Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease

Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.


Background: Anaemia occurs in chronic kidney disease (CKD) and is more prevalent with lower levels of kidney function. Anaemia in CKD is associated with death related to cardiovascular (CV) disease and infection. Established treatments include erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions. Oral hypoxia-inducible factors (HIF) stabilisers are now available to manage anaemia in people with CKD.

Objectives: We aimed to assess the benefits and potential harms of HIF stabilisers for the management of anaemia in people with CKD.

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 22 November 2021 through contact with the Information Specialist using search terms relevant to our review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria: Randomised and quasi-randomised studies evaluating hypoxia-inducible factors stabilisers compared to placebo, standard care, ESAs or iron supplementation in people with CKD were included.

Data collection and analysis: Five authors independently extracted data and assessed the risk of bias. Treatment estimates were summarised using random effects pair-wise meta-analysis and expressed as a relative risk (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Evidence certainty was assessed using GRADE.

Main results: We included 51 studies randomising 30,994 adults. These studies compared HIF stabilisers to either placebo or an ESA. Compared to placebo, HIF stabiliser therapy had uncertain effects on CV death (10 studies, 1114 participants): RR 3.68, 95% CI 0.19 to 70.21; very low certainty evidence), and nonfatal myocardial infarction (MI) (3 studies, 822 participants): RR 1.29, 95% CI 0.31 to 5.36; I² = 0%; very low certainty evidence), probably decreases the proportion of patients requiring blood transfusion (8 studies, 4329 participants): RR 0.51, 95% CI 0.44 to 0.60; I² = 0%; moderate certainty evidence), and increases the proportion of patients reaching the target haemoglobin (Hb) (10 studies, 5102 participants): RR 8.36, 95% CI 6.42 to 10.89; I² = 37%; moderate certainty evidence). Compared to ESAs, HIF stabiliser therapy may make little or no difference to CV death (17 studies, 10,340 participants): RR 1.05, 95% CI 0.88 to 1.26; I² = 0%; low certainty evidence), nonfatal MI (7 studies, 7765 participants): RR 0.91, 95% CI 0.76 to 1.10; I² = 0%; low certainty evidence), and nonfatal stroke (5 studies, 7285 participants): RR 1.06, 95% CI 0.71 to 1.56; I² = 8%; low certainty evidence), and had uncertain effects on fatigue (2 studies, 3471 participants): RR 0.80, 95% CI 0.56 to 1.16; I² = 0%; very low certainty evidence). HIF stabiliser therapy probably decreased the proportion of patients requiring blood transfusion (11 studies, 10,786 participants): RR 0.87, 95% CI 0.76 to 1.00; I² = 25%; moderate certainty evidence), but may make little or no difference on the proportion of patients reaching the target Hb (14 studies, 4601 participants): RR 1.00, 95% CI 0.93 to 1.07; I² = 70%; low certainty evidence), compared to ESA. The effect of HIF stabilisers on hospitalisation for heart failure, peripheral arterial events, loss of unassisted dialysis vascular access patency, access intervention, cancer, infection, pulmonary hypertension and diabetic nephropathy was uncertain. None of the included studies reported life participation. Adverse events were rarely and inconsistently reported.

Authors' conclusions: HIF stabiliser management of anaemia had uncertain effects on CV death, fatigue, death (any cause), CV outcomes, and kidney failure compared to placebo or ESAs. Compared to placebo or ESAs, HIF stabiliser management of anaemia probably decreased the proportion of patients requiring blood transfusions, and probably increased the proportion of patients reaching the target Hb when compared to placebo.

