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Dr ranjith mp.statins for primary prevention of coronary heart disease

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Dr ranjith mp.statins for primary prevention of coronary heart disease

  1. 1. Dr Ranjith MP Senior Resident Department of CardiologyGovernment Medical college Kozhikode
  2. 2. INTRODUCTIONPrimary prevention is treating hypercholesterolemia in patients who do not have clinical evidence of CADWhat is the rationale for this approach ? Grundy et al. Recent Clinical Trials and NCEP ATP III , JACC Vol. 44, No. 3, 2004 August 4, 2004:720–32
  3. 3. STATINSInhibit HMG-CoA reductaseStatin Pleiotropy
  4. 4. Earlier Clinical TrialsWHO Cooperative Trial (clofibrate ) - 10,577 patientsLipid Research Clinics Coronary Primary Prevention Trial (cholestyramine) - 3806 patientsHelsinki Heart Study (gemfibrozil ) - 4081 patientsThese trials demonstrated  Significant reductions in coronary events (25, 19 & 34 % respectively)  No reduction in coronary mortality  Increase in mortality from noncardiovascular causes
  5. 5. West of Scotland CoronaryPrevention Study (WOSCOPS)Designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease James Shepherd, et al, N Engl J Med 1995;333:1301-7
  6. 6. West of Scotland CoronaryPrevention Study Group (WOS)Randomized, double-blind, placebo controlled6595 men, 45 to 64 years of ageAverage follow-up of 4.9 years (seen at 3 month intervals)Pravastatin (40 mg each evening) vs. placebo James Shepherd, et al, N Engl J Med 1995;333:1301-7
  7. 7. Baseline Characteristics (WOS)
  8. 8. WOSCOPS EndpointsPrimary  Non-fatal MI or coronary heart disease death as a first eventSecondary  Non-fatal MI  Coronary heart disease deathOther Endpoints  Cardiovascular mortality  Total mortality  Coronary revascularization procedures
  9. 9. WOSCOPS Reduction in Lipids 200 placebo (intention -to-treat)LDL cholesterol mg/dL 180 placebo (actual treatment) 160 pravastatin (intention-to-treat) 140 pravastatin (actual treatment) 120 100 6 12 18 24 30 36 42 48 54 60 Months 20% reduction in TC 26% reduction in LDL 12% reduction in Trigs 5% increase in HDL James Shepherd, et al, N Engl J Med 1995;333:1301-7
  10. 10. Nonfatal MI or CHD Death (Primary Endpoint) 12 Pravastatin 10 31% Placebo Risk 8 ReductionPercent with 6 P=0.0001Events 4 2 0 0 1 2 3 4 5 6 Years in Study James Shepherd, et al, N Engl J Med 1995;333:1301-7
  11. 11. Non-Fatal MI (Secondary Endpoint) 10 Pravastain Placebo 8 31%Percent 6 Risk with ReductionEvents 4 P=0.000 5 2 0 0 1 2 3 4 5 6 Years in Study James Shepherd, et al, N Engl J Med 1995;333:1301-7
  12. 12. CHD Death (Secondary Endpoint) 2.5 Pravastain Placebo 2 28% RiskPercent 1.5 Reduction with P=0.13Events 1 0.5 0 0 1 2 3 4 5 6 Years in Study James Shepherd, et al, N Engl J Med 1995;333:1301-7
  13. 13. Cardiovascular Death 3.5 3 Pravastain Placebo 32% 2.5 RiskPercent 2 Reduction withEvents 1.5 P=0.03 3 1 0.5 0 0 1 2 3 4 5 6 Years in Study James Shepherd, et al, N Engl J Med 1995;333:1301-7
  14. 14. Total Mortality 6 Pravastain Placebo 22% 5 Risk Reduction 4Percent P=0.051 with 3Events 2 1 0 0 1 2 3 4 5 6 Years in Study James Shepherd, et al, N Engl J Med 1995;333:1301-7
  15. 15. Coronary InterventionsIntervention Placebo Pravastatin Risk (n= 3293) (n=3302) Reductions p-valueCoronaryAngiography 128 90 31% 0.007PTCA / CABG 80 51 37% 0.009 James Shepherd, et al, N Engl J Med 1995;333:1301-7
  16. 16. WOSCOPS Results/Clinical EventsEvent % Reduction p valueNonfatal MI + CHD death 31% < 0.001Definite nonfatal MI 31% < 0.001Definite CHD death 28% 0.13 (NS)Definite and suspected CHD death 33% 0.042All cardiovascular deaths 32% 0.033Total mortality 22% 0.051 (NS)CABG/PTCA 37% 0.029 James Shepherd, et al, N Engl J Med 1995;333:1301-7
  17. 17. WOSCOPS ConclusionsTreatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarctionPravastatin had no effect on noncardiovascular-related hospital admissionsPravastatin therapy also resulted in a 30 percent reduction in the risk of developing diabetes James Shepherd, et al, N Engl J Med 1995;333:1301-7
