Treatment of anemia in patients with chronic kidney disease (CKD) has been a matter of debate over the past 20–30 years. Earlier landmark trials, such as CHOIR (1), CREATE (2), and TREAT (3), tried to address appropriate hemoglobin levels in patients and whether treatment with erythropoiesis-stimulating agents (ESAs) had any short- or long-term complications.
The discovery of the hypoxia-inducible factor (HIF), one of the key regulators that controls how cells respond to hypoxic conditions, has diverted recent trials in this direction. HIF enhances kidney and hepatic erythropoietin synthesis and iron uptake by the intestine and opposes the deleterious effects of hepcidin. This discovery led to the creation of HIF prolyl hydroxylase inhibitors (HIF-PHIs), which are newer medications being developed to treat anemia in patients with CKD. These drugs offer the advantage of being dosed orally as opposed to existing ESAs, which are administered either intravenously or subcutaneously. This process triggers multiple phenomena, including an increase in erythropoietin and transferrin production and in iron bioavailability and a decrease in hepcidin levels, which all aid in treating anemia in patients with CKD.
In the PRO2TECT study (4), patients with CKD who were not on dialysis were randomized to receive either vadadustat, an HIF-PHI, or darbepoetin. The study included two, phase 3, randomized, open-label, active-controlled, noninferiority trials to compare vadadustat with darbepoetin alfa. The study showed that vadadustat was noninferior to darbepoetin alfa with regard to hematologic efficacy, but vadadustat was inferior to darbepoetin alfa in the time to the first occurrence of major adverse cardiovascular events, which were defined as the composite of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke.
The ANDES trial (5) was a randomized clinical trial in 916 patients with CKD with anemia who were not on dialysis. The study found that oral roxadustat was superior to placebo in hemoglobin correction and maintenance with the same overall tolerability. In the OLYMPUS trial (6), nondialysis patients with CKD with anemia received roxadustat versus placebo. The study showed a significant increase in the hemoglobin level and a decreased need for blood transfusions in the roxadustat group with a side effect profile similar to that of placebo. The ALPS study had similar findings (7). In the HIMALAYAS study (8), 1043 patients with anemia, who were new to dialysis and had never received an ESA, received either roxadustat or epoetin alfa. The study showed that roxadustat was noninferior to epoetin alfa in correcting and maintaining hemoglobin levels, with comparable adverse-event rates with either treatment. Vadadustat demonstrated comparable efficacy (maintenance of target hemoglobin level) and safety noninferiority to ESAs in its phase 3 INNO2VATE global clinical trial involving 3950 patients on dialysis (9) (Table 1).
Summary of major trials on HIF-PHI agents in patients with CKD on dialysis and not on dialysis
Five HIF-PHIs (including roxadustat and vadadustat) have been approved in Japan; roxadustat has also been approved in China, South Korea, Chile, and the European Union, but recently, the US Food and Drug Administration (FDA) voted against roxadustat and vadadustat. FDA's Cardiovascular and Renal Drugs Advisory Committee indicated that roxadustat's benefit-risk profile does not support approval for anemia of CKD in adults. The FDA questioned signals of increased all-cause death, major adverse coronary events, thrombotic events, thrombosis in vascular access sites among patients receiving dialysis, infections, and seizures in patients who received roxadustat compared with control patients. Similar concerns were raised about vadadustat. Now, we should wait and see if the FDA will approve daprodustat to treat anemia in patients with CKD who are and are not on dialysis in February 2023.
Singh AK, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–2098. doi: 10.1056/NEJMoa065485
Drüeke TB, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071–2084. doi: 10.1056/NEJMoa062276
Pfeffer MA, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361:2019–2032. doi: 10.1056/NEJMoa0907845
Chertow GM, et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med 2021; 384:1589–1600. doi: 10.1056/NEJMoa2035938
Chen N, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 2019; 381:1001–1010. doi: 10.1056/NEJMoa1813599
Coyne DW, et al. Roxadustat for CKD-related anemia in non-dialysis patients. Kidney Int Rep 2020; 6:624–635. doi: 10.1016/j.ekir.2020.11.034
Fishbane S, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: Results from a randomized phase 3 study. J Am Soc Nephrol 2021; 32:737–755. doi: 10.1681/ASN.2020081150
Provenzano R, et al. Roxadustat for anemia in patients with end-stage renal disease incident to dialysis. Nephrol Dial Transplant 2021; 36:1717–1730. doi: 10.1093/ndt/gfab051
Eckardt KU, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med 2021; 384:1601–1612. doi: 10.1056/NEJMoa2025956