Anemia is common in patients with chronic kidney disease and has been associated with increased risk of cardiovascular morbidity and mortality in observational studies as well as decreased patient quality of life and increased healthcare utilization. |
The current standard of care includes supplemental iron, erythropoiesis-stimulating agents, and red blood cell transfusions, although each has drawbacks. |
High doses of erythropoiesis-stimulating agents have been associated with increased cardiovascular complications and mortality. |
Hypoxia-inducible factor-prolyl hydroxylase inhibitors are novel treatments for anemia of chronic kidney disease that prevent degradation of the transcription factor hypoxia-inducible factor, which stimulates erythropoiesis to physiologic levels. |
Digital Features
Introduction
Disease Burden
Prevalence
Cardiovascular Risk and Mortality
Health-Related Quality of Life
Healthcare Resource Use
Current Standard of Care
Short-acting ESAs | Long-acting ESAs | HIF-PH inhibitors | |
---|---|---|---|
Pros | Reduces need for RBC transfusions [31] May reduce fatigue and improve HR-QOL [29] IV administration is preferred in patients on hemodialysis [32] | Reduces need for RBC transfusions [21] May reduce fatigue and improve HR-QOL [29] Can be administered less frequently than short-acting ESAs [33] May be cheaper than short-acting ESAs [34] IV administration is preferred in patients on hemodialysis [32] | Have been shown to be noninferior to ESAs in raising or maintaining Hb [35] Can be administered orally [36] May reduce the need for iron supplementation by mobilizing stored iron [37] |
Cons | Higher doses required to reach high Hb targets may increase risk of adverse cardiovascular outcomes [20] Often requires supplemental iron administration [3] Administered 3 times per week [31] | Higher doses required to reach high Hb targets may increase risk of adverse cardiovascular outcomes [21] Often requires supplemental iron administration [3] May confer increased risk of mortality compared with short-acting ESAs [38] | Additional research needed to evaluate potential effects on tumor growth [36] |
Iron
Erythropoiesis-Stimulating Agents
Impact of ESA-Mediated Anemia Correction
Impact of ESAs on HR-QOL
Red Blood Cell Transfusion
Special Populations
Elderly Patients
Diabetes
End-Stage Renal Disease
Kidney Transplantation
Emerging Alternatives
HIF-PH Inhibitors
Trial identifier | Participants | Nb | Study design | Comparator | Location | Treatment duration |
---|---|---|---|---|---|---|
Roxadustata | ||||||
Patients with DD-CKD | ||||||
NCT01596855 [86] | ESRD, hemodialysis, Hb 9–12 g/dl, stable epoetin 7 weeks | 87 | Phase 2 RCT OL | Epoetin alfa | China | 6 weeks |
NCT01147666 [87] | ESRD, maintenance hemodialysis ≥ 4 months, Hb 9.0–13.5 g/dl for 8 weeks, epoetin alfa and intravenous iron 4 weeks | 144 | Phase 2 RCT OL | Epoetin alfa | US | 6 weeks |
NCT01414075 [88] | Incident dialysis (2 weeks–4 months), Hb ≤ 10 g/dl, ferritin 50–300 ng/ml, TSAT 10%–30%, ESA-naïve, no intravenous iron ≥ 4 weeks | 60 | Phase 2b RCT OL | None | US, Russia, Hong Kong | 12 weeks |
NCT02652806 [35] | ESRD, dialysis ≥ 16 week, Hb 9.0–12.0 g/dl, stable epoetin alfa ≥ 6 weeks | 305 | Phase 3 RCT OL | Epoetin alfa | China | 26 weeks |
