New Insights into the New Insights into the Benefits of Early Statin Benefits of Early Statin

Initiation in Acute Initiation in Acute Coronary SyndromesCoronary Syndromes

4. Plaque rupture,4. Plaque rupture, cholesterol content,cholesterol content, inflammation (hs-CRP)inflammation (hs-CRP) (statins)(statins)

3. Platelet adhesion/3. Platelet adhesion/ activation/aggregationactivation/aggregation (aspirin, clopidogrel,(aspirin, clopidogrel, GP IIb/IIIa inhibitors)GP IIb/IIIa inhibitors)

2. Activation of clotting 2. Activation of clotting cascade – thrombincascade – thrombin (heparin/LMWH)(heparin/LMWH)

1. Downstream from thrombus1. Downstream from thrombus myocardial ischaemia/necrosismyocardial ischaemia/necrosis ((-blockers, nitrates etc)-blockers, nitrates etc)

PlateletPlatelet

GP IIb/IIIaGP IIb/IIIareceptor receptor

FibrinogenFibrinogenThrombinThrombin

Fibrin Fibrin clotclot

Pathophysiology of ACS and potential Pathophysiology of ACS and potential pharmacological interventionspharmacological interventions

Braunwald (1996)Braunwald (1996)

Deaths/100 patients/monthDeaths/100 patients/month

Time (months after hospital admission)Time (months after hospital admission)

Risk of death in patients with coronary heart Risk of death in patients with coronary heart disease is greatest early after an ACSdisease is greatest early after an ACS

Acute MIAcute MIUnstable anginaUnstable anginaStable anginaStable angina

00

55

1010

1515

2020

2525

00 11 22 33 44 55 66

Survival (%)Survival (%)

DaysDays

100100

9999

9898

9797

9696

9595

9494

9393

92920 0 30 60 90 30 60 90 120 120 150 150 180 180

Log rank Log rank 22=87, =87, pp<0.001<0.001

No lipid-lowering agents (n=6374)No lipid-lowering agents (n=6374)

Lipid-lowering agents (n=2141)Lipid-lowering agents (n=2141)

Aronow et al (2000)Aronow et al (2000)

PURSUIT: Retrospective analysis shows early PURSUIT: Retrospective analysis shows early mortality reduction with lipid-lowering therapymortality reduction with lipid-lowering therapy

GUSTO IIb/PRISM: Early reduction in death/MI GUSTO IIb/PRISM: Early reduction in death/MI in patients on lipid-lowering therapyin patients on lipid-lowering therapy

GUSTO IIbGUSTO IIb – Retrospective analysis of 12,630 ACS patients – Retrospective analysis of 12,630 ACS patients ((±±ST elevation)ST elevation)

Mortality at 30 days and 6 months was significantly reduced in Mortality at 30 days and 6 months was significantly reduced in patients receiving lipid-lowering agentpatients receiving lipid-lowering agent

52% reduction in 6-month mortality (RR 0.48, 95% CI 0.28-0.83) 52% reduction in 6-month mortality (RR 0.48, 95% CI 0.28-0.83) after adjusting for other variablesafter adjusting for other variables

PRISMPRISM – Retrospective analysis of 1616 patients – Retrospective analysis of 1616 patients 302 patients were continued on background statin therapy302 patients were continued on background statin therapy Death/MI rate at 30 days was significantly lower in these Death/MI rate at 30 days was significantly lower in these

patients (patients (pp<0.01)<0.01)

Aronow et al, Hamm et al (AHA 2000)

XXII ESC Congress (2000)XXII ESC Congress (2000)

StatinsStatins RevascularisationRevascularisation Combined therapyCombined therapy00

1010

2020

3030

4040 34%34% 36%36%

64%64%

5050

6060

Swedish registry: Early statin and Swedish registry: Early statin and revascularisation significantly reduces mortalityrevascularisation significantly reduces mortality

7070

Relative risk reduction in Relative risk reduction in mortality after 1 yearmortality after 1 year

Statin therapy after stent placement Statin therapy after stent placement in ACS patientsin ACS patients

Prospective study of statin therapy initiation Prospective study of statin therapy initiation immediately after coronary stent implantation in 224 immediately after coronary stent implantation in 224 ACS patientsACS patients

