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Comignani Pablo Jefe Unidad de Cuidados Críticos, Terapia Intensiva-Unidad Coronaria Hospital Alemán, Buenos Aires Insuficiencia.

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Presentación del tema: "Comignani Pablo Jefe Unidad de Cuidados Críticos, Terapia Intensiva-Unidad Coronaria Hospital Alemán, Buenos Aires Insuficiencia."— Transcripción de la presentación:

1 Comignani Pablo Jefe Unidad de Cuidados Críticos, Terapia Intensiva-Unidad Coronaria Hospital Alemán, Buenos Aires Insuficiencia cardíaca crónica

2 The view of CHF as a mechanical problem might hipothesized that an improve in the charges conditions and an improvement in the inotropism state will translate in a improved survival CHF as a Mechanical Problem Normal Contractility Depressed Contractility Normal Contractility Depressed Contractility PRECHARGEPOSTCHARGE

3 CHF as a Mechanical Problem PRECHARGEPOSTCHARGE Normal Contractility Depressed Contractility VENOUS AND ARTERIAL VASODILATATION

4 CHF as a Mechanical Problem Survival with adrenergic agonist % SURVIVAL Days

5 Incremento en el riesgo de muerte asociado a dobutamina en infusión ( 14 días ). FIRST Study

6 OPTIME CHF Study

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8 CHF as a Mechanical Problem Survival with Digoxin % SURVIVAL Months

9 Diuretic treatment in contemporany care of CHF: An analysis of the VALHEFT Study Debido a que las características de los pacientes que reciben o no reciben diuréticos difieren sustancialmente la comparación entre los grupos se realizó utilizando un score de propensión que consideró: Cinco categorías (quintilos) de riesgo (progresivo) construidos en función de: FEY – DDVI – NYHA – EDAD & SEXO Y dentro de cada una de estas 5 categorías, los sujetos que recibian y no recibian diuréticos estaban matcheados.

10 Diuretic treatment in contemporany care of CHF: An analysis of the VALHEFT Study GROUP 1GROUP 2GROUP 3GROUP 4GROUP 5P Matched variables Age (median) < Males957 (95.6)863 (86.1)773 (77.1) 640 (63.9)< LVEF (median) < LVIDD3,273,543,683,563,86< NYHA II1001 (100)1002 (100)882 (88.0)205 (20.5)8 (0.8)< NYHA III00120 (12.0)797 (79.5)896 (89.5)< NYHA IV (9.7)< NYHA III / IV00120 (12.0)797 (79.5)993 (99.2)<0.0001

11 Diuretic treatment in contemporany care of CHF: An analysis of the VALHEFT Study

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13 HR95% CIpEventos PS = 1 (n=1001) – PS = 2 (n=1002) – PS = 3 (n=1002) – PS = 4 (n=1002) – PS = 5 (n=1001) – Diuretic treatment in contemporany care of CHF: An analysis of the VALHEFT Study Cox regression model adjusted by age, sex, NYHA class, HF etiology, HF duration, diabetes, body mass index (BMI), electrocardiographic rhythm, EF, LVDD, haemoglobin, WBC count, serum sodium, potassium, creatinine, uric acid, total cholesterol, BNP, plasma renin activity, aldosterone, norepinephrine, ACE inhibitors, beta blockers, amiodarone and digoxin.

14 NEUROHORMORAL STATE Plasma norepinephrine CONTROLASYMPTOMATICSYMPTOMATIC HEART FAILURE

15 Survival Probability Days NEUROHORMORAL STATE Plasma norepinephrine

16 P< Annual Mortality: bisoprolol=8.2%; placebo=12% Mean Follow-up 1.4 years Days Bisoprolol11.8% Placebo17.3% Survival ICCC NYHA III-IV n= CIBIS-II Lancet 1999;353:9 ß-Adrenergic Blockers BETA BLOCKERS IN CHF CIBIS II

