1 / 28

How Aggressive do we get on Lipids?

How Aggressive do we get on Lipids?. Christopher Cannon, M.D. Senior Investigator, TIMI Study Group Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA. A2Z 20. A2Z 80. TNT 10. IDEAL S20/40. TNT 80. IDEAL A80. CHD Event Rates in Secondary Prevention and ACS Trials. 30.

margarita-vargas
Download Presentation

How Aggressive do we get on Lipids?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. How Aggressive do we get on Lipids? Christopher Cannon, M.D. Senior Investigator, TIMI Study Group Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA

  2. A2Z 20 A2Z 80 TNT 10 IDEAL S20/40 TNT 80 IDEAL A80 CHD Event Rates in Secondary Prevention and ACS Trials 30 y = 0.1629x · 4.6776R² = 0.9029p < 0.0001 4S-P 25 20 HPS-P LIPID-P 4S-S CHD Events (%) 15 HPS-S CARE-P LIPID-S 10 PROVE-IT-AT CARE-S PROVE-IT-PR 5 0 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dl) Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

  3. TNT IDEAL Cholesterol Trialist CollaborationMeta-Analysis of Dyslipidemia Trials Major Vascular Events 50% 40% 30% 20% 10% 0% -10% Proportional Reduction in Event Rate (SE) 0.5 1.0 1.5 2.0 Reduction in LDL Cholesterol (mmol/L) Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78

  4. Recent Coronary IVUS Progression Trials Relationship between LDL-C and Progression Rate 1.8 CAMELOT placebo REVERSAL pravastatin 1.2 Median Change In Percent AtheromaVolume (%) ACTIVATE placebo 0.6 REVERSAL atorvastatin A-Plus placebo 0 r2= 0.95 p<0.001 -0.6 ASTEROID rosuvastatin -1.2 50 60 70 80 90 100 110 120 Mean Low-Density Lipoprotein Cholesterol (mg/dL) Nissen S. JAMA 2006

  5. Meta-Analysis of Intensive Statin Therapy All Endpoints Odds Ratio (95% CI) OR, 0.84 95% CI, 0.80-0.89 p<0.0001 OR, 0.84 95% CI, 0.77-0.91 p=0.00003 OR, 0.88 95% CI, 0.78-1.00 p=.054 OR, 1.03 95% CI, 0.88-1.20 p=0.73 OR, 0.94 95% CI, 0.85-1.04 P=0.20 OR 0.82 95% CI, 0.71-0.96 p=0.012 0.5 1 2.5 High-dose statin better High-dose statin worse Cannon CP, et al. Cannon CP, et al. JACC 2006; 48: 438 - 445.

  6. Meta-Analysis of Intensive Statin Therapy CHF Study (n) Odds ratio (95% CI) Treatment Achieved LDL (mg/dl) Moderate Intensive TNT (10,001) 0.74 (0.58,0.94) Atorvastatin 80 77 Atorvastatin 10 101 A to Z (4497) 0.72 (0.52,0.98) Simvastatin 80 63 Simvastatin 20 77 PROVE-IT (4162) 0.54 (0.34,0.85) Atorvastatin 80 62 Pravastatin 40 95 IDEAL (8888) 0.80 (0.61,1.05) Atorvastatin 80 81 Simvastatin 20 104 Overall (95% CI) 0.73 (0.63,0.84), p<0.001 0.5 3.0 1 Moderate statin therapy better Intensive statin therapy better Odds ratio Scirica BM, et al. AHA 2005

  7. Meta-Analysis of Intensive Statin Therapy in ACS Any Cardiovascular Event HR (95% Cl) 1.02 (0.95-1.09) 0.84 (0.72-1.02) 0.76 (0.70-0.84) 0.80 (0.76-0.84) 0.81 (0.77-0.87) 0.84 (0.76-0.94) Hulten E, et al. Arch Intern Med. 2006;166:1814-1821

  8. ACS Patients: Major Coronary Events MI + CHD Death + Resuscitated Cardiac Arrest 20 Simvastatin Atorvastatin 16 34% RRR 12 Cumulative Hazard (%) 8 4 HR = .66 (95% CI = 0.46, 0.95), P=.02 0 0 1 2 3 4 5 Years Since Randomization Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

  9. PROVE IT MI or UA IDEAL All MI 18% RRR P=0.04 Pravastatin 40 mg Simvastatin 20-40 mg 16% RRR P=0.005 Summary: 5 Years Of Follow-Up In IDEAL Is The Longest Period Of Follow-Up Of ACS Patients On Statin Therapy 60 50 40 Cardiac Event (%) 30 20 Atorvastatin 80 mg 10 0 0 30 months 5 years Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

  10. Hazard Ratio Referent >80 - 100 0.80 (0.59, 1.07) >60 - 80 0.67 (0.50, 0.92) > 40 - 60 <40 0.61 (0.40, 0.91) 0 1 2 Lower Better Higher Better Month 4 LDL and Long-Term Risk of Death or Major CV Event *Adjusted for age, gender, DM, prior MI, baseline LDL Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416. Wiviott SD, et al. JACC. 2005

  11. Major CV Events Across Quintiles of Achieved LDL P < 0.0001* P < 0.0001* % patients P < 0.05* P < 0.01* *P-value for trend across LDL-C LaRosa JC. AHA. 2005

  12. IMPROVE IT 66 52 The Statin Decade: For LDL: “Lower is Better” R² = 0.9029p < 0.0001 4S LIPID CHD Events (%) CARE HPS TNT PROVE IT –TIMI 22 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dl) Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

