ANEMIA OF CKD: Hemoglobin Control – Landmark Trials Summary Z Dumont BSP, P Ricci, L Gross, B Lang, A Wiebe © www.RxFiles.

Z Dumont BSP, P Ricci, L Gross, B Lang, A Wiebe © www.RxFiles.ca May 2021

Trials Intervention Population Key Baseline Indices Results Comments
Mean follow-up, n CKD stage, age, etc. (e.g. Iron Studies)
Charytan et al. 1
Oral vs IV iron for ND-CKD ND-CKD; Age mean ~61; mostly ♀, Hgb (g/L): 97 oral vs 98 IV  Hgb (g/L): +7 oral vs +10 IV; NS Iron therapy:
43 days; n=96; FeSO4 325mg po TID x 29 days vs (71% oral, 60% IV); multi-racial Ferritin (ng/mL): 103 oral vs 125 IV  Ferritin (ng/mL): -5.1 oral vs 288 IV; p<0.0001  Should be guided by iron status tests, Hgb
RCT, OL Iron sucrose 200mg IV weekly x 5 doses; Included: CrCl(C-G)≤40ml/min, TSAT (%): 15.6 oral vs 16.6 IV  Change in TSAT (%): day 36=2.1 oral vs 5.1 IV | day 43=0.5 oral vs 4.5 IV; sig levels, ESA dose, & pt status CSN 2008 Guidelines
assessments made up to 14 days after last Hgb<105g/L, TSAT<25%, increase for IV, but not oral
dose ferritin<300ug/L | Excluded: iron tx  # of pts achieved Hgb >110g/L: 31.3% vs 54.2% IV (p=0.028) Iron Therapy in Non-hemodialysis CKD pts
or blood transfusion w/in last month,  AE: similar between groups, most common is GI in oral group, & taste- (ND-CKD)
apparent GI bleed, Alb<30g/L disturbances more common in IV group
 Route of admin has been shown to have no
Van Wyck et al. 2 Oral vs IV iron for ND-CKD pts Stage 3-5 ND-CKD; Age mean ~63; Hgb (g/L): 101 oral vs 102 IV  % of pts w/Hgb ↑ of ≥10g/L: 28% po vs 44.3% IV; p=0.0344 difference in reaching Hgb targets Charytan, & IV is
~56 days; n=161; FeSO4 325mg po TID for 56 days vs mean eGFR ml/min/1.73m2: 28.5 oral vs Ferritin (ug/L): 104 oral vs 93 IV  % of IV pts with outcome: 53.1 ESA-use oral vs 38.3 no ESA; NS superior to oral Van Wyck; but in light of lack of
30.4 IV; 98 pts NOT on ESAs TSAT (%): 17 oral vs 16 IV  % of oral pts with outcome: 32.2 ESA-use oral vs 25.5 no ESA; NS
RCT, OL, ITT Iron sucrose 1g IV x2 doses over 14 days
{Primary outcome was a Hgb increase > or =1 g/dL} conclusive superiority evidence & due to ↑
Included: Hgb≤110g/L, TSAT≤25%,
ferritin≤300ug/L; if on Epo, no  for  eGFR (ml/min/1.73m2): -4.4 oral vs -1.45 IV; p=0.01 access risk problems & ↑cost, recommend oral
 QOL: no statistically significant differences iron first CSN 2008 Guideline
8 wks prior or during study
 QOL has not been shown to differ between
DeVita et al. 3 IV iron to high>400 vs low>200 HD-CKD; Age mean ~66.5; Hct (%): 30.5 High vs 29.5 Low  Hct (%): 34.0 High vs 36.1 Low {NS diff.}
Ferritin (ug/L): 203.7 High vs  Mean Ferritin (ug/L): 387 high-ferritin vs 261 low-ferritin patients treated with oral or IV iron Van Wyck
~5mos; n=36; ferritin for HD-CKD pts on ESAs Included: Hct≤33, Ferritin 70-400
Each subject below target received an IV iron
166.4 Low  End Ferritin (ug/L): 298.6 high-ferritin vs 469.4 low-ferritin  Studies show that ↑Hgb may occur following
RCT dextran load, Hct was maintained between 32.5-
 Epo dose (u/kg/wk): -154 high-ferritin vs -31 low-ferritin;
p<0.001
iron tx with ferritin ~100ug/L Charytan & Van Wyck
36% by adjusting Epo dose
 IV iron produces greater results regardless of
