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Dislipemias 2009: ¿estatinas a dosis alta o terapia combinada? Rafael Carmena Catedrático de Medicina, Universidad de Vale...
<ul><li>¿Qué hemos aprendido? </li></ul><ul><li>Estatinas más potentes dan mejores resultados </li></ul><ul><li>Cuanto más...
The Statin Decade: For LDL: “Lower is Better” R² = 0.9029 p < 0.0001 LDL Cholesterol (mg/dl) CHD Events (%) Adapted and Up...
Primary Efficacy Outcome Measure:  Major Cardiovascular Events* LaRosa JC, et al.  N Engl J Med.  2005;352:1425-35 HR = 0....
Intensive lipid lowering with atorvastatin in patients with CHD, DM, & CKD (Stage 3) markedly reduces CV events Shepherd J...
Cholesterol Treatment Trialists (CTT) Collaborators <ul><li>Meta-analysis, 14 randomised statin trials, n=90,056  </li></u...
Statins vs placebo or usual care (control) in adults Outcomes   Number of Weighted event rates  At mean 4.1 y   trials (n)...
Intensive statin therapy was more effective than moderate statin therapy  in reducing coronary death or any CV event in a ...
JUPITER - Primary Endpoint   Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or ar...
<ul><li>La eficacia de las estatinas para prevenir complicaciones aterotrombóticas y CI ha sido convincentemente estableci...
 
Statins: Limited coronary risk reduction when baseline HDL-C level is low ≥ 52 ≤ 38 ≤ 37 ≤ 43 ≤ 35 ≥ 37 ≥ 43 ≥ 35 HDL-Chol...
“ On-treatment” HDL-C Predicts Cardiovascular Events: TNT On treatment HDL-C (mg/dL)  Barter et al. ACC 2006. Abstract 914...
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 mon...
* 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...
Elevated TG significantly increased the risk of death, AMI or ACS at 30 days in patients on statin therapy with LDL-C < 70...
STELLAR Trial. Effects of statins on triglycerides N= 2431 dyslipidemic patients treated for 6 weeks Jones PH et al.  Am J...
El problema del elevado riesgo residual en enfermos tratados con estatinas <ul><li>-Incluso con  LDL-C < 70 mg/dl, la coex...
¿Podemos reducir el riesgo residual mediante la combinación de estatinas y otros agentes hipolipemiantes? <ul><li>Efecto d...
Efecto de distintos fármacos sobre el perfil lipídico Nicholls SJ, Kalidindi S, Nissen SE.  Reducción Intensiva de los Líp...
Ezetimibe/Simvastatin vs Atorvastatin in patients with type 2 DM and hypercholesterolemia   The VYTAL study E/S 10/20 E/S ...
Effects of 80 mg/d of Simvastatin and Combined Therapy with Simvastatin plus Ezetimibe on Levels of Cholesterol and Trigly...
Mean (±SE) Intima-Media Thickness of the Carotid Artery during 24 Months of Therapy Kastelein JJP et al. N Engl J Med 2008...
Statin+Fenofibrate vs. Statin monotherapy (The SAFARI Trial) TG LDL-C HDL-C Simva 20 + Feno 160 Simva 20 monotherapy 618 p...
Greater percentage of patients met lipid targets* at week 12 after treatment with NER2000/Simva 40 than with Atorva 40 Num...
Reducir riesgo residual mediante la combinación de estatinas y otros agentes hipolipemiantes <ul><li>Efecto de la combinac...
Combinación de estatinas y otros fármacos sobre morbimortalidad cardiovascular. ¿Existen pruebas? <ul><li>+ Fenofibrato: A...
Estudios con A. Nicotínico donde se han observado beneficios cardiovasculares  <ul><li>Coronary Drug Project. 8341 hombres...
Estudios con NLP + Laropiprant  (“Tredaptive”) <ul><li>HPS2- THRIVE ( T reatment of  H DL to  R educe the  I ncidence of  ...
Conclusions <ul><ul><li>Lower is better </li></ul></ul><ul><ul><ul><li>LDL </li></ul></ul></ul><ul><ul><ul><li>CRP  </li><...
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Rafael Carmena Rodriguéz en Clinicardio09: Novedades en práctica clínica sobre dislipemias 2009

