IDEAL:
Incremental Decrease In
End Points Through
Aggressive Lipid Lowering
The IDEAL Steering Committee
And Investigators
Background
CVD: A Major Global
Health Issue
• CHD and stroke are two major components of CVD
• 16.7 million worldwide die each year from CVD
• CVD affects 34.2% of US population
• Elevated plasma lipids are one of the most prevalent
risk factors for CVD
American Heart Association. Heart Disease and Stroke Statistics - 2005 Update. Available at:
http://www.americanheart.org/downloadable/heart/1105390918119HDSStats2005Update.pdf. Accessed 11/9/05.
World Health Organization. The Atlas of Heart Disease and Stroke. Available at:
http://www.who.int/cardiovascular_diseases/resources/atlas/en/. Accessed 11/3/05.
2
Although CVD-Related Deaths Remain
High, the CVD-Related Death Rate Is
Decreasing
US 1979-2002
600
1000
500
800
400
600
300
400
200
200
100
0
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Annual CVD Deaths x1000 (bar)
1st Statin Introduced
Year
NCEP ATP II
NCEP ATP I
There are nearly 1 million CVD-related deaths each year
0
CVD Deaths/100,000 Population (line)
1200
NCEP ATP III
Adapted from National Institutes of Health. Morbidity & Mortality: 2004 Chart Book on Cardiovascular, Lung, and Blood
Diseases. Available at: http://www.nhlbi.nih.gov/resources/docs/04_chtbk.pdf. Accessed 11/9/05; Mevacor approval history.
Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed December 8, 2005; Expert Panel. Arch Intern
Med. 1988;148:36–69; Expert Panel. JAMA. 1993;269:3015–3023; Expert Panel. JAMA. 2001;285:2486-2497.
3
Global Economic Impact of CVD
Global
• CVD = leading cause of mortality and disability
European Union
• Costs = €168.9 billion for CVD in 2003, of which €45.0 billion
was for treating CHD
United States
• CVD = single greatest economic burden on health care system
• Costs = $393.5 billion for CVD in 2005
– Total costs for all cancers = $190 billion in 2004
American Heart Association. Heart Disease and Stroke Statistics - 2005 Update. Available at:
http://www.americanheart.org/downloadable/heart/1105390918119HDSStats2005Update.pdf. Accessed 11/9/05; British Heart
Foundation. Total Costs of CVD in Europe. Available at: http://www.heartstats.org/topic.asp?id=4545. Accessed 11/3/05; Bonow
RO et al. Circulation. 2002;106:1602-1605.
4
Elevated Cholesterol Levels
Associated With High Risk of CHD
18
16
14
12
10
8
6
4
2
0
140 160 180 200 220 240 260 280 300 320
Framingham Study
(N=5209)
6-Year CHD Incidence
Per 1000 Men
Age-Adjusted 6-Year CHD
Mortality Per 1000 Men
Multiple Risk Factor Intervention Trial
(MRFIT) (N=361,662)
150
125
100
75
50
25
0
204 205-234 235-264 265-294
Total Cholesterol (mg/dL)
Each 1% Reduction in Total Cholesterol Level
Resulted in a 2% Decrease in CHD Risk
295
Total Cholesterol (mg/dL)
Each 1% Increase in Total Cholesterol Level
Associated With a 2% Increase in CHD Risk
Adapted from Martin MJ et al. Lancet. 1986;2:933-936, with permission.
Reproduced from Castelli WP. Am J Med. 1984;76:4-12, with permission.
