CardioExchange Archive

(SEE PART II OF SERIES) When the FDA approved the use of recombinant erythropoietin for patients with renal disease in 1989 it was based upon the ability of this agent to reduce the need for blood transfusion, increase patient’s exercise tolerance and improve quality of life. At the time, the perceived risk of blood transfusion was high following the association of AIDS and ‘non-A non-B’ hepatitis with blood product use, and the mean hemoglobin of patients entering the clinical trials was 7.5 g/dl. In the last decade this group of compounds has dramatically reduced the need for transfusion in dialysis patients and become the single biggest drug cost in Medicare. Meanwhile, it has become clear that the greater risk to patients with kidney disease is that of cardiovascular disease and there are now serious questions about the role of recombinant erythropoietins in exacerbating this already high cardiovascular risk.
 
The TREAT study is notable as one of the few placebo-controlled trials of anaemia management (albeit with almost half of the placebo group receiving some active treatment) in patients with kidney disease. The findings are broadly in accord with those of previous trials and meta-analyses, suggesting no benefit (and perhaps harm) with anaemia correction beyond hemoglobin values of greater than 12. The existing data on quality of life benefits associated with anaemia correction nearing the normal range are questionable, and the TREAT results will not alter the skepticism around this outcome. TREAT confirms the benefit of reducing the use of blood transfusion but also reinforces concerns about the safety of these agents in groups with near-normal hemoglobin targets. The effect of drug dose upon the vascular risk of recipients has not been fully explored and a planned individual patient data meta-analysis along with a trial of fixed dose regimens are likely to provide important new evidence to guide the use of these agents. Until such data further clarifies these effects, the evidence does not justify a return to the iron overload, profound anemia, frequent transfusions and attendant complications of only 20 years ago.
 
The majority of recombinant erythropoietin is prescribed for dialysis patients.  Most guidelines, dialysis units and clinicians are targeting hemoglobin values around 10.5-11.5 in these patients and trying to stay below 12. In the pre-dialysis population, treating more aggressively than as was done with the placebo group in TREAT should only be done with great caution.
 
Are we on the flat part of the benefit curve for increasing hemoglobin in patients with anaemia associated with kidney disease, with the greatest gains derived by increasing hemoglobin from 7.5 to 10?

Would fixed dosage schedules rather than hemoglobin targeted therapy be safer?
 
What importance will these findings have for existing clinical guidelines in anaemia management?