Trial registration: ClinicalTrials.gov NCT02019719 NCT01964196 NCT02952092 NCT02969655 NCT02988973 NCT01887600 NCT01750190 NCT02879305 NCT03029208 NCT02876835 NCT03409107 NCT03400033 NCT00761657 NCT01047397 NCT02652806 NCT02652819 NCT01596855 NCT01599507 NCT02021370 NCT02021409 NCT01975818 NCT02021318 NCT02052310 NCT01977573 NCT02865850 NCT02892149 NCT01977482 NCT03543657 NCT03350321 NCT03350347 NCT03439137 NCT03329196 NCT02791763 NCT01888445 NCT03054337 NCT02174627 NCT01906489 NCT02680574 NCT02648347 NCT01147666 NCT02278341 NCT02174731 NCT02273726 NCT02780726 NCT02780141 NCT03457701 NCT03029247 NCT02689206 NCT01414075 NCT03054350 NCT01587898 NCT01587924 NCT01381094 NCT01679587 NCT01971164 NCT03992066 NCT04059913 NCT01244763 NCT03799627 NCT03446612 NCT04012957 NCT04215120 NCT04027517 NCT04134026 NCT04313153.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Anemia* / drug therapy
  • Anemia* / etiology
  • Cardiovascular Diseases*
  • Cause of Death
  • Fatigue
  • Humans
  • Hypoxia
  • Iron / therapeutic use
  • Renal Insufficiency, Chronic* / therapy


  • Iron

Associated data

  • ClinicalTrials.gov/NCT02019719
  • ClinicalTrials.gov/NCT01964196
  • ClinicalTrials.gov/NCT02952092
  • ClinicalTrials.gov/NCT02969655
  • ClinicalTrials.gov/NCT02988973
  • ClinicalTrials.gov/NCT01887600
  • ClinicalTrials.gov/NCT01750190
  • ClinicalTrials.gov/NCT02879305
  • ClinicalTrials.gov/NCT03029208
  • ClinicalTrials.gov/NCT02876835
  • ClinicalTrials.gov/NCT03409107
  • ClinicalTrials.gov/NCT03400033
  • ClinicalTrials.gov/NCT00761657
  • ClinicalTrials.gov/NCT01047397
  • ClinicalTrials.gov/NCT02652806
  • ClinicalTrials.gov/NCT02652819
  • ClinicalTrials.gov/NCT01596855
  • ClinicalTrials.gov/NCT01599507
  • ClinicalTrials.gov/NCT02021370
  • ClinicalTrials.gov/NCT02021409
  • ClinicalTrials.gov/NCT01975818
  • ClinicalTrials.gov/NCT02021318
  • ClinicalTrials.gov/NCT02052310
  • ClinicalTrials.gov/NCT01977573
  • ClinicalTrials.gov/NCT02865850
  • ClinicalTrials.gov/NCT02892149
  • ClinicalTrials.gov/NCT01977482
  • ClinicalTrials.gov/NCT03543657
  • ClinicalTrials.gov/NCT03350321
  • ClinicalTrials.gov/NCT03350347
  • ClinicalTrials.gov/NCT03439137
  • ClinicalTrials.gov/NCT03329196
  • ClinicalTrials.gov/NCT02791763
  • ClinicalTrials.gov/NCT01888445
  • ClinicalTrials.gov/NCT03054337
  • ClinicalTrials.gov/NCT02174627
  • ClinicalTrials.gov/NCT01906489
  • ClinicalTrials.gov/NCT02680574
  • ClinicalTrials.gov/NCT02648347
  • ClinicalTrials.gov/NCT01147666
  • ClinicalTrials.gov/NCT02278341
  • ClinicalTrials.gov/NCT02174731
  • ClinicalTrials.gov/NCT02273726
  • ClinicalTrials.gov/NCT02780726
  • ClinicalTrials.gov/NCT02780141
  • ClinicalTrials.gov/NCT03457701
  • ClinicalTrials.gov/NCT03029247
  • ClinicalTrials.gov/NCT02689206
  • ClinicalTrials.gov/NCT01414075
  • ClinicalTrials.gov/NCT03054350
  • ClinicalTrials.gov/NCT01587898
  • ClinicalTrials.gov/NCT01587924
  • ClinicalTrials.gov/NCT01381094
  • ClinicalTrials.gov/NCT01679587
  • ClinicalTrials.gov/NCT01971164
  • ClinicalTrials.gov/NCT03992066
  • ClinicalTrials.gov/NCT04059913
  • ClinicalTrials.gov/NCT01244763
  • ClinicalTrials.gov/NCT03799627
  • ClinicalTrials.gov/NCT03446612
  • ClinicalTrials.gov/NCT04012957
  • ClinicalTrials.gov/NCT04215120
  • ClinicalTrials.gov/NCT04027517
  • ClinicalTrials.gov/NCT04134026
  • ClinicalTrials.gov/NCT04313153