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Statin Landmark Trials Across the Spectrum of Risk: Secondary CV Prevention

Statin Landmark Trials Across the Spectrum of Risk: Secondary CV Prevention . TNT: Study Design Treating to New Targets. Patient Population. Clinically evident CHD LDL-C 130  250 mg/dL following up to 8-week washout and 8-week open-label run-in with atorvastatin 10 mg.

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Statin Landmark Trials Across the Spectrum of Risk: Secondary CV Prevention

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  1. Statin Landmark Trials Across the Spectrum of Risk: Secondary CV Prevention

  2. TNT: Study Design Treating to New Targets Patient Population • Clinically evident CHD • LDL-C 130250 mg/dL following up to 8-week washout and 8-week open-label run-in with atorvastatin 10 mg Atorvastatin 10 mg LDL-C target: 100 mg/dL 10,001 Patients Primary End Point Atorvastatin 80 mg LDL-C target: 75 mg/dL • Time to first occurrence of a major cardiovascular event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke) 5 years LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

  3. TNT Primary Efficacy Outcome Measure:Major Cardiovascular Events* 0.14 HR = 0.78 (95% CI, 0.69–0.89) P < .001 0.12 Atorvastatin 10 mg (n = 5006) LDL-C 101 mg/dL (2.6 mmol/L) 0.10 0.08 Cumulative Incidence of Major Cardiovascular Events, % 0.06 Atorvastatin 80 mg (n = 4995) LDL-C 77 mg/dL (2.0 mmol/L) 0.04 0.02 Relative risk reduction = 22% 0 0 1 2 3 4 5 6 Time, years *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

  4. TNT: Primary and Secondary Efficacy Outcomes Primary Efficacy Measure HR P Value Major CV event 0.78 .001 CHD death 0.80 .09 Nonfatal non–procedure-related MI 0.78 .004 Resuscitated cardiac arrest 0.96 .89 Fatal/nonfatal stroke 0.75 .02 Secondary Efficacy Measures Any cardiovascular event 0.81 <.001 Major coronary event* 0.80 .002 Any coronary event 0.79 <.001 Cerebrovascular event 0.77 .007 Hospitalization for CHF 0.74 .01 Peripheral arterial disease 0.97 .76 All-cause mortality 1.01 .92 Atorvastatin 80 mg Better Atorvastatin 10 mg Better *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest. LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

  5. Atorvastatin 10 mg Atorvastatin 80 mg TNT: Time to First Fatal or Nonfatal Stroke 0.04 HR = 0.75 (95% CI 0.59-0.96) P=0.02 0.03 Relative RR = 25% Proportion of patients experiencing events 0.02 0.01 0 0 1 2 3 4 5 6 Time (years) LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

  6. TNT: Safety Profile 10 P<0.001 8.1 8 P =0.72 5.8 6 4.8 4.7 % of Patients 4 P<0.001 1.2 2 0.2 (n=9) (n=406) (n=289) (n=241) (n=234) (n=60) 0 Treatment-Related Adverse Events Treatment-Related Myalgia Elevated Liver Enzymes* Atorvastatin 80 mg (n=4,995) Atorvastatin 10 mg (n=5,006) Persistent = 2 consecutive measurements. LaRosaJC et al. N Engl J Med. 2005;352:1425-1435.

  7. IDEAL (Incremental Decrease in EndPoints Through Aggressive Lipid Lowering): Study Design Patient Population • Previous hospitalization with definite acute MI or a history of definite MI • Eligibility for statin therapy according to respective national guidelines at discharge Atorvastatin 80 mg 8888 Patients Primary End Point Simvastatin 20 mg; titrationto 40 mg for TC >190 mg/dL • Time to occurrence of a major cardiovascular event (CHD death, nonfatal acute MI, resuscitated cardiac arrest) 4.8 years Open label with blinded end-point evaluation Pedersen TR et al. JAMA. 2005;294:2437-2445.

  8. IDEAL: Primary and Secondary End Points Major coronary events – primary end point Major CV events – secondary end point 16 16 Simvastatin Atorvastatin Simvastatin Atorvastatin 13%RRR 12 12 11%RRR Cumulative Hazard, % Cumulative Hazard, % 8 8 4 4 HR = 0.89 (95% CI, 0.76–1.01) P = .07 HR = 0.87 (95% CI, 0.78–0.98) P = .02 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Since Randomization Years Since Randomization Any coronary event – secondary end point Any CV event – secondary end point 40 40 Simvastatin Atorvastatin Simvastatin Atorvastatin 16%RRR 30 30 16%RRR Cumulative Hazard, % Cumulative Hazard, % 20 20 10 10 HR = 0.84 (95% CI, 0.78–0.91) P < .001 HR = 0.84 (95% CI, 0.76–0.91) P < .001 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Since Randomization Years Since Randomization The primary end point of IDEAL (a composite of CHD death, nonfatal MI, and resuscitated cardiac arrest) did not reach statistical significance (HR = 0.89; 95% CI, 0.78-1.01; P = 0.07). Pedersen TR et al. JAMA. 2005;294:2437-2445.

