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Heart Risk Seen in Drug for Anemia

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The New York Times
November 16, 2006

A medical study to be released today suggests that high doses of a best-selling drug used to treat anemia in dialysis and cancer patients may increase the risk of heart problems and deaths.

Almost a million Americans a year receive prescriptions for the drug, known as epoetin, or darbepoetin, a closely related drug also used in anemia treatment. Worldwide, sales of the two drugs — sold under the brand names Epogen, Procrit and Aranesp — topped $9 billion last year for Amgen and Johnson & Johnson, their makers.

Researchers for the study, to be published in The New England Journal of Medicine, divided anemic patients with kidney disease into two groups. One group received epoetin with a goal of almost fully correcting their anemia, a lack of red blood cells associated with fatigue and shortness of breath.

The others were allowed to remain more anemic and generally received less epoetin. Patients in the first group were 34 percent more likely to die or suffer heart problems than those in the second.

Dr. Ajay Singh, an associate professor at Harvard Medical School and the study’s lead author, said the results were surprising and should encourage doctors to treat anemia less aggressively.

The study tested anemia in kidney patients who did not yet need dialysis, a mechanical blood-filtering technique used to keep alive patients whose kidneys have almost entirely failed. But its findings should apply to patients on dialysis as well, Dr. Singh said.

The findings reinforce mounting concerns that kidney patients may be receiving too much epoetin, in part because dialysis clinics make bigger profits for providing larger doses. Studies show that the clinics make little, if any, profit on the actual dialysis services they provide for Medicare patients, who are the vast majority of patients.

The amount of epoetin received by the typical American dialysis patient has nearly tripled since the early 1990s. The average patient now gets epoetin doses similar to those given to the first group in Dr. Singh’s study. Death rates for dialysis patients are higher in the United States than in Europe, where doses are comparable to the second group’s, although doctors say other factors may also explain the difference. About 22 percent of American patients die every year, compared with about 15 percent in Europe.

Dr. Singh said his study, with a second trial with similar results also to be published today in The New England Journal, did not necessarily prove that epoetin use was harmful.

But the studies show that the anemia of many patients is being overcorrected and that doctors should aim for lower levels of red blood cells in their patients, he said. The simplest way to do that would be to give patients less epoetin.

Susan Cruzan, a spokeswoman for the Food and Drug Administration, said the agency was aware of the study results and would evaluate the data. She noted that Epogen’s label already offered advice for doctors. The F.D.A., she said, will release a more complete advisory today.

Amgen, which sells epoetin under the brand name Epogen and darbepoetin under the name Aranesp, said its drugs had been a boon for people with anemia and are properly used in the vast majority of patients. In fact, anemia may be undertreated in cancer and kidney patients, scientists at Amgen argue.

Amgen said it was committed to the safety of its drugs and was conducting a clinical trial to study Aranesp in 4,000 kidney patients. But some scientists say that trial will not settle the most crucial issue about epoetin and darbepoetin: whether the drugs are routinely overused.

In the first nine months of 2006, Amgen sold $4.9 billion of Aranesp and Epogen, accounting for almost half its revenue. Sales of the two drugs rose almost 15 percent compared with the period in 2005.

Johnson & Johnson, which sells epoetin under the brand names Procrit in the United States and Eprex everywhere else, reported sales of $2.4 billion in the first nine months of 2006, down slightly from 2005.

Epoetin, a naturally occurring protein produced mainly in the kidneys, stimulates bone marrow cells to produce hemoglobin, the main component of red blood cells. Darbepoetin, which was introduced in 2001, is a version of epoetin that has been slightly modified so that it does not need to be given as frequently. Both drugs are given via injection.

Since epoetin was approved in 1989, it has become a standard treatment for more than 90 percent of dialysis patients in the United States, and it is increasingly used for patients with earlier-stage kidney disease. The drug is also widely used for cancer patients, who often suffer from anemia as a side effect of chemotherapy. Some cancers can also cause anemia on their own.

Many kidney and cancer doctors and patients say epoetin has greatly improved the lives of people receiving dialysis or chemotherapy. Severe anemia can be debilitating, leaving patients unable to work, walk for over a few minutes or even think clearly, as well as increasing their risk of infection and heart disease.

Before epoetin, blood transfusions were the only effective treatment for anemia. But transfusions carry a risk of infection and can eventually prevent patients from receiving transplants. For most patients, epoetin appeared a safe alternative.

“The drug in and of itself has really advanced care for patients, so that they’re able to go back to do the things that they previously couldn’t,” said Kris Robinson, the executive director of the American Association of Kidney Patients and a kidney transplant recipient. “It makes a huge difference.”

There are no set doses of epoetin. Instead, it is given with the goal of raising hemoglobin levels to a specific target level. Aiming for a higher average hemoglobin target effectively raises the amount of epoetin that patients receive.

The prescribing label for Epogen, which is approved by the F.D.A., says dialysis patients should have a target hemoglobin level of 10-12 grams per deciliter of blood. In general, healthy adult men have hemoglobin levels of 14 grams or more per deciliter and patients are considered to need treatment if their levels are below 10 grams.

But guidelines devised by the National Kidney Foundation say a target of 11 to 13 grams is appropriate. Amgen sponsored the development of those guidelines, though the National Kidney Foundation said the company had not influenced them.

The difference between the F.D.A. and Kidney Foundation guidelines may seem small. But Dr. Singh’s study compared patients with an average hemoglobin of 12.6 grams with those who had an average of 11.3 grams, and found a 34 percent greater incidence of deaths and heart attacks in those with the higher levels.

In the United States, the average dialysis patient has a hemoglobin level just under 12 grams , according to data from the United States Renal Data System, which monitors kidney patient care. Almost 20 percent of patients have levels above 13 grams.

Davita, the second-largest dialysis provider, is especially aggressive about increasing hemoglobin levels, according to the data system. A paper that will be presented Saturday at the American Society of Nephrology’s annual conference in San Diego found that 37 percent of Davita patients reported hemoglobin levels greater than 14 grams at least once in a nine-month period, an abstract of the paper posted online said.

The paper’s authors did not return calls for comment on it.

Dr. Charles McAllister, Davita’s chief medical officer, said the company did not aim for hemoglobin targets higher than 13 grams per deciliter. But some patients go over that benchmark because hemoglobin levels naturally vary over time, he said.

Despite Dr. Singh’s study and the F.D.A. label on Epogen, Dr. McAllister said he thought patients would benefit from hemoglobin as high as 13 grams per deciliter.

But Daniel Coyne, a kidney doctor and professor of medicine at Washington University in St. Louis, said Dr. Singh’s study adds to a growing body of evidence that American patients receive too much epoetin and that hemoglobin targets are too high.

“There’s enough study evidence to say that a higher hemoglobin carries an increased risk of harm,” Dr. Coyne said. “Above 12 carries increasing risk that is unacceptable given the occasional improvements of quality of life.”

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