Besarab et al. 4 IV iron to high30-50 vs low20-30 HD-CKD; Age mean ~60.8; Hgb (g/L): 105 control vs 106 study  Hgb (g/L): 103 control vs 104 study
Ferritin (ug/L): 287 control vs 285 study  Ferritin (ug/L): 298 control vs 731 study ESA use Van Wyck
~6mos; n=42; TSAT for HD-CKD pts on ESAs 25 males, 17 females
Iron Trials

TSAT (%): 23.9 control vs 24.6 study

{16-20wk run-in period with IV iron dextran &
 TSAT (%): 27.6 control vs 32.6 study Iron Therapy in Hemodialysis
RCT, OL, ITT, erythropoietin to get to study levels of TSAT=20- Epo dose (units 3X/wk):
30% & Hgb=95-120}
3782 control vs 3625 study  Epo dose @6mos: 40% lower dose for study group vs control group CKD pts (HD-CKD)
single-centre 25-150mg IV iron dextran VS load of 100mg x6
control
(significant)
doses for 2wk then 25-150mg/wk study  Patients with higher ferritin (~400 vs 200 mcg/L)
Macdougall et Oral vs IV iron vs No iron for HD-CKD HD-CKD; Age mean ~58 Hgb (g/L): 72 oral vs 73 IV vs 73 no iron  Hgb (g/L): 102 oral vs 119 IV vs 99 no iron; p<0.05 require lower doses of ESAs DeVita, thus it is
al.5 pts on ESAs oral, 47 IV, & 54 no iron Ferritin (ug/L): 309 oral vs 345 IV vs 458 no iron
 ESA dose (unit/dose): 1294 oral vs 1202 IV vs 1475 no recommended to treat when ferritin ≤500
Oral ferrous sulfate 200mg TID vs iron dextran
~4mos; n=25; RCT 250mg q2wks vs no iron iron; NS mcg/L with iron therapy KDIGO 2012 Guidelines
 Weigh benefits vs risks of initiating iron tx in
Fishbane et al. 6 Oral vs IV iron for HD-CKD pts on HD-CKD; Age mean ~49.5 Hgb (g/L): 106 oral vs 108 IV  Hgb (g/L): 106 oral vs 115 IV; p<0.05 pts with ferritin >800ug/L & TSAT <25% DRIVE
ESA dose (units/treatment): 
~4mos; n=52 ESAs Included: TSAT>15%,
6750 oral vs 7100 IV 
Hct (%): 31.8 oral vs 34.4 IV; p<0.05
 Pts with higher TSAT% (30-50 vs 20-30)
Oral iron vs Iron dextran 100mg IV x2 wkly ferritin<100ng/mL ESA dose (units/treatment): 7563 oral vs 4050 IV; p<0.05
 Serum ferritin (ng/mL): 157.3 oral vs 753.9 IV; p<0.05
maintain Hgb with lower doses of ESAs Besarab,
therefore recommend to treat when TSAT
DRIVE I 7 IV iron vs No iron in HD-CKD pts with HD-CKD; Age mean ~59-60; Hgb (g/L): 104 IV vs 102 no iron  Hgb (g/dL): 1.6 IV vs 1.1 no iron; p=0.028
high ferritin, low TSAT ~1:1male:female; multi-racial Ferritin (ug/L): 759 IV vs 765 no iron  % of responders ≥20g/L ↑ (%): 49.6 IV vs 29.2 no iron; p=0.041 ≤30% with iron therapy KDIGO 2012Guidelines
~6wks; n=129 Ferrous gluconate 125mg IV with 8 TSAT (%): 18 IV vs 19 no iron   Studies looking at oral iron vs placebo have
modified ITT; RCT, consecutive HD sessions vs no iron; epo
Included: Hgb≤110g/L, TSAT≤25%, ferritin (ug/L): 173 IV vs -174 no iron; p<0.001
OL, multi-centre doses ↑ 25% in both groups at trial onset
ferritin=500-1200ug/L (stratified  baseline ferritin was not predictive of iron response shown that oral iron is no better than
(no other  permitted) before rand’n to < or > 800ug/L)  safety was no different if < or > 800 baseline ferritin (not powered to show safety) placebo (in Hgb improvements Mcdougall or ESA dose
 TSAT (%): 7.5 IV vs 1.8 no iron; p<0.001 minimization)
