Treatment of anemia in chronic kidney disease: known, unknown, and both

Figures & data

Table 1 Major anemia management trials in patients with chronic kidney disease

TRIAL (n)	CHOIR (1432)^Citation50	CREATE (603)^Citation49	USNH (1233)^Citation47	CENH (596)^Citation48,Citation58	TREAT (4038)^Citation51
Major enrolment criteria
On hemodialysis	E	E	I	I (3–18 months)	E
eGFR (mL/min/1.73 m^2)	15.0–50.0	15.0–35.0	–	–	20.0–60.0
Type 2 diabetes	–	–	–	–	I
CVD, inclusion	–	–	CHF or IHD ≤ 2 yrs.	–
CVD, exclusion	Unstable angina	Advanced CVD ≤ 3 months	MI, PTCA or CABG ≤ 3 months NYHA Class IV	Symptomatic IHD or CHF, critical angiographic HD	CV event ≤ 12 weeks
LV dimensions	–	–	–	LVVI < 90 mL/m^2	–
Hemoglobin (g/dL)	<11.0	11.0–12.5	9.0–11.0	8.0–12.0	≤11.0
Interventions and primary outcomes
Blinding	No	No	No	Patients	Blinding
Placebo	No	No	No	No	Placebo
Real-time central monitoring	No	No	No	Yes	Yes
Hemoglobin targets (g/dL)
Low	10.5–11.0^Citation1	No epoetin until < 10.5	10.0 ± 1	9.5–11.5	13.0
High	13.0–13.5^Citation1	Immediate epoetin 13.0–15.0	14.0 ± 1	13.5–14.5	None (rescue if <9.0)
Treatment strategies	High and low target groups received 10,000 U epoetin alfa once weekly for three weeks. Thereafter, a “prespecified” dosing algorithm, not reported in primary publication.	Dose reviewed every four weeks. If hemoglobin increment < 0.5 g/dL, ↑by 25% to 50%; if hemoglobin increment > 0.5 g/dL, ↓by 25%–50%.	With high target, dose initially ↑1.5-fold on study entry; thereafter if 2-week Δ hematocrit < 2%- ↑by 25%; if >2% ↓25 U/kg. With low target, adjust by 10–25 U/kg.	Epoetin-naïve patients in the higher target initially given 150 IU/kg per week. For hemoglobin deviating from target, Δ 25% or 25 IU/kg.	Initial dose of darbepoetin or placebo equivalent 0.75 μg/kg every two weeks, could be extended to every four weeks if hemoglobin levels stable, to maximum dose of 600 μg.
Primary outcome	Time to the first occurrence of death, MI hospitalization for CHF (excluding renal replacement therapy), or stroke.	Time to first occurrence of sudden death, MI, acute heart failure, stroke, transient ischemic attack, angina pectoris resulting in hospitalization for 24 hours or more or prolongation of hospitalization, complication of peripheral vascular disease, or cardiac arrhythmia resulting in hospitalization for 24 hours or more)	Time to death or a first nonfatal MI	Echocardiographic LVVI	First primary outcome (spendable α 0.048): time to earliest occurrence of death, nonfatal MI, CHF, stroke, or hospitalization for myocardial ischemia. Secondary primary outcome (spendable α 0.002): time to earliest occurrence of death or end-stage renal disease.
Results
Success of randomization	↑Hypertension and CABG in high target	↑Body mass index and use of beta blockers in immediate treatment	↑Angina pectoris in normal hematocrit	↑Age in higher target	↑CVD, placebo ↑CHF, placebo ↓eGFR, placebo ↑HbA1c, darbepoetin
Hemoglobin levels (g/dL)
Increment during month 1	>1 in both arms	≈0.3 in high target	≈0.3 in high target	≈0.3 in high target	≈0.9 in high target
During maintenance phase	High, ≈13.0 Low, ≈11.0	High, ≈13.3 Low, ≈11.4	High, ≈13.3 Low, ≈10.1	High, ≈13.0 Low, ≈10.8	High, ≈12.5 Low, ≈10.6
Epoetin doses	High, 11,000 IU/week Low, 5000 IU/week	High, 5000 IU/week Low, 2000 IU/week	High, 450 IU/kg/week Low, 150 IU/kg/week	High, 150 IU/kg/week Low, 75 IU//kg/week	–
Darbepoetin doses	–	–	–	–	High, ≈176 μg Low, ≈0 μg
Blood pressure	High, ↑by 0.2 mmHg Low, ↓by 0.7 mmHg	No difference	No differences	No differences, but ↑antihypertensive agents with high target	Higher diastolic High, 134/73 Low, 134/70
Primary outcome, unadjusted	↑CV events in high target. Hazards ratio (P = 0.03).	No difference in CV events	No difference in CV events	Unadjusted analysis was not reported.	No difference in either coprimary outcome
Primary outcome, adjusted for baseline characteristics	Not reported in primary publication. However, clinical study report, available at www.clinicaltrials.gov of September 12, 2006 reports findings from adjusted analysis. With adjustment for demographic variables such as gender, race, and age, and baseline clinical variables, such as renal history, NHANES scores, diabetes mellitus status, GFR, albumin, reticulocyte count, and iron status, hazards ratio no longer statistically significant (P = 0.111).	Analysis not reported	No difference in CV events	No difference in LVVI when adjustment made for age, epoetin use at randomization, and baseline LVH.	Analysis not reported
Quality of life	Patients not blinded. Similar evolution of LASA, KDQ, and SF-36 scores in both treatment arms, except for the score for the emotional role subscale of the SF-36, which was significantly higher in the low-hemoglobin group. Timing of quality of life assessments not reported.	Patients not blinded. Quality of life with SF-36 better with high hemoglobin target at year 1 (general health, mental health, physical function, physical role, social function, and vitality) and at year 2 (general health, vitality).	Quality of life was assessed but not formally reported in primary publication.	Patients were blinded. SF-36 vitality scores improved more in the higher than in the lower target group. No significance between-group differences were seen in the time course of FACIT Fatigue scores and the KDQ Quality of Social Interaction scores.	Patients were blinded. FACT fatigue scores increased more in the darbepoetin group. No differences in SF-36 energy and physical functioning domains.
Transfusions	Not reported	High 5.4% Low 8.6%	High 21% Low 31%	High 0.26 units/year. Low 0.66 units/year.	High 14.8% Low 24.5%
Major nonprimary adverse events	No differences	↑Renal replacement therapy with higher target.	↑Vascular access loss with higher target	↑Stroke with higher target.	Individual components of composite primary outcomes: no difference in death, CHF, MI or myocardial ischemia. ↑CVA with darbepoetin. Other outcomes: no difference in cancer, death in subjects with cancer baseline; ↑venous thromboembolism; arterial thromboembolism and death attributed to cancer among subjects with cancer at baseline with darbepoetin

Abbreviations: CV, cardiovascular; CHF, congestive heart failure; MI, myocardial infarction; SF, Short Form; eGFR, estimated glomerular filtration rate; LASA, linear analog scale assessment; KDQ, Kidney Disease Questionnaire; FACIT; Functional Assessment of Chronic Illness Therapy; NHANES, National Health and Nutrition Examination Survey; I, inclusion criteria; E, exclusion criteria; CVA, cerebrovascular accident; CVD, cardiovascular disease; CABG, coronary artery bypass grafting; IHD, ischemic heart disease; LV, left ventricular; LVVI, left ventricular volume index; HD, heart disease; PTCA, percutaneous transluminal coronary angioplasty; NYHAC, New York Heart Association Class.

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