Francesco Locatelli Department of Nephrology, Dialysis and Renal - - PowerPoint PPT Presentation

Cagliari, April 30-May 3, 2011

Francesco Locatelli

Department of Nephrology, Dialysis and Renal Transpant

• Alessandro Manzoni

Hospital, Lecco, Italy INTERNATIONAL Renal Meeting and Mayo Clinic Day in Sardinia

DEBATE

• The TREAT study has turned the world of

anemia upside down

Singh AK. J Am Soc Nephrol 2010; 21: 2-6

Hb Targets should be changed

Pro (Dr. Singh): Hb targets should be changed because:

• 1. Hb is not a reliable surrogate marker. Targeting higher Hb

is harmful as seen in TREAT/CHOIR/CREATE/Besarab study

• 2. Observational cohorts suggest toxicity in high dosages of

ESA used and

• 3. Other adverse outcomes seen in non-renal populations (i.e.
• ncology).

Recommendation: Hb target should be < 9 g/dL. Avoid ESAs in CKD patients not undergoin dialysis. Tailoring Hb for each individual target clinical goal.

Singh AK. Am J Nephrol. 2010 May 21;31(6):552-556.

Hb Targets should NOT be changed

1. Heterogeneity in populations may influence results seen in these higher targeted Hb studies. 2. High ESA dose is not correlated with toxicity (ESA dose is related to the inflammatory state which correlates with severity and cormorbidity of the patients instead) 3. TREAT data should not have changed our practice as study is not powered to study stroke (as a secondary endpoint) and that there are study design issues with TREAT (e.g. use

• f Darb in placebo arm, inclusion of iron deficient patients

etc.).

Locatelli F and Del Vecchio L. Am J Nephrol. 2010 May 21;31(6):557-560.

Hb Targets should NOT be changed

Recommendation:

• 1. Hb target for CKD population should be maintained

at 11-12 g/dL , while caution in patients with CKD with Type 2 diabetes not undergoing dialysis, history

• f stroke &/or malignancies.
• 2. Transfusion avoidance is important
• 3. Maximum dose of iron should be determined with

ESA dose. Caution for hyporesponsive patients on dose of ESA used.

Locatelli F and Del Vecchio L. Am J Nephrol. 2010 May 21;31(6):557-560

Time to the Primary End Point of a First Cardiovascular Event

Drueke T, Locatelli F et al, N Engl J Med 2006

Hb 13-15 Hb 10.5-11.5 Group 1: 58 events (2%) Group 2: 47 events (1.5%) HR 0.78; 95% CI 0.53 to 1.14; P = 0.20

CREATE study: Hemoglobin levels over time

Control arm target Hb Drueke T, Locatelli F et al. N Engl J Med 2006; 355; n°20, 2071-84

Primary Composite End-Point

Singh et al, N Engl J Med 2006

Hb 13.5 Hb 11.3 Median FU of 16 months Group 1: 125 events (17%) Group 2: 97 events (13%) HR 1.34; 95% CI 1.03 to 1.74; P=0.03

The CHOIR Trial

1432 CKD patients not on dialysis; half of them were diabetics

N: 1432 CKD pts

CHOIR Study: an open label randomised study

Singh AK et al. N Engl J Med 2006; 355:2085- 98

Group 1 target: Hb 13.5 g/dl Group 2 target: Hb 11.3 g/dl Median study duration: 16 months

Pfeffer MA et al. N Engl J Med 2009; 361:2019-32

The TREAT Study

Cardiovascular composite end point (ITT)

Months since randomization Placebo

Hazard ratio, 1.05 (95% CI, 0.94 1.17) P = 0.41

Darbepoetin alfa Patients with events (%)

6 12 18 24 30 36 42 48 10 20 30 40 50

Composite and Component End Points

Locatelli, Del Vecchio, Casartelli N ENGL MED 362; 7 Feb 18, 2010

Should we stop treating our patients?

Locatelli, Del Vecchio, Casartelli N ENGL MED 362; 7 Feb 18, 2010

Nearly half these patients received darbepoetin alfa; this cannot be considered true placebo Given that the mean achieved hemoglobin level in the control group (10.6g per deciliter) there is no evidence that we should stop treating anemia

TREAT : mean haemoglobin levels

• ver 48 months

Pfeffer MA et al. N Engl J Med 2009; 361(21):2019-32

9 g/dl 10.6 g/dl 12.5 g/dl Guidelines

Complete anemia correction in CKD patients not receiving HD

Comparison of event rates and HR on primary end-points TREAT CREATE CHOIR

• The TREAT placebo results would seem to suggest that at least some

patients with mild anemia in CKD may only temporarily require ESA treatmetn as the severity of their anemia may improve but definitely varies over time.

