Safety of Roxadustat Combined with Epoetin Alfa in Hemodialysis Patients with Anemia: A Cohort Study

doi:10.21203/rs.3.rs-2222877/v1

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Safety of Roxadustat Combined with Epoetin Alfa in Hemodialysis Patients with Anemia: A Cohort Study

https://doi.org/10.21203/rs.3.rs-2222877/v1

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Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis¹, China was the first country in the world to complete phase III clinical trials and was officially approved for marketing in 2018². Recombinant human erythropoietin(rhEPO) is a traditional exogenous supplement of erythropoietin for the treatment of renal anemia.Due to a lack of research on the combination therapy, the FDA(Food and Drug Administration)does not recommend using roxadustat and recombinant human erythropoietin(rhEPO) together³.

Methods: This cohort study was carried out at Nanyang Central Hospital in Nanyang, Henan, China, between January 2020 and January 2022.We compared roxadustat combined with epoetin alfa(combination group) with roxadustat and epoetin alfa for post-dialysis systolic pressure, adverse events(AEs) and major adverse cardiovascular events(MACEs) in end-stage renal disease(ESRD) patients with anemia who were undergoing hemodialysis.The primary outcomes were the mean change in the postdialysis systolic pressure from baseline(BL) to 28 weeeks,and the secondary outcomes were MACEs and AEs.

Results: A total of 96 participants were included. From baseline to weeks 28,the mean(±SE) change in the postdialysis systolic pressure was -6.6±23.3mmHg in the epoetin alfa group,-5.5±26.9mmHg in the roxadustat group, and 8.8±21.0mmHg in the combination group. During a follow-up of 28 weeks, a worsening hypertension occurred in 3 of 42 patients (7.1%) in the epoetin alfa group, in 1 of 35 patients (2.9%) in the raxadustat group and in 0 of 19 patients(0%) in the combination group. The proportion of patients with MACEs and AEs were similar across the three groups.

Conclusions: We found that roxadustat combined with epoetin alfa had greater risk of elevated systolic pressure compared to oral roxadustat or parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis in the 28 weeks, and the proportion of patients experiencing AEs and MACEs was generally similar across the three grouos.At this time, clinical studies with larger sample size and longer follow-up time are needed to confirm.

Roxadustat

Epoetin alfa

Anemia

Hemodialysis

Safety

China has a prevalence of chronic kidney disease(CKD) of about 10.8%,the prevalence of hypertension in maintenance hemodialysis patients is about 80%, and the prevalence of anemia is about 90%, both of which are independent risk factors affecting prognosis 4,5. Clinical trials have shown that rhEPO is the standard therapy for anemia in patients with CKD 6-8. However, high-dose rhEPO use is associated with increased risks of hypertension, cardiovascular disease,and death, according to research 9-12.

Roxadustat is a reversible and potent inhibitor of hypoxia-inducible factor(HIF) prolyl hydroxylase.HIF elevated in the body following roxadustat use involved in the regulation of peripheral blood pressure.Experiments on animals showed that roxadustat treatment did not elevate blood pressure 13. However, some clinical research showed roxadustat was non-inferior to darbepoetin alfa for change in mean arterial pressure(MAP) and time to occurrence of hypertension 14,15,the incidence rate for AEs and MACEs were similar between roxadustat and rhEPO patients16-18.A research had shown that roxadustat combined with ESAs treatment might be more beneficial to improve renal anemia in hemodialysis patients with rhEPO resistance19,but there are still no studies on the safety of roxadustat combined with erythropoietin.

We now report AEs and MACEs,particularly changes in postdialysis systolic pressure in a 28-weeks, retrospective cohort study involving patients undergoing hemodialysis at Nanyang Central Hospital.

Patients

Those eligible patients were between the ages of 18 and 75 years, had end-stage kidney disease, and were receiving epoetin alfa on a daily basis for at least eight weeks.Patients who had anemia that was unrelated to CKD, received hormones, NSAIDs, and SCLT-2 inhibitors which affect blood pressure were excluded.A complete process of inclusion and exclusion is provided in Figure 1.

