Statin Landmark Trials
Across the Spectrum of Risk:
Secondary CV Prevention
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)
Atorvastatin 80 mg
LDL-C target: 75 mg/dL
5 years
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
TNT Primary Efficacy Outcome
Measure: Major CV 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
Time, years
4
5
6
*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.
TNT: Primary and Secondary
Efficacy Outcomes
Primary Efficacy Measure
HR
Major CV event
CHD death
Nonfatal non–procedure-related MI
Resuscitated cardiac arrest
Fatal/nonfatal stroke
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
Atorvastatin 10 mg
Better
*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest.
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
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.
TNT: Safety Profile
10
P<0.001
8.1
% of Patients
8
5.8
6
P =0.72
4.8
4.7
4
P<0.001
2
0
(n=406)
(n=289)
Treatment-Related
Adverse Events
(n=241)
(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.
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)
Simvastatin 20 mg; titration
to 40 mg for TC >190 mg/dL
4.8 years
Open label with blinded
end-point evaluation
Pedersen TR et al. JAMA. 2005;294:2437-2445.
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.
Effects of Atorvastatin 80 mg/d vs
Simvastatin 20 to 40 mg/d on Any
CV Event
Events
Subjects
Relative Risk
With
Event Reduction (%)
HR (95% CI)*
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
1.50
*Adjusted for sex and age at baseline.
Tikkanen MJ et al. J Am Coll Cardiol. 2009;54:2353-2357.
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)
Placebo
16 weeks double-blind
Schwartz GG et al. JAMA. 2001;285:1711-1718.
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.
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.
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
Primary End Point
• Time to first occurrence of
a major cardiovascular
event (death from any
cause, MI, unstable
angina, revascularization,
stroke
Atorvastatin 80 mg
4162
Patients
Pravastatin 40 mg
Double-blind
925 primary end points
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
PROVE IT: Primary End Point (AllCause 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.
PROVE IT-TIMI 22: Intensive Therapy
With Statins in Patients With ACS: Early
and Long-term Benefits
Month 6 to end of study
5
4
n = 2063
RRR = 28%
P = .046
3
n = 2099
2
1
0
0
5
10
15
20
25
30
Composite triple end point* (%)
Composite triple end point* (%)
Randomization to 30 days
12
n = 1752
10
8
n= 1812
6
4
2
0
6
Days following randomization
RRR = 28%
P = .003
12
18
24
Months following randomization
Atorvastatin 80 mg
Pravastatin 40 mg
*Death, MI, or rehospitalization with recurrent ACS.
Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:1405-1410.
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%)
†Newman
*Consecutive measurements.
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.
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.
TNT: Changes in LDL-C by
Treatment Group
160
Baseline
Atorvastatin 80 mg (n = 4995)
140
120
3.5
Mean LDL-C level = 101 mg/dL (2.6 mmol/L)
3.0
100
2.5
80
2.0
60
Mean LDL-C level = 77 mg/dL (2.0 mmol/L)
40
1.5
1.0
Mean LDL-C, mmol/L
Mean LDL-C, mg/dL
4.0
Atorvastatin 10 mg (n = 5006)
P < .001
20
0
Screen
0.5
0
3
12
24
36
48
60
0.0
Final
Study Visits, months
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
PROVE IT: Reductions in Major
Cardiac End Points
RR
2-Year Event Rates
Atorva 80
Prava 40
All-Cause Mortality
28%
2.2%
3.2%
CHD Death
30%
1.1%
1.4%
MI
13%
6.6%
7.4%
Death or MI
18%
8.3%
10.0%
Revasc >30 d
14%
16.3%
18.8%
UA Req Hosp
29%
3.8%
5.1%
Death/MI/Urg. Revasc
25%
12.9%
16.7%
0.5
0.75
Atorvastatin 80 mg Better
1.0
1.25
1.5
Pravastatin 40 mg Better
Cannon CP et al. N Engl J Med. 2004;350:1495-1504.
