AMSTERDAM — Ferric carboxymaltose (FCM) did not go so far as to improve hard outcomes in people with Heart Failure with reduced ejection fraction (HFrEF) and iron deficiency in the well-powered HEART-FID trial, and it is questionable whether it is headed in that direction based on the totality of the evidence.

Between study participants randomized to FCM or placebo, and dosed every 6 months depending on iron repletion biomarkers, a hierarchical efficacy composite endpoint based on the following components produced an overall win ratio of 1.10 that numerically favored FCM but narrowly missed significance (95% CI 0.99-1.23):

• All-cause mortality at 12 months: 8.6% with FCM vs 10.3% with placebo
• Heart failure hospitalizations at 12 months: 13.3% vs 14.8%
• Change in 6-minute walk distance at 6 months: +8 meters vs +4 meters

The secondary endpoint of time to first heart failure hospitalization or cardiovascular death also came out statistically similar between groups over a median 1.9 years (31.0% vs 32.2%, HR 0.93, 95% CI 0.81-1.06), reported Robert Mentz, MD, of Duke Clinical Research Institute in Durham, North Carolina, at the European Society of Cardiology (ESC) annual conference.

As for safety, treatment-emergent adverse events were no different between groups (27.0% for FCM vs 26.2% for placebo).

Published in the New England Journal of Medicine, HEART-FID joins other IV iron trials that have suggested possible improvement in hard outcomes without proving so definitively.

Last year’s IRONMAN trial showed a non-significant trend toward lower risks of hospital admission and cardiovascular death in iron-deficient HFrEF patients who had been monitored for over 2 years and received IV iron whenever they became deficient.

Earlier, people stabilized after a recent episode of acute heart failure showed a significant reduction in heart failure hospitalization or cardiovascular death in the AFFIRM-AHF trial.

“The totality of evidence with IV FCM from prior studies assessing symptomatic and functional status endpoints, combined with recent clinical outcomes studies including HEART-FID, show overall safety and potential benefits in HFrEF with iron deficiency,” Mentz told the audience.

Heart failure patients are known to commonly be deficient in iron, an essential micronutrient for many metabolic and physiologic processes. Iron deficiency in this setting is believed to be related to factors such as insufficient dietary iron, poor gastrointestinal absorption, and inflammation.

During the same ESC session, Piotr Ponikowski, MD, PhD, of Wroclaw Medical University in Wroclaw, Poland, presented a meta-analysis that confirmed a narrow miss for IV iron being of benefit for preventing heart failure hospitalizations and cardiovascular death at 12 months (22.5% vs 25.2%, RR 0.87, 95% CI 0.75-1.01). For this largest pooled analysis of FCM trials to date, published also in the European Heart Journal, investigators had relied on individual participant-level data from HEART-FID as well as CONFIRM-HF and AFFIRM-AHF, totaling 4,475 individuals.

Ponikowski said efforts are underway to identify subgroups that are real responders to FCM. Preliminary data suggest that higher TSAT and greater cumulative iron dosing are predictors of treatment benefit, he stated.

The optimal timing of iron re-dosing should also be reconsidered, Ponikowski said, citing the current ferritin and TSAT biomarker-based approach. “We use, in my humble opinion based on this analysis, the wrong approach,” he suggested. “I personally believe biomarkers should be used only for safety … not to disqualify patients.”

In any case, Edward Fry, MD, of Ascension St. Vincent Heart Center in Indianapolis, and immediate past president of the American College of Cardiology, said in an interview that iron supplementation is already in practice, having made it to the guidelines, and “people will continue to follow that direction” in the wake of HEART-FID.

“It’s one of those trials where the message is there but didn’t get to a statistical basis,” Fry told MedPage Today.

Importantly, the HEART-FID group set the P-value required for rejecting the null hypothesis at 0.01, not the usual 0.05. As such, the results “might have been positive in another universe,” said ESC session discussant Scott Solomon, MD, of Brigham And Women’s Hospital and Harvard Medical School, both in Boston.

“Nevertheless, whichever metric we look at, the benefit was clearly modest. Most of the decisions in the win ratio component were contributed by 6-minute walk distance which itself was quite modest … and when we look at traditional time to cardiovascular death or first heart failure hospitalization, it’s hard to argue that we’re not disappointed with this endpoint,” said Solomon.

HEART-FID was an event-driven randomized study that had 3,065 patients enrolled from 14 countries. All were ambulatory HFrEF patients with iron deficiency (with or without anemia) and New York Heart Association II-IV symptoms.

Participants had a mean age of 69, 34% were women, and 86% white. Baseline ejection fraction averaged 31% and hemoglobin 12.5 g/dL. Patients were on good background medical therapy, Solomon observed.

The discussant pointed out several caveats of the trial, including common drug interruptions and IV iron drop-ins, despite it being well-powered.

ESC just released new guidelines recommending IV iron supplementation in iron-deficient patients with HFrEF or mildly reduced ejection fraction to improve symptoms and quality of life (class I-A endorsement) and consideration of iron to reduce the risk of heart failure hospitalization (class IIa-A).

Meanwhile, the U.S. guideline still gives IV iron replacement a class IIa recommendation as a reasonable option to improve functional status and quality of life alone in these patients.