High-Dose Iron Safe, Effective in Hemodialysis Patients

Pam Harrison

October 26, 2018

SAN DIEGO — The proactive use of high-dose intravenous (IV) iron can reduce the amount of erythropoiesis-stimulating agent needed to treat anemia in dialysis patients with no short-term increase in the risk for vascular complications or infections, the first randomized trial of its kind suggests.

"There are adverse safety signals associated with the use of higher doses of the erythropoietins, including increased vascular access thrombosis, increased cardiovascular events, and increased risk of cancer and recurrent cancers," said David Wheeler, MB ChB, from University College London.

"We are, after all, giving a growth factor to our patients and, with high doses, we promote malignant events," he said during a press briefing here at Kidney Week 2018.

With this strategy, "you can use a lower dose of an ESA with a higher dose of iron and get the same level of hemoglobin as you would with a low-dose iron regimen," he told Medscape Medical News.

"And there is no additional treatment burden; patients get the IV iron on dialysis," he added.

Until now, the concern has been that high-dose intravenous iron would increase the risk for infection in a dialysis population already heavily predisposed to infection, as previous observational studies have shown.

When the 1093 hemodialysis patients were enrolled in the Proactive IV on Therapy in Hemodialysis Patients (PIVOTAL) randomized controlled trial, their serum ferritin levels were below 400 ug/L and their transferrin saturation levels were below 30%. Results were published online in the New England Journal of Medicine just ahead of their presentation.

At enrolment, all patients were receiving an erythropoiesis-stimulating agent, at various doses. The study target was a hemoglobin level of 10 g/dL to 12 g/dL, Wheeler reported.

Patients were randomized to a high-dose regimen in which IV iron sucrose 400 mg/month was administered until ferritin levels exceeded 700 µg/L or transferrin saturation levels reached at least 40%, or to a low-dose regimen in which iron was administered only if ferritin levels dropped below 200 g/L or transferrin saturation levels dipped below 20%.

Wheeler and his colleagues hypothesized that the high dose would better than the low dose for the primary study outcome: the first occurrence of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death from any cause.

At 1 year, the median cumulative dose of iron was higher in the high-dose group than in the low-dose group (3.8 vs 1.8 g).

The median monthly iron dose was also higher in the high-dose group (264 vs 145 mg).

During the first year of the study, there was a sharp increase in serum ferritin in the high-dose group, but levels stabilized at a mean of about 600 µg/L. In contrast, serum ferritin levels were significantly lower in the low-dose group, at approximately 150 to 200 µg/L (P < .001).

More important, at a median follow-up of 2.1 years, the median monthly dose of the erythropoiesis-stimulating agent was almost 20% lower in the high-dose group than in the low-dose group (P < .01).

During this short follow-up interval, the incidence of the primary outcome was numerically lower in the high-dose group than in the low-dose group (30.5% vs 32.7%).

These data show that there was "indeed noninferiority between these two iron doses, so the study met its noninferiority end point," said Wheeler.

Safety Issues

"We were keen to look at safety issues because there had been concerns that high doses of IV iron might promote vascular access thrombosis or infection," he explained.

However, there were no significant differences in any of the safety end points between the two groups.

For example, rates of vascular access thrombosis were not significantly different in the high- and low-dose groups (approximately 24% vs 21%), nor were rates of all-cause hospitalization (59% vs 59%), the number of hospitalizations for infection (approximately 30% vs 30%), or the total number of infections.

"Whether this regimen is safer in terms of preventing long-term cardiovascular outcomes and mortality requires a longer and larger study," Wheeler acknowledged.

It has not been established that the high-dose iron regimen is safer than the low-dose regimen, but with the higher dose, "we used less ESA and, in using less ESA, we may, in the longer-term, be protecting our patients from the CV risk associated with higher ESA doses," he explained.

Anemia in End-Stage Renal Disease

In patients with end-stage renal disease, anemia is often treated with erythropoietin to eliminate the need for transfusions, said Pascale Lane, MD, from Oklahoma University in Norman, who moderated the news briefing.

"At first, we tried normalizing hemoglobin in these patients but discovered that this was associated with a higher risk of CV events," she told Medscape Medical News.

It is "unclear whether this risk was from normalizing hemoglobin or whether it was perhaps a direct effect of the erythropoietin-like agents," she explained, but we no longer "treat to the same level of hemoglobin."

Moreover, erythropoiesis-stimulating agents are expensive, "so if you can use less of them, you may not only have beneficial clinical effects, it could be cost-saving as well," she noted.

As a pediatric nephrologist, Lane said she often has to throw away half a single-use vial of iron because her patients are so small.

"If we could give our patients higher doses of iron less frequently, it would be a big convenience for patients and a cost-saving measure for us," she pointed out.

"And now we have a study that can help justify doing this same kind of study in children," she added.

The study was funded by Kidney Research UK and a grant from Vifor Fresenius. Wheeler and Lane have disclosed no relevant financial relationships.

Kidney Week 2018: American Society of Nephrology Annual Meeting: Abstract 143. Presented October 26, 2018.

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