The debate! Ajay Singh � YES, WE CAN � Dr. Locatelli � NO, WE CAN � T � Should hemoglobin targets for anemia patients with chronic kidney disease be changed?
DISCLOSURES � PI of the CHOIR study, received research support and consulting income from J and J � Member, Executive Steering Committee of the TREAT study, received research support and consulting income from Amgen � Consultant for Rockwell, Fibrogen, GSK, Sandoz, AHSP, ConCert. Past income from Watson, Roche, AMAG � Member of MEDCAC � Steering Committee for the National Quality Forum � Member Scientific Advisory Board, National Kidney Foundation 2
Gerard Dou 1662, Louvre � Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing � Voltaire (French Philosopher and Writer. One of the greatest of all French authors, 1694-1778)
The clinical context � Patient with CKD, either non-dialysis or dialysis � Anemic iron replete � What level of Hb should treatment be initiated? � What target Hb should you aim for?
Should Hb targets be changed? � Yes! � Initiate ESA at 9 g/dL not at 10 g/dL � Aim for >9 g/dL and <12 g/dL � Because the evidence supports it! � Lower Hb threshold should be 9 g/dL � Data from Normal Hematocrit in dialysis patients � Data from TREAT in non-dialysis CKD patients � Upper Hb level should be left unchanged at 12 g/dL � Focus should be on using lower doses of ESA
Lower Hb threshold should be 9 g/dL � Normal Hematocrit Study � Symptomatic, high-risk dialysis patients � Similar mortality to the USRDS dialysis population � Representative, generalizible study Besarab et al. N Engl J Med 339:584-590, 1998
Normal Hematocrit Study Randomization was to 2 Hb arms: 27-33% -- versus 39-45% Ie, >9 g/dL and <11 g/dL versus >13 g/dL and <15 g/dL
Normal Hematocrit Study � Tested hypothesis that patients with normal Hb 13-15 g/dL will have better outcomes than patients with Hb 9-11 g/dL � 1233 HD patients with CAD or CHF � Primary end-point: Death or MI 8 Besarab et al. N Engl J Med 339:584-590, 1998
Normal Hematocrit Study Low Hct Normal Hct n 618 615 Hct 30 42 (achieved 39%) Epoetin dose 160 460 Total deaths 150 183 Non-fatal MI 14 19 RR 1.3 (0.9-1.9) Study terminated early due increased risk Higher rate of vascular access thrombosis in normal Hct group: (243 patients, or 39 percent, vs. 176 patients, or 29 percent; P=0.001). 9 Besarab et al. N Engl J Med 339:584-590, 1998
Normal Hematocrit Study
In dialysis patients, the only well powered study, demonstrates that patients treated to a range of 9-11 g/dL have better outcomes than those treated to a range of 13-15 g/dL
Lower Hb threshold should be 9 g/dL � What about non-dialysis patients? � TREAT study � Type 2 diabetic patients with kidney disease � Over 50% of kidney disease patients have type 2 diabetes
Hypothesis In patients with type 2 diabetes, chronic kidney disease not requiring dialysis, and concomitant anemia, raising hemoglobin with darbepoetin alfa would lower the rates of death and cardiovascular morbidity and/or death and end- stage renal disease 13 Pfeffer MA, et al N Engl J Med. Oct 30. 2009
TREAT Pfeffer MA, et al N Engl J Med. Oct 30. 2009
TREAT tested maintaining a Hb of > 9g/dL versus 13 g/dL Achieved Hb of Hb Median: 10.6 IQR [9.9 � 11.3] versus Hb Median: 12.5 IQR [12.0 � 12.8]
TREAT: Hemoglobin levels 13.5 Darbepoetin alfa Placebo 13.0 Mean Hemoglobin (g/dL) 12.5 12.0 Median dose: 176 � g IQR [104 � 305] Hb Median: 12.5 IQR [12.0 � 12.8] Mean: 225 � g ± 208 11.5 11.0 10.5 Median dose: 0 � g IQR [0 � 5] Hb Median: 10.6 IQR [9.9 � 11.3] Mean: 5 � g ± 11 10.0 9.5 0 0 6 12 18 24 30 36 42 48 Month Pfeffer MA, et al N Engl J Med 2009; 361:2019-203 16