DRIVE II 8 Observational study of duration Extension Epo dose in DRIVE (units/wk):  Epo dose (units/wk) from dose given in DRIVE: -7527  IV iron has been shown to be superior to
~6wks; n=129 of effect from IV iron
under usual (i.e. used same DRIVE pts) 45,000 IV vs 43,700 no iron IV (p=0.003) vs 649 no iron (p=0.809) oral iron with respect to ↑Hgb Fishbane & Besarab
clinical mgt  % of pts with Hgb>110(g/L): 83.9 IV vs 67.9 no iron; p<0.05 & ↓ESA dose Fishbane
PIVOTAL 20 IV iron sucrose monthly: HD-CKD (new last 12mos); Age Hgb (g/L):~106 high vs ~105 low  Hard, patient-meaningful 1’ end-point: composite  Proactive IV iron sucrose doses (400mg) given
2.1 years; High-dose (400mg unless ferritin mean ~63; 65% males, 79% white Ferritin (ug/L): 214 high vs 217 low (nonfatal MI/stroke, hospitalization for HF, or death) monthly when ferritin ≤700 & TSAT <40% shown
n=2141; ITT, RCT, >700ug/L or TSAT ≥40%) vs low- race, ~45% had DM, ~72% had TSAT (%): 20 high vs 20 low  High-dose: 320 events (29.3%) vs low-dose: 338 (32.3%) to decrease CV events & ESA doses. PIVOTAL
OL, multi-centre dose (0-400mg when ferritin HTN. Included: ferritin <400ug/L, ESA dose (IU/wk): 8000 high vs (HR 0.85, 95% CI 0.73-1, P<0.001 for NI, P<0.04 for
(UK) <200ug/L or TSAT <20%). TSAT <30% & on ESA (stratified 8000 low superiority); consistent across subgroups
Median HD=264mg vs LD=145mg before rand’n by type of vascular  ESA median monthly dose 19.4% lower in high-dose
qmo access, DM, & HD during < or ≥5mos). group (~29,700 IU/mos vs ~38,800 IU/mos)
 Trend toward ↑vascular access thrombosis (NS), other
safety parameters not noticeably different
 Revicki et al. 9 Erythropoietin vs placebo in ND- ND-CKD; Age mean ~57, Hct (%): 26.8 ESA & untreated gp  HRQL Physical function: +7.8 ESA vs -4.8 untreated; ESA Therapy:
~48wks; n=83; CKD pts on health-related QOLHRQL ~67.5% female, Physical function score (/100): p=0.006 / all other tests NS  Goal of treating iron-replete pts with ESAs is to
Initially erythropoietin 50u/kg/dose SC mean GFR~10.1ml/min 44.3 ESA vs 49.1 untreated  Hct (%): +4.7 ESA vs -1 untreated (P < 0.0001)
RCT, OL, ITT 3xweekly or untreated; all treated pts could improve QOL, while minimizing any AE of the
have dosage ↑ (max 450u/kg/wk) unfil Hct  Withdrawals: 53.5 % (23/43) ESA vs 62.5% (25/40) drug & decreasing the need for transfusions
reached 36, then titrated to target 35
untreated  ESAs: ↑ blood pressure; caufion
Roth et al. 10 Erythropoietin vs placebo in ND- Used same pt population as GFR (ml/min): 10.2 ESA vs 10  GFR (ml/min): -2.1 ESA vs -2.8 untreated; NS p=0.376  ESAs: ↓ need for blood transfusions, which
(as with Revicki et al.) CKD pts, effect on rate of CKD decline Revicki untreated come with their own set of complications
Levin et al. 11 Early&High vs Delayed&Low ESA in ND-CKD; Age mean ~57, Hgb (g/L): 117.3 delayed vs  Hgb (g/L): -3 delayed vs 9.8 early  No clinical benefit has been shown with tx
~24mos; n=152; ND-CKD pts ~30% female, 38% DM, 117.6 early  LVMI@24mos(g/m2):+5.2 delayed vs +0.4 early; with ESAs early Levin & CREATE, therefore
RCT, OL, ITT
Erythropoietin 2000IU/wk initial dose given to: GFRmean~29ml/min; all pts “iron LVMI (g/m2): 98.3 delayed vs NS p=0.28 Tx should be withheld until Hgb is
1) study group to maintain Hgb 120-140g/L,
