Simposio pfizer. riesgo cardiovascular global. estatinas 2012
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Simposio pfizer. riesgo cardiovascular global. estatinas 2012
- 1. Simposio Simposio "Prevención Cardiovascular Global. Un Desafío "Prevención Cardiovascular Global. Un Desafío Permanente“ Permanente“ Reduciendo el Colesterol ¿Cuál es el Límite? Reduciendo el Colesterol ¿Cuál es el Límite? Dr. Alvaro Sosa Liprandi MTSAC FACC Dr. Alvaro Sosa Liprandi MTSAC FACC Jefe de Cardiología Director Director Sanatorio Güemes Instituto Cardiovascular Lezica Instituto Cardiovascular Austral Buenos Aires San Isidro, Buenos Aires Ushuaia, Tierra del Fuego Buenos Aires. Septiembre 2012
- 2. XIII Jornadas de Cardiología del Litoral XIII Jornadas de Cardiología del Litoral “Prevención del Riesgo Cardiovascular Global. “Prevención del Riesgo Cardiovascular Global. Un concepto consolidado” Un concepto consolidado” Reduciendo el Colesterol ¿Cuál es el Límite? Reduciendo el Colesterol ¿Cuál es el Límite? Dr. Alvaro Sosa Liprandi MTSAC FACC Dr. Alvaro Sosa Liprandi MTSAC FACC Jefe de Cardiología Director Director Sanatorio Güemes Instituto Cardiovascular Lezica Instituto Cardiovascular Austral Buenos Aires San Isidro, Buenos Aires Ushuaia, Tierra del Fuego Santa Fé. Septiembre 2012
- 3. Jornadas Interdistritales del Conurbano Riesgo Cardiovascular Global. Un concepto Riesgo Cardiovascular Global. Un concepto consolidado consolidado Reduciendo el Colesterol ¿Cuál es el Límite? Reduciendo el Colesterol ¿Cuál es el Límite? Dr. Alvaro Sosa Liprandi MTSAC FACC Dr. Alvaro Sosa Liprandi MTSAC FACC Jefe de Cardiología Director Director Sanatorio Güemes Instituto Cardiovascular Lezica Instituto Cardiovascular Austral Buenos Aires San Isidro, Buenos Aires Ushuaia, Tierra del Fuego Buenos Aires, Agosto 2012
- 4. Vigilancia de enfermedades no transmisibles y factores de riesgo Mortalidad por causas en las Américas año 2000 Países muy avanzados en su Países no avanzados en su transición epidemiológica Argentina transición epidemiológica 100 83.2% 62.3% 51.5% 80 % AVAD 60 40 30 0 muy baja en niños y baja en niños y baja alta en niños y alta muy baja en adultos en adultos en adultos Traumatismos Enf. Transmisibles, afecciones maternas y Enf. No Transmisibles perinatales y carencias nutricionales
- 5. Enfermedades No Transmisibles Argentina Tasa de mortalidad general 7,48 por mil Varones 8,32 por mil Mujeres 6,68 por mil Tasa de mortalidad por causas Enf. cardiovasculares 247 por 100.000 34% Cáncer 150 por 100.000 20% Enf. infecciosas 63 por 100.000 8% Causas externas 51 por 100.000 7% Todas las demás causas 236 por 100.000 31% 0 50 100 150 200 250 5 de cada 10 muertes son por CV y Cáncer Mortalidad Prematura: 30 % de los AVPP son por CV y Cáncer Fuente: Indicadores básicos Argentina 2001
- 6. Causas de muerte en la Argentina (Tasa de mortalidad anual 1980-2004) 450 TbrMA por 100.000 habitantes 400 * * 27 % reducción 350 p<00001 300 * 250 Enf. cardiovascular 200 150 Tumores malignos Enf. respiratorias 100 50 Accidentes 0 86 00 94 80 82 84 88 90 92 96 98 02 04 19 19 19 19 19 19 19 19 19 19 20 20 20 Sosa Liprandi MI y col. Rev Argent Cardiol 2006; 74:297-303
- 7. Entidades clínicas responsables de la Mortalidad Cardiovascular. Frecuencia Relativa (%) % 35 30,2 30,4 30 Insuficiencia 24,2 Cardíaca 25 22 Enf cerebrovascular 20 15 IAM 14 15 Enf. Coronaria 10 6 5,8 5,9 3,5 HTA 5 0 1990 2003 Sosa Liprandi MI y col. Rev Argent Cardiol 2006
- 8. Estimación del riesgo cardiovascular global RIESGO RIESGO CV GENÉTICO CLÍNICO (Factores (Factores de heredofamiliares) Riesgo) RIESGO CV RIESGO CV BIOQUÍMICO TISULAR (Marcadores de (Marcadores de riesgo riesgo tisular) bioquímicos)
- 9. Evaluacion del Riesgo Cardiovascular Global Factores Riesgo vs Estimación del Riesgo Factores de riesgo Scores de Riesgo LDL Enfermedad HDL Vascular Alto Riesgo Hipertension Diabetes Equivalentes Tabaco PCR Lp(a) Varios FRC Score Sme.Metabolico Homocisteina ApoB/ApoA Historia Familiar Sedentarismo 0-1 FRC Bajo Riesgo Stress F. Psico-Sociales ? Shape Task Force Report Am. J. Cardiology Julio 17, 2006
- 10. Tendencias en las Tasas de Mortalidad Cardiovascular y el PBI en Argentina. 1995-2005 Crisis del SE Caída de la * Asiático Convertibilidad 500 474,89 438,37 450 435,62 442,26 429,66 406,63 406,65 400 383,65 396,6 TMCV 357,54 esperada 350 TMCV 356,29 *-25% 304,76 300 277,4 288,1 279,1 276,2 264 PBI NETO 256 278,4 256 243,2 250 235,2 200 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Sosa Liprandi MI y col. Rev Arg Cardiol 2012