  18. 18. WOS Projected BenefitsTreatment of 1000 hypercholesterolemic middle aged men with pravastatin for five years will avoid:  14 coronary angiograms  8 revascularization procedures  20 nonfatal MIs  7 CHD deaths  2 additional deaths James Shepherd, et al, N Engl J Med 1995;333:1301-7
  19. 19. Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial7,832 ,men age 40-70 years and postmenopausal women up to age 70 with total cholesterol 220-270 mg/dL Mean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers, baseline total cholesterol 242.6 mg/dL, LDL 157 mg/dL, HDL 57.5 mg/dL, triglycerides 127 mg/dL 32% Female, Mean Age 58 years, Mean Follow-Up 5.3 years Prospective. Randomized. Open-label. Diet Modification Diet Modification + Pravastatin 10-20 mg/day n=3,966 n=3,866Primary Endpoints: Composite of coronary heart disease events, defined as cardiacand sudden death, fatal and nonfatal myocardial infarction (MI), angina and cardiac orvascular intervention.Secondary Endpoints: Stroke, CHD composite or cerebral infarction, anycardiovascular event, total mortality. Eishu Nango et al, lancet 2006;368:11555-63
  20. 20. MEGA Trial: Cholesterol and Triglyceride Levels Total LDL HDL Triglycerides Cholesterol 5.8 • Total cholesterol, 3.2 LDL, Triglyceride 4 1.3 reduction was larger 0 in the pravastatin group -4 -2.1mg/dL -3.2 -3.1 -8 •HDL increase was greater in the -12 pravastatin group -11.5 -16 -20 -18.0 Pravastatin+diet Diet Eishu Nango et al, lancet 2006;368:11555-63
  21. 21. MEGA Trial: Primary Composite Endpoint Primary composite endpoint of coronary heart disease events p = 0.01 5 5.0 3.3 vs 5.0 per 1000 patient years, hazard ratio 0.67,# per 1000 patient years 4 p=0.01 3.3 3 2 1 0 Pravastatin+diet Diet Eishu Nango et al, lancet 2006;368:11555-63
  22. 22. MEGA Trial: Secondary Endpoints•Total mortality was non-significantly lower in the pravastatin group (2.7 vs 3.8, HR 0.71,p=0.055)•MI occurred less often in the pravastatin group (0.9 vs 1.6, p=0.03)•No significant difference was observed in stroke (2.5 vs 3.0, p=0.33) or cerebral infarctionplus TIA (2.0 vs 2.6, p=0.23) p=0.055 4 3.8 p=0.33 p=0.23 # per 1000 patient years 3.0 3 2.7 2.6 2.5 p=0.03 2.0 2 1.6 0.9 1 0 Total mortality MI Stroke Cerebral infarction+TIA Pravastatin+diet Diet Eishu Nango et al, lancet 2006;368:11555-63
  23. 23. MEGA Trial: Safety Data Frequency of cancer Frequency of elevated liver function (per 1000 patient years) abnormalities (%) 6 5.5 5.7 3.0% 2.8% 2.8% 5 2.5%# per 1000 patient years 4 2.0% % 3 1.5% 2 1.0% 1 0.5% 0 0.0% Pravastatin+diet Diet Pravastatin+diet Diet • There was no difference in the frequency of cancer or elevated liver function abnormalities and no cases of rhabdomyolysis. Eishu Nango et al, lancet 2006;368:11555-63
  24. 24. MEGA Trial: Summary Among Japanese patients with hypercholesterolemia,treatment with pravastatin was associated with a reductionin the primary composite endpoint of coronary heart disease The cardiac morbidity and mortality in Japan is muchlower than in the U.S. and other western countries wherestatin therapy has been predominantly studied. The present study demonstrated that even in this lowerrisk population, primary prevention with low-dose statintherapy can be effective in reducing cardiac events, with amodest reduction in lipid parameters. Eishu Nango et al, lancet 2006;368:11555-63
  25. 25. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and ALLHAT–Lipid- Lowering Trial (ALLHAT) ALLHAT: N = 42,418: stage 1/2 hypertension + >1 CV risk factor Chlorthalidone Amlodipine Lisinopril Doxazosin* 12.5–25 mg/d 2.5–10 mg/d 10–40 mg/d 2–8 mg/d n = 15,255 n = 9048 n = 9054 n = 9061 Step 1: titration Step 2: open-label atenolol 25–100 mg/d, clonidine 0.1–0.3 mg bid, reserpine 0.05–0.2 mg/d Step 3: open-label hydralazine 25–100 mg bidALLHAT-LLT: N = 10,355; CHD, LDL-C 100 to 129 mg/dL or no CHD, LDL-C 120 to 189 mg/dL Pravastatin 40 mg/d (n = 5170) Usual care (n = 5185) ALLHAT Collaborative Research Group. *Arm discontinued JAMA. 2002;288:2981-2997, 2998-3007.
