IV iron modestly improves HFrEF outcomes but misses prespecified endpoint: HEART-FID
Key takeaways:
- IV ferric carboxymaltose did not significantly improve death, HF hospitalization or 6-minute walk distance vs. placebo in adults with HFrEF.
- The study population was lower-risk than in previous IV iron trials.
In adults with HF with reduced ejection fraction and iron deficiency, ferric carboxymaltose modestly improved the endpoint of death, HF hospitalization and 6-minute walk distance but did not achieve the prespecified significance level.
Robert J. Mentz, MD, associate professor of medicine and population health science at Duke University School of Medicine and chief of the heart failure section at Duke University Medical Center, who reported findings from the HEART-FID trial, said the lack of a long-term reduction in HF hospitalizations for patients with HFrEF who received IV ferric carboxymaltose was unexpected, as previous IV iron trials have suggested a HF hospitalization benefit. However, Mentz told Healio that the totality of evidence supports the safety and clinical benefits of IV ferric carboxymaltose.
“What we saw was a modest benefit for clinical outcomes, but [it is] safe,” Mentz said during a press conference at the European Society of Cardiology Congress. “As a practicing HF cardiologist, we are using this [drug] more in practice to help patients feel and function better and to see a reduction in each of the component [endpoints]. Yes, it is not statistically significant, but this does give us another important tool in our toolkit.”
Stringent study design
Mentz and colleagues analyzed data from 3,065 adults with HFrEF (EF 40%) and iron deficiency from 14 countries who were randomly assigned IV ferric carboxymaltose (n = 1,532) or placebo (n = 1,533) in addition to standard HF therapy. The mean age of participants was 69 years and 34% were women; 11% were Black and 26% of participants lived in the U.S. The study is the largest trial to assess the long-term safety and efficacy of IV ferric carboxymaltose in people with HFrEF and iron deficiency.
Participants received ferric carboxymaltose or placebo every 6 months as needed on the basis of iron indexes and hemoglobin levels.
The primary outcome was a hierarchical composite of death within 12 months after randomization, HF hospitalizations within 12 months or change from baseline to 6 months in 6-minute walk distance.
“This allows you to combine those clinical outcomes with 6-minute walk distance, so in our trial, nearly every patient can contribute to the primary endpoint either through a clinical event or a functional status point,” Mentz said during the press conference.
Researchers designed the trial as a single pivotal study instead of two based upon a special protocol assessment with the FDA that called for a higher threshold. As a result, the study included a significance level of 0.01 specified for regulatory purposes, Mentz said.
The findings were simultaneously published in The New England Journal of Medicine.
Death by month 12 occurred in 8.6% of participants in the ferric carboxymaltose group and 10.3% of participants in the placebo group; HF hospitalizations by month 12 occurred in 13.3% of patients in the ferric carboxymaltose group and 14.8% of patients in the placebo group; the mean change from baseline to 6 months in the 6-minute walk distance was 8 m and 4 m in the IV iron and placebo groups, respectively (Wilcoxon-Mann-Whitney P = .019; unmatched win ratio, 1.1; 99% CI, 0.99-1.23).
For the secondary endpoint of time to CV death or first HF hospitalization, there were 16 events per 100 patient-years in the IV iron group and 17.3 events per 100 patient-years in placebo group, for an HR of 0.93 that did not reach significance (96% CI, 0.81-1.06).
Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile. Serious adverse events occurring during the treatment period were similar between the iron and placebo groups (27% vs. 26.2%).
“In this exciting time of quadruple therapy for HFrEF, IV ferric carboxymaltose is an effective therapy that is not another daily pill but rather a straightforward injection in the clinic or hospital — a ‘one and done’ injection to benefit many patients with HFrEF and iron deficiency,” Mentz told Healio.
