The normal hematocrit cardiac trial revisited

The Normal Hematocrit Cardiac Trial (NHCT) was the first large, randomized study of patients receiving hemodialysis to examine the outcomes of treating anemia to a target hematocrit range of 42 +/- 3% versus maintaining partial correction in a range of 30 +/- 3%. The results of the NHCT and a meta-analysis adding eight subsequent trials of normalization of hematocrit/hemoglobin in chronic kidney disease (CKD) have demonstrated increased thrombovascular events and mortality associated with the higher targets. This article expands and clarifies the results of the NHCT, including data that were edited from the original publication, and highlights findings from more recent studies in the field. Paradoxically, none of the randomized trials has reported an association between higher attained hemoglobin concentration and mortality within randomized groups. Mean platelet count did not increase among the patients in the normal-hematocrit group in the NHCT or in two other large trials, CREATE and CHOIR. Exposure to high doses of erythropoietic stimulating agents and/or intravenous iron could be mediating complications in the CKD anemia-normalization studies, but post-hoc analyses to probe such potential associations have yielded conflicting results and are clearly hindered by the risk of confounding by indication. The mechanisms underlying the deleterious outcomes associated with efforts to correct renal anemia fully remain unproven.