- 11. Tendencias de las Tasas de Mortalidad Cardiovascular (TMCV) y el Producto Bruto Interno (PBI). Argentina, 1995-2005 500 474,9 Crisis del SE Asiático Caída de la Convertibilidad 450 442,3 438,4 429,7 435,6 406,6 406,6 396,6 TMCV* 400 383,6 350 356,3 357.5 Valores de las TMCV 300 288,1 279,1 304,76 y del PBI neto por año 277,4 278,4 276,2 264 256 256 * por 100.000 habitantes 243,2 235,2 250 PBI neto A 200 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Observed 300.0 295.0 Slope 1 = 17.18 290.0 Modelo con 2 joinpoint 285.0 Slope 2 = -12.90 280.0 Slope 3 = 19.88 en la tendencia del PBI 275.0 PBI 270.0 265.0 P=0.001 260.0 255.0 250.0 245.0 B 240.0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 470 Observed 460 450 Slope 1 = -17.74 440 Slope 2 = -6.80 Modelo con 2 joinpoint 430 Slope 3 = -16.73 420 TMCV 410 en la tendencia de la TMCV 400 390 P=ns 380 370 360 C 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
- 12. Evaluacion Indirecta vs. Directa Factores Riesgo vs Presencia de Enfermedad Carótida: IMT Factores de riesgo Carótida y Aorta: detección de placa por RMN LDL Test estructurales HDL Coronarias: Score Hipertension de calcio por TC Diabetes Tabaco MMII: Índice Tobillo brazo PCR Lp(a) Sme.Metabolico Braquial: vasoreactividad Homocisteina medida por doppler ApoB/ApoA Historia Familiar Compliance vascular: Test Sedentarismo medida por tonometría Funcionales Stress ? VOP Velocidad de Onda de Pulso Shape Task Force Report Am. J. Cardiology Julio 17, 2006
- 13. PCR: Implicancia pronóstica Muerte Cardiaca - IAM Stroke Muerte Cardiaca IAM Angina inestable Angina inestable - IAM 0 1,0 2,0 3,0 4,0 5,0 Riesgo relativo (mayor vs menor quintilo) Ridker PM et al. N Engl J Med 2000;342:836-843
- 14. PROVE IT-TIMI 22 Trial Estatinas.Tratamiento intensivo vs moderado en SCA IAM ó Muerte de acuerdo a niveles alcanzados de C-LDL ó PCR 0.10 0.10 IM recurrente o muerte coronaria (%) C-LDL > 70 mg/dl PCR > 2 mg/dl 0.08 0.08 0.06 0.06 0.04 0.04 PCR < 2 mg/dl C-LDL < 70 mg/dl 0.02 0.02 0.00 0.00 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 Seguimiento (años) Ridker PM y col. N Engl J Med 2005; 352: 20-8
- 15. PROVE IT-TIMI 22 Trial Estatinas.Tratamiento intensivo vs moderado en SCA Relación entre niveles alcanzados de C-LDL y PCR luego de 30 días de tratamiento con estatinas 0.10 10 CRP (mg/l) 1 0.1 30 80 130 180 C-LDL (mg/dl) Ridker PM y col. N Engl J Med 2005; 352: 20-8
- 16. PROVE IT-TIMI 22 Trial Estatinas.Tratamiento intensivo vs moderado en SCA IAM ó Muerte de acuerdo a niveles alcanzados de C-LDL y PCR 0.10 LDL > 70 mg/dl, PCR > 2 mg/dl IM recurrente o muerte coronaria (%) 0.08 LDL > 70 mg/dl, PCR < 2 mg/dl LDL < 70 mg/dl, PCR > 2 mg/dl 0.06 LDL < 70 mg/dl, PCR < 2 mg/dl 0.04 LDL < 70 mg/dl, CRP < 1 mg/dl 0.02 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Seguimiento (años) Ridker PM y col. N Engl J Med 2005; 352: 20-8
- 17. PROVE IT-TIMI 22 Trial Estatinas.Tratamiento intensivo vs moderado en SCA IAM ó Muerte de acuerdo a niveles alcanzados de C-LDL y PCR 0.10 IM recurrente o muerte coronaria (%) LDL > 70 mg/dl, PCR > 2 mg/dl 0.08 Objetivo doble no alcanzado 0.06 LDL < 70 mg/dl, PCR < 2 mg/dl Objetivo doble alcanzado 0.04 LDL < 70 mg/dl, PCR < 1 mg/dl Objetivo doble alcanzado máx. 0.02 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Seguimiento (años) Ridker PM y col. JACC 2005; 45: 1644-8
- 18. PCR. Es sólo un marcador inflamatorio? Encontrada en íntima ateroesclerótica pero no en la normal Inducción de activación Inducción en la producción de moléculas del complemento de adhesión, MCP-1, ET-1 Reclutamiento de monocitos Atenuación de la producción de NO dentro de la pared arterial Disminución en la expresión de eNOS Inducción de la producción de Factor Tisular en monocitos Inducción en la expresión de PAI-1 Estabilización del PAI-1 mRNA Inducción de vasoreatividad Inducción en la oxidación de endotelial Colesterol LDL Mediador en el uptake de LDL por macrófagos
- 19. JUPITER Trial Design JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP MI Rosuvastatin 20 mg (N=8901) Stroke No Prior CVD or DM Men >50, Women >60 Unstable LDL <130 mg/dL Angina 4-week Placebo (N=8901) CVD Death hsCRP >2 mg/L run-in CABG/PTCA Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker et al, Circulation 2003;108:2292-2297.
