Boston, MA - In 2005, epoetin alfa for the treatment of anemia in end-stage renal disease (ESRD) was the highest-expenditure drug in all of Medicare Part B, and financial incentives may be leading to overuse of epoetin, writes Dr Robert Steinbrook (Dartmouth Medical School, Hanover, NH), a national correspondent for the New England Journal of Medicine (NEJM). His thoughts appear as a Perspective in the January 4, 2007 issue of the Journal.

Previously, Steinbrook wrote a commentary questioning current hemoglobin-level guidelines in chronic kidney disease that were developed by the Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation (NKF), pointing out that the foundation also receives donations from companies that make these drugs; this opinion piece was apparently rejected by the New England Journal but was subsequently published online November 17, 2006 in the Lancet [2].

Wall Street Journal: NEJM "spiked" the editorial

According to a news story by David Armstrong published online December 26, 2006 in the Wall Street Journal, the Lancet commentary was originally commissioned by the New England Journal of Medicine as an editorial for its November 16, 2006 issue, which featured results from the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) and the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trials [3].

Armstrong wrote that the journal "spiked" Steinbrook's editorial since it was critical of the National Kidney Foundation's funding from companies that make antianemia drugs. Instead, it published an editorial by deputy editor Dr Julie Ingelfinger and editorial board member Dr Giuseppe Remuzzi that does not mention the foundation's funding, although it does note that KDOQI recommendations are not based on randomized controlled trials.

In the Wall Street Journal report, Dr Richard Horton, editor of the Lancet, told Armstrong that he was surprised to be approached by Steinbrook with the editorial. "We thought it extremely important—because of the significant clinical implications and because of the questions it raised about the propriety of the arrangements over funding and guideline development."

Steinbrook said that he had no further comment to make about these developments.

Responding to the Wall Street Journal article, Sandra Jacobs, communications director at the New England Journal of Medicine, said: "In our November 16, 2006 issue, we published two pivotal, original research articles, along with an editorial by Drs Ingelfinger and Remuzzi, on the use of erythropoietin in end-stage renal disease. . . . We believe that our coverage of this topic was scholarly, comprehensive, and far-reaching." She added, "We have a long-standing policy at NEJM not to discuss articles that we have not published. . . . We do want to point out that the journal's three national correspondents do not write exclusively for [us]."

NEJM Perspective: Erythropoietin spending has soared

In his January Perspective, Steinbrook points out that "dialysis facilities can make more money from administering epoetin than from dialysis and related routine services." He adds that in 2007, Congress may consider whether to eliminate financial incentives that may lead to the overuse of dialysis medications (mainly epoetin) that are billed separately from dialysis services by changing to a combined (bundled) payment system.

He explains that the three erythropoietin products marketed in the US to treat anemia in chronic renal failure are epoetin alfa (Epogen, Amgen; Procrit, Ortho Biotech) and darbepoetin alfa (Aranesp, Amgen). Among ESRD patients in the US treated with epoetin, 95% receive Epogen and the rest receive Aranesp.

He notes that monthly spending for erythropoietin per patient has "soared" to almost half of that for dialysis, where spending has remained relatively flat. In 2005, Medicare spent $7.9 billion for dialysis services, including $2.9 billion for medications, with $2 billion of that for epoetin alfa.

He goes on to say that about half the patients undergoing dialysis in the US have hemoglobin levels maintained at values above 12 g/dL, the maximum FDA-approved target. This high level may confer quality-of-life benefits but, according to the CHOIR trial, also increases the risk of cardiovascular complications.

The CHOIR investigators reported that among chronic kidney disease patients who were not yet on dialysis, those treated to a hemoglobin target of 13.5 g/dL, as opposed to 11.3 g/dL, had a significantly higher risk of a composite end point of death, MI, hospitalization for congestive heart failure (without renal-replacement therapy), and stroke. Steinbrook adds that the FDA's November 16, 2006 health advisory underscored "the importance of following the currently approved prescribing information" for raising hemoglobin levels no higher than 12 g/dL.

Congress must decide whether to wait at least several more years for the results of a not-yet-started study of bundled payments or create a bundled-payment system before the study results become available, he concludes.

In his Lancet commentary, Steinbrook writes that physicians and dialysis facilities need updated guidelines about anemia management. He notes: "Given the billions of dollars at stake for the drug and dialysis industries, such guidance is likely to receive the broadest acceptance if developed without industry support and by experts without relevant financial associations."

He notes that half the dialysis patients in the US have hemoglobin concentrations maintained at values higher than specified by the FDA and speculates that this may possibly be due to reimbursement methods that reward the increased use of epoetin or to the view reflected by the National Kidney Foundation guidelines that higher hemoglobin values improve quality of life. The foundation's most recent May 2006 KDOQI clinical practice guidelines increased target hemoglobin levels from 11 to 12 g/dL (as in the 2000 guidelines) to 11 to 13 g/dL.

Steinbrook writes that based on available data, however, there is "considerable doubt" that hemoglobin values between 12 and 13 g/dL are as safe as values between 11 and 12 g/dL. Maintaining the higher values requires substantially more epoetin, greatly increases the cost of care, and does not agree with prescribing information.

He also points out potential conflicts of interest in the development of guidelines. In 2005, the National Kidney Foundation received $4.1 million from Amgen and $3.6 million from Ortho Biotech. "Amgen supported the development of the anemia guidelines and is acknowledged as 'the founding and principal sponsor of KDOQI,' " in the guidelines document, he writes. Also, of the 18 members of the KDOQI anemia guidelines work group, two thirds disclosed financial associations with Amgen or other epoetin manufacturers or marketers.

He notes that in an October 2006 fact sheet, the foundation responded to questions about this sponsorship, saying, "the NKF continually reviews its policies and procedures to safeguard the work product of KDOQI and to ensure that no sponsorship funds contributed to the NKF ever influence the content of any of the KDOQI guidelines."

Steinbrook concludes that updated anemia-treatment guidance is needed to establish what is best for patients, and this might be accomplished under the auspices of the National Institutes of Health Consensus Development Program or the Agency for Healthcare Research and Quality.

The National Kidney Foundation announced December 7, 2006 that it had formalized plans for a review of its KDOQI anemia management guidelines based on the new evidence. "The cochairs of KDOQI have asked the anemia work group to reconvene on February 3, 2007 to discuss the implications of recently published studies and studies accepted for publication on anemia," a press release from NKF notes. "When the anemia work group completes its analysis of new studies, appropriate announcements or publications will be developed."