5
Evolution of Guidelines Driven
By Clinical Evidence
First Joint
European
1994
NCEP
ATP I
1988
1980s
Early Data
Framingham 1981
Atherosclerosis Study
Group 1984
LRC-CPPT 1984
MRFIT 1986
Coronary Drug Project 1986
Helsinki Heart Study 1987
Second Joint
European
1998
NCEP
ATP II
1994
1990s
Angiographic Trials
CLAS 1987
FATS 1990
POSCH 1990
Lifestyle Heart Trial 1990
STARS 1992
Meta-Analyses
NCEP
ATP III
2001
Third Joint
European
2003
NCEP
Report
2004
2000s
Outcomes Trials
4S 1994
WOSCOPS 1995
CARE 1996
LIPID 1998
AFCAPS/TexCAPS 1998
VA-HIT 1999
Recent Data
TNT 2005
IDEAL 2005
HPS 2002
ALLHAT 2002
PROSPER 2002
ASCOT-LLA 2003
PROVE IT 2004
CARDS 2004
Holme 1990
Rossouw 1991
6
Current Lipid Treatment
Guidelines
The Primary Focus of Treatment Guidelines Is to Reduce LDL-C
NCEP Guidelines
• Low risk:
LDL-C <160 mg/dL
• Moderate risk:
LDL-C <130 mg/dL for individuals with
2 risk factors
• High risk:
LDL-C <100 mg/dL for individuals with
CHD or CHD equivalents
• Very high risk (optional):
LDL-C <70 mg/dL for high-risk
individuals (eg, those with CHD
and diabetes)
European Guidelines
• LDL-C <100 mg/dL for at-risk
individuals
• <100 mg/dL for high-risk
individuals (eg, those with
diabetes)
• Triglycerides:
secondary target for lowering
• HDL-C:
secondary target for raising
Expert Panel. JAMA. 2001;285:2486-2497; Grundy SM et al. Circulation. 2004;110:227-239; De Backer G et al. Eur Heart J.
2003;24:1601-1610.
7
4S to IDEAL
11 Years of Landmark Statin Trials
1994
4S
1995
WOSCOPS
1996
CARE
1998
AFCAPS/TexCAPS
LIPID
2001
2002
MIRACL
HPS
PROSPER
ALL-HAT LLT
ASCOT-LLA
PROVE IT
ALLIANCE
CARDS
A to Z
2003
2004
2005
TNT
IDEAL
Early Trials Proved Relative Risk
Reduction in Morbidity and Mortality
vs Placebo
Second Wave of Trials
• Focus on other high-risk groups
– ACS, elderly, DM, HTN
• Comparisons beyond placebo
– vs usual care (ALLIANCE, ALL-HAT)
– active comparator (PROVE IT, A to Z)
Intensity of Statin Treatment in Stable CHD
Patients Receiving
Contemporary Therapy
8
4S Proved 2º Prevention With Statins
Could Lower Mortality and CV Events
Primary End Point:
Total Mortality
Secondary End Point:
Major Coronary Events*
1.00
Proportion Alive
Simvastatin
0.95
30% RRR
0.90
Placebo
P=.0003
0.85
0.80
0
1
2
3
4
5
6
Years Since Randomization
Proportion Without Major
Coronary Event
1.00
Simvastatin
0.90
0.80
34% RRR
Placebo
0.70
P=.00001
0.60
0.50
0
1
2
3
4
5
6
Years Since Randomization
* Defined as coronary death, nonfatal definite or probable MI, silent MI, or resuscitated cardiac arrest.
Reproduced from Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389, with permission.
9
4S Left Important Questions To Be
Answered By Subsequent Trials In
Secondary Prevention
1994
1995–2005
Confirmation
of 4S Findings
 CARE
 LIPID
Finding the Optimal
LDL-C Target
 HPS
 TNT
Benefit of Early Start
in ACS Patients
(excluded in 4S)
 MIRACL
 PROVE IT
 A to Z
Evolving
Standard Therapy
 IDEAL
10
LDL-C Level at Beginning and
End of Therapy (mg/dL)
Usual-Dose Statin Therapy Established
As Standard for CHD Patients
Regardless of Baseline LDL-C
Statin vs Placebo
190
170
150
130
110
90
70
50
Relative Risk
Reduction*
Event Rate*
On Statin
4S
Simvastatin
20 mg
LIPID
Pravastatin
40 mg
CARE
Pravastatin
40 mg
HPS
Simvastatin
40 mg
34%
24%
24%
27%
19.0%
12.3%
10.2%
8.7%
*End points cited (not primary end points): 4S and TNT=CHD death, nonfatal MI, and cardiac resuscitation; LIPID, CARE, and
HPS=CHD death and nonfatal MI.
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Long-Term Intervention with Pravastatin in
Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al. N Engl J Med. 1996;335:10011009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
11
LDL-C Level at Beginning and
End of Therapy (mg/dL)
TNT Reached Lower LDL-C Levels
With Intensive Therapy
Intensive vs Usual-Dose
Lipid Lowering
Statin vs Placebo
190
170
150
130
110
90
70
50
Relative Risk
Reduction*
Event Rate*
On Statin
4S
Simvastatin
20 mg
LIPID
Pravastatin
40 mg
CARE
Pravastatin
40 mg
HPS
Simvastatin
40 mg
TNT
Atorvastatin
10 mg
TNT
Atorvastatin
80 mg
34%
24%
24%
27%
NA
20%
19.0%
12.3%
10.2%
8.7%
8.3%
6.7%
*End points cited (not primary end points): 4S and TNT=CHD death, nonfatal MI, and cardiac resuscitation; LIPID, CARE, and
HPS=CHD death and nonfatal MI. Atorvastatin is not indicated for secondary prevention of CHD.