- 20. JUPITER Ridker et al NEJM 2008 Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP 140 60 120 50 LDL (mg/dL) 100 HDL (mg/dL) 40 80 30 60 20 40 20 10 LDL decrease 50 percent at 12 months HDL increase 4 percent at 12 months 0 0 5 140 120 4 hsCRP (mg/L) 100 TG (mg/dL) 3 80 2 60 40 1 20 hsCRP decrease 37 percent at 12 months TG decrease 17 percent at 12 months 0 0 0 12 24 36 48 0 12 24 36 48 Months Months
- 21. JUPITER Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI 0.46-0.69 Placebo 251 / 8901 0.08 P < 0.00001 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 0 1 2 3 4 Number at Risk Follow-up (years) Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
- 22. JUPITER Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI 0.46-0.69 Placebo 251 / 8901 0.08 P < 0.00001 Number Needed to Treat (NNT5) = 25 - 44 % 0.06 Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 0.00 0 1 2 3 4 Number at Risk Follow-up (years) Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
- 23. JUPITER Ridker et al NEJM 2008 Grouped Components of the Primary Endpoint Myocardial Infarction, Stroke, or Arterial Revascularization or Cardiovascular Death Hospitalization for Unstable Angina HR 0.53, CI 0.40-0.69 HR 0.53, CI 0.40-0.70 P < 0.00001 P < 0.00001 0.05 0.06 Placebo Placebo 0.05 0.04 0.04 Cumulative Incidence Cumulative Incidence 0.03 - 47 % 0.03 - 47 % 0.02 0.02 Rosuvastatin 0.01 Rosuvastatin 0.01 0.00 0.00 0 1 2 3 4 0 1 2 3 4 Follow-up (years) Follow-up (years)
- 27. JUPITER Eventos Cardiovasculares – Mortalidad según LDL basal Hsia J et al J Am Coll Cardiol 2011; 57: 1666-75
- 28. JUPITER. Eventos Cardiovasculares de acuerdo a tratamiento asignado y LDL alcanzada Placebo Rosuvastatina LDL > 50 Rosuvastatina LDL < 50 Hsia J et al J Am Coll Cardiol 2011; 57: 1666-75
- 29. JUPITER. Relación entre eventos cardiovasculares y LDL alcanzada a 1 año en Estudios de Prevención Primaria Hsia J et al J Am Coll Cardiol 2011; 57: 1666-75
- 32. Hipertensos: >160 TAS o >100 TAD, 40-79 a, Mas 3 FR CV como: HVI, ECG anormal, DBT , EVP, TIA, Varon, >55 a, microalbuminuria, fumadores, TC/HDL>6, AHF EC precoz Estructura Internacional Gothenburg • • London
- 33. ASCOT: Dislipemia + HTA Tratada x 2 ramas R = Randomizados 18,000 pacientes R 9000 β-bloq ± diuretico 9000 BCC ± IECA 5000 Colesterol (≤250 mg/dL) 4000 Colesterol (>250 mg/dL) + 4000 Colesterol (>250 mg/dL) 5000 Colesterol (≤250 mg/dL) 500 500 Abierto x Abierto x 4500 4500 lipidos lipidos R R 2250 8000 2250 2250 placebo 2250 placebo Atorvast Abierto x Lipidos Atorvastat Hipertensos: >160 TAS o >100 TAD, 40-79 a, 3+ FR CV como: HVI ,ECG anormal, DBT , EVP, TIA, Varon, >55 a, microalbuminuria., fumadores, TC/HDL>6, AHF EC precoz
- 34. Ascot: Punto final primario: IAM no fatal y EC fatal Atorvastatina 10 mg Eventos 100 4 Placebo Eventos 154 Cumulative Incidence (%) 3 36% de reduccion 2 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 ACV: 27 % de reduccion P= 0.0236
- 35. CARDS: Collaborative Atorvastatin Diabetes Study Poblacion de pacientes Atorvastatina 10 mg Diabetes mellitus tipo 2 (n=1428) Ambos sexos 40–75 años 2838 4-años de seguim pacientes Placebo doble ciego Prevencion primaria de (n=1410) Eventos coronarios, ACV Puntos Finales Primarios: tiempo hasta el primer evento CV LDL-C ≤160 mg/dL (muerte coronaria, IAM no fatal , angina TG ≤600 mg/dL inestable, paro resuscitatado, revascularizacion ≥1 FR adicional coronaria, ACV – HTA o treatmiento – Retinopatia Secundarios: mortalidad total , cualquier punto – Albuminuria final CV, lipidos y lipoproteinas Colhoun HM et al. Lancet 2004;364:685-696.
- 36. CARDS: Efecto de Atorvastatina en el Punto Final Primario: Eventos CV mayores Incluyendo ACV Reduccion de Riesgo Relativa 37% (95% CI, 17–52) p = 0.001 15 Riesgo Cumulativo, (%) Placebo 127 events 10 5 Atorvastatin 83 events 0 0 1 2 3 4 4.75 Años Placebo 1410 1351 1306 1022 651 305 Atorvastatin1428 1392 1361 1074 694 328 Colhoun HM et al. Lancet 2004;364:685-696.