  26. 26. ALLHAT-LLT: Effects of statin or usual care on outcomesN = 10,355 with treated hypertension, baseline LDL-C 120–189 mg/dL(no CHD) or LDL-C 100–129 mg/dL (CHD)At 4 yrs, LDL-C  by 28% (statin) and 11% (usual care) All-cause mortality CHD death + nonfatal MI 18 18 15 RR = 0.99 15 RR = 0.91 12 (95% CI, 0.89–1.11) 12 (95% CI, 0.79–1.04)Cumulativerate 9 9(%) 6 6 3 3 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Time to death (years) Time to event (years) Pravastatin Usual care
  27. 27. ALLHAT: Clinical implicationsBP-lowering trial Diuretic, ACEI, CCB equivalent in  CHD death and MILipid-lowering trial (ALLHAT-LLT) Statin, usual care equivalent in  all-cause mortality  Modest differential in on-treatment cholesterol levels may have contributed to result ALLHAT BP results support importance of BP lowering, regardless of drug class used ALLHAT-LLT results are consistent with other statin trials
  28. 28. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)5804 patients aged 70–82 years with a history of vascular disease or with cardiovascular risk factorsRandomized to pravastatin 40 mg/d or placeboBaseline TC 155–348 mg/dLFollow-up 3.2 years (mean)Primary endpoint (composite): coronary death, nonfatal MI, fatal or nonfatal stroke Shepherd J et al. Lancet 2002;360:1623–1630
  29. 29. Major Endpoints: PROSPER Pravastatin Placebo HazardEndpoint (%) (%) ratio pPrimary endpoint:CHD death/MI/stroke 14.1 16.2 0.85 0.014Secondary endpoints:CHD death/MI 10.1 12.2 0.81 0.006Fatal or nonfatal stroke 4.7 4.5 1.03 0.81Other outcomes:Nonfatal MI 7.7 8.7 0.86 0.10Nonfatal stroke 4.0 4.1 0.98 0.85Transient ischemic attack 2.7 3.5 0.75 0.051All CV events 15.7 18.0 0.85 0.012 Shepherd J et al. Lancet 2002;360:1623–1630
  30. 30. Mortality by Cause: PROSPER Pravastatin Placebo HazardCause of death (%) (%) ratio pCHD 3.3 4.2 0.76 0.043Stroke 0.8 0.5 1.57 0.19Vascular 4.7 5.4 0.85 0.16Nonvascular 5.6 5.1 1.11 0.38Cancer 4.0 3.1 1.28 0.082Trauma/suicide 0.1 0.2 NA NAAll causes 10.3 10.5 0.97 0.74 Shepherd J et al. Lancet 2002;360:1623–1630
  31. 31. PROSPER ConclusionPravastatin given for 3 years reduced the risk of coronary disease in elderly individuals PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people Shepherd J et al. Lancet 2002;360:1623–1630
  32. 32. Air Force/Texas Coronary AtherosclerosisPrevention Study (AFCAPS/TexCAPS) Randomized, double-blind, placebo-controlled trial To compare lovastatin with placebo for prevention of the first acute major coronary event (UA, fatal and non- fatal MI and sudden cardiac death) 6605 pts without CHD , 5608 men and 997 women Average follow-up was 5.2 years Lovastatin (20-40 mg daily) or placebo Downs JR, et al, JAMA 1998;279:1615-1622
  33. 33. AFCAPS/TexCAPS EndpointsPrimary  First Acute Major Coronary Event (UA, Fatal or Non-fatal MI ,Sudden Cardiac Death)Secondary  Fatal or Non-Fatal MI  Unstable Angina  Fatal or Non-Fatal Cardiovascular Events  Fatal or Non-Fatal Coronary EventsTertiary Endpoints  Total Mortality, Non-Cardiovascular Mortality  Fatal and Non-Fatal Cancer  Discontinuation of Medication because of Adverse Effects Downs JR, et al, JAMA 1998;279:1615-1622
  34. 34. Baseline Characteristics(AFCAPS) Downs JR, et al, JAMA 1998;279:1615-1622
  35. 35. Baseline Characteristics(AFCAPS) Downs JR, et al, JAMA 1998;279:1615-1622
  36. 36. Baseline Lipid Levels Compared with U.S. Reference Population Based Upon NHANES III Wilford Hall U.S. NHANES Ref. Avg + SD Population2 Lipid Level (mg/dL) NHANES Mean + SD (mg/dL) N=6605 Percentile1 (mg/dL) Mean TC 221 + 21 51 225 + 45 Mean LDL 150 + 17 60 142 + 37 Mean HDL 50 + 16 Men 36 + 5 25 Women 40 + 5 16 Median TG 158 + 76 63 140 + 1201 Percentile ranks from US NHANES III reference population for study population averages2 Men aged 45-73, and women aged 55-73, without cardiovascular disease Downs JR, et al, JAMA 1998;279:1615-1622