Data Collection

We collected demographics,coexisting condition,28-week predialysis and postdialysis blood pressure,laboratory values,AEs,MACEs,and medication.To calculate the average postdialysis systolic pressure for four times in the middle of the week, such as Monday, Wednesday, and Friday,take the average value of the mean postdialysis systolic pressure value for four times on Wednesday.The laboratory values are based on the clinical results of the month of the first blood test after January 2020.The laboratory values of the patients in the roxadustat group were the one month before the long-term use of rhEPO was changed to roxadustat. The laboratory values of the patients in the combination group were the one month before the first combined use of rhEPO and roxadustat.The principal secondary outcomes were the time to the first occurrence of a MACEs and AEs.

Statistical Analysis

Measurement data were expressed as Mean±SD. Differences among groups were analyzed by Student t test or one-way ANOVA , SNK or LSD method was used for multiple comparison. Qualitative data were described as percentages and analyzed using Chi-square (x2) test or Fishers exact test as indicated. The P-value reported was two-sided and value of less than 0.05 was considered statistically significant.All the analyses were performed with Free Statistics software versions I.VI or GraphPad Prism 9.

Patients

From January 2020 to January 2022, a total of 96 patients were selected, 35 in the roxadustat group,42 in the epoetin alfa group,and 19 in the combination group(Figure 1).

The characteristics of the patients—including age,gender,weight, coexisting conditions and the majority of the laboratory values were well balanced among the three groups at baseline.The mean(±SD) baseline postdialysis systolic pressure was 149.3±21.6mmHg across the three groups. There were more patients who required changes in on-treatment blood pressure medication in the daprodustat group and the combination group,with 16 patients (38.1%)receiving epoetin alfa,15(42.9%) receiving daprodustat,and 8(42.1%)receiving combination therapy needing at least one change(Table 1).

Table 1.Characteristics of the Patients at Baseline.