17 MERIT-HF Lancet 1999; 353: 2001 Months Mortality% Placebo Metoprolol p= Risk Reduction 34% ß-Adrenergic Blockers NYHA II-IV N=3991 BETA BLOCKERS IN CHF MERIT HF

18 Placebo Carvedilol Months N = 2289 III-IV NYHA COPERNICUS NEJM 2001;344:1651 Survival% ß-Adrenergic Blockers p= % RR BETA BLOCKERS IN CHF COPERNICUS

19 1 Survival Years Carvedilol 116 / 975 (12%) Placebo 151 / 984 (15%) HR 0.77 ( ) p<0.031 CAPRICORN Lancet 2001;357:1385 ß-Adrenergic Blockers LVD / HF Post AMI BETA BLOCKERS IN CHF CAPRICORN

20 BETA BLOCKERS IN CHF A Metanalysis TRIAL Months of FU Mortality Placebo Mortality Beta Blockers RRIC 95 %P MDC 1518 / 189 (10.1 %)23 / 193 (11.9 %) – CIBIS I 2167 / 321 (20.9 %)53 / 320 (16.6 %) – ANZ 1826 / 208 (12.5 %)20 / 207 (9.7 %) – US Trial / 398 (7.8 %)22 / 696 (3.2 %) – CIBIS II / 1320 (17.3 %)156 / 1327 (11.8 %) – MERIT / 2001 (10.8 %)145 / 1990 (7.3 %) – BEST / 1354 (33 %)411 / 1354 (30 %) – COPERNICUS / 1133 (16.8 %)130 / 1156 (11.2 %) – CAPRICORN / 984 (15 %)116 / 975 (12 %) – TOTAL / 7908 (17.4 %)1074 / 8218 (13.1 %) – 0.79 <

21 ALL BETA BLOCKERS ARE THE SAME ? Carvedilol Or Metoprolol European Trial CARVEDILOLMETOPROLOL N Age61.6 ± ± 11.4 Male (%)1200 (79)1217 (80) NYHA II/III/IV48 / 48 / 349 / 47 / 1 ACE Previous (%)9291 ARB67 Diuretics (%)99 Digitalis (%)7275 Aldosterone antagonist11 Ejection Fraction (%)26.0 ± ± 7 Systolic Pressure126 ± ± 19.7 Ischemic heart disease5154 Diabetes24 Poole-Wilson PA et al.Lancet 2003;362:7-13

22 ALL BETA BLOCKERS ARE THE SAME ? Carvedilol Or Metoprolol European Trial CARVEDILOLMETOPROLOLHRIC 95 %P N All Death (KM 5 years) Yearly mortality rate Cardiovascular Deaths438 (29)534 (35) Non Cardiovascular Deaths74 (5)66 (4) All death and all cause admissions 1116 (74)1160 (76) Poole wilson PA et al.Lancet 2003;362:7-13

23 NEUROHORMORAL STATE Renin activity CONTROLASYMPTOMATICSYMPTOMATIC HEART FAILURE

24 NEUROHORMORAL STATE Renin activity NEUROHUMORAL CHANGES AFTER 6 W TREATMENT AngiotensinAldosterone PNA Norepinephrine

25 SURVIVAL % MORTALITY % MORTALITY Months NEUROHORMORAL STATE Renin activity

26 NEUROHORMORAL STATE Renin activity SURVIVAL MORTALITY % Asymptomatic dysfunction post AMI YEARS N –16 days post AMI EF < 41%

27 NEUROHORMORAL STATE Renin activity EJECTION FRACTION % Placebo BetterEnalapril Better SOLVD TREATMENT % DEATH RISK REDUCTION

28 NEUROHORMORAL STATE Post Trial Benefits SOLVD PREVENTION SOLVD TREATMENT ENALAPRIL N 2111 PLACEBO N 2117 HRIC 95 %P ALL CAUSE MORTALITY 1074 (50.9)1195 (56.4) ENALAPRIL N 1285 PLACEBO N 1284 HRIC 95 %P ALL CAUSE MORTALITY 1025 (79.8)1038 (80.8) Jong P. Lancet 2003;361:

