The PROVE IT Trial
Pravastatin or Atorvastatin Evaluation and
Infection Therapy
Overview
• Rationale
• Design
• Results and conclusions
What Is PROVE IT?
• Background: Lipid-lowering therapy with statins
reduces the risk of CV events, but the optimal level of
LDL-C is unclear
• Objective: To compare the effects of moderate lipid
lowering with pravastatin 40 mg to an LDL-C level of
~2.6 mmol/L (100 mg/dL) with intensive lipid lowering
with atorvastatin 80 mg to a lower level of ~1.8 mmol/L
(70 mg/dL) on the prevention of death or major CV
events in patients with ACS
• Significance: The first head-to-head morbidity and
mortality trial involving statins
• PROVE IT was funded by Bristol-Myers Squibb
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
PROVE IT Is the First Head-to-Head Morbidity
and Mortality Trial Involving Statins
Comparator
Follow-up
(y)
1st efficacy
parameter
RR reduction
(%)
1st prevention
WOSCOPS1
AFCAPS/TexCAPS2
ASCOT3
Placebo
Placebo
Placebo
4.9
5.2
3.3
MI + CHD death
MI/CHD death/UA
MI + CHD death
31
36
36
1st/2nd prevention
HPS4
Placebo
5.0
MI + CHD death
24
2nd prevention
4S5
CARE6
LIPID7
Placebo
Placebo
Placebo
5.4
5.0
6.1
Total mortality
MI + CHD death
CHD death
30
24
24
PROVE IT8
Head-to-head
2.0
All cause mortality/
Major CV event
???
Study
1 Shepherd
2 Downs
3 Sever
4 Heart
J, et al. N Engl J Med. 1995;333:1301-1307.
PS,
al. Lancet.
2003;361:1149-1158.
2Downs JR, et
al.etJAMA
1998;279:1615-1622.
5 Scandinavian Simvastatin Study Group. Lancet. 1994;344:1383-1389.
3Sever
7 LIPID
PS, et
al. Lancet.
.
Study
Group.2003;361:1149-1158
N Engl J Med. 1998;339:1349-1357.
4Heart
.
Protection Collaborative Group. Lancet 2002;360:7-22
5Scandinavian
Simvastatin Study Group. Lancet 1664;344:1383-9.
JR, et al. JAMA. 1998;279:1615-1622.
Protection Collaborative Group. Lancet. 2002;360:7-22.
6 Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.
8 Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators.
N Engl J Med. 2004;350:1495-1504.
Is Aggressive LDL-C Lowering More Effective
in Reducing Clinical Events?
Moderate LDL-C
lowering
(pravastatin 40 mg)
Intensive LDL-C
lowering
(atorvastatin 80 mg)
Baseline LDL-C
 25-35%
 50%
On-treatment LDL-C
EVENT REDUCTION
????
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Current NCEP III LDL-C goal
2.6 mmol/L (100 mg/dL)
Overview
• Rationale
• Design
• Results and conclusions
PROVE IT: Study Design
Randomized, double-blind trial in 4162 patients with ACS
< 10 days and TC  6.2 mmol/L (240 mg/dL)
ASA + standard medical therapy
Pravastatin
40 mg/d
Gatifloxacin*
Placebo*
Atorvastatin
80 mg/d
Gatifloxacin*
Placebo*
Duration: mean 2-y follow-up (925 events)
Primary end point: death, MI, stroke, unstable angina requiring
hospitalization, or revascularization (> 30 days after randomization)
*2x2 factorial design. Results of the antibiotic arm are not reported in this slide set.
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Patient Population
• Inclusion criteria:
– Hospitalization for acute MI or high-risk unstable angina < 10 days
– TC ≤ 6.2 mmol/L (240 mg/dL) (< 5.2 mmol/L [200 mg/dL] if on lipid
 Rx)
– Stabilized (ie, without ischemia, CHF, post–PCI if performed)
• Major exclusion criteria:
–
–
–
–
–
–
Comorbidity: patient survival < 2 y
Current therapy with simvastatin or atorvastatin 80 mg
Need for, or anticipated use of, fibrates or niacin
CABG for treatment of qualifying ACS
Liver disease or unexplained CPK elevations
Strong inhibitors of CYP450 3A4 (2nd atorvastatin metabolism)
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Overview
• Rationale
• Design
• Results and conclusions
Baseline Characteristics
Atorvastatin 80 mg
(n = 2099)
Pravastatin 40 mg
(n = 2063)
58
78/22
58
78/22
History of hypertension (%)
Current smoker (%)
51
36
49
37
History of diabetes (%)
Prior MI (%)
18
18
18
19
STEMI-NSTEMI-UA (%)
Prior statin use (%)
36/36/29
26
33/37/30
25
Mean age (y)
Male/Female (%)
MI, myocardial infarction; STEMI, ST-elevation myocardial infarction;
NSTEMI, non–ST-elevation myocardial infarction; UA, unstable angina.
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Concomitant Medications Given During
Treatment Period
Concomitant medication
% of overall patient population
Aspirin
Warfarin
93
8
Clopidogrel or ticlopidine
At study start
After 1 y
β-Blocker
72
20
85
ACE inhibitor
Angiotensin-receptor blocker
69
14
ACE, angiotensin-converting enzyme.