- 37. Estatinas en prevención primaria. Metaanálisis Beneficios en función del riesgo (N = 175 000) Baseline risk (risk of CV Risk reduction (95% CI) per event over five years), % 1-mmol LDL reduction <5 0.57 (0.36-0·89) 5-10 0.61 (0.50-0·74) 10-20 0.77 (0.69-0·85) 20-30 0.77 (0.71-0·83) 20-30 0.78 (0.72-0·84) Overall 0.76 (0.73-0·79) CTT. Lancet 2012
- 38. Ascot / Cards MIRACL / TIMI 22 / HPS TNT / REVERSAL
- 39. PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22)
- 40. PROVE IT - TIMI 22: Study Design 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy Double-blind “Standard Therapy” “Intensive Therapy” Pravastatin 40 mg Atorvastatin 80 mg 2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
- 41. Changes from (Post-ACS) Baseline in Median LDL-C 120 Median LDL-C (Q1, Q3) 95 (79, 113) 100 Pravastatin 40mg 21% 62 (50, 79) LDL-C 80 (mg/dL) 60 Atorvastatin 80mg 49% 40 P<0.001 20 <24h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event • ACS response lowers LDL-C from true baseline
- 42. All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg 25 (26.3%) 20 % with Atorvastatin 80mg Event 15 (22.4%) 10 16% RR 5 (P = 0.005) 0 0 3 6 9 12 15 18 21 24 27 30 Months of Follow-up
- 43. Primary Endpoint Over Time Events Rates RR Atorva 80 Prava 40 30 Days 17% 1.9% 2.2% 90 Days 18% 6.3% 7.7% 180 Days 14% 12.2% 14.1% End of Follow-up 16% 22.4%* 26.3%* 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80mg Better Pravastatin 40mg Better *2-year event rates
- 44. All-Cause Death, Non-Fatal MI, or Urgent Revascularization 20 % Pravastatin 40mg with 16.7% Event 15 10 Atorvastatin 80mg 12.9% 5 25% RR P = 0.0004 0 0 3 6 9 12 15 18 21 24 27 30 Months of Follow-up
- 45. The Treating to New Targets (TNT) Study: Rationale 30 Patients with CHD events (%) 25 TNT 20 Screening ? 15 10 Atorvastatin 10 mg Atorvastatin 80 mg 5 0 70 90 110 130 150 170 190 210 LDL-C, mg/dL Adapted from Kastelein JJP. Atherosclerosis. 1999;143 (suppl 1):S17-S21
- 46. TNT: Study Design Patient population: Primary efficacy outcome measure: CHD Time to occurrence of a major CV event: LDL-C: 130-250 mg/dL (3.4-6.5 mmol/L) – CHD death Triglycerides ≤600 mg/dL (≤6.8 mmol/L) – Nonfatal, non-procedure-related MI – Resuscitated cardiac arrest – Fatal or nonfatal stroke Baseline Screening Open-label run-in Double-blind period and wash-out n=15,464 n=10,001 n=10,001 n=18,469 LDL-C <130 mg/dL (<3.4 mmol/L) n=5006 Atorvastatin 10 mg Atorvastatin 10 mg LDL-C target: 100 mg/dL (2.6 mmol/L) n=4995 Atorvastatin 80 mg LDL-C target: 75 mg/dL (1.9 mmol/L) 1-8 weeks 8 weeks Median follow-up = 4.9 years Adapted from LaRosa JC et al. N Engl J Med. 2005;352:epub.
- 47. TNT: Changes in Lipids Adapted from LaRosa JC et al. N Engl J Med. 2005;352:epub.
- 48. TNT: Endpoints P<.001 P=.002 ,% ,% ,% P<.001 ,% P=.02 Adapted from LaRosa JC et al. N Engl J Med. 2005;352:epub.
- 49. REVERSAL: Study Design 502 symptomatic coronary artery disease patients with elevated LDL-C Randomized, double-blind, multicenter Aggressive lipid-lowering strategy Moderate lipid-lowering strategy Atorvastatin (80 mg) Pravastatin (40 mg) n=253 n=249 Endpoints (follow-up 18 months) • Primary: percent change in atheroma volume on IVUS between baseline and 18-mo follow-up • Secondary: absolute change in atheroma volume, change in percent obstructive volume IVUS = Intravascular Ultrasonography. Adapted from Nissen SE, et al. JAMA. 2004;291:1071-1080.
- 50. REVERSAL: Atheroma Regression Pre-Statin Post-Statin EEM Area EEM Area 13.2 mm2 11.43 mm2 5.07 mm2 5.18 mm2 Atheroma Area 8.13 mm2 Atheroma Area 6.31 mm2 Adapted from Nissen SE, et al. JAMA. 2004;291:1071-1080.
- 51. REVERSAL: Atheroma Regression Change in atheroma volume Change in percent obstruction volume P=.02, atorvastatin vs P=.0002, atorvastatin vs 4 2 pravastatin pravastatin 1.6 3 2.7 2 2 1 1 1 0 0.2 -0.4 -1 0 Atorvastatin Pravastatin Adapted from Nissen SE, et al. JAMA. 2004;291:1071-1080.
- 52. Significant Benefit in Lowering LDL-C below 100 mg/dL with Atorvastatin 80 mg 30 4S-P Patients with CHD events (%) 25 20 4S-S LIPID-P 15 CARE-P LIPID-S HPS-P 10 CARE-S HPS-S TNT: Atorvastatin 10 mg 5 TNT: Atorvastatin 80 mg S = statin treated P = placebo treated 0 70 90 110 130 150 170 190 210 LDL-C (mg/dL) Adapted from LaRosa JC et al. N Engl J Med. 2005;352:epub.