Incidence of major cardiovascular events, including Incidence of major cardiovascular events, including death and MI, at 6 months were:death and MI, at 6 months were:

– 1.0% in statin patients1.0% in statin patients– 7.9% in control group (7.9% in control group (pp<0.03)<0.03)

Statin therapy associated with profound clinical benefitStatin therapy associated with profound clinical benefit Suggests pivotal role of statins for plaque passivation Suggests pivotal role of statins for plaque passivation

to reduce death and MIto reduce death and MI

Walter et al (AHA 2000)Walter et al (AHA 2000)

Gives constant reduction in riskGives constant reduction in risk most effective when absolute most effective when absolute risk is highest risk is highest

May stabilise plaqueMay stabilise plaque maximum benefit when given maximum benefit when given earlyearly

Other non-lipid-lowering effectsOther non-lipid-lowering effects eg anti-inflammatory, effects on eg anti-inflammatory, effects on endothelial dysfunctionendothelial dysfunction

Patient already in hospitalPatient already in hospital patient more likely to adhere to patient more likely to adhere to therapytherapy

Discharged on statin therapyDischarged on statin therapy underscores need for continued underscores need for continued statinsstatins

Rationale for early statin therapy Rationale for early statin therapy

Timing of statin therapy initiation after ACS Timing of statin therapy initiation after ACS in recent clinical studies in recent clinical studies

DaysDays

Secondary preventionSecondary prevention

00 66MonthsMonths

3322

PTTPTT

LAMILLAMIL

L-CADL-CAD

RECIFERECIFE

CARECARE

LIPIDLIPID

PAISPAIS

2424HoursHours

1010 66 88 12121212 1818 44

PACTPACT MIRACLMIRACL

4S4S

66

AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatin

PROVE ITPROVE IT

WOSCOPSWOSCOPS

Primary Primary preventionprevention

ACSACS

FluvastatinFluvastatin

FLORIDAFLORIDA

11 Pravastatin and Thrombolytic Therapy Pravastatin and Thrombolytic Therapy 22 Lipids in Coronary Artery Disease Lipids in Coronary Artery Disease 33 Reduction of Cholesterol in Ischaemia and Function of the Endothelium Reduction of Cholesterol in Ischaemia and Function of the Endothelium44 FLuvastatin On RIsk Diminishing after Acute myocardial infarction FLuvastatin On RIsk Diminishing after Acute myocardial infarction55 Myocardial Ischaemia Reduction with Aggressive Cholesterol LoweringMyocardial Ischaemia Reduction with Aggressive Cholesterol Lowering

Clinical evidence for the benefits of early Clinical evidence for the benefits of early statin initiationstatin initiation

StudyStudy Time toTime to Statin Statin ResultsResultsinitiationinitiation

PTT1 6 h pravastatin coronary events restenosis rates

L-CAD2 6 d pravastatin Improved outcomes mean progression coronary lesion regression

RECIFE3 10 d pravastatin Rapid improvement of (mean) endothelial function FLORIDA4 8 d fluvastatin No significant benefitMIRACL5 24–96 h atorvastatin time to first event

Kayikcioglu et al (1999)Kayikcioglu et al (1999)

Timing of statin therapy initiation after ACS Timing of statin therapy initiation after ACS in recent clinical studies in recent clinical studies

DaysDays

Secondary preventionSecondary prevention

00 66MonthsMonths

3322

PTTPTT

LAMILLAMIL

L-CADL-CAD

RECIFERECIFE

CARECARE

LIPIDLIPID

PAISPAIS

2424HoursHours

1010 66 88 12121212 1818 44

4S4S

66

AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatin

WOSCOPSWOSCOPS

Primary Primary preventionprevention

ACSACS

FluvastatinFluvastatin

FLORIDAFLORIDA

MIRACLMIRACL

Patients with event (%)Patients with event (%)

0

10

20

30

Non-fatal MI **Non-fatal MI ** RecurrentRecurrentangina **angina **

In-hospitalIn-hospitaldeathdeath

Pravastatin (n=72)Pravastatin (n=72)Control (n=78)Control (n=78)

† ‡

Kayikcioglu et al (1999)Kayikcioglu et al (1999)

Pravastatin and Thrombolytic Therapy trial: Pravastatin and Thrombolytic Therapy trial: Early* therapy improves event-free survivalEarly* therapy improves event-free survival