		Treatment group			Treatment group
Characteristic	Total(n=96)	ESA(n=42)	Both(n=19)	P	Roxadustat(n=35)	Both(n=19)	P
Demographic
Age,years	55.6±14.8	56.5±13.1	57.7±17.0	0.75	53.5±15.5	57.7±17.0	0.36
Sex,n(%)				0.26			0.58
Male	55(57.3)	21(50)	13(68.4)		21(60)	13(68.4)
Female	41(42.7)	21(50)	6(31.6)		14(40)	6(31.6)
Weight,kg	66.4±12.8	65.4±11.8	64.7±13.0	0.84	68.5±13.9	64.7±13.0	0.34
Coexisting condition,n(%)
Coronary artery disease	32(33.3)	13(31)	7(36.8)	0.77	12(34.3)	7(36.8)	1
Heart failure	38(39.6)	13(31)	9(47.4)	0.27	16(45.7)	9(47.4)	1
Valvular heart disease	2(2.1)	1(2.4)	1(5.3)	0.52	0(0)	1(5.3)	0.34
Angina pectoris	6(6.2)	2(4.8)	2(10.5)	0.60	2(5.7)	2(10.5)	0.60
Atrial fibrillation	2(2.1)	0(0)	2(10.5)	0.09	0(0)	2(10.5)	0.12
Myocardial infarction	13(13.5)	1(2.4)	0(0)	1	3 (8.6)	0(0)	1
Transient ischemic attack	1(1.1)	0(0)	0(0)	1	1(2.9)	0(0)	1
Cardiac arrest	1(1.0)	0(0)	0(0)	1	1(2.9)	0(0)	1
Thromboembolic events,n(%)	3(3.1)	0(0)	0(0)	1	3(8.6)	0(0)	0.55
Hypertension,n(%)	87(90.6)	39(92.9)	15(78.9)	0.19	33(94.3)	15(78.9)	0.19
Diabetes,n(%)	39 (40.6)	20 (47.6)	6(31.6)	0.30	13(37.1)	6(31.6)	0.78
Infection,n(%)	24 (25.0)	7 (16.7)	7(36.8)	0.10	10(28.6)	7(36.8)	0.56
Tumor,n(%)	5(5.2)	2(4.8)	1(5.3)	1	2(5.7)	1(5.3)	1
Blood pressure,mmHg
Postdialysis Systolic pressure,mmHg	149.3±21.6	151.2±21.7	138.8±20.6	0.04	152.8±20.8	138.8±20.6	0.02
Postdialysis Diastolic pressure,mmHg	79.9±12.4	80.7±13.6	75.2±11.9	0.13	81.5±10.8	75.2±11.9	0.05
Laboratory values
Hemoglobin,g/L	89.7±18.9	95.3±21.1	83.9±16.2	0.04	86.1±15.7	83.9±16.2	0.62
White blood cell count,No.*10⁹/L	6.6±2.4	6.0 ± 1.7	6.1±1.8	0.89	7.4±3.1	6.1±1.8	0.09
Platelets,No.*10⁹/L	192.8±66.0	183.8±60.9	180.7±74.2	0.86	210.2±65.6	180.7±74.2	0.14
Total iron,umol/L	9.3±2.7	9.4±2.7	8.7±3.0	0.48	9.4±2.4	8.7±3.0	0.47
Ferritin,ng/mL	169.6±103.0	189.3±92.8	151.5±62.8	0.11	155.8±127.6	151.5±62.8	0.89
TG,mmol/L	1.3±0.6	1.3±0.5	1.3±0.8	0.83	1.4±0.6	1.3±0.8	0.56
Cholesterol,mmol/L
Total	3.8±1.1	4.0±0.9	3.4±1.0	0.02	3.8±1.4	3.4±1.0	0.34
Low density lipoprotein	2.1±0.7	2.2±0.4	2.0±0.5	0.08	2.1±0.9	2.0±0.5	0.60
High density lipoprotein	1.2±0.2	1.2±0.1	1.1±0.3	0.18	1.1±0.3	1.1±0.3	0.86
P,mmol/L	1.9±0.5	2.0 ± 0.6	1.9±0.3	0.61	1.9±0.5	1.9±0.3	0.65
Albumin,g/L	37.0(34.0, 40.9)	37.8(34.2, 42.0)	35.8(31.6, 39.0)	0.065	36.9(34.7, 41.0)	35.8(31.6, 39.0)	0.13
CRP,mg/L	7.5(5.8, 11.1)	7.3(5.7,8.8)	8.5(6.3,12.5)	0.10	7.5(5.7,14.4)	8.5(6.3,12.5)	0.57
PTH,pg/mL	403.3(322.7,486.6)	475.2 (347.2, 663.6)	388.2 (303.7, 447.8)	0.03	380.6(301.7,436.4)	388.2 (303.7, 447.8)	0.75
Medication,n(%)
ACE/ARB	22(22.9)	9(21.4)	6(31.6)	0.52	7(20)	6(31.6)	0.51
βRB	23(24.0)	14(33.3)	3(15.8)	0.23	6(17.1)	3(15.8)	1
CCB	42(43.8)	22(52.4)	8(42.1)	0.59	12(34.3)	8(42.1)	0.77
αRB	12(12.5)	9(21.4)	0(0)	0.04	3(8.6)	0(0)	0.55
Iron
Oral	46(47.9)	18(42.9)	11(57.9)	0.42	17(48.6)	11(57.9)	0.59
Intravenous	12(12.5)	5(11.9)	4(21.1)	0.43	3(8.6)	4(21.1)	0.21
Changes in on- treatment BP medications,n(% )				0.19			0.10
No change	57(59.4)	26(61.9)	11(57.9)		20(57.1)	11(57.9)
At least one change	39(40.6)	16(38.1)	8(42.1)		15(42.9)	8(42.1)
Decrease	9(9.4)	3(7.1)	0(0)		6(17.1)	0(0)
Increase	26(27.1)	9(21.4)	8(42.1)		9(25.7)	8(42.1)
Switch	4(4.2)	4(9.5)	0(0)		0(0)	0(0)

Primary Outcomes

In the combination group, there was an upward trend in the change in mean postdialysis systolic pressure from baseline to 28 weeks(Figure 2).