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Long-Term Intervention with Pravastatin in
Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al. N Engl J Med. 1996;335:
1001-1009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; LaRosa JC et al. N Engl J Med.
2005;352:1425-1435.
12
TNT Primary End Point:
Time to First Major CV Event*
15
Atorvastatin 10 mg
Major CV Event (%)
Atorvastatin 80 mg
22% RRR
10
5
HR = 0.78, P<.001
0
0
1
2
3
4
Time (years)
5
6
*CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from LaRosa JC et al. N Engl J Med. 2005;352:1425-1435, with permission.
13
4S Left Important Questions to Be
Answered by Subsequent Trials In
Secondary Prevention
1994
1995–2005
Confirmation
of 4S Findings
 CARE
 LIPID
Finding the Optimal
LDL-C Target
 HPS
 TNT
Benefit of Early Start
in ACS Patients
(excluded in 4S)
 MIRACL
 PROVE IT
 A to Z
Evolving
Standard Therapy
 IDEAL
14
Of The 5 Major ACS Trials, Only MIRACL
and PROVE IT Showed a Significant
Benefit in Patients With ACS
Treatment
Initiated
Within
N
Risk
Reduction
Follow- (%) In 1º
Up
End Point
P
Value
Study
Intervention
FLORIDA
Fluva 80 mg
vs placebo
8 days
540
1 year
8
NS
Prava 20/40 mg
vs placebo
24 hours
3408
30 days
6.4
NS
Simva 40/80 mg
vs placebo/simva 20 mg
5 days to
4 months
4497
2 years
11
NS
Atorva 80 mg
vs placebo
24–96 hours
3086
16 weeks
16
.048
Atorva 80 mg
vs prava 40 mg
10 days
4162
4 months
2 years
19
16
.03
.005
PACT
A to Z
MIRACL
PROVE IT
Atorvastatin is not indicated for secondary prevention of CHD.
Liem AH et al. Eur Heart J. 2002;23:1931-1937; Thompson PL et al. Am Heart J. 2004;148:e2; de Lemos JA et al. JAMA.
2004;292:1307-1316; Schwartz GG et al. JAMA. 2001;285:1711-1718; Cannon CP et al. N Engl J Med. 2004;350:1495-1504;
Ray KK et al. Am J Cardiol. 2005;46:1405-1410.
15
PROVE IT Primary End Point*
All-Cause Mortality or Major CV Event
Death or Major CV Event (%)
30
Pravastatin 40 mg
16% RRR
Atorvastatin 80 mg
25
20
15
10
5
HR = .84, P=.005
0
0
3
6
9
12
15
18
21
24
27
30
Months Of Follow-Up
*Death from any cause, MI, unstable angina, revascularization, or stroke.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Cannon CP et al. N Engl J Med. 2004;350:1495-1504, with permission.
16
4S Left Important Questions to Be
Answered By Subsequent Trials in
Secondary Prevention
1994
1995–2005
Confirmation
of 4S Findings
 CARE
 LIPID
Finding the Optimal
LDL-C Target
 HPS
 TNT
Benefit of Early Start
in ACS Patients
(excluded in 4S)
 MIRACL
 PROVE IT
 A to Z
Evolving
Standard Therapy
 IDEAL
17
Study Rationale
IDEAL Begins Where 4S
Left Off
4S
IDEAL
Simvastatin 20 mg:
Titrate to 40 mg for TC <4.9 mmol/L
Placebo
4444
Patients
No prior
statin
8888
Patients
Simvastatin 20 mg:
Titrate to achieve TC 3.0-5.2 mmol/L
188 mg/dL
(4.9 mmol/L)
LDL-C
~75% on
statins
Atorvastatin 80 mg
125 mg/dL
122 mg/dL
(3.2 mmol/L)
(3.1 mmol/L)
LDL-C
The Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Pedersen TR et al.
Am J Cardiol. 2004;94:720-724.