*Within 6 hours of MI; **6 months follow-up†p=0.01, ‡p=0.03

Arntz (1999)Arntz (1999)

Timing of statin therapy initiation after ACS Timing of statin therapy initiation after ACS in recent clinical studies in recent clinical studies

DaysDays

Secondary preventionSecondary prevention

00 66MonthsMonths

3322

PTTPTT

LAMILLAMIL

L-CADL-CAD

RECIFERECIFE

CARECARE

LIPIDLIPID

PAISPAIS

2424HoursHours

1010 66 88 12121212 1818 44

4S4S

66

AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatin

WOSCOPSWOSCOPS

Primary Primary preventionprevention

ACSACS

FluvastatinFluvastatin

FLORIDAFLORIDA

MIRACLMIRACL

L-CAD study designL-CAD study design

L-CAD = Lipids in Coronary Artery Disease L-CAD = Lipids in Coronary Artery Disease

126 men and women post 126 men and women post acute MI and/or PTCA for UAacute MI and/or PTCA for UA

Pravastatin 20–40 mg (+cholestyramine Pravastatin 20–40 mg (+cholestyramine and nicotinic acid) to achieve an LDL and nicotinic acid) to achieve an LDL

<3.4 mmol/L (130 mg/dL)<3.4 mmol/L (130 mg/dL)

Clinical Clinical –– 2 years, Angiography 2 years, Angiography –– 6 months and 2 years 6 months and 2 years

QCA and major CV clinical eventsQCA and major CV clinical events

Baseline cholesterol Baseline cholesterol 3.43.4––6.5 mmol/L (1306.5 mmol/L (130––250 mg/dL)250 mg/dL)

Usual careUsual care

Pravastatin-basedPravastatin-basedintensified (n=70)intensified (n=70)

Conventional (n=56)Conventional (n=56)

L-CAD: Survival without major L-CAD: Survival without major cardiovascular eventscardiovascular events

Time (months)Time (months)

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 242400

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Log rank = 0.0024Log rank = 0.0024Breslow = 0.0042Breslow = 0.0042

Arntz et al (1998)Arntz et al (1998)

Dupuis et al (1999)Dupuis et al (1999)

Timing of statin therapy initiation after ACS Timing of statin therapy initiation after ACS in recent clinical studies in recent clinical studies

DaysDays

Secondary preventionSecondary prevention

00 66MonthsMonths

3322

PTTPTT

LAMILLAMIL

L-CADL-CAD

RECIFERECIFE

CARECARE

LIPIDLIPID

PAISPAIS

2424HoursHours

1010 66 88 12121212 1818 44

4S4S

66

AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatin

WOSCOPSWOSCOPS

Primary Primary preventionprevention

ACSACS

FluvastatinFluvastatin

FLORIDAFLORIDA

MIRACLMIRACL

Time (weeks)Time (weeks)*60 patients admitted for acute MI or unstable angina, *60 patients admitted for acute MI or unstable angina, enrolled before hospital dischargeenrolled before hospital discharge

Flow-mediated Flow-mediated dilatation (%)* dilatation (%)*

44

55

66

77

88

00 66

Pravastatin Pravastatin 40 mg/day40 mg/day

PlaceboPlacebo

pp<0.05<0.05

The RECIFE study: Pravastatin rapidly The RECIFE study: Pravastatin rapidly improves endothelial function after ACSimproves endothelial function after ACS

Dupuis et al (1999)Dupuis et al (1999)

Schwartz et al (1998)Schwartz et al (1998)

Timing of statin therapy initiation after ACS Timing of statin therapy initiation after ACS in recent clinical studies in recent clinical studies

DaysDays

Secondary preventionSecondary prevention

00 66MonthsMonths

3322

PTTPTT

LAMILLAMIL

L-CADL-CAD

RECIFERECIFE

CARECARE

LIPIDLIPID

PAISPAIS

2424HoursHours

1010 66 88 12121212 1818 44

4S4S

66

AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatin

WOSCOPSWOSCOPS

Primary Primary preventionprevention

ACSACS

FluvastatinFluvastatin

FLORIDAFLORIDA

MIRACLMIRACL

What MIRACL was designed to showWhat MIRACL was designed to show

The HypothesisThe Hypothesis

Early plaque Early plaque stabilisationstabilisation

Rapid and early Rapid and early cholesterol cholesterol reductionreduction

Diminished Diminished incidence of incidence of recurrent ischaemic recurrent ischaemic eventsevents

