AsianCardiovascularMasterClass<br />June  26 -27, 2010<br />Ho Chi Minh City, Vietnam<br />Presentation topicPractical cha...
The lessons learned in the 90ies<br />(Most) Statins are Safe! <br />25 – 30 % risk reduction<br />Benefit extends to <br ...
CHD Reduction in Secondary Prevention Trials<br />
LDL-C Reduction across separate studies<br />0<br />-10<br />20<br />-30<br />-40<br />-50<br />-60<br />-5<br />-15<br />...
Cholesterol Goal Attainment in the Real World: The REALITY Asia StudyAsia REALITY Study<br />Current status of cholesterol...
Cholesterol Goal Attainment in the Real World: The REALITY Asia StudyLDL-C Goal Attainment by Risk and Country<br />Adapte...
Target lipidlevels<br />Can J CardiolVol 25 No 10 October 2009<br />
Percentage of patients achieving total cholesterol target (< 5.0 mmol/L)<br />	Switch cohort 	Control cohort<br />	(n=1,25...
Time to Death or First Major Cardiovascular Event<br />Br J Cardiol 2007;14:280-5<br />
Time to Discontinuation of Statin Therapy<br />Br J Cardiol 2007;14:280-5<br />
12<br />Crystalline vs amorphous atorvastatin<br />Atorvastatin amorphous<br />Atorvastatin crystalline<br />Readily degra...
The National Lipid AssociationStatin Safety Task Force Report<br />NLA Statin Safety Task Force<br />JM McKenney, Chairman...
Liver Panel (DE Cohen et al.)
Renal Panel (BK Kasiske et al.)
Neurology Panel (LM Brass et al.)</li></ul>Final Conclusions and Recommendations<br /><ul><li>Evidence-Based
Practical Treatment Guidelines</li></ul>Am J Cardiol 2006; 97 (8, Suppl 1):S1-S98<br />
Transaminases and Liver Disease<br />measuring aminotransferases at baseline cannot adequately identify those who have und...
Use of Atorvastatin or Pravastatin in Patients with NASH<br />5 patients with NASH 20 mg Prava for 6 months1<br /><ul><li>...
Some improvement in hepatic inflammation and steatosis (liver biopsies)
7 patients with NASH 20 mg Atorvastatin 21 months (± 2 months)2
Well tolerated
No increase in liver enzymes
Significant improvement of hepatic histology in some patietns</li></ul>Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin i...
Use of Simvastatin in Patients with Hepatitis C<br />219 patients with HCV <br />17 were identified as using statin <br />...
Transaminases and Liver Disease<br />Dallas Heart Study1<br />79% of patients with hepatic steatosis normal LFT<br />Patie...
Statin Tolerability and Safety– Liver Effects<br /><ul><li>Elevations in liver transaminaselevels are infrequent but recog...
Before statin therapy:
Liver function tests recommended
Caution in patients who consume excessive quantities of alcohol and/or have a historyof liver disease
Contraindicated in patients with active liver disease</li></ul>*ALT >3 x ULN on 2 successive occasions<br />
Some Definitions…<br />Myalgia:Muscle symptoms reported by the patient<br />Myopathy:Muscle symptoms with CK elevation >10...