  37. 37. AFCAPS Reduction in Lipids-year Placebo LovastatinMean TC 228.1 + 27.7 183.7 + 23.8Mean LDL-C 156.4 + 24.5 114.6 + 20.1Mean HDL-C 37.5 + 7.9 39.3 + 8.0 162.8 + 82.1 142.8 + 72.8Median TG Ratios 4.3 1.1 + 3.0 + 0.8Mean LDL-C/HDL-C 6.3 2.5 + 4.8 + 1.0Mean TC/HDL-C Downs JR, et al, JAMA 1998;279:1615-1622
  38. 38. Percent Change in Lipid Parameters Baseline to Year 1 30 p-value < 0.001 for all lovastatin treatment groups 20 42% of lovastatin patients achieved LDL-C goal of < 110 mg/dL (placebo 3%) 81% of lovastatin patients achieved LDL-C goal of < 130 mg/dL (placebo 12%) 10 6 0.9 1.5 1.2 1.7 1.6Percent 0 -2.3 -10 -20 -15 -18.4 -21.8 -30 -25 Placebo -28 Lovastatin, avg dose 30 mg -40 TC LDL HDL TG TC/HDL LDL/HDL Downs JR, et al, JAMA 1998;279:1615-1622
  39. 39. Primary Endpoint ~ First Acute Major Coronary Event* 0.06 *Includes unstable angina, fatal and non-fatal MI & 0.05 sudden cardiac deathCumulative Incidence Placebo 37% Risk Reduction 0.04 (p < 0.001) 0.03 Lovastatin 0.02 0.01 0.00 0 1 2 3 4 5 5+ Years# At Risk Years of Follow-upLovastatin N=3304 N=3270 N=3228 N=3184 N=3134 N=1688Placebo N=3301 N=3251 N=3211 N=3159 N=3092 N=1644 Downs JR, et al, JAMA 1998;279:1615-1622
  40. 40. Primary Endpoint ~ First Acute Major Coronary Event* Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac Death 250 reduced by 37% (p < 0.0008)Cumulative Number of Participants Placebo (n=3301) 200 Lovastatin (n=3304) 183 with Events 150 135 116 100 91 100 66 70 40 46 50 23 0 1 2 3 4 5+ years Years Since Randomization Downs JR, et al, JAMA 1998;279:1615-1622
  41. 41. Lovastatin Reduced the Risk of First Acute Major Coronary Events > Median Men Women by Age Smokers Hypertension Diabetes N=5608 N=997 N=3180 N=818 N=1448 N=156 0 -10Percent Risk Reduction -20 -30 -31 -40 -37 -38 -42 -50 -46 -60 -58 -70 Downs JR, et al, JAMA 1998;279:1615-1622
  42. 42. Lovastatin Reduced the Risk of First Acute MajorCoronary Events in All Baseline LDL Tertiles 0 -10 Percent Change -20 -30 -40 -34 -36 -41 -50 Relative Risk Reduction -60 90.4-141.9 142.0-156.8 156.9-235.4 Baseline LDL Tertiles Downs JR, et al, JAMA 1998;279:1615-1622
  43. 43. AFCAPS/TexCAPS Role of Baseline LDL on Outcomes 90 Placebo 77 80 70 LovastatinNumber of Events 60 54 52 50 46 40 37 33 30 20 10 0 < 142, n=2210 143-156, n=2195 > 157, n=2199 Baseline LDL Level (mg/dL) Downs JR, et al, JAMA 1998;279:1615-1622
  44. 44. AFCAPS/TexCAPS Role of Baseline HDL on Outcomes 80 71 68 Placebo 70 Lovastatin 60Number of Events 50 44 40 41 40 35 30 20 10 0 < 34 35-39 > 40 Baseline HDL Level (mg/dL) Downs JR, et al, JAMA 1998;279:1615-1622
  45. 45. Secondary Endpoint Analyses Fatal and Non-Fatal MI Cardiovascular Events* 0.08 0.03 0.07 Placebo 25% Risk Reduction Placebo 40% Risk Reduction (p = 0.003) Cumulative Incidence Cumulative Incidence 0.06 (p = 0.002) 0.02 0.05 0.04 0.01 Lovastatin 0.03 Lovastatin 0.02 0.01 0.00 0.00 0 1 2 3 4 5 5+ years 0 1 2 3 4 5 5+ years Years of Follow-up Years of Follow-up # At Risk# At Risk Lovastatin N=3304 N=3260 N=3206 N=3147 N=3088 N=1651 Lovastatin N=3304 N=3281 N=3249 N=3214 N=3174 N=1717 Placebo N=3301 N=3242 N=3187 N=3124 N=3045 N=1615 Placebo N=3301 N=3270 N=3237 N=3200 N=3148 N=1692 Unstable Angina Coronary Events* 0.03 0.07 25% Risk Reduction 0.06 Placebo 32% Risk Reduction Placebo Cumulative Incidence Cumulative Incidence 0.05 0.02 (p = 0.02) 0.04 (p = 0.006) Lovastatin 0.03 Lovastatin 0.01 0.02 0.01 0.00 0.00 0 1 2 3 4 5 5+ years 0 1 2 3 4 5 5+ years Years of Follow-up Years of Follow-up # At Risk # At Risk Lovastatin N=3304 N=3281 N=3250 N=3217 N=3174 N=1707 Lovastatin N=3304 N=3264 N=3215 N=3160 N=3106 N=1666 Placebo N=3301 N=3267 N=3240 N=3205 N=3150 N=1678 Placebo N=3301 N=3246 N=3201 N=3141 N=3069 N=1634 Downs JR, et al, JAMA 1998;279:1615-1622