?
19
The Face Of CV Risk Has
Changed Since 4S
• Coronary atherosclerosis is
changing in its clinical
manifestations
• There appear to be fewer
nonfatal MIs and coronary
deaths than in the past, at least
according to projections from
Framingham scoring
• ….Improved management of
established CHD results in fewer
deaths
• Other forms of atherosclerotic CV
disease now predominate and
probably represent the preferred
end point for clinical trial
Grundy SM. J Am Coll Cardiol. 2005;46:173-175.
20
Study Design
Open-Label Period With Blinded
End Point Evaluations
Patient Population
•
•
•
•
Enrolled at 190 sites
History of MI
Eligible for statin therapy
9689 screened
Atorvastatin 80 mg/day
8888
Patients
Randomized
Simvastatin 20 mg/day
(titrated to 40 mg/day at week 24*)
Plan For 5.5-Year Follow-Up
Primary Composite End Point
• Major coronary event
Secondary Composite End Points
• Major CV event
• Any CHD event
• Any CV event
*Simvastatin dose was increased to 40 mg/day at week 24 in patients whose plasma total cholesterol remained >5.0 mmol/L (190
mg/dL) or whose LDL cholesterol remained >3.0 mmol/L (115 mg/dL).
Pedersen TR et al. Am J Cardiol. 2004;94:720-724.
21
Study Eligibility
Inclusion Criteria
Selected Exclusion Criteria
• Men and women aged
80 years
• TG > 600 mg/dL (6.8 mmol/L)
• History of definite MI
• Qualified for statin therapy
• > Simva 20 mg/day or
equivalent statin dose
• Rx with nonstatin lipid agents
• Usual statin contraindications
Pedersen TR et al. Am J Cardiol. 2004;94:720-724.
22
From 4S To IDEAL:
Comparison of Features
of 2º Prevention Trials
IDEAL: Real-World Statin Trial
• Used Prospective Randomized Open Blinded End-point
(PROBE) study design
• Only statin trial with no run-in/washout phase
• 76% of patients receiving statins at randomization
• Majority on concomitant aspirin or β-blockers
– reflects improved standard of care for CHD patients
since 4S
Pedersen TR et al. JAMA. 2005;294:2437-2445.
24
IDEAL: Enrolled Older Patients
With History of MI
4S
CARE
(N=4444)
(N=4159)
81
86
83
75
81
81
35-70
21-75
31-75
40-80
35-75
80
% >65
23
51*
39
46**
37
43
History of MI (%)
79
100
64
41
58
100
Study
Men (%)
Age range (y)
LIPID
HPS
TNT
IDEAL
(N=9014) (N=20,536) (N=10,001) (N=8888)
*Age breakout provided for 60 years and above. **HPS included both primary and secondary prevention patients.
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; The Scandinavian Simvastatin
Survival Study group. Am J Cardiol. 1993;71:393-400; Long-Term Intervention with Pravastatin in Ischaemic
Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al. N Engl J Med.
1996;335:1001-1009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; LaRosa JC et al.
N Engl J Med. 2005;352:1425-1435; MBC/BHF Heart Protection Study Collaborative Group. Eur Heart J.
1999;20:725-741; Pedersen TR et al. Am J Cardiol. 2004;94:720-724; Pedersen TR et al. JAMA.
2005;294:2437-2445; Waters DD et al. Am J Cardiol. 2004;93:154-158.
25
IDEAL: Baseline Characteristics
Reflect Improvement in Care Since 4S
Study
4S
CARE
LIPID
HPS
TNT
1994
1996
1998
2002
2005
(N=4444) (N=4159) (N=9014) (N=20,536) (N=10,001)
IDEAL
2005
(N=8888)
Concomitant medications (%)
Aspirin
37
83
83
63
88
79
β-blocker
57
41
47
26
55
75
Calcium antagonist
31
40
36
–
26
19
Revascularization (%)
8
54
41
–
86
40
LDL-C (mg/dL)
188
139
150
132
98
122
Statin use (%)
0
0
0
0
57
~76
Simvastatin
Atorvastatin
Pravastatin
Others
50%
11%
10%
4%
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Long-Term Intervention with
Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357; Sacks FM et al.
N Engl J Med. 1996;335:1001-1009; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22;
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; McGowan MP et al. Circulation. 2004;110:2333-2335;
Pedersen TR et al. JAMA. 2005;294:2437-2445; Waters DD et al. Am J Cardiol. 2004;93:154-158.
