LA SINDROME CARDIORENALE NEL PAZIENTE CRITICO Cuneo, 16 maggio 2012 Il ruolo dell anemia e le scelte terapeudche Lucia Del Vecchio Divisione di Nefrologia, Dialisi e Trapianto Renale Ospedale A. Manzoni, Lecco
Sindrome cardio-renale: definizione E una malattia del cuore e dei reni in cui una disfunzione acuta o cronica di un organo può indurre una disfunzione acuta o cronica dell altro organo
Sindrome cardio-renale: classificazione SCR tipo 1 = peggioramento acuto funzione cardiaca (scompenso acuto, sindrome coronarica acuta) che determina danno/disfunzione renale SCR tipo 2 = cardiopatia cronica che determina danno o disfunzione renale SCR tipo 3 = IRA che determina danno o disfunzione cardiaca SCR tipo 4 = CKD che determina danno o disfunzione cardiaca SCR tipo 5 = condizioni sistemiche che determinano simultaneamente danno/ disfunzione del cuore e dei reni ANEMIA FATTORE PROGNOSTICO SFAVOREVOLE
The prognostic significance of early and late anaemia in acute coronary syndrome 448 consecutive patients with ACS! Prevalence of anaemia went from 20% on admission to 40% at 7-weeks follow-up! Baseline anaemia predicted CV endpoints independent of the admission GRACE score [adjusted RR 2.54 (95% CI 1.73-3.71)].! Patients with anaemia at 7 weeks were at an increased risk of death or AMI compared to those with normal Hb [unadjusted RR 3.58 (95% CI 2.04-6.29)]. And DS et al. QJM. 2012 May;105(5):445-54.
The Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study The Kaiser Permanente chronic HF cohort Crude rates of death from any cause by Hb level Rate (per 100 person-years) 90 80 70 60 50 40 30 20 10 14.9 n =59 772 9.7 9.7 10.1 11.7 15.0 21.8 31.6 44.3 73.9 0 17.0 16.0-16.9 15.9-15.0 14.9-14.0 13.9-13.0 12.9-12.011.9-11.0 10.9-10.0 9.9-9.0 <9.0 Hemoglobin (g/dl) Go AS et al. Circulation. 2006;113(23):2713-23.
! 34 studies, comprising 153,180 patients! 37.2% were anemic! Minimum FU: 6 months! 46.8% of anemic patients died compared to 29.5% of non anemic J Am Coll Cardiol 2008 Sep 2;52(10):818-27
Risk of all-cause mortality of anemic versus non-anemic CHF patients After adjustment: HR of 1.46 (1.26, 1.69; p < 0.001) Overall 1.96 (1.74, 2.27).4.5 1 2 4 8 10 Lower risk of anemic High risk of anemic Groenveld HF et al. J Am Coll Cardiol 2008; 52(10):818-27
Sindrome cardio-renale Sindrome cardio-renale-anemia CardiopaDa MalaKa renale Anemia
Sindrome cardio-renale + anemia: «La tempesta perfetta» Palazzuoli A et al. Heart Fail Rev. 2011 Nov;16(6):603-7.
Pathophysiology of Fluid Retention in CHF and Anemia CHF Anemia Impaired worsening CHF cell death LV Mass LV Remodelling Work Load heart rate peripheral vasoconstriction fluid retention plasma volume Peripheral vasodilation blood pressure neurohormones RAAS AVP Natriuretic peptides blood flow GFR Palazzuoli A et al. Heart Fail Rev. 2011 Nov;16(6):603-7.
Cause di anemia nella sindrome cardio-renale! Inibizione iatrogena della sintesi di eritropoietina! Ridotta produzione di eritropoietina da IRC! Emodiluizione! Carenza marziale, da scarso apporto! Carenza marziale, da sanguinamento! Ridotto assorbimento intestinale di folati e vitamina B12! Stato infiammatorio cronico
This study measured EPO levels and studied their relation to GFR (51Cr-EDTA R=-0.22 p=0.04 renal clearance) in 336 all-stage CKD patients not receiving any ESA R=0.09 p=0.35 Anemic Non anemic Anemic Non anemic Obesity, diabetes with nephropathy other than diabetic glomerulopathy, absolute iron deficiency, and high C-reactive protein were associated with increased EPO levels, independent of Hb and mgfr Clin J Am Soc Nephrol. 2012 Jan;7(1):35-42
Endogenous Erythropoietin and the Association with 1.00 Inflammation and Mortality in Diabetic CKD 215 patients with type 2 diabetes, mean GFR 49 ml/min per 1.73 m2 followed for up to 7.0 years 0.75 Survival 0.50 0.25 0.00 Low EPO tertile: 10.6 U/L Medium EPO tertile: 10.7 to 15.9 U/L High EPO tertile: 16.0 U/L P = 0.056 0 500 1000 1500 2000 2500 Days Wagner M et al. Clin J Am Soc Nephrol 2011;6:1573 79
SCR tipo 1 Peggioramento acuto funzione cardiaca (scompenso acuto, sindrome coronarica acuta) che determina danno/disfunzione renale
EPO receptors are expressed by many tissues EPO Erythropoiesis Neurotrophy Neuroprotection Angiogenesis Vascular tone Cardioprotection Tumor growth?