  46. 46. AFCAPS/TexCAPS Coronary Revascularizations 0.05 0.04 Cumulative Incidence 33% Risk Reduction Placebo (p = 0.001) 0.03 0.02 Lovastatin 0.01 0.00 0 1 2 3 4 5 5+ Years# At Risk Years of Follow-up Lovastatin N=3304 N=3277 N=3237 N=3192 N=3148 N=1691 Placebo N=3301 N=3258 N=3221 N=3174 N=3108 N=1659 Downs JR, et al, JAMA 1998;279:1615-1622
  47. 47. AFCAPS/TexCAPS Mortality Placebo LovastatinEvent n=3301 n=3304 P-valueTotal Mortality 77 80 N.S.Cardiovascular 25 17 too few*Non-cardiovascular 52 63 N.S.*Too few for survival analyses Downs JR, et al, JAMA 1998;279:1615-1622
  48. 48. Tertiary Analysis Fatal and Non-Fatal Cancer* 0.08 *Excludes non-melanoma skin cancer 0.07 P = NS Placebo Cumulative Incidence 0.06 0.05 Lovastatin 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 5+ years Years of Follow-up# At Risk Lovastatin N=3304 N=3249 N=3188 N=3117 N=3059 N=1626 Placebo N=3301 N=3234 N=3171 N=3105 N=3043 N=1603 Downs JR, et al, JAMA 1998;279:1615-1622
  49. 49. AFCAPS/TexCAPS Summary of Results Clinical benefit  appeared within the first year of treatment and continued  was apparent for all LDL-C tertiles  Range 90-235 mg/dl  was consistent for subgroups  Women  Risk Factors - Age, DM, HTN, Smokers Downs JR, et al, JAMA 1998;279:1615-1622
  50. 50. AFCAPS/TexCAPS ConclusionsIn conjunction with a prudent diet, regular exercise and risk factor modification Lovastatin 20-40 mg/day could be used to lower the risk of the first acute major coronary event for primary prevention candidates -  Men > 45 years, Women > 55 years  HDL < 50 mg/dl  LDL > 130 mg/dl Downs JR, et al, JAMA 1998;279:1615-1622
  51. 51. The Anglo-Scandinavian Cardiac outcomes Trial (ASCOT ) Multicenter trial with 2 treatment comparison  A prospective, randomized, open, blinded end point design comparing 2 antihypertensive regimen  A double blind placebo controlled trial of atorvastatin 10mg/day in the substrate of patients with total cholesterol ≤250mg/dl Primary end point: nonfatal MI or CHD death Planned follow up average of 5yr
  52. 52. The Anglo-Scandinavian Cardiac outcomes Trial Sever PS et al, Lancet 2003; 361:1149.
  53. 53. ASCOT-LLA trial Sever PS et al, Lancet 2003; 361:1149.
  54. 54. ASCOT-LLA trial Sever PS et al, Lancet 2003; 361:1149.
  55. 55. ASCOT-LLA trial Sever PS et al, Eur Heart J 2008;29:499–508
  56. 56. ASCOT-LLA trial Sever PS et al, Eur Heart J 2008;29:499–508
  57. 57. ASCOT-LLA trial Extension Sever PS et al, Eur Heart J 2008;29:499–508
  58. 58. The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the UK • The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in ASCOT Trial—8 years after closure of the lipid-lowering arm of the trial among the UK population • Post trial mortality data were collected every 2- 3months Sever PS et al, Eur Heart J August 28, 2011
  59. 59. ASCOT-LLA 11 year mortality study profile Sever PS et al, Eur Heart J August 28, 2011
  60. 60. ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011
  61. 61. ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011
  62. 62. ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011
  63. 63. ASCOT-LLA trial Extension Sever PS et al, Eur Heart J August 28, 2011
  64. 64. Collaborative Atorvastatin Diabetes Study (CARDS) Patient Population Atorvastatin 10 mg • Type 2 diabetes mellitus (n=1428) • Men and women 40–75 2838 patients 4-year follow-up years of age • LDL-C 160 mg/dL (4.14 Double-blind placebo mmol/L) (n=1410) • TG 600 mg/dL (6.78 mmol/L)  Primary endpoint: time to first major CV event • 1 additional RF (CHD death, nonfatal MI, unstable angina, – HTN (or on HTN resuscitated cardiac arrest, coronary treatment) revascularization, stroke – Retinopathy  Secondary endpoints: total mortality, any CV endpoint, lipids, and lipoproteins – Albuminuria – Current smoking Colhoun HM et al. Lancet 2004;364:685-696.
