As kidney drug doses rise, so do warnings

As kidney drug doses rise, so do warnings
Many on Medicare relying on Epogen
By Christopher Rowland, Globe Staff | September 14, 2006
Kidney dialysis patients covered by Medicare are receiving escalating doses of an expensive anti-anemia drug, despite growing evidence that aggressive treatment raises the risk of fatal heart attacks and strokes.

Epogen, made by Amgen Inc., is taken by most of the 325,000 Americans with kidney failure, making it Medicare’s single-largest drug expenditure at $2 billion a year and rising. It boosts oxygen-carrying red blood cells to counteract anemia, and without it, patients would require blood transfusions.

Statistics suggest patients feel better and have more energy with higher red blood cell counts. But weekly Epogen doses for dialysis patients have increased more than 200 percent since the drug’s introduction in 1989, prompting questions about the safety of higher doses. Federal data show that more than half of the dialysis patients taking Epogen are being treated with enough to elevate red blood cell counts beyond what the Food and Drug Administration says is safe. About 20 percent – 65,000 patients – had red blood cells boosted high enough to be in a range that a clinical trial last year revealed as potentially dangerous.

The trial, called CHOIR, was intended to document the benefits of larger Epogen doses. Instead, safety reviewers halted testing because participants were dying at an unexpectedly high rate.

Patients given the highest doses of Epogen suffered 16 more deaths – 72 out of about 700 patients – than those treated within FDA guidelines, who suffered 56 deaths. The results have not been published in an academic journal. But they have triggered fresh warnings that the FDA’s recommended dosing levels should be heeded.

``We need to be more conservative in where we target and maintain patients," said Dr. Jeffrey Berns, an associate professor of medicine at the University of Pennsylvania and a kidney-care specialist.

Amgen does not dispute the trial results but said they are not cause for alarm because they do not apply to typical clinical practice. The company said it has never promoted dosing levels above FDA recommendations.

The CHOIR trial was not the first to show higher doses of Epogen carried risks. Fatal heart attacks, strokes, and other problems forced clinical investigators to suspend at least seven other trials using Epogen or similar drugs to treat kidney and cancer patients. The trials weighed the benefits and risks of raising blood cell counts beyond what the FDA says is safe: 12 grams of red cells per deciliter of blood.

Unsettled questions A key trial sponsored by Amgen was suspended in 1996 when it revealed 33 more deaths in patients whose anemia was treated with Epogen in order to reach a target red blood cell count of 14 grams per deciliter than in those whose doses were targeted at a lower count. In all, 183 of 618 patients in the upper range of dosing died, compared with 150 of 615 in a group that received less Epogen.

The deaths ``shocked" Amgen scientists expecting to prove additional benefits of higher blood cell counts, according to Dr. William Bennett , a transplant specialist in Portland, Ore., who served on the review panel that suspended the trial. Bennett said the trial raised lingering questions about aggressive use of the drug, which has a thickening effect on the blood he likened to increasing the viscosity of motor oil.

``Are we actually increasing the chance of death? It’s an important issue that’s unsettled," he said.
An analysis of national mortality data published in 2004 uncovered a correlation between higher Epogen doses and dialysis patients’ deaths. It was conducted by a small nonprofit research group, the Medical Technology and Practice Patterns Institute , in Bethesda, Md. Because it was based on computer data, not rigorous clinical trials, the analysis is considered inconclusive. The National Institutes of Health has funded a more extensive, ongoing review of the data .

Specialists say dialysis patients are so ill that it is difficult to separate the effects of Epogen from health problems like diabetes and cardiac disease that could readily explain fatalities. Also, doctors may give more Epogen to their sickest patients .

This is a vulnerable population," said Dr. Josephine Briggs , former director of the NIH division responsible for kidney disease.We are trying to balance risk factors."

In a 2004 analysis of six suspended clinical trials in cancer patients, the FDA warned that pushing red blood cell counts higher is ``potentially unsafe."

``If you regularly see the hemoglobin above 12, that is more than necessary," said Patricia Keegan , director of the FDA’s division of therapeutic biological oncology products.

Looser Medicare policies Despite the warning signs, Medicare in April loosened reimbursement policies to allow blood counts to be boosted higher, effectively increasing the use of Epogen. A Medicare official said the agency does not believe red blood cell counts above FDA recommendations pose a danger.

The FDA sets minimum guidelines in terms of what people should be achieving" for red blood cell counts, said Dr. Barry Straube , chief medical officer for Medicare.If anything, we are too restrictive at the moment."

Keegan said the FDA ``can’t comment" on Medicare’s reimbursement policies for Epogen.
Amgen, based in Thousand Oaks, Calif., said the CHOIR study and other suspended trials should not worry patients and doctors because they tested higher doses of drugs over a longer period than patients would typically be on the drug. During actual treatment, the company said, red blood cell counts don’t usually stay above FDA guidelines for long because doctors react by lowering doses.

``I wouldn’t want patients to be frightened, because there’s no evidence at this time that those temporary excursions [beyond guidelines] are posing any risk to patients," said Joshua Ofman , Amgen’s vice president of reimbursement and payment policy.

Amgen said federal regulators were aware of the possibility of such temporary spikes when they approved the drug. But the drug maker has not sponsored its own study to specifically determine if short-term dosing at higher levels is safe.