26
Baseline Characteristics
Evaluation Groups
9689
Screened
801
Excluded*
8888
Randomized
4449
Assigned to Simvastatin 20 mg
4439
Assigned to Atorvastatin 80 mg
4427
Followed for End Points Through End of Study
3 Withdrew Consent, Vital Status Unknown†
2 Lost to Follow-Up‡
4407
Followed for End Points Through End of Study
10 Withdrew Consent, Vital Status Unknown†
4 Lost to Follow-Up‡
*801 excluded: 416 met exclusion criteria, 246 unwilling to participate, 14 lost to follow-up, 125 other.
†13 patients (0.1%) withdrew consent prior to study close-out, vital status unknown; ‡6 patients (0.1%) lost to follow-up
prior to study close-out.
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
28
Baseline Characteristics
% Of Patients
Atorvastatin
(N=4439)
Simvastatin
(N=4449)
Age, y
61.8
61.6
Male
81
81
CABG/PCI
39
40
7
6
Smoker
20
21
Hypertension
33
33
Diabetes
12
12
Heart failure
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
29
Baseline Characteristics
CV History
% Of Patients
Atorvastatin
(N=4439)
Simvastatin
(N=4449)
Cardiovascular history
More than 1 previous MI
16.6
17.0
Months since last MI ≤ 2
11.1
11.4
Coronary angioplasty only
19.9
19.7
Coronary bypass only
16.5
16.8
Both angioplasty and bypass
2.9
3.7
Cerebrovascular disease
8.0
8.5
Peripheral vascular disease
4.1
4.4
Congestive heart failure
6.6
5.5
Atrial fibrillation or flutter
7.8
7.6
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
30
Concomitant CV Medications
at Baseline
% Of Patients
Atorvastatin
(N=4439)
Simvastatin
(N=4449)
Aspirin
79
80
Warfarin
13
13
-Blocker
76
74
Calcium antagonists
20
19
ACE inhibitors
29
31
6
6
Angiotensin II blockers
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
31
Prerandomization Statin Use
% of Patients
Atorvastatin
(N=4439)
Simvastatin
(N=4449)
Simvastatin
50
50
Atorvastatin
11
12
Pravastatin
9
10
Other statins
4
5
75.1
75.8
Any statin
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
32
Statin Dose
and Adherence
Last Dose Prescribed at
End of Study*
13.2%
40 mg
86.8%
80 mg
Atorvastatin
(N=4439)
23.3%
40 mg
76.7%
20 mg
Simvastatin
(N=4449)
*Values are number of subjects (%) with prescription data from routine clinic visit forms at last study visit.
Pedersen TR et al. JAMA. 2005;294:2437-2445.
34
Adherence With Treatment
Simvastatin
Atorvastatin
100
92%
86%
Adherence (%)
80
60
Overall Adherence:
40
Simvastatin
Atorvastatin
95%
89%
20
0
Baseline
Year 1
Data on file. Pfizer Inc, New York, NY.
Pedersen TR et al. JAMA. 2005;294:2437-2445.
Year 2
Year 3
Year 4
Year 5
35
Lipid Parameter Changes
LDL-C by Statin Use at Baseline
170
No
Statin
Percent Change at 1 Year:
LDL-C (mg/dL)
130
On
Statin
Atorvastatin
No Statin: - 47%
On Statin: - 27%
3.5
3.0
Simvastatin
110
2.5
90
Atorvastatin
2.0
LDL-C (mmol/L)
Simvastatin
No Statin: - 33%
On Statin: - 5%
150
4.0
70
1.5
0
0
Randomization
12
Weeks
Data on file. Pfizer Inc, New York, NY.
1
2
3
4
5
Years
37
Reductions in LDL-C by
Treatment Group
Atorvastatin
130
3.4
Simvastatin
120
100
90
3.1
2.8
2.6
Mean LDL-C at 1 Year = 79 mg/dL (2.0 mmol/L)
Mean LDL-C During Treatment = 81 mg/dL (2.1 mmol/L)
2.3
80
2.0
70
1.8
0
Randomization
LDL-C (mmol/L)
LDL-C (mg/dL)
110
Mean LDL-C at 1 Year = 102 mg/dL (2.6 mmol/L)
Mean LDL-C During Treatment = 104 mg/dL (2.7 mmol/L)
0
12
Weeks
Pedersen TR et al. JAMA. 2005;294:2437-2445.