““To prove that early, rapid, and intensive cholesterol To prove that early, rapid, and intensive cholesterol lowering therapy will reduce early recurrent ischaemic lowering therapy will reduce early recurrent ischaemic

events in patients with unstable angina or non-Q-wave MI”events in patients with unstable angina or non-Q-wave MI”

ObjectiveObjective

Schwartz et al (1998)Schwartz et al (1998)

MIRACL = The Myocardial Ischemia MIRACL = The Myocardial Ischemia Reduction with Aggressive Cholesterol Reduction with Aggressive Cholesterol Lowering studyLowering study

MIRACL study designMIRACL study designProspective, randomised, multicentre, double-blind Prospective, randomised, multicentre, double-blind

3,086 patients3,086 patients

80 mg atorvastatin, commenced 80 mg atorvastatin, commenced within 24–96 h of eventwithin 24–96 h of event

Follow up at 2, 6 and 16 weeks for Follow up at 2, 6 and 16 weeks for endpoints, ECG, labs and AEsendpoints, ECG, labs and AEs

Inclusion criteriaInclusion criteriaUA or non-Q-wave MI UA or non-Q-wave MI in previous 1–4 daysin previous 1–4 days

Exclusion criteriaExclusion criteria• Serum cholesterol Serum cholesterol

>7 mmol/L (270 mg/dL)>7 mmol/L (270 mg/dL)• Concurrent or previous Concurrent or previous

interventional therapy interventional therapy (6 months) or surgery (6 months) or surgery (3 months) (3 months)

• Concurrent lipid-lowering Concurrent lipid-lowering therapy therapy

• Any agent likely to induce Any agent likely to induce rhabdomyolysis when rhabdomyolysis when taken with statinstaken with statins

Placebo, commenced within Placebo, commenced within 24–96 h of event24–96 h of event

MIRACL study outcome measuresMIRACL study outcome measures PrimaryPrimary

Time from randomisation to first occurrence of any of thefollowing: Death (any cause) Non-fatal MI Resuscitated cardiac arrest Worsening angina pectoris with new objective evidence of

myocardial ischaemia, requiring urgent rehospitalisation SecondarySecondary

Time to occurrence and incidence of each of the primaryoutcome components, plus: Stroke Myocardial revascularisation (CABG or PTCA) Worsening congestive heart failure Worsening angina without new objective evidence

of ischaemia

MIRACL patient dispositionMIRACL patient disposition

Number of patientsNumber of patients AtorvastatinAtorvastatin PlaceboPlacebo

RandomisedRandomised 1538 1538 1548 1548

Lost to follow-upLost to follow-up 8 8 4 4

AtorvastatinAtorvastatin PlaceboPlacebo n=1538n=1538 n=1548n=1548

Mean age (years)Mean age (years) 6565 6565MaleMale 64%64% 66%66%CaucasianCaucasian 86%86% 85%85%Prior MIPrior MI 25%25% 25%25%Prior CABG or PTCAPrior CABG or PTCA10%10% 11%11%Current smokingCurrent smoking 28%28% 28%28%HypertensionHypertension 55%55% 55%55%DiabetesDiabetes 22%22% 24%24%

Baseline characteristics of patientsBaseline characteristics of patients

Baseline characteristics of patientsBaseline characteristics of patients

AtorvastatinAtorvastatin PlaceboPlacebo n=1538n=1538 n=1548n=1548

Inclusion event:Inclusion event: Unstable angina Unstable angina 47% 47% 46% 46% Non-Q-wave MI Non-Q-wave MI 53% 53% 55% 55%

Median time from Median time from hospital admissionhospital admissionto randomisationto randomisation 63 h 63 h 63 h 63 h

00 44 88 1212 1616

1515

1010

55

00

Cumulative incidence (%)Cumulative incidence (%)

Time since randomisation (weeks)Time since randomisation (weeks)

