1. New Insights into the Benefits of Early Statin Initiation in Acute Coronary Syndromes

2. 4. Plaque rupture, cholesterol content, cholesterol content, inflammation (hs-CRP) inflammation (hs-CRP) (statins) (statins) 3. Platelet adhesion/ activation/aggregation activation/aggregation (aspirin, clopidogrel, (aspirin, clopidogrel, GP IIb/IIIa inhibitors) GP IIb/IIIa inhibitors) 2. Activation of clotting cascade – thrombin cascade – thrombin (heparin/LMWH) (heparin/LMWH) 1. Downstream from thrombus myocardial ischaemia/necrosis myocardial ischaemia/necrosis (  -blockers, nitrates etc) (  -blockers, nitrates etc) Platelet GP IIb/IIIa receptor Fibrinogen Thrombin Fibrinclot Pathophysiology of ACS and potential pharmacological interventions

3. Braunwald (1996) Deaths/100 patients/month Time (months after hospital admission) Risk of death in patients with coronary heart disease is greatest early after an ACS Acute MI Unstable angina Stable angina 0 5 10 15 2025 0123456

4. Survival (%) Days 1009998979695949392 0 30 60 90 120 150 180 Log rank  2 =87, p<0.001 No lipid-lowering agents (n=6374) Lipid-lowering agents (n=2141) Aronow et al (2000) PURSUIT: Retrospective analysis shows early mortality reduction with lipid-lowering therapy

5. GUSTO IIb/PRISM: Early reduction in death/MI in patients on lipid-lowering therapy nGUSTO IIb – Retrospective analysis of 12,630 ACS patients (±ST elevation) nMortality at 30 days and 6 months was significantly reduced in patients receiving lipid-lowering agent n52% reduction in 6-month mortality (RR 0.48, 95% CI 0.28-0.83) after adjusting for other variables nPRISM – Retrospective analysis of 1616 patients n302 patients were continued on background statin therapy nDeath/MI rate at 30 days was significantly lower in these patients (p<0.01) Aronow et al, Hamm et al (AHA 2000)

6. XXII ESC Congress (2000) StatinsRevascularisation Combined therapy 0 10 20 30 40 34% 36% 64% 50 60 Swedish registry: Early statin and revascularisation significantly reduces mortality 70 Relative risk reduction in mortality after 1 year

7. Statin therapy after stent placement in ACS patients nProspective study of statin therapy initiation immediately after coronary stent implantation in 224 ACS patients nIncidence of major cardiovascular events, including death and MI, at 6 months were: –1.0% in statin patients –7.9% in control group (p<0.03) nStatin therapy associated with profound clinical benefit nSuggests pivotal role of statins for plaque passivation to reduce death and MI Walter et al (AHA 2000)

8. Gives constant reduction in riskmost effective when absolute risk is highest Gives constant reduction in riskmost effective when absolute risk is highest May stabilise plaquemaximum benefit when given early May stabilise plaquemaximum benefit when given early Other non-lipid-lowering effectseg anti-inflammatory, effects on endothelial dysfunction Other non-lipid-lowering effectseg anti-inflammatory, effects on endothelial dysfunction Patient already in hospitalpatient more likely to adhere to therapy Patient already in hospitalpatient more likely to adhere to therapy Discharged on statin therapyunderscores need for continued statins Discharged on statin therapyunderscores need for continued statins Rationale for early statin therapy

9. Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 06 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 10 6 8 12 1212184 PACTMIRACL 4S 6 Atorvastatin Pravastatin Simvastatin PROVE IT WOSCOPS Primary prevention ACS Fluvastatin FLORIDA

10. 1 Pravastatin and Thrombolytic Therapy 2 Lipids in Coronary Artery Disease 3 Reduction of Cholesterol in Ischaemia and Function of the Endothelium 4 FLuvastatin On RIsk Diminishing after Acute myocardial infarction 5 Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering Clinical evidence for the benefits of early statin initiation StudyTime to Statin Results initiation Study Time to Statin Results initiation PTT 1 6 hpravastatin  coronary events  restenosis rates L-CAD 2 6 dpravastatin Improved outcomes  mean progression  coronary lesion regression RECIFE 3 10 dpravastatin Rapid improvement of (mean) endothelial function FLORIDA 4 8 dfluvastatin No significant benefit MIRACL 5 24–96 hatorvastatin  time to first event

11. Kayikcioglu et al (1999) Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 06 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 10 6 8 12 1212184 4S 6 Atorvastatin Pravastatin Simvastatin WOSCOPS Primary prevention ACS Fluvastatin FLORIDA MIRACL

