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The overwhelming case for LDL-C lowering

The overwhelming case for LDL-C lowering. Prof Kausik Ray, BSc ( hons ), MBChB , FRCP, MD, MPhil ( Cantab ), FACC, FESC Professor of Cardiovascular Disease Prevention St Georges University of London Honorary Consultant Cardiologist St Georges Hospital.

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The overwhelming case for LDL-C lowering

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  1. The overwhelming case for LDL-C lowering Prof Kausik Ray, BSc (hons), MBChB, FRCP, MD, MPhil (Cantab), FACC, FESC Professor of Cardiovascular Disease Prevention St Georges University of London Honorary Consultant Cardiologist St Georges Hospital

  2. 4S Primary Endpoint: Total Mortality 1.00 Simvastatin 0.95 30% Risk Reduction (P=0.0003) 0.90 Placebo Proportion Alive 0.85 0.80 0.00 0 1 2 3 4 5 6 Years Since Randomization Scandinavian Simvastatin Survival Study Group. Lancet. 1994 ;344:1383-1389.

  3. < 116 598/3389 756/3404 116 - 139 484/2549 646/2514 139 951/4331 1183/4349 ALL PATIENTS 2033 2585 (19.8%) (25.2%) HPS: Effects of Simvastatin on First Major Vascular Event According to Baseline LDL-C Risk ratio and 95% CI STATIN PLACEBO (n=10269) (n=10267) LDL-C (mg/dL) 24% reduction p<0.0001 0.4 0.6 0.8 1.0 1.2 1.4 STATIN better STATIN worse Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22.

  4. ASCOT-LLA: Primary Prevention in HTN Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 4 3.0% Baseline LDL 132 mg/dl 36% reduction 3 Cumulative Incidence (%) 2 1.9% 1 HR = 0.64 (0.50-0.83) p=0.0005 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58.

  5. CARDS-Cumulative Hazard for Primary Endpoint Relative Risk -37% (95% CI: -52, -17) 15 P=0.001 Placebo 127 events 10 Cumulative Hazard (%) Atorvastatin 10mg 83 events 5 0 0 1 2 3 4 4.75 Years Placebo 1410 1351 1306 1022 651 305 Atorva 1428 1392 1361 1074 694 328

  6. CTT Collaboration Effects on Major Coronary Events per mmol/L LDL Cholesterol Reduction Subdivided by Baseline Lipid Values Heterogeneity/trend p-value Events (%) RR & CI Groups (mmol/L) Treatment Control (Treatment : Control) Total cholesterol: ≤5.2 748 (6·9) 940 (8·6) p = 0·7 5.2-6.5 1678 (7·0) 2246 (9·4) >6.5 896 (8·8) 1220 (12·1) LDL cholesterol: ≤3.5 1130 (6·8) 1443 (8·7) 3.5-4.5 1374 (7·3) 1814 (9·6) p = 0·5 >4.5 801 (9·3) 1120 (12·9) HDL cholesterol: ≤0.9 1167 (9·3) 1538 (12·1) p = 0·8 0.9-1.1 939 (7·4) 1270 (10·2) >1.1 1207 (6·2) 1595 (8·1) Triglycerides: ≤1.4 1162 (7·3) 1521 (9·6) 1.4-2.0 937 (7·1) 1304 (9·8) p = 0·6 >2.0 1217 (7·9) 1564 (10·2) 0·77 (0·74 – 0·80) Overall 3337 (7·4) 4420 (9·8) p < 0·00001 0·5 1·0 1·5 Treatment Control better better CTT Collaborators. Lancet. 2005; 366:1267-78

  7. Cholesterol Trialist CollaborationMeta-Analysis of Dyslipidemia Trials 50% 40% 30% 20% 10% 0% -10% Major Vascular Events 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

  8. Only high dose statins have been tested immediately after ACS 16 ACS 4S CARE LIPID/ HPS/IDEAL 12 Death/Nonfatal MI(%) 8 PROVE IT-TIMI 22/ A to Z/ IDEAL 4 Stable CAD 0 0 2 4 6 4 5 6 Months Of Follow-Up Years

  9. 0 30 3 6 9 12 15 18 21 24 27 All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 10 16% RR (P = 0.005) 5 0 Months of Follow-up Cannon CP, et al. NEJM 2004;350:1495-504.

