Alberto Martínez-Castelao Bellvitge´s Univ. Hospital. IDIBELL. Hospitalet. Barcelona President of the S.E.N.
IS ANAEMIA STILL
A CARDIO-VASCULAR
RISK FACTOR
IN 2012 ?
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESASs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
Anemia & hospitalization predialisis
Tiempo libre de estancia hospitalaria
13,3
21,5
0
5
10
15
20
25
< 9,9 g/dl > 9,9 g/dl
meses
• Independent predictors for hospitalization in CKD predialysis
patients:
• Advanced age
• CV disease
• Anemia
ANEMIA AS AN INDEPENDENT PREDICTOR OF
PERIOPERATIVE & LONG-TERM CV OUTCOME IN
PATIENTS SCHEDULED FOR ELECTIVE VASCULAR
SURGERY. Dunkelfgrun M et al. Am J Cardiol 2008;101(8):1196-200
• N= 1211 p , average 68 y.old
• Anemia was present in 399 p (33%)
– 133 mild
– 133 moderate
– 133 severe
30-days MACE* HR 5-y MACE HR
mild 1.8 2.4
moderate 2.3 3.6
severe 4.7 6.1
MACE= major Adverse CV Event
Anemia development & CV risk management in
non-anaemic Stage 3 CKD patients. NADIR-3
study. Portolés JM et al. Renal Fail 2009; 31(10): 869-75
Remain
non-anemic n=242
Developed
anemia n=102
Statistical
significance
Mortality 6,6 % 10,3 < 0,005
Hospitalization
annual rate
16,1 % 31,4 < 0,001
Major CV events 7,2 16,4 < 0,01
Δ MDRD (mL/min/3
years)
-1,6 6,8 < 0,001
Reached CKD 4-5 32,8 % 74,3 <0.001
K-M survival per Hb level (inicial Hb >12; 11-12; 10-11; <10)
Supervivencia desde inicio seguimiento
14121086420
1,0
,9
,8
,7
,6
Hb Basal
> 12
11.1-12
10.1-11
< 10
1-Y survival : 0,76 vs 0,82 vs 0,89 vs 0,92
Log Rank=37.48
p<0.001
HAEMOGLOBIN LEVEL & MORBIMORTALITY
IN HAEMODIALYSIS PATIENTS : MAR Study.
Portolés et al. Nefrologia 2009 (n= 1710 HD p)
Mortality in incident haemodialysis patients: time-
dependent haemoglobin levels and ESA dose are
independent predictive factors in the ANSWER study.
Fort J et al. ANSWER study. Nephrol Dial Transplant.
2010;25(8):2702-10.
• Multicentre, observational, prospective, 24-mo.
study, which recruited Spanish incident
haemodialysis patients (N = 2310).
• For Hb = or < 10 gr/dl HR 1.36 (1.01-1.86)
• for 10-11 g/dl, 0.93 (0.68-1.26)
• for 12-13 g/dl 0.69 (0.49-0.97) for
• patients on sustained ESA doses of
• 4000 -16 000 IU/ week had better survival than
non-treated patients
HR 0.61 (0.41-0.90)
0.68 (0.49-0.94)
• No significant difference was found for doses of
• >16,000 IU/week 0.89 (0.63-1.28),
MORTALITY DECREASED WITH INCREASING Hb.
Fort et al. NDT 2010;25(8):2702-10
Higher Hb levels lower mortality
Survival decrease is assciated with Hb < 11 g/dL in
hemodialysis patients
Retrospective longitudinal study in 44.550 patients on hemodialysis (Fresenius Medical Care)
Ofsthun N y col. Kidney Int 2003;63:1908–1914
Follow-up days
80
% d
e s
urv
iva
l
180 0 30 60 80 120 150
100
90
Hb Hb ≥13,0 12,0 ≤ Hb < 13,0 11,0 ≤ Hb < 12,0 10,0 ≤ Hb < 11,0 9,0 ≤ Hb < 10,0 Hb < 9,0
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESASs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
Hb Cycling Parameters
Hb cycle
Hb excursion
excursion
amplitude excursion
duration
Epoetin (1000 U/wk) Hb (g/dL)
Fishbane & Berns 2005
4
6
8
10
12
14
16
0
2
4
6
8
10
12
14
16
18
20
Epoetin (1000 U/tx)
Hb
Month
1 2 3 4 5 6 7 8 9 10 11 12
Disordered cardiac growth signals effects on cardiac
estructure and function
New patients
≥12,0 g/dL
11,0-11,9 g/dL
10,0-10,9 g/dL
9,0-9,9 g/dL
< 9,0 g/dL
End of 1998
≥12,0 g/dL
11,0-11,9 g/dL
< 9,0 g/dL
Hb variability over time is very frequent in individual patients on Haemodialysis
Hb fluctuations in a cohort of United Kingdom Haemodilaysis
patients
Start of 1998
10,0-10,9 g/dL
9,0-9,9 g/dL
Pati
en
ts (
%)
UK Renal Registry Report 1999, www.renalreg.com
0
20
40
60
80
100
Hb level
• N= 420 p. On Hemodialysis.