29 Which Dose should we use ? ATLAS Study Low doseHigh doseHazard RatioP All cause mortality717 (44.9)666 (42.5)0.92 ( )0.128 Cardiovascular mortality641 (40.2)583 (37.2)0.90 ( )0.073 All cause mortality + Hospitalization any reason 1338 (83.8)1250 (79.7)0.88 ( )0.002 All cause mortality + Hospitalization CV reason 1182 (74.1)1115 (71.1)0.92 ( )0.036 All cause mortality + Hospitalization CHF 964 (60.4)864 (55.1)0.85 ( )< 0.001

30 NEUROHORMORAL STATE Angiotensin Receptor Antagonism SURVIVAL Days

31 Angiotensin Receptor Antagonism ELITE II ELEGILIBILITY CRITERIA Age > 60 years with 85 % > 65 New York Heart association II - IV Ejection Fraction < 40 % 298 Centers in 46 Countries Median Follow up 1.5 years Event-driven superiority trial designed with 90 % power to detect a relative 25 % difference in total mortality beetween treatments. Assumption of annual mortality rate of 9.4 %.

32 Angiotensin Receptor Antagonism ELITE II LOSARTANCAPTOPRILHRIC 95 %P N TOTAL MORTALITY280 (17.7)250 (15.9) – Sudden death130 (8.2)101 (6.4)1.301 – 1.69 Progresive HF46 (2.9)53 (3.4) – 1.3 TOTAL MORTALITY OR READMISSION 752 (47.7)707 (44.9) – ANY CAUSE HOSPITAL READMISSION 659 (41.8)638 (40.5) – HF HOSPITAL READMISSION 270 (17.1)293 (18.6) –

33 Angiotensin Receptor Antagonism Val-HeFT ELEGILIBILITY CRITERIA RCT, DB, PC, Paralel Groups. 302 Centers in 16 Countries. Age > 18 years AND 3 months with signs and symptoms of HF New york heart Association II – IV. Ejection fraction 2.9 cm /m 2 2 – 4 weeks RUN IN and thenafter Valsartan 40 mg twice up to 160 mg twice. Follow up planned at 2 – 4 – 6 months and then after 3 months Primary end point : TOTAL MORTALITY and MORTALITY + MORBIDITY (Sudden death-HF Hospitalization-Inotropic drugs > 4 hs Cohn J. N Engl J Med 2001;345:

34 Val-HeFT All Cause Mortality VALSARTAN PLACEBO Months of FU (Time from randomization) P = 0.8 % Survival

35 Risk Reduction: 13,3 % p = VALSARTAN PLACEBO Months of FU (Time from randomization) % Survival Val-HeFT Morbidity & Mortality

36 Risk Reduction: 27,5 % p = VALSARTAN PLACEBO Val-HeFT Heart Failure Hospitalization Months of FU (Time from randomization) % Survival

37 CHARM OVERALL C andesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity

38 SPIRONOLACTONE Randomized ALdactone Evaluation Study PLACEBOSPIRONOLACTONE N Age65 ± 12 Male / Female73 / 27 NYHA II/III/IV0.4 / 69 / / 72 / 27 ACE Previous (%)9495 Beta Blockers (%)1011 Diuretics (%)100 Digitalis (%)7275 Ejection Fraction (%)25.2 ± ± 6.7 Systolic Pressure122 ± ± 21 Diastolic Pressure75 ± 1175 ± 12

39 SPIRONOLACTONE Randomized ALdactone Evaluation Study PLACEBOSPIRONOLACTONEHRIC 95 %P N TOTAL MORTALITY – 0.82<0.001 CARDIAC CAUSES Progression of HF Sudden death AMI – – – 0.95 <0.001 OTHER CV CAUSES1312 STROKE118 NON CV CAUSES4129 UNKNOWN79 RELATIVE RISK OF DEATH

