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Guideline 3.12 – Caution in Prescribing ESA in Certain People with CKD

Guideline 3.12 – Caution in Prescribing ESA in Certain People with CKD

We suggest exerting caution while prescribing ESA therapy in people with CKD with a history of stroke, or malignancy, particularly in those with active malignancy when cure is the anticipated outcome. (2C)

Rationale

In the TREAT trial, there was an increased risk of stroke in the high ESA group (HR 1.92; 95% CI 1.38– 2.68): 5.0% of the high Hb group had a stroke compared to 2.6% in the placebo group (P<0.001).

Venous thrombo-embolic events occurred significantly more frequently in the high Hb arm (2.0%) compared to the placebo arm (1.1%, P=0.02) (1). A post-hoc analysis of TREAT trial showed that: 7.4% of those with a history of malignancy at baseline died from cancer in the ESA arm compared to 0.6% in the placebo arm (P=0.002) (2). In a meta-analysis comparing possible adverse events related to ESA therapy, The higher Hb concentrations in ESA treated people with NDD-CKD increased risk for stroke (RR 1.51, 95% CI: 1.03– 2.21), hypertension (RR 1.67, 95% CI: 1.31–2.12), and vascular access thrombosis (RR 1.33; 95% CI: 1.16–1.53), and possibly the risk of death (RR 1.09; 95% CI: 0.99–1.20), serious cardiovascular events (RR 1.15, 95% CI: 0.98–1.33) or ESRD (RR 1.08; 95% CI: 0.97–1.20). (3) However, the risk of stroke was independent of Hb level or dose of ESA suggesting other factors such as iron deficiency (4). Patients with neoplasia who received ESA in randomised clinical trials had an increased risk of tumor progression and reduced overall survival compared with study controls (5). The MHRA advised that r-HuEPOs should not be given to people with cancer who do not fulfil the criteria in the authorised cancer indications, and that patients should be monitored closely to ensure that the lowest approved dose of r-HuEPO is used to adequately control of symptoms of anaemia (5). The joint guideline from the American Society of Clinical Oncology and the American Society of Haematology (6) recommends using ESA therapy with great caution in people with active malignancy, particularly when cure is the anticipated outcome. NICE evaluated the efficacy and safety of ESA in treating anaemia in people with cancer receiving chemotherapy (7). Although NICE researchers identified 23 randomised controlled trials evaluating the effectiveness and safety of erythropoiesis-stimulating agents (ESAs) for treating cancer treatment-related anaemia, NICE assessment focused only on trials that evaluated ESAs at a starting dose reflecting the current license (Hb <100 g/L). In total 16 studies were included in the analysis of the outcome related to anaemia and 7 trials in the outcome related to overall survival. NICE analysis of available trials concluded that erythropoiesis-stimulating agents are recommended, within their marketing authorisations, as options for treating anaemia in people with cancer who are having chemotherapy. ESAs were effective in increasing haemoglobin concentrations, improving haematological responses, reducing the need for blood transfusions and improving health-related quality of life, but that it could not assume that ESA treatment either prolonged or shortened survival compared with treatment without an ESA (7).

References

  1. Pfeffer MA, Burdmann EA, Chen CY, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009 Nov 19;361(21):2019-32.
  2. FDA presentation at Cardiovascular and Renal Drugs Advisory Committee (CRDAC) meeting, 18 October 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardi ovascularandRenalDrugsAdvisoryCommittee/UCM231978.pdf (accessed 15/06/2017).
  3. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010 Jul 6;153(1):23-33.
  4. Streja E, Kovesdy CP, Greenland S et al. Erythropoietin, iron depletion, and relative thrombocytosis: a possible explanation for haemoglobin-survival paradox in haemodialysis. Am J Kidney Dis 2008; 727-736.
  5. MHRA Drug Safety Update Recombinant human erythropoietins: treating anaemia in cancer. https://www.gov.uk/drug-safety-update/recombinant-human-erythropoietins-treating-anaemia-in-cancer. (accessed 15/06/2017).
  6. Rizzo JD, Brouwers M, Hurley P, et al; American Society of Haematology and the American Society of Clinical Oncology Practice Guideline Update Committee. American Society of Haematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010 Nov 18;116(20):4045-59.
  7. National Collaborating Centre for Chronic Conditions, Royal College of Physicians. Erythropoiesis stimulating agents Erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating anaemia in people with cancer ha anaemia in people with cancer having chemotherapy. 2014. National Institute for Clinical Excellence. https://www.nice.org.uk/guidance/ta323/resources/erythropoiesisstimulatingagentsepoetin-and- darbepoetin-for-treating-anaemia-in-people-with-cancer-having chemotherapy-includingreview-of-ta142- 82602485230021(accessed 15/06/2017)