IDEAL: Incremental Decrease In End Points Through Aggressive Lipid Lowering

1
IDEALIncremental Decrease InEnd Points
ThroughAggressive Lipid Lowering

• The IDEAL Steering CommitteeAnd Investigators
  

2
Background
3
CVD A Major GlobalHealth 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/11
05390918119HDSStats2005Update.pdf. Accessed
11/9/05. World Health Organization. The Atlas of
Heart Disease and Stroke. Available at
http//www.who.int/cardiovascular_diseases/resourc
es/atlas/en/. Accessed 11/3/05.
4
Although CVD-Related Deaths Remain High, the
CVD-Related Death Rate Is Decreasing
1st Statin Introduced
1200
600
US 1979-2002
1000
500
800
400
600
300
Annual CVD Deaths x1000 (bar)
CVD Deaths/100,000 Population (line)
400
200
200
100
0
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
Year
NCEP ATP II
NCEP ATP III
NCEP ATP I
There are nearly 1 million CVD-related deaths
each year
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/d
ocs/04_chtbk.pdf. Accessed 11/9/05 Mevacor
approval history. Available at
http//www.accessdata.fda.gov/scripts/cder/drugsat
fda. Accessed December 8, 2005 Expert Panel.
Arch Intern Med. 19881483669 Expert Panel.
JAMA. 199326930153023 Expert Panel. JAMA.
20012852486-2497.
5
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/11
05390918119HDSStats2005Update.pdf. Accessed
11/9/05 British Heart Foundation. Total Costs of
CVD in Europe. Available at http//www.heartstats
.org/topic.asp?id4545. Accessed 11/3/05 Bonow
RO et al. Circulation. 20021061602-1605.
6
Elevated Cholesterol Levels Associated With High
Risk of CHD
Framingham Study(N5209)
Multiple Risk Factor Intervention Trial (MRFIT)
(N361,662)
150
18
16
125
14
100
12
6-Year CHD Incidence Per 1000 Men
10
Age-Adjusted 6-Year CHD Mortality Per 1000 Men
75
8
6
50
4
25
2
0
0
204
205-234
235-264
265-294
295
160
200
260
300
140
180
220
240
280
320
Total Cholesterol (mg/dL)
Total Cholesterol (mg/dL)
Each 1 Increase in Total Cholesterol
LevelAssociated With a 2 Increase in CHD Risk
Each 1 Reduction in Total Cholesterol Level
Resulted in a 2 Decrease in CHD Risk
Adapted from Martin MJ et al. Lancet.
19862933-936, with permission. Reproduced from
Castelli WP. Am J Med. 1984764-12, with
permission.
7
Evolution of Guidelines DrivenBy Clinical
Evidence
First JointEuropean 1994
Third JointEuropean 2003
Second JointEuropean 1998
NCEP ATP III 2001
NCEP Report 2004
NCEP ATP I 1988
NCEP ATP II 1994
1980s
1990s
2000s
Early Data
Angiographic Trials
Recent Data
Outcomes Trials
TNT 2005 IDEAL 2005
CLAS 1987 FATS 1990 POSCH 1990 Lifestyle Heart
Trial 1990STARS 1992
4S 1994WOSCOPS 1995 CARE 1996 LIPID 1998
AFCAPS/TexCAPS 1998VA-HIT 1999
HPS 2002 ALLHAT 2002PROSPER 2002ASCOT-LLA
2003PROVE IT 2004CARDS 2004
Framingham 1981 Atherosclerosis Study Group 1984
LRC-CPPT 1984 MRFIT 1986 Coronary Drug Project
1986 Helsinki Heart Study 1987
Meta-Analyses
Holme 1990 Rossouw 1991
8
Current Lipid Treatment Guidelines
The Primary Focus of Treatment Guidelines Is to
Reduce LDL-C

• NCEP Guidelines
• Low riskLDL-C lt160 mg/dL
• Moderate riskLDL-C lt130 mg/dL for individuals
  with ?2 risk factors
• High risk LDL-C lt100 mg/dL for individuals with
  CHD or CHD equivalents
• Very high risk (optional)LDL-C lt70 mg/dL for
  high-risk individuals (eg, those with CHDand
  diabetes)

• European Guidelines
• LDL-C lt100 mg/dL for at-risk individuals
• lt100 mg/dL for high-risk individuals (eg, those
  with diabetes)
• Triglycerides secondary target for lowering
• HDL-C secondary target for raising