  65. 65. CARDS: Patient Baseline Characteristics Placebo Atorvastatin (n = 1410) (n = 1428)Age Mean (SD) years 61.8 (8.0) 61.5 (8.3) <60 529 (38%) 558 (39%) 60–70 708 (50%) 703 (49%) >70 173 (12%) 167 (12%)Women 453 (32%) 456 (32%)White ethnicity 1326 (94%) 1350 (95%)BMI Mean (SD), kg/m2 28.8 (3.5) 28.7 (3.6) Obese (BMI >30 kg/m2) 538 (38%) 515 (36%) Colhoun HM et al. Lancet 2004;364:685-696.
  66. 66. CARDS: Patient Baseline Lipids Placebo Atorvastatin (n = 1410) (n = 1428) Mean (SD) Mean (SD) Total cholesterol (mg/dL) 207 (32) 207 (32) (mmol/L) 5.35 (0.82) 5.36 (0.83) LDL cholesterol (mg/dL) 117 (27) 118 (28) (mmol/L) 3.02 (0.70) 3.04 (0.72) HDL cholesterol (mg/dL) 55 (13) 54 (12) (mmol/L) 1.42 (0.34) 1.39 (0.32) Triglycerides* (mg/dL) 148 (104–212) 150 (106–212) (mmol/L) 1.67 (1.17–2.40) 1.70 (1.20–2.40)*Median (interquartile range) Colhoun HM et al. Lancet 2004;364:685-696.
  67. 67. CARDS: Lipid Levels by Treatment Total Cholesterol (mg/dL) LDL Cholesterol (mg/dL) Average difference 26%, Average difference 40%, 54 mg/dL; P<0.0001 46 mg/dL; P<0.0001 240 Placebo 160 Median LDL-C (mg/dL)*Median TC (mg/dL)* Placebo 120 160 Atorvastatin 80 80 Atorvastatin 40 0 0 0 1 2 3 4 4.5 0 1 2 3 4 4.5 Years of Study Years of Study Colhoun HM et al. Lancet 2004;364:685-696.
  68. 68. CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Relative Risk Reduction 37% (95% CI, 17–52) P = 0.001 Cumulative Hazard, (%) 15 Placebo 127 events 10 5 Atorvastatin 83 events 0 0 1 2 3 4 4.75 YearsPlacebo 1410 1351 1306 1022 651 305Atorvastatin 1428 1392 1361 1074 694 328 Colhoun HM et al. Lancet 2004;364:685-696.
  69. 69. CARDS: Adverse and Serious Adverse Events Patients (%) with Event Placebo Atorvastatin 10 mg Type of Event (n = 1410) (n = 1428) Serious adverse event 20 (1.1%) 19 (1.1%) possibly associated with study drug Discontinued for AE 145 (10%) 122 (9%) Rhabdomyolysis 0 0 Myopathy AE report 1 (0.1%) 1 (0.1%) CPK 10  ULN 10 (0.7%) 2 (0.1%) ALT 3  ULN 14 (1%) 17 (1%) AST 3  ULN 4 (0.3%) 6 (0.4%) Colhoun HM et al. Lancet 2004;364:685-696.
  70. 70. CARDS Implications and Clinical RelevanceIn patients with Type 2 DM with lower LDL-C levels, atorvastatin 10 mg daily was safe, well tolerated & significantly efficacious in reducing the risk of first CHD events CARDS supports recommendations that made by the ADA that patients with Type 2 DM should be considered as candidates for statin treatment—even at lower LDL-C levels Colhoun HM et al. Lancet 2004;364:685-696.
  71. 71. Primary Prevention Trials of Lipid-Altering Therapy Including Patients with Diabetes Total N CHD* Risk vs Diabetic,* in Lipid-Altering Placebo in Diabetic Trial n Study Drug, mg/d Patients, % CARDS † 2,838 2,838 Atorvastatin 10 –37 (p=.001) AFCAPS 155 6,605 Lovastatin 20–40 ‡ –44 (NS) HPS § 2,912 7,150 Simvastatin 40 –33 (p=.0003) ASCOT 2,532 10,305 Atorvastatin 10 –16 (NS) PROSPER 623 5,804 Pravastatin 40 +27 (NS) HHS 135 4,081 Gemfibrozil 1200 –68 (NS) * By history † Prospective trial in diabetic subjects; others are subgroup analyses ‡ Mean 30 mg/d § Type 1 or 2 diabetesBays H et al. Future Cardiology 2005;1:39-59. | Colhoun HM et al. Lancet 2004;364:685-696. | Downs JR et al. JAMA1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Sever PS et al. Lancet 2003;361:1149-1158. | Shepherd J et al. Lancet 2002;360:1623-1630. | Koskinen P et al. Diabetes Care 1992;15:820-825.
