Anemie, DM en CNS: hoe verder na TREAT?

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1 Anemie, DM en CNS: hoe verder na TREAT? Dr M van Buren internist-nefroloog HAGA ziekenhuis Den Haag Dr CAJM Gaillard internist-nefroloog Meander Medisch Centrum Amersfoort VU Medisch Centrum Amsterdam

2 TREAT studie wat ging vooraf resultaten beperkingen consequentie discussie

3 TREAT Wat vooraf ging

4 TREAT Wat vooraf ging Volume 31:3- January, 1 Number 2 Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial JW Eschbach, JC Egrie, MR Downing, JK Browne, and JW Adamson

5 TREAT Wat vooraf ging Volume 31:3- January, 1 Number 2 Abstract Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial JW Eschbach, JC Egrie, MR Downing, JK Browne, and JW Adamson recombinant human erythropoietin to 2 anemic patients undergoing hemodialysis. Over a range of doses between 1 and 00 units per kilogram of body weight, dose-dependent increases in effective erythropoiesis were noted. At 00 units per kilogram, changes in the hematocrit of as much as percentage points were seen within three weeks, and increases in ferrokinetics of three to four times basal values, as measured by erythron transferrin uptake, were observed. Of 1 patients receiving effective doses of recombinant human erythropoietin, 12 who had required transfusions no longer needed them, and in 11 the hematocrit increased to 3 percent or more. Along with the rise in hematocrit, four patients had an increase in blood pressure, and a majority had increases in serum creatinine and potassium levels. These results demonstrate that recombinant human erythropoietin is effective, can eliminate the need for transfusions with their risks of immunologic sensitization, infection, and iron overload, and can restore the hematocrit to normal in many patients with the anemia of end-stage renal disease.

6 Volume 31:3- January, 1 Number 2 1 Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial JW Eschbach, JC Egrie, MR Downing, JK Browne, and JW Adamson

7 Volume 31:3- January, 1 Number 2 1 Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial JW Eschbach, JC Egrie, MR Downing, JK Browne, and JW Adamson 1 Treatment of the anemia of progressive renal failure with recombinant human erythropoietin JW Eschbach, MR Kelly, NR Haley, RI Abels, and JW Adamson

8 Volume 31:3- January, 1 Number 2 1 Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial JW Eschbach, JC Egrie, MR Downing, JK Browne, and JW Adamson 1 1 Treatment of the anemia of progressive renal failure with recombinant human erythropoietin JW Eschbach, MR Kelly, NR Haley, RI Abels, and JW Adamson Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, Evans RW, Friedman EA, Graber SE, Haley NR, et al.

9 1 Treatment anemia associated with CKD, maintain hemoglobin level and decrease need for transfusions

10 1 Treatment anemia associated with CKD, maintain hemoglobin level and decrease need for transfusions

11 1 Treatment anemia associated with CKD, maintain hemoglobin level and decrease need for transfusions Transfusion threshold QoL HD g/dl mmol/l 3

12 August 2, g/dl mmol/l Transfusion threshold QoL HD g/dl mmol/l Transfusion threshold QoL HD

13 August 2, g/dl mmol/l Transfusion threshold QoL HD Normalization threshold! g/dl mmol/l Transfusion threshold QoL HD Normalization threshold!

14 November 1, 200

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16 Transfusion threshold QoL Normalization threshold Predial! HD! g/dl mmol/l 3

17 FDA warnings

18 FDA warnings march 200: november 200:

19 Nieuwe Target,-, Transfusion threshold QoL Start,2 Predial HD g/dl mmol/l 3

20 What is the Optimal Target Hb? TREAT Placebo/control mean Hb Lower Hb arm: mean achieved Hb Higher Hb arm: mean achieved Hb Target range Adapted and from NKF-K/DOQI Target Hb 200 update

27 TREAT: Trial to Reduce Cardiovascular Events With Aranesp (Darbepoetin alfa) Therapy Hypotheses: Treatment of anemia with Aranesp in subjects with chronic kidney disease (CKD) and type 2 diabetes mellitus decreases mortality and cardiovascular (CV) morbidity Treatment of anemia with Aranesp in subjects with CKD and type 2 diabetes mellitus will delay the progression to ESRD Study Population Hb. mmol/l egfr 20-0 ml/min/1.3 m 2 Type 2 DM N ~ 2000 Aranesp (Target Hb.1 mmol/l) Design randomized (1:1), double blind, placebo-controlled N ~ 2000 Placebo (rescue if Hb <. mmol/l) Event-driven: :~1,203 patients with cardiovascular primary endpoint Pfeffer MA, et al. Am J Kidney Dis. 200;:-. Pfeffer MA, et al. N Engl Med. 200;31:

28 Primary Endpoints CV Endpoint: Time to the first confirmed composite event, comprising all-cause mortality and CV events including myocardial ischemia, CHF, MI and CVA Renal Endpoint: Time to ESRD (end-stage renal disease) or allcause mortality Pfeffer MA, et al. Am J Kidney Dis. 200;:-. Pfeffer MA, et al. N Engl Med. 200;31:

