Triferic: Any Better Than IV Iron for Dialysis Patients?

Jeffrey S. Berns, MD


September 03, 2015

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This is Jeffrey Berns, editor-in-chief of Medscape Nephrology. In January 2015, the US Food and Drug Administration (FDA) approved a new iron preparation—Triferic (ferric pyrophosphate citrate)[1]—a water-soluble iron salt that is added to the bicarbonate concentrate used to prepare dialysate. From the dialysate, this compound diffuses into the blood across the dialyzer and is said to donate its iron directly to transferrin. The pyrophosphate moiety is then apparently rapidly cleared from the circulation. This is different from our currently available intravenous (IV) iron preparations, which undergo handling and storage in the reticuloendothelial system.

Before discussing this further, I want to set the context. According to the most recent Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor survey findings,[2] about 20% of US dialysis patients have serum ferritin levels > 1200 ng/mL and nearly half have ferritin levels > 800 ng/mL, which I find astounding. About half of patients on dialysis have transferrin saturation (TSAT) levels > 50%. About 80% of patients received IV iron at some time over a 3-month period. A lot of IV iron is being given to our dialysis patients. The vast majority—more than 90% of IV iron—is iron sucrose.

Erythropoietin (EPO) use fell several years ago, presumably related to the introduction of the bundled payment system, but it has really leveled off over the past several years. Giving more iron has not led to further reductions in erythropoiesis-stimulating agent (ESA) use over the past 2-3 years. It is not clear whether transfusion rates have gone down and hemoglobin levels are, if anything, continuing to fall slightly. They have not stabilized and clearly are not going up despite all of this IV iron.

Triferic is being marketed as a more physiologic way to deliver iron (without increasing iron stores) and reduce the need for IV iron. I am not sure whether adding iron to dialysate qualifies as "more physiologic," but maybe that's just my opinion.

I could find only three published studies relating to the use of this compound in hemodialysis patients. In the first study, published in Kidney International in 1999,[3] 10 patients who received dialysate iron were compared with 11 who received IV iron dextran. This was an unblinded study. It does not appear to have been randomized. Hemoglobin and iron measures were similar at the end of 6 months in both groups, with the only major difference being that in the dialysate iron group, a lower weekly dose of IV iron was required to maintain iron balance and fewer patients required IV iron. A theoretical concern is that although there were no significant clinical adverse events, TSAT levels often exceeded 90% in patients who were given dialysate iron, and some TSAT levels were actually higher than 100%, although this was transient. This is the only study that I could find that compared ferric pyrophosphate citrate with IV iron.

Two other studies have been published this year, published by Steve Fishbane and colleagues in Nephrology Dialysis Transplantation.[4] These studies used dialysate iron at a concentration of 2 µmol/L. They were randomized and placebo-controlled, but not double-blind.

In another study published in Kidney International, over 9 months,[5] ESA use was 35% lower with dialysate iron compared with placebo (standard dialysate without iron). Interestingly, ESA use increased in both groups, but much more in the placebo group. Fewer patients in the dialysate iron group needed or received IV iron, of course. Serum iron and TSAT levels increased markedly after dialysis in the dialysate iron group, as was seen in the earlier study.

In the studies by Fishbane and colleagues,[4] ferric pyrophosphate citrate was compared with placebo for up to 48 weeks. No IV or oral iron was allowed in these studies, and ESA doses tended to be higher in the placebo group and lower in the dialysate iron group. Also, more transfusions were required in the placebo group. Ferritin and TSAT levels fell in both groups, but much more so in the placebo group. In none of these studies were any important safety signals identified.

What do we conclude from these studies? There is no question that Triferic provides more iron than no iron or standard dialysate. Is it as good as or better than IV iron? Is it safer? Does it reduce the need for transfusions compared with IV iron? Is there an improvement in patient outcomes? We don't really know.

One concern is that the use of dialysate iron may be all or none. In other words, you can't give a little bit one month and a little bit more the next month. A fixed amount is delivered across the dialyzer. The dose can't be varied, as far as I know.

It also makes me inherently nervous to have staff adding things to dialysate, although it makes me nervous when anything is given intravenously in a dialysis unit. We will have to see whether any safety issues arise over the long term with the use of this form of iron delivery. Cost also may be an issue.

It is an interesting way to deliver iron. Will it deliver less? Should we just be giving less IV iron? It would be interesting, and important, to see additional head-to-head comparisons between ferric pyrophosphate citrate and iron sucrose.


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