Monday, November 20, 2006

Guidelines in Whose Interest? - Epoetin Revisited

We previously posted about how influential guidelines that suggested aggressive use of epoetin to increase and try to normalize hemoglobin levels in patients with anemia and chronic liver disease were funded by Amgen Inc., the maker of one version of epoetin (Epogen). These guidelines appeared to have influenced the US Medicare program to pay handsomely for aggressive use of epoetin, even though the evidence supporting high doses of the drug was not very clear.

This week, the results of two new randomized trials of other versions of epoetin were published in the New England Journal of Medicine.

Preliminary results of the CHOIR study had been mentioned in our earlier post. In short, CHOIR (Correction of Hemoglobin and Outcomes in Renal Insuffiency) was a randomized controlled trial of epoetin alfa dosed either to normalize hemoglobin (target range of 13.0 to 13.5 g/dl) or maintain it in the 10.5 to 11.0 range.(1) The rate of a composite endpoint (death, myocardial infarction, hospitalization for congestive heart failure, stroke) was statistically significantly higher in the more aggressively treated group (17.5%) than in the less aggressively treated group (13.5%). The rates of death and hospitalization for congestive heart failure were numerically higher in the more aggressively treated groups, and the differences were almost statistically significant. Thus this trial suggested that aggressive use of epoetin actually increased the risk of cardiac complications and possibly death.

The CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta) trial was a randomized controlled of epoetin beta dosed either to normalize hemoglobin (13.0 -15.0 target) or maintain it in the 10.5 - 11.5 range.(2) The rate of a somewhat more complex combination endpoint (including cardiac and vascular events, as well as death) was numerically higher in the more aggressively treated group, although the difference between groups did not achieve statistical significance. The death rate was also higher in the more aggressively treated group. The study did show that more aggressively treated patients had somewhat better scores on measures of health status, although their improvements did not appear very large. Thus, this trial at best suggested no advantageous effect of aggressive use of epoetin on death or cardiac events, and was consistent with the possibility that it may have had a disadvantageous effect.

Combined, these two studies raise even more concern that aggressive use of epoetin for patients with anemia and chronic renal disease may do more harm than good.

Following the publication of these articles, the Boston Globe reported that the US Food and Drug Administration (FDA) officially warned against excessively aggressive use of epoetin.

This new data underscores the concerns we raised earlier. Guidelines developed with financial support of pharmaceutical or biotechnology companies may favor aggressive use of those companies' products, even in the absence of strong evidence for such use. At best, this can lead to excess costs and treatment that does patients little good, and risks harming them. In this case, we have now gone from a situation in which there was an absence of strong evidence for aggressive use of epoetin to one in which there is evidence suggesting such aggressive use may be actively harmful.

So the bottom line should be just because a guideline advocates something does not mean physicians should obey. Not all guidelines are created equal. Guidelines that have not been rigorously developed using evidence-based medicine principles, especially when they may also have been affected by conflicts of interest, should be viewed with extreme skepticism. Yet, turning such guidelines into "pay for performance" (P4P) incentives is the latest rage in health care management circles (see post here). Such a rage, however, can be bad for patients and doctors.


1. Singh AK, Szczech L, Tang KL et al. Correction of anemia with eopetin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085-98.
2. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: 2071-2084.

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