1
2
3
4
5
Years
38
Reductions in TC by
Treatment Group
Atorvastatin
200
5.2
Simvastatin
4.9
190
180
4.7
170
4.4
160
Mean TC at 1 Year = 147 mg/dL (3.8 mmol/L)
TC (mmol/L)
TC (mg/dL)
Mean TC at 1 Year = 176 mg/dL (4.6 mmol/L)
4.1
3.9
150
0
Randomization
0.0
12
Weeks
Pedersen TR et al. JAMA. 2005;294:2437-2445.
1
2
3
4
5
Years
39
Reductions in HDL-C by
Treatment Group
55
Mean HDL-C at 1 Year = 47 mg/dL (1.22 mmol/L)
1.4
50
1.2
HDL-C (mg/dL)
Mean HDL-C at 1 Year = 46 mg/dL (1.19 mmol/L)
40
1.0
35
0.8
30
Atorvastatin
HDL-C (mmol/L)
45
Simvastatin
25
0.6
20
0
Randomization
0.0
12
1
Weeks
Pedersen TR et al. JAMA. 2005;294:2437-2445.
2
3
4
5
Years
40
Reductions In TG By
Treatment Group
Atorvastatin
155
Simvastatin
150
Mean TG at 1 Year = 139 mg/dL (1.57 mmol/L)
145
1.6
135
1.5
130
125
Mean TG at 1 Year = 116 mg/dL (1.31 mmol/L)
1.4
TG (mmol/L)
140
TG (mg/dL)
1.7
120
115
1.3
110
1.2
0
Randomization
0.0
12
1
Weeks
Pedersen TR et al. JAMA. 2005;294:2437-2445.
2
3
4
5
Years
41
Efficacy Outcome
Measures
Composite End Point Definitions
Primary
Composite
End Point
Secondary
Composite
End Point
Major Coronary
Event
Composite of CHD death, nonfatal MI,
resuscitated cardiac arrest
Major CV Events
Composite of major coronary event and
stroke
Any CHD Event
Composite of major coronary event,
revascularization, and hospitalization
for unstable angina
Any CV Event
Composite of any CHD event, stroke,
hospitalization for CHF, PAD
TNT
Primary
End Point
Similar to
PROVE IT
Primary
End Point*
*PROVE IT primary end point = composite of death from any cause, MI, revascularization, hospitalization for unstable angina,
or stroke.
Pedersen TR et al. JAMA. 2005;294:2437-2445.
43
Primary Composite End Point
No. of Patients (%)
Atorvastatin
Simvastatin
(N=4439)
(N=4449)
Hazard Ratio
411 (9.3)
463 (10.4)
0.89
.07
CHD death
175 (3.9)
178 (4.0)
0.99
.90
Nonfatal MI
267 (6.0)
321 (7.2)
0.83
.02
10 (0.2)
7 (0.2)
-
-
Major coronary event
Resuscitated cardiac arrest
Atorvastatin is not indicated for secondary prevention of CHD.
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
P Value
44
Post Hoc Analysis Of
Primary End Point
• In a post hoc analysis, the primary end point was
adjusted for baseline characteristics, including
gender, age, statin use at randomization, duration
since last MI, TC, HDL-C (Cox regression analysis)
• 13% reduction in major coronary events with
atorvastatin 80 mg vs simvastatin 20 mg to 40 mg
(hazard ratio = 0.87; P=.04)
Atorvastatin is not indicated for secondary prevention of CHD.
Pedersen TR et al. JAMA. 2005;294:2437-2445.
45
Major Coronary Events*
12
Simvastatin
11% RRR
Major Coronary Events
Cumulative Hazard (%)
Atorvastatin
8
4
HR = 0.89, P=.07
0
0
1
2
3
4
5
Years Since Randomization
*CHD death, nonfatal MI, and resuscitated cardiac arrest.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
46
Nonfatal MI
10
Simvastatin
Nonfatal MI Cumulative
Hazard (%)
Atorvastatin
8
17% RRR
6
4
2
HR = 0.83, P=.02
0
0
1
2
3
4
5
Years Since Randomization
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
47
Secondary Composite End Points
No. of Patients (%)
Atorvastatin
(N=4439)
Simvastatin
(N=4449)
Hazard
Ratio
533 (12.0)
608 (13.7)
0.87
.02
151 (3.4)
174 (3.9)
0.87
.20
898 (20.2)
1059 (23.8)
0.84
<.001
Revascularization
579 (13.0)
743 (16.7)
0.77
<.001
Hospitalized unstable angina
196 (4.4)
235 (5.3)
0.83
.06
1176 (26.5)
1370 (30.8)
0.84
<.001
Hospitalized nonfatal CHF
99 (2.2)
123 (2.8)
0.81
.11
Peripheral arterial disease
127 (2.9)
167 (3.8)
0.76
.02
Major CV event
Fatal or nonfatal stroke
Any CHD event
Any CV event
Atorvastatin is not indicated for secondary prevention of CHD.
