- Early initiation of high-intensity statin therapy in acute coronary syndrome patients significantly reduces mortality and morbidity rates compared to later initiation or lower-intensity statins. Clinical trials found a 16-36% reduction in major coronary events with early high-dose statin use. - Guidelines recommend high-intensity statins like atorvastatin 80mg or simvastatin 80mg for acute coronary syndrome patients, though risks like side effects must be considered. Long-term statin therapy is also generally advised after acute coronary syndrome.

1. Statins in Acute Coronary Syndrome

2. Acute Myocardial Infarction AMI is fatal in about 30-50% of cases Approximately 50% of AMI deaths occur within 1 hour of symptom onset.

3. Risk of death in patients with coronary heart disease is greatest early after an ACS Braunwald (1996) Deaths/100 patients/month Time (months after hospital admission) Acute MI Unstable angina Stable angina 0 5 10 15 20 25 0 1 2 3 4 5 6

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

5. Outline Pathophysiology of ACS How to statin working Which of statin and dose recommendation in ACS (Clinical outcome of statin in ACS) Morbidity/ Mortality LDL consideration in ACS Side effect and efficacy How about other lipid modifying agents in ACS Guideline

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

7. Pleiotropic effects of statins Liao JK. Am J Cardiol . 2005;96(suppl 1):24F-33F. MMPs = matrix metalloproteinases  Platelet activation  Coagulation  Endothelial progenitor cells  Effects on collagen  MMPs  AT 1 receptor  VSMC proliferation  Endothelin  Macrophages  Inflammation  Immunomodulation  Endothelial function  Reactive oxygen species  NO bioactivity Statins

8. Statin Endpoint Trials: Reduction in Major Coronary Events 4S 4444 -36% AF/TexCAPS 6605 -27% LIPID 9014 -25% CARE 4159 -28% WOS 6595 -26% Trial N  LDL Secondary Primary -38* -25* -25 § -31* -38* -27 ‡ HPS 20,536 -29% High Risk Reduction (%) ASCOT 10305 -26% -36 † * P <0.001; † P =0.0005; ‡ P <0.0001; § P =0.002. HPS Collaborative Group. Lancet . 2002;360:7-22; LaRosa et al. JAMA . 1999;282:2340-2346; Sever et al. Lancet . 2003;361:1149-1158.

9. PURSUIT: Retrospective analysis shows early mortality reduction with lipid-lowering therapy Aronow et al (2000) Survival (%) Days 100 99 98 97 96 95 94 93 92 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)

10. PRISM: Event Rates After Statin Withdrawal in Acute Coronary Syndrome Heeschen C, et al. Circulation. 2002;105:1446  1452. Event Rates in % (mortality, MI) 0 5 10 15 20 25 30 0 2 4 6 8 10 12 14 16 18 30-Day Follow-Up Period Statin continued Statin discontinued (N = 1616)

11. Rationale for early statin therapy Gives constant reduction in risk most effective when absolute risk is highest May stabilise plaque maximum benefit when given early Other non-lipid-lowering effects e.g. anti-inflammatory, effects on endothelial dysfunction Patient already in hospital patient more likely to adhere to therapy Discharged on statin therapy underscores need for continued statins

12. Timing of statin therapy initiation after ACS in recent clinical studies Days Secondary prevention 0 6 Months 3 2 PTT LAMIL L-CAD RECIFE CARE LIPID PAIS 24 Hours 10 6 8 12 12 18 4 PACT MIRACL 4S 6 Atorvastatin Pravastatin Simvastatin PROVE IT WOSCOPS Primary prevention ACS Fluvastatin FLORIDA A to Z

13. MIRACL: central hypothesis Early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute MI Schwartz GG et al. Am J Cardiol 1998; 81 :578–581.

14. MIRACL: study design Hospitalization for unstable angina or non-Q MI n =3086 Randomized 24–96 hours after admission Placebo + diet 16 weeks Assessments conducted at weeks 0, 2, 6 and 16 Schwartz GG et al. Am J Cardiol 1998; 81 :578–581. Atorvastatin 80 mg + diet

15. MIRACL Study Schwartz GG, et al. JAMA . 2001 ; 285 : 1711-1718. Relative risk = 0.84 P = .048 95% CI 0.701-0.999 Atorvastatin Placebo 0 5 10 15 0 4 8 12 16 Time Since Randomization (weeks) Cumulative Incidence (%) Time to first occurrence of: Death (any cause) Nonfatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalization 17.4% 14.8% Primary Efficacy Measure Very early benefit

16. MIRACL: worsening angina with new objective evidence of ischemia requiring urgent rehospitalization 0 3 6 9 0 4 8 12 16 Time since randomization (weeks) Cumulative Incidence (%) Relative risk = 0.74 p =0.02 Atorvastatin Placebo 8.4% 6.2% Data on file, Pfizer Inc.

