Table 12:

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

Benefits and harms	Small net benefit or little difference between alternatives
Molidustat reduced patients requiring blood transfusion from 16 to 52 weeks by 5/1000 as compared to darbepoetin alpha. However, evidence on this was uncertain. Only 6% of GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. Molidustat further reduced need for ESA up to 36 weeks by 22/1000 as compared to darbepoetin alpha. However, evidence on this was uncertain. The molidustat group had little or no difference in hemoglobin levels from baseline up to 36 weeks as compared to darbepoetin alpha. However, evidence on this was uncertain. All GDG members (not including patients) find such a scenario acceptable to switch to HIF-PHIs. Molidustat had little or no difference on need for intravenous iron supplementation up to 52 weeks as compared to darbepoetin alpha. About 27% of GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. However, evidence on this was uncertain. Molidustat increased the treatment emergent adverse events up to 52 weeks for 16/1000 participants as compared to darbepoetin alpha. However, evidence on this was uncertain. Almost 97% of GDG members (not including patients) find this unacceptable for using HIF-PHIs. In the group that received molidustat, there were 26/1000 more incidences of MACE and MACE plus as compared to darbepoetin alpha. This evidence was uncertain. Nonetheless, all GDG members (not including patients) find this unacceptable to switch to HIF-PHIs. In addition, molidustat increased all-cause mortality up to 52 weeks by 8/1000 compared to darbepoetin alpha. Almost 86% of GDG members (not including patients) find this unacceptable for preferring HIF-PHI over ESAs. However, this evidence was uncertain. Molidustat increased need for oral iron supplementation up to 52 weeks by 133/1000 compared to darbepoetin alpha, which was unacceptable to 100% of GDG members (excluding patients). However, this evidence was also uncertain. The molidustat group further has 83/1000 more incidences of progression to end-stage kidney disease (defined by stage 5 CKD) up to 52 weeks when compared to darbepoetin alpha. However, this evidence was uncertain. None of the included studies examined health-related QoL or fatigue as outcomes. Overall, the panel judged that the desirable anticipated effects of molidustat were trivial and that there were moderate harms, noting that there was very low certainty on the evidence base.
Certainty of the evidence	Very low [Table 11]
Values and preferences	No substantial variability expected
Empirical examinations of patients’ values and preferences from South Asia are not available. 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 informed patient might be reluctant to use molidustat due to the very low certainty of evidence and the lack of evidence on QoL and fatigue which are of importance to patients.
Resources	Important issues or potential issues not investigated
Molidustat is currently not available in India, so it is not possible to compare the cost. 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 molidustat can reduce the additional resource requirements.
Equity	No important issues with the recommended alternative
Molidustat 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
Molidustat 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 molidustat 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 molidustat due to the differences in dose frequency requirements. Overall, for NDD patients, the oral nature of molidustat was thought to be more acceptable by the GDG.
Feasibility	Intervention is likely difficult to implement
Molidustat can be orally administered and does not require cold chain, unlike darbepoetin alpha, which is relatively easy to administer and store. In addition, molidustat may increase accessibility, particularly for non-dialysis patients, as it does not require hospital visitation or self-injection. However, the availability and accessibility, including in the government sector, under the essential medicine list is still a challenge. As molidustat 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, HIF PHI: Hypoxia-inducible factor prolyl hydroxylase inhibitor