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The Importance of Potential Statin in High Risk Patient

The Importance of Potential Statin in High Risk Patient. Masrul Syafri Bagian Kardiologi & Kedokteran Vaskular FKUA/RS M Djamil Padang. CRE/006/FEB14-FEB15/BR. CVD is a leading cause of death worldwide. According to the WHO, 1 “An estimated 17.3 million people died from CVDs in 2008.”

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The Importance of Potential Statin in High Risk Patient

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  1. The Importance of Potential Statin in High Risk Patient Masrul Syafri Bagian Kardiologi & Kedokteran Vaskular FKUA/RS M Djamil Padang CRE/006/FEB14-FEB15/BR

  2. CVD is a leading cause of death worldwide According to the WHO,1 “An estimated 17.3 million people died from CVDs in 2008.” “By 2030, almost 23.6 million people will die from CVDs.” CHD remains the main cause of global mortality and a major cause of morbidity and loss of quality of life.2 CVD: Cardiovascular disease 1. http://www.who.int/cardiovascular_diseases/en/ 2. De Backer GG. Medicographia. 2009;31:343348.

  3. New Paradigm: Multi-Risk Factor Approach Traditional CVD perspective New CVD risk perspective New targets and goals for therapy DM Gender Reduction of total CVD risk is the primary goal Age HTN Hyper- cholesterol- emia HTN Diabetes Hypercholesterolemia Organ damage Smoking Multiple independentrisk factors (silo approach) Integrated identification and management of risk factors contributing to CVD risk (global approach) CVD: Cardiovascular disease; DM: Diabetes mellitus; HTN: Hypertension Volpe M, et al. J Human Hypertens. 2008;22:154–157.

  4. On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials – Lower is Better 30 4S - Placebo 25 Rx - Statin therapy PRA – pravastatin ATV - atorvastatin Secondary Prevention 4S - Rx 20 Event rate (%) LIPID - Placebo 15 CARE - Placebo LIPID - Rx CORONA - Placebo CARE - Rx Primary Prevention CORONA - Rx HPS - Placebo TNT – ATV10 HPS - Rx 10 PROVE-IT - PRA WOSCOPS – Placebo TNT – ATV80 AFCAPS - Placebo PROVE-IT – ATV 6 5 AFCAPS - Rx WOSCOPS - Rx ASCOT - Placebo ASCOT - Rx 0 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2) LDL-C achieved mg/dL (mmol/L) Adapted from Rosensen RS. Exp OpinEmerg Drugs 2004; 9(2): 269-279 LaRosa JC et al. N Engl J Med 2005; 352: 1425-1435

  5. On-Treatment LDL-C is Closely Related to Stroke Events in Statin Trials – Lower is Better Relationship between protection from stroke events and LDL-C reduction 1.2 GISSI PROSPER 1.0 ALLHAT-LLT WOSCOPS AFCAPS/TexCAPS 0.8 Odds ratio for stroke reduction LIPID ASCOT-LLA HPS 4S CARE 0.6 GREACE MIRACL 0.4 0.2 -10 -20 -30 -40 -50 Reduction in LDL-C (%) Amarenco P, et al. Stroke 2004;35:2902-2909

  6. Relationship Between Proportional Reduction in Events and Mean LDL-C Reduction at 1 Year A prospective meta-analysis of data from 90,056 individuals from 14 statintrials A 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a ….. …. 21% reduction in major vascular events …. 23% reduction in major coronary events 50 50 40 40 30 30 Proportional reduction in event rate (%SE) 20 Proportional reduction in event rate (%SE) 20 10 10 0 0 0.5(19) 1.0(38) 1.5(58) 2.0(77) 0.5(19) 1.0(38) 1.5(58) 2.0(77) -10 -10 Reduction in LDL-C mmol/L (mg/dL) Reduction in LDL-C mmol/L (mg/dL) CTT Collaborators. Lancet 2005;366:1267–1278.

  7. History of U.S. Dyslipidemia Guideline Development 1988 1993 2001 2004 2013 *ASCVD, Atherosclerotic Cardiovascular Disease • 1. NCEP. Arch Intern Med .1988;148:36-69. 2. NCEP ATP II. Circulation .1994;89:1333-445. 3. NCEP ATP III. Circulation. 2002;106:3143. • 4. Grundy SM, et al. Circulation. 2004;110:227-239.. 5. Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

  8. Target of LDL-C: NCEP-ATP III Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239

  9. Recommendation for treatment target LDL-C (ESC/EAS 2011)

  10. 2013 ACC/AHA Guideline Recommendations for Statin Therapy ASCVD Statin Benefit Groups Heart healthy lifestyle habits are the foundation of ASCVD prevention ASCVD prevention benefit of statin therapy may be less clear in other groups . Consider additional factors influencing ASCVD risk , potential ASCVD risk benefits and adverse effects, drug-drug interactions, and patient preferences for statin treatment. * With LDL-C of 70-189 mg/dL †Estimated using the Pooled Cohort Risk Assessment Equations Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

  11. Intensity of Statin Therapy Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in concert with the use of cholesterol lowering drug therapies. Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics †Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL ‡Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.