NCT02779764 [89] | Hemodialysis 3 times/weeks for ≥ 12 weeks, ESA ≥ 8 weeks, mean of 2 latest Hb levels 10–12 g/dl, TSAT ≥ 20% or ferritin ≥ 100 ng/ml | 164 | Phase 3 | None | Japan | 52 weeks |
NCT02780141 [89] | Hemodialysis ≥ 1 time/weeks, ESA-naïve, mean of 2 latest Hb levels ≤ 10 g/dl, TSAT ≥ 5% or ferritin ≥ 30 ng/ml | 75 | Phase 3 RCT OL | None | Japan | 24 weeks |
NCT02273726 (SIERRAS) [90] | ESRD, dialysis ≥ 3 months, Hb 8.5–12.0 g/dl, ferritin ≥ 100 ng/ml, TSAT ≥ 20%, ESA ≥ 4 weeks | 741 | Phase 3 RCT OL | Epoetin alfa | US | 52 weeks to 3 years |
NCT02174731 (ROCKIES) [91] | Hemodialysis or peritoneal dialysis; Hb < 12.0 g/dl in those on ESA, < 10 g/dl in those not on ESA; ferritin ≥ 100 ng/ml; TSAT ≥ 20% | 2133 | Phase 3 RCT OL | Epoetin alfa | North America, Asia, Australia, EU, India, South America | 52 weeks to 4 years |
NCT02278341 (PYRENEES) [92] | Stable hemodialysis or peritoneal dialysis, Hb 9.5–12 g/dl, epoetin alfa or darbepoetin alfa ≥ 8 weeks | 836 | Phase 3 RCT OL | ESA (epoetin alfa or darbepoetin alfa) | EU | 52–104 weeks |
NCT02052310 (HIMALAYAS) [93] | ESRD, incident dialysis (2 weeks–4 months) | 1043 | Phase 3 RCT OL | Epoetin alfa | US, Asia, EU, South America | 52 weeks to 3 years |
Patients with NDD-CKD | ||||||
NCT01599507 [86] | NDD-CKD (eGFR < 60 ml/min/1.73 m2), Hb < 10 g/dl | 91 | Phase 2 RCT DB | China | 8 weeks | |
NCT01244763 [94] | NDD-CKD (eGFR 15–59 ml/min/1.73 m2), Hb < 10.5 g/dl, ferritin > 30 ng/ml, TSAT ≥ 5%, no ESA use ≤ 12 weeks | 145 | Phase 2 RCT OL | None | US | 16 or 24 weeks |
NCT00761657 [95] | NDD-CKD stage 3–4 (eGFR 15–59 ml/min/1.73 m2), Hb < 11 g/dl | 117 | Phase 2a RCT | US | 4 weeks | |
NCT02652819 [96] | NDD-CKD stage 3–5, Hb 7– < 10 g/dl, no ESA use ≤ 5 weeks | 154 | Phase 3 RCT DB followed by OL extension | China | 8 weeks (RCT); 18 weeks (OL) | |
NCT01750190 (ANDES) [97] | NDD-CKD stage 3–5 | 922 | Phase 3 RCT DB | US, Asia, Australia, South America | < 52 weeks to 3 years | |
NCT01887600 (ALPS) [92] | NDD-CKD stage 3–5 (eGFR < 60 ml/min/1.73 m2), Hb ≤ 10 g/dl, ferritin ≥ 30 ng/ml, TSAT ≥ 5%, ESA-naïve | 594 | Phase 3 RCT DB | EU | 52–104 weeks | |
NCT02174627 (OLYMPUS) [98] | NDD-CKD stage 3–5 (eGFR < 60 ml/min/1.73 m2), Hb ≤ 10 g/dl, ferritin ≥ 50 ng/ml, TSAT ≥ 15%, ESA-naïve | 2781 | Phase 3 RCT DB | North America, Asia, EU, India, South America | 52 weeks | |
Daprodustata | ||||||
Patients with DD-CKD | ||||||
NCT02019719 [99] | Hemodialysis ≥ 8 weeks, Hb 9.5–12.0 g/dl, ferritin ≥ 100 μg/l, TSAT ≥ 20%, stable ESA use ≥ 4 weeks | 97 | Phase 2, RCT DB | Japan | 4 weeks | |
NCT01587924 [100] | Hemodialysis ≥ 8 weeks, Hb 9.5–12.0 g/dl, ferritin ≥ 40 ng/ml, stable ESA use ≥ 4 weeks | 83 | Phase 2a RCT DB | ESA | US, Canada, EU | 4 weeks |
NCT02075463 [101] | Stable hemodialysis ≥ 12 weeks, ESA hyporesponsiveness, ferritin ≥ 100 ng/ml, TSAT ≥ 20% | 15 | Phase 2a OL | None | US | 16 weeks |
NCT01977482 [102] | Adequate hemodialysis, Hb 9–11.5 g/dl, ferritin < 100 ng/ml, TSAT < 12%– > 57%, stable ESA use ≥ 4 weeks | 177 | Phase 2b RCT DB | ESA | US, Australia, EU, Canada, Asia | 24 weeks |
NCT02829320 [103] | Hemodialysis (newly initiated < 12 weeks and ESA-naïve or maintenance ≥ 12 weeks and no ESA use ≥ 8 weeks), Hb ≥ 8– < 10 g/dl, ferritin ≥ 100 ng/ml | 28 | Phase 3 RCT OL | None | Japan | 24 weeks |
