PROVE IT研究
PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22)
Disclosure Statement: Dr. Cannon currently receives research grant support from Bristol-Myers Squibb, Merck and Sanofi-Synthelabo. He serves as a consultant to AstraZeneca, Glaxo Smith Kline, Guilford Pharmaceuticals and Vertex
Background
Statin therapy is highly effective vs. placebo in long-term treatment of CHD
Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)?
Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical events than “standard” LDL-C lowering to an average of 95 mg/dL?
4,162 patients with an Acute Coronary Syndrome < 10 days
ASA + Standard Medical Therapy
“Standard Therapy”
Pravastatin 40 mg
“Intensive Therapy”
Atorvastatin 80 mg
Duration: Mean 2 year follow-up (>925 events)
Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
PROVE IT - TIMI 22: Study Design
2x2 Factorial: Gatifloxacin vs. placebo
Double-blind
Patient Population
Inclusion Criteria:
Hospitalization for acute MI or high-risk unstable angina < 10 d
Total cholesterol < 240 mg/dL (< 200 mg/dL if on Lipid ? Rx)
Stabilized (i.e., without ischemia, CHF, post PCI if performed)
Major Exclusion Criteria:
Co-morbidity: patient survival < 2 years
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 CK elevations
Strong inhibitors of CYP450 3A4 (2o atorvastatin metabolism)
Patient Enrollment by Country
Australia A. Tonkin, I. Meridith 18 266
Canada J. Rouleau 20 349
France A. Castaigne 20 132
Germany H. Darius 21 93
Italy G. DeFerrari 15 86
Spain J. Velasco 14 102
United Kingdom G. Jackson 20 186
United States C. Cannon 221 2948
Total 349 4162
# Sites # Pts
Top Ten Enrolling Clinical Centers
Huntsville Hospital, Huntsville AL W. Haught K. Griffin
Fremantle Hospital, Fremantle WA R. Hendriks D. Greenwell
Detar Hospital, Victoria, TX H. Chandna D. Holly
St. Francis Hospital, Tulsa, OK J. M. Cassidy N. Ritchie
Advanced Health Institute, Galax, VA J. Puma E. Jones
Michigan Heart, Ypsilanti, MI J. Bengtson C. Carulli
N. Mississippi Medical Center, Tupelo, MS B. Bertolet M. Jones
Wilford Hall Med Center, Lackland AFB, TX R. Krasuski U. Ward
Queen Elizabeth Hospital, Woodville, Sa J. Horowitz R. Prideaux
Moses H. Cone Hospital, Greensboro, NC T. Kelly K. Cochran
Principal Research Hospital Investigator Coordinator
TIMI Study Group Eugene Braunwald, MD
Brigham and Women’s Hosp. Christopher Cannon, MD
Carolyn McCabe, BS
Data Coordinating Center Allan Skene PhD.
Nottingham Karen Hill
Sponsors: Rene Belder, MD
Bristol-Myers Squibb Steven Joyal, MD
and Sankyo Co. LTD Gabriella Cucinotta
Chen-Sheng Lin, PhD
Clinical Events Committee: Marc Pfeffer, MD, PhD
Trial Organization
Baseline Characteristics
Atorvastatin 80mg Pravastatin 40mg
(2099) (2063)
Mean Age (years) 58 58
Male/Female (%) 78 / 22 78 / 22
History of HTN (%) 51 49
Current Smoker (%) 36 37
History of Diabetes (%) 19 18
History of CHD (%) 37 39
STEMI / NSTEMI / UA (%) 36 / 36 / 29 33 / 37 / 30
Prior Statin Use (%) 26 25
Concomitant Therapies
PCI for initial ACS pre-Rand 69%
Aspirin 93%
Warfarin 8%
Clopidogrel (initial) 72% (at F/U) 20%
B-blockers 85%
ACE 69%
ARB 14%
Changes from (Post-ACS) Baseline in Median LDL-C
Note: Changes in LDL-C may differ from prior trials:
25% of patients on statins prior to ACS event
ACS response lowers LDL-C from true baseline
LDL-C
(mg/dL)
20
40
60
80
100
120
Rand.
30 Days
4 Mos.
8 Mos.
16 Mos.
Final
Pravastatin 40mg
Atorvastatin 80mg
49% ?
21%?
P<0.001
Median LDL-C (Q1, Q3)
95 (79, 113)
62 (50, 79)
<24h
All-Cause Death or Major CV Events in All Randomized Subjects
% with Event
Months of Follow-up
Pravastatin 40mg
(26.3%)
Atorvastatin 80mg
(22.4%)
16% RR
(P = 0.005)
30
25
20
15
10
5
0
Events Rates
RR Atorva 80 Prava 40
17% 1.9% 2.2%
18% 6.3% 7.7%
14% 12.2% 14.1%
16% 22.4%* 26.3%*
30 Days
90 Days
180 Days
End of Follow-up
Primary Endpoint Over Time
Atorvastatin 80mg Better
0.5 0.75 1.0 &nb