The FDA Black Box Warning for ESAs

On May 9, 2007, the U.S. Food and Drug Administratio issued a public health advisory outlining new safety information about ESAs [1] . This included a new black box warning advising physicians to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid the need for a blood transfusion. Physicians and patients were to weigh the risks of ESAs against the risks of a blood transfusion.

The American Association of Kidney Patients, in cooperation with its Medical Advisory Board quickly responded, noting that:

• The history of ESAs dates to 1989 [2, 3] . Since their introduction, the

hospitalization rate, blood transfusion rate and blood borne illness rate have

dropped. In addition, ESRD mortality rates and quality of life for all CKD

patients have improved [4] .

• Although originally designed and approved by the FDA as a measure to avoid

blood transfusions, the clinical practice patterns since 1989 have evolved such

that current standard of care, is to use ESAs to achieve a hemoglobin greater

than 11 to get the best health benefits for CKD patients.

• If the renal community were to revert to dosing ESA just to avoid blood

transfusions, the hemoglobin levels would likely be lower than 11, and there are

serious concerns that the quality of life, activity level and productivity of many

patients will suffer [5] [6-8] .

• The management of anemia should be determined by the patient’s needs and the

decision-making shared with the physician. It should be based on the results of

recent clinical trials [9] [10] .

• The AAKP Medical Advisory Board agrees with current practice standards and

evidence and supports targeting the hemoglobin between 11 and 12 to achieve a

hemoglobin of at least 11.

• Temporary increases of hemoglobin to greater than 12 are common because of

the variability in patient responses and have not been proven to be harmful.

These temporary increases are usually well tolerated and easily treated by

decreasing the ESA dose.

 

Background

Patients with chronic kidney disease (CKD) have anemia, or decreased red blood cell formation because they lack the hormone erythropoietin that stimulates the production of red blood cells by the bone marrow. Since 1989, a synthetic form of erythropoietin, epoetin alfa or Epogen, developed by the biotech company, Amgen, has been given regularly to dialysis patients, causing the hemoglobin to rise. In addition, darbepoetin alfa or Aranesp has been frequently used in patients with CKD but not yet receiving dialysis. Although both of the products used in U.S. markets are made by Amgen, Ortho Biotech distributes epoetin alfa under the trade name Procrit to patients with CKD not yet on dialysis. These products are now collectively termed ESAs, erythropoiesis stimulating agents.

The CHOIR and CREATE studies published in the New England Journal of Medicine [9] [10] highlighted that cardiovascular outcomes were no better, and in fact were 34 percent worse when the hemoglobin target is 13.5 in comparison to 11.3 and 22 percent worse when the hemoglobin level is normalized between 13 grams and 15 verses 10.5 to 11.5 in patients with CKD. The studies randomized patients with CKD, but not on dialysis into two study groups divided by the targeted hemoglobin – approached the current target, the other higher approached values closer to normal. That a range of 11.3 to 13.5 (achieved mean hemoglobin of 12.6) was associated with worse outcomes was a surprise to the renal community since the updated NKF guidelines recently established the upper target for hemoglobin at 13.

It has never been clear whether the hemoglobin level in patients with predialysis CKD should be brought to the level of patients with normal kidney function, or kept slightly below, until these two papers were published. An earlier study showed adverse events were higher in dialysis patients with hemoglobin values greater than 14 (Hematocrit 42 percent) [11] . Although many within the dialysis community felt the hemoglobin should be below 13, there was clearly the argument that because hemoglobin carries oxygen to tissues, normalizing hemoglobin would improve the exercise and general functional capacity of patients receiving dialysis [12-15] . There was a further need to study this in patients who were not yet on dialysis, but someday would be. In the absence of contrary data, it remained logical for nephrologists in practice and as consultants to dialysis companies to have previously targeted a hemoglobin of 13 with the main motive to achieve the best outcome for the patient.

In practice, the target hemoglobin levels have historically been 11 to 12, but recent National Kidney Foundation (NKF) anemia guidelines recommended increasing the upper limit of hemoglobin to 13 [16] . The recently published articles pertained to the predialysis, not the dialysis population, as patients requiring renal replacement therapy (RRT) were terminated from the trials.