  9. Effects of Atorvastatin 80 mg/d vsSimvastatin 20 to 40 mg/d on Any CV Event SubjectsWithEvent Relative RiskReduction (%) PValue Events HR (95% CI)* 2546104841619293 (0.77 – 0.90) <.0001 1st 17 (0.67 – 0.86) 2nd 24 <.0001 (0.67 – 0.99) 3rd 19 .035 (0.57 – 1.01) 4th 24 .058 (0.48 – 1.09) 5th 28 .117 0.50 0.75 1.25 1.50 1.0 Atorvastatinbetter Simvastatinbetter *Adjusted for sex and age at baseline. Tikkanen MJ et al. J Am Coll Cardiol. 2009;54:2353-2357.

  10. MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering): Study Design Patient Population • Non-Q-wave MI orunstable angina • Randomized 24–96 hoursfrom admission Atorvastatin 80 mg 3086 Patients Primary End Point Placebo • Time to ischemic events (CHD death, nonfatal MI, documented angina requiring hospitalization) 16 weeks double-blind Schwartz GG et al. JAMA. 2001;285:1711-1718.

  11. MIRACL: Primary Efficacy Measure—Time to First Event* 17.4% 16% RRR Placebo (n = 1548) LDL-C 135 mg/dL (3.5 mmol/L) 15 14.8% Atorvastatin 80 mg (n = 1538) LDL-C 72 mg/dL (1.9 mmol/L) 10 Cumulative Incidence, % 5 RR = 0.84P = .048 95% CI, 0.701–0.999 0 0 4 8 12 16 Time Since Randomization, weeks *Death (any cause), nonfatal MI, resuscitated cardiac arrest, worsening angina with new objective evidence and urgent rehospitalization. Schwartz GG et al. JAMA. 2001;285:1711-1718.

  12. MIRACL: Stroke Water DD et al. Circulation. 2002;106:1690-1695.

  13. PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction) 22: Study Design Patient Population • Hospitalized for an acute coronary syndrome in the preceding 10 days • TC ≤240 mg/dL (6.2 mmol/L) or TC ≤200 mg/dL (5.2 mmol/L) if receiving lipid-lowering therapy Atorvastatin 80 mg 4162 Patients Primary End Point Pravastatin 40 mg • Time to first occurrence of a major cardiovascular event (death from any cause, MI, unstable angina, revascularization, stroke Double-blind 925 primary end points Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

  14. PROVE IT: Primary End Point (All-Cause Death or Major CV Events in All Randomized Subjects) 26.3% 30 16% RRR (P = .005) Pravastatin 40 mg (n = 1548) 95 mg/dL (2.5 mmol/L) 25 22.4% 20 Atorvastatin 80 mg (n = 2099) 62 mg/dL (1.6 mmol/L) 15 –35% LDL reduction Death or Major CV Event, % 10 5 0 30 0 12 15 18 21 24 27 3 6 9 Months of Follow-up Major CV event = MI, unstable angina requiring rehospitalization, revascularization, or stroke. Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

  15. 12 10 8 6 4 2 0 0 PROVE IT-TIMI 22: Intensive Therapy With Statins in Patients With ACS: Early and Long-term Benefits Month 6 to end of study Randomization to 30 days 5 n = 1752 RRR = 28% P = .003 4 n = 2063 RRR = 28%P = .046 3 Composite triple end point* (%) n= 1812 Composite triple end point* (%) n = 2099 2 1 0 5 10 15 20 25 30 6 12 18 24 Days following randomization Months following randomization Pravastatin 40 mg Atorvastatin 80 mg *Death, MI, or rehospitalization with recurrent ACS. Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:1405-1410.

  16. Safety of Atorvastatin 80 mg in Clinical Trials *Consecutive measurements. †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; for the IDEAL Study Group. JAMA. 2005;294:2437-2445; Amarenco P et al. N Engl J Med. 2006;355:549-559.