Expert Panel. JAMA. 20012852486-2497 Grundy
SM et al. Circulation. 2004110227-239 De
Backer G et al. Eur Heart J. 2003241601-1610.
9
4S to IDEAL 11 Years of Landmark Statin Trials
10
4S Proved 2º Prevention With StatinsCould Lower
Mortality and CV Events
Primary End Point Total Mortality
Secondary End Point Major Coronary Events
1.00
1.00
Simvastatin
Simvastatin
0.90
0.95
30 RRRP.0003
0.80
34 RRR P.00001
0.90
Placebo
Proportion Without Major Coronary Event
Proportion Alive
Placebo
0.70
0.85
0.60
0.80
0.50
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Years Since Randomization
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.
19943441383-1389, with permission.
11
4S Left Important Questions To Be Answered By
Subsequent Trials In Secondary Prevention
1994
19952005

• CARE
• LIPID

Confirmation of 4S Findings
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

12
Usual-Dose Statin Therapy Established As Standard
for CHD Patients Regardless of Baseline LDL-C
Statin vs Placebo
190
170
150
LDL-C Level at Beginning andEnd of Therapy
(mg/dL)
130
110
90
70
50


Relative Risk Reduction 34 24 24 27
Event Rate On Statin 19.0 12.3 10.2 8.7

4S
LIPID
CARE
HPS
Simvastatin 20 mg
Pravastatin 40 mg
Pravastatin 40 mg
Simvastatin 40 mg
End points cited (not primary end points) 4S
and TNTCHD death, nonfatal MI, and cardiac
resuscitation LIPID, CARE, and HPSCHD death and
nonfatal MI. Scandinavian Simvastatin Survival
Study Group. Lancet. 19943441383-1389
Long-Term Intervention with Pravastatin in
Ischaemic Disease (LIPID) Study Group. N Engl J
Med. 19983391349-1357 Sacks FM et al. N Engl
J Med. 19963351001-
1009 Heart Protection Study Collaborative Group.
Lancet. 20023607-22.
13
TNT Reached Lower LDL-C LevelsWith Intensive
Therapy
Intensive vs Usual-Dose Lipid Lowering
Statin vs Placebo
LDL-C Level at Beginning andEnd of Therapy
(mg/dL)


Relative Risk Reduction 34 24 24 27 NA 20
Event Rate On Statin 19.0 12.3 10.2 8.7

Simvastatin 20 mg
Pravastatin 40 mg
Pravastatin 40 mg
Simvastatin 40 mg
Atorvastatin 10 mg
Atorvastatin 80 mg
8.3
6.7
End points cited (not primary end points) 4S
and TNTCHD death, nonfatal MI, and cardiac
resuscitation LIPID, CARE, and HPSCHD death and
nonfatal MI. Atorvastatin is not indicated for
secondary prevention of CHD. Scandinavian
Simvastatin Survival Study Group. Lancet.
19943441383-1389 Long-Term Intervention with
Pravastatin in Ischaemic Disease (LIPID) Study
Group. N Engl J Med. 19983391349-1357 Sacks
FM et al. N Engl J Med. 1996335
1001-1009 Heart Protection Study
Collaborative Group. Lancet. 20023607-22
LaRosa JC et al. N Engl J Med.
20053521425-1435.
14
TNT Primary End PointTime to First Major CV
Event
15
Atorvastatin 10 mg
Major CV Event ()
Atorvastatin 80 mg
10
5
HR 0.78, Plt.001
0
0 1 2 3 4 5 6 Time (years)
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.
20053521425-1435, with permission.
15
4S Left Important Questions to Be Answered by
Subsequent Trials In Secondary Prevention
1994
19952005
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

