A little over 3 years ago, researchers reported findings from PIVOTAL, the largest prospective, randomized trial to assess an aggressive versus conservative iron-repletion strategy in patients with end-stage kidney disease on hemodialysis, in The New England Journal of Medicine.
The results showed that the more aggressive approach — whereby patients were proactively given a monthly dose of intravenous (IV) iron sucrose but a dose was withheld whenever blood ferritin levels reached or exceeded 700 µg/L or when their transferrin saturation (TSAT) hit 40% or more — was safe and significantly better for survival and preventing cardiovascular events than a more conservative and reactive strategy. The latter deferred supplemental iron until a patient’s monthly ferritin level fell below 200 µg/L or their TSAT was 20% or less.
Patients with end-stage kidney disease on hemodialysis routinely require iron supplementation because of ongoing iron loss from bleeding; their chronic inflammatory state inhibits iron absorption from the gut and dampens iron mobilization and other causes related to the condition.
Despite PIVOTAL’s publication in early 2019, data collected through May 2021 by the Dialysis Outcomes and Practice Patterns Study (DOPPS) from a random, size-stratified sample of more than 100 US dialysis centers showed that average monthly iron doses administered to US patients as well as their maintained blood ferritin levels remained essentially unchanged during the periods both preceding and subsequent to PIVOTAL’s report.
“Convincing Evidence” for High-Dose Iron Supplementation
PIVOTAL’s findings were hailed by many experts. A pair of Canadian nephrologists wrote in an October 2019 commentary in the Clinical Journal of the American Society of Nephrology that PIVOTAL is a “landmark trial” that “provides convincing evidence” in favor of proactive, high-dose iron supplementation in patients on hemodialysis because of its safety, its ability to allow reduction of the necessary dose of erythropoietin-stimulating agents (ESA), and its protection against the adverse endpoints collectively tallied as the primary endpoint in PIVOTAL of death, myocardial infarction, stroke, and hospitalization for heart failure.
PIVOTAL’s results showed a significant 15% relative risk reduction in the incidence of this primary endpoint in patients on the higher iron dose, with reductions of roughly the same magnitude across all four individual components of the combined endpoint.
“Only PIVOTAL has been of sufficient sample size [2141 randomized patients] and duration [median follow-up of 2.1 years] to allow statistically valid conclusions regarding the effects of iron administration on hard clinical outcomes” in patients with chronic kidney disease on hemodialysis, concluded a panel of nephrology experts assembled in late 2019 by the Kidney Disease: Improving Global Outcomes (KDIGO) organization to review recent evidence about anemia management in patients with chronic kidney disease.
Current prevailing recommendations from KDIGO for iron management in patients on hemodialysis date from 2012 and suggest only giving patients supplemental iron if their ferritin level is at or below 500 µg/L and their transferrin saturation is 30% or less.
While KDIGO has begun the process of updating this guideline, no recommendations that reference PIVOTAL have yet appeared, which gives nephrologists who manage patients on hemodialysis leeway to apply whichever iron regimen they think best suits each patient.
Although PIVOTAL’s results may — to some extent — have changed practice in Europe and elsewhere, the DOPPS numbers suggest that changes have not happened in most US practice. That’s because much of US practice was already there.
US Patients Already on PIVOTAL-Like Regimens
The US DOPPS data show that for a decade, starting in 2012, average serum ferritin levels in patients on hemodialysis at a representative sample of US centers, both large and small, hovered at about 750 µg/L (750 ng/mL), with roughly half of patients maintained at a serum ferritin level of at least 800 µg/L.
“Possibly a few US clinicians were a bit nervous” about aggressively treating patients on hemodialysis with IV iron, “but they are now reassured” by the PIVOTAL results, said Iain C. Macdougall, MBChB, MD, lead author of PIVOTAL and a professor and nephrologist at King’s College Hospital in London, UK.
“In the UK, some dialysis units follow PIVOTAL but they don’t mandate an iron dose every month,” MacDougall said in an interview.
“Many dialysis physicians in the UK are aggressive about IV iron but they don’t yet follow the PIVOTAL protocol. They’re waiting for new guidelines,” added MacDougall, who estimates these may take another 2-3 years to appear. Until that happens, a segment of the dialysis clinical community will remain cautious about iron dosing, he predicts.
“PIVOTAL was the first study of its kind, and it appropriately answered the need for a study of its type. The results were a validation for nephrologists like me” who believed that patients did better with more liberal doses of iron, commented Jay B. Wish, MD, medical director of the outpatient dialysis unit at Indiana University Hospital and professor of clinical medicine at the Indiana University School of Medicine in Indianapolis.
“It showed that a higher dose of iron was not dangerous and might even be safer” than the comparator lower dose. “I’m now convinced that iron is not dangerous,” Wish said.
For example, a secondary analysis from PIVOTAL, published in 2020, showed nearly identical rates of any infection, hospitalization for infection, and death from infection in the two treatment groups. Increased infections had been a major concern about regular iron supplementation.
Even before PIVOTAL, the mean ferritin level in US dialysis patients was about 800 µg/mL, and PIVOTAL stopped treatment at 700 µg/mL. Despite the trial’s unprecedented design and findings, “I don’t think PIVOTAL changed practice” in the United States, Wish said in an interview.
“It gives us reassurance about the safety of what the US approach already was,” he added.
Both Wish and MacDougall agreed that further prospective assessment of the safety and efficacy of iron doses even higher than those tested in PIVOTAL is highly unlikely.
As Good as It Gets
PIVOTAL “is as good as it’s going to get,” for solid evidence of safety for a relatively higher dose of iron in patients on hemodialysis, said Wish. He predicts that the pending revision of the KDIGO guideline will specify a target ferritin of not more than 700 µg/mL, based largely on PIVOTAL.