Intraindividual variability in Hb levels in 3143 CKD with no ESA use

Hb change (%)

All consecutive Hb change 5 g/L 25.1% Consecutive Hb decrease >5 g/L 19.9 % Consecutive Hb increase >5 g/L 24.1 % Both consecutive Hb decrease and increase >5 g/L 30.9 %

A minimum of 18 months of potential follow-up Boudville NC et al. Clin J Am Soc Nephrol 2009; 4(7): 1176-82

TREAT study:

..any further comments?

CJASN ePress. Published on January 6, 2011

Darbepoetin Alfa Impact On Health Status In Diabetes Patients With Kidney Disease: A Randomized Trial

Lewis EF Locatelli F. et al. for the TREAT Investigators

Clinically meaningful improvement in FACT-Fatigue scores

A higher score is associated with less fatigue Lewis EFLocatelli F. et al. Clin J Am Soc Nephrol 2011; Jan 6. [Epub ahead of print]

The TREAT Trial

* * * * * P < 0.05

Placebo Darbepoetin

Week 13 Week 25 Week 49 Week 73 Week 97 10 20 30 40 50 60 % pts wtih 3 point improvement

Treat the patient as an individual,

• r

treat in line with the latest empirical study

TREAT Versus Treatment: A Patient s View of a Scientific Interpretation

Prisant A. American Journal of Kidney Diseases, Vol 55, No 3 (March), 2010

• I feel that it is relevant to consider studies like

TREAT from the patient s view, particularly in conditions like anemia which can impact patients well-being independent of hard

• utcomes such as incident-free longevity

TREAT Versus Treatment: A Patient s View of a Scientific Interpretation

Prisant A. American Journal of Kidney Diseases, Vol 55, No 3 (March), 2010

Am J Kidney Dis 2010 Mar;55(3):A31-2.

Prisant A.

TREAT Versus Treatment: A Patient's View of a Scientific Interpretation All individual patients would not weigh the risks and benefits and do not arrive at the same risk-benefit calculation Quality-of-life should be considered along with more classic hard clinical end- points such as those studied in TREAT, to inform physician and policy- making guidelines and facilitate informed patient consent.

Quality of life

F.Locatelli et al.Nephrol Dial Transplant 2009; 24(2):348-54

The position of ERBP

The available quality of life data vary in quality and are often inconclusive More reliable methods of assessing patient-related outcomes and functional status are now available There is room for new studies testing the effect of anaemia correction

• n more robust measures of the quality of life

Revised European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure

Volume 19 ( May 2004 ) Supplement 2

Nephrology Dialysis Transplantation

Official Publication of the European Renal Association European Dialysis and Transplantation Association

ISSN 0931 - 0509

Produced by Francesco Locatelli, Chairman (Italy) Pedro Alijama (Spain) Peter Barany (Sweden) Bernard Canaud (France) Fernando Carrera (Portugal) Kai-Uwe Eckardt (Germany) Walter H. Hörl (Austria) Ian C. Macdougall (UK) Alison Macleod (UK) Ardrzej Wiecek (Poland) Stewart Cameron, Chairman Emeritus (UK)

European Best Practice Guidelines

Recommendation

The optimal target Hb concentration may vary in patients with co-morbidity or non-standard causes of renal failure

Locatelli et al. Nephrol Dial Transpl 2004; 19, suppl 2

• Hb > 11 -12 g / dl are not recommended for patients with severe

cardiovascular disease (class II of NYHA classification) unless continuing severe symptoms dictate otherwise

• Until data become available, patients with diabetes should be

maintained at a Hb of 11-12 g/dl

• Patients with chronic hypoxaemic pulmonary disease
• Patients with sickle celle disease (homozygotes) -> Hb of 7-9 g/dl

