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