2) control group with a Hgb of 90g/L or less
replete” (TSAT>20%, ferritin>60ug/L) 100.6 early sustained below 100g/L & iron stores
before treatment with a target of 90-105g/L
are repleted & other causes of anemia
CREATE 12 Early/High-Hgb vs Late/Low- Stage 3-4 ND-CKD; Age mean ~59, Hgb (g/L): 116 early/high vs 116  CV Composite (sudden death, MI, acute HF, stroke, TIA, hosp’n for angina,
considered CSN 2008 Guidelines
~3yrs; n=603; Hgb Erythropoietin in CKD pts ~46% female, 26% DM late/low complication of PVD, or hosp’n for arrhythmia): 18% 58 events early/high vs
Erythropoietin beta given to target: Included: CrCl=15-35ml/min,Hgb<110g/L Ferritin (ug/L): 174 early/high vs 189 late/low 14% 47 events late/low; HR=0.78, NS p=0.20  LV mass: Pts treated to low or high Hgb targets
RCT, OL 
TSAT (%):25.6 early/high vs 38.1 late/low
1) start when Hgb 110-125g/L, Excluded: uncontrolled HTN LVMI @2yrs(g/m2): -4.6 early/high vs -3.3 late/low; NS do not show difference in progression of LV
target 130-150g/L 
LVMI (g/m2): 120 early/high vs 118 late/low QOL@2yr(SF-36): better general health with early/high p=0.008 & vitality p=0.01
2) start when Hgb 100g/L, target 105-115g/L
Of Note: Wt (kg): 74.7 early/high-Hgb vs

GFR (ml/min): 24.9 early/high vs 24.2 late/low eGFR (ml/min/yr): -3.6 early/high vs -3.1 late/low; NS mass in HD-CKD Parfrey & Foley or ND-CKD Levin & CREATE
71.8 late/low-Hgb; p=0.05
 Dialysis: 127 early/high vs 111 late/low; p=0.03  QOL in HD-CKD: high Hgb showed
 HTN (sys>160): 89 early/high vs 59 late/low; p=0.005
improvement in quality of life, but the effect
CHOIR 13 Erythropoietin to High- 130 (130-135) Stage 3-4 ND-CKD; Age mean ~66, Hgb (g/L): 101 high vs 101 low  Composite (death, MI, hosp’n for HF, stroke): 125 events waned over time Parfrey & Foley
Median 16mos; vs Low-Hgb 113 (105-110) in CKD pts ~55% female, GFR~27ml/min Ferritin (ug/L): 168 high vs 179 low (18%) high vs 97 events (14%) low; HR=1.34, p=0.03,
n=1432; RCT, OL  QOL in ND-CKD: Varying results show few
Included: CrCl=15-50ml/min, Hgb<110g/L TSAT (%): 25.2 high vs 24.6 low NNH=25 over 16months (driven by death & hosp’ns)
EARLY  Death: 52 high vs 36 low; NS, HR=1.48, p=0.07 areas are improved by treating with ESAs early
Excluded: uncontrolled HTN
TERMINATION Of Note:  QOL: significant differences in only 1 of 12 categories (emotional role) & to higher targets CREATE, CHOIR, & TREAT, & what
ND-CKD PEARL n=983, ≥52wks peginesatide monthly vs darbepoetin HTN (%): 95.8 high-Hgb vs 93.2 low-Hgb;  Any serious AE: 376 (54.8%) high vs 334 (48.5%) low; p=0.02
effects are seen do diminish over time CREATE
q2wk: Hgb target 110-120g/L, peg ↑CV mortality HR=1.32 p=0.03 CABG (%): 17.4 vs 13.5; p=0.05
 Any serious AE assoc’d w/ESA: 10 (1.5%) high vs 3 (0.4%) low; p=0.05
 HF: 77 (11.2%) high vs 51 (7.4%) low; p=0.02; [? ↑CKD Inrig’12]  Worsening kidney function in ND-CKD: No
Canadian EPO Erythropoietin to high-Hgb 115-130 vs HD-CKD; Hgb (g/L): 71 high vs 69 low vs  Sickness impact profile: 7.8 high vs 5.3 low vs 2.9 placebo studies have shown significant difference in tx
Erythropoietin to low-Hgb 95-110 vs Age mean ~43-44 EPO vs 48 71 placebo   Stress test m walked: 51 high vs 33 low vs 19 placebo to high vs low Hgb targets & the contribution
