Few of the participants in the national dialysis scene escape the overt or implied criticism in comments found in an editorial by Dr. Daniel W. Coyne, a professor of medicine and nephologist at Washington University School of Medicine, in the April 18,2007 issue of JAMA. This is one of a number of articles and commentaries that have the same too-much-of-a-good-thing theme namely that the erythropoeisis stimulating agents(ESAs) have been over used both in renal failure patients and in patients with malignancies.
The medications on the table are:
epoetin alfa (branded as Epogen and Procrit)
darbepoetin (branded as Aranesp)
The recipients of criticism are:
1.The for-profit dialysis centers: An article in the same issue finds that the for-profits use more EPO and try to keep the hemoglobin levels higher than do the not for profit dialysis centers..The editorialist points out the profit margin for use of these drugs and possible marketing and rebate arrangements with the drugs manufacturer and distributors. Data from observational studies which have provided evidence for the improved quality of life associated with higher levels of hemoglobin are said by the editorial author are to be seriously confounded and he presents an array of selected data from several studies (some of which are randomized trials) which seem to indicate that mortality wise just the opposite is true.The increased mortality data associated with higher achieved hemoglobin levels was a key factor in the FDA's recent actions (see below)
2.The National Kidney Foundation and particularly its KDOQI (Kidney Disease Outcomes Quality Initiative). In this regard ,we are reminded that Amgen and other corporate contributors donate a good deal of money to the organization and that the chairman of the anemia working group works part time for a large for-profit dialysis company and 11/16 members of the work groups reportedly have conflicts of interest with the EPO producer.The reader is left to infer that the panel's recommendations may have been less influenced by sound data than by the source of funding. Dr. Coyne asserts that the panel's recommendations are based solely on quality of life studies. The NKF is expected to release new recommendations but Coyne believes that physicians "should not wait for the NKF opinions ,or necessarily trust of follow them."
Strong words, indeed.A reply from the Kidney Assocation folks surely will follow and I await their reply.
3.The nephrologists. While the practicing renal disease specialist does not make more money for using more EPO, he too does not appear blameless based on this editorial. Why? Even though he followed the guidelines (isn't this what everyone want doctors to do?) and even though he may have honestly believed there was the evidence base to support higher hemoglobin levels, he should have carefully analyzed the data and appropriately discounted the observational data and gone with what RCTs. Perhaps he should have concluded that contrary to the widely used guidelines, higher hemoglobin levels are not better. (OK Dr. Coyne didn't say any of those things, but I cannot help but think there is an undercurrent of unspoken criticism). I have to believe that most renal docs have acted in good faith here i.e.doing what they thought would benefit their patients and acting according to national guidelines.
I do not know if the data used to conclude that higher hemoglobin levels are better is so flawed as to conclude it should be discounted and I do not know if the conflicting data is so sound that clearly we should go with lower goals. But, I will admit Dr. Coyne's arguments seem persuasive and I would have to agree with the lower goals now recommended by the FDA. I obviously also do not know if the NKF panel was acting in anyway other than honestly and analysed the available data they had access to at the time in any way other fairly and appropriately. There is the perception of conflict of interest but concern about that should not be determinative. Analysis of the relevant data ideally should not factor in the possible conflict of interest but being human it is hard to not let that issue influence one's opinion. Moreover, I worry that we have been so guideline oriented and so herded by the views of organizations whose motives at times seem at best suspect that we really can't win.Go by the guidelines and then we learn the guidelines are thought to be bogus; don't comply with them and you are not practicing quality medicine and won't recieve your bribe (a.k.a. pay for performance.) We are learning how goldfish feel.
The FDA has also spoken on this topic and makes 3 points:
1.Use the lowest dose of an ESA to gradually increase the hemoglobin to the lowest level necessary to avoid a transfusion.
2.Realize that raising the hemoglobin level to greater than 12 increases the risk for cardiovascular events.
3.Realize that there has been reported a higher incidence of deep vein thrombosis in patients receiving epoetin preop to avoid blood transfusion.
ESAs are approved by the FDA for:
1.treatment of anemia in chronic kidney failure patients.
2.treatment of cancer patient whose chemotherapy has caused anemia.