The mean change in the mean postdialysis systolic pressure from baseline to the average value during weeks 25 through 28 was -6.6 ± 23.3mmHg in the epoetin alfa group,-5.5±26.9mmHg in the roxadustat group and 8.8 ± 21.0mmHg in the combination group. From baseline to the average value during weeks 25 through 28,the mean change in the mean postdialysis systolic pressure in the daprodustat group as compared with the epoetin alfa group(β,1.15mmHg;95%CI,-10.57 to 12.8),in the combination group as compared with the epoetin alfa group (β,15.43mmHg;95%CI,2.29 to 28.56), in the combination group as compared with the raxadustat group(β,14.28mmHg;95%CI,0.79 to 29.35).(Table 2).

Table2. Summary of Primary and Principal Secondary Outcomes among ESA, Roxadustat and Both.

A Roxadustat vs ESA

Variable	Epoetin Alfa(n = 42)	Roxadustat(n =35)	Treatment Effect(95%CI)	P
Primary outcome—mmHg^a
Change in postdialysis systolic pressure from BL to Wk28	-6.6 ± 23.3	-5.5 ± 26.9	1.15(-10.57,12.8)	0.85
Key Secondary Outcomes,n(%)
Adverse events^b	20 (47.6)	18 (51.4)	-	-
Hypertension	1 (2.4)	0 (0)	-	-
Hypotension	4 (9.5)	2 (5.7)	-	-
Heart failure	7 (16.7)	6 (17.1)	0.99(0.33,2.96)	0.99
Worsening hypertension^c	3 (7.1)	1 (2.9)	0.58 (0.05,6.42)	0.66
Thromboembolic events^d	1 (2.4)	2 (5.7)	2.4 (0.22,26.43)	0.48
Infection	9 (21.4)	8 (22.9)	-	-
Esophageal or gastric erosions	1 (2.4)	3 (8.6)	-	-
MACEs^e	5 (11.90)	2 (5.71)	0.19 (0.02,1.55)	0.12
Death from any cause	1 (2.4)	1 (2.9)	-	-
Nonfatal myocardial infarction	2 (4.8)	0 (0)	-	-
Nonfatal stroke	2 (4.8)	1 (2.9)	-	-

B Combination vs ESA

Variable	Epoetin Alfa(n = 42)	Combination(n =19)	Treatment Effect(95%CI)	P
Primary outcome—mmHg
Change in postdialysis systolic pressure from BL to Wk28,mmHg	-6.6 ± 23.3	8.8 ± 21.0	15.43 (2.29,28.56)	0.02
Key Secondary Outcomes,n(%)
Adverse events	20 (47.6)	6 (31.6)	-	-
Hypertension	1 (2.4)	1 (5.3)	-	-
Hypotension	4 (9.5)	0 (0)	-	-
Heart failure	7 (16.7)	3 (15.8)	0.9 (0.23,3.49)	0.88
Worsening hypertension	3 (7.1)	0 (0)	0 (0,Inf)	0.99
Thromboembolic events	1 (2.4)	1 (5.3)	2.22 (0.14,35.43)	0.57
Infection	9 (21.4)	1 (5.3)	-	-
Esophageal or gastric erosions	1 (2.4)	0 (0)	-	-
MACE	5 (11.90)	1 (5.3)	0.35 (0.04,2.94)	0.34
Death from any cause	1 (2.4)	0 (0)	-	-
Nonfatal myocardial infarction	2 (4.8)	0 (0)	-	-
Nonfatal stroke	2 (4.8)	1 (5.3)	-	-