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

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  • Reference: Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78
  • In adults witout established CVD but with CVD risk factors, statins reduce all-cause mortality by 0.6% (is this clinically meaningfull?), and major coronary and cerebrovascular events. We need to treat between 100 and 450 persons for 4 years to prevent 1 death. However, to prevent 1 major coronary event, we only need to treat 65 persons for the same period. This is the important message of the paper.
  • Results : At the time of study termination (median follow-up 1.9 years, maximal follow up 5.0 years), 142 first major cardiovascular events had occurred in the rosuvastatin group and 251 in the placebo group which represented a 44% relative risk reduction (HR 0.56; 95% CI: 0.46 to 0.69; p&lt;0.00001). The rates of the primary endpoint were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively. The number of patients who would need to be treated with rosuvastatin for 2 years to prevent one primary endpoint event is 95, the number needed to treat (NNT) for 4 years is 31. If this figure is projected out to 5 years based on the model proposed by Altman and Andersen then the NNT is 25. Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207 NOTE: COPYRIGHT PERMISSIONS REQUIRED FOR THIS SLIDE
  • Figure 2. Effects of Simvastatin and Combined Therapy with Simvastatin plus Ezetimibe on Levels of Cholesterol and Triglycerides. All measures of cholesterol - low-density lipoprotein (LDL) cholesterol (Panel A), high-density lipoprotein (HDL) cholesterol (Panel B), and total cholesterol (Panel C) - were calculated with the use of analysis for variance for each time point. The I bars represent standard errors. An analysis for covariance on rank-transformed data for each time point was used for the triglyceride curve (Panel D).
  • Figure 3. Mean (±SE) Intima-Media Thickness of the Carotid Artery during 24 Months of Therapy.
  • PROVE-IT is well designed to (1) determine whether a standard degree of LDL-C lowering (~25-35%) with pravastatin 40 mg provides a clinical benefit similar to more aggressive LDL-C lowering (~50%) with atorvastatin 80 mg, (2) determine whether pravastatin and atorvastatin differ in their safety profiles and (3) examine the effect of a quinolone antibiotic in preventing CV events in an ACS population. These, and other questions, will be answered in chronic atherosclerosis populations by other trials.
  • Transcript of "Rafael Carmena Rodriguéz en Clinicardio09: Novedades en práctica clínica sobre dislipemias 2009"