AtorvastatinAtorvastatin

PlaceboPlacebo 17.4%17.4%

14.8%14.8%

Risk reduction = 16%Risk reduction = 16%pp=0.048=0.048

Time to first occurrence of Time to first occurrence of composite endpoint of:composite endpoint of:

Primary efficacy measurePrimary efficacy measure

95% CI = 0.701–0.99995% CI = 0.701–0.999

Death (any cause)Death (any cause) Non-fatal MINon-fatal MI Resuscitated cardiac arrestResuscitated cardiac arrest Worsening angina with new Worsening angina with new

objective evidence and urgent objective evidence and urgent rehospitalisationrehospitalisation

Individual endpoint results – incidenceIndividual endpoint results – incidence

Event Event AtorvastatinAtorvastatin PlaceboPlacebo % reduction% reduction pp

Worsening angina*Worsening angina* 6.2%6.2% 8.4%8.4% 26%26% 0.020.02

Total strokeTotal stroke 0.75%0.75% 1.5%1.5% 50%50% 0.0450.045

DeathDeath nsns

Non-fatal acute MINon-fatal acute MI nsns

Resuscitated Resuscitated cardiac arrest cardiac arrest nsns

*with new objective evidence of ischaemia*with new objective evidence of ischaemia requiring urgent rehospitalisation requiring urgent rehospitalisation

Blood lipidsBlood lipids

Total cholesterolTotal cholesterol

LDL cholesterolLDL cholesterol

HDL cholesterolHDL cholesterol

TriglyceridesTriglycerides

206206

124124

4646

182182

217217(+7%)(+7%)

135135(+12%)(+12%)

4646(+4%)(+4%)

187187(+9%)(+9%)

147147(-27%)(-27%)

7272(-40%)(-40%)

4848(+5%)(+5%)

139139(-16%)(-16%)

BaselineBaselineMean of both groupsMean of both groups

mg/dlmg/dl

End of studyEnd of studyPlaceboPlacebo AtorvastatinAtorvastatin

mg/dl (% change)mg/dl (% change)

SafetySafety

AtorvastatinAtorvastatin PlaceboPlacebo n=1538n=1538 n=1548n=1548

Elevated liver transaminasesElevated liver transaminases(>3 times ULN on 2 occasions)(>3 times ULN on 2 occasions) 2.5% 2.5% 0.6% 0.6%

MyositisMyositis(with CK >10 times ULN(with CK >10 times ULNon 2 occasions) on 2 occasions) 0% 0% 0% 0%

Statins*Statins*LDL-C reduction

Reduction inchylomicron and VLDL remnants,IDL, LDL-C • Restore endothelial function

• Maintain SMC function • Anti-inflammatory effects• Decreased thrombosis

Lumen

Lipid core

Macrophages

Smooth muscle cells

Potential mechanisms of benefit of Potential mechanisms of benefit of statins in ACSstatins in ACS

*Statins differ *Statins differ significantly significantly in terms of these in terms of these effects/mechanismseffects/mechanisms

InflammationInflammation RepairRepair

Unstable plaque

Increased lipidsLipid oxidation

Infection?Genetic susceptibility

Lipid-lowering drugs Antioxidants?Antibiotics?

Mechanical injury

Stable plaque

Modified from Weissberg (1999)Modified from Weissberg (1999)

Balancing the stability equationBalancing the stability equation

BMS Data on fileBMS Data on file

Timing of statin therapy initiation after ACS Timing of statin therapy initiation after ACS in recent clinical studies in recent clinical studies

DaysDays

Secondary preventionSecondary prevention

00 66MonthsMonths

3322

PTTPTT

LAMILLAMIL

L-CADL-CAD

RECIFERECIFE

CARECARE

LIPIDLIPID

PAISPAIS

2424HoursHours

1010 66 88 12121212 1818 44

PACTPACT

4S4S

66

AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatin

WOSCOPSWOSCOPS

Primary Primary preventionprevention

ACSACS

FluvastatinFluvastatinPROVE ITPROVE IT

FLORIDAFLORIDA

MIRACLMIRACL

Pravastatin Acute Coronary Pravastatin Acute Coronary Treatment (PACT)Treatment (PACT)

