Anemie, DM en CNS: hoe verder na TREAT?

Anemie, DM en CNS: hoe verder na TREAT ? Dr M van Buren internist-nefroloog

Dr CAJM Gaillard internist-nefroloog

HAGA ziekenhuis Den Haag

Meander Medisch Centrum Amersfoort VU Medisch Centrum Amsterdam

woensdag 17 februari 2010

TREAT studie wat ging vooraf resultaten beperkingen consequentie

discussie


TREAT Wat vooraf ging



Volume 316:73-78

January 8, 1987

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



Volume 316:73-78

January 8, 1987

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 Abstract recombinant human erythropoietin to 25 anemic patients undergoing hemodialysis. Over a range of doses between 15 and 500 units per kilogram of body weight, dose-dependent increases in effective erythropoiesis were noted. At 500 units per kilogram, changes in the hematocrit of as much as 10 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 18 patients receiving effective doses of recombinant human erythropoietin, 12 who had required transfusions no longer needed them, and in 11 the hematocrit increased to 35 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. woensdag 17 februari 2010

Volume 316:73-78

1987


January 8, 1987

Number 2


Volume 316:73-78

1987

1989


January 8, 1987

Number 2


Treatment of the anemia of progressive renal failure with recombinant human erythropoietin JW Eschbach, MR Kelly, NR Haley, RI Abels, and JW Adamson

Volume 316:73-78

1987

1989 1989

January 8, 1987

Number 2


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.


1989 woensdag 17 februari 2010

“Treatment anemia associated with CKD, maintain hemoglobin level and decrease need for transfusions”

1989 “Treatment anemia associated with CKD, maintain hemoglobin level and decrease need for transfusions”


1989 “Treatment anemia associated with CKD, maintain hemoglobin level and decrease need for transfusions” Transfusion threshold QoL

HD

g/dl

4

2

mmol/l woensdag 17 februari 2010

5

3

6

7

4

8

5

9

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8

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August 27, 1998

Transfusion threshold QoL

HD

g/dl

4

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5

3

6

7

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7

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August 27, 1998


Normalization threshold

!

HD

g/dl

4

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5

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6

7

4

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5

9

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6

11

7

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13

8

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November 16, 2006





!

Predial

!

HD

g/dl

4

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5

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7

4

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8

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FDA warnings


FDA warnings 9 march 2007:

8 november 2007:


Nieuwe Target 6,8-7,4 Transfusion threshold QoL

Start 6,2

Predial

HD

g/dl

4

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5

3

6

7

4

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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” 2007 update


TREAT



Target range



TREAT



Target range



TREAT



Target range



TREAT



Target range



TREAT



Target range



TREAT



Target range


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

N ~ 2000

Study Population • Hb ≤ 6.8 mmol/l • eGFR 20-60 mL/min/1.73 m2 • Type 2 DM

Aranesp® (Target Hb 8.1 mmol/l)

Design – randomized (1:1), double blind, placebo-controlled N ~ 2000

Placebo (rescue if Hb < 5.6 mmol/l)

Event-driven: :~1,203 patients with cardiovascular primary endpoint

Pfeffer MA, et al. Am J Kidney Dis. 2009;54:59-69. Pfeffer MA, et al. N Engl Med. 2009;361:2019-2032. woensdag 17 februari 2010

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


Cardiovascular-Related Patient Characteristics: Darbepoetin alfa Versus Placebo


Mean Hemoglobin Levels

Hb Median: 12.5 g/dl (7.8 mmol/l) IQR [7.4 – 7.9]

Hb Median: 10.6 g/dl (6.6 mmol/ l) IQR [6.1 – 7.0]

Pfeffer MA, et al. N Engl Med. 2009;361:2019-2032. woensdag 17 februari 2010





Median dose: 176 µg IQR [104 – 305]

46% received rescue therapy Median dose: 0 µg IQR [0 – 5]





Median dose: 176 µg IQR [104 – 305] 66.8% received oral iron 14.8 % received i.v. iron

46% received rescue therapy Median dose: 0 µg IQR [0 – 5] 68.6% received oral iron 20.4 % received i.v. iron

“Placebo” Hb effect Hb stijgt in placebo groep

• • • • •

Hawthorne effect 46 % placebo kreeg tenminste 1 gift EPO survival benefit ijzer iv/ ijzer dosis transfusie


Cardiovascular Composite End Point


Fatal or Nonfatal Stroke


Fatal or Nonfatal Stroke


Composite and Component End Points


Stroke Vragen

• •

wie kreeg aspirin?

• • •

hoe was de DM instelling?

wie had atrium fibrilleren en/of acenocoumarol? voorgeschiedenis voorspellend? was de follow up time bepalend?


Post-Hoc Analysis of Patients With a Prior History of Cancer


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: 84 patients (4.2%) – Placebo group: 117 patients (5.8%) – Hazard ratio, 0.71; 95% CI, 0.54 to 0.94; P = 0.02  Red-cell transfusions: – 297 patients in the darbepoetin alfa group (14.8%) – 496 patients in the placebo group (24.5%) – hazard ratio = 0.56; 95% confidence interval [CI], 0.49 to 0.65; P<0.001  Fatigue subscale of Functional Assessment of Cancer Therapy (FACTFatigue) score: – darbepoetin alfa group: an increase of 4.2±10.5 points – placebo group: an increase of 2.8±10.3 points (P<0.001) – An increase of three or more points (considered to be a clinically meaningful improvement) • 963 of 1762 patients assigned to darbepoetin alfa (54.7%) • 875 of 1769 patients assigned to placebo (49.5%) (P = 0.002) Pfeffer MA, et al. N Engl Med. 2009;361:2019-2032. woensdag 17 februari 2010

Wat betekenen deze • • •

wetenschappelijk gezien voor toekomstig onderzoek voor de klinische praktijk




Predial DM

! !

Predial

!

HD

g/dl

4

2


5

3

6

7

4

8

5

9

10

6

11

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Predial DM

Predial

HD

g/dl

4

2


5

3

6

7

4

8

5

9

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6

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8

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Predial DM

Predial

HD

g/dl

4

2

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7

8

4


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9

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6

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Een groene zone? Transfusion threshold QoL

Predial DM

Predial

HD

g/dl

4

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5

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8

4


5

9

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6

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Een groene zone? Eén negatieve, “placebo” studie


Predial DM

Predial

HD

g/dl

4

2

5

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6

7

8

4


5

9

10

6

11

7

12

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8

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Een groene zone? Eén negatieve, “placebo” studie


Targets met elkaar vergeleken Target studies: patiënten die EPO resistent zijn krijgen hoogste doses

Predial DM

Predial

HD

g/dl

4

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5

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6

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9

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EPO dosis en patiënt factoren spelen een rol in de balans gunstige/ongunstige effecten

Wat weten we • • •

Epo reduceert transfusie behoefte

•

(hoge doses geassocieerd met m&m)

EPO verbetert QoL hoge targets (is niet hetzelfde als het bereiken van een hoog Hb) geassocieerd met morbiditeit en mortaliteit


Welke vragen zijn er nu


Welke vragen zijn er nu •

Welke dosis aan welke patiënt?

• • •

welke target? welke dosis? is iets meer dan niets?


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


Mijn conclusies •

gebruik lage doses EPO (50-100 e/kg/week), accepteer “lage” Hb’s (<6 mmol/l)

•

geen algemene target, maar individuele afstemming

•

definieer per patiënt uw doelen

•

re-evalueer ijzer behandeling


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


Anemie, DM en CNS: hoe verder na TREAT?

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