Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis

Figures & data

Figure 1. (A) PRISMA flow diagram of study selection process.

Table 1. Study participant characteristics.

Studies	Years	Country	ClinicalTrials.gov number	Participants(n)	Gender	Age	does	Patient disease	Control	Iron supplementation
Besarab et al. [16]	2015	USA	NCT00761657	117	Both sexes	18 − 80 years old	1.5,2.0 or 0.7 mg/kg	anemia and Stage 3 or 4 CKD	Placebo - controlled	Yes (IV iron)
Chen et al. [17]	2017	China	NCT01599507	91	Both sexes	18 − 80 years old	Low (1.1–1.75 mg/kg) or high (1.50–2.25 mg/kg)	Chronic Kidney Disease Not Receiving Dialysis	Placebo -controlled	Yes (IV iron)
Chen et al. [17]	2017	China	NCT01596855	96	Both sexes	18 − 80 years old	low (1.1–1.8 mg/kg), medium (1.5–2.3 mg/kg)	Chronic Kidney Disease patinets undergoing dialysis	ESA- controlled	Yes (IV iron)
Chen et al. [20]	2019	China	NCT02652806	1043	Both sexes	18 to 75 years old	70 mg (in patients weighing40 to < 60 kg) or 100 mg (in patients weighing ≥ 60 kg)	end-stage kidney disease, had Chronic Kidney Disease patinets received dialysis for at least 16 weeks	Epoetin Alfa active- controlled	Yes (intravenous iron)
Chen et al. [19]	2019	China	NCT02652819	152	Both sexes	18 and 75 years old	According to a weight based starting dose of 70 mg (in patients weighing 40 to < 60kg)or 100 (in patients weighing ≥ 60kg)	Anemia in Patients with Kidney Disease Not Receiving Dialysis	Placebo - controlled	Yes (intravenous iron)
Akizawa et al. [24]	2019	Japan	NCT01964196	107	Both sexes	20–74 years old	(50, 70, or 100 mg) TIW	Japanese patients with anemia associated with NDD-CKD	Placebo- controlled	Yes (oral iron)
Akizawa et al. [20]	2020	Japan	NCT02952092.	303	Both sexes	≥20 years old	Initial dose of roxadustat (70 mg or 100 mg) TIW	CKD Patients with Anemia on Hemodialysis in Japan	ESA- controlled	Yes (oral and IV iron)
Coyne et al. [30]	2020	USA	NCT01750190	616	Both sexes	≥ 18 years old	Patients weighing 45 to <70 kg received 70 mg roxadustat or placebo, and those weighing ≥70 kg received 100 mg TIW	Stage 3–5 CKD and not on dialysis	Placebo - controlled	Yes(i.v. iron. Oral iron)
Akizawa et al. [25]	2021	Japan	NCT02988973	334	Both sexes	≥20 years old	Initial Dose Conversion to Roxadustat, Based on ESA Use	Anemia in NDD CKD	ESA- controlled	Yes (ferric citrate hydrat)
Hou et al. [26]	2021	China	ChiCTR2000035054	129	Both sexes	18–75 years old	The initial dose of roxadustat was given according to weight: 100 mg for patients weighing 45 to <60 kg and 120 mg for patients weighing 60 kg	CKD and renal anemia who received peritoneal dialysis	ESA- controlled	Yes (oral iron)
Shotov et al. [27]	2021	Russia	NCT01887600	597	Both sexes	≥ 18 years old	weight 45 to 70 kg = 70 mg; weight >70 to 160 kg= 100 mg	Anemia in chronic kidney	Placebo - controlled	Yes (oral iron)
Fishbane et al. [28]	2021	USA	NCT02174627	922	Both sexes	≥ 18 years old	The starting dose of roxadustat and placebo was 70 mg TIW The maximum dose was capped at the lower of 3.0 mg/kg or 300 mg per dose administration.	Anemia in chronic kidney disease patients not on dialysis	Placebo - controlled	Yes(iv iron or oral iron)
Barratt et al. [22]	2021	UK	NCT02021318	305	Both sexes	≥ 18 years old	weight-based dose weight 45.0 to 70.0 kg, roxadustat 70 mg; weight >70.0 to 160.0 kg, roxadustat 100 mg)	Stages 3–5 CKD who were not receiving dialysis	ESA- controlled	Yes (oral iron)
Provenzanoet al. [31]	2021	Russia	NCT02052310	741	Both sexes	≥18 years old	roxadustat was 70 mg (patients weighing	Chronic Kidney Disease patinets on hemodial dialysis or peritoneal dialysis for ESRD	Placebo- controlled	Yes(intravenous iron)
Charytan et al. [32]	2021	USA	NCT02273726	834	Both sexes	≥18 years old	Roxadustat starting doses were 70, 100, 150, or 200 mg TIW based on the patient’s prescribed prestudy ESA dose.	ESKD and were on dialysis for ≥3 months	ESA- controlled	Yes(i.v. iron or Oral iron)
Csiky et al. [23]	2021	Hungary	number 2013-001497-16	143	Both sexes	at least 18 years old	Roxadustat was supplied as 20-mg, 50-mg, and 100-mg tablets for oral administration TIW	Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis	ESA- controlled	Yes(i.v. iron or Oral iron)
Wu et al. [33]	2022	China	2021-KY-0271	143	Both sexes	18–75 years old	Roxadustat was 100 mg (in patients weighing between 45 and <60 kg) or 120 mg (in patients weighing ≥60 kg) three times a week orally	anemia and residual renal function in patients new to peritoneal dialysis	ESA- controlled	Yes (oral iron)
Fishbane et al. [29]	2022	USA	NCT02174731	2133	Both sexes	≥18 years	roxadustat who were receiving an ESA at entry, starting doses were 70–200 mg TIW, based on prior ESA dose; ESAnaive patients at entry started roxadustat on either 70 mg (patients with dry weights 45–70 kg) or 100 mg (dry weights 70–160 kg) TIW	CKD on hemodialysis or peritoneal dialysis	ESA- controlled	Yes (oral iron)

The table represents data from studies stratified by the intervention and comparator.