C Combination vs roxadustat

Variable	Roxadustat(n = 35)	Combination(n =19)	Treatment Effect(95%CI)	P
Primary outcome—mmHg
Change in postdialysis systolic pressure from BL to Wk28,mmHg	-5.5 ± 26.9	8.8 ± 21.0	14.28 (-0.79,29.35)	0.06
Key Secondary Outcomes,n(%)
Adverse events	18 (51.4)	6 (31.6)	-	-
Hypertension	0 (0)	1 (5.3)	-	-
Hypotension	2 (5.7)	0 (0)	-	-
Heart failure	6 (17.1)	3 (15.8)	0 (0,Inf)	0.99
Worsening hypertension	1 (2.9)	0 (0)	0 (0,Inf)	0.99
Thromboembolic events	2 (5.7)	1 (5.3)	0.92 (0.08,10.13)	0.95
Infection	8 (22.9)	1 (5.3)	-	-
Esophageal or gastric erosions	3 (8.6)	0 (0)	-	-
MACE	2 (5.71)	1 (5.3)	1.96 (0.12,31.3)	0.64
Death from any cause	1 (2.9)	0 (0)	-	-
Nonfatal myocardial infarction	0 (0)	0 (0)	-	-
Nonfatal stroke	1 (2.9)	1 (5.3)	-	-

a Primary outcome excluded those data that death or loss to follow-up.

b Adverse events were defined as treatment-emergent if they started or became worse on or after

treatment start, up to the day after the last nonzero dose date.

c Based on adverse-event reported,including brain or fundus hemorrhage, etc ¹⁷.

d Thromboembolic events included deep vein thrombosis, vascular access thrombosis and

pulmonary embolism.

e MACE:a composite of death from any cause, nonfatal myocardial infarction,or nonfatal stroke.

Key Secondary Outcome

A total of 20 of 42 patients(47.6%) treated with epoetin alfa,18 of 35 patients(51.4%) treated with roxadustat,and 6 of 19 patients(31.6%) treated with the combination of epoetin alfa and roxadustat reported at least one adverse event during treatment.All treatment groups experienced similar rates of adverse events during the trial.More patients in the epoetin alfa group(3[7.1%]) compared with the roxadustat group(1[2.9%]) and the combination group(0[0%]) experienced a worsening of hypertension.The most frequently reported adverse event was infection,which occurred in 9 patients(21.4%) in the epoetin alfa group,8 patients(22.9%) in the roxadustat group and 1 patients(5.3%) in the combination group(Table 2).

The results of superiority testing were not significant for MACEs, thromboembolic events,hospitalization for heart failure,and worsening hypertension.The first occurrence of MACEs in the daprodustat group as compared with the epoetin alfa group(hazard ratio,1.15;95%CI,-10.57 to 12.8),thromboembolic events(hazard ratio,2.4;95%CI,0.22 to 26.43),hospitalization for heart failure(hazard ratio,0.99;95%CI,0.33 to 2.96),and worsening hypertension(hazard ratio, 0.58;95%CI,0.05 to 6.42).The first occurrence of MACEs in the combination group as compared with the epoetin alfa group(hazard ratio,0.35;95%CI,0.04 to 2.94),thromboembolic events(hazard ratio,2.22;95%CI,0.14 to 35.43),hospitalization for heart failure(hazard ratio,0.9;95%CI,0.23 to 3.49),and worsening hypertension(hazard ratio,0;95% CI, 0 to lnf).The first occurrence of MACEs in the combination group as compared with the roxadustat group(hazard ratio,1.96;95%CI,0.12 to 31.3), thromboembolic events (hazard ratio,0.92; 95% CI, 0.08 to 10.13), hospitalization for heart failure (hazard ratio,0;95%CI,0 to lnf),and worsening hypertension(hazard ratio,0;95%CI,0 to lnf).(Table 2 and Figure 3).