• 61 y old, (63% m)
• 222 with EPO α or β
• 198 with Darbep. α
• 4654 Hb determinations.
• Only 3,8 % maintained Hb 11-13 gr/dl for 1 y.
• Variability factors:
– Short-acting EPO
– EPO doses change
– High EPO Resistivity Index
– Hospitalization
Factors involved in Hb variability
Comorbidities Intercurrent
effects
Hb variability
Clínical practice
Chronic inflammation
Secondary HPT
Iron status
Nutritional status
haematologic alterations
Red cell Life span
Infections
Acute inflammation
Hospitalizations
Bleding / hemolysis
Pure red cell aplasia
Medications
Interdialytic weight gain
Dialysis modality
Hb determination
Hb variability technique
Dialyis adequacy
Anaemia protocol treatment
Breiterman-White R. Nephrol Nurs J 2006;33:319–324; Breiterman-White R. Nephrol Nurs J 2005;32:549–552; Messana T. Nephrol Nurs J 2006;33:209–215; Lacson E. Am J Kidney Dis 2003;41:111–124
Impact of Time With Hb <11 g/dL Mortality Risk
Hazard ratio
Time with Hb <11 g/dL (%) Ofsthun et al. EDTA 2005
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
1-20 21-40 41-60 61-80 81-100
All patients (n=41,919)
Cardiac patients (n=14,631)
* P<0.05 vs reference
** P<0.001 vs reference
**
**
**
*
*
Non-cardiac patients (n=27,288)
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESAs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
“r-HuEPO has been the most important innovative advance introduced in the treatment of chronic kidney disease patients in hemodialysis, 36 years ago” Eschbach New Engl J Med vol 339: 625-627, 1998
THERAPEUTIC POTENTIAL OF EPO IN
CV DISEASE: ERYTHROPOIESIS &
BEYOND
• EPO
– detected in the CV system
– Protective effects on the heart during AMI
– Improves cardiac function in experimental CHF
– Acute protection through reduction of apoptotic cell death
– Myocardial neovascurization
Westenbrink BD et al. Curr heart Fail Rep 2007; 4(3): 127-33
EPO FOR CV PROTECTION
• EPO stimulates normal progenitor cell-mediated endothelial turnover
• Neovascularization only in presence of local ischemia
Westem¡nbrink BD et al Cardiovasc Drugs Tjer 008; 22(4): 265-74
EFFECT OF CENTRALLY ADMINISTERED EPO
IN CV & RESPIRATORY SYSTEM OF
ANAESTHETIZED RATS
• EPO doses of 0,06;0,12;0,25 & 0,5 IU intracerebroventricularly.
• increase BP
heart rate
respiratory rate
tidal volume
minute ventilation
• EPO 0,5 IU i.v. no effects
• --> a central mechanism of action is suggested
• central regulation of CR system as a neuromodulator
• neuromediator
Yalcin M et al. Auton Neurosci 2007; 134(11-2):1-7
ESAs for ANAEMIA in CHF • Anaemia in CHF is frequent 12-55% m worsening symptoms &
increasing mortality
• Cochrane Central Register CT, MEDLINE & EMBASR till 2008
• 11 studies, n= 794 ESAs treated patients.