  12. LDL Cholesterolis The Primary Targetin Dyslipedmia Treatment NCEP ATP III 2003/ NCEP ATP III Update 2004 ADA/ACC Guideline Update for Secondary Prevention 2006 ESC/EAS Guidelines for the management of Dyslipidemias 2011 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

  13. Common dislipidemia patient in Primary practice • In Germany dyslipidemia was highly frequent in primary care (76% overall)1. • Life style intervention only control 10% dyslipidemia of the patients1 • After using pharmacotherapy, still many patient do not achieve LDL-C1, same thing happens in Asia2,3 • Starting doses is important, because commonly used in clinical practice, and most of clinicians often fail to titrate doses after initiating therapy to reach LDL cholesterol goals1 1. Steinhagen-Thiessen, Cardiovascular Diabetology 2008, 7:31 doi:10.1186/1475-2840-7-31 2. Park et al, European Journal of Cardiovascular Prevention & Rehabilitation published online 7 March 2011 DOI:10.1177/1741826710397100 3. Pearson TA, et al The Lipid Treatment Assessment Project (L-TAP) Arch Intern Med 2000;160:459–467.

  14. Management of Hypercholesterolaemia remains Sub-optimal: Pan-Asian CEPHEUS • Survey conducted in eight Asian countries of 7281 patients on lipid-lowering therapy for ≥3 months • Only 34.9% of very high risk patients reached NCEP ATP III goal and it was below from overall result • 65.1% of very high risk patients did not reach NCEP ATP III goal High<100 mg/dL) Overall Very-high<70 mg/dL Moderate<130 mg/dL Lower<160 mg/dL Risk category and NCEP ATP III goal Park JE et al. Eur J Cardiovasc Prevent Rehabil 2011; epub ahead of print.

  15. Percentage of Patients at LDL-C goals recommended by the 2004 updated NCEP ATP III* guidelines % of Patients at LDL-C goals recommended by 2004 updated NCEP ATP III* guidelines • For patients in Hong Kong the treatment goal attainment rate was 82.9% while patients in other countries had very low LDL-C attainment rate (31.3 – 52.7%). Park JE et al. Eur J Cardiovasc Prevent Rehabil 2011; epub ahead of print.

  16. PAN-ASIAN CEPHEUS Study: Follow-up of Patients not achieving LDL-C goals • Follow-up of patients not achieving LDL-C goals Park JE, et al. Eur J PrevCardiol. 2012;19(4):781-794..

  17. Treatment Gap • 31.3% of patients had attained their therapeutic LDL-C goals. • This result was below that of the overall Asian rate (49.1%) • Patients compliance with drug treatment appeared to be very poor in the Indonesian population.

  18. Intensive treatment is needed1 • Target LDL-C <100mg/dL and optionally <70mg/dL Examples of higher risk patients who may benefit from intensive treatment TIA/stroke patients Type 2 diabetes Atherosclerosis Acute coronary syndromes Hyperlipidaemic VTE patients Women with CVD Patients need >50% LDL-C reduction and optimize HDL-C Third report of the NCEP expert panel on detection, evaluation and treatment of high blood cholesterol on adults (ATP III). May 2001

  19. Rosuvastatin in Acute Coronary Syndrome

  20. Acute Coronary Syndrome No ST Elevation ST Elevation Non ST Elevation MI Myocardial Infarction Non Qw MI Qw MI Unstable Angina Acute coronary syndromes Braunwald E et al. J Am CollCardiol2000;36:970–1062.

  21. 16 12 8 4 0 Outcomes in primary prevention, stable and unstable coronary disease Unstable angina/non-Q-wave MI (FRISC II) Stable angina (SAPAT) Death/nonfatal MI (%) Primary prevention (WOSCOPS) 0 6 8 10 12 2 4 Months of follow-up Wallentin L et al. Lancet 2000;356:9–16. Juul-Moller S et al. Lancet 1992;340:1421–1425. Shepherd J et al.N Engl J Med 1995;333:1301–1307.