2006 May; 47(5 Suppl 3):S11-145

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease

WORK GROUP MEMBERSHIP

Work Group Co-Chairs David B. VanWyck, Kai-Uwe Eckardt Work Group

• JohnW. Adamson, Jeffrey S. Berns, Steven Fishbane, Robert N. Foley,

Sana Ghaddar, John S. Gill, Kathy Jabs, Patricia Bargo McCarley, Allen

• R. Nissenson, Gregorio T. Obrador, John C. Stivelman, Colin T. White

Liaison Members Francesco Locatelli, Iain C. Macdougall

2007 Sept; Vol 50 (3):474-530

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease

WORK GROUP MEMBERSHIP

Work Group Co-Chairs David B. VanWyck, Kai-Uwe Eckardt Work Group

• JohnW. Adamson, Jeffrey S. Berns, Steven Fishbane, Robert N. Foley,

Sana Ghaddar, John S. Gill, Kathy Jabs, Patricia Bargo McCarley, Allen

• R. Nissenson, Gregorio T. Obrador, John C. Stivelman, Colin T. White

Liaison Members Francesco Locatelli, Iain C. Macdougall

• In the opinion of the Work Group, in dialysis and nondialysis patients

with CKD receiving ESA therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dL

• In dialysis and nondialysis patients with CKD receiving ESA therapy,

the Hb target should not be greater than 13.0 g/dL.

• MODERATELY STRONG EVIDENCE

KIDNEY DISEASE GLOBAL OUTCOMES

Locatelli F et al. Kidney Int 2008 Nov;74(10):1237- 40

The current evidence, based on mortality data, for hemoglobin target levels intentionally aimed with ESA treatment in CKD patients treated indicates that levels of 9.5 11.5 g/dl are associated with better outcomes compared with >13 g/dl Locatelli F et al. Kidney Int 2008 Nov;74(10):1237- 40

Kidney Disease: Improving Global Outcome (KDIGO)

Position statement on anemia

New evidences about Hb target will be available only after the completion of the TREAT study

Anaemia management in patients with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP)

Francesco Locatelli, Adrian Covic, Kai-Uwe Eckardt, Andrzej Wiecek, and Raymond Vanholder; On behalf of the ERA-EDTA ERBP Advisory Board

In the opinion of the ERBP Work Group, it appears reasonable to maintain the lower limit of the target, although the actual evidence for choosing this value is also very limited. On the basis of new evidence, Hb values of 11-12 g/dl should be generally sought in the CKD population without intentionally exceeding 13 g/dl.

Nephrol Dial Transplant. 2009 Feb; 24(2): 348-54

Targeted and achieved hemoglobin concentrations in landmark trials of erythropoiesis-stimulating agents in patients with kidney disease

Achieved hemoglobin g/dl Target hemoglobin g/dl Low High Low High NHT CREATE CHOIR TREAT 10 14 10.3 13.3 11-12.5 13-15 11.5 13.5 11.3 13.5 11.4 12.8 > 9* 13 10.6 12.5

Wolfang C. Winkelmayer Seminars in Dialysis Vol 23; 5; 486 491 2011

Where are we going?

Target haemoglobin to aim for with erythropoiesis stimulating agents: a position statement by ERBP following publication of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Study

Francesco Locatelli, Pedro Aljama, Bernard Canaud, Adrian Covic, Angel De Francisco, Iain C. Macdougall, Andrzej Wiecek, Raymond Vanholder and on behalf of the Anaemia Working Group of European Renal Best Practice (ERBP)

Broadly speaking, anaemia management consists of ESA therapy, iron supplementation and red cell transfusions. Avoidance of the latter is particularly important in patients eligible for renal transplantation where exacerbation of HLA sensitization should be avoided. Other potential hazards of blood transfusions are well known

Treatment of renal anaemia

Locatelli F. et al Nephrol Dial Transplant; 2010 Sep;25(9):2846-50

In patients with type 2 diabetes not undergoing dialysis (and probably in diabetics at all CKD stages), more caution is needed when treating anaemia with ESA therapy. In diabetic patients with a history of stroke, a lower target is more sensible (1012 g/dL), balancing the riskbenefit of treatment and the desired Hb target in the individual patient. It is also of paramount importance to involve the patient in the decision making, and seek their personal views after a discussion about the benefits/risks of treatment. On this respect, the patients

• pinion should be carefully taken into consideration.