  10. Is there benefit from an LDL of 2 mmol/L vs 2.6mmol/L in stable CAD? IDEAL TNT -13% RRR 15 Atorvastatin 10 mg 16 Simvastatin 20/40 Atorvastatin 80 mg Atorvastatin 80 -22% RRR 12 10 Major CV Event* (%) 8 MCVE Cumulative Hazard (%) 5 4 HR = 0.78, P<.001 HR = 0.87, P=.02 0 0 0 1 2 3 4 5 6 Time (years) 0 1 2 3 4 5 Years Since Randomization *CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa JC, et al. NEJM. 2005; 352:1425-1435 Pedersen TR, et al. JAMA. 2005; 294:2437-2445

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

  12. Meta-Analysis of Intensive Statin Therapy LDL Cholesterol by Trial 160 140 120 Baseline      LDL-C (mg/dL) .  100 Standard  Intensive    80   60 40 PROVE IT- A-to-Z TNT IDEAL Pooled LDL-C TIMI 22 Cannon CP, et al. JACC 2006; 48: 438 - 445.

  13. Meta-Analysis of Intensive Statin Therapy - All Endpoints Odds Ratio (95% CI) OR, 0.84 95% CI, 0.80-0.89 P=.0000000000006 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. JACC 2006; 48: 438 - 445.

  14. PROVE IT-TIMI 22: Relationship Between Month 4 LDL and Long-Term Risk of Death or Major CV Event Hazard Ratio Referent >2.05 – 2.56 0.80 (0.59, 1.07) >1.54 – 2.05 0.67 (0.50, 0.92) > 1.03 -1.54 <1.03 0.61 (0.40, 0.91) 0 1 2 Lower Better Higher Better *Adjusted for age, gender, DM, prior MI, baseline LDL Wiviott SD, Cannon, Ray et al. JACC. 2005

  15. TNT: Incidence of First Major Cardiovascular Events Across Quintiles P < 0.0001* P < 0.0001* % patients P < 0.05* P < 0.01* *P-value for trend across LDL-C LaRosa JC. AJC. 2007, 100, 747-52

  16. Event rates by achieved LDL-C in trials Optimal standard Minimum audit standard 2° Prevention Stable CHD ATP III JBS2 ESC GMS 30 25 20 % with CHD event 15 1° Prevention 10 5 0 1.8 2.3 2.8 3.3 3.8 4.4 Mean LDL-C level at follow-up (mmol/L) Ray IJCP 2007, 61, 1608-11

  17. PROVE IT Safety Results: Side Effects Wiviott, et al. JACC. 2005

  18. Adverse Event Profiles Across Quintiles- TNT *Number of patients: Atorvastatin 10 mg/atorvastatin 80 mg †Occurring twice within 4-10 days

  19. CTT Lancet 2012

  20. Statins increase risk of Dysglycaemia Sattar N, ……Ray. Lancet 2010; 375: 735-42

  21. Statins and DYSGLYCAEMIA vs CVD Risk Preiss .... Ray. JAMA 2011;305:2556-64

  22. Prognosis of Patients withNew-Onset T2DM Waters DD et al. JACC. 2011;

  23. The Evidence for Clinical Benefit of Statin Therapy for the prevention of CAD ACS Pravastatin L-CAD PACT Simvastatin A to Z Atorvastatin MIRACL PROVE IT-TIMI 22 Primary Prev Pravastatin WOSCOPS PROSPER Simvastatin HPS Atorvastatin ASCOT CARDS Rosuvastatin JUPITER Lovastatin TEXCAPS/AFCAPS Secondary Prev Pravastatin • CARE • LIPID • PROSPER Simvastatin • 4S • HPS • SEARCH Atorvastatin • AVERT • TNT • IDEAL

  24. Summary LDL-C lowering offers similar proportional reductions among those with and without vascular disease The magnitude of benefit is related to the degree of LDL-C reduction LDL-C lowering is safe in general The greatest benefit are in those with the greatest absolute risk

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