Table 15:

Evidence to decision-making matrix for roxadustat as an alternative to ESA for anemia in NDD-CKD patients

Benefits and harms	Small net benefit or little difference between alternatives
Roxadustat decreased treatment emergent adverse up to 108 weeks in ESA-naïve patients by 8/1000 compared to darbepoetin alpha. However, evidence on this was uncertain. Almost 41% of GDG members (not including patients) would find such a scenario acceptable to switch to HIF-PHIs. In ESA-conditioned patients receiving roxadustat decreased all-cause mortality by 5/1000 compared to darbopoetin alpha. About 14% of GDG members (not including patients) would find such a scenario acceptable. Similarly, ESA-naïve patients receiving roxadustat decreased all-cause mortality up to 108 weeks by 12/1000 compared to darbepoetin alpha. Evidence on this was uncertain. About 58% of GDG members (not including patients) would find such a scenario acceptable. Roxadustat reduced incidences of MACE up to 108 weeks in ESA-naïve patients by 22/1000 compared to darbepoetin alpha. However, evidence on this was uncertain. All GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. Similarly, roxadustat reduced incidences of MACE plus up to 108 weeks in ESA-naïve patients by 14/1000 compared to darbepoetin alpha. However, evidence on this was uncertain. About 88% of GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. For ESA-naïve patients, roxadustat decreased the need for intravenous iron supplementation up to 36 weeks by 64/1000 as compared to darbepoetin alpha. However, evidence on this was uncertain. All GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. For ESA-naïve patients, roxadustat decreased the need for bivalent oral iron supplementation up to 36 weeks by 62/1000 as compared to darbepoetin alpha. However, evidence on this was uncertain. All (100%) of the GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. For ESA-naïve patients, roxadustat decreased the need for trivalent oral iron supplementation up to 36 weeks by 96/1000 as compared to darbepoetin alpha. However, evidence on this was uncertain. All (100%) of the GDG members (not including patients) find such a cut-off acceptable for using HIF-PHIs. Roxadustat may have had little or no difference on hemoglobin levels from baseline up to 24 weeks for ESA-conditioned patients 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. In the roxadustat group, there was 84/1000 more treatment emergent adverse events up to 52 weeks in ESA-conditioned patients as compared to darbepoetin alpha. Evidence on this was uncertain. All GDG members (not including patients) would find such a scenario unacceptable. Roxadustat increased the need for patients requiring blood transfusion up to 108 weeks by 22/1000 as compared to darbepoetin alpha group. Evidence on this was uncertain. All GDG members (not including patients) would find such a scenario unacceptable. None of the included studies examined the effect of roxadustat on health-related QoL, fatigue, and end-stage kidney disease. Overall, the panel judged that for roxadustat as compared to darbepoetin alpha, moderate benefits as well as moderate harm were anticipated, noting that there was very low certainty in the evidence base.
Certainty of the evidence	Very low [Table 14]
Values and preferences	Substantial variability is expected or uncertain
Empirical examination of patients’ values and preferences from South Asia is not available. 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 informed patient might be reluctant to use roxadustat due to the very low certainty of evidence and the lack of evidence on QoL and fatigue, which are of importance to patients.
Resources	No important issues with the recommended alternative
Roxadustat 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 group which is injectable and requires refrigeration prior to administration. The ease of administration and easy storage for roxadustat can reduce the additional resource requirements.
Equity	No important issues with the recommended alternative
Roxadustat 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
Roxadustat 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 roxadustat 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 roxadustat due to the differences in dose frequency requirements. Overall, for NDD patients, the oral nature of roxadustat was thought to be more acceptable by the GDG.
Feasibility	Intervention is likely difficult to implement
Roxadustat can be orally administered and does not require cold chain, unlike darbepoetin alpha, which is relatively easy to administer and store. In addition, roxadustat may increase accessibility, particularly for non-dialysis patients, as it does not require hospital visitation or self-injection. As roxadustat is not yet approved in India or in 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, MACE: Major adverse cardiovascular events, HIF PHI: Hypoxia-inducible factor prolyl hydroxylase inhibitor, QoL: Quality of life, GDG: Guideline development group