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  1. 1. AsianCardiovascularMasterClass<br />June 26 -27, 2010<br />Ho Chi Minh City, Vietnam<br />Presentation topicPractical challenges in optimalCV risk management <br />Slide lecture prepared and held by:<br />Peter Lansberg, MD<br />Academic Medical Centre,<br />Amsterdam, The Netherlands<br />
  2. 2. The lessons learned in the 90ies<br />(Most) Statins are Safe! <br />25 – 30 % risk reduction<br />Benefit extends to <br />Patients with CAD<br />Stable disease<br />ACS <br />Patients with CVD <br />Patients with diabetes and/or multiple risk factors<br />Majority of patients not adequately treated!<br />More patients need to be treated<br />Patients are not treated aggressively enough<br />
  3. 3. CHD Reduction in Secondary Prevention Trials<br />
  4. 4. LDL-C Reduction across separate studies<br />0<br />-10<br />20<br />-30<br />-40<br />-50<br />-60<br />-5<br />-15<br />-25<br />-35<br />-45<br />-55<br />20<br />mg<br />40<br />mg<br />10<br />mg<br />rosuvastatin<br />10<br />mg<br />20<br />mg<br /> 80<br /> mg<br />40<br />mg<br />atorvastatin<br />simvastatin<br />pravastatin<br />10<br />mg<br />20<br />mg<br />40<br />mg<br />80<br />mg<br />40<br />mg<br />10<br />mg<br />20<br />mg<br />Adapted from Law et al bmj.com 2003;326:1423<br />
  5. 5. Cholesterol Goal Attainment in the Real World: The REALITY Asia StudyAsia REALITY Study<br />Current status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia <br />In Asian countries and region:the Return on ExpenditureAchieved for Lipid Therapyin Asia (REALITY-Asia) study <br />Hyo-SooKima, YangfengWub, Shing-Jong Linc, ChaicharnDeerochanawongd, RobaayahZambaharie, LianchengZhaof, QiaoyiZhangg and Peter Yanh<br />aSeoul National University Hospital, Seoul, South Korea<br />bPeking University School of Public Health, Beijing, China<br />cTaipei Veterans General Hospital, Taipei, Taiwan <br />dRajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand <br />eNational Heart Institute, Kuala Lumpur, Malaysia <br />fFuWai Hospital, Beijing, China<br />gOutcomes Research, Reimbursement & Health Technology Assessment, Merck & Co., Inc., Whitehouse Station, New Jersey, USA <br />hGleneagles Medical Centre, Singapore<br />
  6. 6. Cholesterol Goal Attainment in the Real World: The REALITY Asia StudyLDL-C Goal Attainment by Risk and Country<br />Adapted from: Return on Expenditure Achieved for Lipid Therapy in Asia - REALITY-Asia study <br />
  7. 7.
  8. 8. Target lipidlevels<br />Can J CardiolVol 25 No 10 October 2009<br />
  9. 9. Percentage of patients achieving total cholesterol target (< 5.0 mmol/L)<br /> Switch cohort Control cohort<br /> (n=1,257) (n=4,792)<br />Patients achieving cholesterol target (%)<br />At baseline 60 74<br />One-year 65 72<br />post-index<br />Br J Cardiol 2007;14:280-5<br />
  10. 10. Time to Death or First Major Cardiovascular Event<br />Br J Cardiol 2007;14:280-5<br />
  11. 11. Time to Discontinuation of Statin Therapy<br />Br J Cardiol 2007;14:280-5<br />
  12. 12. 12<br />Crystalline vs amorphous atorvastatin<br />Atorvastatin amorphous<br />Atorvastatin crystalline<br />Readily degrades<br />More Stable<br />
  13. 13. The National Lipid AssociationStatin Safety Task Force Report<br />NLA Statin Safety Task Force<br />JM McKenney, Chairman<br />Review of the <br />Literature<br />Review of <br />Drug Interaction<br />Literature<br />Meta-analysis <br />of Randomized,<br />Clinical Trials<br />Analysis of <br />Managed Care <br />Databases<br />Analysis of <br />FDA AERS <br />Database<br />Review of Data <br />from NDA<br />Submissions<br />Independent Analysis by Subspecialist Panels<br /><ul><li>Muscle Panel (PD Thompson et al.)
  14. 14. Liver Panel (DE Cohen et al.)
  15. 15. Renal Panel (BK Kasiske et al.)