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Changes From Baseline (Post–ACS) in
Median LDL-C
120
LDL-C (mg/dL)
100
Pravastatin 40 mg
80
60
Atorvastatin 80 mg
40
20
Baseline
30 days
4 mo
8 mo
16 mo
Time of visit
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Final
Atorvastatin 80 mg Reduced LDL-C More
Than Pravastatin 40 mg
Moderate LDL-C
lowering
(pravastatin 40 mg)
Baseline LDL-C
mmol/L (mg/dL)
2.74 (106)
Intensive LDL-C
lowering
(atorvastatin 80 mg)
2.74 (106)
Current NCEP III LDL-C goal
2.6 mmol/L (100 mg/dL)
End-of-study LDL-C
mmol/L(mg/dL)
2.46 (95)
1.60 (62)
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Effects on Primary End Point
Atorvastatin 80 mg had a significantly greater effect than pravastatin 40 mg
on the incidence of death or a major CV event
% patients with event*
30
16%
reduction
Pravastatin 40 mg
26.3%
25
20
Atorvastatin 80 mg
22.4%
15
10
5
P = 0.005
0
0
3
6
9
12
15
18
21
24
Months of follow-up
*All-cause mortality or major CV event.
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
27
30
Primary End Point Over Time
Event rates
RR Atorvastatin Pravastatin
80 mg
40 mg
Hazard ratio (95% CI)
30 days
17%
1.9%
2.2%
90 days
18%
6.3%
7.7%
180 days
14%
12.2%
14.1%
End of follow-up
16%
22.4%
26.3%
0.5
0.75
1.0
Atorvastatin Better
1.25
1.5
Pravastatin Better
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Reductions in Major Cardiac End Points
2-y event rates
RR Atorvastatin Pravastatin
80 mg
40 mg
28%
2.2%
3.2%
30%
1.1%
1.4%
27%
1.2%
1.8%
13%
6.6%
7.4%
18%
8.3%
10.0%
16%
7.2%
8.3%
Hazard ratio (95% CI)
Death from any cause
Death from CHD
Death—other causes
MI
Death or MI
Death from CHD or MI
Revascularization
14%
16.3%
18.8%
MI, revascularization,
or death from CHD
14%
19.7%
22.3%
UA requiring
hospitalization
29%
3.8%
5.1%
Stroke
-9%
1.0%
1.0%
0.5
1.0
Atorvastatin Better
1.5
Pravastatin Better
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Subgroups: Reduction in All-Cause
Mortality or Major CV Events
% of patients
Hazard ratio
2-y event rates
Atorvastatin Pravastatin
80 mg
40 mg
Male
Female
78
22
23.0%
20.3%
26.2%
27.0%
 65 y
< 65 y
30
70
28.1%
20.1%
29.5%
25.0%
Diabetes
No diabetes
18
82
28.8%
21.0%
34.6%
24.6%
Prior smoker
Not prior smoker
74
26
22.8%
21.3%
26.5%
25.9%
Prior statin
No prior statin
25
75
27.5%
20.6%
28.9%
25.5%
UA†
NSTMI†
STMI†
29
36
35
26.5%
19.0%
22.6%
31.4%
24.1%
24.2%
LDL-C*  3.2 (125)
LDL-C* < 3.2 (125)
27
73
20.1%
23.5%
28.2%
25.6%
HDL-C*  1.0 (40)
HDL-C* < 1.0 (40)
44
56
21.7%
23.1%
26.7%
26.0%
0.5
*mmol/L (mg/dL)
Atorvastatin Better
1.0
1.5
Pravastatin Better
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Safety: Adverse Events
Atorvastatin
80 mg
Pravastatin
40 mg
P-value
Discontinued due to AEs
1y
2y
22.8%
30.4%
21.4%
33.0%
0.30
0.11
ALT elevation > 3 x ULN
3.3%
1.1%
< 0.001
Dosage reduction*
1.9%
1.4%
0.20
Discontinued for myalgia/CPK
3.3%
2.7%
0.23
There were no cases of rhabdomyolysis in either group.
*Dosage reduced due to side effects or liver function abnormalities.
AE, adverse event; ALT, alanine aminotransferase; ULN, upper limit of normal;
CPK, creatinine phosphokinase.
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
Summary
• PROVE IT is the first head-to-head morbidity and
•
mortality trial involving statins
Atorvastatin 80 mg/d demonstrated superior clinical
benefits over pravastatin 40 mg/d and a comparable
safety profile in patients with ACS
• Superiority of atorvastatin 80 mg/d began to emerge
•
at 30 days, was significant at 180 days, and was
maintained throughout the study
Results especially compelling given the short
duration and study design
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.
PROVE IT Supports and Extends Results
From REVERSAL
• PROVE IT demonstrates that the difference between
•
atorvastatin 80 mg and pravastatin 40 mg in effects
on atherosclerotic progression translate to
differences in effects on CV end points in patients
with ACS
PROVE IT confirms the findings from REVERSAL:
atorvastatin 80 mg has a comparable safety profile to
pravastatin 40 mg
• Results of PROVE IT substantiate the use of IVUS in
the REVERSAL study as an early predictive tool for
assessing the clinical benefits of a cardiopreventive
intervention
Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.