40 SPIRONOLACTONE Randomized ALdactone Evaluation Study PLACEBOSPIRONOLACTONEHRIC 95 %P N CARDIAC CAUSES Worsening HF Angina Ventricular arrhytmia AMI 336 / / / / / / / / / / <0.001 OTHER CV CAUSES112 / / 169 STROKE20 / 2414 / 15 NON CV CAUSES232 / / 361 RELATIVE RISK OF HOSPITALIZATION

41 Aldactone Placebo Survival months p < Annual Mortality Aldactone 18%; Placebo 23% N = 1663 NYHA III-IV Mean follow-up 2 y RALES NEJM 1999;341:709 Spironolactone SPIRONOLACTONE Randomized ALdactone Evaluation Study

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44 Una historia de éxitos ARTICLES Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure. Masoudi FA, Havranek EP, Wolfe P, et al. Masoudi FA. Am Heart J 2003;146:250-7 Aunque no para todos….

45 SOLVD 18 % MERIT HF 13 % RALES 25 % Insuficiencia Cardíaca / Ancianidad / Comorbilidad 20,338 Pacientes mundo real (VA) Masoudi FA. Am Heart J 2003;146:250-7

46 Insuficiencia Cardíaca / Ancianidad / Comorbilidad TODOS p IECA (SOLVD) Todos <0.001 Hombres <0.001 Mujeres <0.001 Bloqueantes (MERIT HF) Todos Hombres NS Mujeres NS Espironolactona (RALES) Todos <0.001 Hombres <0.001 Mujeres <0.001 Masoudi FA. Am Heart J 2003;146:250-7

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48 ARTICLES Effects of Oral Tolvaptan in Patients Hospitalized for Worsening Heart Failure. The EVEREST Outcome Trial. Konstan M JAMA March , 297,12:1319

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52 Anemia is highly prevalent in HF Prevalence of anemia is related to HF severity Clear association between anemia & mortality / morbidity and quality of life Small RCT demonstrate benefits Time to enroll patients in big RCT ANEMIA AND CONGESTIVE HEART FAILURE A staircase to construct knowledge

53 Anemia is highly prevalent in HF Prevalence of anemia is related to HF severity Clear association between anemia & mortality / morbidity and quality of life Small RCT demonstrate benefits Time to enroll patients in big RCT ANEMIA AND CONGESTIVE HEART FAILURE A staircase to construct knowledge

54 ANEMIA AND CONGESTIVE HEART FAILURE Prevalence of anemia in CHF patients McClellan (Hct<40%)Androne (Hct<41% - 38%)Silverberg (Hb<12 g/dl) Wexler (Hb<12 g/dl) Wisniacki (Hb<12 g/dl) OPTIME-CHF (Hb<13 -<12 g/dl) Kosiborod (Hct<37%) STAMINA-CHF (Hb<13 -<12 g/dl) Horwich (Hb<13 -<12 g/dl)Herzog (ICD-9 Codes) Euro HF survey (Hb<11g/dl) PRAISE (Hct<37.6%) RENAISSANCE (Hb<11g/dlCOPERNICUS (Hb<12.5 g/dl) ELITE II (Hb<12.5 g/dl) Szachniewicz (Hb<11g/dl) Ezekowitz (ICD-9 Codes) IN-CHF (Hb<12 -<11 g/dl)Tanner (Hb<12 g/dl)Cromie (Hb<11g/dl) Val-HeFT (Hb<12 -<11 g/dl) The prevalence of anemia in heart failure patients is approximately: 30% for In-patients 20% for Out-patients

55 Anemia is highly prevalent in HF Prevalence of anemia is related to HF severity Clear association between anemia & mortality / morbidity and quality of life Small RCT demonstrate benefits Time to enroll patients in big RCT ANEMIA AND CONGESTIVE HEART FAILURE A staircase to construct knowledge

