of the primary endpoint, there was no difference Among the components of the primary endpoint, there was no difference in CHD death or cardiac arrest with resuscitation, but nonfatal MI occurred in CHD death or cardiac arrest with resuscitation, but nonfatal MI occurred less frequently in the atorvastatin group.less frequently in the atorvastatin group.


IDEAL Trial: Secondary EndpointsIDEAL Trial: Secondary EndpointsIDEAL Trial: Secondary EndpointsIDEAL Trial: Secondary Endpoints

12.0

26.5

13.7

30.8

0

8

16

24

32

Major CV events Any CV event


12.0

26.5

13.7

30.8

0

8

16

24

32

Major CV events Any CV event


• Major cardiovascular Major cardiovascular events, defined as any events, defined as any primary event plus primary event plus stroke, occurred less stroke, occurred less often in the atorvastatin often in the atorvastatin group.group.

•Any cardiovascular Any cardiovascular event, defined as major event, defined as major CV event plus CV event plus hospitalization for CHF hospitalization for CHF and peripheral artery and peripheral artery disease, also occurred disease, also occurred less often in the less often in the atorvastatin group.atorvastatin group.

Major cardiovascular events and any Major cardiovascular events and any cardiovascular event (%)cardiovascular event (%)


%%

p=0.02

p<0.001


IDEAL Trial: Serious Adverse Events IDEAL Trial: Serious Adverse Events IDEAL Trial: Serious Adverse Events IDEAL Trial: Serious Adverse Events


9.6

46.5

4.2

47.4

0%

8%

16%

24%

32%

40%

48%

SAE SAE drug discontinuation


9.6

46.5

4.2

47.4

0%

8%

16%

24%

32%

40%

48%

SAE SAE drug discontinuation


• There was no difference in There was no difference in the frequency of serious the frequency of serious adverse events, but adverse adverse events, but adverse event resulting in event resulting in permanent drug permanent drug discontinuation was more discontinuation was more frequent in the atorvastatin frequent in the atorvastatin group.group.• Liver enzyme elevation Liver enzyme elevation occurred more frequently in occurred more frequently in the atorvastatin group as the atorvastatin group as did myalgia.did myalgia.

%%

p=0.42p=0.42

p<0.001p<0.001

Serious adverse events and adverse event resulting Serious adverse events and adverse event resulting in permanent study drug discontinuation (%)in permanent study drug discontinuation (%)


IDEAL Trial: Serious Adverse Events cont. IDEAL Trial: Serious Adverse Events cont. IDEAL Trial: Serious Adverse Events cont. IDEAL Trial: Serious Adverse Events cont.


2.2%

0.97%1.1%

0.11%

0%

1%

2%

Liver Enzyme Elevation Myalgia


2.2%

0.97%1.1%

0.11%

0%

1%

2%

Liver Enzyme Elevation Myalgia


•Liver enzyme Liver enzyme elevation elevation occurred more occurred more frequently in the frequently in the atorvastatin atorvastatin group as did group as did myalgia.myalgia.

%%

p<0.001p<0.001

ALT >3x upper ALT >3x upper limit of normallimit of normal

p<0.001p<0.001

Liver enzyme elevation and myalgia (%)Liver enzyme elevation and myalgia (%)


IDEAL Trial: SummaryIDEAL Trial: SummaryIDEAL Trial: SummaryIDEAL Trial: Summary

• Among patients with a previous myocardial infarction, treatment with Among patients with a previous myocardial infarction, treatment with

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

• The present trial further extends the evaluation of aggressive lipid-The present trial further extends the evaluation of aggressive lipid-lowering to the setting of post-myocardial infarction patients.lowering to the setting of post-myocardial infarction patients.

• While there was a reduction in the secondary endpoint of recurrent While there was a reduction in the secondary endpoint of recurrent MI, adverse events and liver enzyme elevations were more frequent in MI, adverse events and liver enzyme elevations were more frequent in the high-dose atorvastatin group, highlighting the need for careful the high-dose atorvastatin group, highlighting the need for careful monitoring of patients on this regimen.monitoring of patients on this regimen.

• Among patients with a previous myocardial infarction, treatment with Among patients with a previous myocardial infarction, treatment with

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

• The present trial further extends the evaluation of aggressive lipid-The present trial further extends the evaluation of aggressive lipid-lowering to the setting of post-myocardial infarction patients.lowering to the setting of post-myocardial infarction patients.

• While there was a reduction in the secondary endpoint of recurrent While there was a reduction in the secondary endpoint of recurrent MI, adverse events and liver enzyme elevations were more frequent in MI, adverse events and liver enzyme elevations were more frequent in the high-dose atorvastatin group, highlighting the need for careful the high-dose atorvastatin group, highlighting the need for careful monitoring of patients on this regimen.monitoring of patients on this regimen.


Documents

The IDEAL Cholesterol