  22. Unstable angina: prognosis • Patients with unstable angina have a far worseshort-term prognosis than do patients with stable angina • Despite recent advances in therapy, the relative risk of death or nonfatal MI in patients with unstable angina versus those with stable disease is higher over the first year Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062. Wallentin L et al. Lancet 2000;356:9–16. Juul-Moller S et al. Lancet 1992;340:1421–1425.

  23. Benefits assigned to statins • Improve cholesterol parameters •  To achieve target LDL-C < 70 mg/dL • Pleiotropic effects • Plaque stabilization • Anti-inflammation • Anti-thrombogenicity • Arterial compliance • Modulation of endothelial function O’Sullivan, TSMJ 2007 (8): 52-56

  24. Statin in dyslipidemia with ACS PROVE-IT MIRACL

  25. Statin effect on inflammation A to Z PROVE-IT

  26. CENTAURUS and statins in ACS CRE/021/Jun12-Jun13/MF 1. Lablanche JM et al, Archives of Cardiovascular Diseases, 2010, 103 (3) :160-169 2. Schwartz GG, et al , JAMA 2001; 285:1711-1718 3. Cannon CP, et al. N Engl J Med 2004;350:1495-504. 4. De Lemos JA, et al JAMA 2004; 292:1307-1316

  27. Comparison of the EffectsNotedin TheApoB/ApoA-I ratio UsingRosuvastatin and atorvastatin in patients with Acute Coronary Syndrome Lablanche JM et al, Archives of Cardiovascular Diseases, 2010, 103 (3) :160-169

  28. CENTAURUSStudy Design • Patients ≥18 years with non-ST-elevation-ACS hospitalized <48 hours after symptom onset and for whom a PCI was planned/anticipated within 4 days for treatment of the index event • Two double-blind periods • 1st study period: admission to hospital discharge, max 6 days • 2nd study period: hospital discharge (day 0) to 3 months • 1108 subjects randomized and received at least 1 dose of study drug Placebo n=887 Atorvastatin 80 mg n=450 Rosuvastatin 20 mg n=221* Rosuvastatin 20 mg n=437 Day -4 PCI Day -6 Day 0 3 months PCI=percutaneous coronary intervention *Results of this group not reported Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.

  29. CENTAURUSPatient Population • Baseline Characteristics • Approximately 75% were male • Mean age approximately 60 years • 35% had dyslipidemia • Treatment of ACS • PCI completed: • 68% in the RSV group • 64% in the ATV group • Time to PCI after admission: 1.2 days in both groups • Mean time to start of drug treatment after onset of ACS: • 4.5 days in the RSV 20 mg group • 4.6 days in the ATV 80 mg group Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.

  30. CENTAURUSPrimary End pointPercent Change in ApoB/Apo A-1 After 1 and 3 Months versus Baseline Data are median (mean ± standard deviation) or median (95% confidence interval) Intention to treat population *Hodges-Lehman estimate †Wilcoxon Rank Sum test Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.

  31. CENTAURUSChanges in Lipid Parameters Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.

  32. CENTAURUSMajor Adverse Clinical Events *Number of patients (%) with at least one major adverse clinical event in the period/category All events were confirmed by the independent clinical adjudicating committee Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.

  33. CENTAURUSSafety Data are number of patients (%) ALT=alanine aminotransferase; CK=creatine kinase; SCr=serum creatinine; ULN=upper limit of normal Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.

  34. CENTAURUS Conclusion • In the CENTAURUS trial, after an ACS: • Rosuvastatin 20 mg was superior to Atorvastatin 80 mg to decrease the ApoB/ApoA1 ratio at 1 month whereas no difference was shown at 3 months • The ApoB/ApoA1 ratio decreased more rapidly with Rosuvastatin 20mg than Atorvastatin 80mg • Rosuvastatin 20 mg and Atorvastatin 80 mg induced a similar reduction in LDL-cholesterol • No meaningful differences were shown whenRosuvastatin 20mg was started at admission or at discharge • Both treatments were well tolerated Lablanche JM et al, Archives of Cardiovascular Diseases, 2010, 103 (3) :160-169

