Table 9:

Evidence to decision table for earodustat as an alternative to ESA for anemia in NDD-CKD patients

Benefits and harms	Small net benefit or little difference between alternatives
Enarodustat decreased all-cause mortality up to 26 weeks by 6/1000 as compared to darbepoetin alpha. Evidence on this was uncertain. About 14% of GDG members (not including patients) would find such a scenario acceptable. In the group that received enarodustat, there was 171/1000 fewer adverse events up to 26 weeks compared to the darbepoetin alpha group. Evidence on this was uncertain. All GDG members (not including patients) would find such a scenario acceptable. In ESA-naïve patients receiving enarodustat, there were 146/1000 fewer adverse events up to 26 weeks as compared to darbepoetin alpha group. However, evidence on this was uncertain. All GDG members (not including patients) would find such a scenario acceptable. Similarly, in ESA-conditioned patients receiving enarodustat, there were 196/1000 fewer adverse events up to 26 weeks compared to darbepoetin alpha group. However, evidence on this was uncertain. Almost all GDG members (not including patients) would find such a scenario acceptable. Enarodustat had little or no difference on hemoglobin levels from baseline up to 24 weeks. However, evidence on this was uncertain. All GDG members (not including patients) find such a scenario acceptable to switch to HIF-PHI. There were no included studies that examined the impact on the QoL, fatigue, incidence of MACE/MACE plus, need for iron supplementation, need for blood transfusion, progression to end-stage kidney disease, or need for ESA as outcomes. Overall, the panel judged that the desirable anticipated effects of enarodustat (compared to darbepoetin alpha) were moderate, as it was trivial/no harm. They noted that there was very low certainty in the evidence base. There is also concern regarding the lack of robust evidence on cardiovascular safety in NDD-CKD patients with anemia.
Certainty of the evidence	Very low [Table 8]
Values and preferences	No substantial variability expected
Empirical examinations of patients’ values and preferences from South Asia are unavailable. The 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 enarodustat due to the very low certainty of evidence, and the lack of evidence on QoL and fatigue, which are outcomes of importance for patients.
Resources	Important issues or potential issues not investigated
Enarodustat is currently not available in India, so it is not possible to compare the cost at this time. It is administered orally, thereby requiring minimal resources as compared to darbepoetin alpha which is injectable and requires refrigeration prior to administration. The ease of administration and easy storage for enarodustat can reduce the additional resource requirements.
Equity	Important issues or potential issues not investigated
Enarodustat does not need refrigeration (cold chain) as compared to darbepoetin alpha. It is thus more useful in remote areas with irregular supply of electricity and in equity groups, who might not have refrigeration in their homes. Furthermore, as darbepoetin alpha 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
Enarodustat 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 enarodustat 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 enarodustat due to the differences in dose frequency requirements. Overall, for NDD patients, the oral nature of enarodustat was thought to be more acceptable by the GDG.
Feasibility	Intervention is likely difficult to implement
Enarodustat can be orally administered and does not require cold chain, unlike darbepoetin alpha, which is relatively easy to administer and store. In addition, Enarodustat may increase accessibility, particularly for non-dialysis patients, as it does not require hospital visitation or self-injection. As enarodustat is not yet approved in India or any other South Asian country, the treatment is not feasible at the current time.

ESA: Eythropoiesis-stimulating agents, NDD: Nondialysis dependent, CKD: Chronic kidney disease, GDG: Guideline development group, MACE: Major adverse cardiovascular events