IRONMAN Misses but Lends Support to IV Iron Repletion in HF

CHICAGO, IL—(UPDATED) Another randomized, controlled trial of iron repletion therapy in heart failure (HF) patients is pointing to a benefit of intravenous supplementation in reducing HF hospitalizations, but like the AFFIRM-AHF trial before it, narrowly missed its primary endpoint.

Both trials, however, faced challenges posed by the COVID-19 lockdowns and both showed similar reductions in their primary composite outcome of HF hospitalization and cardiovascular death—particularly in sensitivity analyses with follow-up censored to absorb the pandemic’s challenges—leading IRONMAN investigators to conclude that intravenous iron repletion is safe and beneficial across a broad range of HF patients.

“Although neither AFFIRM-AHF nor IRONMAN met their primary endpoints, the totality of evidence suggests that intravenous administration of iron does reduce hospital admissions for heart failure, although uncertainty persists about a reduction in cardiovascular mortality,” write Paul Kalra, MB BChir (Portsmouth Hospitals University NHS Trust, England, and University of Glasgow, Scotland), and colleagues in the Lancet today.

The IRONMAN results were simultaneously released at a late-breaking session of the American Heart Association 2022 Scientific Sessions.

"I believe the implications of [IRONMAN] are—building upon the other data we have at hand—that correcting iron deficiency could help improve patients’ well-being and in particular reduce the risk of hospitalization in a broad range of patients,” Kalra said during a morning press conference. “We have simple, readily available blood tests with which to identify the patients.” 

More Evidence for IV Iron Repletion

International guidelines already recommend screening for iron deficiency in heart failure, and the most recent European Society of Cardiology heart failure guidelines (but not the most recent US guidelines) state that intravenous ferric carboxymaltose—the agent tested in AFFIRM-AHF—can be considered to prevent further heart failure admissions in symptomatic patients recently hospitalized. Smaller, placebo-controlled trials in HF have also shown benefits of IV iron supplementation on exercise capacity and quality of life.

Unlike AFFIRM-AHF, which enrolled patients at the time of an acute HF hospitalization, IRONMAN enrolled outpatients with chronic heart failure and used a different iron formulation, ferric derisomaltose, which can be given as a rapid, high-dose infusion.

IRONMAN enrolled 1,137 patients between the August 2016 and October 2021, randomizing them to usual care or the ferric derisomaltose infusion, with redosing at week 4, month 4, and then at 4-month intervals thereafter if ferritin remained low. All patients at baseline had a left ventricular ejection fraction of 45% or less and transferrin saturation less than 20% or serum ferritin less than 100 µg/L.

At a median of 2.7 years, 336 primary endpoints had occurred in the iron group and 411 in the controls (rate ratio [RR] 0.82; 95% CI 0.66-1.02), narrowly missing statistical significance. Heart failure hospitalizations, expressed as the number of events per 100 patient-year, trended higher in the usual-care arm (20.9 vs 16.7; P = 0.085), whereas CV deaths were similar (24% vs 21%; P = 0.23).

This study reinforces the message that we should be routinely monitoring our heart failure patients for iron deficiency, because our patients will benefit. Paul Kalra

As COVID-19 lockdowns were being put in place in early 2020, investigators prespecified a number of sensitivity analyses to account for the fact that patients who’d received an iron infusion prior to March 31, 2020, would likely remain iron replete for 6 months, but thereafter would not be returning to clinic for their subsequent doses.

In an analysis looking only at follow-up into the first 6 months of the pandemic—thereby excluding patients who did not return for blood analysis or for redosing of iron as needed—the impact of IV iron repletion on hospitalizations/CV deaths was larger and inched into the bounds of statistical significance (RR 0.76; 95% CI 0.58-1.00). That benefit again appeared to be driven primarily by the reduction in repeat hospitalizations.

The findings echo those of AFFIRM-AHF, which also saw a nonsignificant 21% reduction in HF hospitalizations and CV death at 52 weeks (RR 0.79; 95% CI 0.62-1.01) but a significant reduction in a COVID-19 sensitivity analysis. Notably, both trials also suggested a greater benefit of iron supplementation in patients with ischemic heart disease, although the difference between ischemic and nonischemic HF patients in IRONMAN was not statistically significant.

Still, said Kalra, the consistency of the results from IRONMAN and AFFIRM-AHF suggests that there is a generic benefit accompanying IV iron therapy in a broad range of patients with heart failure with iron deficiency. On top of prior studies, he concluded, there are compelling reasons for clinicians to be testing for iron deficiency in their heart failure patients. “This study reinforces the message that we should be routinely monitoring our heart failure patients for iron deficiency, because our patients will benefit,” Kalra said, adding that he’d like to see testing at intervals of 4 months, as was done in this study.

Consensus Builds

Importantly, IRONMAN followed patients much longer—nearly double the follow-up in other trials, thus “reinforcing the safety of giving intravenous iron to achieve iron repletion for up to 5.4 years,” write Theresa McDonagh MBChB, MD (King's College London, England), et al note in an accompanying editorial.

“The results of IRONMAN add considerably to the growing, consistent body of evidence showing that intravenous iron supplementation in patients who have iron deficiency, heart failure, and reduced ejection fraction or mildly reduced ejection fraction reduces hospital admissions for heart failure and improves quality of life,” the editorialists write. “Further research is needed to establish whether these benefits also extend to patients across the entire heart failure spectrum to include those with heart failure with preserved ejection fraction or asymptomatic left ventricular dysfunction.”

Also unknown, the investigators write in their paper, is whether similar benefits could be achieved through the use of an oral supplement, although they note that prior small, short-term studies have failed to show that oral iron can correct deficiency to the point of having an impact in HF. “Further trials of oral iron might be considered, but parenteral administration of iron is required to correct iron deficiency rapidly; oral iron, even if well absorbed, will take many months to do so,” Kalra and colleagues explain.

Lastly, the signal that patients with ischemic cardiomyopathy might have the most to gain from intravenous supplementation warrants a second look, since neither of these two large trials were powered for this subgroup.

“I think we need to look at this in meta-analyses to try and understand this better,” Kalra told TCTMD. “As to what the reason is, iron deficiency and platelet activation work together, so there could be some impact on vascular events through that mechanism.”

Gregory Lewis, MD (Massachusetts General Hospital, Boston, MA), discussing the results following their presentation, pointed out that two ongoing trials will help resolve any lingering questions about iron supplementation: FAIR-HF2, with a target enrollment of 1,200 patients, and HEART-FID, aiming for more than 3,000 patients. 

With three times the sample size of IRONMAN, the HEART-FID trial will hopefully corroborate outcomes of the earlier studies, he said, but other questions remain. Still to be resolved is whether racial/ethnic minority patients fare as well with supplementation—more than 90% of participants in IRONMAN were white. Also unclear is whether IV iron is of benefit if patients are optimized on guideline-directed medical therapies, most notably SGLT2 inhibitors, said Lewis.

Whether the guidelines will be updated on both sides of the pond to not only recommend iron tests, but also use of different IV iron formulations remains to be seen, he concluded.