Conclusions and guidance

Locatelli F. et al Nephrol Dial Transplant; 2010 Sep;25(9):2846-50

The TREAT Study reinforces the message of anaemia guidelines suggesting the importance of an integrated approach using iron and ESA therapy. It is still a matter of debate how much iron can safely be given to patients in

• rder to minimize the ESA dose and what the highest doses
• f IV iron and ESA are that can safely be administered for

reaching and maintaining a Hb target range

Treatment of renal anaemia

Locatelli F. et al Nephrol Dial Transplant; 2010 Sep;25(9):2846-50

NICE 2011 updates guidance on how to treat anaemia in people with chronic kidney disease

• In 2006, NICE advised healthcare professionals to

maintain the haemoglobin levels of their patients with CKD between 10.5 and 12.5 g/dl for adults, teenagers and children aged 2 and above

• Further studies have since been published which

indicate that having haemoglobin levels above 12 g/dl doesn't bring any additional clinical benefit and may even possibly cause some health risks

NICE 2011 updates guidance on how to treat anaemia in people with chronic kidney disease

• In response, NICE has updated these recommendations

and is now advising healthcare professionals treating anaemia of CKD with erythropoiesis stimulating agents to maintain the haemoglobin range between 10 and 12g/dl for adults, teenagers and children over two years

• NICE is also urging doctors to not wait until their patients'

haemoglobin levels are outside of these ranges before adjusting their treatments (e.g. they should act when their patient's haemoglobin levels are within 0.5 g/dl of the range's limit)

No safe target Hb levels, darbepoetin dosages, or dosing strategies had been established A substantial majority of the panel voted against recommending withdrawal of the labeled indication for darbepoetin for the treatment of anemia of CKD patients not on dialysis The current label calls for the lowest Hb target necessary to avoid transfusions within a Hb target range of 10 to 12 g/dl EDITORIALS

www.jasn.org

Against TREATing All Patients Alike: Lessons from an FDA Advisory Committee Meeting

Wolfgang C. Winkelmayer

J Am Soc Nephrol 22: 1 2, 2011.

Transfusion risk

as reported in large trials for anemia correction

Higher hemoglobin Lower hemoglobin

Besarab (1998; 1233 pts) 129 (21%)

192 (31%)

CREATE (2006; 603 pts)

26 (8.7%) 33 (10.9%)

TREAT (2009; 4038 pts)

297 (14.8%) 496 (24.5%)

CHOIR (2006; 1432 pts)

not available

• Epoetin alfa was approved in 1989 by the Food and

Drug Administration (FDA) for the treatment of anemia associated with chronic kidney disease to elevate or maintain the red blood cell level and to decrease the need for transfusions.

• Unger EF et al. N Engl J Med 2010; 362:189

92

The 'lucky 13' first chronic haemodialysis patients Royal Free Hospital, January 1st 1965

Never forget where we come from

Locatelli F, Del Vecchio L. Am J Nephrol 2010;31(6):557-60

The FDA calculated that for each five patients spared from transfusion, there was one additional stroke event Lowering the labeled Hb target range would inevitably increase the risk for transfusion and with it the risk for allosensitization for future kidney transplant candidates

Wolfgang C. Winkelmayer. J Am Soc Nephrol 22: 12, 2011

< 7 7-7.9 8-8.9 9-9.9 10-10.9 11-11.9 12+

Probability of transfusion(%) Hemoglobin (g/dl)

10 20 30 40 50 60 70 No therapy Iron ESA ESA + Iron Lawler ev et al Clin J Am Soc Nephrol 5: 667 672, 2010.

Transfusion rates by Hb level according to the treatment status

Original Article

Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes

Scott D. Solomon, M.D et al. for the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators N Engl J Med 2010; 363: 1146-55 September 16, 2010

Placebo Poor initial response

Proporion of patients

Better initial response

Year

Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes Cardiovascular composite outcome

Rate per 100 patient-yr (95% CI) 12.3 (11.3 13.4) 16.3 (14.0 18.9) 12.4 (11.2 13.6)

Adjusted HR: 1.31 (1.09 1.59) Solomon et al. N Engl J Med 2010; 363: 1146-55

10 30 20 40 50 1 2 3 4

Scott D. Solomon et. Al. N Engl J Med 363;12 September 16, 2010

Fatal or Nonfatal Stroke

CORRESPONDENCE

Erythropoietin in Kidney Disease and Type 2 Diabetes

N Engl J Med 2011; 364:384-386 January 27, 2011 Article To the Editor: F Locatelli, L Del Vecchio, D Casartelli The between-group difference in the median monthly dose of darbepoetin alfa was only 65 g There was substantial overlap in doses between groups Patients with a poor initial response had increased CRP levels and an increased rate of CVD at baseline. These findings suggest that the presence of coexisting illnesses in the patients may have been more important than the dose of darbepoetin alfa with respect to outcome.