ESA

Study group 14 Placebo in HD-CKD pts Mean dose (units/kg/wk): 248 high vs 204 low
placebo; Hgb<90g/L  to worsening eGFR Roth & TREAT (may ↑ dialysis if tx
~6mos; n=118; Initially erythropoietin 100u/kg/dose 3xweekly; all
 Hgb (g/L): 117 high vs 102 low vs 74 placebo to higher targets CREATE, or may have no
pts with ferritin<250ug/L received oral or IV iron 1
RCT, DB month prior, & prn during the study  Dialysis access site clots: 7/38 high vs 4/40 low vs 1/40 placebo association TREAT)
 BP (sys/dia): 0/+7 high vs 0/+2 low vs -4/-1 placebo
 Hard endpoints in HD-CKD: Studies showing
Parfrey et al. 15 Erythropoietin to High135-145- vs HD-CKD; Agemean~50.8, ~60% male LVVI (ml/m2) gp: 296 high vs 300 low  %LVVI (%): 7.6 high-Hgb vs 8.3 low-Hgb; NS
%LVMI (%): 16.8 high vs 14.2 low; NS
hard endpoints, such as time to death or 1st MI
Low 95-115 Hgb in dialysis pts without Of Note: LVMI (g/m2) gp: 122 high vs 123 low 
~96wks; n=596; Mean Hgb (g/L) @24wks: 133 high vs 109 low Besarab
, show treating to high Hgb targets >130
symptomatic heart dx or LV dilation Age: 52.2 high-Hgb vs 49.4 low-Hgb; p=0.02 Hgb (g/L): 110 high vs 110 low 
RCT, DB Arms divided into “concentric LVH” & “LV dilation” SBP mmHg: 144 high-Hgb vs 140 low-Hgb; p=0.02
TSAT (%): 35.7 high vs 36.8 low  QOL @ (SF-36): 1.21 high vs -2.31 low; p=0.036 may produce more harm than good FDA warnings
 TSAT (%): 34.6 high vs 34.2 low  Hard(er) endpoints in ND-CKD: Studies
Foley et al. 16 Erythropoietin to High135 (130-140) HD-CKD; Age mean ~62, LVMI (g/m2): 147 high vs 139 low  LVMI @48wks (g/m2): NS; p=0.35Mann-Whitney U-test comparing composite CV endpoints show tx to
~48wks; n=146; vs Low100 (95-105) Hgb effect on ~45% male in LVH group, LVCVI (g/m2): 122 high vs 123 low  LVCVI @48wks (g/m2): NS; p=0.13Mann-Whitney U-test high Hgb targets >130 may lead to ↑CV events
cardiomyopathy in dialysis pts ~78% male in dilation group  Hgb (g/L): 122.5 high vs 104 low
RCT  Improvement in high group: fatigue p=0.009, depression p=0.02, & relationship p=0.004
CREATE & CHOIR
and stroke TREAT, though there are
some limitations to studies {CREATE: ?under-
Besarab 17 1998 Erythropoietin to “Normal”- 42% vs HD-CKD; Age mean ~65, Hct (%): 30.5 high vs 30.5 low  Time to death or 1st non-fatal MI: didn’t reach SS, term’d early
Low-HCT 30% in CKD pts w/ clinical  Death/1st non-fatal MI: 202 high vs 164 low; RR=1.3 95% CI 0.9-1.9; powered, CHOIR: see “Of note”; no iron protocol
Median 14mos; n=1233; ~50% female, Deaths: 183 high vs 150 low; Non-fatal MI: 19 high vs 14 low
EARLY evidence of HF or ischemic heart dx used, TREAT: 46% of “placebo” group received
Dialysis duration ~3.2yrs, ~44% DM,  reportedly improved physical functioning originally, but not confirmed in reanalysis. study drug for rescue}
TERMINATION “Normal Hematocrit Study” ~51% Class II NYHA HF (no class IV)  reanalysis: ↑Death/MI 1.28 95% CI 1.06-1.56; ↑Death 1.27 95% CI 1.04-1.54 Coyne ’12

 Meta-analysis of 9 RCTs (all n>100, follow-up

Tonelli et al. 18 Erythropoietin to High- vs Low- Hgb HD-CKD; IV Dose (units 3X/wk) to achieve Hgb  Cost/QALY: 110-120 vs 95-105 =$ 55,295;
