Table 30:

Evidence profile for molidustat as an alternative to ESA for DD-CKD patients

Benefits and harms	Small net benefit or little difference between alternatives
Molidustat reduced all-cause mortality up to 52 weeks by 7/1000. However, evidence on this was uncertain. About 14% of GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. Molidustat reduced the need for intravenous iron supplementation up to 52 weeks by 10/1000, but evidence on this was uncertain. Almost 27% of GDG members (not including patients) are comfortable using HIF-PHIs over ESAs. Molidustat lowered hemoglobin levels from baseline up to 36 weeks. However, evidence on this was uncertain. All GDG members (not including patients) find such a scenario acceptable to switch to HIF-PHIs. Molidustat increased the need for blood transfusion up to 20 weeks by 21/1000 compared to ESAs. However, evidence on this was uncertain. All GDG members (not including patients) find such a scenario unacceptable to switch to HIF-PHIs. Compared to ESA, molidustat increased the risk of treatment emergent adverse events up to 52 weeks by 21/1000. Evidence on this was uncertain. All GDG members (not including patients) would find such a scenario unacceptable. In the group that received molidustat, there was 6/1000 more incidences of MACE up to 52 weeks compared to the group that received ESAs. Evidence on this was uncertain. About 81% of GDG members (not including patients) would find such a scenario unacceptable. Uncertain evidence also reported an increased need for oral iron supplementation up to 52 weeks by 84/1000 in the molidustat group as compared to the ESA group. All GDG members (not including patients) would find such a scenario unacceptable. There was increased need for ESA up to 52 weeks by 84/1000 in the molidustat group as compared the ESA group. However, evidence on this was uncertain. None of the included studies measured health-related fatigue as an outcome. Overall, the panel judged that the desirable anticipated effects of molidustat compared to ESA were small and that there were moderate harms, noting that there was very low certainty in the evidence base.
Certainty of the evidence	Very low [Table 29]
Values and preferences	Substantial variability is expected or uncertain
Empirical examinations of patients’ values and preferences from South Asia are not available. This section is based on unstructured interactions with individual patients and caregivers and discussions with panel members. Subcutaneous ESA administration is challenging due to its invasive nature, its use has a learning curve, and there are logistic issues (refrigeration). Use of HIF-PHIs might have concerns around pill burden and adherence in some patients. However, some patients might prefer injections because of the need to limit fluid intake
Resources	Important issues or potential issues not investigated
Molidustat is currently not available in India, so it is not possible to compare the cost at this time. Although molidustat does not need refrigeration and can be administered orally (unlike ESAs), this may not be of added benefit for DD patients, as they would already be undertaking regular hospital visits for dialysis. In this case, they can receive the intervention during hospital visits, which is unlikely to require extra resources from the patient.
Equity	No important issues with the recommended alternative
Although molidustat does not need refrigeration and can be administered orally (unlike ESAs), this is less likely to decrease equity for DD patients, as they would already have to make regular hospital visits for dialysis purposes. In this case, it would put minimal additional strain to have ESA administered.
Acceptability	Important issues or potential issues not investigated
There are no qualitative studies on preference of South Asian patients with DD-CKD with respect to the acceptability of HIF-PHIs. Patients with hemodialysis might get ESAs intravenously, thus not requiring additional pricks through subcutaneous routes. However, there are concerns around polypharmacy on the use of HIF-PHIs.
Feasibility	Intervention is likely difficult to implement
There are no formal studies on facilitators and barriers to the use of HIF-PHIs in South Asia. The panel adjudged that molidustat, although preferred because of its oral route of administration, is not licensed by the national drug regulators in India or in any other South Asian country. As such, it is probably not feasible.

DD: Dialysis-Dependent, CKD: Chronic kidney disease, ESA: Eythropoiesis-stimulating agents, HIF PHI: Hypoxia-inducible factor prolyl hydroxylase inhibitor, GDG: Guideline development group, MACE: Major adverse cardiovascular events