EPO e Ferro in Emodialisi: Il PBM al suo esordio
Lucia Del Vecchio
Divisione di Nefrologia e DialisiOspedale A. Manzoni, ASST Lecco
PATIENT BLOOD MANAGEMENT DALLA TEORIA ALLA PRATICA16 FEBBRAIO 2018
Perché i malati con CKD sviluppano anemia?
• Primary cause– Low erythropoietin production
• Secondary cause– Iron deficiency– Hyperparathyroidism– Chronic inflammation– Infection– Nutritional deficiency– Bleeding
Anemia Worsens as Kidney Function Declines
Hb = hemoglobin Adapted from Kausz AT, et al. Dis Manage Health Outcomes. 2002;10:505-513.
14% 20%43%
62%
5%8%
8%
15%
9%
17%
15%
10%
0%10%20%30%40%50%60%70%80%90%
100%
< 2 2.0–2.9 3.0–3.9 ≥ 4
Prev
alen
ce o
f Ane
mia
(%)
Serum Creatinine Level (mg/dL)
Hb = 11–12 g/dL (n = 181)Hb = 10–11 g/dL (n = 105)Hb < 10 g/dL (n = 315)
Hb Levels
Anemia treatment in CKD patientsESAIron
Both
Blood transfusions
Lawler ev et al Clin J Am Soc Nephrol 5: 667–672, 2010.
Transfusion rates by Hb level according to thetreatment status
• 97,636 patients with CKD not on dialysis and anemia• Retrospective analysis between 2002 and 2007
< 7 7-7.9 8-8.9 9-9.9 10-10.9 11-11.9 12+
Prob
abili
ty o
f tra
nsfu
sion
(%)
Hemoglobin (g/dl)
0
10
20
30
40
50
60
70 No therapyIron
ESA
ESA + Iron
The 'lucky 13' first chronic haemodialysis patientsRoyal Free Hospital, January 1st 1965
The early times of dialysisLocatelli F, Del Vecchio L. Am J Nephrol 2010;31(6):557-60
http://renux.dmed.ed.ac.uk/EdREN/Unitbits/historyweb/HomeHD.html
Early ninetiesrHuEPO become available in everyday clinical practice
Label indication: “Treatment of anemia associated with chronic renal
failure, including patients on dialysis (end stage renal disease) and
patients not on dialysis.”
Volume 328, Issue 8517, 22 November 1986, Pages 1175-1178
EFFECT OF HUMAN ERYTHROPOIETIN DERIVED FROM RECOMBINANT DNA ON THE ANAEMIA OF PATIENTS MAINTAINED BY CHRONIC HAEMODIALYSIS
Winearls CG et al.
ABSTRACT
Fattore di rischio ?Marker di comorbidità?
P=0.06
1.22
P=0.84
1.02
Ref
1
P=0.45
0.9
RR overall = 0.94 per1g/dl higher Hb
Relative Risk of Death
1.4
1.2
1.0
0.8
0.6
RR
< 10 >1211-11.910-10.9N = 1671 N = 947 N = 763 N = 639
Haemoglobin (g/dl) at study entry
Mortality and hospitalisation risks and anemia
Locatelli et al. Nephrol Dial Transplant 2004; 19: 108-120
Hemoglobin target and ESA
The higher the better?
Complete anemia correction did not give
the awaited results
Probability of death or first non - fatal myocardial infarction
Normal versus low haematocrit
0 3 6 9 12 15 18 21 24 27 300
10
20
30
40
50
60
Months after randomization
Prim
ary
end
poin
ts %
Besarab A et al. N Engl J Med 1998 ; 339 : 584 - 90
Hct 42 % Age 65 ± 12
Hct 30 % Age 64 ± 12
N = 1233
Clinical evidence of congestive heart failure or ischemic heart disease
Pfeffer MA et al. N Engl J Med 2009; 361:2019-32
The TREAT StudyCardiovascular composite end point (ITT)
Months since randomization
Placebo
Hazard ratio, 1.05 (95% CI, 0.94 – 1.17)P = 0.41 Darbepoetin alfa
Patie
nts
with
eve
nts
(%)
0 6 12 18 24 30 36 42 480
10
20
30
40
50
4,044 pts with type 2 diabetes, eGFR 20-60 mL/min/1.73 m2), and Hb< 11 g/dL
http://www.google.it/imgres?imgurl=http://cdn.everyjoe.com/files/2009/03/1006530_broken_glass.jpg&imgrefurl=http://everyjoe.com/sports/former-nfl-player-komlo-killed-in-crash/&usg=__5pe-DhQuEGkkBUu_O6oBkGY2tag=&h=300&w=225&sz=28&hl=it&start=16&zoom=1&um=1&itbs=1&tbnid=k8yG6oET0hdHIM:&tbnh=116&tbnw=87&prev=/images?q=broken+glass&um=1&hl=it&tbm=isch&ei=UpOlTdvZLofUsgan-YmsBw
Pfeffer MA et al. N Engl J Med 2009; 361:2019-32
The TREAT Study: Secondary end-points
Fatal or non fatal stroke
Placebo
Hazard ratio, 1.92 (95% CI, 1.38 – 2.68)P < 0.001
Darbepo. alfa
Placebo: 53/2026 (2.6%), 1.1 per 100 patient-years
Darbepoetin alfa: 101/2012 (5.0%), 2.1% per 100 patient-years
Pfeffer MA et al. N Engl J Med 2009; 361:2019-32
Morte per tutte le cause (P=0.13 al log-rank test)
Darbepoetina alfa Placebo60 su 188 (31.9%) 37 su 160 (23.1%)
Sottogruppo: 348 pazienti con storia di pregressa neoplasia
Criteri di esclusione:Pazienti con neoplasia attiva (eccetto basalioma o Ca spinocellulare localizzato)
Morte per neoplasia (P=0.002 al log-rank test)
Darbepoetina alfa Placebo14 su 188 (7.4%) 1 su 160 (0.06%)
Popolazione globale: 20.5% Popolazione globale : 19.5%
Lo studio TREATAnalisi secondaria sulle neoplasie
KDIGO CLINICAL PRACTICE GUIDELINE
FOR ANEMIA IN CKD
- ESA- Hb
+FERROTRASFUSIONI
USE OF ESAs AND OTHER AGENTS TO TREAT ANEMIA IN CKD
KDIGO CLINICAL PRACTICE GUIDELINE FOR ANEMIA IN CKD
In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (2C)
8.00 9.00 10.0 11.0 12.0 13.0Hb g/dl
11.5
ESA MAINTENANCE THERAPY
The ERBP position statement about KDIGO guidelines on anaemia
ESA MAINTENANCE THERAPY
Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, Hörl W, London G, Vanholder R, Van Biesen W; ERA-EDTA ERBP Advisory Board Nephrol Dial Transplant. 2013 Jun;28(6):1346-59.