  13. Study Design • Patients stabilized post Acute Coronary Syndrome < 10 daysLDL < 125 mg/dL (or < 100 mg/dL if prior statin) Double-blind N=10,000 ASA + Standard Medical Therapy Simvastatin 40 mg* Vytorin 10/40 mg* *uptitrated to 80mg if LDL>79 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

  14. 0.10 0.10 0.08 0.08 LDL > 70 mg/dL, CRP < 2 mg/L LDL < 70 mg/dL, CRP > 2 mg/L 0.06 0.06 Recurrent MI or Coronary Death (percent) 0.04 0.04 LDL < 70 mg/dL, CRP < 2 mg/L LDL < 70 mg/dL, CRP < 1 mg/L 0.02 0.02 0.00 0.0 0.0 0.0 0.0 0.5 0.5 0.5 0.5 1.0 1.0 1.0 1.0 1.5 1.5 1.5 1.5 2.0 2.0 2.0 2.0 2.5 2.5 2.5 2.5 Follow-Up (Years) Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy LDL > 70 mg/dL, CRP > 2 mg/L Ridker PM. NEJM 2005;352:20-28

  15. Achieved CRP and LDL vs. Outcomes Figure 4 Cumulative probability of death or MI (%) CRP ≥ 2 and LDL ≥ 70N = 1244 CRP ≥ 2 and LDL < 70N = 500 CRP <2 and LDL ≥ 70N = 1140 CRP < 2 and LDL< 70N = 659 Follow-up after Month 4 (days)

  16. 0.14 0.12 Combined Endpoint Probability 0.10 0.08 0.06 0.4 0.6 0.8 1.0 Month 4 Apo-B/Apo-A Ratio Death/MI/UA post-month 4, by Month 4 Apo-B/Apo-A ratio

  17. The long term clinical risk of Apo B/AI can be further discriminated by achieved CRP levels 0.14 CRP>=2 0.12 Endpoint Probability 0.10 0.08 CRP<2 0.06 1.0 0.4 0.6 0.8 Month 4 Apo-B/Apo-A Ratio Ray AHA 05

  18. Prava 40 Atorva 80 PROVE IT A to Z 1 mo 1 mo 8 mo 2 yrs 4 mo 4 mo Median Achieved hsCRP 3 2 hsCRP mg/dl 1 0 p < 0.001 p < 0.001 p < 0.001 3 2 hsCRP mg/dl Placebo  Simva 20 Simva 40  Simva 80 1 0 p < 0.001 p = NS p < 0.001

  19. Death, MI or ACS Rehospitalization (Early Phase) 5 Hazard ratio = 0.72 (CI 0.52,0.99) P=0.046 Pravastatin 40 mg 4 3 % of patients with death, MI or ,rehospitalization for ACS Atorvastatin 80 mg 2 1 0 0 5 10 15 20 25 30 Days following randomization KK Ray et al. JACC Oct. 2005 (in press)

  20. What Factors are Associated with Elevated CRP levels? Age (years) 1.01 <0.0001 Female on HRT vs Male 2.4 <0.0001 Female not on HRT vs Male 1.5 <0.0001 Current Smoker 1.5 <0.0001 BMI >25 kg/m2 1.4 <0.0001 HDLC <50mg/dl 1.2 0.0001 LDL 70 mg/dl 1.2 0.0003 Glucose >110 mg/dl 1.2 0.0009 Clinical Event Pre-month 4 1.4 0.0027 Trig >150 mg/dl 1.1 0.003 Atorvastatin 80mg 0.7 <0.0001

  21. Achieved CRP on Statin Therapy vs. Number of Risk Factors Risk factors 1) BMI >25 2) Current smoker 3) HDL <50 4) TG > 150 5) Glucose >110 6) BP > 130/85 7) LDL >70 Ptrend <0.0001 for each KK Ray et al. JACC 2005

  22. Kaplan-Meier Estimates based on LDL-C < 70 mg/dL or TG < 150 mg/dL between 30 d and 2 yr follow-up Miller M AHA 2006

  23. Triple Goal: Hazard ofdeath, MI and recurrent ACS with number of goals achieved based on LDL-C (< 70 mg/dL), CRP (< 2 mg/L) & TG (< 150 mg/dL) Miller M AHA 2006

  24. ATP III Update 2004:LDL-C Goals and Cutpoints for Therapy in Different Risk Categories Adapted from Grundy, S. et al., Circulation 2004;110:227-39.

  25. Vytorin (Ezetimibe + Simvastatin) Greater LDL Reduction at Each Dose Ezetimibe +Simva 10 mg (n=67) Ezetimibe +Simva 20 mg (n=69) Ezetimibe+Simva 40 mg (n=73) Ezetimibe +Simva 80 mg (n=65) Simva 10 mg (n=70) Simva 20 mg (n=61) Simva 40 mg (n=65) Simva 80 mg (n=67) Mean %Change in LDL-C From Untreated Baseline simvastatin Vytorin (ezetimibe +simvastatin) P0.01 for Vytorin vs. simvastatin for each comparison Source: Vytorin package insert

  26. Vytorin Reduces CRP More than Simvastatin at Each Dose 872 patients with LDL 145-250 enrolled in 2 RCTs 10 mg 20 mg 40 mg 80 mg * p < 0.01 # p = 0.03 Sager PT, Atherosclerosis 2005;179:361-7

  27. Conclusions: Early Benefit of Intensive Statin Therapy PROVE IT-TIMI 22 • Lower is better • LDL • CRP • Triglycerides • “Dual goal” and “triple goal” with statins Lower LDL and CRP and Trig, and probably HDL • Dual and triple therapy is frequently needed to achieve dual and triple goals (and probably) higher is better for HDL

More Related