TNT: Study Design Treating
to New Targets
Patient Population
• Clinically evident CHD
• LDL-C 130250 mg/dL
following up to 8-week
washout and 8-week
open-label run-in with
atorvastatin 10 mg
Atorvastatin 10 mg
LDL-C target: 100 mg/dL
10,001
Patients
Primary End Point
• Time to first occurrence of
a major cardiovascular
event (CHD death,
nonfatal non–procedurerelated MI, resuscitated
cardiac arrest, fatal or
nonfatal stroke)
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
Atorvastatin 80 mg
LDL-C target: 75 mg/dL
5 years
2
TNT Primary Efficacy Outcome Measure:
Major Cardiovascular Events*
Cumulative Incidence of Major
Cardiovascular Events, %
0.14
HR = 0.78 (95% CI, 0.69–0.89)
P < .001
0.12
Atorvastatin 10 mg (n = 5006)
LDL-C 101 mg/dL (2.6 mmol/L)
0.10
0.08
0.06
Atorvastatin 80 mg (n = 4995)
LDL-C 77 mg/dL (2.0 mmol/L)
0.04
0.02
Relative risk reduction = 22%
0
0
1
2
3
4
5
6
Time, years
*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
3
TNT: Primary and Secondary
Efficacy Outcomes
Primary Efficacy Measure
Major CV event
CHD death
Nonfatal non–procedure-related MI
Resuscitated cardiac arrest
Fatal/nonfatal stroke
HR
P Value
0.78
0.80
0.78
0.96
0.75
.001
.09
.004
.89
.02
0.81
0.80
0.79
0.77
0.74
0.97
1.01
<.001
.002
<.001
.007
.01
.76
.92
Secondary Efficacy Measures
Any cardiovascular event
Major coronary event*
Any coronary event
Cerebrovascular event
Hospitalization for CHF
Peripheral arterial disease
All-cause mortality
Atorvastatin 80 mg
Better
*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest.
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
Atorvastatin 10 mg
Better
4
Proportion of patients experiencing events
TNT: Time to First Fatal or Nonfatal Stroke
0.04
HR = 0.75 (95% CI 0.59-0.96)
P=0.02
Atorvastatin 10 mg
0.03
Atorvastatin 80 mg
Relative
RR = 25%
0.02
0.01
0
0
1
2
3
4
5
6
Time (years)
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
5
TNT: Safety Profile
10
P<0.001
8.1
% of Patients
8
P =0.72
5.8
6
4.8
4.7
4
P<0.001
2
0
(n=406)
(n=289)
(n=241)
Treatment-Related
Adverse Events
(n=234)
Treatment-Related
Myalgia
1.2
0.2
(n=60)
(n=9)
Elevated
Liver Enzymes*
Atorvastatin 80 mg (n=4,995)
Atorvastatin 10 mg (n=5,006)
Persistent = 2 consecutive measurements.
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
6
IDEAL (Incremental Decrease in End
Points Through Aggressive Lipid Lowering):
Study Design
Patient Population
• Previous hospitalization
with definite acute MI or a
history of definite MI
• Eligibility for statin
therapy according to
respective national
guidelines at discharge
Atorvastatin 80 mg
8888
Patients
Primary End Point
• Time to occurrence of a
major cardiovascular
event (CHD death,
nonfatal acute MI,
resuscitated cardiac
arrest)
Pedersen TR et al. JAMA. 2005;294:2437-2445.
Simvastatin 20 mg; titration
to 40 mg for TC >190 mg/dL
4.8 years
Open label with blinded
end-point evaluation
7
IDEAL: Primary and Secondary End Points
16
Simvastatin
Atorvastatin
12
11%
RRR
8
4
HR = 0.89 (95% CI, 0.76–1.01) P = .07
0
0
1
2
3
4
Major CV events – secondary end point
Cumulative Hazard, %
Cumulative Hazard, %
Major coronary events – primary end point
16
12
8
4
HR = 0.87 (95% CI, 0.78–0.98) P = .02
0
5
0
Years Since Randomization
16%
RRR
20
10
HR = 0.84 (95% CI, 0.76–0.91) P < .001
0
0
1
2
3
4
Years Since Randomization
2
3
4
5
5
Any CV event – secondary end point
Cumulative Hazard, %
Cumulative Hazard, %
Simvastatin
Atorvastatin
30
1
Years Since Randomization
Any coronary event – secondary end point
40
13%
RRR
Simvastatin
Atorvastatin
40
Simvastatin
Atorvastatin
30
16%
RRR
20
10
HR = 0.84 (95% CI, 0.78–0.91) P < .001
0
0
1
2
3
4
5
Years Since Randomization
The primary end point of IDEAL (a composite of CHD death, nonfatal MI, and resuscitated
cardiac arrest) did not reach statistical significance (HR = 0.89; 95% CI, 0.78-1.01; P = 0.07).
Pedersen TR et al. JAMA. 2005;294:2437-2445.
8
Effects of Atorvastatin 80 mg/d vs
Simvastatin 20 to 40 mg/d on Any CV Event
Events
HR (95% CI)*
Subjects
Relative Risk
With
Event Reduction (%)
P
Value
1st
(0.77 – 0.90)
2546
17
<.0001
2nd
(0.67 – 0.86)
1048
24
<.0001
3rd
(0.67 – 0.99)
416
19
.035
4th
(0.57 – 1.01)
192
24
.058
5th
(0.48 – 1.09)
93
28
.117
0.50
0.75
Atorvastatin
better
1.0
1.25
Simvastatin
better
*Adjusted for sex and age at baseline.
