Wish reviews progress in anemia management and potential for a new drug class
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Healio | Nephrology News & Issues interviewed Jay B. Wish, MD, professor of clinical medicine at Indiana University School of Medicine and chief medical officer for dialysis at Indiana University Health in Indianapolis, about the role of anemia management in kidney care. Wish is also chair of the Editorial Advisory Board for Healio | Nephrology News & Issues.
Healio | Nephrology News & Issues: You treated patients before erythropoiesis-stimulating agents (ESAs) were available. How did your patients cope with anemia?
Jay B. Wish, MD: The quality of life was terrible. Patients felt tired all the time; they had no energy, no stamina and no libido. Transfusions were the primary option we had available to increase hemoglobin levels and even that only helped to maintain patients at 6 g/dL to 7 g/dl.
You can imagine what life would be like if you lived with those levels. Today our target is between 10 g/dL and 11 g/dL.
Healio | Nephrology News & Issues: Once approved by the FDA in 1989, there was a lot of hand wringing about best practices for dosing ESAs and how Medicare was going to pay for the drug. Was there any doubt that Medicare would cover it?
Jay B. Wish, MD: I do not think coverage was really an issue because the phase 3 trials for Epogen (epoetin alfa, Amgen) showed such a dramatic improvement in the quality of life for patients.
Once approved, EPO was a godsend. This drug eliminated multiple transfusions in 90% of patients, and transfusions had their own problems. There were a lot of blood-borne illnesses and patients got so iron-overloaded they needed chelation therapy. Ferritins were sometimes more than 2,000 ng/mL – imagine that level today. And there were risks with chelation therapy too.
Healio | Nephrology News & Issues: Review the role of iron in assuring the efficacy of EPO. In your view, have we succeeded at balancing the right dose for each?
Jay B. Wish, MD: There was a cultural change from the pre-EPO era to the post-EPO era in terms of iron management. Iron toxicity was rampant because of the overdosing of iron from the days when transfusions were performed, and once it is in your body, there is no physiologic way of getting rid of it. There was a view that iron was something we had to avoid, something we had to stay away from when Epogen was approved. For the first 5 years, practitioners were stingy with iron and that limited the efficacy of EPO.
Healio | Nephrology News & Issues: What impact did the Normal Hematocrit Cardiac Trial and later, the Correction of Hemogloblin and Outcomes in Renal Insufficiency (CHOIR) trial, and the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) have on EPO dosing?
Jay B. Wish, MD: Results of the Normal Hematocrit Cardiac Trial were the first indication that higher hemoglobins were a problem for patients on dialysis. The study evaluated patients who had a history of cardiac disease, including heart failure or coronary artery disease. This was thought to be the most vulnerable population to test the value of higher hemoglobin levels, and it was believed the higher hemoglobins would lead to higher oxygen levels delivered to the myocardium and that would improve outcomes.
In this study, patients were randomized to a normal hemoglobin level, which was around 14 mg/dL, and compared with patients with a targeted normal hemoglobin level for patients on dialysis – around 10 mg/dL. Those in the higher hemoglobin group – who needed more than three times the EPO dose – saw an increase in adverse events, hospitalizations and mortality. The trial had to be stopped early.
That was the first clue that driving hemoglobin levels higher was a bad idea. The second indication was from results of the CHOIR trial published in 2006 and the TREAT study published in 2009. By that time, the use of ESAs had expanded to patients with non-dialysis dependent chronic kidney disease. These two studies looked at patients in CKD stages 3 and 4 who were anemic and randomized to hemoglobin targets of 9-11.3 g/dL vs. 13.0-13.5 g/dL. In those studies, no advantages were seen for patients with higher target hemoglobin levels. What they did find is patients who had higher doses of ESA also had the most adverse events.
Healio | Nephrology News & Issues: That suggests the high dose – perhaps not the hemoglobin level – led to more adverse events.
Jay B. Wish, MD: I think the jury is still out on that issue. In a secondary analysis of CHOIR data, it was shown that patients who achieved the highest hemoglobins with the lowest EPO doses did the best. It is still not clear, after all the secondary analyses that have been done, whether the safety issues that were found in the CHOIR study were due to the EPO dose itself or the achieved hemoglobin.
Healio | Nephrology News & Issues: How do you compare the ESAs with GlaxoSmithKline’s recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) Jesduvroq?
Jay B. Wish, MD: If the patient is doing very well and maintaining a hemoglobin level between 9 g/dL and 11 g/dL at a very modest dose of EPO, there is really no reason to change the prescription. But there are subsets of patients who might benefit from a different choice. They include the ESA hyporesponsive patients as potential candidates, particularly those patients who go in and out of a state of hypo responsiveness.
Likewise, for patients who do not like injections and are on home dialysis, HIF-PHIs are oral treatments. That means patients can avoid injections and do not have to come into a clinic.
If it isn’t broken don’t fix it. If it is broken, try something else. That is where the HIF-PHIs may have a role.
- For more information:
- Jay B. Wish, MD, can be reached at jaywish@earthlink.net.
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