The PROVE IT Trial

1
The PROVE IT Trial

• Pravastatin or Atorvastatin Evaluation and
  Infection Therapy

2
Overview

• Rationale
• Design
• Results and conclusions

3
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. 20043501495-1504.
4
PROVE IT Is the First Head-to-Head Morbidity and
Mortality Trial Involving Statins

• Follow-up 1st efficacy RR reductionStudy Com
  parator (y) parameter ()
• 1st prevention
• WOSCOPS1 Placebo 4.9 MI CHD death 31
• AFCAPS/TexCAPS2 Placebo 5.2 MI/CHD death/UA 36
• ASCOT3 Placebo 3.3 MI CHD death 36
• 1st/2nd prevention
• HPS4 Placebo 5.0 MI CHD death 24
• 2nd prevention
• 4S5 Placebo 5.4 Total mortality 30
• CARE6 Placebo 5.0 MI CHD death 24
• LIPID7 Placebo 6.1 CHD death 24
• PROVE IT8 Head-to-head 2.0 All cause
  mortality/ ??? Major CV event

1 Shepherd J, et al. N Engl J Med.
19953331301-1307. 2 Downs JR, et al. JAMA.
19982791615-1622. 3 Sever PS, et al. Lancet.
20033611149-1158. 4 Heart Protection
Collaborative Group. Lancet. 20023607-22. 5
Scandinavian Simvastatin Study Group. Lancet.
19943441383-1389. 6 Sacks FM, et al. N Engl J
Med. 19963351001-1009. 7 LIPID Study Group. N
Engl J Med. 19983391349-1357. 8 Cannon CP, et
al, for the PROVE IT-TIMI 22 Investigators. N
Engl J Med. 20043501495-1504.
2Downs JR, et al. JAMA 19982791615-1622.
3Sever PS, et al. Lancet. 20033611149-1158.
4Heart Protection Collaborative Group. Lancet
20023607-22.
5Scandinavian Simvastatin Study Group. Lancet
16643441383-9.
5
Is Aggressive LDL-C Lowering More Effective in
Reducing Clinical Events?
Baseline LDL-C
? 25-35
? 50
Current NCEP III LDL-C goal 2.6 mmol/L (100 mg/dL)
On-treatment LDL-C
????
EVENT REDUCTION
Cannon CP, et al, for the PROVE IT-TIMI 22
Investigators. N Engl J Med. 20043501495-1504.
6
Overview

• Rationale
• Design
• Results and conclusions

7
PROVE IT Study Design
Randomized, double-blind trial in 4162 patients
with ACS lt 10 days and TC ? 6.2 mmol/L (240 mg/dL)
ASA standard medical therapy
Pravastatin 40 mg/d
Atorvastatin 80 mg/d
Gatifloxacin
Gatifloxacin
Placebo
Placebo
Duration mean 2-y follow-up (925 events)
Primary end point death, MI, stroke, unstable
angina requiring hospitalization, or
revascularization (gt 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. 20043501495-1504.
8
Patient Population

• Inclusion criteria
• Hospitalization for acute MI or high-risk
  unstable angina lt 10 days
• TC 6.2 mmol/L (240 mg/dL) (lt 5.2 mmol/L 200
  mg/dL if on lipid ? Rx)
• Stabilized (ie, without ischemia, CHF, postPCI
  if performed)
• Major exclusion criteria
• Comorbidity patient survival lt 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. 20043501495-1504.
9
Overview

• Rationale
• Design
• Results and conclusions

10
Baseline Characteristics

• Atorvastatin 80 mg Pravastatin 40 mg (n
  2099) (n 2063)
• Mean age (y) 58 58
• Male/Female () 78/22 78/22
• History of hypertension () 51 49
• Current smoker () 36 37
• History of diabetes () 18 18
• Prior MI () 18 19
• STEMI-NSTEMI-UA () 36/36/29 33/37/30
• Prior statin use () 26 25

MI, myocardial infarction STEMI, ST-elevation
myocardial infarctionNSTEMI, nonST-elevation
myocardial infarction UA, unstable
angina. Cannon CP, et al, for the PROVE IT-TIMI
22 Investigators. N Engl J Med.
20043501495-1504.
11
Concomitant Medications Given During Treatment
Period