Tikkanen MJ et al. J Am Coll Cardiol. 2009;54:2353-2357.
1.50
9
MIRACL (Myocardial Ischemia Reduction
With Aggressive Cholesterol Lowering):
Study Design
Patient Population
• Non-Q-wave MI or
unstable angina
• Randomized 24–96 hours
from admission
Atorvastatin 80 mg
3086
Patients
Primary End Point
• Time to ischemic events
(CHD death, nonfatal MI,
documented angina
requiring hospitalization)
Schwartz GG et al. JAMA. 2001;285:1711-1718.
Placebo
16 weeks double-blind
10
MIRACL: Primary Efficacy Measure—
Time to First Event*
17.4%
Placebo (n = 1548)
LDL-C 135 mg/dL (3.5 mmol/L)
Cumulative Incidence, %
15
14.8%
16%
RRR
Atorvastatin 80 mg (n = 1538)
LDL-C 72 mg/dL (1.9 mmol/L)
10
5
RR = 0.84
P = .048
95% CI, 0.701–0.999
0
0
4
8
12
16
Time Since Randomization, weeks
*Death (any cause), nonfatal MI, resuscitated cardiac arrest, worsening angina with new objective
evidence and urgent rehospitalization.
Schwartz GG et al. JAMA. 2001;285:1711-1718.
11
MIRACL: Stroke
Placebo (n=1548)
Atorvastatin (n=1538)
Total strokes
25
13
Fatal stroke
2
3
Nonfatal stroke
23
10
Hemorrhagic
3
0
Embolic
1
0
Thrombotic/embolic
19
10
Indeterminate
2
3
Number patients experiencing
a stroke (P=0.04) (%)
24 (1.6)
12 (0.8)
Fatal stroke
2 (0.1)
3 (0.2)
Nonfatal stroke (P=0.02)
22 (1.4)
9 (0.6)
Type of stroke
Water DD et al. Circulation. 2002;106:1690-1695.
12
PROVE IT-TIMI (Pravastatin or Atorvastatin
Evaluation and Infection Therapy–
Thrombolysis in Myocardial Infarction) 22:
Study Design
Patient Population
• Hospitalized for an acute
coronary syndrome in the
preceding 10 days
• TC ≤240 mg/dL (6.2
mmol/L) or TC ≤200
mg/dL (5.2 mmol/L) if
receiving lipid-lowering
therapy
Atorvastatin 80 mg
4162
Patients
Primary End Point
• Time to first occurrence of
a major cardiovascular
event (death from any
cause, MI, unstable
angina, revascularization,
stroke
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
Pravastatin 40 mg
Double-blind
925 primary end points
13
PROVE IT: Primary End Point (All-Cause Death or
Major CV Events in All Randomized Subjects)
26.3%
Death or Major CV Event, %
30
16% RRR
Pravastatin 40 mg (n = 1548)
95 mg/dL (2.5 mmol/L)
25
(P = .005)
22.4%
20
–35% LDL
reduction
Atorvastatin 80 mg (n = 2099)
62 mg/dL (1.6 mmol/L)
15
10
5
0
0
3
6
9
12
15
18
21
24
27
30
Months of Follow-up
Major CV event = MI, unstable angina requiring rehospitalization, revascularization, or stroke.
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
14
PROVE IT-TIMI 22: Intensive Therapy
With Statins in Patients With ACS: Early
and Long-term Benefits
5
4
n = 2063
RRR = 28%
P = .046
3
n = 2099
2
1
0
0
5
10
15
20
25
Month 6 to end of study
Composite triple end point* (%)
Composite triple end point* (%)
Randomization to 30 days
12
n = 1752
10
RRR = 28%
P = .003
8
n= 1812
6
4
2
30
Days following randomization
Atorvastatin 80 mg
0
6
12
18
24
Months following randomization
Pravastatin 40 mg
*Death, MI, or rehospitalization with recurrent ACS.
Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:1405-1410.
15
Safety of Atorvastatin 80 mg
in Clinical Trials
Follow-up
Patients
ALT/AST
>3x ULN*
CK >10x
ULN*
Newman et al†
variable
4798
26 (0.6%)
2 (0.06%)
PROVE-IT
2 years
2099
69 (3.3%)
NA
TNT
4.9 years
4995
60 (1.2%)
0
IDEAL
4.8 years
4439
61 (1.38%)
0
SPARCL
4.9 years
2365
51 (2.2%)
2 (0.08%)
Total
variable
18,696
267 (1.43%)
4 (0.021%)
*Consecutive measurements.
†Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa
JC, et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al; for the IDEAL Study Group. JAMA.
2005;294:2437-2445; Amarenco P et al. N Engl J Med. 2006;355:549-559.
16
Overview of Adverse Events for
Atorvastatin 10 mg and 80 mg and Placebo
Placebo
(n=2180)
Atorvastatin 10 mg
(n=7258)
Atorvastatin 80 mg
(n=4798)
All cause
768 (35.2%)
3870 (53.3%)
2285 (47.6%)
Treatment associated
270 (12.4%)
983 (13.5%)
699 (14.6%)
All cause
51 (2.3%)
251 (3.5%)
136 (2.8%)
Treatment associated
27 (1.2%)
171 (2.4%)
84 (1.8%)
All cause
122 (5.6%)
453 (6.2%)
385 (8.0%)
Treatment associated
92 (4.2%)
12 (0.2%)
25 (0.5%)
Parameter
≥1 AE
Withdrawals due to AEs
Serious nonfatal AEs
Newman C et al. Am J Cardiol. 2006;97:61-67.
17