16
Of The 5 Major ACS Trials, Only MIRACL and PROVE
IT Showed a Significant Benefit in Patients With
ACS
Study Intervention Treatment Initiated Within N Follow-Up Risk Reduction () In 1º End Point P Value
FLORIDA Fluva 80 mg vs placebo 8 days 540 1 year 8 NS
PACT Prava 20/40 mg vs placebo 24 hours 3408 30 days 6.4 NS
A to Z Simva 40/80 mg vs placebo/simva 20 mg 5 days to 4 months 4497 2 years 11 NS
MIRACL Atorva 80 mg vs placebo 2496 hours 3086 16 weeks 16 .048
PROVE IT Atorva 80 mg vs prava 40 mg 10 days 4162 4 months 2 years 19 16 .03 .005
Atorvastatin is not indicated for secondary
prevention of CHD. Liem AH et al. Eur Heart J.
2002231931-1937 Thompson PL et al. Am Heart
J. 2004148e2 de Lemos JA et al. JAMA.
20042921307-1316 Schwartz GG et al. JAMA.
20012851711-1718 Cannon CP et al. N Engl J
Med. 20043501495-1504 Ray KK et al. Am J
Cardiol. 2005461405-1410.
17
PROVE IT Primary End PointAll-Cause Mortality
or Major CV Event
30
25
20
Death or Major CV Event ()
15
10
5
HR .84, P.005
0
3
6
9
12
15
18
21
24
27
30
0
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. 20043501495-1504, with permission.
18
4S Left Important Questions to Be Answered By
Subsequent Trials in Secondary Prevention
1994
19952005
19
Study Rationale
20
IDEAL Begins Where 4S Left Off
4S
IDEAL
Placebo
Simvastatin 20 mg Titrate to 40 mg for TC lt4.9
mmol/L
4444 Patients
8888 Patients
Simvastatin 20 mg Titrate to achieve TC 3.0-5.2
mmol/L
Atorvastatin 80 mg
75 onstatins
No priorstatin
125 mg/dL
122 mg/dL
188 mg/dL(4.9 mmol/L)
LDL-C
LDL-C
?
(3.2 mmol/L)
(3.1 mmol/L)
The Scandinavian Simvastatin Survival Study
Group. Lancet. 19943441383-1389 Pedersen TR
et al.Am J Cardiol. 200494720-724.
21
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. 200546173-175.
22
Study Design
Open-Label Period With BlindedEnd Point
Evaluations
Patient Population
Atorvastatin 80 mg/day

• Enrolled at 190 sites
• History of MI
• Eligible for statin therapy
• 9689 screened

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
Secondary Composite End Points

• Major coronary event

• 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 gt5.0 mmol/L (190 mg/dL) or
whose LDL cholesterol remained gt3.0 mmol/L (115
mg/dL). Pedersen TR et al. Am J Cardiol.
200494720-724.
23
Study Eligibility

• Inclusion Criteria
• Men and women aged?80 years
• History of definite MI
• Qualified for statin therapy

• Selected Exclusion Criteria
• TG gt 600 mg/dL (6.8 mmol/L)
• gt Simva 20 mg/day or equivalent statin dose
• Rx with nonstatin lipid agents
• Usual statin contraindications

Pedersen TR et al. Am J Cardiol.
200494720-724.
24
From 4S To IDEAL Comparison of Featuresof 2º
Prevention Trials
25
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 ß-blockers
• reflects improved standard of care for CHD
  patients since 4S