  72. 72. Measuring Effects of Intima-Media Thickness: An Evaluation of Rosuvastatin METEOR Trial Evaluated the effect of rosuvastatin compared with placebo on carotid intima-media thickness (CIMT) among asymptomatic patients at low risk for cardiovascular disease Study period was two-year Randomized controlled trial Rosuvastatin 40 mg daily vs placebo Crouse JR 3rd, et al, JAMA 2007; 297:1344.
  73. 73. METEOR Trial: Study Design 984 asymptomatic patients with moderately elevated cholesterol and low risk of CVDaccording to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk factor and LDL 120-190mg/dL or > 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk < 10%); HDL-C <60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) 5:2 Randomized. Double-blinded. Placebo-controlled. Mean age = 57 years. 40% Female. R Rosuvastatin (40mg) Placebo n=702 n=282 6, 12, 18 and 24 mos. follow-up  Primary Endpoint: Annualized rate of change in maximum CIMT  Secondary Endpoint: Annualized rate of change in maximum CIMT derived from the near and far walls of the right and left common carotid artery; the right and left carotid bulb; the right and left internal carotid artery; and annualized rate of change in mean CIMT for the near and far walls of the right and left common carotid artery.
  74. 74. METEOR Trial: Primary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo 0.015 0.0131 • After two years,Change in CIMT for 12 Carotid Artery sites treatment with rosuvastatin was 0.010 associated with a p < 0.001 statistically significant reduction in the rate of (mm/year) progression of CIMT 0.005 thickening in overall carotid segments, while Rosuvastatin n = 282 the placebo group 0.000 displayed progression n = 702 Placebo (p<0.001). -0.0014 -0.005
  75. 75. METEOR Trial: Secondary Endpoint Change in maximum CIMT with rosuvastatin vs. placeboChange in CIMT for common carotid sites (mm/year) 0.010 • After two years, 0.0084 treatment with rosuvastatin was associated with a 0.005 p < 0.001 statistically significant reduction in the rate of progression of CIMT thickening in common Rosuvastatin n = 282 carotid sites, while the 0.000 placebo group n = 702 Placebo displayed progression (p<0.001). -0.005 -0.0039
  76. 76. METEOR Trial: Secondary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo 0.020 • After two years,Change in CIMT for carotid bulb sites (mm/year) 0.0172 treatment with rosuvastatin was 0.015 associated with a p < 0.001 statistically significant reduction in the rate of 0.010 progression of CIMT thickening in carotid 0.005 bulb sites, while the placebo group displayed progression Rosuvastatin n = 282 0.000 (p<0.001). n = 702 Placebo -0.005 -0.0040
  77. 77. METEOR Trial: Secondary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo 0.015 0.0145Change in CIMT for internal carotid artery sites • After two years, treatment with rosuvastatin was 0.010 p = 0.02 associated with a statistically significant (mm/year) lower progression in CIMT thickening in internal carotid sites as 0.005 0.0039 compared with the placebo group (p=0.02) n = 702 n = 282 0.000 Rosuvastatin Placebo
  78. 78. METEOR Trial: Limitations & SummaryCompared with placebo, subjects treated with rosuvastatin had a marked reduction in LDL-cholesterol (-49 versus -0.3 percent)The study was not designed to evaluate clinical events,It is uncertain how well changes in CIMT predict clinical events, particularly in this low risk population.This study does not convincingly support the use of high dose statins (such as rosuvastatin 40 mg daily) for primary prevention in patients at low risk for CHD events
  79. 79. Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRPNearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-ChsCRP predicts cardiovascular disease independent of LDL-C levels Ridker et al, NEJM 2008359:2195-07
  80. 80. JUPITER Rosuvastatin 20 mg (N=8901) MINo Prior CVD or DM StrokeMen >50, Women >60 Unstable LDL <130 mg/dL 4-week Placebo (N=8901) Angina hsCRP >2 mg/L run-in CVD Death CABG/PTCA Baseline LDLC 104 mg/dL Baseline HDLC 49 mg/dL Baseline hsCRP 4.2 mg/L Women 6,800 Non-Caucasian 5,000 Ridker et al, NEJM 2008359:2195-07
  81. 81. JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI 0.46-0.69 Placebo 251 / 0.08 P < 0.00001 8901 Number Needed to Treat (NNT5) = 25 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 0.02 8901 0.00 0 1 2 3 4 Number at Risk Follow-up (years) Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 Ridker et al, NEJM 2008359:2195-07