Exercise dur + 96,8 sec 0.04
6-m walking distance + 69,3 m 0.009
Peak VO2 + 2,29 ml/kbw/min 0.007
Ejection fract + 5,8 % 0,.001
BNP - 226 ug/ml 0,001
NYHA class - 0,73 0.001
Hospitalisations - RR 0,62
Mortality - RR 0,61
Ngo K et AL. Cochrane Database Syst Rev 2010; Jan 20(1): cd007613
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESASs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
Primary Outcome: time to non fatal MI or death:
HR: 1,3 (IC 95%, 0,9-1,9)
Besarab st: hemoglobin levels & Primary Outcome
Normal Hte Group (43%): 183 deaths, 19 non fatal MI
Low Hte group (30%): 150 deaths, 14 non fatal MI
Besarab A y col N Engl J Med 1998;339:594-590
Hem
ato
crito
(%
)
Pro
ba
bili
dad d
e m
ue
rte o
in
fart
o
de
mio
ca
rdio
(%
) High Hb
High Hb
Standard Hb Standard Hb
Meses Meses
CREATE: Hb level & Primary Outcome
Primary Outcome: time to first CV event HR : 0,78 (0,53; 1,14; p = 0,20)
Hem
oglo
bin
a (
g/d
L)
58 events (high hemoglobin) vs 47 events (standard hemoglobin)
Hb, hemoglobina; CV, cardiovascular
Drüeke TB y col. N Eng J Med 2006;355:2071-2084
standar High Hb
stándar
Hb
Months Months
Su
pe
rviv
en
cia
CREATE, CHOIR & Besarab studies differences
CREATE1 CHOIR2 Besarab3
Hb target (g/dL) Low Hb 10,5 = 11,5
High Hb 13 = 15
Low Hb 11,3
High Hb 13,5
Low Hb ~10
High Hb ~14
Hb reached (g/dL) 11,6 11,6 10,1 10,1 10,2 10,2
GFR(ml/min/1,73m2) 24,2 24,9 27,3 27,0 - -
Age 58,8 59,3 66,3 66,0 64 65
CKD due to DM 21% 20% 51% 47% 46% 42%
CKD due to HyT 19% 23% 28% 30% 27% 28%
Hb (g/dL) 11,5 13,5 ~ 11,3 12,6 ~ 10,5 ~ 13,5
EPO doses (U/sem) 2000 5000 6276 11215 146* 153*
*(U/kg/semana) 1. Drueke TB y col. N Eng J Med 2006; 355:2071-2084
2. Singh Ak y col. N Eng J Med 2006; 355:2085-2098
3. Besarak y col. N Eng j Med 1998; 339:584-590
KDOQI Metanalysis: Target Hb value & CV events
HR for CV events with High Hb levels
CKD not on dialysis CKD on Dialysis
KDOQI™ Work Group. Am J Kidney Dis 2007;50(3):471-530
Estudio Año
TOTAL
Total
Estudio Año
HR IC 95% HR IC 95%
Favourirs treatment Favors control
Favors control Favors treatment
KDOQI Metanalysis Hb target & risk of Mortality
Mortality HR & Hb target
CKD patients not on dialysis CKD patients on dialysis
Estudio Año Estudio Año
Total
Total
Relación de riesgo IC 95% Relación de riesgo IC 95%
Favours treatment
Favours treatment Favours control
Favours control
KDOQI™ Work Group. Am J Kidney Dis 2007;50(3):471-530
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESASs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
N= 4038 type-2 DM p.
2012 random. Darbep-α Hb 13 gr/dl
2026 rand. “placebo” with rescue when Hb<9gr/dl
TREAT study results overview
• Mean Hb level 10,4 gr/dl
• Hb achieved levels in darbe 12 -12,8 “
• Hb “ “ placebo 9,9 -11,3 “
• Red cell transfusions 14,8 vs 24,5%
• CV events 31,4 vs HR 1.05
• Stroke 5 % vs 2,6% HR 1.92
• Cancer deaths 39 vs 25 p= 0.08
• Death in malignant cond
at base-line 60 vs 37
due to cancer 14 vs 1 p= 0.02
Pfeffer MA et al N Engl J Med 2009;361:2019-32
STROKE IN PATIENTS WITH TYPE-2
DM, CKD & ANEMIA TREATED WITH
DARBEPOETIN : THE TREAT STUDY
• N= 4038 p
• Post random BP, Hb level, platelet c, ESA dose nested case-control analysis 1:10 matching vs non-stroke controls
• Stroke in 154 p 101/2012 darbep
53 /2026 controls
Independent predictors of stroke: Hb , darbe dose, SBP, DBP, platelet c, did not differ between those with/without stroke
Skali H et al. Circulation 2011>; 124 (25): 2903-08
PREDICTORS OF FATAL & NON FATAL CV
EVENTS IN THE TREAT St. A post hoc TREAT
analysis.