Proceedings of the National Academiy of Sciences of the United States of America Medical Sciences Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling Laura Calvillo, Roberto LaFni, Jan Kajstura, Annarosa Leri, Piero Anversa, Pietro Ghezzi, Monica Salio, Anthony Cerami, and Michael Brines Proc Natl Acad Sci USA 2003; 100: 4802-6
Carbamylated EPO (CEPO): EPO analog that does not bind to the dimeric EPO receptor and lack erythropoietic activity Histomorphometric evaluation of infarct size of Sham-operated rats and in coronary-ligated rats untreated or treated with CEPO Infarct size ( % LV ) 30 20 10 0 * * SHAM CEPO VEHICLE PNAS 2005; 102: 2046 51
Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial! A dose-escalation safety phase and a single dose (60 000 U of epoetin alfa) efficacy phase! 222 patients with STEMI who underwent successful percutaneous coronary intervention Main Outcome Measure: Infarct size, expressed as percentage of LV mass, assessed by CMR 2 to 6 days after study medication and again 12±2 weeks later Najjar SS et al.jama. 2011 May 11;305(18):1863-72.
REVEAL: a randomized controlled trial Comparison of Infarct Size Between Epoetin Alfa and Placebo Groups HOWEVER In the safety cohort, 5 patients who received epoetin alfa had an event (death, MI, stroke, or stent thrombosis) compared to none in the placebo group; P=.04. Subgroup analyses raised concerns about an increase in infarct size among older patients Najjar SS et al. JAMA 2011;305(18):1863-72.
Single high-dose erythropoietin administration immediately after reperfusion in patients with ST-segment elevation MI: Results of the Erythropoietin in Myocardial Infarction Trial! 110 patients with first STEMI undergoing primary coronary intervention! Randomization to standard care alone or intravenous administration of 1,000 U/kg of epoetin β immediately after reperfusion! Erythropoietin significantly decreased the incidence of MVO (43.4% vs 65.3% in the control group, P =.03) and reduced LV volume, mass, and function impairment at 5-day follow-up.! After 3 months, median infarct size, LV mass, volume and function were not different between the two groups Prunier F Am Heart J. 2012;163(2):200-7.e1.
Effect of erythropoiesis- sdmuladng agents in acute ST- segment elevadon myocardial infarcdon: a systemadc review Left ventricular ejection fraction nine RCTs involving 1,244 participants were identified Li J et al. Eur J Clin Pharmacol. 2012 May;68(5):469-77.
LVEF Subgroup WMD (95% CI, %) p Follow-up duration <3 months 0.92 ( 0.38 to 2.23) 0.17 >3 months 1.99 (0.47 3.52) 0.01* Time of first ESAs Immediately after PCI 1.25 ( 0.04 to 2.53) 0.06 Before or >4 h after PCI 2.22 ( 0.10 to 4.55) 0.06 First dosage of ESAs <20,000 IU 3.29 ( 2.19 to 8.76) 0.24 >20,000 IU 1.31 (0.30 2.32) 0.01* Total dosage of ESAs 30,000 IU 1.31 ( 0.66 to 3.28) 0.19 >30,000 IU 1.40 (0.25 2.54) 0.02* Li J et al. Eur J Clin Pharmacol. 2012 May;68(5):469-77.
SCR tipo 2 Cardiopatia cronica che determina danno o disfunzione renale
Randomized trials of darbepoetin alfa in symptomatic heart failure and anemia Pre-specified pooled-analysis Ghali JK et al. Circulation 2008 N = 319 van Veldhuisen DJ et al. Eur Heart J 2007 N = 165 Composite outcome of death or hospitalization for CHF Darbepoetin α: 39 of 266 (15%) Placebo: 46 of 209 (22%) HR 0.67, 95% CI 0.44 1.03, p=0.06 in the darbepoetin treated patients
Erythropoietin as a treatment of anemia in heart failure: Systematic review of randomized trials 11 RCTs with 794 parfcipants comparing any ESA with control over 2 to 12 months of FU Heart failure hospitalizations All-cause mortality Favors ESA Favors control Favors ESA Favors control Kotecha D et al. Am Heart J. 2011 May;161(5):822-831.e2
Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency Anker SD et al. December 17, 2009 459 patients with:! chronic heart failure NYHA II- III! left ventricular ejection fraction 40% (class II) or 45 (class III)! ferritin <100 µg/l or 100-299 µg/l if TSAT < 20%! Hb 9,5-13,5 g/dl 2:1 ratio FCM 200 mg IV Placebo
Ferric Carboxymaltose in Heart Failure and Iron Deficiency Self-reported patient global assessment at week 24 Ferric carboxymaltose Placebo Better Worse Anker SD et al. N Engl J Med 2009; 361:2436-48
Ferric Carboxymaltose in Heart Failure and Iron Deficiency NYHA functional class at week 24 Ferric carboxymaltose Placebo Better Worse Anker SD et al. N Engl J Med 2009; 361:2436-48
Riassunto e conclusioni! Nei pazienti con sindrome cardio-renale l anemia è un fattore prognostico negativo! L eritropoietina ha degli effetti pleiotropici positivi post-ima in studi sperimentali! I risultati degli studi clinici di fase II sono controversi! Nei pazienti con scompenso cardiaco cronico la terapia dell anemia con eritropoietina o ferro sembra dare risultati favorevoli Grazie per l attenzione