  82. 82. JUPITER Grouped Components of the Primary Endpoint Myocardial Infarction, Stroke, or Arterial Revascularization or Cardiovascular Death Hospitalization for Unstable Angina HR 0.53, CI 0.40-0.69 HR 0.53, CI 0.40-0.70 P < 0.00001 P < 0.00001 0.05 0.06 Placebo Placebo 0.05 0.04 0.04Cumulative Incidence Cumulative Incidence 0.03 - 47 % 0.03 - 47 % 0.02 0.02 Rosuvastatin 0.01 Rosuvastatin 0.01 0.00 0.00 0 1 2 3 4 0 1 2 3 4 Follow-up (years) Follow-up (years) Ridker et al, NEJM 2008359:2195-07
  83. 83. JUPITER Individual components of the Primary EndpointEndpoint Rosuvastatin Placebo HR 95%CI PPrimary Endpoint* 142 251 0.56 0.46-0.69 <0.00001Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001Any MI 31 68 0.46 0.30-0.70 <0.0002Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003Any Stroke 33 64 0.52 0.34-0.79 0.002Revascularization or Unstable Angina 76 143 0.53 0.40-0.70 <0.00001MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001 *Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death Ridker et al, NEJM 2008359:2195-07
  84. 84. JUPITER Primary Endpoint – Subgroup Analysis N P for Interaction Men 11,001 0.80 Women 6,801 Age < 65 8,541 0.32 Age > 65 9,261 Smoker 2,820 0.63 Non-Smoker 14,975 Caucasian 12,683 0.57 Non-Caucasian 5,117 USA/Canada 6,041 0.51 Rest of World 11,761 Hypertension 10,208 0.53No Hypertension 7,586 All Participants 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior Ridker et al, NEJM 2008359:2195-07
  85. 85. JUPITER Primary Endpoint – Subgroup Analysis N P for Interaction Family HX of CHD 2,045 0.07 No Family HX of CHD 15,684 2 BMI < 25 kg/m 4,073 0.70 BMI 25-29.9 kg/m 2 7,009 2 BMI >30 kg/m 6,675 Metabolic Syndrome 7,375 0.14No Metabolic Syndrome 10,296Framingham Risk < 10% 8,882 0.99Framingham Risk > 10% 8,895hsCRP > 2 mg/L Only 6,375 hsCRP > 2 mg/L Only 6,375 All Participants 17,802 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior Ridker et al, NEJM 2008359:2195-07
  86. 86. JUPITER Adverse Events and Measured Safety Parameters Event Rosuvastatin Placebo P Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34 Myopathy 10 (0.1) 9 (0.1) 0.82 Rhabdomyolysis 1 (0.01)* 0 (0.0) -- Incident Cancer 298 (3.4) 314 (3.5) 0.51 Cancer Deaths 35 (0.4) 58 (0.7) 0.02 Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44 GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02 ALT > 3xULN 23 (0.3) 17 (0.2) 0.34 Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12 HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01 Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64 Incident Diabetes** 270 (3.0) 216 (2.4) 0.01*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)**Physician reported Ridker et al, NEJM 2008359:2195-07
  87. 87. JUPITER Statins and the Development of Diabetes HR (95% CI)WOSCOPS Pravastatin 0.70 (0.50–0.98)PROSPER Pravastatin 1.34 (1.06–1.68)HPS Simvastatin 1.20 (0.98–1.35)ASCOT-LLA Atorvastatin 1.20 (0.91–1.44)PROVE-IT Atorvastatin 1.11 (0.67–1.83) VS PravastatinJUPITER Rosuvastatin 1.25 (1.05–1.54) 0.25 0.5 1.0 2 4 Statin Better Statin Worse Ridker et al, NEJM 2008359:2195-07
  88. 88. JUPITER Secondary Endpoint – All Cause Mortality HR 0.80, 95%CI 0.67-0.97 0.06 Placebo 247 / P= 0.02 8901 - 20 % 0.05 Cumulative Incidence 0.04 0.03 Rosuvastatin 198 / 8901 0.02 0.01 0.00 0 1 2 3 4Number at Risk Follow-up (years) Rosuvastatin 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 Placebo 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 Ridker et al, NEJM 2008359:2195-07
  89. 89. JUPITER ConclusionsIn this trial of low LDL/high hsCRP individuals who do not currently qualify for statin therapy, rosuvastatin significantly reduced  All-cause mortality by 20 percent  Incident myocardial infarction, stroke, and cardiovascular death by 47 percent Ridker et al, NEJM 2008359:2195-07
  90. 90. CONCLUDEStatin trials in primary prevention, starting with the landmark WOSCOPS trial, have found substantial relative reductions in cardiovascular events without an increase in noncardiovascular mortalityIn view of the evidence, statins should be seriously considered in people with diabetes at least by age 50 in men and 60 in womenAlso, men aged 55 years or above with multiple risk factors, and women aged 65 years or above, should be seriously considered for generic statin use.
  91. 91. THANK YOU

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