• Independent predictors of CV events/death in
• n= 3847 p
McMurray JJ et al. Am Heart J 2012; 162(4):748-55
HR
Prior HF 1.74
Age 1.03
Ur Prot/creat ratio 1.19
C-React-Protein 1.44
Abnormal EKG 1.42
N-term ProBNP 1.30
Troponin T 1.20
RELATIONSHIP BETWEEN EPO RESISTANCE
INDEX, LVH & FUNCTION & CV EVENTS IN
PATIENTS ON CHRONIC HAEMODIALYSIS
• N= 72 HD patients, EPO resistant Index by tertiles.
• Frequency of CV events was higher in high ERI tertiles HR 3.00, p =0.042
• Independent predictors for CV events:
LVMass
LV systolic function
Identify ERI to predict CV risk
Chung et al Hemodial Int 2011; nov 22, doi º10.1111/j.1542-
High Hb levels & increased CV co-morbidity.
Mechanisms of Vascular damage
Blood viscosity
Shear stress
Endothelial dysfnction
Atheromatosis
Increased CV risk
i.v. Iron
Oxidative stres
Endothelial dysfunction
Post HD
haemoconcentration
Blood Pressure
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESASs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
McFarlane PE et al. Kidney Int 2010; 78:215-23
EUROPEAN MEDICINES AGENCY 18 May 2010
Special General Warnings & Precautions:
• In patients with CKD maintenance Hb should not exceed the upper limit of 12 gr/dl.
• An increase in death, serious CV events, stroke & vascular access thromobosis has been observed with Hb> 12 gr/dl
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESASs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
Individualization
OUTLINE
1. Anaemia is a CV & mortality risk factor
2. Hb variability
3. Anaemia treatment with ESASs
4. Studies showing increased CV risk: Besarab, CHOIR, CREATE.
5. The revolution: TREAT study
6. Guidelines recommendations
7. KDIGO 2012
8. European Medicines Agency: Pharmacovigilance Working Party questions
Pharmacovigilance Working Party (PhVWP)
Questions to Healthcare Professionals
Organisations in the area of Nephrology
• According to your clinical experiences, do you target different haemoglobin levels for patients on dialysis and not on dialysis when using erythropoiesis-stimulating agents?
• In respect thereof, do you differ between diabetic and non-diabetic patients?
• Is there a specific subset of patients for which higher/ lower levels of Hb might be required?
• Given the evidence available, do you consider that there is a need to further strengthening the current SmPC recommendation for the use of ESA in patients with chronic kidney disease?
EUROPEAN MEDICINES AGENCY 3 April 2012
Pharmacovigilance Working Party (PhVWP) –
Questions to Healthcare Professionals
Organisations in the area of Nephrology
• Do you consider that the changes in the dosing regimen recommended by the FDA are appropriate to minimise the cardio- and cerebrovascular risks?
• Do you consider that the dosing regimen recommended by the FDA is acceptable considering the impact of anaemia on the cardiovascular risk and the quality of life of CKD patients?
• Could you advise whether, and if yes, which additional measures should be implemented to minimise the cardiovascular and cerebrovascular risks or to increase the benefits in ESA-treated CKD patients?
• Do you think that the introduction of routine parenteral iron therapy in chronic kidney disease patients in recent years might have an influence on the risk of cardiovascular morbidity and death?
EUROPEAN MEDICIENS AGENCY 3 April 2012
Epo for anaemic patients , not for promote
policitemya!!!
Alberto Martínez-Castelao Belvitge´s Univ. Hospital. IDIBELL. Hospitalet. Barcelona President of the S.E.N.
IS ANAEMIA STILL
A CARDIO-VASCULAR
RISK FACTOR
IN 2012 ?