  35. LUNAR Study Limiting UNder-treatment of lipids in ACS with Rosuvastatin Objective : • A number of studies have compared the effectiveness of high-dose atorvastatin (ATV80) to rosuvastatin 20 mg (RSV20) and rosuvastatin 40 mg daily (RSV40), but none to date in patients with acute coronary syndromes (ACS) • The objective of LUNAR (Limiting UNder-treatment of lipids in ACS with Rosuvastatin) was therefore to compare the efficacy of once-daily regimens of RSV20 and RSV40 with ATV80 in reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with ACS Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  36. LUNARStudy Design Rosuvastatin 20 mg (n=277) Patients (n=825) 18–75 years Hospitalised for ACS (STEMI, NSTEMI, UA) within 48hrs of ischaemic symptoms LDL-C >70mg/dL (~1.8 mmol/L) TGs <500 mg/dL (~5.6 mmol/L) Rosuvastatin 40 mg (n=270) Atorvastatin 80 mg (n=278) Prospective, multi-centre, randomised, open-label, parallel-group phase IIIb study Visit: Week: 3 2 4 6 5 12 1 2 0 Symptom Onset LipidsSafety Lipids CRP Safety LipidsCRPSafety Screening / baseline blood analysis Average time from symptom onset to study drug treatment = 3.9 days ACS = acute coronary syndrome, STEMI = ST elevation myocardial infarction, NSTEMI = non-ST elevation myocardial infarction, UA = unstable angina, LDL-C = low-density lipoprotein cholesterol, TGs = triglycerides, CRP = C-reactive protein Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  37. LUNARPrimary & Secondary Endpoints • Primary Endpoint • % change in LDL-C (direct measurement) from baseline, averaged over measurements at 6 and 12 weeks • Secondary Endpoints • % change from baseline in LDL-C at 2, 6, and 12 weeks • % change from baseline in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), TG, non-HDL-C, apolipoprotein A-I (Apo A-I), apolipoprotein B (Apo B), LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, Apo B/Apo A-I, and LDL-C (Friedewald calculation) averaged over 612 weeks and at 2, 6, and 12 weeks • % change from baseline in the inflammatory marker high- sensitivity C-reactive protein (hsCRP) averaged over 612 weeks Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  38. LUNARBaseline Characteristics a Reported by investigators as history of dyslipidemia, hyperlipidaemia, or elevated cholesterol ACS = acute coronary syndrome, STEMI = ST elevation myocardial infarction, NSTEMI = non-ST elevation myocardial infarction, MI = myocardial infarction, PCI = percutaneous coronary intervention Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  39. LUNARBaseline Characteristics * Median value LDL-C = low density lipoprotein cholesterol, HDL-C = high density lipoprotein cholesterol, TC = total cholesterol, Apo=apolipoprotein, hs-CRP = high sensitivity C-reactive protein Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  40. Atorvastatin80 mg Rosuvastatin40 mg Rosuvastatin20 mg Average change in LDL-C from baseline (%) * LUNARPrimary Endpoint *p< 0.05 versus atorvastatin 80 mg Similar results were achieved in all subcategories of ACS (unstable angina, non-STEMI, and STEMI) Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  41. LUNARPrimary Endpoint 0 -10 -20 -30 -40 -50 -60 Rosuvastatin 20mg Rosuvastatin 40mg Atorvastatin 80 mg Mean Change in LDL-C from Baseline (%) ** * * 0 2 4 6 8 10 12 Time (weeks) *p0.05; **p0.01 versus atorvastatin 80 mg Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  42. LUNARSecondary Endpoint *** ** Mean change in HDL-C from baseline (%) Atorvastatin80 mg Rosuvastatin40 mg Rosuvastatin20 mg **p< 0.01, *** p<0.001 versus atorvastatin 80 mg Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  43. LUNARSecondary Endpoints *** ** Mean Change in Parameter from Baseline (%) †† † *** ** *** *** Rosuvastatin 20mg Rosuvastatin 40mg Atorvastatin 80mg ** p<0.01, ***p<0.001 versus atorvastatin 80 mg †p< 0.05, †† p<0.01 versus rosuvastatin 20mg Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  44. LUNARSafety & Tolerability *None of the serious AEs, serious cardiovascular AEs or deaths were considered by the investigators to be related to study treatment AE = adverse event Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  45. LUNARSafety & Tolerability ULN = upper limit of normal Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  46. LUNARSafety & Tolerability SD = standard deviation Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

  47. LUNARSummary • RSV20 was as effective as ATV80 in reducing LDL-C, and had a significantly greater effect than ATV80 in raising HDL-C • RSV40 was significantly more effective than ATV80 in reducing LDL-C and increasing HDL-C • RSV40 was also significantly more effective than ATV80 in improving several other important lipid parameters • Apo A-I , LDL-C/HDL-C, nonHDL-C/ HDL-C, TC/HDL-C, and Apo B/Apo A-I • The safety profile of RSV20, RSV40 and ATV80 were similar Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

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