• Concomitant medication of overall patient
  population
• Aspirin 93
• Warfarin 8
• Clopidogrel or ticlopidine At study
  start 72 After 1 y 20
• ß-Blocker 85
• ACE inhibitor 69
• Angiotensin-receptor blocker 14

ACE, angiotensin-converting enzyme. Cannon CP, et
al, for the PROVE IT-TIMI 22 Investigators. N
Engl J Med. 20043501495-1504.
12
Changes From Baseline (PostACS) in Median LDL-C
120
100
Pravastatin 40 mg
80
LDL-C (mg/dL)
60
Atorvastatin 80 mg
40
20
Baseline
30 days
4 mo
8 mo
16 mo
Final
Time of visit
Cannon CP, et al, for the PROVE IT-TIMI 22
Investigators. N Engl J Med. 20043501495-1504.
13
Atorvastatin 80 mg Reduced LDL-C More Than
Pravastatin 40 mg
Baseline LDL-Cmmol/L (mg/dL)
2.74 (106)
2.74 (106)
Current NCEP III LDL-C goal 2.6 mmol/L (100 mg/dL)
End-of-study LDL-Cmmol/L(mg/dL)
2.46 (95)
1.60 (62)
Cannon CP, et al, for the PROVE IT-TIMI 22
Investigators. N Engl J Med. 20043501495-1504.
14
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
30
Pravastatin 40 mg26.3
25
20
Atorvastatin 80 mg22.4
patients with event
15
10
5
P 0.005
0
30
3
6
9
12
15
18
21
24
27
0
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. 20043501495-1504.
15
Primary End Point Over Time
Event rates
RR Atorvastatin Pravastatin 80 mg 40 mg
Hazard ratio (95 CI)
17 1.9 2.2
30 days
18 6.3 7.7
90 days
14 12.2 14.1
180 days
16 22.4 26.3
End of follow-up
Pravastatin Better
Atorvastatin Better
Cannon CP, et al, for the PROVE IT-TIMI 22
Investigators. N Engl J Med. 20043501495-1504.
16
Reductions in Major Cardiac End Points
2-y event rates
RR Atorvastatin Pravastatin 80 mg 40 mg
Hazard ratio (95 CI)
28 2.2 3.2
Death from any cause
30 1.1 1.4
Death from CHD
27 1.2 1.8
Deathother causes
13 6.6 7.4
MI
18 8.3 10.0
Death or MI
16 7.2 8.3
Death from CHD or MI
14 16.3 18.8
Revascularization
MI, revascularization,or death from CHD
14 19.7 22.3
UA requiringhospitalization
29 3.8 5.1
-9 1.0 1.0
Stroke
0.5
1.0
1.5
Pravastatin Better
Atorvastatin Better
Cannon CP, et al, for the PROVE IT-TIMI 22
Investigators. N Engl J Med. 20043501495-1504.
17
Subgroups Reduction in All-Cause Mortality or
Major CV Events
2-y event rates
Atorvastatin Pravastatin 80 mg 40 mg
of patients
Hazard ratio
23.0 26.220.3 27.0
Male 78
Female 22
28.1 29.520.1 25.0
? 65 y 30
lt 65 y 70
28.8 34.621.0 24.6
Diabetes 18
No diabetes 82
22.8 26.521.3 25.9
Prior smoker 74
Not prior smoker 26
Prior statin 25
27.5 28.920.6 25.5
No prior statin 75
26.5 31.419.0 24.1 22.6 24.2
UA 29
NSTMI 36
STMI 35
20.1 28.223.5 25.6
LDL-C ? 3.2 (125) 27
LDL-C lt 3.2 (125) 73
21.7 26.723.1 26.0
HDL-C ? 1.0 (40) 44
HDL-C lt 1.0 (40) 56
0.5
1.0
1.5
Atorvastatin Better
Pravastatin Better
mmol/L (mg/dL)
Cannon CP, et al, for the PROVE IT-TIMI 22
Investigators. N Engl J Med. 20043501495-1504.
18
Safety Adverse Events

• Atorvastatin Pravastatin 80 mg 40 mg P-value
• Discontinued due to AEs
• 1 y 22.8 21.4 0.30
• 2 y 30.4 33.0 0.11
• ALT elevation gt 3 x ULN 3.3 1.1 lt 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. 20043501495-1504.
19
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. 20043501495-1504.
20
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. 20043501495-1504.