Efficacy of HIF-PHIs in the Treatment of Anaemia of Chronic Kidney Disease
Current literature suggests that HIF-PHIs are superior to placebo and non-inferior to conventional ESA in treating anaemia in patients living with chronic kidney disease (CKD) ( Table 2 ). It should be noted that trials evaluating the efficacy of HIF-PHIs in anaemia have used established KDIGO targets. The safety of using HIF-PHIs to target normalized haemoglobin concentrations in CKD is therefor
Current literature suggests that HIF-PHIs are superior to placebo and non-inferior to conventional ESA in treating anaemia in patients living with chronic kidney disease (CKD) (Table 2).
It should be noted that trials evaluating the efficacy of HIF-PHIs in anaemia have used established KDIGO targets. The safety of using HIF-PHIs to target normalized haemoglobin concentrations in CKD is therefore not known, and it should be noted that increased risk of thrombosis has been reported with treatment with HIF-PHIs (see below).
Trials of HIF-PHI efficacy have also not been designed to specifically evaluate iron parameters and use. At present, therefore, the need to adjust iron treatment protocols in patients receiving HIF-PHIs remains uncertain.
Table 2. Efficacy of HIF-PHI in the Treatment of Anaemia of Chronic Kidney Disease
Non-dialysis dependant CKD
| Trial | ASCEND-ND2 |
| HIF-PHI | Daprodustat |
| Comparator | Darbepoetin alfa |
| n | 3872 |
| Change in haemoglobin from baseline to evaluation period* | 0.08 g/dL greater (non-inferior) |
| Haemoglobin response rate** | Not reported |
| Trial | DREAM-ND3 |
| HIF-PHI | Desidustat |
| Comparator | Darbepoetin alfa |
| n | 588 |
| Change in haemoglobin from baseline to evaluation period* | 0.11 g/dL greater (non-inferior) |
| Haemoglobin response rate** | 77.8% vs. 68.5% |
| Trial | ALPS4 |
| HIF-PHI | Roxadustat |
| Comparator | Placebo |
| n | 594 |
| Change in haemoglobin from baseline to evaluation period* | 1.69 g/dL greater |
| Haemoglobin response rate** | 79.2% vs. 9.9% |
| Trial | ANDES5 |
| HIF-PHI | Roxadustat |
| Comparator | Placebo |
| n | 922 |
| Change in haemoglobin from baseline to evaluation period* | 1.8 g/dL greater |
| Haemoglobin response rate** | 86% vs. 6.6% |
| Trial | OLYMPUS6 |
| HIF-PHI | Roxadustat |
| Comparator | Placebo |
| n | 2781 |
| Change in haemoglobin from baseline to evaluation period* | 1.35 g/dL greater |
| Haemoglobin response rate** | 77% vs. 8.5% |
| Trial | DOLOMITES7 |
| HIF-PHI | Roxadustat |
| Comparator | Darbepoetin alfa |
| n | 616 |
| Change in haemoglobin from baseline to evaluation period* | Not reported |
| Haemoglobin response rate** | 89.5% vs. 78% |
| Trial | PRO2TECT8 |
| HIF-PHI | Vadadustat |
| Comparator | Darbepoetin alfa |
| n | 1751 |
| Change in haemoglobin from baseline to evaluation period* | 0.05 g/dL greater+ |
| Haemoglobin response rate** | 50.4% vs. 50.2%+ |
| Trial | PRO2TECT8 |
| HIF-PHI | Vadadustat |
| Comparator | Darbepoetin alfa |
| n | 1725 |
| Change in haemoglobin from baseline to evaluation period* | 0.01 g/dL less++ |
| Haemoglobin response rate** | 60.1% vs. 60.7%++ |
Dialysis-dependent CKD
| Trial | ASCEND-D9 |
| HIF-PHI | Daprodustat |
| Comparator | Epoetin or Darbepoetin alfa |
| n | 2964 |
| Change in haemoglobin from baseline to evaluation period* | 0.18 g/dL greater |
| Haemoglobin response rate** | Not reported |
| Trial | HIMALAYAS10 |
| HIF-PHI | Roxadustat |
| Comparator | Epoetin alfa |
| n | 1043 |
| Change in haemoglobin from baseline to evaluation period* | 1.18 g/dL greater |
| Haemoglobin response rate** | 84.3% vs. 79.5% |
| Trial | PYRENEES11 |
| HIF-PHI | Roxadustat |
| Comparator | Epoetin or Darbepoetin alfa |
| n | 838 |
| Change in haemoglobin from baseline to evaluation period* | 0.23 g/dL greater |
| Haemoglobin response rate** | 84.2% vs. 82.4% |
| Trial | ROCKIES12 |
| HIF-PHI | Roxadustat |
| Comparator | Epoetin alfa |
| n | 2133 |
| Change in haemoglobin from baseline to evaluation period* | 0.09 g/dL greater |
| Haemoglobin response rate** | 79% vs. 76% |
| Trial | SIERRAS13 |
| HIF-PHI | Roxadustat |
| Comparator | Epoetin alfa |
| n | 741 |
| Change in haemoglobin from baseline to evaluation period* | 0.48 g/dL greater |
| Haemoglobin response rate** | 66.1% vs. 58.6% |
| Trial | INNO2VATE14 |
| HIF-PHI | Vadadustat |
| Comparator | Darbepoetin alfa |
| n | 3554 |
| Change in haemoglobin from baseline to evaluation period* | 0.17 g/dL less |
| Haemoglobin response rate** | 49.2% vs. 53.2% |
*mean Hb in HIF-PHI group less mean Hb in control group; **% of participants reaching trial Hb target
+ESA naïve; ++ESA-treated
Improvement in haemoglobin and reductions in invasive therapies may reasonably be expected to improve quality-of-life scores in patients prescribed HIFPHIs. Whilst such improvements have been evaluated in some trials,4-6,11 the effect of these drugs on this outcome parameter remains inconclusive at present.
South African Nephrology Society (SANS). Consensus Statement on the Use of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors (HIF-PHIs). South African Nephrology Society; 2023.