Since 1973, nearly all dialysis treatment in the United States has been paid for by the federal Medicare program, regardless of a patient’s age. When Amgen began marketing Epogen in 1989, it became a major source of revenue for dialysis clinics. Amgen also sponsored the development of dosing guidelines, paying for work performed by a panel of doctors convened by the National Kidney Foundation.

Fueling Amgen’s growth The drug – known generically as epoetin – replaces a missing hormone in patients with kidney failure and stimulates the production of red blood cells by bone marrow. Because it helps build stamina, Epogen is also popular with some athletes and has been at the center of doping scandals in bicycle racing .

Epogen was the primary reason Amgen became a global powerhouse. In 2005, it earned $3.7 billion on $12.4 billion in revenue, making it the 13th-largest drug company in the world.

Amgen owns a set of Epogen-related patents that, if they continue to withstand challenges from would-be competitors, could assure the company of an exclusive market for Epogen use in dialysis patients until 2015. Investment-banking firm Morgan Stanley has called the company’s Epogen franchise ``one of the great monopolies of our generation behind Microsoft’s Windows."

Two dialysis clinic chains – DaVita Inc. and Fresenius Medical Care-- also depend heavily on Medicare reimbursements for Epogen. Together, they treat about two-thirds of all dialysis patients in the United States. Overall, according to an article published in the academic journal Health Affairs this week , about 22 percent of revenues for dialysis clinics are derived from administration of Epogen.

This year, in response to dialysis industry requests, Medicare loosened its reimbursement policies to allow for payments for anemia treatment up to a red blood cell level of 13 grams per deciliter, close to the level the halted studies determined were dangerous. The change was meant to allow for short-term fluctuations in the way individuals respond to Epogen, based on factors such as diet, weight, iron deficiencies, infection and inflammation.

Clinicians’ doubts Dr. Ajay K. Singh , chief of the renal division at Brigham and Women’s Hospital and a principal investigator in the CHOIR study halted last year, said Medicare’s dosing policy is out of step with the clinical evidence uncovered in his trial. He presented his findings at a meeting of the National Kidney Foundation earlier this year.

``It certainly would not be in keeping with the recommendation that I made at the National Kidney Foundation meeting, which is there is increased risk in patients with chronic kidney disease," Singh, also an associate professor at Harvard Medical School , said of Medicare’s new policy.

The CHOIR study focused on Procrit, a drug virtually identical to Epogen, and involved 1,432 subjects. It was sponsored by Procrit’s manufacturer, Ortho Biotech Products LP , a unit of Johnson & Johnson . The intent was to determine whether patients had lower death rates and fewer cardiovascular ailments if their red blood cell counts were elevated to 13.5 grams per deciliter.

Singh said further study is required to better assess the risks of using epoetin to achieve higher red blood cell counts. For now, he said, ``I would be concerned about having my hemoglobin run above 13 grams."

Fresenius Medicare Care dismissed the CHOIR results as ``preliminary." The company said it does not intend to change dosing practices based on the halted trial because it focused on increased hemoglobins in patients with chronic kidney disease, not those on dialysis.

DaVita’s national medical director, Charles McAllister , said Singh’s recommendation that the FDA’s limit be observed does a ``disservice" to dialysis patients.

Our doctors continue to aggressively manage anemia -- there isn't any over-utilization," McAllister said.I think we should be using more epo."

Christopher Rowland can be reached at

Before everyone gets anxious about their Hgb level and EPO dose, the CHOIR study reported in this article was a study of patients with chronic kidney disease not yet on dialysis and the drug in question was Procrit which made by Amgen and marketed by Ortho Biotech. The CHOIR study did not exclude CKD patients with other serious health problems including cardiac disease. It’s hard to know if they may have died anyway, but it’s my understanding that the study was halted just in case. There have been multiple studies on ESRD patients that show that anemia contributes to left ventricular hypertrophy which can also cause death.

Medicare coverage in the US for EPO requires that clinics reduce the dose of EPO by 25% when a patient’s hemoglobin level reaches 13%. To continue to get paid for the drug they provide, most dialysis clinics try to keep the Hgb level within the 11-12% range that the K/DOQI guidelines recommend. In 2004, the last year data were available, 91% of US dialysis patients had hemoglobin levels of 11-12%. I suspect most of the 9% that were not in this range had hemoglobin levels lower than 11%.

Correcting anemia is not easy. Patients who have higher hemoglobin levels say they feel better and are more able to do activities of daily living, including work than those who have lower hemoglobin levels. I assume that the the patient’s doctor will be the best judge of whether the patient is safe with a hemoglobin level that may occasionally go as high as 13% but in most instances stays between 11% and 12%.

Keep in mind that hemoglobin can be as high as 18% and still be considered “normal” in someone without kidney disease.

As a pre-dialysis ESRD patient on EPO, I have to say that I’m thankful for the drug. Before I started taking Aranesp, I had so little energy I didn’t think I could even continue working. I feel like Aranesp has literally saved my life. I feel better and I still work full time. My doctor monitors my blood levels very closely, I have blood tests every two weeks, and it has been a little difficult to get the level under control. But, I think it’s the same with all of the drugs we’re on for ESRD, you just have to be careful.