in CKD pts: Cost-effectiveness targets: 95-105=3523, 110-120=5078, 120- 120-125 vs 110-120 =$ 613,015; >12wks) with CKD patients who were randomly
“typical US dialysis centre” population
Target Hgb g/L: 110-120, 120-125, 140 vs 95-105 125=6097,140=9341 140 vs 120-125 = $ 828,215 assigned to receive ESAs showed that targeting
HD-CKD EMERALD n=1608, ≥52wks peginesatide ~5mg/monthly vs ND-CKD & diabetes Hgb (g/L): 105 High vs 104 Low  1° outcome (death or CV event nonfatal MI, HF, stroke, hosp’n higher Hgb levels lead to ↑ all-cause mortality
epoetin 4600-9900 IU/1-3x/week: Hgb target 100-120g/L, Age mean ~68, ~56% female, Ferritin (ug/L): 131 darbe vs 137 Low for angina): 632 31.4% High 130 Target vs 302 29.7%Low 90 Target; NS (RR=1.17, p=0.031) & AV access thrombosis
peginesatide as effective as epoetin. TSAT (%): 23 High vs 23 Low  1° outcome (death or ESRD): 652 32.4% High vs 618 30.5% Low; NS (RR=1.34, p=0.0001)
eGFR ~33ml/min, BMI=30, CV hx
~65%, DM: 15yr history, A1C ~7%, Heart Failure (%): 31.5 High vs  ↑stroke 101 5% High vs 53 2.6% Low, HR=1.92 95%CI 1.38-2.68;  Results of TREAT reinforce that treating to
TREAT 19 Darbepoetin to High- vs Low- 35.2 low; p=0.01 p<0.001, NNH=42 / 2.4yr
on iron tx ~44%  higher i.e. physiologic Hgb levels Target: 130 g/L, achieved 125
Median 29mos; Hgb in CKD pts with type 2
Hgb (g/L) achieved: 125 High vs 106 Low
Included: eGFRMDRD 20-60ml/min/1.73m^2, FACT-Fatigue score (0least tired-  Venous Thromboembolisms: 41 2.0% High vs. 23 1.1%Low; p=0.02 may come with significant risks & only modest
n~4038; diabetes 52most tired): 30.2 High vs 30.4 Low.  Arterial Thromboembolisms: 178 8.9% High vs. 144 7.1%Low; p=0.04
Hgb<110g/L, TSAT>15% improvements in quality of life. Those with a
Target Hgb g/L: 130 in study group vs  ESRD: 338 16.8% High vs. 330 16.3% Low; NS
RCT, DB, ITT, multi- “placebo” control (≥90 placebo or if <90, Excluded: uncontrolled HTN, kidney
 Transfusions: 15% High vs. 25% Low; p<0.001 poor initial hematopoietic response to
centred then darbepoetin to >90) transplant, Ca, HIV, bleeding, preg  Fatigue: +4.2 High vs. +2.8 Low; p<0.001 darbepoetin had worse CV outcomes & death.
Note: 46% “placebo” had darbepoetin rescue, but ↓QOL  ESA:FDA June/11 if Hgb >110, then assoc. ↑MI/stroke.
CKD=chronic kidney dx C-G=Cockcroft-Gault dx=disease ESA=Erythropoiesis stimulating agent ESRD=end-stage renal dx FeSO4=ferrous sulfate Hct=hematocrit HD-CKD=dialysis-CKD HF=heart failure Hgb=hemoglobin HRQL=health-related QOL ITT=intention to treat LFT=liver function tests
LVMI=left ventricular mass index LVVI=left ventricular volume index LVCVI=left ventricular cavity volume index MCV=Mean corpuscular volume MI=myocardial infarction ND-CKD=non-dialysis CKD OL=open label pt=patient QALY=quality-adjusted life year QOL=quality of life RCT=randomized control trial
RDW=Red cell distribution width TIBC=total iron binding capacity TSAT=transferrin saturation TSH=thyroid stimulating hormone ♀=female =changes
References: Anemia - Hemoglobin Control: Landmark Outcome Trials – Summary (www.RxFiles.ca)
1 Charytan C, Qunibi W, Bailie GR, Venofer Clinical Studies G. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron 2005;100(3):55-62.