- 53. Tratamiento intensivo vs. moderado. Metaanálisis Niveles de colesterol LDL Muerte o Infarto Cannon CP. JACC 2006
- 54. Tratamiento intensivo vs. moderado. Metaanálisis Muerte o Infarto Cannon CP. JACC 2006
- 55. Tratamiento intensivo vs. moderado. Metaanálisis Muerte o eventos cardiovasculares mayores Cannon CP. JACC 2006
- 56. Tratamiento intensivo vs. moderado. Metaanálisis Muerte o ACV Cannon CP. JACC 2006
- 57. Tratamiento intensivo vs. moderado. Metaanálisis Mortalidad (n = 170 000) Baigent CTT. Lancet 2010
- 58. Tratamiento intensivo vs. moderado. Metaanálisis Beneficio en función de reducción de LDL Baigent C, CTT. Lancet 2010
- 59. Atorvastatina y ACV en el SPARCL : Stroke Prevention by Aggressive Reduction of Cholesterol Levels Pacientes ACV /TIA 1-6 meses Placebo previos 4,200 Pacientes LDL 100-190 mg/dl atorvastatina 80 mg Exclusiones: 5 years <18 years Hx of EC Endarterectomia Punto final primario •Tiempo hasta 1ªACV fatal o no-fatal •Punto final secundario: Eventos coronarios mayores o eventos CV
- 60. SPARCL: Eventos coronarios y ACV 30 20% RRR HR 0.80 (0.69–0.92) Placebo NNT = 29 20 P = 0.002 pacientes Eventos por 5 años Mayores CV* 10 Atorvastatina (%) 0 0 1 2 3 4 5 6 Tiempo desde randomizacion (años) *Cardiac death, MI, resuscitated SPARCL Investigators. N Engl J Med. 2006;355:549-59. cardiac arrest, and stroke
- 61. SPARCL: Reduccion Ev. coronarios mayores 10 8 35% RRR Placebo HR 0.65 (0.49–0.87) Major 6 P = 0.003 coronary events* 4 (%) Atorvastatin 2 0 0 1 2 3 4 5 6 Time since randomization (years) *Cardiac death, MI, resuscitated cardiac arrest SPARCL Investigators. N Engl J Med. 2006;355:549-59.
- 62. Descensos % de c-LDL con dosis habituales y máximas de estatinas Estatina 27% 34% 41% 48% 55% 60% Pravastatina* 20 mg 40 mg Fluvastatina 40 mg 80 mg Lovastatina 20 mg 40 mg 80 mg Simvastatina 10 mg 20 mg 40 mg Atorvastatina 10 mg 20 mg 40 mg 80 mg Rosuvastatina* 5 mg 10 mg 20 mg 40 mg *Estatinas hidrosolubles Netherland Journal of Medicine 2010;68 (4): 168-174 62
- 63. Solamente el 38.3% de los pacientes hospitalizados por SCA entre 2005 y 2009, recibieron terapia intensiva con estatinas.
- 64. Seguridad de Atorvastatina: Perfil de seguridad comparable a Placebo y a otras estatinas Todas las otras Atorvastatina estatinas Placebo (todas dosis) combinadas Sistema n=1789 n=9416 n=5526 Digestivo 4% 8% 9% Cualquier efecto adverso 5% 5% 6% Musculoesquelético 1% 3% 3% Neurológico 2% 3% 3% Cutáneo 1% 2% 2% Metabólico/nutricional 1% 1% 1% Efectos muy raros <1% 1% <1% Urogenital 1% 1% 1% CV 2% 1% 1% Newman CB, et al. Am J Cardiol. 2003;92:670-676. Data on file, Pfizer Inc. 64
- 65. Seguridad de Atorvastatina: No Relación Dosis-Respuesta con los EAs Porcentaje de pacientes que experimentaron ≥ 1 evento adverso a dosis fija por grupo 20 16 15 15 15 13 Pacientes (%) 10 8 5 0 Placebo 10 mg 20 mg 40 mg 80 mg n = 293/1949 n = 839/6343 n = 19/242 n = 30/186 n = 344/2345 Atorvastatina Newman CB, et al. Am J Cardiol. 2003;92:670-676. Data on file, Pfizer Inc. 65
- 66. Seguridad de Atorvastatina: Baja Tasa de Descontinuación Debido a EAs por Placebo, Atorvastatina y otras Estatinas Datos Agrupados de los Estudios 5 sacados de los estudios debido a AEs asociados al tratamiento) % de pacientes que fueron 4 3.6 3 2.6 2 0.9 1 0 Placebo Atorvastatina Todas las otras n = 16/1789 (todas dosis) estatinas combinadas n = 241/9416 n = 198/5526 Newman CB, et al. Am J Cardiol. 2003;92:670-676. Data on file, Pfizer Inc. 66
- 67. Seguridad de Atorvastatina: No Relación Dosis-Respuesta para Mialgia Dosis Fija Agrupada 6 Pacientes experimentaron 4 mialgia (%) 3.2 2.7 2.6 2.0 2 1.5 0 Placebo 10 mg 20 mg 40 mg 80 mg n = 30/1949 n = 173/6343 n = 5/242 n = 30/186 n = 61/2345 Atorvastatina Newman CB, et al. Am J Cardiol. 2003;92:670-676. Data on file. Data on file, Pfizer Inc. 67
- 68. EAs Musculoesqueléticos a través del rango de dosis Atorvastatina Placebo 10 mg 20 mg 40 mg 80 mg n=1949 n=6343 n=242 n=186 n=2345 Mialgia 2% 3% 2% 3% 2% Artralgia 1% 2% 0% 3% 1% Artritis 1% 1% 2% 0% <1% Alteración articular <1% <1% 0% 1% <1% Miopatia* 0% 0% 0% 0% 0% *En vigilancia postmarketing, raros casos de miopatia y rabdomiolisis han sido reportados con atorvastatina y otras estatinas. Newman CB, et al. Am J Cardiol. 2003;92:670-676. Data on file, Pfizer Inc. 68
- 69. Seguridad de Atorvastatina: Baja Ocurrencia de Elevaciones Persistentes de ALT/AST Dosis Fija Agrupada 1.0% 0.89% 0.8% Pacientes (%) 0.6% 0.4% 0.40% 0.2% 0.0% 0.13% 0.12% 10 mg 20 mg 40 mg 80 mg En promedio, 0.5% de los pacientes tratados con atorvastatina experimentaron incrementos de los valores de ALT/AST Newman CB, et al. Am J Cardiol. 2003;92:670-676. Data on file, Pfizer Inc. 69
