Table 6:

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

Benefits and harm	Small net benefit or little difference between alternatives
Daprodustat reduced the incidences of MACE plus up to 32 weeks by 9/1000 compared to rhEPO. Evidence on this was uncertain. About 19% of GDG members (not including patients) would find such a scenario acceptable. In the group that received daprodustat, there was 7/1000 less patients requiring blood transfusion up to 52 weeks as compared to rhEPO. Evidence on this was uncertain. Only 6% of GDG members (not including patients) would find such a scenario acceptable. The daprodust group made little or no difference in hemoglobin levels from baseline up to 52 weeks for ESA-naïve and ESA-conditioned patients. All GDG members (not including patients) find such a scenario acceptable to switch to HIF-PHIs. Similarly, in ESA-conditioned patients only, the daprodustat group had little or no difference in hemoglobin levels from baseline up to 52 weeks as compared to rhEPO. However, evidence on this was uncertain. All GDG members (not including patients) find such a scenario acceptable to switch to HIF-PHI. Daprodustat may have little or no difference on all-cause mortality up to 60 weeks as compared to rhEPO. About 14% of GDG members (not including patients) find such a scenario acceptable to switch to HIF-PHI. Similarly, patients receiving daprodustat had little or no difference in progression to end-stage kidney disease up to 60 weeks. Evidence on this was uncertain. Daprodustat increased adverse events up to 52 weeks by 28/1000 as compared to rhEPO. All the GDG members (not including patients) find such a cut-off unacceptable for using HIF-PHIs. In the group that received daprodustat, there was 11/1000 more incidences all-cause mortality up to 52 weeks. All the GDG members (not including patients) find such a cut-off unacceptable for using HIF-PHIs. However, the evidence was uncertain. Daprodustat increased the incidences of MACE by 12/1000 up to 60 weeks as compared to rhEPO. Evidence on this was uncertain. All (100%) GDG members (not including patients) find such a cut-off unacceptable for using HIF-PHIs. None of the included studies measured health-related QoL, fatigue, need for iron supplementation, or need for ESA as outcomes. Overall, the panel judged that the desirable anticipated effects of daprodustat compared to rhEPO were small but that there were moderate harms, noting that there was very low certainty in the evidence base.
Certainty of the evidence	Very low [Table 5]
Values and preferences	No substantial variability expected
Empirical examinations of patients’ values and preferences from South Asia are unavailable. This section is based on unstructured interactions with individual patients and caregivers and discussions with panel members. Our recommendation reflects a belief that patients and caregivers prefer oral drugs over subcutaneous injections for those who are not DD. However, the GDG also inferred that some well-informed healthcare workers and patients might be reluctant to use daprodustat due to the very low certainty of evidence.
Resources	No important issues with the recommended alternative
Daprodustat is currently not available in South Asia, so it is not possible to compare the cost. It is administered orally, requiring minimal resources compared to rhEPO which is injectable and requires refrigeration before administration. The ease of administration and easy storage for daprodustat can reduce the additional resource requirements.
Equity	No important issues with the recommended alternative
Daprodustat does not need refrigeration (cold chain) as compared to rhEPO. It is thus more useful in remote areas with an irregular supply of electricity and in equity groups who might not have refrigeration in their homes. Furthermore, as rhEPO requires injection, a certain level of health literacy may be needed on how to self-administer the treatment.
Acceptability	No important issues with the recommended alternative
Daprodustat has a preferable route of administration for patients; patients either must self-administer ESA injections or make a hospital visit for the injection. However, ESAs have weekly/fortnightly dose requirements, whereas daprodustat should be taken daily or on alternate days. Both these factors can impact compliance and treatment adherence. ESAs may also be easier to supervise than daprodustat due to the differences in dose frequency requirements. Overall, for NDD patients, the oral nature of daprodustat was thought to be more acceptable by the GDG.
Feasibility	Intervention is likely difficult to implement
Daprodustat can be orally administered and does not require a cold chain, unlike rhEPO, which is relatively easy to administer and store. In addition, daprodustat may increase accessibility, particularly for non-dialysis patients, as it does not require hospital visitation or self-injection. As daprodustat is not yet approved in India or any other South Asian country, the treatment is currently not feasible.

ESA: Eythropoiesis-stimulating agents, NDD: Nondialysis dependent, CKD: Chronic kidney disease, rhEPO: Epoetins or their biosimilars or darbepoetin, MACE: Major adverse cardiovascular events, GDG: Guideline development group, HIF PHI: Hypoxia-inducible factor prolyl hydroxylase inhibitor