  16. 16. Neurology Panel (LM Brass et al.)</li></ul>Final Conclusions and Recommendations<br /><ul><li>Evidence-Based
  17. 17. Practical Treatment Guidelines</li></ul>Am J Cardiol 2006; 97 (8, Suppl 1):S1-S98<br />
  18. 18. Transaminases and Liver Disease<br />measuring aminotransferases at baseline cannot adequately identify those who have underlying liver disease<br />There is no sound rationale why statins should not be used in patients with chronic liver disease who otherwise need statin therapy<br />
  19. 19. Use of Atorvastatin or Pravastatin in Patients with NASH<br />5 patients with NASH 20 mg Prava for 6 months1<br /><ul><li>Normalization of liver enzymes in all patients
  20. 20. Some improvement in hepatic inflammation and steatosis (liver biopsies)
  21. 21. 7 patients with NASH 20 mg Atorvastatin 21 months (± 2 months)2
  22. 22. Well tolerated
  23. 23. No increase in liver enzymes
  24. 24. Significant improvement of hepatic histology in some patietns</li></ul>Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174: 193-196.<br />Horlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH. Gastroenterology 2001;120:A544.<br />
  25. 25. Use of Simvastatin in Patients with Hepatitis C<br />219 patients with HCV <br />17 were identified as using statin <br />Men with a mean age of 58.9 years. <br />All were taking simvastatin<br />Mean dose of 23 (±18 mg) /day<br />Five patients had a LFT = 1.5 x ULN<br />statins are not associated with significant liver enzyme elevations in patients with HCV infection<br /> Kimberly Gibson, PharmDa, and Joseph P. Rindone, PharmDb. Experience With Statin Use in Patients With Chronic Hepatitis C Infection Am J Cardiol 2005;96:1278 –1279<br />
  26. 26. Transaminases and Liver Disease<br />Dallas Heart Study1<br />79% of patients with hepatic steatosis normal LFT<br />Patients with documented NASH2<br />36% normal LFT but signs of liver cirrhosis<br />Browning JD, et al. Prevalence of hepatic steatosis in an urban population in the United States:impact of ethnicity. HEPATOLOGY 2004;40:1387-1395<br />Mofrad P et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values HEPATOLOGY 2003;37:1286-1292.<br />
  27. 27. Statin Tolerability and Safety– Liver Effects<br /><ul><li>Elevations in liver transaminaselevels are infrequent but recognised complication of treatment with statins*
  28. 28. Before statin therapy:
  29. 29. Liver function tests recommended
  30. 30. Caution in patients who consume excessive quantities of alcohol and/or have a historyof liver disease
  31. 31. Contraindicated in patients with active liver disease</li></ul>*ALT >3 x ULN on 2 successive occasions<br />
  32. 32. Some Definitions…<br />Myalgia:Muscle symptoms reported by the patient<br />Myopathy:Muscle symptoms with CK elevation >10xULN<br />Rhabdomyolysis:Widespread muscle injury with CK >10xULN andaccompanying organ (renal) damage. Myoglobinuria/emia feature<br />
  33. 33. Reported Cases of Serious Rhabdomyolysis for Statins: AERS<br />Davidson MH et al. Am J Cardiol. 2006;97:32C-43C<br />
  34. 34. In Summary…The Risk is Small!<br />There were only 73 reported cases of fatal rhabdomyolysis associated with 484,273,000 prescriptions of statinsin the USA<br />
  35. 35. FDA WarningMarch 2010<br /><ul><li>No Simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone.
  36. 36. No simvastatin >10 mg with gemfibrozil, cyclosporine, or danazol
  37. 37. No simvastatin >20 mg with amiodarone or verapamil
  38. 38. No simvastatin >40 mg with diltiazem
  39. 39. Patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products.