‘Unexpected’ lower iron treatment effects
In a related editorial published in NEJM, Pieter Martens, MD, PhD, and Wilfried Mullens, MD, PhD, both of Ziekenhuis OostLimburg in Genk, Belgium, noted that the treatment effect of ferric carboxymaltose on the 6-minute walk distance was “surprisingly small” in HEART-FID and the lack of a long-term reduction in hospitalizations for HF was “unexpected” given the results of the AFFIRM-AHF and IRONMAN trials. Mentz suggested that the lower-risk population in HEART-FID might explain the lower treatment effects compared with AFFIRM-AHF and IRONMAN.
“Although more patients were enrolled in the HEART-FID trial than in the AFFIRM-AHF and IRONMAN trials, the numbers of deaths and hospital admissions for heart failure were lower in the HEART-FID trial than in the other two trials combined,” Martens and Mullens wrote. “Characteristics of a trial population at baseline will clearly influence the absolute treatment effects (absolute risk reductions) but will typically have less influence on the relative treatment effects (win ratios or rate ratios), making the lower event rate a less likely explanation of the lower observed relative treatment effect in this event-driven trial.
“However, the number of patients with true iron deficiency in the HEART-FID trial is unclear, and whether the absence of true iron deficiency could have influenced the observed lower relative treatment effect is unknown,” Martens and Mullens wrote.
New meta-analysis data
In a related presentation, Piotr Ponikowski, MD, PhD, FESC, head of the department of heart diseases at Wroclaw Medical University in Poland, presented findings from a prespecified individual patient-level analysis assessing 12-month outcomes from HEART-FID, CONFIRM-HF and AFFIRM-AHF. That analysis included data from 4,475 participants from all three trials that compared ferric carboxymaltose (n = 2,241) with placebo (n = 2,234).
In that analysis, researchers found that ferric carboxymaltose reduced the composite endpoint of CV death or total CV hospitalizations (RR = 0.86; 95% CI, 0.75-0.98; P = .029), without evidence of heterogeneity by trial. Similarly, researchers demonstrated a trend toward reduction of the composite of CV death or total HF hospitalizations (RR = 0.87; 95% CI, 0.75-1.01; P = .076) also without evidence of heterogeneity by trial. These effects were mainly driven by a reduction in CV and HF hospitalizations, respectively.
Patients with low transferrin saturation levels were more likely to achieve benefit from ferric carboxymaltose than those with higher levels (P for interaction for CV death or total CV hospitalizations = .019), according to the researchers.
“The totality of evidence with ferric carboxymaltose from prior studies showing symptomatic, quality of life and functional status/exercise capacity benefits, now combined with the ferric carboxymaltose meta-analysis data, showed clinical benefit,” Mentz told Healio.
References:
- Martens P, et al. N Engl J Med. 2023;doi:10.1056/NEJMe2308305.
- Mentz RJ, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2304968.
Perspective
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A negative trial is a negative trial. Randomized controlled trials are our gold standard. That does not mean the trial tells us the absolute truth, but it tells us the best truth we have. I am heartened by the prior trials of IV iron therapy, and we do know that there is a signal that IV iron can be beneficial for iron-deficient patients with HF with reduced ejection fraction. This is perhaps a cautionary tale that you only get so much truth from a randomized controlled trial.
I was quite impressed by the optimal medical therapy these patients were receiving; about 90% or more on angiotensin receptor neprilysin inhibitors (ARNI), ACE inhibitors or angiotensin receptor blockers; 90% on a beta-blocker; and 30% of participants were women. In routine clinical practice, patients are not this well-treated and IV iron therapy may be more beneficial.
After prescribing maximally tolerated guideline-directed medical therapy, I would put IV iron in the category of a special situation. It might not be the first priority for your patients with HFrEF, but it is a very reasonable second priority because it is easy enough to do: Screen the patient for iron deficiency and give them IV iron. It will not harm the patient, and it may, in fact, help the patient.
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Mentz R, et al. Hot line 2. Presented at: European Society of Cardiology Congress; Aug. 25-28, 2023; Amsterdam (hybrid meeting).