2 Van Wyck DB. Roppolo M. Martinez CO. Mazey RM. McMurray S. for the United States Iron Sucrose (Venofer) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-
dependent CKD. Kidney Int. 2005 Dec;68(6):2846-2856.
3 DeVita MV, Frumkin D, Mittal S, Kamran A, Fishbane S, et al. Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients. Clin.Nephrol. 2003 Nov;60(5):335-340.
4 Besarab A, Amin N, Ahsan M, Vogel SE, Zazuwa G, Frinak S, et al. Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J.Am.Soc.Nephrol. 2000 Mar;11(3):530-538.
5 Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996 Nov;50(5):1694-1699.
6 Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am.J.Kidney Dis. 1995 Jul;26(1):41-46.
7 Coyne DW, Kapoian T, Suki W, Singh AK, Moran JE, Dahl NV, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to
IV Iron with Elevated Ferritin (DRIVE) Study. J.Am.Soc.Nephrol. 2007 Mar;18(3):975-984.
8 Kapoian T, O'Mara NB, Singh AK, Moran J, Rizkala AR, Geronemus R, et al. Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J.Am.Soc.Nephrol. 2008 Feb;19(2):372-379.
9 Revicki DA, Brown RE, Feeny DH, Henry D, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am.J.Kidney Dis. 1995 Apr;25(4):548-554.
10 Roth D, Smith RD, Schulman G et al. Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. Am J Kidney Dis 1994; 24: 777–784.
11 Levin A, Djurdjev O, Thompson C, Barrett B, Ethier J, et al. Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Am.J.Kidney Dis. 2005 Nov;46(5):799-811.
12 Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N.Engl.J.Med. 2006 Nov 16;355(20):2071-2084. (CREATE)
13 Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N.Engl.J.Med. 2006 Nov 16;355(20):2085-2098. (CHOIR)
Inrig JK, Barnhart HX, Reddan D, et al. Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial.
Am J Kidney Dis. 2012 Sep;60(3):390-401.
14 Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group. BMJ 1990 Mar 3;300(6724):573-578.
Muirhead N, Keown PA, Churchill DN, et al. Dialysis patients treated with Epoetin α show improved exercise tolerance and physical function: A new analysis of the Canadian Erythropoietin Study Group trial. Hemodial Int. 2010 Dec 7.
doi: 10.1111/j.1542-4758.2010.00508.x.
15 Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J.Am.Soc.Nephrol. 2005 Jul;16(7):2180-2189.
16 Foley RN, Parfrey PS, Morgan J, Barre PE, Campbell P, Cartier P, et al. Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int. 2000 Sep;58(3):1325-1335.
17 Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N.Engl.J.Med.
1998 Aug 27;339(9):584-590. (Normal Hematocrit Study)
Coyne DW. The health-related quality of life was not improved by targeting higher hemoglobin in the normal hematocrit trial. Kidney Int , doi:10.1038/ki.2012.76.
18 Tonelli M, Winkelmayer WC, Jindal KK, Owen WF, Manns BJ. The cost-effectiveness of maintaining higher hemoglobin targets with erythropoietin in hemodialysis patients. Kidney Int. 2003 Jul;64(1):295-304.
19 Mix TC, et al. Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Am.Heart J. 2005 Mar;149(3):408-413.
Pfeffer, Marc A., Burdmann, Emmanuel A., Chen, Chao-Yin, et al. the TREAT Investigators, A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. N Engl J Med 2009 0: NEJMoa0907845.
Solomon Scott D, Lewis Eldrin F., Eckardt Kai-Uwe, et al. for the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic Response and Outcomes in Kidney Disease and Type 2 Diabetes. N Engl J
Med 2010; 363:1146-1155.
Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with darboetin alfa: the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) experience.
Circulation. 2011;124:2903–2908.
Mc Causland FR, Claggett B, Burdmann EA, et al. Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).
Am J Kidney Dis. 2018 Dec 19.
20. Macdougall IC, White C, Anker SD, et al; PIVOTAL Investigators and Committees. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis. N Engl J Med. 2019;380:447-58. DOI: 10.1056/NEJMoa1810742