The Relationship Between Hemoglobin Targets with Erythropoiesis-Stimulating Agents and Cardiovascular Risk in Chronic Kidney Disease: A Review of Pivotal Trial Evidence

Abstract

Introduction: Anemia is a near-universal complication of Chronic Kidney Disease (CKD), contributing to poor quality of life and a high burden of cardiovascular disease. The development of Erythropoiesis-Stimulating Agents (ESAs) effectively treated this anemia, leading to the widespread hypothesis that correcting hemoglobin to normal levels would be cardioprotective.

Literature Review: A review of pivotal randomized controlled trials reveals a consistent and unexpected pattern of harm associated with this approach. Multiple large-scale trials were designed to test the hypothesis that targeting a normal or near-normal hemoglobin level with ESAs was superior to a more conservative strategy with a lower hemoglobin target. Contrary to expectations, these trials, including the landmark CHOIR and CREATE studies, were terminated prematurely. They consistently demonstrated that the pursuit of higher hemoglobin targets did not reduce cardiovascular risk and, in fact, significantly increased the risk of death, myocardial infarction, heart failure, and stroke. Subsequent large trials and meta-analyses confirmed these hazardous outcomes.

Conclusion: This body of evidence definitively refuted the long-held belief that normalizing hemoglobin with ESAs would improve cardiovascular outcomes in patients with CKD. It established that such a strategy is harmful, prompting a fundamental reversal of clinical practice and leading to new guidelines that advocate for more conservative hemoglobin targets and the use of the lowest effective ESA dose.