Since the publication of the CHOIR study in November 2006, many physicians are moving their target hemoglobins in the predialysis CKD population back to 11 to 12 to realign with optimal outcomes. Since physicians are responsible for the protocols and the orders necessary to infuse drugs such as Epoetin and darbepoetin in the dialysis setting as well as in their clinic practices, as a matter of safety, have elected to also lower the target in their dialysis patients.

In dialysis patients, attempts to maintain the hemoglobin levels within a certain target is difficult without either overshooting some of the time. Increasing the range from 11 to 13 was at the time a wise move by the NKF K/DOQI workgroup, since it would make it more practical to stay within the range. Newer ESA agents such as continuous erythropoietin receptor activator (CERA) are being evaluated in Phase III trials [17] .

On December 6, 2006, in response to the New England Journal of Medicine publications, hearings by the Ways and Means Committee were held before Congress. USRDS data was cited, claiming in a cross sectional analysis 40 percent of dialysis patients had a hemoglobin greater than 12 g/dL. The inaccuracies in this type of measurement were quickly pointed out to Congress.

Patient variability was also addressed; it was also noted that whenever the hemoglobin rose above 12 g/dL, physicians took action to lower the drug dose [18] . Many kidney patients are in a chronic inflammatory state because of diabetes and severe vascular disease. This varies between patients, but also varies in an individual from day to day. Cells recruited to fight inflammation arise from the same pool of precursors as cells that form mature red blood cells. They share the same substrates or food sources required for growth and maturity. The body has a choice: fight the inflammation or form new red cells. On the days the stimuli for inflammation are low, the blood count rises faster and the cells are more responsive to ESAs. But, when inflammation is worse, it takes more ESA to raise the hemoglobin level. Thus, the red cell formation rate in a patient with CKD varies even with the same dose of ESA based upon the inflammatory status.

The cost of bringing genetically engineered biological products, like the ESAs, to market is enormous, and corporations that take this risk expect a good return on their investment. In the case of Amgen, much of the profit was used to further develop the colony stimulating factors, Neupogen and then Neulasta.

These two drugs have been life-saving to oncology patients receiving chemotherapy because they help prevent the white blood cell counts from staying at critically low levels, leading to a fatal septic event. But, the expense of any pharmaceutical is always weighed against its benefit.

This is the dilemma of health economics, as the burden of this benefit is distributed among taxpayers and employer groups. ESAs contributes substantially to the expense of caring for the 390 thousand Medicare beneficiaries in the ESRD program. Medicare spends around two billion dollars yearly on these drugs [19] .

Congress has the fiduciary responsibility to make certain CMS is not overspending for healthcare. Right now, healthcare costs in America are almost two trillion dollars 15.9 percent of the Gross Domestic Product [20] . As American consumers spend $6,697 per person, we put Government policy makers under extreme pressure to reduce healthcare spending. Faced with evidenced-based adverse outcomes described in the CHOIR study, they are duty-bound to carefully examine this as an opportunity to reduce costs and improve patient safety.

Recent testimony before the House Ways and Means Committee suggested that CMS spends 36 percent more than it should for ESAs [19] . The Government Accountability Office (GAO) testified before the same committee that since the Medicare composite rate was not automatically adjusted for inflation, it inadequately covered dialysis services. Since program payments for separately billable drugs like the ESAs exceeded the providers’ cost to purchase them, the profit margin subsidized the under-funded composite rate. In summary, reimbursement for billable drugs made up for the inadequate reimbursement for dialysis [21] [22] .

In view of the CHOIR study, Congress now has the duty to 350,000 dialysis patients to consider how this shortfall will be covered [23] . In 2003, lawmakers voted to require CMS to submit a report on an alternate system of payment – raising dialysis payment level to include billable drugs – a bundling of services.

This report was due in 2005, and a three year demonstration project was to have commenced in 2006. We have yet to see either, as of this date, and controversy about how to fully fund an expensive procedure that is truly a miracle of care continues. One thing is for certain: when decisions for healthcare are based upon economics without evidenced based science, bundling can carry the potential to negatively impact on patient care. At risk service has been a major problem in managed care plans. Ideally, patient care and service will be reimbursed based upon performance and always focused upon the patient as the key factor.

