Rafael Carmena Rodriguéz en Clinicardio09: Novedades en práctica clínica 2009 sobre dislipemias 2009: Estatinas a dosis alta versus terapia combinada

1. Dislipemias 2009: ¿estatinas a dosis alta o terapia combinada? Rafael Carmena Catedrático de Medicina, Universidad de Valencia Jefe Servicio de Endocrinología y Nutrición Hospital Clínico Universitario de Valencia Barcelona, SEC. 23 octubre 2009 VALENCIA

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

4. Primary Efficacy Outcome Measure: Major Cardiovascular Events* LaRosa JC, et al. N Engl J Med. 2005;352:1425-35 HR = 0.78 (95% CI 0.69, 0.89) P <0.001 0.15 0.10 0.05 0 Relative risk reduction = 22% *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke Atorvastatin 10 mg Atorvastatin 80 mg Proportion of patients experiencing major cardiovascular event* 0 1 2 3 4 5 6 Time (years)

5. Intensive lipid lowering with atorvastatin in patients with CHD, DM, & CKD (Stage 3) markedly reduces CV events Shepherd J at el. Mayo Clin Proc 2008; 83: 870-79 T N T TREATING TO NEW TARGETS

7. Statins vs placebo or usual care (control) in adults Outcomes Number of Weighted event rates At mean 4.1 y trials (n) Statins Control RRR (95% CI) NNT (CI) All-cause mortality 9 (67 476) 5.1% 5.7% 11% (4-18) 154 (97-464) Major coronary events 8 (50 681) 3.8% 5.3% 29% (18-38) 65 (50-104) Major cerebrovascular 9 (67 476) 1.9% 2.3% 19% (7-29) 234 (153-635) events Statins reduce mortality and cardiovascular events in adults at risk for cardiovascular diseases but without evidence of CVD (Primary prevention) Brugts JJ et al. The benefits of statins in people without established CV disease but with CV risk factors: meta-analysis of randomized controlled trials. BMJ 2009; 338: b2376 Mean age 63 y, 66% men, 23% with diabetes All differences statistically significant

8. Intensive statin therapy was more effective than moderate statin therapy in reducing coronary death or any CV event in a meta-analysis of four trials including 27,548 patients with either stable CHD or acute coronary syndromes Atar D, Carmena R, Clemmensen P et al. Ann Med 2009

9. JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization Placebo Rosuvastatin 20 mg Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Ridker P et al . N Eng J Med 2008; 359 : 2195-2207 *Extrapolated figure based on Altman and Andersen method 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Follow-up (years) Number at Risk Rosuvastatin Placebo 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 -44% LDL-C -50% hsCRP -37%

12. Statins: Limited coronary risk reduction when baseline HDL-C level is low ≥ 52 ≤ 38 ≤ 37 ≤ 43 ≤ 35 ≥ 37 ≥ 43 ≥ 35 HDL-Cholesterol (mg/dl) Statin Placebo 4S CARE WOSCOPS HPS Coronary events (%)

13. “ On-treatment” HDL-C Predicts Cardiovascular Events: TNT On treatment HDL-C (mg/dL) Barter et al. ACC 2006. Abstract 914-203. Major Cardiovascular Events % Mean LDL-C 73 mg/dL Mean LDL-C 99 mg/dL

14. Barter PJ et al. TNT N Engl J Med 2007; 357:1301-1310 TNT post-hoc analysis: The level of HDL-C achieved after 3 months of treatment was a significant predictor of MCV events in 2,661 patients with LDL-C < 70 mg/dl

15. * P<0.002 RSV 20 mg vs ATV 20, 40 & 80 mg; RSV 40 mg vs ATV 40 & 80 mg 7.7% 9.6% * 2.1% 0 2 4 6 8 10 12 Mean change in HDL-C from baseline (%) rosuvastatin atorvastatin * 10 20 40 80 STELLAR Trial: Dose-response Effect of Statins on HDL-C Dose, mg (log scale) Jones P.H. et al. Am J Cardiol 2003;92:152–160 5.7% Percentage changes from baseline in HDL cholesterol at week 6 across dose ranges. N= 2431 dyslipidemic patients 3.2 % 5.6% pravastatin 6.8% simvastatin 5.3%

16. Elevated TG significantly increased the risk of death, AMI or ACS at 30 days in patients on statin therapy with LDL-C < 70 mg/dl Post-hoc analysis of PROVE IT-TIMI-22 Trial. N= 3399 patients Miller M et al. JACC 2008

17. STELLAR Trial. Effects of statins on triglycerides N= 2431 dyslipidemic patients treated for 6 weeks Jones PH et al. Am J Cardiol 2003; 92: 152-160 ROSUVA PRAVA SIMVA ATORVA

20. Efecto de distintos fármacos sobre el perfil lipídico Nicholls SJ, Kalidindi S, Nissen SE. Reducción Intensiva de los Lípidos en el Paciente Cardiovascular: ¿A quién, cuánta reducción y por cuánto tiempo? Current Cardiovascular Risks Reports; Edición en Español 2008; 2: 77-84. Estatina + Pioglitazona =  14%-20%  15%-20%  45%-50%  30%-35%  45%-50% Estatina + Niacina  50%-55%  15%-20%  35%-45% Estatina + Fenofibrato  30%-35%  10%-15%  50%-60% Estatina + Ezetimiba COMBINACIONES  20%-50%  15%-35%  5%-25% Niacina  30%-50%  10%-25%  5%-20% Fibratos = o  10%  3%-5%  20%-25% Resinas  6%-11% = o  2%-3%  7%-20% Ezetimiba  10%-24%  5%-15%  10%-58% Estatinas TRIGLICÉRIDOS COLESTEROL HDL COLESTEROL LDL FÁRMACO Niacina Estatina+Niacina

21. Ezetimibe/Simvastatin vs Atorvastatin in patients with type 2 DM and hypercholesterolemia The VYTAL study E/S 10/20 E/S 10/40 A 10 A 20 A 40 P<0.001 P<0.001 Goldberg RB et al. Mayo Clin Proc 2006; 81: 1579-88 N=1229 Randomized, double-blind, multicenter % LDL-C reduction from baseline

22. Effects of 80 mg/d of Simvastatin and Combined Therapy with Simvastatin plus Ezetimibe on Levels of Cholesterol and Triglycerides. The ENHANCE Trial Kastelein JJP et al. N Engl J Med 2008;358:1431-1443

23. Mean (±SE) Intima-Media Thickness of the Carotid Artery during 24 Months of Therapy Kastelein JJP et al. N Engl J Med 2008;358:1431-1443 “ You cannot ↓ CIMT if you don’t have IMT to begin with” E. Braunwald, IAS Boston, June 2009

24. Statin+Fenofibrate vs. Statin monotherapy (The SAFARI Trial) TG LDL-C HDL-C Simva 20 + Feno 160 Simva 20 monotherapy 618 patients with combined hyperlipidemia & high CHD risk treated for 12 weeks Grundy SM et al. Am J Cardiol 2005; 95: 462-8 P<0,001 P<0,001 P<0,001

25. Greater percentage of patients met lipid targets* at week 12 after treatment with NER2000/Simva 40 than with Atorva 40 Number of patients not at target at baseline NER/S 45 67 52 79 Atorva 47 58 44 65 *HDL-C ≥40 mg/dl; LDL-C adjusted by CV Risk goals; TG ≤150 mg/dl Insull WJr et al. J Clin Lipidol 2009; 3: 109-118 p<0.001 p<0.001