- 70. RABDOMIOLISIS DOSIS DOSIS ALTAS ESTANDAR PROVE IT 0% 0% A to Z 0% 0,13% TNT 0.06% 0.04% IDEAL 0.07% 0.05% J Am Coll Cardiol 2006; 48: 438-445
- 71. CPK TOTAL > 10 LSN DOSIS DOSIS ALTAS ESTANDAR PROVE IT 0,10% 0,15% A to Z 0,04% 0,4% TNT 0% 0% IDEAL 0% 0% J Am Coll Cardiol 2006; 48: 438-445
- 72. ALT/AST > 3 LSN DOSIS DOSIS ALTAS ESTANDAR PROVE IT 1,1% 3,3% A to Z 0,36% 0,84% TNT 0,18% 1,2% IDEAL 0,16% 1,37% J Am Coll Cardiol 2006; 48: 438-445
- 73. Resumen de los efectos adversos • Riesgo de rabdomiolisis: 0.05% • Riesgo de miopatías: 0.15% • Riesgo de elevacion de AST/ALT: 3.3% • Riesgo de mialgias: 5 a 15% • Porcentaje de pacientes que deben suspender la terapia: < 9%
- 74. Factores de riesgo que aumentan los efectos adversos de las estatinas • Edad > 75 años • Medicamentos concomitantes – Fibratos – Macrólidos – Antifúngicos – Ciclosporina • Ingesta de alcohol • Disfunción hepática o renal
- 75. ESTUDIO SATURN Nicholls S et al. N Engl J Med 2011 365;22: 2078-87. 75
- 76. Estudio Saturno. Regresión Ateroesclerosis Atorvastatina vs rosuvastatina Nicholls SJ. N Engl J Med 2011; 365: 2078
- 77. Evolución de las guias terapéuticas NCEP NCEP NCEP ATP 1970s ATP I ATP II ATP III 04 IV 1988 1993 2001 2012 Framingham Angiograficos WOSCOPS, Improve It MRFIT (FATS, POSCH, 4S,CARE, TNT, IDEAL LFC-CPPT SCOR, STARS, LIPID, A to Z, Coronary Drug Omish, MARS) AFCAPS, HPS,Jupiter Project Meta-Analisis VA-HIT, SPARCL Helsinki (Holme, Rossouw) Otros PROSPER ASCOT MIRACL
- 78. Reduciendo el Colesterol ¿Cuál es el Límite? Conclusiones El uso de estatinas se asocia a una marcada reducción en la tasa combinada de mortalidad y eventos vasculares en el seguimiento, tanto en prevención primaria como secundaria. No ha podido establecerse un umbral de tratamiento ¨Cuanto mas bajo mejor¨ En Prevención Primaria, la estratificación del riesgo clínico como criterio de selección de pacientes para tratamiento con estatinas, debe ser validado En prevención secundaria, el tratamiento intensivo es marcadamnete superior al moderado No hay diferencias entre las distintas estatinas en términos de efectividad clínica
- 79. Reducción del RR de mortalidad de diferentes estrategias de prevención secundaria del IAM Betabloqueantes Freemantle N et al 23% BMJ 1999; 318: 1730-1737 Estatinas Pignone M et al 29% BMJ 2000; 321: 983-986 IECA Flather MD et al 23% Lancet 2000; 355: 1575-1581 Aspirina Collaborative Meta-analysis 15% BMJ 2002; 324: 71-86 Cesación de tabaco Critchley JA et al 36% JAMA 2003; 290: 86-97 0 10 20 30 40 50 % RR
- 80. It is time for cardiologists to be less passive about their patients’ smoking status and public health approaches to tackle smoking. After all, a reduction in smoking at the patient and population level would have a bigger impact on cardiovascular disease than any of the high-tech interventions delegates in Orlando will hear about. ■ The Lancet 2009; 373: 867. Cardiologists should be less passive about smoking cessation
- 81. Reduciendo el Colesterol ¿Cuál es el Límite? Conclusiones Huang Dee: Nai - Ching (2600 B.C) 1st Chinese Medical Text • Los buenos médicos previenen la enfermedad. • Los mediocres tratan la enfermedad antes que ésta se haga evidente • Los malos sólo lo hacen frente a su presencia.
Notas del editor
- Argentina se encuentra en proceso de transición epidemiológica.Usando como indicador los años de vida ajustados por discapacidad se observa que Nuestro pais esta en un punto intermedio entre los paises mas avanzados y los menos avanzados en el proceso de transicion (estamos a mitad de camino)
- Hoy se puede ver la estructura de la arteria sin necesidad de poner un pedazo de arteria en el microscopio, con el eco. (mas adelante hay un ejemplo mejor)
- PAD Prevalence > 55 Years The blue bars in the graph show the prevalence of PAD, confirmed by an ankle-brachial index value of less than 0.9, as reported in six different studies. Overall, age-adjusted prevalence of PAD is approximately 12%, affecting men and women about equally. Claudication was present in 1% to 6% of the subjects, depending on the study. The six studies by and large enrolled patients older than 55 years; however, one of the six, by Zheng et al, enrolled patients between the ages of 45 and 64 years. In this study, the prevalence of PAD and claudication was by far the lowest of any of the six studies. Five of the six studies also tracked the prevalence of clinical cardiovascular disease (CVD). In the studies enrolling older patients (>55), CVD prevalence ranged between 33% and 56%. Patients with PAD, even when they do not have a history of previous MI or ischemic stroke, are at approximately equal risk of death from cardiovascular causes as are patients with a history of coronary or cerebrovascular disease. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med . 2001;344:1608-1621.
