Greater use of erythropoiesis-stimulating agents (ESAs) and IV iron in hemodialysis (HD) patients at lower hematocrit levels are associated with decreased mortality, according to a new study.
“What we found was that the facilities treating anemia most aggressively with an ESA among people who were severely anemic, with a hematocrit of less than 30%, had better outcomes,” said senior study author Wolfgang Winkelmayer, MD, Associate Professor of Medicine at Stanford University School of Medicine in Stanford, Calif.
“But using ESAs most aggressively among those patients whose anemia was relatively mild, at a hema-tocrit of 36% and higher, was associated with higher mortality.”
Dr. Winkelmayer, who helped conduct the research while on the faculty at Harvard Medical School in Boston, said this study may help dispel mounting confusion over the safety of ESAs for dialysis patients. This study, published in the Journal of the American Medical Association (2010;303:857-864), comes in advance of federal regulators preparing additional restrictions on the use of ESAs. The agents are the most expensive medications reimbursed by Medicare in patients requiring long-term dialysis, costing the agency nearly $2 billion annually.
Dr. Winkelmayer and his col- leagues assessed the 12-month mortality risk associated with different dialysis center-level patterns of ESA and intravenous iron use for 269,717 new HD patients. Using 1999-2007 data from Medicare’s end-stage renal disease program, the researchers characterized each U.S. dialysis center’s annual anemia management practice by estimating its typical use of ESAs and IV iron in hemodialysis patients within four hematocrit categories. The mean age of the patients was 6.2 years and 62.5% were male.
Among patients with hematocrits less than 30%, those in the highest quintile of ESA dose (more than 5,896 units/day) had a 6% decreased risk of death compared with patients in the first quintile (less than 3,744 units/day), after adjusting for potentially confounding variables. Patients in the highest quintile of the probability of IV iron use (greater than 71.4%) had a 3% decreased mortality risk compared with those in the lowest quintile (less than 50.1%). Among patients with a hematocrit of 30-32.9%, subjects in the highest quintile had a 5% decreased risk versus the lowest quintile.
Among subjects with hematocrits of 36% or higher, patients in the highest quintile of ESA use (above 2,141 units/day) had an 11% increased risk of death compared with those in the lowest quintile (less than 1,392 units/day). Those in the highest quintile of iron use probability (73.5%) had a 7% increased risk compared with those in the lowest quintile (less than 39.1%).
These findings are very timely, Dr. Winkelmayer noted. Over the next four months, the FDA and the Centers for Medicare and Medicaid Services are set to review the use of ESAs in treating anemia in CKD patients. “Eliminat- ing coverage or severely restricting marketability of ESAs might mean pouring out the baby with the bath water,” Dr. Winkelmayer said. “We give glimpses that show that such extreme action might not be warranted,” he added.
Three ESAs products are available in United States to treat anemia: epoetin alfa, marketed by Amgen as Epogen and by Johnson & Johnson as Procrit, and darbepoetin alfa, marketed by Aranesp. Although the ESAs were approved for treating anemia in 1989, questions have emerged in recent years over their safety for different subsets of patients.
Cancer patients with anemia often initially respond well to ESAs, but studies have shown that the drugs can cause tumors to grow faster and shorten patients’ lives. Consequently, on February 16, the FDA unveiled a plan requiring physicians to complete special training before prescribing ESAs for cancer patients.
Over the past 20 years, researchers have tried to assess the impact of ESA prescribing on patients’ risks for serious, potentially fatal cardiovascular events, such as myocardial infarction and stroke. Researchers had observed that patients receiving higher levels of ESAs had increased risk of these negative outcomes, but proof of a cause-and-effect relationship eluded them.
“Researchers have looked at this 100 different ways,” Dr. Winkelmayer said. “It’s occupied a generation of drug safety researchers. Unfortunately, patients requiring lower ESA doses for the management of their anemia are inherently different from patients requiring larger doses, making it almost impossible to discern whether the inferior outcomes experienced by patients receiving ESA doses were attributable to the medication itself or to differences in patient characteristics, which were usually poorly described in the available datasets.”
It is important to look at dialysis patients because their biology might be different, he continued. “Some studies have indicated that ESAs may cause tumors to grow faster and reduce survival in some cancer patients, but that is not the main problem in this patient group,” he told Renal & Urology News. The findings from our study are a wake-up call because they show how important it is to look at different patient groups and how important it is to look at different studies with great, great care.” n