Patients with NDD-CKD | ||||||
NCT01977573 [104] | NDD-CKD stage 3–5; Hb 8–11 g/dl (ESA-naïve), 9–11.5 g/dl (ESA users); for ESA users, stable ESA use ≥ 4 weeks | 252 | Phase 2 RCT | ESA | US, Australia, EU, Canada, Asia | 24 weeks |
NCT01587898 [100] | NDD-CKD stage 3–5, Hb 8.5–11.0 g/dl, ferritin ≥ 40 ng/ml or TSAT in reference range, no ESA use ≥ 7 weeks | 73 | Phase 2a RCT DB | US, Canada, EU | 4 weeks | |
Patients with NDD-CKD or DD-CKD | ||||||
NCT01047397 [105] | CKD stage 3–4 (eGFR 15–59 ml/min/1.73 m2), CKD stage 5 (eGFR 10– < 15 ml/min/1.73 m2), or CKD stage 5d (eGFR 10– < 15 ml/min/1.73 m2 and hemodialysis); ESA-naïve with Hb ≤ 11 g/dl or no ESA use ≥ 7 days | 107 | Phase 2a RCT | Australia, India, Russia | 28 days | |
Vadadustata | ||||||
Patients with DD-CKD | ||||||
NCT02260193 [106] | Maintenance hemodialysis thrice weekly ≥ 3 months, epoetin alfa and intravenous iron ≥ 3 months | 94 | Phase 2 OL | None | US | 16 weeks |
Patients with NDD-CKD | ||||||
NCT01906489 [107] | NDD-CKD stage 3a–5, ferritin level ≥ 50 ng/ml with TSAT ≥ 18% or a ferritin level ≥ 100 ng/ml regardless of TSAT | 210 | Phase 2 RCT DB | US | 20 weeks | |
NCT01381094 [108] | CKD stage 3 or 4 (eGFR 30–59 or 15–29 ml/min/1.73 m2), no ESA ≥ 11 weeks, Hb ≤ 10.5 g/dl, ferritin ≥ 50 ng/ml, TSAT ≥ 20% | 93 | Phase 2a, RCT | US | 6 weeks | |
Molidustata | ||||||
Patients with DD-CKD | ||||||
NCT01975818 (DIALOGUE 4) [109] | DD-CKD, Hb 9.0–11.5 g/dl, stable epoetin use ≥ 8 weeks | 199 | Phase 2b RCT OL | Epoetin alfa/beta | US, Japan | 16 weeks |
NCT02064426 (DIALOGUE 5) [110] | DD-CKD (from DIALOGUE 4) | 88 | OL extension of DIALOGUE 4 | Epoetin alfa/beta | US, Japan | ≤ 36 months |
Patients with NDD-CKD | ||||||
NCT02021370 (DIALOGUE 1) [109] | NDD-CKD (ESA-naïve eGFR < 60 ml/min/1.73 m2), Hb < 10.5 g/dl, ESA-naïve or no ESA use ≥ 8 weeks | 121 | Phase 2b RCT DB | EU, Asia–Pacific | 16 weeks | |
NCT02021409 (DIALOGUE 2) [109] | NDD-CKD (eGFR < 60 ml/min/1.73 m2), Hb 9–12 g/dl, stable darbepoetin use ≥ 8 weeks | 124 | Phase 2b RCT OL | Darbepoetin | EU, Asia–Pacific | 16 weeks |
NCT02055482 (DIALOGUE 3) [110] | NDD-CKD (from DIALOGUE 1 and 2) | 164 | OL extension of DIALOGUE 1 and 2 | Darbepoetin | EU, Asia–Pacific | ≤ 36 months |
Enarodustata | ||||||
Patients with DD-CKD | ||||||
JapicCTI-152892 [111] | Hemodialysis or hemodiafiltration 3 times per weeks ≥ 12 weeks, ESA therapy ≥ 4 weeks, mean Hb at screening and 2 weeks later 9.5–12.0 g/dl with absolute difference of ≤ 1.0 g/dl, TSAT > 20% or ferritin > 75 ng/ml | 85 | Phase 2b RCT DB followed by OL extension | Japan | 6 weeks (RCT); 24 weeks (OL) | |
Patients with NDD-CKD | ||||||
JapicCTI-152881 [112] | CKD not on dialysis (eGFR < 60 ml/min/1.73 m2), mean Hb 8.0–10.5 g/dl for correction group (ESA-naïve: no ESA ≥ 12 weeks) and 9.5–12.0 g/dl for conversion group (ESA-treated: stable ESA ≥ 8 weeks) | 201 | Phase 2b RCT DB followed by OL extension | Japan | 6 weeks (RCT); 24 weeks (OL) | |
Desidustata | ||||||
Patients with NDD-CKD | ||||||
CTRI/2017/05/008534 [113] | NDD-CKD stage 1–4, Hb 6.5–11 g/dl, ferritin 100–1000 μg/l or TSAT ≥ 20%, body weight ≥ 45 kg | 117 | Phase 2 RCT DB | India | 6 weeks |