8.00 9.00 10.0 11.0 12.0 13.0Hb g/dl
12 10
Da 6,2% a 18.8%
22%
64%
63%%
Grande spinta alla terapia marziale ……
TREAT Study
The ERBP position statement about KDIGO guidelines on anaemia management in chronic kidney disease
There is absolute iron deficiency (TSAT < 20% and serum ferritin < 100 ng/ml)
ORAn increase in Hb concentration or a decrease in ESA dose are desired
ANDTSAT is < 25% (
Intervention arms:Optimal → 100-200 mg IV iron per week Suboptimal → < 100 mg per week
IV iron and ESA in haemodialysis:A systematic review and meta-analysis
Of the 28 RCTs identified, 7 met the criteria for inclusion
Roger SD et al. Nephrology (Carlton). 2016 Oct 3
-23% OVERALLrange -7% to -55%
Weighted average percentage reduction in ESA dose/week
Available et: http://www.dopps.org/DPM/
40% con ferritina ≥ 800 ng/ml
50% con ferritina ≥ 800 ng/ml
Hazard ratio (95% CI) of mortality across the ferritin categories using time-averaged cox regression analyses in MHD patients without polycystic kidney disease.
Iron indices and survival in maintenance HD patients with and without polycystic kidney disease
Hatamizadeh P et al. Nephrol Dial Transplant 2013; 28(11): 2889–2898
2969 MHD patients with and 128 054 without PKD from 580 outpatient HD facilities between July 2001 and June 2006.
Ferritin (ng/ml) categories
HR
of a
ll-ca
use
mor
talit
y
Associations between IV iron dose and clinical outcomes in 32,435 HD patients in 12 countries from 2002 to 2011 in the DOPPS Study
HR 1.1395% CI 1.00–1.27
HR 1.1895% CI 1.07–1.30
All-cause mortality
Average montly IV iron dose (mg/month)
Haza
rdra
tio (9
5% C
I)
Kidney Int 2015 Jan;87(1):162-8
IV iron therapy
Traditional iron molecules
Parenteral Iron TherapyTraditional molecules
HMV iron dextranLMV iron dextran
Iron sucroseIron gluconate
Hypersensitivity reactionsNeed of resuscitation Team and medications
HypotensionLow dosesRepeated administration
New iron molecules
Ferric carboxymaltose
Ferumoxytol
Iron Isomaltoside
Possible advantages:No free ironLarge dose, rapid infusionLower number of administrations
Ferric carboxymaltose
Good safety
IN DIALISI DOSE MASSIMA DA SCHEDA TECNICA 200 MG
Ferric hydroxide molecules
Ribbon-like carboxymaltose
Onken JE et al. Nephrol Dial Transplant 2013 Aug 20. [Epub ahead of print]
2584 ND-CKD patients
FCM 750 mg2 doses in one week
Iron sucrose 200 mgup to five inf. in 14 days
Primary efficacy endpoint
Mean change to highest Hb from baseline to Day 56
All-cause mortality, nonfatal MI, nonfatal stroke, unstable angina, CHF, arrhythmias and hyper- and hypotensive events
Primary composite safety endpoint
The REPAIR-IDA trialProportion of subjects with an increase in Hb ≥1.0 g/dL between baseline and Day
56 or time of intervention (modified intent-to-treat population)
FCM (n = 1249)607/1249 (48.60%)
Iron sucrose (n = 1244)510/1244 (41.00%)
7.60% (3.63 to 11.57%)
Treatment difference (95% CI)
Onken JE et al. Nephrol Dial Transplant. 2014 Apr;29(4):833-42
Onken JE et al. Nephrol Dial Transplant. 2014 Apr;29(4):833-42
The REPAIR-IDA trialComponents of the primary composite safety endpoint (safety population)
Troppo basso a volte non funziona!!
Grazie per l’attenzione
Diapositiva numero 1Perché i malati con CKD sviluppano anemia?Anemia Worsens as Kidney Function DeclinesDiapositiva numero 4Diapositiva numero 5Diapositiva numero 6Diapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14Diapositiva numero 15Diapositiva numero 16Diapositiva numero 17Diapositiva numero 18Diapositiva numero 19Diapositiva numero 20Diapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Diapositiva numero 25Diapositiva numero 26Diapositiva numero 27Diapositiva numero 28Diapositiva numero 29Diapositiva numero 30Diapositiva numero 31Diapositiva numero 32Diapositiva numero 33Diapositiva numero 34Diapositiva numero 35Diapositiva numero 36