Pedersen TR et al. JAMA. 20052942437-2445.
26
IDEAL Enrolled Older Patients With History of MI
Study 4S (N4444) CARE (N4159) LIPID (N9014) HPS (N20,536) TNT (N10,001) IDEAL (N8888)
Men () 81 86 83 75 81 81
Age range (y) gt65 35-70 23 21-75 51 31-75 39 40-80 46 35-75 37 ?80 43
History of MI () 79 100 64 41 58 100
Age breakout provided for 60 years and above.
HPS included both primary and secondary
prevention patients.
Scandinavian Simvastatin Survival Study Group.
Lancet. 19943441383-1389 The Scandinavian
Simvastatin Survival Study group. Am J Cardiol.
199371393-400 Long-Term Intervention with
Pravastatin in Ischaemic Disease (LIPID) Study
Group. N Engl J Med. 19983391349-1357 Sacks
FM et al. N Engl J Med. 19963351001-1009
Heart Protection Study Collaborative Group.
Lancet. 20023607-22 LaRosa JC et al.N Engl J
Med. 20053521425-1435 MBC/BHF Heart
Protection Study Collaborative Group. Eur Heart
J. 199920725-741 Pedersen TR et al. Am J
Cardiol. 200494720-724 Pedersen TR et al.
JAMA. 20052942437-2445 Waters DD et al. Am J
Cardiol. 200493154-158.
27
IDEAL Baseline CharacteristicsReflect
Improvement in Care Since 4S
Study 4S1994 (N4444) CARE 1996 (N4159) LIPID 1998 (N9014) HPS 2002 (N20,536) TNT 2005 (N10,001) IDEAL 2005 (N8888)
Concomitant medications ()
Aspirin 37 83 83 63 88 79
ß-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 50 Atorvastatin 11 Pravastatin 10 O
thers 4
Scandinavian Simvastatin Survival Study Group.
Lancet. 19943441383-1389 Long-Term
Intervention with Pravastatin in Ischaemic
Disease (LIPID) Study Group. N Engl J Med.
19983391349-1357 Sacks FM et al. N Engl J
Med. 19963351001-1009 Heart Protection Study
Collaborative Group. Lancet. 20023607-22
LaRosa JC et al. N Engl J Med.
20053521425-1435 McGowan MP et al.
Circulation. 20041102333-2335 Pedersen TR et
al. JAMA. 20052942437-2445 Waters DD et al.
Am J Cardiol. 200493154-158.
28
Baseline Characteristics
29
Evaluation Groups
9689 Screened
801Excluded
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. 20052942437-2445, with permission.
30
Baseline Characteristics
Of Patients
Atorvastatin (N4439) Simvastatin (N4449)
Age, y 61.8 61.6
Male 81 81
CABG/PCI 39 40
Heart failure 7 6
Smoker 20 21
Hypertension 33 33
Diabetes 12 12
Adapted from Pedersen TR et al. JAMA.
20052942437-2445, with permission.
31
Baseline CharacteristicsCV History
Of Patients
Atorvastatin (N4439) Simvastatin (N4449)
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.
20052942437-2445, with permission.
32
Concomitant CV Medications at Baseline
Of Patients
Atorvastatin (N4439) Simvastatin (N4449)
Aspirin 79 80
Warfarin 13 13
?-Blocker 76 74
Calcium antagonists 20 19
ACE inhibitors 29 31
Angiotensin II blockers 6 6
Adapted from Pedersen TR et al. JAMA.
20052942437-2445, with permission.
33
Prerandomization Statin Use
of Patients
Atorvastatin (N4439) Simvastatin (N4449)
Simvastatin 50 50
Atorvastatin 11 12
Pravastatin 9 10
Other statins 4 5

Any statin 75.1 75.8
Adapted from Pedersen TR et al. JAMA.
20052942437-2445, with permission.
34
Statin Dose and Adherence
35
Last Dose Prescribed at End of Study
13.2 40 mg
23.3 40 mg
86.8 80 mg
76.7 20 mg
Atorvastatin (N4439)
Simvastatin (N4449)
Values are number of subjects () with
prescription data from routine clinic visit forms
at last study visit. Pedersen TR et al. JAMA.
20052942437-2445.
36
Adherence With Treatment
92
86
Overall Adherence
Adherence ()
Simvastatin 95 Atorvastatin 89
Data on file. Pfizer Inc, New York,
NY. Pedersen TR et al. JAMA.
20052942437-2445.
37
Lipid Parameter Changes
38
LDL-C by Statin Use at Baseline
170
4.0
150
3.5
130
3.0
Simvastatin
LDL-C (mg/dL)
110
LDL-C (mmol/L)
2.5
90
Atorvastatin
2.0
70
1.5
0
0
Randomization
12
1
2
3
4
5
Years
Weeks
Data on file. Pfizer Inc, New York, NY.
39
Reductions in LDL-C by Treatment Group
Atorvastatin
130
3.4
Simvastatin
120
3.1
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)
110
2.8
100
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)
90
2.3
80
2.0
70
1.8
0
0
Randomization
12
1
2
3
4
5
Years
Weeks
Pedersen TR et al. JAMA. 20052942437-2445.
40
Reductions in TC by Treatment Group
Atorvastatin
200
5.2
Simvastatin
4.9
190
Mean TC at 1 Year 176 mg/dL (4.6 mmol/L)
180
4.7
TC (mg/dL)
TC (mmol/L)
170
4.4
Mean TC at 1 Year 147 mg/dL (3.8 mmol/L)
4.1
160
150
3.9
0
0.0
Randomization
12
1
2
3
4
5
Weeks
Years
Pedersen TR et al. JAMA. 20052942437-2445.
41
Reductions in HDL-C by Treatment Group
Mean HDL-C at 1 Year 47 mg/dL (1.22 mmol/L)
55
1.4
50
1.2
45
Mean HDL-C at 1 Year 46 mg/dL (1.19 mmol/L)
40
1.0
HDL-C (mg/dL)
HDL-C (mmol/L)
35
0.8
30
Atorvastatin
Simvastatin
25
0.6
20
0
0.0
Randomization
12
1
2
3
4
5
Weeks
Years
Pedersen TR et al. JAMA. 20052942437-2445.
42
Reductions In TG By Treatment Group
Atorvastatin
155
Simvastatin
1.7
150
Mean TG at 1 Year 139 mg/dL (1.57 mmol/L)
145
1.6
140
135
1.5
TG (mg/dL)
TG (mmol/L)
130
125
Mean TG at 1 Year 116 mg/dL (1.31 mmol/L)
1.4
120
115
1.3
110
1.2
0
0.0
Randomization
12
1
2
3
4
5
Weeks
Years
Pedersen TR et al. JAMA. 20052942437-2445.
43
Efficacy OutcomeMeasures
44
Composite End Point Definitions
Primary Composite End Point Major Coronary Event Composite of CHD death, nonfatal MI, resuscitated cardiac arrest