  40. 40. caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products</li></ul>The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients not of Chinese descent (0.03%) taking 40 mg simvastatin plus cholesterol-modifying doses (≥1 g/day) of a niacin-containing product. It is not known if the increased risk for myopathy observed in these patients applies to other patients of Asian descent.<br />
  41. 41. Atorvastatin 2003 and 2006 Safety Meta-analyses*<br />American Journal of Cardiology<br />Newman et al, 2006<br /><ul><li>Analysis of 49 studies
  42. 42. N = 14,236 (atorvastatin & placebo patients)
  43. 43. 10 mg, 80 mg, and placebo</li></ul>Newman et al, 2003<br /><ul><li>Analysis of 44 studies
  44. 44. N = 9416 (atorvastatin patients)
  45. 45. 10 mg-80 mg and placebo</li></ul>Newman C et al. Am J Cardiol. 2003;92:670-676; Newman C et al. Am J Cardiol. 2006;97:61-67.<br />
  46. 46. Increased Patient Exposure to Atorvastatin 80 mg in Clinical Trials<br />4925<br />4681<br />5000<br />3910<br />3000<br />Patient-years<br />1780<br />1388<br />1000<br />167<br />1996<br />2001<br />2004<br />Atv 10 mg<br />Atv 80 mg<br />>121 million patient-years of exposure to atorvastatin in the real world<br />Newman C et al. Am J Cardiol. 2006;97:61-67.<br />
  47. 47. Musculoskeletal Adverse Events With the 80-mg Dose<br />NR, not reported<br />*Studies not included in 2006 safety meta-analysis<br />†Investigator-reported cases: did not meet criteria for definition of myopathy (persistent CPK elevations >10 x ULN with muscle symptoms)<br />Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al. JAMA. 2005;294:2437-2445.<br />
  48. 48. Placebo<br />13,365 (98%)<br />609 (25%)<br />920 (31%)<br /> 20 (1.1%)<br />145 (10%)<br />Adverse and Serious Adverse Events in CARDS<br />Atorvastatin 10mg<br />Type of Event<br />No of events (% of patients with event)<br />13,238 (97%)<br />Any adverse event<br />599 (23%)<br />Associated AE<br />835 (29%)<br />Serious AE<br /> 19 (1.1%)<br />Associated SAE<br />122 (8.5%)<br />Discontinued for AE<br />
  49. 49. Intensive vs Aggressive Lipid Lowering<br /><ul><li>190 NSTEMI patients randomized (PROBE)
  50. 50. Severe CAD – invasive intervention not possible
  51. 51. 12 monts follow up
  52. 52. 146 pts Atorva 20 mg (up titrated ) <100 mg/dl
  53. 53. Average dosage 24.8 mg
  54. 54. LDL-c 94 mg/dl ± 5
  55. 55. 144 pts Atorva 80 mg
  56. 56. LDL-C 62 mg/dl ± 5
  57. 57. Event rate
  58. 58. Atorva 24.8 mg  39/146 (26.7%)
  59. 59. Atorva 80 mg  23/144 (16%)</li></ul>HR: 0.56 (0.33-0.93) p=0.027<br />Colivicchi – ESC 2008<br />
  60. 60. High Dose Statins after ACS<br />Dept. of Cardiology Stoke on trent<br />September/October 2005<br />Suspension of Atorvastatin due to costs<br />Audit patients with UA or MI<br />December 2004 – February 2005<br />Atorvastatine 80 – 40 mg<br />December 2005 – February 2006<br />Simvastatin 20 – 40 mg<br /><ul><li>Acute coronary syndrome event
  61. 61. Cardiac readmissions
  62. 62. Non cardiac readmissions
  63. 63. Death</li></ul>Lancet 2007;369:27<br />
  64. 64. High Dose Statins after ACS<br />Rob Butler, James Wainwright . Lancet 2007;369:27<br />
  65. 65. Incidence of Musculoskeletal Adverse Events Were Similar Across Dose Range<br />Data from 2003 safety meta-analysis involving 11,205 patients from 44 trials <br />Newman CB et al. Am J Cardiol. 2003;93:670-676.<br />
  66. 66. Factors that Increase the Risk of Statin Induced Myopathy<br />Patient characteristics<br />Increasing age<br />Female gender<br />Renal insufficiency<br />Hepatic dysfunction<br />Hypothyroidism<br />Diet (i.e. grapefruit juice)<br />Polypharmacy<br />Statin properties<br />High systemic exposure<br />Lipophilicity<br />High bioavailability<br />Limited protein binding<br />CYP 450 3A4 metabolism<br />Am J Cardiol 2006; 97 (8, Suppl 1):S1-88c<br />
  67. 67. Statin Safety in Perspective<br />Number needed to treat for 1 year to:<br /> Cause a GI Bleed1 Cause a Fatal GI Bleed1<br />Aspirin <br />Cause Severe Myositis2 Cause Fatal Myositis2<br />Statins <br />248<br />2066<br />100,000<br />1,000,000<br />1Derry S, Loke YK. 2000<br />2Thompson PD, et al. 2003<br />

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