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
P Value
48
Composite End Points
Major Coronary Events
Simvastatin
Atorvastatin
12
11% RRR
8
4
HR = 0.89, P=.07
0
0
Simvastatin
Atorvastatin
16
1
2
3
4
Years Since Randomization
Cumulative Hazard (%)
16
Cumulative Hazard (%)
Major CV Events
12
8
4
HR = 0.87, P=.02
0
5
0
1
2
3
4
Years Since Randomization
Cumulative Hazard (%)
Simvastatin
Atorvastatin
30
16% RRR
20
10
HR = 0.84, P<.001
0
0
1
2
3
4
Years Since Randomization
5
Any CV Event
5
Cumulative Hazard (%)
Any CHD Event
40
13% RRR
40
Simvastatin
Atorvastatin
16% RRR
30
20
10
HR = 0.84, P<.001
0
0
1
2
3
4
Years Since Randomization
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
5
49
Major CV Events*
16
Simvastatin
13% RRR
Major CV Events
Cumulative Hazard (%)
Atorvastatin
12
8
4
HR = 0.87, P=.02
0
0
1
2
3
4
5
Years Since Randomization
*Major coronary event + stroke.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
50
Any CHD Event*
40
Simvastatin
Any CHD Events
Cumulative Hazard (%)
Atorvastatin
30
16% RRR
20
10
HR = 0.84, P<.001
0
0
1
2
3
4
5
Years Since Randomization
*Any CHD event = major coronary event + revascularization + unstable angina.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
51
Any CV Event*
40
Simvastatin
16% RRR
Any CV Events
Cumulative Hazard (%)
Atorvastatin
30
20
10
HR = 0.84, P<.001
0
0
1
2
3
4
5
Years Since Randomization
*Any CHD + CHF + PAD.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
52
Selected Secondary
End Points
Stroke
Simvastatin
Atorvastatin
10
8
17% RRR
6
4
2
HR = 0.83, P=.02
0
0
1
2
3
4
Years Since Randomization
Cumulative Hazard (%)
Cumulative Hazard (%)
Nonfatal MI
Simvastatin
Atorvastatin
10
8
6
13% RRR
4
2
HR = 0.87, P=.20
0
5
0
1
2
3
4
Years Since Randomization
PAD
Simvastatin
Atorvastatin
20
23% RRR
16
12
8
4
HR = 0.77, P<.001
0
0
1
2
3
4
Years Since Randomization
5
Cumulative Hazard (%)
Cumulative Hazard (%)
Revascularization
5
Simvastatin
Atorvastatin
10
8
6
24% RRR
4
2
HR = 0.76, P=.02
0
0
1
2
3
4
Years Since Randomization
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
5
53
Mortality
No. of Patients (%)
Atorvastatin
Simvastatin
Hazard
(N=4439)
(N=4449)
Ratio
P Value
All-cause mortality
366 (8.2)
374 (8.4)
0.98
.81
Cardiovascular mortality
223 (5.0)
218 (4.9)
1.03
.78
Noncardiovascular mortality
143 (3.2)
156 (3.5)
0.92
.47
99 (2.2)
112 (2.5)
0.89
.38
5 (0.1)
9 (0.2)
-
-
32 (0.7)
30 (0.7)
-
-
7 (0.2)
5 (0.1)
-
-
Malignant disease*
Suicide, violence, accident
Other
Unclassified
*No significant differences in cancer mortality for any particular body system.
Atorvastatin is not indicated for secondary prevention of CHD.
