What Caused Excess Strokes in Patients Randomized to Darbepoetin in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)?

Erythropoiesis-stimulating agents (ESAs) have been the treatment of choice for patients with renal anemia for >2 decades. Epoetin alfa was first approved in 1989 on the basis of its ability to increase hematocrit swiftly and to reduce the burden of transfusion in patients with chronic kidney disease (CKD) receiving dialysis.1 In addition to transfusion avoidance, recombinant human erythropoietin and its longer-acting cousins were also prescribed on the basis of the common belief that reducing anemia would improve relevant hard clinical end points, including cardiovascular morbidity and mortality. However, an earlier trial of patients receiving chronic hemodialysis who also had significant cardiovascular disease was halted owing to futility and safety considerations, and seemed to signal that a more aggressive anemia treatment target (normalization) would lead to an increased risk of mortality or nonfatal myocardial infarction (hazard ratio, 1.3; 95% confidence interval, 0.9–1.9; the Table).2 The findings of this Normal Hematocrit Trial were readily pushed aside owing to what was perceived as an extremely selected and nonrepresentative study population and a nonsignificant primary result, and did not appear to have a sustained effect on overall prescriber behavior.View this table:Table. Key Features of 4 Landmark Studies of Erythropoesis-Stimulating Agents in Patients With Chronic Kidney DiseaseArticle see p 2903It was not until relatively recently that large randomized trials in populations with non–dialysis-dependent CKD were conducted to test for that putative cardiovascular benefit from more aggressive anemia correction. In 2006, 2 randomized trials comparing higher and lower hemoglobin treatment targets in patients with CKD were simultaneously published (for pertinent details, see the Table). The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial found no difference between treatment groups in cardiovascular risk using a comprehensive composite end point.3 The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) …