In Europe,there were 6+2 RCTs investigating the efficacy and safety of roxadustat,and the results showed that roxadustat had a prominent signal of serious thrombotic events and seizure in dialysis patients,and mortality is higher3.In China,there was a 6-month,phase 3 trial involving patients undergoing dialysis conducted by N.Chen,that study found roxadustat appears to have no particularly prominent adverse events relative to epoetin alfa1.In a post-hoc exploratory analysis of four phase 3 studies showed there was no evidence of an increased cardiovascular event or mortality risk among anemia-related dialysis patients treated with roxadustat compared to ESA20.

The results of a multicenter cross-sectional study showed that rhEPO treatment was an independent risk factor for predialysis hypertension and poor blood pressure control21. It had been shown that hypoxia-inducible factor(HIF) regulates peripheral blood pressure in mice and reduces hypertension in a dose-dependent manner13.Nevertheless,about 10% of dialysis patients in phase II clinical studies22 and about 12.3% of patients in a phase III clinical trial1, experienced increased blood pressure after using roxadustat,the mechanism needs to be further studied.

Since the first clinical use of roxadustat in China in December 2018,there has been disagreement about its safety.At present,there is no domestic study comparing the safety of rhEPO combined with roxadustat in the treatment of anemia in hemodialysis patients.This study is a retrospective cohort study.According to the anemia medication, the enrolled patients were divided into three groups in this retrospective cohort study,and baseline data,28-week blood pressure changes, incidence of AEs and MACEs were reported.

Our study initially demonstrated that epoetin alfa or roxadustat had a similar effect on postdialysis systolic pressure,while the combination of epoetin alfa and roxadustat increased postdialysis systolic pressure in 28 weeks.Additionally,age,sex,weight,most of coexisting condition including coronary artery disease,heart failure,valvular heart disease,atrial fibrillation,myocardial infarction,stroke,diabetes,infection and other comorbidities,laboratory values such as hemoglobin,white blood cell count, albumin,CRP,serum iron,blood lipids,antihypertensive drugs,etc.,were all associated with changes in blood pressure at 28 weeks.We also found the incidence of AEs or MACEs were similar among the three groups.

This trial has several limitations.First,there were some adverse events that were not hospitalized,which may have biased reporting of adverse events.Second,our sample size was insufficient and the follow-up period was not sufficient.As a final point,the effect of dose and frequency of anemia-correcting drugs on blood pressure was not taken into account.Further studies with larger sample size and longer follow-up time are needed for the effect of combined use of roxadustat and erythropoietin on blood pressure and its mechanism to apply these two drugs in better ways.

Acknowledgments

We thank the Free Statistics software for data analysis.We would like to

thank Jie Liu(People’s Liberation Army of China General Hospital, Beijing,China)and Qi-lin Yang(The Second Afﬁliated Hospital of Guangzhou Medical University, Guangzhou, China) for revision.

Authors’ contributions

Jian-gang Wang provided ideas and formulation or evolution of overarching research goals and aims.Yi Lu conducted data collection and analysis,wrote the manuscript;Xin-yu Liu carried out final preparation of the manuscript.All authors had critically read and approved the last version of the manuscript.

Funding

The authors received no financial support for the research,authorship,and/or publication of this article.

Availability of data and materials

The data of the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The project was reviewed by the ethies committee of the Nanyang Central Hospital,in accordance with the"Ethical Review Measures for Biomedical Research InvolvingI Human Beings(Trial)" of the Ministry of Health and the relevant provisions of the Declaration of Helsinki on biological human trials,and the application of the research project was approved.This retrospective study was approved by the medical research ethics review in the Nanyang Central Hospital No.2022.011,Approval Date:2022-07-20,and the requirement to obtain informed written consent was waived.

Consent for publication

Not applicable.

Competing interests

The authors declared no potential conflicts of interest with respect to the research,anthorship,and/or publication of this article.

Author details

1 Department of Endocrinology,Nanyang Central Hospital,Nanyang,Henan,China.

2 Department of Nephrology,Nanyang Central Hospital,Nanyang,Henan,China.

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No competing interests reported.

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Safety of Roxadustat Combined with Epoetin Alfa in Hemodialysis Patients with Anemia: A Cohort Study

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