Intravenous iron supplementation improved CV outcomes for patients with HF, iron deficiency
CHICAGO — In the IRONMAN trial, long-term IV iron supplementation in patients with HF and iron deficiency was safe and reduced risk for recurrent HF hospitalizations and CV death compared with usual care.
“Iron deficiency is very common in patients with heart failure. For ambulatory outpatients, around 30% to 50% of patients are iron deficient, and if you look at patients with decompensated heart failure who are hospitalized, it's around 75%,” Paul R. Kalra, MD, consultant cardiologist and heart failure specialist at Portsmouth Hospitals University National Health Service Trust and honorary senior lecturer at the University of Glasgow in the United Kingdom, said during a presentation at the American Heart Association Scientific Sessions. “Treatment of iron deficiency with intravenous infusion of ferric carboxymaltose has been shown to be able to improve quality of life and exercise capacity out to 24 weeks for patients with heart failure and reduced ejection fraction. ... The hypothesis for IRONMAN was to evaluate a different intravenous iron product with ferric derisomaltose.”
The trial compared the effects of IV iron supplementation with ferric derisomaltose ( 400 µg/L) and usual care in patients with HF with reduced ejection fraction ( 45%) and iron deficiency, which was defined as low transferrin saturation (< 20%) or ferritin less than 100 µg/L. A total of 1,137 patients recruited at 70 U.K. sites were randomly assigned to receive IV iron supplementation or usual care. After the initial IV iron, re-dosing occurred at week 4, month 4 and every 4 months thereafter if either ferritin was continuously below 100 µg/L or transferrin saturation remained under 25%. Median follow-up was 2.7 years.
The primary outcome was recurrent HF hospitalizations and CV death. The primary safety outcome was deaths and hospitalizations due to infection.
A total of 336 primary endpoint events occurred in the ferric derisomaltose group and 411 in the usual care group, for an event rate of 22.4 per 100-patient-years compared with 27.5 per 100-patient-years (RR = 0.82; 95% CI, 0.66, 1.02; P = .07), according to the results.
Due to the COVID-19 pandemic, recruitment and event rates were lower than anticipated. Kalra said as the trial progressed, fewer patients attended the in-person follow-up visits. Although 98% of participants received at least one injection, only about half received a second. Among patients assigned to usual care, 17% received one or more doses of IV iron.
The researchers conducted a prespecified sensitivity analysis that included all patients randomized until March 31, 2020, with a censoring date of September 30, 2020. In the COVID-19 analysis, IV iron supplementation remained significantly associated with fewer primary outcome events out to 1 year compared with usual care (210 events [22.3 per 100 patient-years] vs. 280 events [29.3 per 100 patient-years; RR = 0.76; 95% CI, 0.58-1; P = .047), according to the results.
Among key secondary outcomes, researchers reported better 4-month quality of life as assessed by the Minnesota Living With Heart Failure Questionnaire in the IV iron group compared with usual care (P = .05). The difference in quality of life was no longer significant at 20 months (P = .23).
Researchers reported no difference in deaths or hospitalization due to infection between the two groups.
“In patients with heart failure, iron deficiency and reduced ejection fraction, in the main cohort there were fewer heart failure hospitalizations and CV deaths [and IV iron] was well tolerated with no safety concerns,” Kalra said during the presentation. “In a trial that was markedly impacted by COVID-19, with an underdosing for periods of time and 1 in 6 people in the usual care arm getting intravenous iron, when we look at the COVID-19 sensitivity analysis, [the benefits of IV iron remained] statistically significant, with a 24% risk reduction.
“I believe the implications of this are building upon the other data we have at hand — that correcting iron deficiency can help improve patients’ wellbeing and particularly reduce the risk of hospitalization in a broad range of patients. We have simple, readily available blood tests in which to identify patients,” Kalra said.
This trial provides “reassurance about the long-term safety of IV ferric derisomaltose” in this population, Kalra concluded.
References:
- Kalra PR, et al. Lancet. 2022;doi:10.1016/S0140-6736(22)02083-9.
- Intravenous iron improved long-term outcomes for people with heart failure and iron deficiency. https://newsroom.heart.org/news/intravenous-iron-improved-long-term-outcomes-for-people-with-heart-failure-and-iron-deficiency. Published on Nov. 5, 2022. Accessed on Nov. 5, 2022.
Perspective
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IRONMAN is an important trial. It's confirmatory with some earlier trials, there are some unique aspects in terms of duration of follow-up and the frequency of treatment as well as how they used laboratory screening to identify patients.
This trial is another piece in the puzzle to show us that iron replacement in HF patients is important. There may be some mechanisms that we don't understand, because the degree to which hemoglobin went up was pretty small, yet, to have a significant functional capacity, symptom relief, quality of life improvement and a mortality benefit. That's pretty important.
Iron replacement has been incorporated into the European guidelines. Iron measurement in the evaluation of patients with HF has been incorporated into the American Heart Association/American College of Cardiology Heart Failure guidelines. But when we go through the planned regular update process of the guidelines, this may be something that gets addressed in terms of being a recommended therapy. The one drawback, again, not only with IRONMAN but also with the TRANSFORM-HF trial, there is still a very small uptake of SGLT2 inhibitor therapy. Is that going to change? Is that going to change some of the outcomes for some of the studies? Especially TRANSFORM-HF, which was comparing two diuretic strategies. The utilization of SGLT2 inhibitors may impact such considerations.
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Kalra PR, et al. LBS.02. Late Breaking Science: Breakthrough Strategies in the HF Journey. Presented at: American Heart Association Scientific Sessions; Nov. 5-7, 2022; Chicago (hybrid meeting).
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