DesignDesign– safety and short-, medium- and long-term efficacysafety and short-, medium- and long-term efficacy– 4 weeks double-blind treatment with pravastatin4 weeks double-blind treatment with pravastatin– initiation within 24 hours of the onset of symptoms initiation within 24 hours of the onset of symptoms

in patients with AMI or UAin patients with AMI or UA– 12 months open-label follow-up12 months open-label follow-up

ObjectiveObjective– to demonstrate conclusively that early treatment to demonstrate conclusively that early treatment

with a statin is both safe and effective in the acute with a statin is both safe and effective in the acute phase after MI or UAphase after MI or UA

PACT design featuresPACT design features

Randomised, double-blindRandomised, double-blind Acute MI or unstable angina, n=10,000Acute MI or unstable angina, n=10,000 Pravastatin 20 or 40 mg daily or placebo for 4 weeksPravastatin 20 or 40 mg daily or placebo for 4 weeks Initiation within 24 hours of the onset of symptomsInitiation within 24 hours of the onset of symptoms Primary endpoint recurrent coronary eventsPrimary endpoint recurrent coronary events Ongoing lipid management after 4 weeks open-label Ongoing lipid management after 4 weeks open-label

determined by the patient’s local physician determined by the patient’s local physician Follow up for clinical and adverse events at 4, 26, and 52 Follow up for clinical and adverse events at 4, 26, and 52

weeksweeks Includes PIMS Includes PIMS

(Pravastatin Inflammatory Markers Study) (Pravastatin Inflammatory Markers Study)

BMS Data on fileBMS Data on file

Timing of statin therapy initiation after ACS Timing of statin therapy initiation after ACS in recent clinical studies in recent clinical studies

DaysDays

Secondary preventionSecondary prevention

00 66MonthsMonths

3322

PTTPTT

LAMILLAMIL

L-CADL-CAD

RECIFERECIFE

CARECARE

LIPIDLIPID

PAISPAIS

2424HoursHours

1010 66 88 12121212 1818 44

PACTPACT

4S4S

66

AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatin

WOSCOPSWOSCOPS

Primary Primary preventionprevention

ACSACS

FluvastatinFluvastatinPROVE ITPROVE IT

FLORIDAFLORIDA

MIRACLMIRACL

PROVE IT: PRavastatin Or AtorVastatin PROVE IT: PRavastatin Or AtorVastatin Evaluation and Infection TherapyEvaluation and Infection Therapy

The definitive head-to-head comparison The definitive head-to-head comparison of pravastatin and atorvastatinof pravastatin and atorvastatin

The first major trial to compare the effects The first major trial to compare the effects of pravastatin versus atorvastatin in of pravastatin versus atorvastatin in reducing the risk of heart attacks and other reducing the risk of heart attacks and other cardiac eventscardiac events

Designed to evaluate further the role of Designed to evaluate further the role of infection in cardiovascular diseaseinfection in cardiovascular disease

Standard medical therapyStandard medical therapy

PravastatinPravastatin40 mg qhs40 mg qhs

AtorvastatinAtorvastatin80 mg qhs80 mg qhs

GatifloxacinGatifloxacin PlaceboPlacebo

PROVE IT study designPROVE IT study designDouble-blind, randomised, 4,000 patients with ACS Double-blind, randomised, 4,000 patients with ACS

<10 days and total cholesterol <240 mg/dL (6.2 mmol/L)<10 days and total cholesterol <240 mg/dL (6.2 mmol/L)

PlaceboPlaceboGatifloxacinGatifloxacin

Follow-up visit 30 daysFollow-up visit 30 days

Minimum duration 18 monthsMinimum duration 18 months

ConclusionsConclusions

Several clinical trials with pravastatin have indicated Several clinical trials with pravastatin have indicated the benefits of early treatment in ACSthe benefits of early treatment in ACS

MIRACL with atorvastatin supports this in a large trialMIRACL with atorvastatin supports this in a large trial Effects beyond lipid lowering may contribute to the Effects beyond lipid lowering may contribute to the

early benefitearly benefit PACT with pravastatin will answer whether even earlier PACT with pravastatin will answer whether even earlier

initiation (within 24 h) is beneficialinitiation (within 24 h) is beneficial PROVE IT, a head-to-head trial of pravastatin vs PROVE IT, a head-to-head trial of pravastatin vs

atorvastatin, will determine any difference between atorvastatin, will determine any difference between these two agentsthese two agents