pravastatin or atorvastatin evaluation and infection therapy (timi 22) disclosure statement: dr....
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PRPRavastatin avastatin OOr atorr atorVVastatin astatin EEvaluation and valuation and IInfection nfection TTherapy (TIMI 22)herapy (TIMI 22)
Disclosure Statement: Dr. Cannon currently receives research grant support from Disclosure Statement: Dr. Cannon currently receives research grant support from Bristol-Myers Squibb, Merck and Sanofi-Synthelabo. He serves as a consultant to Bristol-Myers Squibb, Merck and Sanofi-Synthelabo. He serves as a consultant to
AstraZeneca, Glaxo Smith Kline, Guilford Pharmaceuticals and VertexAstraZeneca, Glaxo Smith Kline, Guilford Pharmaceuticals and Vertex
BackgroundBackground
Statin therapy is highly effective vs. placebo in long-Statin therapy is highly effective vs. placebo in long-term treatment of CHD term treatment of CHD
Are statins effective in reducing events in patients Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)? with an acute coronary syndrome (ACS)?
Does “intensive” LDL-C lowering to an average of Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical 65 mg/dL achieve a greater reduction in clinical events than “standard” LDL-C lowering to an events than “standard” LDL-C lowering to an average of 95 mg/dL?average of 95 mg/dL?
4,162 patients with an Acute Coronary Syndrome < 10 days 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
Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
PROVE IT - TIMI 22: PROVE IT - TIMI 22: Study DesignStudy Design
2x2 Factorial: Gatifloxacin vs. placebo
Double-blindDouble-blind
Patient PopulationPatient Population
Inclusion Criteria:Inclusion Criteria: Hospitalization for acute MI or high-risk unstable angina < 10 Hospitalization for acute MI or high-risk unstable angina < 10
dd Total cholesterol Total cholesterol << 240 mg/dL (< 200 mg/dL if on Lipid 240 mg/dL (< 200 mg/dL if on Lipid Rx) Rx) Stabilized (i.e., without ischemia, CHF, post PCI if performed) Stabilized (i.e., without ischemia, CHF, post PCI if performed)
Major Exclusion Criteria:Major Exclusion Criteria: Co-morbidity: patient survival < 2 yearsCo-morbidity: patient survival < 2 years Current therapy with simvastatin or atorvastatin 80 mg Current therapy with simvastatin or atorvastatin 80 mg Need for, or anticipated use of fibrates or niacin Need for, or anticipated use of fibrates or niacin CABG for treatment of qualifying ACSCABG for treatment of qualifying ACS Liver disease or unexplained CK elevationsLiver disease or unexplained CK elevations Strong inhibitors of CYP450 3A4 (2Strong inhibitors of CYP450 3A4 (2o o atorvastatin metabolism)atorvastatin metabolism)
Patient Enrollment by CountryPatient Enrollment by Country
Australia Australia A. Tonkin, I. Meridith 18A. Tonkin, I. Meridith 18 266266
CanadaCanada J. Rouleau J. Rouleau 20 20 349349
FranceFrance A. CastaigneA. Castaigne 20 20 132 132
GermanyGermany H. DariusH. Darius 21 21 93 93
ItalyItaly G. DeFerrari G. DeFerrari 15 15 8686
SpainSpain J. VelascoJ. Velasco 14 14 102102
United Kingdom United Kingdom G. Jackson G. Jackson 20 20 186186
United StatesUnited States C. CannonC. Cannon 221 221 29482948
TotalTotal 349 349 4162 4162
# Sites # Pts# Sites # Pts
Top Ten Enrolling Clinical CentersTop Ten Enrolling Clinical Centers
Huntsville Hospital, Huntsville ALHuntsville Hospital, Huntsville AL W. Haught W. Haught K. GriffinK. Griffin
Fremantle Hospital, Fremantle WAFremantle Hospital, Fremantle WA R. Hendriks R. Hendriks D. GreenwellD. Greenwell
Detar Hospital, Victoria, TXDetar Hospital, Victoria, TX H. Chandna H. Chandna D. Holly D. Holly
St. Francis Hospital, Tulsa, OKSt. Francis Hospital, Tulsa, OK J. M. CassidyJ. M. Cassidy N. RitchieN. Ritchie
Advanced Health Institute, Galax, VAAdvanced Health Institute, Galax, VA J. Puma J. Puma E. JonesE. Jones
Michigan Heart, Ypsilanti, MI Michigan Heart, Ypsilanti, MI J. Bengtson J. Bengtson C. CarulliC. Carulli
N. Mississippi Medical Center, Tupelo, MSN. Mississippi Medical Center, Tupelo, MS B. BertoletB. Bertolet M. Jones M. Jones
Wilford Hall Med Center, Lackland AFB, TXWilford Hall Med Center, Lackland AFB, TX R. Krasuski R. Krasuski U. Ward U. Ward
Queen Elizabeth Hospital, Woodville, Sa Queen Elizabeth Hospital, Woodville, Sa J. Horowitz J. Horowitz R. Prideaux R. Prideaux
Moses H. Cone Hospital, Greensboro, NCMoses H. Cone Hospital, Greensboro, NC T. Kelly T. Kelly K. CochranK. Cochran
PrincipalPrincipal ResearchResearchHospital Hospital InvestigatorInvestigator CoordinatorCoordinator
TIMI Study GroupTIMI Study Group Eugene Braunwald, MD Eugene Braunwald, MD Brigham and Women’s Hosp.Brigham and Women’s Hosp. Christopher Cannon, MD Christopher Cannon, MD
Carolyn McCabe, BSCarolyn McCabe, BS