Secondary Composite End Point Major CV Events Composite of major coronary event and stroke
Secondary Composite End Point Any CHD Event Composite of major coronary event, revascularization, and hospitalization for unstable angina
Secondary Composite End Point Any CV Event Composite of any CHD event, stroke, hospitalization for CHF, PAD
PROVE IT primary end point composite of death
from any cause, MI, revascularization,
hospitalization for unstable angina,or
stroke. Pedersen TR et al. JAMA.
20052942437-2445.
45
Primary Composite End Point
No. of Patients ()
Atorvastatin (N4439) Atorvastatin (N4439) Simvastatin (N4449) Hazard Ratio P Value
Major coronary event CHD death Nonfatal MI Resuscitated cardiac arrest Major coronary event CHD death Nonfatal MI Resuscitated cardiac arrest 411 (9.3) 175 (3.9) 267 (6.0) 10 (0.2) 463 (10.4) 178 (4.0) 321 (7.2) 7 (0.2) 0.89 0.99 0.83 - .07 .90 .02 -
Atorvastatin is not indicated for secondary
prevention of CHD. Adapted from Pedersen TR et
al. JAMA. 20052942437-2445, with permission.
46
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.
20052942437-2445.
47
Major Coronary Events
12
8
Major Coronary Events Cumulative Hazard ()
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. 20052942437-2445,
with permission.

48
Nonfatal MI
Atorvastatin is not indicated for secondary
prevention of CHD. Reproduced from Pedersen TR
et al. JAMA. 20052942437-2445, with
permission.

49
Secondary Composite End Points
No. of Patients ()
Atorvastatin (N4439) Atorvastatin (N4439) Simvastatin (N4449) Hazard Ratio P Value
Major CV event Fatal or nonfatal stroke Any CHD event Revascularization Hospitalized unstable angina Any CV event Hospitalized nonfatal CHF Peripheral arterial disease Major CV event Fatal or nonfatal stroke Any CHD event Revascularization Hospitalized unstable angina Any CV event Hospitalized nonfatal CHF Peripheral arterial disease 533 (12.0) 151 (3.4) 898 (20.2) 579 (13.0) 196 (4.4) 1176 (26.5) 99 (2.2) 127 (2.9) 608 (13.7) 174 (3.9) 1059 (23.8) 743 (16.7) 235 (5.3) 1370 (30.8) 123 (2.8) 167 (3.8) 0.87 0.87 0.84 0.77 0.83 0.84 0.81 0.76 .02 .20 lt.001 lt.001 .06 lt.001 .11 .02
Atorvastatin is not indicated for secondary
prevention of CHD. Adapted from Pedersen TR et
al. JAMA. 20052942437-2445, with permission.
50
Composite End Points
Major Coronary Events
Major CV Events
16
16
12
12
8
8
Cumulative Hazard ()
Cumulative Hazard ()
4
4
HR 0.89, P.07
HR 0.87, P.02
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Years Since Randomization
Years Since Randomization
Any CHD Event
Any CV Event
40
40
30
30
Cumulative Hazard ()
20
20
Cumulative Hazard ()
10
10
HR 0.84, Plt.001
HR 0.84, Plt.001
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Years Since Randomization
Years Since Randomization
Atorvastatin is not indicated for secondary
prevention of CHD. Reproduced from Pedersen TR
et al. JAMA. 20052942437-2445, with
permission.
51
Major CV Events
16
Simvastatin
Atorvastatin
12
Major CV Events Cumulative Hazard ()
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.
20052942437-2445, with permission.

