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Revised data show higher iron levels reduce cardiovascular and mortality risk in patients with ESRD
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A re-analysis of data from the results of the Proactive IV Iron Therapy in Haemodialysis Patients trial, originally presented at a High Impact Clinical Trial Session during Kidney Week 2018, shows that higher iron stores in patients with ESRD not only help reduce the dosing levels for erythropoiesis-stimulating agents needed to treat anemia but also prove more effective in reducing cardiovascular-related hospitalizations and the risk of myocardial infarction compared with lower iron levels.
“[T]he effect of iron levels on cardiovascular events in hemodialysis patients has previously been given little recognition,” Javed Butler, MD, professor of cardiology at the University of Mississippi, said in a Vifor Pharma press release on the re-analysis. “The PIVOTAL trial has demonstrated the significant benefits of effective treatment with intravenous iron by improving major cardiovascular outcome parameters in this high-risk population.” Vifor manufactures Venofer, the IV iron drug used in the trial, and provided an unrestricted grant to Kidney Research UK to conduct the PIVOTAL trial.
The original results, published in the New England Journal of Medicine by McDougall and colleagues simultaneously with the Kidney Week 2018 session, concluded that the higher levels of iron stores reduced erythropoiesis-stimulating agent (ESA) doses and were not associated with higher risks of death, major adverse cardiovascular events or infection. However, the greater iron doses had no influence on cardiovascular or mortality risk.
The trial followed 2,141 patients (1,093 patients randomized to the high-dose group and 1,048 to the low-dose group) from 50 sites in the United Kingdom with a median follow-up of 2.1 years.
Patients in the high-dose group received a median monthly iron dose of 264 mg as compared with 145 mg in the low-dose group. For use of ESAs, the median monthly dose was 29,757 IU in the high-dose group and was 38,805 IU in the low-dose group. The study allowed ferritin levels of up to 700 µg/L and TSAT up to 40% in the high-dose group; the low-dose group allowed for serum ferritin of 200 µg/L and TSAT of 20%.
In the updated results, Vifor said the primary endpoint the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death – reached statistically significant superiority for the proactive, high-dose Venofer regimen compared with the low-dose Venofer group.
“Similarly, the rates of the individual components of fatal or non-fatal myocardial infarction and hospitalization for heart failure were lower among patients receiving high-dose IV iron. Results on deaths, as well as all safety endpoints (vascular access thrombosis, hospitalization for any cause and for infection), reduction in ESA dose requirements and number of blood transfusions did not differ between the two treatment arms,” Vifor said in the press release. The re-analysis was necessitated after “identification of a programming error in the original analysis by the investigators,” the company said.
Francesco Locatelli, MD , professor of nephrology at Hospital Alessandro Manzoni in Lecco, Italy, said in the release that the PIVOTAL trial “was a long-awaited landmark study in nephrology and the results mark a significant milestone in the treatment of hemodialysis patients. It is expected that the results from this study will impact guidelines and clinical practice for the benefit of these patients.” – by Mark E. Neumann
References:
MacDougall IC, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1810742.
Perspective
The introduction of ESAs in 1989 for the treatment of anemia in patients on dialysis produced a transformation in our approach to iron therapy in this population. In the pre-ESA era, patients received multiple transfusions and were typically iron overloaded with serum ferritin levels in the 1500 ng/mL range. There was little, if any, role for supplemental iron.
The use of ESAs dramatically reduced the need for transfusions and unmasked the ongoing iron losses that patients on hemodialysis (HD) sustain due to blood left in the dialyzer circuit, blood oozing from needle sites, phlebotomy for blood testing, vascular access procedures and increased gastrointestinal blood losses due to coagulopathy. It is estimated that the average annual blood loss in patients on HD is 2,000 mg/year to 3,000 mg/year.
Oral iron is not sufficiently bioavailable to replace these losses, so IV iron is required in about 80% of patients on HD in any 3-month period, according to Dialysis Outcome Practice Pattern Study (DOPPS) research. Due to the inflammatory state of ESKD, serum ferritin must be maintained at much higher levels than in the normal population to override the impaired release of storage iron due to elevated hepcidin levels. The question has remained regarding a safe ceiling for serum ferritin level and the safe doses of IV iron required to achieve it.
Decisions on iron load
Two schools of thought have emerged regarding IV iron supplementation in patients on HD: 1) a conservative “load and hold” or reactive approach which provides sufficient IV iron on an intermittent basis to keep the serum ferritin level above a floor, such as 200 ng/mL; and 2) a more liberal maintenance or proactive approach which provides weekly or biweekly IV iron unless the serum ferritin level exceeds a ceiling such as 700 ng/mL, 800 ng/mL or 1200 ng/mL. Proponents of the conservative approach cite the adverse effects of IV iron therapy including acute reactions, cardiovascular toxicity, susceptibility to infections and iron overload. Proponents of the liberal approach cite the ESA-sparing effect which decreases costs and may decrease the major adverse cardiovascular effects (MACE) of higher dose ESA therapy.