29 Cardiovascular-Related Patient Characteristics: Darbepoetin alfa Versus Placebo Pfeffer MA, et al. Am J Kidney Dis. 200;:-. Pfeffer MA, et al. N Engl Med. 200;31:

30 Mean Hemoglobin Levels Hb Median: 12. g/dl (. mmol/l) IQR [..] Hb Median:. g/dl (. mmol/ l) IQR [.1.0] Pfeffer MA, et al. N Engl Med. 200;31:

31 Mean Hemoglobin Levels Hb Median: 12. g/dl (. mmol/l) IQR [..] Median dose: 1 µg IQR [ 30] Hb Median:. g/dl (. mmol/ l) IQR [.1.0] % received rescue therapy Median dose: 0 µg IQR [0 ] Pfeffer MA, et al. N Engl Med. 200;31:

32 Mean Hemoglobin Levels Hb Median: 12. g/dl (. mmol/l) IQR [..] Median dose: 1 µg IQR [ 30].% received oral iron 1. % received i.v. iron Hb Median:. g/dl (. mmol/ l) IQR [.1.0] % received rescue therapy Median dose: 0 µg IQR [0 ].% received oral iron 20. % received i.v. iron Pfeffer MA, et al. N Engl Med. 200;31:

33 Placebo Hb effect Hb stijgt in placebo groep Hawthorne effect % placebo kreeg tenminste 1 gift EPO survival benefit ijzer iv/ ijzer dosis transfusie

34 Cardiovascular Composite End Point Pfeffer MA, et al. N Engl Med. 200;31:

35 Fatal or Nonfatal Stroke Pfeffer MA, et al. N Engl Med. 200;31:

36 Fatal or Nonfatal Stroke Pfeffer MA, et al. N Engl Med. 200;31:

37 Composite and Component End Points Pfeffer MA, et al. N Engl Med. 200;31:

38 Stroke Vragen wie kreeg aspirin? wie had atrium fibrilleren en/of acenocoumarol? hoe was de DM instelling? voorgeschiedenis voorspellend? was de follow up time bepalend?

39 Post-Hoc Analysis of Patients With a Prior History of Cancer Pfeffer MA, et al. N Engl Med. 200;31:

40 Other outcomes Cardiac revascularization procedures were performed less frequently in the patients assigned to darbepoetin alfa than in those assigned to placebo: Darbepoetin alfa group: patients (.2%) Placebo group: 11 patients (.%) Hazard ratio, 0.1; % CI, 0. to 0.; P = 0.02 Red-cell transfusions: 2 patients in the darbepoetin alfa group (1.%) patients in the placebo group (2.%) hazard ratio = 0.; % confidence interval [CI], 0. to 0.; P<0.001 Fatigue subscale of Functional Assessment of Cancer Therapy (FACT- Fatigue) score: darbepoetin alfa group: an increase of.2±. points placebo group: an increase of 2.±.3 points (P<0.001) An increase of three or more points (considered to be a clinically meaningful improvement) 3 of 12 patients assigned to darbepoetin alfa (.%) of 1 patients assigned to placebo (.%) (P = 0.002) Pfeffer MA, et al. N Engl Med. 200;31:

41 Wat betekenen deze wetenschappelijk gezien voor toekomstig onderzoek voor de klinische praktijk

42 Transfusion threshold QoL Normalization threshold Predial DM! Predial! HD! g/dl mmol/l 3

43 g/dl mmol/l Transfusion threshold QoL HD Predial Predial DM g/dl mmol/l Transfusion threshold QoL HD Predial Predial DM

44 Transfusion threshold QoL Predial DM Predial HD g/dl mmol/l 3

45 Een groene zone? Transfusion threshold QoL Predial DM Predial HD g/dl mmol/l 3

46 Een groene zone? Transfusion threshold QoL Eén negatieve, placebo studie Predial DM Predial HD g/dl mmol/l 3

47 Een groene zone? Transfusion threshold QoL Eén negatieve, placebo studie Targets met elkaar vergeleken Predial DM Predial Target studies: patiënten die EPO resistent zijn krijgen hoogste doses HD g/dl EPO dosis en patiënt factoren spelen een rol in de balans gunstige/ongunstige effecten 2 mmol/l 3

48 Wat weten we Epo reduceert transfusie behoefte EPO verbetert QoL hoge targets (is niet hetzelfde als het bereiken van een hoog Hb) geassocieerd met morbiditeit en mortaliteit (hoge doses geassocieerd met m&m)

49 Welke vragen zijn er nu

50 Welke vragen zijn er nu Welke dosis aan welke patiënt? welke target? welke dosis? is iets meer dan niets?

51 Welke vragen zijn er nu Welke dosis aan welke patiënt? welke target? welke dosis? is iets meer dan niets? Welke studies zijn nodig? fixed dose, placebo gecontroleerde studies patiënt stratificatie

52 Mijn conclusies gebruik lage doses EPO (0-0 e/kg/week), accepteer lage Hb s (< mmol/l) geen algemene target, maar individuele afstemming definieer per patiënt uw doelen re-evalueer ijzer behandeling

53 Take home message(s): EPO gebruik kent risico s Voordelen (QoL, Tx) afwegen tegen nadelen Geen universele targets Accepteer lage Hb waarden afhankelijk kliniek