    1. 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
    2. 2. <ul><li>¿Qué hemos aprendido? </li></ul><ul><li>Estatinas más potentes dan mejores resultados </li></ul><ul><li>Cuanto más bajo el LDL-C mejor </li></ul><ul><li>Eficaces en muy diversos subgrupos: </li></ul><ul><li>Diabetes mellitus, sin y con ECV clínica </li></ul><ul><li>Síndrome metabólico </li></ul><ul><li>Hipertensos </li></ul><ul><li>Insuficiencia cardíaca congestiva </li></ul><ul><li>Insuficiencia renal crónica </li></ul><ul><li>Mujeres, ancianos, etnias, etc. </li></ul><ul><li>Seguras, los efectos secundarios graves son raros: </li></ul><ul><li>Mialgia, miopatía, rabdomiolisis </li></ul>Las estatinas cumplen 22 años
    3. 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. 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. 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
    6. 6. Cholesterol Treatment Trialists (CTT) Collaborators <ul><li>Meta-analysis, 14 randomised statin trials, n=90,056 </li></ul><ul><li>Relationship between LDL-C lowering and CV events remains constant throughout entire range of LDL-C (linear) </li></ul><ul><li>No apparent loss of benefit at very low LDL-C levels </li></ul>CTT Collaborators Lancet 2005; 366:1267-78 1 mmol/L LDL-C MCV events 23% =
    7. 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. 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. 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%
    10. 10. <ul><li>La eficacia de las estatinas para prevenir complicaciones aterotrombóticas y CI ha sido convincentemente establecida en numerosos estudios prospectivos incluyendo miles de sujetos: 4S, WOSCOPS, PROVE IT-TIMI 22, HPS, A to Z, TNT, IDEAL, JUPITER, CTT Meta-analysis, etc. </li></ul><ul><li>Sin embargo, los beneficios que pueda aportar la monoterapia con estatinas más potentes buscando valores de LDL-C cada vez más bajos siguen siendo debatidos. </li></ul>
    11. 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 (%)
    12. 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
    13. 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
    14. 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%
    15. 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
    16. 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
    17. 18. El problema del elevado riesgo residual en enfermos tratados con estatinas <ul><li>-Incluso con LDL-C < 70 mg/dl, la coexistencia de HDL-C bajo (< 40 H y < 50 mg/dl en M) y de TG > 200 mg/dl limita significativamente la reducción de accidentes cardiovasculares </li></ul><ul><li>Las estatinas no resuelven por completo el problema del riesgo atribuible a HDL-C bajo y TG elevados. La dislipidemia diabética como paradigma </li></ul>El riesgo residual de un accidente coronario en diabéticos tratados con estatinas es el doble del observado en no diabéticos (HPS, Lancet , 2002)
    18. 19. ¿Podemos reducir el riesgo residual mediante la combinación de estatinas y otros agentes hipolipemiantes? <ul><li>Efecto de la combinación sobre el perfil lipídico </li></ul><ul><li>Efecto de la combinación sobre el riesgo y la morbimortalidad cardiovascular </li></ul>
    19. 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
    20. 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
    21. 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
    22. 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
    23. 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
    24. 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
    25. 26. Reducir riesgo residual mediante la combinación de estatinas y otros agentes hipolipemiantes <ul><li>Efecto de la combinación sobre el perfil lipídico: Mejoría significativa de la dislipidemia </li></ul><ul><li>¿Efecto de la combinación sobre el riesgo y la morbimortalidad cardiovascular? </li></ul>
    26. 27. Combinación de estatinas y otros fármacos sobre morbimortalidad cardiovascular. ¿Existen pruebas? <ul><li>+ Fenofibrato: ACCORD </li></ul><ul><li>+ Ezetimiba: SHARP (CKD), IMPROVE-IT (ACS), (2012) </li></ul><ul><ul><ul><li>ENHANCE y SEAS: no beneficio </li></ul></ul></ul><ul><li>+ Pioglitazona (DM2): PROACTIVE, CHICAGO, PERISCOPE </li></ul><ul><li>+ Niaspan: AIM-HIGH (2011) </li></ul><ul><li>+ ANLP/Laropiprant: THRIVE-HPS2 (2013) </li></ul><ul><li>+ Ezetimiba + Colesevelam (heterozigotos HF) </li></ul><ul><li>+ Omega-3: ASCEND (2012) </li></ul><ul><li>+ Inhibidores CEPT, Agonistas PPAR α / γ </li></ul>
    27. 28. Estudios con A. Nicotínico donde se han observado beneficios cardiovasculares <ul><li>Coronary Drug Project. 8341 hombres con CHD </li></ul><ul><ul><li>6 años; -28% IAM y -12% mortalidad por CHD </li></ul></ul><ul><li>FATS. Coronariografía. AN+Colestipol </li></ul><ul><li>HATS. Coronariografía. AN+Simvastatina </li></ul><ul><li>ARBITER-3. CIMT. AN+Estatinas </li></ul>
    28. 29. Estudios con NLP + Laropiprant (“Tredaptive”) <ul><li>HPS2- THRIVE ( T reatment of H DL to R educe the I ncidence of V ascular E vents) Incluye 25.000 pacientes de alto riesgo de los que 1/3 son diabéticos. Finaliza 2013. </li></ul><ul><li>MK-524A-069: Evaluar la eficacia a 12 semanas de Niacina LP/Laropiprant vs placebo en 798 diabéticos tipo 2 tratados con estatinas. </li></ul><ul><ul><ul><li>Valorar los efectos sobre perfil lipídico y: </li></ul></ul></ul><ul><ul><ul><li>HbA1c </li></ul></ul></ul><ul><ul><ul><li>Glucemia basal </li></ul></ul></ul><ul><ul><ul><li>% de pacientes que requieran cambios en la medicación antidiabética </li></ul></ul></ul>
    29. 30. Conclusions <ul><ul><li>Lower is better </li></ul></ul><ul><ul><ul><li>LDL </li></ul></ul></ul><ul><ul><ul><li>CRP </li></ul></ul></ul><ul><ul><ul><li>Triglycerides </li></ul></ul></ul><ul><ul><li>“ Dual goal” and “triple goal” with statins: Lower LDL and CRP and TG, and probably higher HDL </li></ul></ul><ul><ul><li>Dual and triple therapy is frequently needed to achieve dual and triple goals. Would these goals translate into lower CV events? </li></ul></ul>(and probably) higher is better for HDL Cannon C. IAS, Boston 2009

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