56 ANEMIA AND CONGESTIVE HEART FAILURE Prevalence and CHF severity NYHA INYHA IINYHA IIINYHA IV Hb <10g/dlHb <11g/dlHb <11.5g/dlHb <12.0g/dlHb <12.5g/dl Source: STAMINA Registry – 45 General Cardiologist sites, n=673, 12 Academic sites (incl. HF Specialists), n=337 (N=32) (N=97)(N=165)(N=244)(N=337)

57 Anemia is highly prevalent in HF Prevalence of anemia is related to HF severity Clear association between anemia & mortality / morbidity and quality of life Small RCT demonstrate benefits Time to enroll patients in big RCT ANEMIA AND CONGESTIVE HEART FAILURE A staircase to construct knowledge

58 ANEMIA AND CONGESTIVE HEART FAILURE Anemia and all-cause mortality IN CHF ANNUALIZED MORTALITY Maggioni AP. J Card Fail 2005;11:91-8 HR = 1.26 ( ) HR = 1.54 ( )

59 < >16.5 Hb (g/dL) Relative Risk HR for Death adjusted for age, SBP, NYHA, BMI, EF, Cr, Na, Diabetes, HF duration, Gender and Carvedilol vs Metoprolol Komajda M. Eur Heart J : ANEMIA AND CONGESTIVE HEART FAILURE Anemia and death/hospitalization

60 Anemia is highly prevalent in HF Prevalence of anemia is related to HF severity Clear association between anemia & mortality / morbidity and quality of life Small RCT demonstrate benefits Time to enroll patients in big RCT ANEMIA AND CONGESTIVE HEART FAILURE A staircase to construct knowledge

61 ANEMIA AND CONGESTIVE HEART FAILURE Small clinical trials results Mancini D. Circulation. 2003;107: Mean Change in Exercise Duration P<0.004 Mean Change in 6-Minute Walk Distance P< Minute Walk Distance (feet) Exercise Duration (seconds) Randomized, placebo-controlled, single-blinded study; N=23 (n=8 for placebo group, n=15 for EPO group) P=NS

62 ANEMIA AND CONGESTIVE HEART FAILURE Anemia is likely to be multifactorial Anemia of Chronic Disease Pharmaco therapy Renal Dysfunction Malnutrition Decreased Cardiac Output Chronic Inflammation Bone marrow dysfunction Abnormal iron homeostasis (uptake, release, utilization) Intravascular fluid imbalance (hemodilution) EPO deficiency or resistance

63 ANEMIA AND CONGESTIVE HEART FAILURE The cardio-renal-anemia syndrome Kidney Bone MarrowAnemia Heart Failure Cardiac output RAS activation Sympathetic tone ACE inhibitor therapy RBC Production Perfusion Malnutrition TNF alpha Vasoconstriction EPO (relative) Hemodilution EPO resistance Ischemia Apoptosis LVH Felker MG. J Am Coll Cardiol 2004;44:959-66

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65 Prevención Primaria MADIT CABG-Patch DEFINITE DINAMIT SCD-HeFT MUST MADIT II

66 MADIT CDI vs. Tratamiento médico (75% amiodarona) 196 pacientes, > de 3 semanas post IAM Con registro de TVNS asintomática CF I, II o III FEY < 35% Arritmia inducida en EEF que no responde a procainamida EP 1°: Mortalidad por todas las causas Disminución significativa de la mortalidad en el grupo CDI NEJM 1996; 335:

67 CABG-Patch 900 pacientes. CRM programada. FEY < 36%, ateraciones en el ECG de señales promediadas. 82% con antecedente de IAM y 50% con antecedente de IC NO hubo diferencia significativa CDI Vs Tratamiento médico EP 1°: Mortalidad por todas las causas

