Treatment of Anemia in Patients With Renal Disease Reviewed

Laurie Barclay, MD

September 18, 2010

December 24, 2009 — The treatment of anemia in patients with renal disease is reviewed in an editorial published online December 24 in the Journal of the American Society of Nephrology.

On the basis of the results of the Trial to Reduce Cardiovascular Events with Aranesp [darbepoeitin] Therapy (TREAT) and other recent studies, Ajay K. Singh, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, suggests that iron or blood transfusions should replace erythropoiesis-stimulating agents (ESAs) in some cases.

"The recently published landmark study [TREAT] has turned the world of anemia management upside down," Dr. Singh writes. "Patients who have chronic kidney disease (CKD) and anemia and literally could not get up in the morning will despair that insurance companies will put [ESAs] beyond their reach.... TREAT provides definitive evidence to justify making tough reimbursement decisions: Restricting the use of ESAs to symptomatic patients or those who are awaiting kidney transplantation."

Anemia develops in most patients with CKD at some point during the course of the illness. Darbepoetin (Aranesp, Amgen) and other ESAs that stimulate red cell production are prescribed to lower blood transfusions requirements and reduce fatigue.

However, Dr. Singh urges caution in light of TREAT findings that stroke incidence was doubled in patients randomly assigned to receive darbepoetin compared with those assigned to receive placebo, even though incidence of myocardial infarction or other cardiovascular event or death were similar in both groups.

In addition, darbepoetin treatment was associated with only modest improvements in quality of life, but there was a nonsignificant trend toward increased risk of developing cancer.

TREAT was a placebo-controlled, double-blind, randomized trial enrolling 4038 patients. In addition to increased stroke risk, darbepoetin-treated patients had a higher rate of thromboembolism and deep venous thrombosis compared with patients receiving placebo.

The other 2 trials reviewed in this editorial are Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta (CREATE). Whereas TREAT studied darbepoeitin-alfa, CHOIR tested epoetin-alfa, and CREATE tested epoetin-beta.

"In each, there was either no benefit or increased risk for mortality or cardiovascular complications," Dr. Singh writes. "In CREATE, the point estimate of risk in the direction of harm was 22% (95% CI 0.53 to 1.14), in CHOIR 34% (95% CI 1.03 to 1.74), and in TREAT 5% (95% CI 0.94 to 1.17), respectively. In other words, targeting a higher Hb concentration with ESAs was certainly not associated with benefit but perhaps increased risk."

According to Dr. Singh, CKD patients with severe anemia requiring frequent blood transfusions, or who are candidates for a kidney transplant and therefore cannot receive blood transfusions, should still be considered for ESA therapy.

He recommends iron therapy for patients with mild to moderate anemia, particularly if they are asymptomatic or have only low-level fatigue and other symptoms. If symptoms develop or anemia worsens, a blood transfusion or a short course of ESA therapy may be indicated. Most CKD patients with cancer should be treated with blood transfusions rather than ESAs.

"Avoiding use of ESAs in managing anemia in nondialysis patients with CKD is now the soundest approach given the remarkable observations from the TREAT study," Dr. Singh writes. "The higher rate of stroke and thromboembolic events and possibly a higher risk for cancer in TREAT with only very modest benefits to quality of life tip the scale in favor of no ESA treatment of anemia in most nondialysis patients with CKD."

However, he recommends more clinical trials to evaluate whether there is a toxic dosage range of ESAs, whether the frequency of administration of ESAs changes efficacy and safety, and whether the risks of ESA observed in TREAT also occur in dialysis patients with CKD.

"Dr. Singh's editorial appropriately pleads for cautious use of intravenous iron and ESAs in patients with CKD," Jeffrey S. Berns, MD, chief and director of the Nephrology Fellowship Training Program of the Renal-Electrolyte and Hypertension at the University of Pennsylvania School of Medicine in Philadelphia, says in a news release.

"All of the major trials he discusses were conducted in patients with a high prevalence of diabetes and heavy burden of cardiovascular and other comorbid conditions. Determining the true generalizability of TREAT would depend on testing younger and healthier patients without comorbid conditions."

In addition, Dr. Berns notes that TREAT and other trials maintained patient hemoglobin levels at or above 10 g/dL and that the risks and benefits of maintaining hemoglobin levels in CKD patients significantly below 10 g/dL is still unknown.

Dr. Singh is a senior nephrologist at the same institution as the primary investigator of the TREAT study, was principal investigator of CHOIR, and is a member of the executive committee for TREAT. He has received consulting income and grant support from Amgen, Johnson and Johnson, and Watson, and consulting income from Fibrogen. Dr. Berns has served on advisory or executive committees for and received consulting income from Amgen, Affymax, GSK, and Wyeth.

J Am Soc Nephrol. Published online December 24, 2009.

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