12. Patients with event (%) 0 10 20 30 Non-fatal MI ** Recurrent angina ** In-hospital death Pravastatin (n=72) Control (n=78) † ‡ Kayikcioglu et al (1999) Pravastatin and Thrombolytic Therapy trial: Early* therapy improves event-free survival *Within 6 hours of MI; **6 months follow-up † p=0.01, ‡ p=0.03

13. Arntz (1999) Arntz (1999) Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 06 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 10 6 8 12 1212184 4S 6 Atorvastatin Pravastatin Simvastatin WOSCOPS Primary prevention ACS Fluvastatin FLORIDA MIRACL

14. L-CAD study design L-CAD = Lipids in Coronary Artery Disease 126 men and women post acute MI and/or PTCA for UA Pravastatin 20–40 mg (+cholestyramine and nicotinic acid) to achieve an LDL <3.4 mmol/L (130 mg/dL) Clinical – 2 years, Angiography – 6 months and 2 years QCA and major CV clinical events Baseline cholesterol 3.4–6.5 mmol/L (130–250 mg/dL) Usual care

15. Pravastatin-based intensified (n=70) Conventional (n=56) L-CAD: Survival without major cardiovascular events Time (months) 024681012141618202224 0 0.2 0.4 0.6 0.8 1.0 Log rank = 0.0024 Breslow = 0.0042 Arntz et al (1998)

16. Dupuis et al (1999) Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 06 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 10 6 8 12 1212184 4S 6 Atorvastatin Pravastatin Simvastatin WOSCOPS Primary prevention ACS Fluvastatin FLORIDA MIRACL

17. Time (weeks) *60 patients admitted for acute MI or unstable angina, enrolled before hospital discharge Flow-mediated dilatation (%)* 4 5 6 7 8 0 6 Pravastatin 40 mg/day Placebo p<0.05 The RECIFE study: Pravastatin rapidly improves endothelial function after ACS Dupuis et al (1999)

18. Schwartz et al (1998) Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 06 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 10 6 8 12 1212184 4S 6 Atorvastatin Pravastatin Simvastatin WOSCOPS Primary prevention ACS Fluvastatin FLORIDA MIRACL

19. What MIRACL was designed to show The Hypothesis Early plaque stabilisation Rapid and early cholesterol reduction Diminished incidence of recurrent ischaemic events “To prove that early, rapid, and intensive cholesterol lowering therapy will reduce early recurrent ischaemic events in patients with unstable angina or non-Q-wave MI” Objective Schwartz et al (1998) MIRACL = The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study

20. MIRACL study design Prospective, randomised, multicentre, double-blind 3,086 patients 80 mg atorvastatin, commenced within 24–96 h of event Follow up at 2, 6 and 16 weeks for endpoints, ECG, labs and AEs Inclusion criteria UA or non-Q-wave MI in previous 1–4 days Exclusion criteria Serum cholesterol >7 mmol/L (270 mg/dL)Serum cholesterol >7 mmol/L (270 mg/dL) Concurrent or previous interventional therapy (6 months) or surgery (3 months)Concurrent or previous interventional therapy (6 months) or surgery (3 months) Concurrent lipid-lowering therapyConcurrent lipid-lowering therapy Any agent likely to induce rhabdomyolysis when taken with statinsAny agent likely to induce rhabdomyolysis when taken with statins Placebo, commenced within 24–96 h of event

21. MIRACL study outcome measures Primary Primary Time from randomisation to first occurrence of any of the following: n nDeath (any cause) n nNon-fatal MI n nResuscitated cardiac arrest n nWorsening angina pectoris with new objective evidence of myocardial ischaemia, requiring urgent rehospitalisation Secondary Time to occurrence and incidence of each of the primary outcome components, plus: n nStroke n nMyocardial revascularisation (CABG or PTCA) n nWorsening congestive heart failure n nWorsening angina without new objective evidence of ischaemia

22. MIRACL patient disposition Number of patients AtorvastatinPlacebo Randomised 1538 1548 Lost to follow-up 8 4

23. Atorvastatin Placebo n=1538 n=1548 Atorvastatin Placebo n=1538 n=1548 Mean age (years)6565 Male64%66% Caucasian86%85% Prior MI25%25% Prior CABG or PTCA10%11% Current smoking28%28% Hypertension55%55% Diabetes22%24% Baseline characteristics of patients