Figure 2. Risk of bias graph. (A) Risk of bias summary, (B) risk for each included study.

Figure 5. Forest Plots of the effect of roxadustat on the risk of progression to ESKD. (A) Forest Plots of the effect of roxadustat in NDD patients on progression to ESKD compared with placebo or ESA. (B) Forest Plots of the effect of roxadustat on progression to ESKD based on continent. All outcomes are reported in risk ratios (RRs) for treatment vs the comparator and 95% credible intervals (95%-CI).

Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015;30(10):1665–1673. doi:10.1093/ndt/gfv302.

 PubMed Web of Science ®Google Scholar

Chen N, Qian J, Chen J, et al. Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China. Nephrol Dial Transplant. 2017;32(8):1373–1386. doi:10.1093/ndt/gfx011.

 PubMed Web of Science ®Google Scholar

Akizawa T, Iwasaki M, Yamaguchi Y, et al. Phase 3, randomized, Double-Blind, Active-Comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol. 2020;31(7):1628–1639. doi:10.1681/ASN.2019060623.

 PubMed Web of Science ®Google Scholar

Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381(11):1001–1010. doi:10.1056/NEJMoa1813599.

 PubMed Web of Science ®Google Scholar

Akizawa T, Iwasaki M, Otsuka T, et al. Roxadustat treatment of chronic kidney disease-associated anemia in japanese patients not on dialysis: a phase 2, randomized, Double-Blind, placebo-controlled trial. Adv Ther. 2019;36(6):1438–1454. doi:10.1007/s12325-019-00943-4.

 PubMed Web of Science ®Google Scholar

Coyne DW, Roger SD, Shin SK, et al. Roxadustat for CKD-related anemia in non-dialysis patients. Kidney Int Rep. 2021;6(3):624–635. doi:10.1016/j.ekir.2020.11.034.

 PubMed Web of Science ®Google Scholar

Akizawa T, Iwasaki M, Otsuka T, et al. Phase 3 study of roxadustat to treat anemia in non-dialysis-Dependant CKD. Kidney Int Rep. 2021;6(7):1810–1828. doi:10.1016/j.ekir.2021.04.003.

 PubMed Web of Science ®Google Scholar

Hou YP, Mao XY, Wang C, et al. Roxadustat treatment for anemia in peritoneal dialysis patients: a randomized controlled trial. J Formos Med Assoc. 2022;121(2):529–538. doi:10.1016/j.jfma.2021.06.004.

 PubMed Web of Science ®Google Scholar

Shutov E, Sułowicz W, Esposito C, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant. 2021;36(9):1629–1639. doi:10.1093/ndt/gfab057.

 PubMed Web of Science ®Google Scholar

Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study. J Am Soc Nephrol. 2021;32(3):737–755. doi:10.1681/ASN.2020081150.

 PubMed Web of Science ®Google Scholar

Barratt J, Andric B, Tataradze A, et al. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant. 2021;36(9):1616–1628. doi:10.1093/ndt/gfab191.

 PubMed Web of Science ®Google Scholar

Provenzano R, Shutov E, Eremeeva L, et al. Roxadustat for anemia in patients with end-stage renal disease incident to dialysis. Nephrol Dial Transplant. 2021;36(9):1717–1730. doi:10.1093/ndt/gfab051.

 PubMed Web of Science ®Google Scholar

Charytan C, Manllo-Karim R, Martin ER, et al. A randomized trial of roxadustat in anemia of kidney failure: SIERRAS study. Kidney Int Rep. 2021;6(7):1829–1839. doi:10.1016/j.ekir.2021.04.007.

 PubMed Web of Science ®Google Scholar

Csiky B, Schömig M, Esposito C, et al. Roxadustat for the maintenance treatment of anemia in patients with End-Stage kidney disease on stable dialysis: a european phase 3, randomized, Open-Label, Active-Controlled study (PYRENEES). Adv Ther. 2021;38(10):5361–5380. doi:10.1007/s12325-021-01904-6.

 PubMed Web of Science ®Google Scholar

Thompson S, James M, Wiebe N, et al. Cause of death in patients with reduced kidney function. J Am Soc Nephrol. 2015;26(10):2504–2511. doi:10.1681/ASN.2014070714.

 PubMed Web of Science ®Google Scholar

Fishbane S, Pollock CA, El-Shahawy M, et al. Roxadustat versus epoetin alfa for treating anemia in patients with chronic kidney disease on dialysis: results from the randomized phase 3 ROCKIES study. J Am Soc Nephrol. 2022;33(4):850–866. doi:10.1681/ASN.2020111638.

 PubMed Web of Science ®Google Scholar