Besarab and colleagues in 1999 demonstrated a greater than 25% reduction in ESA dose for more than 1 year when comparing a “load and hold” approach to a maintenance approach for IV iron therapy. The 1997 Dialysis Outcomes Quality Initiative and 2001 Kidney Disease Outcomes Quality Initiative (KDOQI) anemia guidelines recommended a maintenance approach to IV iron therapy in patients on HD with a ceiling serum ferritin of 800 ng/dL.
In the 2008 DRIVE-II study of anemic patients on HD receiving adequate ESA therapy with TSAT less than 25% and serum ferritin 500 ng/dL to 1,200 ng/dL, patients receiving 1-gm IV iron sustained a 25% reduction in ESA dose at week 12 with fewer adverse events compared to controls. Although this study by Kapoian and colleagues would seem to justify a higher ferritin ceiling, it was criticized as being too short in duration to rule out long-term adverse effects of higher serum ferritin levels. One observational study in patients on HD by Gaweda and colleagues noted a maximal erythropoietic response with TSAT greater than 25% and serum ferritin 400 ng/dL to 1,000 ng/dL. Nonetheless due to fears of IV iron toxicity and decreased efficacy at high serum ferritin levels, the 2007 KDOQI and the 2012 KDIGO anemia guidelines recommend IV iron therapy only if the serum ferritin is less than 500 ng/mL.
It appears this ferritin ceiling for IV iron therapy has been largely ignored in the United States where the mean serum ferritin in patients on HD was 825 ng/mL in Feb. 2018, according to DOPPS.
Results from PIVOTAL study
The PIVOTAL study is the first, long-term randomized controlled trial designed to examine the safety of reactive vs. proactive IV iron management in patients on HD. The study randomized incident (vintage < 12 months) anemic patients on HD receiving ESA to proactive (n=1,093) or reactive (n=1,048) IV iron therapy. Patients in the proactive arm received 400 mg IV iron/month, which was withheld if there was TSAT greater than 40% or serum ferritin greater than 700 ng/mL. Patients in the reactive arm received IV iron only if there was TSAT less than 20% or serum ferritin less than 200 ng/mL. The study duration was event-driven, with 2 years of recruitment and 2 to 4 years follow-up per patient. The patients in the proactive and reactive arms received annual iron doses of 3.8 g and 1.8 g, respectively.
Higher IV iron doses reduced median monthly ESA doses by 19.4% and reduced the need for blood transfusions (HR: 0.79). More importantly, patients in the proactive IV iron arm had a statistically significant decrease in the primary end-point of death, MI stroke or heart failure hospitalization (HR 0.88).
It is not clear whether the mechanism for this decrease in MACE outcomes is due to the decreased ESA doses in the proactive IV iron arm or due to a non-hematologic protective effect of the IV iron itself. Nonetheless, the results of this study would seem to provide reassurance to those practitioners who are already using a ferritin ceiling greater than 500 ng/mL in their IV iron protocols and may provide an evidence-based rationale to adopt a higher ferritin ceiling among those practitioners who are not.
There may be another transformation in our approach to IV iron therapy in patients on HD on the horizon. The hypoxia-inducible factor (HIF) stabilizer class of drugs led to a reduction in hepcidin levels and greater absorption of oral iron, as well as greater mobilization of iron from internal stores. In one study by Besarab and colleagues in 2016 of incident ESA-naïve patients on HD and patients on PD, one of the HIF stabilizers was equally effective in raising hemoglobin levels with oral or IV iron. Whether this also applies to longer-term patients on HD with ongoing iron losses remains to be seen, but the improved iron mobilization from reticuloendothelial stores due to the decrease in hepcidin levels from the HIF stabilizers will likely result in lower ferritin levels and lower IV iron requirements. Phase 2 and 3 studies of HIF stabilizers have demonstrated equal efficacy to ESAs in raising Hb levels in non-inflamed patients and superior efficacy to ESAs in raising Hb levels in inflamed patients due to improved iron mobilization.
The first long-term safety studies of a HIF stabilizer have been completed and the results are due to be announced within the next few months. If the HIF stabilizers prove to be as safe or safer (regarding MACE outcomes) then ESAs, then their widespread adoption may make the results of the PIVOTAL study moot.
– Jay B. Wish, MD
Medical director, Outpatient dialysis unit
Indiana University Hospital
Professor of clinical medicine
Indiana University School of Medicine
Indianapolis
Vice-chair, Nephrology News & Issues
Editorial Advisory Board
References:
Besarab A, et al. Am J Kidney Dis. 1999;doi:10.1681/AJKD.1999537059.
Besarab A, et al. J Am Soc Nephrol. 2016;doi:10.1681/ASN.2015030241.
Gaweda AE, et al. Clin J Am Soc Nephrol. 2010;doi:10.2215/CJN.03540410.
Kapoian T, et al. J Am Soc Nephrol. 2008;doi:10.1681/ASN.2007050606.
Disclosure: Wish reports he has associations with and receives speaker fees from Keryx Pharmaceuticals, Daiichi Sankyo and Pfizer.