24. AtorvastatinPlacebo n=1538 n=1548 AtorvastatinPlacebo n=1538 n=1548 Inclusion event: Unstable angina 47% 46% Non-Q-wave MI 53% 55% Median time from hospital admission to randomisation 63 h 63 h

25. 0481216 15 10 5 0 Cumulative incidence (%) Time since randomisation (weeks) Atorvastatin Placebo 17.4% 14.8% Risk reduction = 16% p=0.048 Time to first occurrence of composite endpoint of: Primary efficacy measure 95% CI = 0.701–0.999 n Death (any cause) n Non-fatal MI n Resuscitated cardiac arrest n Worsening angina with new objective evidence and urgent rehospitalisation

26. Individual endpoint results – incidence Event Atorvastatin Placebo % reduction p Worsening angina*6.2%8.4%26%0.02 Total stroke0.75%1.5%50%0.045 Deathns Non-fatal acute MIns Resuscitated cardiac arrest ns *with new objective evidence of ischaemia requiring urgent rehospitalisation

27. Blood lipids Total cholesterol LDL cholesterol HDL cholesterol Triglycerides 206 124 46 182 217 (+7%) 135 (+12%) 46 (+4%) 187 (+9%) 147 (-27%) 72 (-40%) 48 (+5%) 139 (-16%) Baseline Mean of both groups mg/dl End of study Placebo Atorvastatin mg/dl (% change)

28. Safety AtorvastatinPlacebo n=1538n=1548 AtorvastatinPlacebo n=1538n=1548 Elevated liver transaminases (>3 times ULN on 2 occasions) 2.5% 0.6% Myositis (with CK >10 times ULN on 2 occasions) 0% 0%

29. Statins* LDL-C reduction Reduction in chylomicron 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 statins in ACS *Statins differ significantly in terms of these effects/mechanisms

30. InflammationRepair Unstable plaque Increased lipids Lipid oxidation Infection? Genetic susceptibility Lipid-lowering drugs Antioxidants? Antibiotics? Mechanical injury Lipid-lowering drugs Antioxidants? Antibiotics? Mechanical injury Stable plaque Modified from Weissberg (1999) Balancing the stability equation

31. BMS Data on file Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 06 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 10 6 8 12 1212184 PACT 4S 6 Atorvastatin Pravastatin Simvastatin WOSCOPS Primary prevention ACS Fluvastatin PROVE IT FLORIDA MIRACL

32. Pravastatin Acute Coronary Treatment (PACT) nDesign –safety and short-, medium- and long-term efficacy –4 weeks double-blind treatment with pravastatin –initiation within 24 hours of the onset of symptoms in patients with AMI or UA –12 months open-label follow-up nObjective –to demonstrate conclusively that early treatment with a statin is both safe and effective in the acute phase after MI or UA

33. PACT design features nRandomised, double-blind nAcute MI or unstable angina, n=10,000 nPravastatin 20 or 40 mg daily or placebo for 4 weeks nInitiation within 24 hours of the onset of symptoms nPrimary endpoint recurrent coronary events nOngoing lipid management after 4 weeks open-label determined by the patient’s local physician nFollow up for clinical and adverse events at 4, 26, and 52 weeks nIncludes PIMS (Pravastatin Inflammatory Markers Study)

34. BMS Data on file Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 06 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 10 6 8 12 1212184 PACT 4S 6 Atorvastatin Pravastatin Simvastatin WOSCOPS Primary prevention ACS Fluvastatin PROVE IT FLORIDA MIRACL

35. PROVE IT: PRavastatin Or AtorVastatin Evaluation and Infection Therapy The definitive head-to-head comparison of pravastatin and atorvastatin nThe first major trial to compare the effects of pravastatin versus atorvastatin in reducing the risk of heart attacks and other cardiac events nDesigned to evaluate further the role of infection in cardiovascular disease

36. Standard medical therapy Pravastatin 40 mg qhs Atorvastatin 80 mg qhs GatifloxacinPlacebo PROVE IT study design Double-blind, randomised, 4,000 patients with ACS <10 days and total cholesterol <240 mg/dL (6.2 mmol/L) PlaceboGatifloxacin Follow-up visit 30 days Minimum duration 18 months

37. Conclusions nSeveral clinical trials with pravastatin have indicated the benefits of early treatment in ACS nMIRACL with atorvastatin supports this in a large trial nEffects beyond lipid lowering may contribute to the early benefit nPACT with pravastatin will answer whether even earlier initiation (within 24 h) is beneficial nPROVE IT, a head-to-head trial of pravastatin vs atorvastatin, will determine any difference between these two agents