68 MUST 704 pacientes con antecedente de enfermedad coronaria, FEY< 40%, TVNS asintomática Arritmia inducida en el EEF. No tratamiento Tratamiento CDI Antiarritmicos Reducción significativa del riesgo de paro cardíaco ó muerte arrítmica del 27% con CDI a 5 años Sin diferencias en el tratamiento con drogas Vs placebo

69 MADIT II 1232 pacientes, > de 1 mes post- IAM Fey < 30% Sin EEF previo CDI Vs Tratamiento médico Reducción significativa del riesgo relativo del 28% con CDI a 2 años HR 0,69 IC 95% ( ) p<0.016 EP 1°: Mortalidad por todas las causas

70 MADIT II p<0.016

71 DEFINITE no isquémica 458 pacientes con miocardiopatía no isquémica, antecedentes de IC Fey < 35%, EV ó TVNS. CDI Vs Tratamiento médico HR 0,65 IC 0,40-1,06 HR 0,2 IC 0,06-0,75

72 SCD-HeFT 2521 pacientes con IC CF II/III, Fey < 35% 85% antecedentes de cardiopatía isquémica. Grupo control Tratamiento con amiodarona CDI EP 1°: Mortalitada por todas las causas

73 SCD-HeFT

74 Indicaciones CDI Disfunción del VI post IAM Cardiopatías congénitas Miocarditis Miocardiopatías infiltrativas/endócrinas Miocardiopatía dilatada Miocardiopatía hipertrófica Displasia arritmogénica del VD Insuficiencia cardíaca Sme. QT largo Sme de brugada TV polimórficas catecolaminnérgicas Arritmias en corazones estructuralmente normales

75 Resincronización Ventricular 35% de los pacientes con IC presentan trastornos de la conducción intraventricular (25% BRI) La estimulación ventricular sincronizada mejora ó revierte la contracción asincrónica Mejora el perfil hemodinámico a corto plazo Previene el remodelado reverso a largo plazo

76 COMPANION CARE - HeFT MUSTIC AF MIRACLE MUSTIC Retin Q PROSPECT Resincronización Ventricular

77 COMPANION 1520 pacientes, IC CF III / IV, Fey < 35%, QRS > 120 mseg Ritmo sinusal Seguimiento al año Tratamiento médicoResincroResincro + CDI EP 1°: Muerte ú hospitalización

78 Mortalidad ú hospitalizaciónMortalidad por todas las causas

79 CARE HF 830 pacientes con IC CF III / IV, Fey < 35% QRS > 120 mseg Si QRS e/ 120 y 149: criterios ecocardiográficos de disincronía Resincronización ventricularTratamiento médico óptimo EP 1°: Muerte ú hospitalización de causa cardiovascular

80 CARE HF Muerte por todas las causas ó reinternación por eventos cardiovasculares Mortalidad por todas las causas

81 Especificidad y Sensibilidad de 12 parámetros ecocardiográficos para predecir el EP combinado: muerte por todas las causas, IC, CF y mejoría en la calidad de vida. Prospect

82 INDICACIONES RESINCRO Clase I A Pacientes con IC, Que permanecen sintomáticos a pesar del tratamiento médico óptimo, Ritmo sinusal En CF III / IV QRS > 120 mseg Clase II A Con FA Con dependencia frecuente de MCP Clase II B CF I, II a los que se les implantará MCP ó CDI

83 1820 pacientes, entre el 2004 y Antecedentes de cardiopatía isquémica (CF I ó II) ó miocardiopatía NO isquémica (CF II). RS Fey<30% QRS > 130 mseg

84 Criterios de exclusión Indicaciones para CRT Implante previo de MCP ó CDI CD III / IV CRM previa IAM ó PTCA 3 meses previos FA 1 mes previo

85 Randomización 3:2 CDI Vs CDI + Resincro ECG, Ecocardiograma, examen físico y Test de caminata de 6 minutos pre-randomización Ecocardiograma al año de seguimiento EP 1°: Mortalidad por todas las causas, ó IC

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