Debate: PRO Position. Should Hemoglobin Targets for Anemic Patients with Chronic Kidney Disease Be Changed

a higher Hb in dialysis patients. Aiming for an Hb of 1 9 g/dl as a minimum threshold is commensurate with the placebo arm of the TREAT study as well as the lower Hb arm of the Normal Hematocrit study. Having an upper limit for Hb (i.e. a target range) is not supported by evidence and encourages targeting with ESAs to just below 12 g/dl and within the target range, but beyond the prevailing evidence with respect to safety. The focus needs to be either avoiding ESAs entirely where possible, or reducing exposure to high ESA dosage where necessary. Intervention in these four trials (comprising over 7,000 patients) involved ‘targeting a higher Hb concentration’. This ‘targeting’ of higher Hb embodied treatment with ESAs. In fact, in all of the four trials, an algorithm controlled ESA dosage. In addition, in all of the trials, achieving a higher Hb concentration was associated with better outcomes compared to achieving a lower Hb level. In other words, targeting a higher Hb with ESA, not the actual achieving, is the problem. Thus, the singular focus on an Hb range misses the point. There is no evidence to indicate increased mortality or cardiovascular risk with other interventions in targeting a higher Hb – blood transfusions or iron. Indeed, dialysis patients with higher Hb because of high altitude have better outcomes than patients with lower Hb [9] . Regardless of the achieved Hb, treatment with high dosages of epoetin independently predicts death and cardiovascular complications. Four randomized controlled trials (RCTs) have demonstrated that erythropoiesis-stimulating agents (ESAs) targeted to normalize hemoglobin (Hb) in chronic kidney disease (CKD) patients result in a higher rate of death and/ or cardiovascular complications. In the Normal Hematocrit study, the point estimate of risk in the direction of harm was 30% [1] ; in CREATE, it was 22% (95% CI: 0.53– 1.14) [2] ; in CHOIR, it was 34% (95% CI: 1.03–1.74) [3] , and in TREAT it was 5% (95% CI: 0.94–1.17) [4] . Several observational analyses [5–9] implicate exposure to high dosages of ESAs in explaining these adverse outcomes. Studies in nonrenal settings confirm the direct risk conferred by ESAs. The case for ESA toxicity in explaining the risk of targeting a higher Hb in CKD patients is strong. The case is weak for a continued obsession with the current target range for Hb of 10–12 g/dl (the FDA recommendation) or 11–12 g/dl (K-DOQI). The status quo must change. The anemia RCTs demonstrate that the Hb is a flawed surrogate end point, fundamentally undermining the current focus on an Hb target range. Fleming and DeMets [10] emphasize that a valid surrogate should both correlate with the true clinical outcome and fully capture the net effect of treatment on the clinical outcome. Hb does not do this because targeting a higher Hb in the trials is not associated with a reduction in mortality or a lower rate of cardiovascular complications. On the contrary, the RCTs demonstrate there is increased risk in targeting Published online: May 21, 2010 Nephrology American Journal of