It is highly arguable whether or not dialysis units abused the incentive to administer ESAs for profit because it has always been the physician and patient, in a shared decision making process, who determined the dose of hemoglobin. The decision to use ESAs is based upon the historical perspective that blood transfusions are detrimental to the safety of the dialysis patient [24] and the potential sensitization of a transplant recipient to create antibodies that might interfere with ever receiving a kidney transplant [25] .

It has been shown that the quality of life, as measured by using a valid survey tool, the SF-36, is low in ESRD patients. An important part of the historical perspective is the assessment of quality of life and exercise capacity. These studies were performed shortly after the availability of the first ESA, epoetin alfa. One hundred eighteen hemodialysis patients were randomized to three groups. Group one, a placebo group, was not treated for anemia. In group two, the target hemoglobin was 9.5 to 11.0 g/dL. In group three, the target hemoglobin was 11.5 to 13.0 g/dL. Patients were assessed for quality of life using a disease specific measure, the KDQ. They were followed for six months. Quality of life improved in both groups which had the higher hemoglobins, when compared with controls. The fatique outcome measure was highly significant. There was no significant difference in QOL between groups two and three [26] . In another study, baseline quality of life scores in dialysis patients were well below those in the general population using the SF-36. In patients treated with epoetin alfa (EPO) there was significant improvement in physical functioning, social functioning, mental health, keeping house, social life, hobbies and sexual satisfaction when the hematocrits rose by a mean of 4.6 points from the baseline of 25.5 to over 30 percent. (roughly a hemoglobin of > 10 g/dL) [27] . With respect of exercise capacity, 14 patients were entered into a well-designed study to look at how well dialysis patients can oxygenate their muscles during heavy cycling exercise comparing the hemoglobin of 10 g/dL with 14 g/dL. Measures of exercise performance, were significantly higher in the group with the higher hemoglobin. (The “p” value was less than 0.01) [28] .

In summary, there is a physiologic basis, and evidence as to why physicians and CKD patients desire higher hemoglobin levels, but normalization is not optimal based upon recently published clinical trials. Putting aside the cost factor, the so-called “profit motive” of dialysis facilities, and the media attention rampant [29-33] during the weeks that followed publication of the CHOIR Trial, most physicians modified their targets because of evidenced-based medicine, and to avoid the risks of an adverse outcome in their patients. In doing this, they have received the full support and cooperation of the teammates within large dialysis chains at all levels [34] .

ESAs are mainstay to the therapy of dialysis patients because they not only help avoid blood transfusions and their attendant risks, but increase the quality of life and the productivity of patients receiving renal replacement therapy. Patient safety is a priority to physicians and to AAKP. The results of well-designed, randomized controlled trials showed the risks of heart attacks, strokes blood clots and even death are increased when ESAs are given at a higher than recommended dose. In response, the FDA and the manufacturers of the anemia treatment products agreed to revised product labeling that included an updated, black box warning, and a modification of ESA dosing instructions. Physicians are modifying their dosing strategies to maintain the target hemoglobin levels between 11 g/dL and 12 g/dL.

References

1. FDA Strengthens Safety Information for Erythropoiesis- Stimulating Agents (ESAs). 2007

[cited; Available from: http://www>. fda.gov/bbs/topics/NEWS/2007/ NEW01582.html.

2. Eschbach, J.W. and J.W. Adamson, Guidelines for recombinant human erythropoietin therapy. Am J Kidney Dis, 1989. 14(2 Suppl 1): p. 2-8.

3. Eschbach, J.W., et al., Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med, 1989. 321(3): p. 158-63.

4. Valderrabano, F., Quality of life benefits of early anaemia treatment. Nephrol Dial Transplant, 2000. 15 Suppl 3: p. 23-8.

5. Ritz, E., et al., Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. Am J Kidney Dis, 2007. 49(2): p. 194-207.

6. Bedani, P.L., et al., Erythropoietin and cardiocirculatory condition in aged patients with chronic renal failure. Nephron, 2001. 89(3): p. 350- 3.

7. Foley, R.N., Should hemoglobin be normalized in uremic patients? Clin Nephrol, 2002. 58 Suppl 1: p. S58-61.

8. Yorgin, P.D., et al., The clinical efficacy of higher hematocrit levels in children with chronic renal insufficiency and those undergoing dialysis. Semin Nephrol, 2001. 21(5): p. 451-62.