  17. Overview of Adverse Events forAtorvastatin 10 mg and 80 mg and Placebo Newman C et al. Am J Cardiol. 2006;97:61-67.

  18. TNT: Changes in LDL-C by Treatment Group 160 4.0 Baseline 140 Atorvastatin 10 mg (n = 5006) 3.5 Atorvastatin 80 mg (n = 4995) 120 3.0 100 Mean LDL-C level = 101 mg/dL (2.6 mmol/L) 2.5 80 2.0 Mean LDL-C, mmol/L Mean LDL-C, mg/dL 60 1.5 Mean LDL-C level = 77 mg/dL (2.0 mmol/L) 40 1.0 20 0.5 P < .001 0.0 0 Screen Final 0 3 12 24 36 48 60 Study Visits, months LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

  19. Revasc >30 d UA Req Hosp PROVE IT: Reductions in Major Cardiac End Points • 2-Year Event Rates • RRAtorva 80Prava 40 • 28% 2.2% 3.2% • 30% 1.1% 1.4% • 13% 6.6% 7.4% • 18% 8.3% 10.0% • 14% 16.3% 18.8% 29% 3.8% 5.1% • 25% 12.9% 16.7% All-Cause Mortality CHD Death MI Death or MI Death/MI/Urg. Revasc 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80 mg Better Pravastatin 40 mg Better Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

  20. Effect of Intensive Statin Therapy on Clinical OutcomesAmong Patients Undergoing Percutaneous Coronary Intervention for ACS: PCI-PROVE IT Substudy Post hoc analysis of 2868 patients who underwent PCI just prior to enrollment 30% 25% Pravastatin Pravastatin 25% 20% 20% 15% Atorvastatin 15% Primary End Point Death, MI, RI, UA Atorvastatin 10% 10% Hazard ratio 0.73 95% CI, 0.61–0.87 P < .001 Hazard ratio 0.78 95% CI, 0.67–0.91 P < .001 5% 5% 0% 0% 0 120 240 360 480 600 720 0 120 240 360 480 600 720 Time, days Time, days Gibson CM et al. J Am Coll Cardiol. 2009;54:2290-2295.

  21. Long-term Statin Treatment in IDEAL Maintained Benefit Over 5 Years Longest Period of Follow-up of ACS Patients on Statin Therapy *Composite end point = death, nonfatal MI, hospitalization for UA, or coronary revascularization IDEAL (All MI) PROVE IT (MI or UA) 60 18% RRR P = 0.04 50 40 Composite End Point *, % 16% RRR P = 0.005 30 20 Atorvastatin 80 mg Pravastatin 40 mg 10 Simvastatin 20 -40 mg 0 0 30 months 5 years Cannon CP et al. N Engl J Med.2004;350:1495-1504; Pedersen TR et al. Am J Cardiol. 2010;106:354-359.

  22. MIRACL: Secondary End Points No. of Events (%) Atorvastatin Placebo * Stroke (fatal and nonfatal) 24 (1.6) 12 (0.8) Revascularization (CABG or PTCA) 250 (16.1) 254 (16.5) Worsening angina (without objective evidence of ischemia) 106 (6.8) 91 (5.9) Worsening congestive heart failure 43 (2.8) 40 (2.6) 0.25 0.50 0.75 1.00 1.25 1.50 Atorvastatin Better Placebo Better *P = .045. Relative Risk Schwartz GG et al. JAMA. 2001;285:1711-1718.

  23. Association of Dyslipidemia andmyocardial Infarction Risk: INTERHEART Risk of AMI With Multiple Risk Factors 2.9 2.4 1.9 3.3 13.0 42.3 68.5 182.9 333.7 512 256 128 64 3-fold increase in risk of acute MI 32 OR (99% CI) 16 8 4 2 1 Smk DM HTN Lipids 1+2+3 all4 +O +PS All RFs AMI, acute myocardial infarction; Smk, smoking; DM, diabetes mellitus; HTN, hypertension; O, obesity; PS, psychosocial;RF, risk factors; OR; odds ratio. Yusuf S et al. Lancet. 2004;364:937-952.

  24. ASCOT CRP Analysis Late Breaking Clinical Trials. AHA Scientific Session 2010. Abstract 21685. downloaded from http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#ascot • Post hoc subgroup (nested case control) analysis of ASCOT data • To assess baseline CRP and risk of CV events: 5.5 years follow-up, 485 patients with major CV events matched with 1367 controls from baseline population (ASCOT BPLA) • To assess the effect of statin treatment on CRP and risk of CV events: 5.5 years follow-up, 235 patients with major CV events matched with 777 controls from statin trial population (ASCOT LLA) • Baseline CRP and risk of CV events • Inclusion of CRP in a Framingham risk model modestly improved the prediction of CV events beyond use of standard CV risk factors by a small amount • On-statin-treatment CRP and risk of CV events • Levels of LDL-C were strongly associated with reductions in CV events • On-statin-treatment CRP levels were not predictive of CV outcomes • Atorvastatin 10 mg reduced median CRP by 27%

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