alberto martínez-castelao bellvitge s univ. hospital ... · alberto martínez-castelao...

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).

http://www.ncbi.nlm.nih.gov/pubmed?term=Fort%20J%5BAuthor%5D&cauthor=true&cauthor_uid=20176608

http://www.ncbi.nlm.nih.gov/pubmed?term=ANSWER%20study%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2174515&query_hl=13&itool=pubmed_DocSum

• 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


2. Hb variability





7. KDIGO 2012


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


2. Hb variability

3. Anaemia treatment with ESAs




7. KDIGO 2012


“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


2. Hb variability





7. KDIGO 2012


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


2. Hb variability





7. KDIGO 2012


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


2. Hb variability





7. KDIGO 2012


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


2. Hb variability





7. KDIGO 2012


Individualization

OUTLINE


2. Hb variability





7. KDIGO 2012


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 ?

alberto martínez-castelao bellvitge s univ. hospital ... · alberto martínez-castelao...

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