Effect of Intensive Statin Therapy on Clinical
OutcomesAmong Patients Undergoing Percutaneous
Coronary Intervention for ACS: PCI-PROVE IT
Substudy
Post hoc analysis of 2868 patients who underwent PCI just prior to enrollment
30%
25%
Primary End Point
Pravastatin
Death, MI, RI, UA
Pravastatin
25%
20%
Atorvastatin
15%
10%
Hazard ratio 0.78
95% CI, 0.67–0.91
P < .001
5%
20%
15%
Atorvastatin
10%
Hazard ratio 0.73
95% CI, 0.61–0.87
P < .001
5%
0%
0%
0
120
240
360
Time, days
480
600
720
0
120
240
360
480
600
720
Time, days
Gibson CM et al. J Am Coll Cardiol. 2009;54:2290-2295.
Long-term Statin Treatment in
IDEAL Maintained Benefit Over 5
Years
Longest Period of Follow-up of ACS Patients on Statin Therapy
*Composite end point = death, nonfatal MI, hospitalization for UA, or coronary revascularization
IDEAL (All MI)
PROVE IT (MI or UA)
60
Composite End Point *, %
18% RRR
P = 0.04
50
40
16% RRR
P = 0.005
30
20
Atorvastatin 80 mg
Pravastatin 40 mg
Simvastatin 20 -40 mg
10
0
0
30 months
5 years
Cannon CP et al. N Engl J Med. 2004;350:1495-1504;
Pedersen TR et al. Am J Cardiol. 2010;106:354-359.
MIRACL: Secondary End
Points
No. of Events (%)
Atorvastatin Placebo
Stroke (fatal and
nonfatal)
12 (0.8)
24 (1.6)
Revascularization
(CABG or PTCA)
254 (16.5)
250 (16.1)
Worsening angina (without
objective evidence of ischemia)
91 (5.9)
106 (6.8)
Worsening congestive
heart failure
40 (2.6)
43 (2.8)
*P = .045.
0.25
0.50
0.75
1.00
Atorvastatin Better
1.25 1.50
Placebo Better
Relative Risk
Schwartz GG et al. JAMA. 2001;285:1711-1718.
Association of Dyslipidemia and
myocardial Infarction Risk:
INTERHEART
512
2.9
Risk of AMI With Multiple Risk Factors
2.4
1.9
3.3
13.0
42.3
68.5
182.9
333.7
+PS
All RFs
256
OR (99% CI)
128
64
3-fold
increase in
risk of
acute MI
32
16
8
4
2
1
Smk
DM
HTN
Lipids
1+2+3 all4
+O
AMI, acute myocardial infarction; Smk, smoking; DM, diabetes mellitus; HTN, hypertension; O, obesity; PS, psychosocial;
RF, risk factors; OR; odds ratio.
Yusuf S et al. Lancet. 2004;364:937-952.
ASCOT CRP Analysis
•
Post hoc subgroup (nested case control) analysis of ASCOT data
– To assess baseline CRP and risk of CV events: 5.5 years follow-up, 485 patients
with major CV events matched with 1367 controls from baseline population
(ASCOT BPLA)
– To assess the effect of statin treatment on CRP and risk of CV events: 5.5 years
follow-up, 235 patients with major CV events matched with 777 controls from
statin trial population (ASCOT LLA)
•
Baseline CRP and risk of CV events
– Inclusion of CRP in a Framingham risk model modestly improved the prediction
of CV events beyond use of standard CV risk factors by a small amount
•
On-statin-treatment CRP and risk of CV events
– Levels of LDL-C were strongly associated with reductions in CV events
– On-statin-treatment CRP levels were not predictive of CV outcomes
– Atorvastatin 10 mg reduced median CRP by 27%
Late Breaking Clinical Trials. AHA Scientific Session 2010. Abstract 21685. downloaded from
http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#ascot