- Mortalidad Cv y crisis económica Se observa la tendencia de la tasa de Mortalidad CV en la población mayor de 35 años en el período 1995-2005: se observa una tendencia a la reducción de la mortalidad desde 1995 hasta 1997 coincidiendo con el incremento neto del PBI anual. En 1997 , 1998 y 1999 se observa un incremento en la tasa de mortalidad anual, coincidiendo con la crisis asiática, que se manifiesta sobre todo en 1999. El acmé de descenso neto del PBI que se observa en el 2002, coincide con un comportamiento inverso en la curva de mortalidad. A partir de ese momento se observa un incremento en el PBI que se acompaña de un descenso o plateau de la curva de mortalidad.
- PAD Prevalence > 55 Years The blue bars in the graph show the prevalence of PAD, confirmed by an ankle-brachial index value of less than 0.9, as reported in six different studies. Overall, age-adjusted prevalence of PAD is approximately 12%, affecting men and women about equally. Claudication was present in 1% to 6% of the subjects, depending on the study. The six studies by and large enrolled patients older than 55 years; however, one of the six, by Zheng et al, enrolled patients between the ages of 45 and 64 years. In this study, the prevalence of PAD and claudication was by far the lowest of any of the six studies. Five of the six studies also tracked the prevalence of clinical cardiovascular disease (CVD). In the studies enrolling older patients (>55), CVD prevalence ranged between 33% and 56%. Patients with PAD, even when they do not have a history of previous MI or ischemic stroke, are at approximately equal risk of death from cardiovascular causes as are patients with a history of coronary or cerebrovascular disease. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med . 2001;344:1608-1621.
- Core Unmet Need (CM) 09/28/12 21:54 3
- Core Unmet Need (CM) 09/28/12 21:54 ASCOT employs a 2x2 factorial design, which allows 2 hypotheses to be tested simultaneously. The first hypothesis tested is whether a newer antihypertensive regimen (calcium channel blocker [CCB] ± an angiotensin-converting enzyme inhibitor [ACE]) is more effective than a standard regimen ( -blocker ± a diuretic) in the primary prevention of CHD in hypertensive patients. The second hypothesis tested is whether a statin, compared with placebo, would provide protection against CHD endpoints in hypertensive subjects with normal to moderately elevated levels of TC ( 6.5 mmol/L [ 250 mg/dL]). The ASCOT study is structured in the following manner (target numbers): An estimated sample size of 18,000 patients was required to generate 1150 primary endpoints, giving the study 80% power to detect treatment effects. Of these 18,000 patients, it was intended that 9000 would be randomized to receive therapy with a CCB (amlodipine) ± an ACE (perindopril) and 9000 would be randomized to a -blocker (atenolol) ± a diuretic (bendroflumethiazide+potassium). Of the approximately 9000 patients randomized to the -blocker ± diuretic arm, 5000 patients were expected to have TC levels of 6.5 mmol/L ( 250 mg/dL) and 4000 patients were expected to have TC levels of >6.5 mmol/L (>250 mg/dL). Approximately 500 patients with TC 6.5 mmol/L ( 250 mg/dL) were assigned to open lipid-lowering therapy; the remaining 4500 patients were randomized to therapy with atorvastatin 10 mg/d or placebo. Similarly, of the 9000 patients randomized to therapy with CCB ± ACE, 5000 patients were expected to have TC 6.5 mmol/L ( 250 mg/dL) and 4000 patients were expected to have TC >6.5 mmol/L (>250 mg/dL). All 8000 patients from both antihypertensive arms with TC >6.5 mmol/L (>250 mg/dL) would be assigned to open lipid-lowering therapy (usual care). As in the -blocker ± diuretic arm, the 5000 patients in the CCB ± ACE arm with TC 6.5 mmol/L ( 250 mg/dL) were assigned to open lipid-lowering therapy (n=500) or were randomized to therapy with atorvastatin 10 mg/d (n=2250) or placebo (n=2250).
- Core Unmet Need (CM) 09/28/12 21:54 The primary end point of nonfatal MI (including silent MI) and fatal CHD was significantly lower by 36% (hazard ratio 0.64, CI 0.5 – 0.83, p=0.005) in the atorvastatin group compared with the placebo group.
- Core Unmet Need (CM) 09/28/12 21:54
- Core Unmet Need (CM) 09/28/12 21:54
- PROVE IT is a double-blind, randomized trial that has enrolled 4,160 patients, at approximately 400 sites in the US, Europe, Canada, and Australia, who have experienced an acute coronary syndrome (Q wave and non-Q-wave MI or unstable angina) within the previous 10 days. Patients received either 40 mg of pravastatin or 80 mg of atorvastatin within 10 days of their event and were followed for a mean follow-up period of 2 years. To study the role of infection in ACS, one half of the patients in the trial also received gatifloxacin 400 mg in addition to either pravastatin or atorvastatin. Gatifloxacin was started on day 15 after the initial episode of ACS for a treatment period of 14 days. Gatifloxacin was subsequently given as a pulsed dose of 400mg per day for 10 days each month for a mean of 2 years. The other half of the patient population received an antibiotic placebo.
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- In order to answer this question, we evaluated a large group of patients with established, stable coronary heart disease. First we reduced their LDL to a target of around 100mg/dL with atorvastatin 10mg. Then we randomized the group, leaving half on 10mg of atorvastatin daily, and giving the other half 80mg of atorvastatin daily in order to further reduce their LDL to a target of around 75mg/dL. We wanted to record the impact of this intervention on the incidence of major cardiovascular events.
