|Reversing Anemia Can Threaten Kidney Patients|
FDA to review use of blood-boosting drugs after worrisome findings from two trials
By Serena Gordon
THURSDAY, Nov. 16 (HealthDay News) -- For kidney disease patients, using drugs to reverse anemia by boosting red blood cell counts past U.S. Food and Drug Administration-recommended levels may do more harm than good, two new studies warn.
In fact, one of the studies in this week's issue of the New England Journal of Medicine was stopped prematurely by its safety panel after researchers reported more deaths and complications in the high-hemoglobin group and little likelihood that the treatment would provide any patient benefit.
The findings prompted the FDA on Wednesday to say it would review data from the study -- called the CHOIR trial -- and revisit the question of exactly how much anemia correction is too much.
The outcome of the two NEJM trials is also stirring debate as to whether doctors are over-prescribing blockbuster anti-anemia drugs such as Amgen's Epogen and Johnson and Johnson's Procrit.
"Treatment of anemia is important, but care needs to be taken in how aggressively anemia is treated," said the lead author of the CHOIR trial, Dr. Ajay Singh, clinical chief of the renal division and director of dialysis at Brigham and Women's Hospital in Boston, Mass. "The current evidence suggests that too high a hemoglobin level may be associated with some risk."
Anemia is a common complication of kidney disease, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). That's because normally functioning kidneys produce the hormone erythropoietin (EPO), which is essential to the production of red blood cells. Once kidney disease develops, the kidneys often can't produce enough EPO anymore. Without enough EPO, the body doesn't make enough red blood cells and anemia results.
Hemoglobin is a component of red blood cells and is responsible for carrying oxygen throughout the body. Normal hemoglobin levels are between 13 and 15 grams per deciliter. Without the right number of red blood cells and hemoglobin, the body's tissues don't get enough oxygen to function properly. Anemic people get tired more easily and may develop heart problems, according to the NIDDK.
In the past, blood transfusions were necessary to keep patients' levels of red blood cells and hemoglobin up to healthy levels. In the late 1980s, a synthetic version of erythropoietin called epoetin (brand names Epogen, Procrit) became available and made treating kidney disease-related anemia easier.
However, there has been uncertainty as to how close to normal blood levels hemoglobin should be targeted. Current recommendations from the National Kidney Foundation suggest that doctors try to maintain hemoglobin levels to at least 11, but not above 13 grams per deciliter.
In the first study, Singh and his colleagues recruited more than 1,400 people with chronic kidney disease from 130 centers across the United States. None of these patients yet needed dialysis.
Half of the group was targeted to achieve hemoglobin levels of 13.5 grams per deciliter, while the other half was targeted to achieve 11.3 grams per deciliter. The study lasted 16 months.
Those in the high-hemoglobin group had a 34 percent increased risk of having a serious complication, including death, congestive heart failure and stroke compared to those in the lower group. Quality-of-life improvements were similar in both groups.
The study was funded by drug makers Johnson and Johnson and Ortho Biotech, which together make Procrit.
In the second study, European researchers targeted hemoglobin levels to the normal range of 13 to 15 grams per deciliter for 226 people with chronic kidney disease. Another 250 were given enough epoetin to keep their hemoglobin levels between 10.5 and 11.5 grams per deciliter.
This study found no difference in cardiovascular outcomes, but did find that more people in the group targeted for higher hemoglobin levels ended up needing dialysis sooner. Quality-of-life improvements were greater in the high hemoglobin group in this study, which was funded by Hoffman-LaRoche, the maker of another epoetin drug, NeoRecormon.
In an accompanying editorial, Dr. Julie Ingelfinger and co-author Dr. Giuseppe Remuzzi cautioned doctors about overzealously raising kidney patients' red blood cell counts. They believe there may be several reasons why people with chronic kidney disease don't improve when hemoglobin levels are raised to normal.
"I think there are probably multiple reasons," said Ingelfinger, a professor of pediatrics at Harvard Medical School and a senior consultant in pediatric nephrology at Massachusetts General Hospital in Boston. "Many people think it's because you've got a group of people who have vascular disease that start to feel better and do more once they're treated, and then they may have cardiac events because they're doing more."
Dr. Robert Provenzano, chief of nephrology at St. John Hospital and Medical Center in Detroit said it's possible that "years of chronic kidney disease has caused so much damage that they can't tolerate higher hemoglobin." Provenzano was involved in Singh's study.
Others are concerned that Medicare rules governing kidney dialysis are boosting the use of anti-anemia drugs. According to the Boston Globe, Medicare currently covers most dialysis treatments. Under agency rules, dialysis clinics receive a 6 percent profit on their use of Amgen's Epogen. Critics say this encourages the hazardous overuse of the drug. Dr. Barry Straube, Medicare's chief medical officer, told the Globe that the agency would review the CHOIR study and see whether changes in its reimbursement policy are needed.
In a letter sent yesterday to Medicare, Congressman Bill Thomas (R-Calif.), chairman of the House Ways and Means Committee, and Pete Stark (D-Calif.), ranking member of the Ways and Means subcommittee on health, voiced their concern that Medicare is failing to "stem the systemic abuse of Epogen, resulting in costs to taxpayers and potential health dangers to patients," the Globe reported.
The CHOIR study results are also putting the new National Kidney Foundation guidelines -- developed with drug industry funding -- in the spotlight. In their editorial, Ingelfinger and Remuzzi note the recommendations "are not based on persuasive randomized, controlled trials." Speaking to the Globe, the foundation's vice president for scientific activities, Kerry Willis, said the group would look over the new findings to see if they warrant making changes in the recommendations.
But Ingelfinger also stressed that anti-anemia drugs have been a boon to kidney patients since their introduction two decades ago.
"It's important to remember what life was like before the possibility of transfusion-free correction of anemia," Ingelfinger said. "People felt terrible. Now we know that complete correction isn't needed, and these studies suggest that everybody should be vigilant to not overcorrect anemia."
To learn more about anemia and kidney disease, visit the U.S. National Institute of Diabetes and Digestive and Kidney Diseases.
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SOURCES: Ajay Singh, M.D., clinical chief, renal division, director, dialysis, Brigham and Women's Hospital, and associate professor, medicine, Harvard Medical School, Boston; Robert Provenzano, M.D., chief, nephrology, St. John Hospital and Medical Center, Detroit; Julie Ingelfinger, M.D., deputy editor, New England Journal of Medicine, professor, pediatrics, Harvard Medical School, and senior consultant, pediatric nephrology, Massachusetts General Hospital, Boston; Nov. 16, 2006, New England Journal of Medicine; Nov. 16, 2006, Boston Globe