9. Singh, A.K., et al., Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med, 2006. 355(20): p. 2085-2098.

10. Drueke, T.B., et al., Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med, 2006. 355(20): p. 2071-2084.

11. Besarab, A., et al., The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med, 1998. 339(9): p. 584-90.

12. Eckardt, K.U., Target hemoglobin in patients with renal failure. Nephron, 2001. 89(2): p. 135-43; discussion 143-4.

13. de Francisco, A.L., et al., Past, present and future of erythropoietin use in the elderly. Int Urol Nephrol, 2002. 33(1): p. 187-93.

14. Gomez, J.M. and F. Carrera, What should the optimal target hemoglobin be? Kidney Int Suppl, 2002(80): p. 39-43.

15. Ritz, E. and V. Schwenger, The optimal target hemoglobin. Semin Nephrol, 2000. 20(4): p. 382-6.

16. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis, 2006. 47(5 Suppl 3): p.11-1145.

17. de Francisco, A.L.M., et al., Continuous Erythropoietin Receptor

Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomised, multicentre, multipledose, phase II study. Int J Clin Pract, 2006. 60(12): p. 1687-1696.

18. Thomas, B., Hearing on Patient Safety and Quality Issues in End Stage Renal Disease Treatment, C.o.W.a. Means, Editor. 2006, U.S. House of Representatives.

19. Pizzi, L.T., et al., Economic implications of non-adherence to treatment recommendations for hemodialysis patients with anemia. Dialysis & Transplantation, 2006. 35(11): p. 660-671.

20. Catlin, A., et al., National Health Spending In 2005: The Slowdown Continues. Health Aff, 2007. 26(1): p. 142-153.

21. Walker, D.M., Testimony Before the Committee on Ways and Means, House of Representatives. End- Stage Renal Disease: Medicare Payments for All ESRD Services, Including Injectable Drugs, Should Be Bundled,, U.S.G.A. Office, Editor.2006.

22.Steinbrook, R., Medicare and erythropoietin. N Engl J Med, 2007. 356(1): p. 4-6. 23. U.S. Renal Data System, USRDS 2006 Annual Data Report. 2006.

24. Picard, V.T., et al., Transfusion therapy: associated risks and alternative approaches. Anna J, 1990. 17(6): p. 457-64.

25 .Drueke, T.B., et al., Does early anemia correction prevent complications of chronic renal failure? Clin Nephrol, 1999. 51(1): p. 1-11.

26. Laupacis, A., C. Wong, and D. Churchill, The use of generic and specific quality-of-life measures in hemodialysis patients treated with erythropoietin. The Canadian Erythropoietin Study Group. Control Clin Trials, 1991. 12(4 Suppl): p. 179.

27. Beusterien, K.M., et al., The effects of recombinant human erythropoietin on functional health and well-being in chronic dialysis patients. J Am Soc Nephrol, 1996. 7(5): p. 763-773.

28. McMahon, L.P., et al., Physical performance and associated electrolyte changes after haemoglobin normalization: a comparative study in haemodialysis patients. Nephrol Dial Transplant, 1999. 14(5): p. 1182-7.

29. Berenson, A., Heart Risk Seen in Drug for Anemia, in New York Times. 2006: New York.

30. Berenson, A., Treatment of Anemia Questioned, in New York Times. 2006: New York.

31. Pollack, A., F.D.A. Warning Is Issued On Anemia Drugs’ Overuse, in New York Times. 2007: New York.

32. U.S. to Review Anemia Drugs For Safety, in New York Times. 2007: New York.

33. Pollack, A., Anemia Drugs Under Review by Congress, in New York Times. 2007: New York.

34. (2007) DaVita Will Study New FDA Erythropoiesis-Stimulating Agents Label. Volume,

 Stephen Z. Fadem, MD, FASN, FACP, is Co-Medical Editor of aakpRENALIFE. He serves as a member of the AAKP Medical Advisory Board and is Vice President of the AAKP Board of Directors. Dr. Fadem is a practicing nephrologist in Houston.

This article originally appeared in the May 2007 issue of aakpRENALIFE.