In a recent trial, non-dialysis chronic kidney disease (CKD) patients with anemia who were treated with intravenous (IV) iron experienced a greater number of cardiovascular (CV) events and serious infections than those receiving oral iron.

The REVOKE trial was stopped early after a safety board discovered a higher number of events leading to hospitalization, such as congestive heart failure, pneumonias, and serious skin infections.

The main question of the study—the effect of corrected iron on kidney function—remained unanswered. Rajiv Agarwal, MD, of Indiana University, and colleagues had randomly assigned 136 stage 3 and 4 CKD patients with iron-deficiency anemia to 8 weeks of treatment with oral ferrous sulfate (325 mg 3 times daily) or IV iron sucrose (200 mg every 2 weeks). After 2 years, glomerular filtration rate (measured by plasma clearance of iothalamate) declined similarly in both groups: -3.6 mL/min/1.73m2 for oral iron users vs. -4.0 mL/min/1.73m2 for IV iron users, according to results published in Kidney International (2015;88:905-914). The safety board determined that there was little chance of finding a difference over the study period.

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Thirty-six serious CV events occurred among 19 patients receiving oral iron and 55 events among 17 patients receiving IV iron. In adjusted analyses, this translated into a 2.5 times increased incidence of CV events in the IV iron group. The incidence of infections resulting in hospitalization was double among IV iron users.

According to the researchers, these adverse events are “biologically plausible.” Iron promotes bacterial growth and spurs the inflammatory response to infection. If greater free iron generation results from IV iron, it may also quell nitric oxide and accelerate endothelial dysfunction and atherosclerosis. If it plays a role in impaired sodium handling by the kidney, it may contribute to heart failure.

“Taken together, our findings raise the urgent need for long-term safety of IV iron in vulnerable populations such as CKD [patients],” the investigators wrote.

“The higher frequency of serious cardiovascular events and infections in CKD patients receiving intravenous iron does not come as a surprise,” wrote Tilman B. Drüeke, MD, and Ziad A. Massy, MD, of Hôpital Paul Brousse, Villejuif, France, in an accompanying editorial.

These results cannot be generalized to dialysis patients or those with heart failure, they pointed out. Whether oral iron is preferable is among the many yet-to-be-answered questions, Drs. Drüeke and Massy added.


  1. Agarwal, R; Kusek, JW; Pappas, MK. Kidney International (2015)88,905-914; doi: 10.1038/ki.2015.163.
  2. Drueke, TB; and Massy, ZA. Kidney International (2015)88,673-675; doi: 10.1038/ki.2015.189.