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
54
Safety
Investigator-Reported
Adverse Events
Atorvastatin
(N=4439)
Simvastatin
(N=4449)
2064 (46.5)
2108 (47.4)
426 (9.6)
186 (4.2)
97 (2.2)
38 (0.9)
37 (0.8)
22 (0.5)
51 (1.1)
9 (0.2)
10 (0.2)
7 (0.1)
Investigator-reported myopathy
6 (0.14)
11 (0.25)
Investigator-reported rhabdomyolysis
2 (0.05)
3 (0.07)
Any serious adverse event
Any adverse event resulting in permanent
discontinuation with incidence 0.5%
Myalgia
Diarrhea
Abdominal pain
Nausea
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
56
Protocol-Defined Clinically
Important Lab Abnormalities
Atorvastatin
(N=4439)
Simvastatin
(N=4449)
AST >3 ULN at 2 consecutive
measurements*
18 (0.4)
2 (0.0)
ALT >3 ULN at 2 consecutive
measurements*
43 (1.0)
5 (0.1)
0
0
Myopathy defined as CPK >10 ULN at 2
consecutive measurements* with
muscle symptoms
*4 to10 days apart.
Values are number of unique subjects (%).
Adapted from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
57
Summary and Conclusions
Summary
• Results from 4S showed that simvastatin 20 mg to 40 mg reduces
CV morbidity and mortality
• Since 4S in 1994, clinical landscape has continued to evolve
– lower LDL-C levels recommended by guidelines
– statins are first-line therapy
– increased use of other proven CV meds
• aspirin
• -blockers
• In IDEAL, mean LDL-C levels were 81 mg/dL (2.1 mmol/L) with
atorvastatin 80 mg compared with 104 mg/dL (2.7 mmol/L) with
simvastatin 20 mg to 40 mg
59
Implications of IDEAL Results
High-dose Strategy vs Usual-Dose Strategy:
Treating 1000 MI patients over 5 years
Prevention of 68 patients having CVD events
Atorvastatin is not indicated for secondary prevention of CHD.
Pedersen TR et al. JAMA. 2005;294:2437-2445.
60
IDEAL Secondary
End Point*
16
TNT Primary
End Point*
Simvastatin 20 mg to 40 mg
Atorvastatin 80 mg
13%
RRR
12
Major CV Event Cumulative Hazard
(%)
Major CV Event Cumulative Hazard (%)
IDEAL Results Are
Consistent With TNT
15
Atorvastatin 10 mg
Atorvastatin 80 mg
22%
RRR
10
8
5
4
HR = 0.87, P=.02
0
0
1
2
3
4
Years Since Randomization
5
HR = 0.78, P<.001
0
0
1
2
3
4
5
Years Since Randomization
6
*Major CV event = CHD death, nonfatal MI, resuscitated cardiac arrest, fatal or nonfatal stroke.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from LaRosa JC et al. N Engl J Med. 2005;352:1425-1435, with permission.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
61
IDEAL Results Are
Consistent With PROVE IT
PROVE IT Primary
End Point**
40
Simvastatin 20 mg to 40 mg
Atorvastatin 80 mg
Pravastatin 40 mg
Atorvastatin 80 mg
30
30
16%
RRR
20
10
HR = 0.84, P<.001
0
Death Or Major CV Event (%)
Any CHD Cumulative Hazard (%)
IDEAL Secondary
End Point*
25
16%
RRR
20
15
10
5
HR = 0.84, P=.005
0
0
1
2
3
4
Years Since Randomization
5
*Any CHD event = composite of major coronary
event, revascularization, or hospitalization for
unstable angina.
0
3
6
9 12 15 18 21 24 27 30
Months Of Follow-Up
**Death from any cause, MI, revascularization,
hospitalization for unstable angina, or stroke.
Atorvastatin is not indicated for secondary prevention of CHD.
Reproduced from Cannon CP et al. N Engl J Med. 2004;350:1495-1504, with permission.
Reproduced from Pedersen TR et al. JAMA. 2005;294:2437-2445, with permission.
62
Summary
• IDEAL showed incremental reductions in clinical
end points can be achieved with atorvastatin 80 mg compared
with simvastatin 20 mg to 40 mg without compromising safety
 11% difference in major coronary events (P=.07)
 17% difference in nonfatal MI (P=.02)
 13% difference in major CV events (P=.02)
 16% difference in any CHD event (P<.001)
 16% difference in any CV event (P<.001)
• Reductions in CV events in IDEAL build upon results seen in
TNT and PROVE IT
Atorvastatin is not indicated for secondary prevention of CHD.
63