- So, we tested the TNT hypothesis in a double-blind, parallel-group design. We screened a total of 18,469 patients at 256 sites in 14 countries. Lipid lowering therapy was withdrawn, and all patients entered a wash-out phase. 15,432 patients with established CHD and with an LDL-C level of between 130 and 250 mg/dL and with triglycerides less than or equal to 600 mg/dL were then eligible to enter the 8-week open-label run-in period with atorvastatin 10 mg/day . In order to ensure that we had two groups that met our LDL targets, and because it would have been unethical to under treat patients whose LDL remained above 130, we entered only those patients with a mean LDL-C that was less than 130mg/dL on 10 mg of open label atorvastatin into the randomized phase of the study. We randomized 10,001 patients to double-blind therapy with either atorvastatin 10 or 80 mg/day. 5006 patients remained on atorvastatin 10mg daily, and 4995 patients received 80mg daily. Using t he time of randomization is as the baseline for the study, patients were then followed for a median of 4.9 years. The primary efficacy outcome measure was the time to occurrence of a major cardiovascular event, defined as CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, and fatal or nonfatal stroke.
- In conclusion, we have entered a new era in the treatment of established coronary heart disease. Treating patients with established CHD to an LDL of 77mg/dL with 80mg of atorvastatin daily, from their starting LDL of 100, provided a highly significant reduction in the risk of major cardiovascular events. The event rates recorded in both arms of the TNT study are lower than those achieved in any of the other major secondary prevention studies. The results of the TNT study indicate that the quantitative relationship between reduced LDL cholesterol and reduced CHD risk demonstrated in prior statin secondary prevention trials holds true even at very low LDL cholesterol levels. Significant declines in CHD and cardiovascular morbidity were observed in the atorvastatin 80mg group relative to the atorvastatin 10 mg group. This improved clinical outcome is achieved without significant additional safety risk - even with atorvastatin 80 mg, there was a very low incidence of elevated LFTs or myalgias and there were no definite cases of rhabdomyolysis with high-dose atorvastatin. These data extend the growing body of evidence indicating that lowering LDL cholesterol well below currently recommended levels can further reduce the preventable healthcare burden associated with cardiovascular and cerebrovascular disability. Thank you.
- Core Unmet Need (CM) 09/28/12 21:54 Click to add text
- Core Unmet Need (CM) 09/28/12 21:54 Click to add text
- Analysis of adverse events (AEs) data for the fixed-dose data grouping showed that the proportion of patients experiencing at least 1 AE was similar to placebo at each atorvastatin dose. There was no dose-response relationship in the overall incidence of AEs to atorvastatin exposure across the 10-80 mg dose range. Newman CB, et al. Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol . 2003;92:670-676 . Data on file, Pfizer Inc. Review of 44 completed clinical trials.
- The incidence of discontinuations due to AEs demonstrated in the analysis of the pooled data was low. Only 2.6% of atorvastatin-treated patients, compared with 3.6% of patients receiving other statins, withdrew from studies due to treatment-associated AEs. Newman CB, et al. Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol . 2003;92:670-676 . Data on file, Pfizer Inc. Review of 44 completed clinical trials.
- Analysis of the fixed-dose data grouping found that the incidence of myalgia did not increase across the atorvastatin dose range, and at each dose the proportion of patients experiencing the event was similar to that seen in the patients treated with placebo. Only 1 patient receiving atorvastatin in this group of 44 studies experienced persistent CPK elevations > 10 x ULN. The patient had no other AEs associated with the elevated enzymes. The patient was a 16-year-old male with severe hypercholesterolemia and a history of xanthomas, hypertension, occasional headaches, and slightly elevated creatine kinase levels who had received treatment with atorvastatin 40 mg/d for 28 days followed by treatment with atorvastatin 80 mg/d for 479 days. Study medication was continued and by the end of the study the elevated levels of CPK had returned to baseline. Newman CB, et al. Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol . 2003;92:670-676 . Data on file, Pfizer Inc. Review of 44 completed clinical trials.
- These data are based on a patient population that experienced > 3 x ULN ALT/AST elevations occurring on 2 consecutive occasions within 14 days. An analysis of completed studies showed a low occurrence of persistent ALT/AST elevations. On average, 0.5% of patients treated with atorvastatin 10, 20, 40, and 80 mg experienced increased ALT/AST values. The incidence of elevated ALT/AST values ranged from 0.13% in the atorvastatin 10-mg group to 0.89% in the atorvastatin 80-mg group. The average value for placebo was 0.28% (5/1789). Newman CB, et al. Safety of atorvastatin derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol . 2003;92:670-676 . Data on file, Pfizer Inc. Review of 44 completed clinical trials.
- Core Unmet Need (CM) 09/28/12 21:54
- En la revisión sistemática de Julia Critchley evaluación de 20 estudios demostraron una reducción del RR del 36% de mortalidad de toda causa en pacientes con ECV que abandonaron comparado con los que continuaron fumando. Este 36% de reducción parece tanto o mas impactante que otras intervenciones en prevención secundaria como el uso de BB post IAM, estatinas para bajar los niveles de colesterol, grupo colaborativo de uso de IECA en IAM, meta-análisis sobre la utilidad de anti-agregación para prevención de mortalidad, IAM y Stroke. En un estudio mas reciente de Mohiuddin publicado en CHEST 2007 la reducción del RR de mortalidad total fue del 77% a dos años en el grupo de tratamiento intensivo comparado con un grupo con intervención mínima. Estos eran paciente entre 35 a 75 años hospitalizados en UCO con SCA o IC. La reducción del Riesgo absoluto de mortalidad fue de 9,2% y el numero necesario de tratar fue de 11