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CHICAGO -- Treatment with intravenous ferric derisomaltose showed a non-significant trend toward lower risks of hospital admission and cardiovascular death among patients with heart failure, reduced left ventricular ejection fraction, and iron deficiency, the prospective randomized IRONMAN trial found.

Among over 1,100 patients, 336 primary endpoints (22.4 per 100 patient-years) occurred in those who received intravenous ferric derisomaltose compared with 411 primary events (27.5 per 100 patient-years) in those who received usual care (rate ratio [RR] 0.82, 95% CI 0.66-1.02, P=0.070), reported Paul Kalra, MD, of Portsmouth Hospitals University NHS Trust in England, at the American Heart Association (AHA) annual meeting and in .

While not reaching significance, "the data are compelling that adding intravenous iron to these patients is beneficial," especially when you also consider the results of the and the impact of the COVID-19 lockdowns, Kalra told 番茄社区app.

"Although neither AFFIRM-AHF [P=0.059 for its primary endpoint] 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," he said. "The two trials in combination support the use of intravenous iron in patients with heart failure and iron deficiency."

In a COVID-19 sensitivity analysis, 210 primary endpoints (22.3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29.3 per 100 patient-years) in the usual care group (RR 0.76, 95% CI 0.58-1.00, P=0.047).

Kalra explained the calculations required to adjust the findings due to the impact of COVID-19 on the trial, noting that "we believe we were appropriately powered to detect a significant difference. However, what we weren't powered for was the length of the pandemic. There's no doubt the length of the pandemic impacted the trial."

"For extended periods, research patients were not allowed to come up to hospitals. And even when they were allowed to, because they were deemed a vulnerable group of individuals with heart failure, many didn't want to come up," he added.

At a press conference, designated discussant Kiran Musunuru, MD, PhD, of the University of Pennsylvania in Philadelphia, said, "What we already knew is that patients with heart failure and iron deficiency have improvement in heart failure symptoms, quality of life, and functional capacity when they receive intravenous iron supplementation."

"What is less clear is whether that translates in the long term into a reduction in heart failure hospitalizations and into a reduction in cardiovascular mortality," he continued. "The AFFIRM-AHF trial ... in patients who were hospitalized for heart failure and were iron deficient who then received up to 6 months of intravenous iron after leaving the hospital, after a year were found to have reduced hospital readmission for heart failure but there was no difference in mortality."

"The IRONMAN trial asked whether there was benefit to intravenous iron in the longer term. That does in fact seem to be the case. The patients in this study were monitored for a median of 2 and a half years, they received intravenous iron whenever they became deficient, and we do again see a reduction in heart failure hospital readmissions and we now see a trend towards decreased cardiovascular mortality. Moreover, there were no safety issues with long-term intravenous iron," Musunuru said.

He told 番茄社区app that the manipulation of the P value figures as described by Kalra "is reasonable to question, but in this case, I think it was a legitimate thing to do. These findings are compelling. It accords very nicely with previous studies that have been done, and it extends these results to a longer timeframe than previous studies."

In commenting on the study, Edward Fry, MD, president of the American College of Cardiology (ACC), told 番茄社区app that the use of intravenous iron to treat patients who meet the eligibility criteria for IRONMAN will ultimately depend on reimbursement policies, and changes in guidelines would be needed to move the needle.

"The AHA and ACC have been rewriting the guidelines annually. Now we suggest that patients with heart failure be tested for iron deficiency, but there is no recommendation for what one should do after that," he said, noting that the groups will likely have a recommendation in the next iteration of the guidelines after reviewing IRONMAN and other similar studies.

For the open-label, blinded-endpoint IRONMAN trial, which was conducted across 70 hospitals in the U.K., Kalra and colleagues included adults with heart failure, defined as a left ventricular ejection fraction of ≤45%, and transferrin saturation less than 20% or serum ferritin less than 100 µg/L.

From Aug. 25, 2016 to Oct. 15, 2021, they randomly assigned 569 patients to receive intravenous ferric derisomaltose and 568 patients to usual care. Median follow-up was 2.7 years. Baseline characteristics were well-balanced between the groups. Median age was 73, 74% were men, and most were white. Over half of both groups had a New York Heart Association functional classification of II.

Of these patients, 14% were recruited during a hospital admission for heart failure, 18% had an admission for heart failure within the previous 6 months, and 67% were enrolled from outpatient clinics and had raised plasma concentrations of natriuretic peptides.

There were no differences between groups in deaths or hospitalizations due to infections. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 vs 243 in the usual care group; P=0.016).

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