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Bypass Anemia Drugs in Chronic Kidney Disease, Expert Says
  Medpagetoday Dec 24 2009
The bottom line, Dr. Phrommintikul and colleagues said, is that aiming for higher hemoglobin levels in patients being treated for anemia caused by kidney disease "puts such patients at increased risk of death."....An upper limit on hemoglobin should be considered as part of treatment guidelines, they said, although there is a "paucity of evidence regarding the optimum hemoglobin target concentration." Current clinical trials may provide more data, they added......The meta-analysis comes of the heels of two recently published trials -- both incorporated in the new study -- that also suggested a high hemoglobin target might be dangerous to anemic patients.....Treating kidney patients -- almost all of whom have some degree of anemia -- with recombinant human erythropoietin costs about $10 billion worldwide in 2006, they said, and $2 billion in the U.S. just for Medicare patients on dialysis. Further clinical trials to asses the benefits and hazards of high versus low hemoglobin targets should be stopped, Dr. Strippoli and colleagues argued: "The question has been answered," they said. "Higher hemoglobin target concentrations increase mortality via cardiovascular endpoints."
Anemia in most chronic kidney disease patients should be managed with iron supplements or blood transfusions, if anything, rather than erythrocyte-stimulating agents, a leading nephrologist has recommended.
The only good case for long-term use of erythropoietin drugs in this population is in those who are transplant candidates or have severe anemia with a hemoglobin under 9 g/dl that cannot be managed with transfusions, Ajay K. Singh, of Harvard and Brigham and Women's Hospital in Boston, concluded.
"Avoiding use of erythrocyte-stimulating agents in managing anemia in nondialysis patients with chronic kidney disease is now the soundest approach," he wrote in an editorial online in the Journal of the American Society Nephrology.
This guidance comes in the wake of the TREAT trial findings that "turned the world of anemia management upside down," Singh said.
Action Points
Note that this editorial represented the views of one nephrologist, not consensus guidelines for treatment of anemia in nondialysis chronic kidney disease patients.
That landmark trial, reported nearly two months ago at the American Society of Nephrology meeting and simultaneously online in the New England Journal of Medicine, showed darbepoetin alfa (Aranesp) was no better than placebo in mortality or cardiovascular or renal outcomes in patients with comorbid diabetes.
But the drug nearly doubled stroke risk and increased thromboembolism and possibly cancer as well.
Nephrologists are still trying to digest these findings for their own practices, said Jeffrey S. Berns, MD, of the University of Pennsylvania in Philadelphia. "I'm not even sure whether we have a good sense of whether we should be applying this to nonchronic kidney disease patients, in other words, those who are on dialysis already as opposed to those who have chronic kidney disease who are not yet on dialysis," he toldMedPage Today.
Singh agreed, writing, "My guess is that most nephrologists will be confused, some perhaps incredulous."
Two other large trials of nondialysis patients with chronic kidney disease have also weighed in on the issue, both open-label comparisons.
In CHOIR, epoetin-alfa (Procrit) targeted to a hemoglobin of 13.5 g/dl raised the composite rate of death, MI, heart failure, hospitalization, and stroke by 34% compared with target of 11.3 g/dl.
In CREATE, immediate anemia treatment with epoetin-beta (Micera) targeted to a hemoglobin of 13 to 15 g/dl increased risk of a first cardiovascular adverse event by 22%, though it was not statistically significant, compared with a late strategy holding off treatment (targeted to 10.5 to 11.5 g/dl) until hemoglobin levels dipped below 10.5 g/dl.
Despite differences between the agents and treated populations, the results of all three trials are "complementary rather than contradictory," Singh said. Given the risks observed, with only minor quality-of-life benefits from active treatment compared with placebo, he said the best evidence for nondialysis chronic kidney disease patients suggests the following:
Focus on iron therapy, exclusion of occult bleeding, and suppression of any inflammation in patients with mild to moderate anemia (hemoglobin 9 to 11 g/dl), even those with mild symptoms and low-level fatigue.
Oral iron should be tried for the first three months of anemia management, with intravenous iron attempted only if this fails.
Worsening anemia to under 9 g/dl should be treated with "rescue" short course erythrocyte-stimulating agents or a blood transfusion.
Use a high threshold for erythrocyte-stimulating agents, even in symptomatic patients with a history of cancer or those undergoing chemotherapy.
For transplant candidates or severe anemia that cannot be managed with blood transfusions, consider a dose of 500 to 1,000 U per week of epoetin-alfa (or its equivalent in darbepoetin).
However, Berns called these recommendations too conservative.
"I think what we need to do is figure out what the right level of erythrocyte-stimulating agent treatment is and the right level of hemoglobin to trigger erythrocyte-stimulating agent use," he told MedPage Today, "and then make an individualized decision."
He noted that many physicians are likely to reserve judgement until quality-of-life data from secondary and subgroup analyses from TREAT emerge. "People are not going to be impressed by a very small quality-of-life benefit in a very select group of patients," he said in an interview.
Singh reported being principal investigator of the CHOIR study and a member of the executive committee for the TREAT study. He reported conflicts of interest with Ortho Biotech Clinical Affairs, Johnson & Johnson, Fibrogen, Amgen, Roche, Watson, and AMAG.
Berns reported having served on advisory or executive committees for and received consulting income from Amgen, Affymax, GlaxoSmithKline, and Wyeth.
Primary source: Journal of the American Society of Nephrology
Source reference:
Singh AK "Does TREAT Give the Boot to ESAs in the Treatment of CKD Anemia?" J Am Soc Nephrol 2010; 28.
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