Cagliari, April 30-May 3, 2011 INTERNATIONAL Renal Meeting and Mayo Clinic Day in Sardinia DEBATE Francesco Locatelli Department of Nephrology, Dialysis and Renal Transpant � Alessandro Manzoni � Hospital, Lecco, Italy
� 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. oncology). � 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 of 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 of 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 Hb 10.5-11.5 Hb 13-15 Group 1: 58 events (2%) Group 2: 47 events (1.5%) HR 0.78; 95% CI 0.53 to 1.14; P = 0.20 Drueke T, Locatelli F et al, N Engl J Med 2006
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
The CHOIR Trial 1432 CKD patients not on dialysis; half of them were diabetics Primary Composite End-Point Hb 13.5 Hb 11.3 Group 1: 125 events (17%) Median FU of 16 months Group 2: 97 events (13%) HR 1.34; 95% CI 1.03 to 1.74; P=0.03 Singh et al, N Engl J Med 2006
CHOIR Study: an open label randomised study Median study duration: 16 months Group 1 target: Hb 13.5 g/dl Group 2 target: Hb 11.3 g/dl N: 1432 CKD pts Singh AK et al. N Engl J Med 2006; 355:2085- 98
The TREAT Study Cardiovascular composite end point (ITT) 50 Patients with events (%) Hazard ratio, 1.05 (95% CI, 0.94 � 1.17) P = 0.41 40 Darbepoetin alfa Placebo 30 20 10 0 0 6 12 18 24 30 36 42 48 Months since randomization Pfeffer MA et al. N Engl J Med 2009; 361:2019-32
Composite and Component End Points
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 Locatelli, Del Vecchio, Casartelli N ENGL MED 362; 7 Feb 18, 2010
TREAT : mean haemoglobin levels over 48 months 12.5 g/dl 10.6 g/dl Guidelines 9 g/dl Pfeffer MA et al. N Engl J Med 2009; 361(21):2019-32
Complete anemia correction in CKD patients not receiving HD Comparison of event rates and HR on primary end-points CREATE CHOIR TREAT
� 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?
Darbepoetin Alfa Impact On Health Status In Diabetes Patients With Kidney Disease: A Randomized Trial CJASN ePress. Published on January 6, 2011 Lewis EF � Locatelli F. � et al. for the TREAT Investigators
The TREAT Trial Clinically meaningful improvement in FACT-Fatigue scores 60 * P < 0.05 * % pts wtih � 3 point improvement * * 50 * 40 30 Placebo Darbepoetin 20 10 0 Week 13 Week 25 Week 49 Week 73 Week 97 A higher score is associated with less fatigue Lewis EF � Locatelli F. et al. Clin J Am Soc Nephrol 2011; Jan 6. [Epub ahead of print]
TREAT Versus Treatment: A Patient � s View of a Scientific Interpretation Treat the patient as an individual, or treat in line with the latest empirical study Prisant A. American Journal of Kidney Diseases, Vol 55, No 3 (March), 2010
TREAT Versus Treatment: A Patient � s View of a Scientific Interpretation � 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 � outcomes such as incident-free longevity � Prisant A. American Journal of Kidney Diseases, Vol 55, No 3 (March), 2010
TREAT Versus Treatment: A Patient's View of a Scientific Interpretation Prisant A. � 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. � Am J Kidney Dis 2010 Mar;55(3):A31-2.
The position of ERBP Quality of life 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 on more robust measures of the quality of life F.Locatelli et al.Nephrol Dial Transplant 2009; 24(2):348-54
Nephrology Dialysis Transplantation ISSN 0931 - 0509 Official Publication of the European Renal Association � European Dialysis and Transplantation Association Volume 19 ( May 2004 ) � Supplement 2 Revised European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure 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 • 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 Locatelli et al. Nephrol Dial Transpl 2004; 19, suppl 2
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
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