Power of Observation: Hemoglobin Trends in Placebo Arm of TREAT

What happens to hemoglobin (Hb) trends in patients who do not receive erythropoietin agents in chronic kidney disease (CKD)? This question has not been addressed in prior trials. The investigators of a recent article in the American Journal of Kidney Diseases took on this venture and analyzed the placebo arm of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) trial. 2019 individuals with type 2 DM, moderate anemia, and CKD from the placebo arm of the TREAT trial were followed for 2.3 years with an average 32 monthly Hb measurements per patient. Darbepoetin alfa was administered only if Hb fell below 9 g/dL in that arm. Dr Hicham Skali (HS), corresponding author from the Brigham and Women’s Hospital and Harvard Medical School in Boston, MA, discusses the topic with Dr. Magdalena Madero (eAJKD), eAJKD Contributor.

eAJKD: What prompted you to study hemoglobin stability in CKD patients with anemia and diabetes?

HS: At the conclusion of the TREAT trial published in 2009, we noted on the figure showing hemoglobin (Hb) separation that Hb levels in the placebo arm tended to remain overall stable. We realized that there were several publications describing hemoglobin response (or lack thereof) to erythropoietin-stimulating agents (ESA) in participants with CKD and anemia, but very few studying the natural history of hemoglobin without intervention. CKD participants enrolled in the TREAT placebo arm were all diabetics with moderate anemia who receive protocol-directed darbepoetin alfa if their Hb level fell below 9.0 g/dL. We thought that this cohort would be a good setting to study the natural progression of Hb without intervention.

Figure 1 from Skali et al.

eAJKD: Your study allows us to understand what is the natural progression of the disease without intervention. Can you tell us what you learned from the progression in this cohort?

HS: In this cohort of 2019 patients with type 2 diabetes, moderate anemia, and CKD (eGFR between 20 and 60 mL/min/1.73 m2), Hb levels were measured an average of 32 times over 2.3 years of follow-up. We stratified patients according to how many times they received protocol-directed darbepoetin alfa when their Hb levels fell below 9.0 g/dL into four groups. Only 13% received 5 or more doses of darbepoetin alfa, 16% received only one dose, another 16% received 2-4 doses, and over half the patients (55%) did not received any ESA as their Hb levels remained ≥9.0 g/dL during follow-up (see table 2 of article). The total cumulative dose of darbepoetin alfa received by the group that received only one dose was actually very small: 40 mcg per patient on average. The group that received no darbepoetin alfa demonstrated the highest Hb at baseline and during follow-up.

eAJKD: What is the potential explanation of hemoglobin stability over time in the group that did not receive any ESA therapy?

HS: I can tell you factors that do not explain this stability. Contrary to what may be expected, participants who did not receive any ESA therapy showed a stable and slowly rising Hb over 2.3 years of follow-up. We demonstrated in our analyses that this stability was not due to more iron therapy, PRBC transfusions, or darbepoetin alfa. At baseline, this group had higher hemoglobin levels and eGFR, and a lower degree of proteinuria. It may be that this group was “healthier” to start than the group who received 5 or more doses of darbepoetin alfa, and a wait-and-see approach allowed us to witness the natural progression of anemia in this group with a relatively stable Hb without any administration of ESA.

eAJKD: Do you think your results provide insight of how often we should monitor hemoglobin levels in this population?

HS: Hemoglobin monitoring in the TREAT trial was performed monthly according to the study protocol. We did not evaluate whether this monitoring strategy yielded different outcomes than a more or less frequent monitoring strategy. Our study shows that protocol directed administration of darbepoetin alfa when Hb dropped below 9.0 g/dL may not be necessary. We noted in our manuscript that by increasing the number of Hb determinations, we might be increasing the likelihood of randomly finding one value that was below 9.0 g/dL. In that regard, physicians should consider not necessarily administering ESAs after just one low Hb value, but instead confirming it and monitoring the stability appears reasonable.

eAJKD: What are the key findings and the implications of your results?

HS: The main finding from our study is that in a cohort of participants with diabetes, CKD (eGFR between 20 and 60 mL/min/1.73 m2), and moderate anemia (Hb £11 g/dL) followed for an average of 2.3 years, the majority will maintain a stable Hb of 9.0 g/dL or higher without administration of ESA therapy. Despite receiving 5 or more doses of darbepoetin alfa, a small proportion of patients (13%) demonstrated the lowest Hb values throughout follow-up compared to the other patients.

eAJKD: How do you think clinicians should respond to your results?

HS:Less is more. In many diabetic patients with CKD and moderate anemia, clinicians should consider a period of observation of Hb concentration to establish its stability. If the Hb does not remain consistently below 9 g/dL, the treating physician could delay or avoid administration of ESA. This approach could balance the concerns about ESA-related adverse events and the desire to reduce red cell transfusions.

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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