TREAT: Composite endpoints 17 Pfeffer MA, et al N Engl J Med. Oct 30. 2009
Sensitivity Analysis around endpoints (Source: Amgen) 18
Fatal and Nonfatal Stroke 50 Darbepoetin alfa 101 (5.0%) Patients With Events (%) Placebo 53 (2.6%) 40 30 HR: 1.92 (1.38 � 2.68) P < 0.001 20 10 0 0 6 12 18 24 30 36 42 48 Months 19
MACE Analysis (Source FDA) 20
Stroke Analysis Type of stroke in TREAT DPO Control Overall 101 (2.6%) 101 (5.0%) Non Hem 38 74 Hemorrhagic 8 13 Unknown 7 14 21
� Dr. Locatelli might argue that in TREAT, stroke was not a primary endpoint � and TREAT was not powered for reduction in the rate of stroke, the highly significant P value associated with the increased hazard of a stroke with darbepoietin treatment should be ignored. � Stroke was a pre-specified cardiovascular outcome. � Stroke safety signal is meaningful, don � t need to power for safety signal � TREAT well powered study N=1026 Hazard ratio 1.30 (95% C: 1.06, 1.58)
Malignancy in TREAT Darbepoetin alfa Placebo P-value Overall 139/2012 130/2026 Cancer-related AE 0.53 6.9% 6.4% Deaths attributed to 39/2012 25/2026 0.08 cancer 1.9% 1.2% Subgroup: Baseline � History of malignancy (n = 348) 60/188 37/160 All cause mortality 0.13 31.9% 23.1% Deaths attributed to 14/188 1/160 0.002 cancer 7.4% 0.6% 23
In non-dialysis patients, TREAT demonstrates that patients maintaining a Hb>9 g/dL have improved outcomes over those treated to a range of >13 g/dL
Minimal Improvement in QOL Hb >9 g/dL FACT-Fatigue Score at 25 Weeks 4.2 ± 10.5 P < 0.001 2.8 ± 10.3 Less fatigue 54.7% 49.5% Mean Change P = 0.002 30.2 30.4 Placebo Darbepoetin alfa n = 1769 n = 1762 FACT-Fatigue range: 0: most fatigued, to 52: least fatigued 25
Patient Reported Outcomes Supportive Analysis Short-Form 36 Mean Change at 25 Weeks in 2 Domains Darbepoetin alfa Placebo Domains n = 1138 n = 1157 P-value 2.6 ± 9.9 2.1 ± 9.7 Energy 0.20 1.3 ± 9.2 1.1 ± 8.8 Physical Function 0.51 26
What Dr. Locatelli might say � A cautious approach of treating anemia to a lower target 9 to 12 g/dL with conservative doses of ESA might return us to a pre-ESA era. On the contrary: Hb of 9 g/dL is not returning us to the pre-ESA era of Hb � s of 5 to 9 g/dL Singh et al CJASN 2010 Low Low ESA ESA Patients Patients dose dose % of % of 9 9 10 10 11 11 12 12 13 13 Hb g/dL Hb g/dL � TREAT and other studies show minimal QOL benefit of rasing Hb above 9 g/dL � Individualizing treatment is essential; besides, no-one is arguing that we abandon ESAs
� Dr. Locatelli might dismiss the TREAT study � He might argue that since subjects assigned to the placebo rescue arm achieved an Hb � very close � to the levels recommended in the guidelines, the Hb guidelines should not be changed . � But, the target Hb and achieved Hb are two different concepts � Target Hb should be >9 g/dL, the achieved Hb will likely by in the 10 to 11 g/dL range � The guidelines should be changed to recommend, � In most non-dialysis CKD patients anemia can be treated without the use of ESAs; in those in whom treatment is necessary the target Hb should be >9 g/dL and <12 g/dL � .
Is there risk with achieving Hb >12 g/dL YES! � CHOIR and CREATE � Non-dialysis patients � Diabetic and non-diabetic � CREATE very under-powered
1432 patients, 130 centers, US only Epoetin-alfa Randomization High target Hgb Low target Hgb (13.5 g/dl) (11.3 g/dl) Median f/u 16 months n=715 n=717 Singh et al,New Engl J Med 2006; 355:2085-98 30
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