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Statin in Acute Coronary Syndrome

Statin in Acute Coronary Syndrome. By C. Wongvipaporn Division Cardiology, Medicine Department Faculty of Medicine, Khon Kaen University. Acute Myocardial Infarction. AMI is fatal in about 30-50% of cases Approximately 50% of AMI deaths occur within 1 hour of symptom onset.

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Statin in Acute Coronary Syndrome

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  1. Statin in Acute Coronary Syndrome By C. Wongvipaporn Division Cardiology, Medicine Department Faculty of Medicine, Khon Kaen University

  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 Deaths/100 patients/month 25 Acute MI Unstable angina Stable angina 20 15 10 5 0 0 1 2 3 4 5 6 Time (months after hospital admission) Braunwald (1996)

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

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

  7. Pleiotropic effects of statins  Coagulation  Platelet activation  Endothelial progenitor cells  Endothelial function Effects on collagen  NO bioactivity  Reactive oxygen species  MMPs Statins  Macrophages  Inflammation  Immunomodulation  AT1 receptor  VSMC proliferation  Endothelin MMPs = matrix metalloproteinases Liao JK. Am J Cardiol. 2005;96(suppl 1):24F-33F.

  8. Statin Endpoint Trials: Reduction in Major Coronary Events Secondary Primary High Risk Trial NLDL AF/TexCAPS 6605 -27% WOS 6595 -26% ASCOT 10305 -26% HPS20,536 -29% 4S 4444 -36% LIPID 9014 -25% CARE4159 -28% Reduction (%) -25* -25§ -27‡ -31* -36† -38* -38* *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 Survival (%) 100 99 98 97 96 95 94 93 92 Lipid-lowering agents (n=2141) No lipid-lowering agents (n=6374) Log rank 2=87, p<0.001 0 30 60 90 120 150 180 Days Aronow et al (2000)

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

  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 eg 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 Atorvastatin Pravastatin PACT MIRACL Simvastatin PTT PAIS Fluvastatin PROVE IT 4S LAMIL WOSCOPS FLORIDA CARE L-CAD ACS RECIFE LIPID A to Z Primary prevention Secondary prevention 3 6 0 6 12 18 24 2 4 6 8 10 12 Hours Days Months

  13. 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 MIRACL: central hypothesis Schwartz GG et al. Am J Cardiol 1998;81:578–581.

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

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

  16. MIRACL: worsening angina with new objective evidence of ischemia requiring urgent rehospitalization 9 8.4% Placebo 6.2% 6 Cumulative Incidence (%) Atorvastatin 3 Relative risk = 0.74 p=0.02 0 0 4 8 12 16 Time since randomization (weeks) 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. PROVE-IT: Pravastatin or Atorvastatin Evaluation and Infection Therapy Study Design: N=4,162 with acute coronary syndrome <10 days ASA + Standard medical therapy Standard therapy (Pravastatin 40 mg) Intensive therapy (Atorvastatin 80 mg) 2x2 Factorial: gatifloxacin versus placebo Duration: mean 2-y follow-up (>925 events) Primary end point: death MI, documented UA requiring hospitalization, revascularization (>30 days after randomization), or stroke Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

  20. 0 30 3 6 9 12 15 18 21 24 27 All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 10 16% RR (P = 0.005) 5 0 Months of Follow-up

  21. PROVE IT–TIMI 22(2-Year Trial) Pravastatin40 mg LogCHDRisk Atorvastatin80 mg 16% Reduction in CVD 60 100 LDL-C Level Cannon CP et al. N Engl J Med 2004;350:1495-1504.

  22. A to Z: Phase Z, Early Intensive verses Delayed Simvastatin in Acute Coronary Syndromes - TRIAL DESIGN - Design Multicenter, randomized, double-blind, placebo-controlled Patients 4497 patients, aged 21-80 years, with non-ST-segment-elevation ACS or ST-elevation MI and total cholesterol ≤ 250 mg/dL. Patients receiving statin therapy, or scheduled for CABG or PCI within two weeks, or increased ALT or creatinine were excluded Follow up and primary endpoint Primary endpoint: composite of cardiovascular death, non-fatal MI, readmission for ACS and stroke. Median follow-up: 721 days. Treatment Placebo (4 months) then simvastatin 20 mg/day or simvastatin 40 mg/day (1 month) then simvastatin 80 mg/day

