Table 17:

Evidence profile for vadadustat as an alternative to ESA for anemia in NDD-CKD patients

Population: Anemia in non-dialysis-dependent chronic kidney disease Intervention: Vadadustat (any dose) Comparator: Darbepoetin Alpha
Outcome Time frame	Study results and measurements	Absolute effect estimates		Certainty of the evidence	Plain language summary
		Darbepoetin Alpha	Vadadustat any dose
Adverse events beyond 52 weeks in ESA-naïve patients	Odds ratio: 0.91 (CI 95% 0.66–1.27) Based on data from 1748 participants in one study	916 per 1000	908 per 1000	Very low Due to serious risk of bias, due to very serious imprecision1	We are uncertain whether vadadustat (any dose) decreases adverse events beyond 52 weeks in ESA-naïve patients.
		Difference: 8 fewer per 1000 (CI 95% 38 fewer–17 more)
Adverse events up to 52 weeks	Odds ratio: 0.77 (CI 95% 0.35–1.71) Based on data from 304 participants in one study	922 per 1000	901 per 1000	Very low Due to serious risk of bias, due to serious indirectness, due to very serious imprecision2	We are uncertain whether vadadustat (any dose) decreases adverse events up to 52 weeks in ESA-naïve and ESA-conditioned patients.
		Difference: 21 fewer per 1000 (CI 95% 117 fewer–31 more)
Adverse events beyond 52 weeks in ESA-conditioned patients	Odds ratio: 1.14 (CI 95% 0.85–1.54) Based on data from 1723 participants in one study	877 per 1000	890 per 1000	Very low Due to serious risk of bias, due to very serious imprecision3	We are uncertain whether vadadustat (any dose) increases adverse events beyond 52 weeks in ESA-conditioned patients.
		Difference: 13 more per 1000 (CI 95% 19 fewer–40 more)
Incidence of MACE beyond 52 weeks	Odds ratio: 1.10 (CI 95% 0.93–1.29) Based on data from 3521 participants in one study	199 per 1000	214 per 1000	Very low Due to serious risk of bias, due to very serious imprecision4	We are uncertain whether vadadustat (any dose) increases incidence of MACE beyond 52 weeks in ESA-naïve and ESA-conditioned patients.
		Difference: 16 more per 1000 (CI 95% 11 fewer–44 more)
Incidence of MACE plus beyond 52 weeks	Odds ratio: 1.04 (CI 95% 0.89–1.21) Based on data from 3521 participants in one study	245 per 1000	252 per 1000	Very low Due to serious risk of bias, due to very serious imprecision5	We are uncertain whether vadadustat (any dose) increases incidence of MACE plus beyond 52 weeks.
		Difference: 7 more per 1000 (CI 95% 21 fewer–37 more)
All-cause mortality beyond 52 weeks in ESA-conditioned patients	Odds ratio: 1.00 (CI 95% 0.77–1.29) Based on data from 1723 participants in one study	161 per 1000	161 per 1000	Very low Due to serious risk of bias, due to very serious imprecision6	We are uncertain if vadadustat (any dose) has little or no difference on all-cause mortality beyond 52 weeks in ESA-conditioned patients.
		Difference: 0 fewer per 1000 (CI 95% 32 fewer–37 more)
All-cause mortality up to 52 weeks	Odds ratio: 0.34 (CI 95% 0.01–8.30) Based on data from 304 participants in one study	7 per 1000	2 per 1000	Very low Due to serious risk of bias, due to serious indirectness, due to very serious imprecision7	We are uncertain whether vadadustat (any dose) decreases all-cause mortality up to 52 weeks in ESA-naïve and ESA-conditioned patients.
		Difference: 5 fewer per 1000 (CI 95% 7 fewer–48 more)
All-cause mortality beyond 52 weeks in ESA-naïve patients	Odds ratio: 1.08 (CI 95% 0.85–1.36) Based on data from 1748 participants in one study	193 per 1000	205 per 1000	Very low due to serious risk of bias, due to very serious imprecision8	We are uncertain whether vadadustat (any dose) increases all-cause mortality beyond 52 weeks in ESA-naïve patients.
		Difference: 12 more per 1000 (CI 95% 24 fewer–52 more)
All-cause mortality beyond 52 weeks	Odds ratio: 1.01 (CI 95% 0.85–1.2) Based on data from 3521 participants in one study	177 per 1000	178 per 1000	Very low Due to serious risk of bias, due to very serious imprecision9	Vadadustat (any dose) may have little or no difference on all-cause mortality beyond 52 weeks in ESA-naïve and ESA-conditioned patients.
		Difference: 1 more per 1000 (CI 95% 22 fewer–28 more)
Need for iron supplementation (oral) up to 52 weeks	Odds ratio: 1.26 (CI 95% 0.78–2.05) Based on data from 304 participants in one study	288 per 1000	337 per 1000	Very low Due to serious risk of bias, due to serious indirectness, due to very serious imprecision10	We are uncertain whether vadadustat (any dose) increases the need for iron supplementation (oral) up to 52 weeks in ESA-naïve and ESA-conditioned patients.
		Difference: 50 more per 1000 (CI 95% 48 fewer–165 more)
Need for ESA					No studies were found that viewed a need for ESA.
Progression to end-stage kidney disease					No studies were found that viewed progression to end-stage kidney disease.
Patients requiring blood transfusion					No studies were found that viewed patients requiring blood transfusion.
Health-related QoL					No studies were found that viewed health-related QoL.
Fatigue					No studies were found that viewed fatigue.
Change in hemoglobin levels from baseline up to 52 weeks in ESA-naïve patients	Measured by: Scale: High better Based on data from 3780 participants in two studies	Mean	Mean	Very low Due to serious risk of bias, due to very serious inconsistency11	We are uncertain whether vadadustat (any dose) has little or no difference on hemoglobin levels from baseline up to 52 weeks in ESA-naïve patients.
		Difference: MD 0.00 lower (CI 95% 0.04 lower–0.05 lower)

Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Imprecision: very serious. Only data from one study, wide confidence intervals; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Indirectness: serious. The included study was from only one non-South Asian country and was downgraded for lack of directness by one level; Imprecision: very serious. Wide confidence intervals, low number of patients, only data from one study; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Imprecision: very serious. Wide confidence intervals, only data from one study; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Imprecision: very serious. Wide confidence intervals, only data from one study; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Imprecision: very serious. Only data from one study, wide confidence intervals; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Imprecision: very serious. Only data from one study, wide confidence intervals; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Indirectness: serious. The included study was from only one non-South Asian country and was downgraded for lack of directness by one level; Imprecision: very serious. Wide confidence intervals, low number of patients, only data from one study; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Imprecision: very serious. Only data from one study, wide confidence intervals; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Imprecision: very serious. Only data from one study, wide confidence intervals; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Indirectness: serious. The included study was from only one non-South Asian country and was downgraded for lack of directness by one level; Imprecision: very serious. Low number of patients, wide confidence intervals, only data from one study; Publication bias: not serious. Mostly commercially funded studies. Risk of Bias: serious. Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias, missing intention-to-treat analysis; Inconsistency: very serious. The magnitude of statistical heterogeneity was high, with I^2: 99 %, point estimates vary widely, the confidence interval of some of the studies do not overlap with those of the most included studies/the point estimate of some of the included studies, the direction of the effect is not consistent between the included studies; Publication bias: not serious. Mostly commercially funded studies. ESA: Eythropoiesis-stimulating agents, NDD: Nondialysis dependent, CKD: Chronic kidney disease, CI: Confidence interval, MACE: Major adverse cardiovascular events, MD: Mean difference, QoL: Quality of life