“This will only affect the ferrophobes who still use a maximum ferritin of 500 µg/mL because of the 2012 KDIGO guideline,” Wish added.
“Although US IV iron use prior to PIVOTAL resembled the high-dose arm in PIVOTAL, many experts and guidelines warned against such heavy iron use. We needed PIVOTAL to show the best management path. Concerns about high iron doses were refuted by the PIVOTAL results,” commented Daniel W. Coyne, MD, a nephrologist and professor at Washington University School of Medicine in St. Louis, Missouri.
“Stopping IV iron when the TSAT is 40%-50% is the easiest and safest way to avoid iron overload, but many patients have low TSAT and a ferritin of more than 700 µg/L,” Coyne wrote with a coauthor in a 2020 editorial about PIVOTAL. “Even ferritin levels above 700 µg/L may not indicate fully replete iron stores and may not always necessitate stopping iron.”
At US dialysis centers “a minority of nephrologists thought IV iron was harming patients and kept their ferritin levels low. Maybe they will be swayed by guidelines that recommend more generous iron use,” Coyne said in an interview. “Newer US iron protocols try to maintain ferritin above 800 µg/L.”
Skeptics Remain
One US dialysis physician who remains skeptical about safety and need for higher iron doses is Abhijit V. Kshirsagar, MD, a professor at the University of North Carolina School of Medicine and chief medical director of UNC Dialysis Care in Chapel Hill.
Writing a commentary as part of a published debate that appeared online in Kidney 360 in August 2021, Kshirsagar highlighted several factors he said leave ongoing doubt about the higher-dose approach of PIVOTAL, including:
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High-dose IV iron can potentially overwhelm a person’s transferrin capacity and risks forming labile iron that can produce harmful free radicals.
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Extrapolating the safety and efficacy results of PIVOTAL to US practice is challenging because many US clinicians prescribe higher iron doses than used in the trial.
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The low-dose reactive arm in PIVOTAL may have led to iron deficiency in many patients in the comparator group, skewing the results.
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PIVOTAL did not enroll patients with liver disease, such as hepatitis B or C infection, nonalcoholic fatty liver disease, or cirrhosis.
In an accompanying commentary on the points raised by Kshirsagar, Frank M. Liu, MD, declared that, to the contrary, “the evidence suggests strongly that iron should be used proactively” and that “patients should not be allowed to become iron deficient.”
Despite “plausible biological mechanisms by which high-dose iron may be harmful, it has not been convincingly shown in dialysis patients that these are real-world, clinically significant adverse outcomes,” wrote Liu, a nephrologist at Weill Cornell Medicine in New York City.
Liu summarized his group’s approach to iron treatment for patients on hemodialysis: a weekly 50-mg dose of IV iron sucrose that is not paused unless the patient’s TSAT exceeds 45% and a boosted iron dose of 1 g administered in 10 divided doses if TSAT drops below 25% regardless of ferritin concentration. Liu added that he modifies this approach in patients with a known or suspected infection, if recently hospitalized, or if they have elevated inflammatory markers such as C-reactive protein.
PIVOTAL Results Applicable to Most Patients on Hemodialysis
Macdougall noted that most routine hemodialysis practices will have patients who don’t match the PIVOTAL participants. “We deliberately made it as real-world as we could, with few exclusions, an all-comers trials as much as possible,” so that the results “are more or less applicable to everyone.”
However, PIVOTAL limited enrollment to patients who had been on hemodialysis for no longer than 12 months to reduce the chance that patients had irreversible cardiovascular damage that would muddy the primary endpoint results. Despite this, “most people extrapolate” the results to patients on longer-term dialysis, said Macdougall, an approach also endorsed by Wish and Coyne.
Another limitation is that PIVOTAL did not address how to effectively and safely maintain adequate iron levels in patients on hemodialysis being treated with a hypoxia-inducible factor-proline hydroxylase inhibitor (HIF-PHI). The new class of oral drugs are being studied as alternatives to the standard ESA for treating anemia in patients with hemodialysis and will require new studies.
One such agent, roxadustat (Evrenzo, Astellas Pharma/FibroGen), was approved in the EU last summer for the treatment of adults with symptomatic anemia associated with chronic kidney disease. However the same agent was overwhelmingly rejected by a US Food and Drug Administration advisory panel in July 2021 because of safety concerns.
“There are tantalizing suggestions that while patients on HIF-PHIs may still need iron treatment they may need less,” noted Wish. Agents from this new class lower hepcidin, which may lead to improved iron absorption and metabolism, he explained.
PIVOTAL was supported by an unrestricted grant from Vifor Fresenius Medical Care Renal Pharma. Vifor licenses the IV iron sucrose formulation (Venofer) tested in PIVOTAL. Macdougall has reported receiving speaker fees, honoraria, and consultancy fees from several ESA and IV iron manufacturers including Akebia, AMAG, Astellas, Bayer, FibroGen, GlaxoSmithKline, Pharmacosmos, and Vifor Pharma. Wish has reported being a consultant to Akebia, AstraZeneca, FibroGen, GlaxoSmithKline, Otsuka, Rockwell Medical, and Vifor Pharma. Coyne has reported being a consultant for or receiving honoraria from Akebia, Amgen, AstraZeneca, FibroGen, Fresenius Medical Care Renal Therapies Group, GSK, and Vifor. Kshirsagar has reported being a consultant for Rockwell Medical. Liu has reported being an advisor to Janssen, Medtronic, and Quanta Dialysis Technologies, a speaker on behalf of Janssen, receiving honoraria from NxStage, and receiving research funding from CVS and Outset Medical.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler
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