  23. The Z phase of the A to Z Trial: intense vs leisurely simvastatin, SS • Patients with ACS randomised to either SS 40mg/d for 1/12 then 80mg/d OR placebo for 4/12 then SS 20mg/d • No difference in 1ary end point (composite CV death, non-fatal MI, ACS or need for revasc) in first 4/12 • Differences only obvious after 6-8/12 • Only 10 episodes of myopathy (9 in intense limb)

  24. A to Z: Phase Z, Early Intensive verses Delayed Simvastatin in Acute Coronary Syndromes - SUMMARY - Early initiation of aggressive simvastatin regimen resulted in trend towards reduction in major cardiovascular events Cardiovascular death, MI and readmission for acute coronary syndrome reduced, but not significantly, in patients receiving aggressive simvastatin regimen Total and LDL cholesterol levels decreased over 24 months with simvastatin 40/80 mg/day treatment. Cholesterol levels rose during placebo phase, then fell in second phase of treatment with placebo/simvastatin 20 mg/day

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

  26. CVE over 2 Y

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

  28. GALAXY lipid studies 1. Lablanche J-M et al. Atherosclerosis Supplements 2006 7 (3): 578, Abs Th-P16:384

  29. Efficacy of High dose statin

  30. Safety of High dose statin

  31. Risk of SE from Statin

  32. Risk of SE from Statin

  33. Agents Commonly Used in Combination with Statins Bile acid sequestrants PPAR agonists (fibrates) Fish oils Niacin Ezetimibe

  34. Effect of lipid-modifying therapies on lipids Therapy Bile acid sequestrants Nicotinic acid Fibrates Probucol Statins* Ezetimibe 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 TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. *Daily dose of 40 mg of atorvastatin, simvastatin, pravastatin and fluvastatin. 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. ,

  35. Statin + Placebo (n = 390) Statin + Ezetimibe (n = 379) 0 -4% -10 -20 -25%* Mean LDL-C -30 Statin Monotherapy After Adding Placebo or Ezetimibe 139 mg/dL 133 mg/dL 138 mg/dL 102 mg/dL Ezetimibe: Effects on LDL-C When Added to Ongoing Statin Therapy Mean Change in LDL-C From Treated Baseline (%) *P 0.001 for statin + ezetimibe vs placebo Gagné C, et al. Am J Cardiol. 2002;90:1084-1091.

  36. IMPROVE IT – (TIMI 4 0) IMProved Reduction of Outcomes: Vytorin Efficacy International Trial Patients stabilized post Acute Coronary Syndrome < 10 daysLDL < 125 mg/dL (or < 100 mg/dL if prior statin) ASA + S tandard Medical Therapy Double-blind n~18,000 Simvastatin 40 mg Eze / Simva 10/40 mg Follow-Up Visit Day 30, Every 4 Months Duration: Minimum 2 1/2 year follow-up (>2955 events) Primary Endpoint: CV Death, MI, Hospital Admission for UA, revascularization (> 30 days after randomization), or Stroke

  37. Secondary prevention: Statin therapyNICE CG 67: Lipid modification May 2008 • Offer statin therapy to all patients with established CVD • Do not delay to manage modifiable risk factors • Treat co morbidities and secondary causes of dyslipidaemia • Decision to treat should follow an informed discussion about risks and benefits • Initiate treatment with simvastatin 40mg • offer patients with acute coronary syndrome (ACS) a higher–intensity statin (see later) • if simvastatin 40mg is contraindicated, offer a lower dose or alternative preparation (such as pravastatin)

  38. 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?

  39. What about ezetimibe▼? (1)NICE TA 132 November 2007 (& NICE TA 094 January 2006) • Ezetimibe▼ monotherapy is an option for adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia (at 20% or greater 10–year CVD risk) in whom statins are contraindicated or not tolerated • Ezetimibe▼, co-administered with initial statin therapy, is an option for patients with primary hypercholesterolaemia taking statins when: • TC or LDL ‘is not appropriately controlled’ either after dose titration of initial statin therapy or because dose titration is limited by intolerance to the statin therapy • and • Consideration is being given to changing from initial statin therapy to an alternative statin

  40. What about ezetimibe▼? (2) • But • Although ezetimibe▼ effectively lowers LDL levels,there is currently no published evidence that ezetimibe▼ alone or added to a statin helps patients live longer or live better • ENHANCE study (January 2008): no significant difference in carotid intima-media thickness with ezetimibe▼versus placebo, added to simvastatin 80mg, in familial hypercholesterolaemia • SEAS study (September 2008): no significant difference in major CV events with ezetimibe▼+ simvastatin 40mg, versus placebo in patients with aortic stenosis. Hazard Ratio (HR) for new cancer 1.55, P=0.01

  41. 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.

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