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Guideline 4.3 – Treatment of Anaemia with HIF- PHI therapy – Target Haemoglobin

Guideline 4.3 – Treatment of Anaemia with HIF- PHI therapy – Target Haemoglobin

We suggest that people over the age of 18 years with NDD-CKD on HIF-PHI therapy should achieve a Hb between:

  • 100 and 120 g/L in adults and young people similar to ESA therapy (2B)
  • In children and those younger than 2 years of age no data is currently available (not graded)

Guideline 4.3.1

We suggest that people over the age of 18 years with DD-CKD on HIF-PHI therapy should achieve a Hb between:

  • 100 and 120 g/L in adults and young people similar to ESA therapy but this may depend on the choice of HIF-PHI where a Hb of 100-110 g/|L is recommended. (2B)
  • In children and those younger than 2 years of age no data is currently available

Rationale

Current targets which aim for partial correction of Hb are based on clinical trials conducted more than a decade ago (1-3). These landmark trials compared higher versus lower Hb targets achieved using ESAs, in which major adverse cardiovascular events (MACE), mortality, and thrombotic events were more common among people assigned to the higher of the Hb targets (1-3). In addition, one trial comparing a high Hb target with placebo (and a conservative rescue strategy) in people with NDD-CKD and diabetes found an increased rate of strokes (4). The current HIF-PHI trials compared with active comparator used standard Hb targets based on ESA therapy. These varied depending on the country with lower targets in the USA compared to Europe and the UK. No HIF-PHI trials to date involving people in the UK or Europe have compared Hb normalisation or near-normalisation with the currently recommended lower Hb targets for people with CKD.

For people with symptomatic anaemia associated with non-dialysis dependent chronic kidney disease at the time of treatment initiation, HIF-PHI therapy is recommended by NICE (5) as a treatment option and is comparable to ESA therapy. NICE recommends that the choice between a HIF-PHI and ESA should be made in discussion with the individual.

In determining target Hb guidelines it is important to assess potential benefits (such as possible improved survival, improvement in health-related quality of life (HRQoL) and avoidance of transfusion requirement and hospitalisation) vs. potential harms (increased mortality and vascular events) and patient choice (6, 7).

The randomised open-label phase 3 ESA-controlled DOLOMITES trial in NDD-CKD, included 28 countries and the UK reported that the safety of the HIF-PHI was comparable to the ESA’s in the majority of safety variables in people with NDD-CKD (8). They also reported no evidence of increased cardiovascular safety or mortality risk when compared with ESA’s (8) The study included NDD-CKD people with symptomatic anaemia and stage 3, 4 or 5 CKD with Hb levels <105 g/L at the start of treatment. NICE committee recommends treatment at a Hb of less than 100 g/L. (5).

The NICE Committee reported that HIF-PHI therapy was non inferior to ESA therapy in all measures of quality of Life and that the DOLOMITES trial demonstrated that people with NDD-CKD required less IV iron than those treated with an ESA.

In the case of non-responsiveness, treatment with HIF-PHI should not be continued beyond 24 weeks after the start of treatment and other causes of anaemia be investigated (9).

Meta analysis of RCTS comparing HIF-PHI with ESA therapy have also demonstrated that there was no significant difference in adjudicated MACE events (10 trials) (1.00, 95% CI 0.94-1.07). For MACE+ again no difference was seen between HIF-PHI and ESA therapy (1.01, 95% CI 0.95-1.06) even after sensitivity analysis (10). There was also no difference in the mortality rate, but one must be cautioned as the duration of follow up was relatively short.

Vadadustat, recently approved by the EMA has a recommended Hb range of 100- 110 g/L. The two RCTs, INNO2VATE 1 (n 369) and 2 (n=3554), on pooled analysis showed non inferiority to darbepoetin alpha during 52 weeks follow up (11, 12). The population consisted of 60% US and 40% non-US where the trail Hb ranges were 80 to 110 g/L and 90 to 120 g/L in non-US participants. Overall MACE HR; was 0.96 with 95% CI: 0.83-1.11 and for the US participants only it was HR 1.0 with 95% CI; 0.84- 1.18. The current SmPC recommends a Hb target range of 100-110 g/L (13). The comparative 100 patient year data for vadadustat versus ESA therapy respectively were myocardial infarction 2.9 vs 2.9; Vascaulr access thrombosis 4.8 vs 3.9; stroke 1.1 vs 1.4; DVT 0.5 vs 0.6; PE 0.2 vs 0.3.

References

  1. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339: 584–590.
  2. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–2084.
  3. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–2098.
  4. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361: 2019–203220.
  5. NICE. Final appraisal document – Roxadustat for treating anaemia in people with chronic kidney disease. Issue date: June 2022 Available at: https://www.nice.org.uk/guidance/ta807/documents/final-appraisal-determination-document Accessed 16.09.23
  6. Pafrey PS, Foley RN, Wittreich BH et al. Double-blind comparison of full and partial anaemia correction in incident haemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005 Jul;16(7):2180-9.
  7. National Institute for health Care Excellence (2015) Chronic Kidney Disease: managing anaemia. National Institute for health and Clinical Excellence (NICE): 9-29
  8. Jonathan Barratt, Branislav Andric, Avtandil Tataradze, Michael Schömig, Michael Reusch, Udaya Valluri, Christophe Mariat, Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES), Nephrology Dialysis Transplantation, Volume 36, Issue 9, September 2021, Pages 1616–1628, https://doi.org/10.1093/ndt/gfab191
  9. Evrenzo- SmPC, Available at: Evrenzo (roxadustat) film coated tablets (Great Britain) – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) Accessed 16.09.23
  10. Minutolo R, Liberti ME, Simeon V, Sasso FC, Borrelli S, De Nicola L, Garofalo C, CKJ 2023.
  11. Eckardt KU, Agarwal R, Aswad A, et al. Safety and efficacy of vadadustat for anemia in patients undergoing dialysis. N Engl J Med. 2021;384: 1601–1612.
  12. Nangaku M, Kondo K, Ueta K et al. Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: a Phase 3, multicenter, randomized, double-blind study. Nephrol Dial Transplant 2021.
  13. Vafseo (Vadadustat)- SmPC, Available at: Vafseo (Vadadustat) 300 mg film-coated tablets (Great Britain) – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) Accessed 30.04.24