17. MIRACL: safety Placebo Atorvastatin ( n =1548) ( n =1538) Elevated liver transaminases 0.6% 2.5% (>3xULN on 2 occasions) Myositis 0% 0% (with CPK >10xULN on 2 occasions) Any serious adverse event 8.0% 9.0% Data on file, Pfizer Inc.

18. MIRACL: Conclusions Early, rapid, and profound cholesterol lowering therapy with atorvastatin reduced early recurrent ischemic events in patients with unstable angina or non-Q-wave acute MI Atorvastatin reduced the incidence of recurrent ischemic events within 16 weeks Treatment was generally well tolerated Data on file, Pfizer Inc.

19. Cannon CP et al. N Engl J Med . 2004;350:1495-1504. ASA + Standard medical therapy Duration: mean 2-y follow-up (>925 events) 2x2 Factorial: gatifloxacin versus placebo Standard therapy (Pravastatin 40 mg) Intensive therapy (Atorvastatin 80 mg) Primary end point: death MI, documented UA requiring hospitalization, revascularization (>30 days after randomization), or stroke Study Design: N=4,162 with acute coronary syndrome <10 days PROVE-IT: Pravastatin or Atorvastatin Evaluation and Infection Therapy

20. 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 0 3 18 21 24 27 30 6 9 12 15

21. PROVE IT – TIMI 22 (2-Year Trial) Log CHD Risk 100 LDL-C Level 60 Pravastatin 40 mg 16% Reduction in CVD Atorvastatin 80 mg Cannon CP et al. N Engl J Med 2004;350:1495-1504.

22. Arch Intern Med. 2006;166:1814-1821

24. CVE over 2 Y

26. Effects of Statins on Lipids Statin rosuvastatin (10 mg) atorvastatin (10 mg) simvastatin (20 mg) pravastatin (20 mg) fluvastatin (20 mg) LDL-C % change -52 -39 -33 -32 -22 HDL-C % change TG % change +14 +6 +8 +2 +3 -10 -19 -19 -11 -12 US Product Data Sheets.

27. GALAXY lipid studies 1. Lablanche J-M et al. Atherosclerosis Supplements 2006 7 (3): 578, Abs Th-P16:384 ACRONYM OVERVIEW A 12-week, randomized, open-label study comparing CRESTOR 20mg or 40mg with that of atorvastatin 80 mg on lipid parameters and pleiotropic effects in subjects with acute coronary syndromes A planned study to evaluate CRESTOR in paediatric subjects with heterozygous familial hypercholesterolemia A 3-month, randomised, multicentre, parallel-group study with 2 periods, to compare the efficacy and safety of CRESTOR 20 mg with atorvastatin 80 mg on the ApoB/ApoA-I ratio and other lipid and inflammatory markers in subjects with acute coronary syndrome 1 .

28. Efficacy of High dose statin

29. Safety of High dose statin

30. Risk of Side Effects from Statin

31. Effect of lipid-modifying therapies on lipids Therapy Bile acid sequestrants Nicotinic acid Fibrates Probucol Statins* Ezetimibe TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. *Daily dose of 40 mg of atorvastatin, simvastatin, pravastatin and fluvastatin. TC Down 20% Down 25% Down 15% Down 25% Down 19–37% - LDL Down 15–30% Down 25% Down 5–15% Down 10–15% Down 25–50% Down 18% HDL Up 3–5% Up 15–30% Up 20% Down 20–30% Up 4–12% Up 1% TG Neutral or up Down 20–50% Down 20–50% Neutral Down 14-29% Down 8% Patient tolerability Poor Poor to reasonable Good Reasonable Good Good Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391. Knopp RH. N Engl J Med 1999;341:498–511. Product Prescribing Information. Gupta EK, Ito MK. Heart Dis 2002;4:399-409. ,

32. What about patients with ACS? NICE full guideline May 2008 People with acute coronary syndrome should be treated with a higher–intensity statin “ Any decision to offer a higher intensity statin should take into account the patient's informed preference, co morbidities, multiple drug therapy, and the benefits and risks of treatment” Atorvastatin 80mg and simvastatin 80mg are both cost– effective in ACS No lipid target specified For how long should patients with ACS take higher–intensity statins?

33. Take home massage All of ACS have benefit from statin Morbidity and Mortality High dose or high potency are more benefits (early and magnitude) but SE must be concern Combination of antilipid agents will be achieve NCEP goals but lack of evidence in ACS.

34. THANK YOU