In conclusion, while the general approach to anaemia management in CKD patients should be aiming at Hb levels of 11-12 g/dl, the secondary analysis of the TREAT remind us the importance

• f individualize treatment according to patient

characteristics and comorbidities and that the target Hb should be weighted with the ESA and iron doses needed to achieve it

Locatelli F and Del Vecchio L Nephrol Dial Transplant 2011 IN PRESS

Erythropoietic response to erythropoiesis stimulating agents and outcome: should we give up the haemoglobin target approach?

Conclusions

Anaemia correction improves quality of life; however this effect may vanish over time Partial correction of anaemia improves patient outcome and may decrease LVH

PRO

Complete anaemia correction does not improve patient

• utcome and may be even harmful

Complete anaemia correction has no effect on CKD progression

CONTRA

Finding the magic formula for anemia treatment

A pinch of ESA A pinch of iron Mix everything together using wisdom

62% 11% 9% 15% 3%

North America Latin America West Eu /Autralia Eastern Eu Russia

Subgroup analysis

After adjustment for multiple variables those treated with ESAs had a 30% greater odds of stroke than those untreated The increased risk of stroke with ESA use was most pronounced among patients with cancer ESA use was associated with higher risk of stroke

• nly in patients without previoushistory of stroke

National Veterans Affairs data; 12,426 patients

ESA doses in different trials

CHOIR, epoetin alfa

Low Hb group High Hb group

CREATE, epoetin beta

Low Hb group High Hb group

2,000 UI 5,000 UI

* Median weekly dose

TREAT, darbepoetin alfa

Low Hb group High Hb group

0 UI 8,800 UI

* Median montly dose converted in weekly EPO corresponding IU (ratio 1:200) * Mean weekly dose

6,276 UI 11,215 UI

46% received ESA

Pfeffer MA et al. N Engl J Med 2009; 361:2019-32

The TREAT Study

Secondary analyses about cancer

No significant difference in the number of patients reporting a cancer- related adverse event (P=0.53) Darbepoetin alfa Placebo N=139 (6.9%) N=130 (6.4%) Deaths attributed to cancer (P=0.08 by the log-rank test) Darbepoetin alfa Placebo N=39 (1.93%) N=25 (1.23%) A protocol amendment foresaw to discontinue the study drug in patients in whom cancer developed

Pfeffer MA et al. N Engl J Med 2009; 361:2019-32

The TREAT Study

Secondary analyses about cancer

Deaths from any cause (P=0.13 by the log-rank test) Darbepoetin alfa Placebo 60 out of 188 (31.9%) 37 out 160 (23.1%) Subgroup: 348 patients with a history of malignancy at baseline Enrollment criteria: Patients with active cancer (except basal-cell or squamous-cell carcinoma of the skin) were excluded from the study Deaths from cancer (P=0.002 by the log-rank test) Darbepoetin alfa Placebo 14 out of 188 (7.4%) 1 out 160 (0.06%)

Overall population: 20.5% Overall population: 19.5%

Previous history of HF No previous history of HF

P = 0.643 P = 0.011 Months from randomization Months from randomization

Kaplan-Meier failure estimate (%) Hb 11.3 g/dl (34/490, 14.2%) Hb 13.5 g/dl (56/477, 22.7%)

6 12 18 24 30 36 5 10 15 20 25 30 35 40 45 50 55 5 10 15 20 25 30 35 40 45 50 55 6 12 18 24 30 36

Hb 13.5 g/dl (61/192, 46.3%) Hb 11.3 g/dl (55/183, 50.8%) Kaplan-Meier failure estimate (%)

No diabetes

P = 0.040 Months from randomization

Hb 11.3 g/dl (24/239, 24%) Hb 13.5 g/dl (41/249, 36.4%)

3 6 9 12 15 18 21 24 27 30 33 6 12 18 24 30 36

Diabetes

P = 0.249 Months from randomization

Hb 11.3 g/dl (70/458, 24.7%) Hb 13.5 g/dl (79/436, 24.8%)

6 12 18 24 30 36 36 39 3 6 9 12 15 18 21 24 27 30 33 36 39

Kaplan-Meier failure estimate (%) Kaplan-Meier failure estimate (%)