52
Any CHD Event
40
Simvastatin
Atorvastatin
30
Any CHD Events Cumulative Hazard ()
20
10
HR 0.84, Plt.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.
20052942437-2445, with permission.
53
Any CV Event
40
Simvastatin
Atorvastatin
30
Any CV Events Cumulative Hazard ()
20
10
HR 0.84, Plt.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.
20052942437-2445, with permission.

54
Selected Secondary End Points
Nonfatal MI
Stroke
Revascularization
PAD
Atorvastatin is not indicated for secondary
prevention of CHD. Reproduced from Pedersen TR
et al. JAMA. 20052942437-2445, with
permission.
55
Mortality
No. of Patients ()
Atorvastatin (N4439) Atorvastatin (N4439) Simvastatin (N4449) Hazard Ratio P Value
All-cause mortality Cardiovascular mortality Noncardiovascular mortality Malignant disease Suicide, violence, accident Other Unclassified All-cause mortality Cardiovascular mortality Noncardiovascular mortality Malignant disease Suicide, violence, accident Other Unclassified 366 (8.2) 223 (5.0) 143 (3.2) 99 (2.2) 5 (0.1) 32 (0.7) 7 (0.2) 374 (8.4) 218 (4.9) 156 (3.5) 112 (2.5) 9 (0.2) 30 (0.7) 5 (0.1) 0.98 1.03 0.92 0.89 - - - .81 .78 .47 .38 - - -
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. 20052942437-2445,
with permission.
56
Safety
57
Investigator-ReportedAdverse Events
Atorvastatin (N4439) Simvastatin (N4449)
Any serious adverse event 2064 (46.5) 2108 (47.4)
Any adverse event resulting in permanent discontinuation with incidence ?0.5 426 (9.6) 186 (4.2)
Myalgia Diarrhea Abdominal pain Nausea 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)
Adapted from Pedersen TR et al. JAMA.
20052942437-2445, with permission.
58
Protocol-Defined ClinicallyImportant Lab
Abnormalities
Atorvastatin (N4439) Simvastatin (N4449)
AST gt3? ULN at 2 consecutive measurements 18 (0.4) 2 (0.0)
ALT gt3? ULN at 2 consecutive measurements 43 (1.0) 5 (0.1)
Myopathy defined as CPK gt10? ULN at 2 consecutive measurements with muscle symptoms 0 0
4 to10 days apart. Values are number of unique
subjects ().
Adapted from Pedersen TR et al. JAMA.
20052942437-2445, with permission.
59
Summary and Conclusions
60
Summary

• Results from 4S showed that simvastatin 20 mg to
  40 mg reducesCV 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

61
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.
20052942437-2445.
62
IDEAL Results Are Consistent With TNT
IDEAL Secondary End Point
TNT Primary End Point
15
Atorvastatin 10 mg
16
Simvastatin 20 mg to 40 mg
Atorvastatin 80 mg
Atorvastatin 80 mg
12
10
Major CV Event Cumulative Hazard ()
Major CV Event Cumulative Hazard ()
8
5
4
HR 0.78, Plt.001
HR 0.87, P.02
0
0
0 1 2 3 4 5 6 Years Since Randomization
0
1
2
3
4
5
Years Since Randomization
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.
20053521425-1435, with permission. Reproduced
from Pedersen TR et al. JAMA.
20052942437-2445, with permission.
63
IDEAL Results Are Consistent With PROVE IT
PROVE IT Primary End Point
IDEAL Secondary End Point
40
30
Simvastatin 20 mg to 40 mg
Pravastatin 40 mg
Atorvastatin 80 mg
Atorvastatin 80 mg
25
30
20
Death Or Major CV Event ()
15
Any CHD Cumulative Hazard ()
20
10
10
5
HR 0.84, P.005
HR 0.84, Plt.001
0
0
3
6
9
12
15
18
21
24
27
30
0
0
1
2
3
4
5
Years Since Randomization
Months Of Follow-Up
Any CHD event composite of major
coronaryevent, revascularization, or
hospitalization forunstable angina.
Death from any cause, MI, revascularization,hos
pitalization for unstable angina, or stroke.
Atorvastatin is not indicated for secondary
prevention of CHD. Reproduced from Cannon CP et
al. N Engl J Med. 20043501495-1504, with
permission. Reproduced from Pedersen TR et al.
JAMA. 20052942437-2445, with permission.
64
Summary

• IDEAL showed incremental reductions in
  clinicalend 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 (Plt.001)
• 16 difference in any CV event (Plt.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.