Data Coordinating CenterData Coordinating Center Allan Skene PhD.Allan Skene PhD.Nottingham Nottingham Karen Hill Karen Hill
Sponsors:Sponsors: Rene Belder, MD Rene Belder, MDBristol-Myers SquibbBristol-Myers Squibb Steven Joyal, MD Steven Joyal, MDand Sankyo Co. LTDand Sankyo Co. LTD Gabriella Cucinotta Gabriella Cucinotta
Chen-Sheng Lin, PhDChen-Sheng Lin, PhD
Clinical Events Committee:Clinical Events Committee: Marc Pfeffer, MD, PhD Marc Pfeffer, MD, PhD
Trial OrganizationTrial Organization
Baseline CharacteristicsBaseline CharacteristicsBaseline CharacteristicsBaseline 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
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 TherapiesConcomitant TherapiesConcomitant TherapiesConcomitant 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%
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 Changes from (Post-ACS) Baseline in Median LDL-CMedian LDL-C
Note: Changes in LDL-C may differ from prior trials: Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event25% of patients on statins prior to ACS event• ACS response lowers LDL-C from true baselineACS 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 80mg49% 49%
21%21%
P<0.001P<0.001
Median LDL-C (Q1, Q3)Median LDL-C (Q1, Q3)
95 (79, 113)95 (79, 113)
62 (50, 79) 62 (50, 79)
<24h
All-Cause Death or Major CV Events in All Randomized Subjects
00 33 1818 2121 2424 2727 303066 99 1212 1515
% with Event
Months of Follow-up
Pravastatin 40mgPravastatin 40mg(26.3%)(26.3%)
Atorvastatin 80mgAtorvastatin 80mg(22.4%)(22.4%)
16% RR16% RR
(P = 0.005)(P = 0.005)
3030
2525
2020
1515
1010
55
00
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 TimePrimary Endpoint Over Time
Atorvastatin 80mg Better 0.5 0.75 1.0 1.25 1.5
Pravastatin 40mg Better *2-year event rates*2-year event rates
Reductions in Major Cardiac Reductions in Major Cardiac EndpointsEndpoints
2 Year Event Rates RR Atorva 80 Prava 40
28% 2.2% 3.2%
30% 1.1% 1.4%
13% 6.6% 7.4%
18% 8.3% 10.0%
14% 16.3% 18.8%
29% 3.8% 5.1%
25% 12.9% 16.7%
0.5 1.0 1.5
All-Cause Mortality
Death or MI
Death/MI/Urg.Revasc
MI
Revasc > 30 d
UA Req Hosp
0.75 1.25
Atorvastatin 80 mg Better Pravastatin 40 mg Better
CHD Death
% % with with
EventEvent
00 33 1818 2121 2424 2727 303066 99 1212 1515
2020
1515
1010
55
00
Months of Follow-up
All-Cause Death, Non-Fatal MI, or Urgent Revascularization
All-Cause Death, Non-Fatal MI, or Urgent Revascularization
Pravastatin 40mgPravastatin 40mg16.7%16.7%
Atorvastatin 80mgAtorvastatin 80mg12.9%12.9%
25% RR25% RRP = 0.0004P = 0.0004
Subgroups: Reduction in All-Cause Mortality Subgroups: Reduction in All-Cause Mortality or Major CV Eventsor Major CV Events
All pinteraction = NS except as noted
Age > 65Age < 65
MaleFemale
0.5 0.75 1.0 1.25 1.5
DiabetesNo Diabetes
2 Year Event Rates Atorva 80 Prava 40
23.0% 26.2%20.3% 27.0%
28.8% 34.6%21.0% 24.6%
28.1% 29.5% 20.1% 25.0%
27.5% 28.9% 20.6% 25.5%
21.7% 26.7% 23.1% 26.0%
20.1% 28.2% 23.5% 25.6%
Prior StatinNo Prior Statin
Atorvastatin 80 mg Better Pravastatin 40 mg Better
LDL-C < 125LDL-C > 125 pi = 0.02
HDL-C < 40HDL-C > 40
% of Pts78
22
18
82
30 70
25 75
44 56
27 73
Liver and Muscle EffectsLiver and Muscle Effects
Atorvastatin 80mg Pravastatin 40mg P-value
ALT > 3 ULN 3.3% 1.1% <0.001
CK > 3 ULN 1.5% 1.1% 0.24
D/C for Myalgia/CK elevations 3.3% 2.7% 0.23
Atorvastatin 80mg Pravastatin 40mg P-value
ALT > 3 ULN 3.3% 1.1% <0.001
CK > 3 ULN 1.5% 1.1% 0.24
D/C for Myalgia/CK elevations 3.3% 2.7% 0.23
Summary Summary
In patients recently hospitalized within 10 days for an acute In patients recently hospitalized within 10 days for an acute coronary syndrome: coronary syndrome:
““Intensive” high-dose LDL-C lowering (median LDL-C 62 Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid-lowering mg/dL) compared to “moderate” standard-dose lipid-lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005)mortality or major cardiac events by 16% (p=0.005)
Benefits emerged within 30 days post ACS with continued Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-upbenefit observed throughout the 2.5 years of follow-up
Benefits were consistent across all cardiovascular endpoints, Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups except stroke, and most clinical subgroups
PROVE-IT Conclusion PROVE-IT Conclusion
Our findings indicate that patients recently Our findings indicate that patients recently hospitalized for an acute coronary syndrome hospitalized for an acute coronary syndrome
benefit from early and continued lowering of LDL-C benefit from early and continued lowering of LDL-C to levels substantially below current target levels.to levels substantially below current target levels.
Cannon CP, Braunwald E, McCabe CH, et al. Cannon CP, Braunwald E, McCabe CH, et al. N Engl J MedN Engl J Med 2004;350:15 www.nejm.org 2004;350:15 www.nejm.org
MARCH 8, 2004