AFFIRM-AHF: IV Iron Supplementation Linked to Fewer Repeat Hospitalizations for HF

 

(UPDATED) Correcting iron deficiency in patients with heart failure (HF) can lessen the risk of subsequent hospitalizations following an acute HF event, according to results of the AFFIRM-AHF trial.

The trial narrowly missed its primary endpoint of total hospitalizations and cardiovascular death but did demonstrate a significant 26% drop in total HF hospitalizations, Piotr Ponikowski, MD, PhD (University Hospital, Wrocław, Poland), reported at the virtual American Heart Association 2020 Scientific Sessions.

Regardless of the presence or absence of anemia, iron deficiency is a predictor of poor outcomes for patients with HF and is present in up to 70%, he noted in a press conference prior to his late-breaking presentation. These findings, said Ponikowski, support “the recommendation to administer ferric carboxymaltose in patients with iron deficiency, left ventricular ejection fraction below 50%, stabilized after an episode of acute HF, in order to prevent recurrent heart failure hospitalizations.”

In the study, which was simultaneously published in the Lancet, the iron therapy was given as IV doses during the index hospitalization and repeated as needed.

Commenting on the study in the press conference, physicians focused on the secondary finding of reduced hospitalizations. Nancy K. Sweitzer, MD, PhD (University of Arizona – Tucson), editor-in-chief of Circulation: Heart Failure, called the findings “highly impactful for our patients” and “likely to change practice” in the management of heart failure.

“Since we really don't think that iron is involved in the pathophysiology of established chronic heart failure with low ejection fraction or acute heart failure with low ejection fraction, it makes sense that this would have an impact on a quality of life endpoint and a patient-related outcome, rather than on death itself,” Sweitzer noted. “I think this is an incredibly important endpoint for our patients and for the population studied in this trial.”

It's one thing to have a risk factor. It's another [for it] to be a modifiable risk factor. And I think that's what's so exciting about this. Marc A. Pfeffer

Marc A. Pfeffer, MD, PhD (Brigham and Women's Hospital, Boston, MA), likewise, also commenting in the press conference, said after viewing the results he is no longer a skeptic about the potential role of iron in improving outcomes.

“It's one thing to have a risk factor. It's another [for it] to be a modifiable risk factor,” Pfeffer said. “And I think that's what's so exciting about this.”

John McMurray, MD (University of Glasgow, Scotland), the discussant following Ponikowski’s presentation, said “the $1 million dollar question” is what the results of AFFIRM-AHF may mean with respect to practice guidelines.

“I hope they will change the US guidelines, which have really given a very lukewarm recommendation for intravenous iron, and I think that should probably be stronger,” McMurray said. He added that AFFIRM-AHF joins FAIR-HF, CONFIRM-HF, and EFFECT-HF in demonstrating a benefit of IV iron in HF patients. A fourth trial, IRONOUT, which utilized an oral iron supplement strategy, came up negative.

“So it seems that if we are to replace iron, it needs to be done using intravenous therapy,” McMurray asserted.

HF Hospitalizations Reduced by 26%

The AFFIRM-AHF trial was a multicenter study of 1,108 patients hospitalized for acute HF at 121 centers in Europe, Israel, Lebanon, South America, and Singapore. All had iron deficiency, which was defined as serum ferritin < 100 ng/mL (or 100-299 ng/mL if transferrin saturation < 20%). The average age was 71 years, and average ejection fraction was 33%.

Prior to discharge, patients were randomized to receive IV ferric carboxymaltose or placebo. The first treatment was administered shortly before hospital discharge, with a second treatment given at week 6 to patients whose iron deficiency persisted. Doses of ferric carboxymaltose were determined by the patient's body weight and hemoglobin value, with the average dose being 1,350 milligrams. Ponikowski said 80% of patients had resolution of their iron deficiency with one or two treatments, with the remaining patients receiving additional IV doses at weeks 12 and 24.

At follow-up of 52 weeks, the incidence of CV death was not different between the treatment and placebo groups. For the combined primary endpoint of total hospitalizations and CV death, the total number of events was numerically lower in the those treated with ferric carboxymaltose compared with placebo (RR 0.79; 95% CI 0.62-1.01), driven by a significant 26% reduction in the risk of HF hospitalizations.

I think this is an incredibly important endpoint for our patients and for the population studied in this trial. Nancy K. Sweitzer

A treatment benefit was also seen in the secondary endpoint, a time-to-first-event analysis that found a statistically significant reduction in the risk of first HF hospitalization or CV death (HR 0.80; 95% CI 0.66-0.98). Given the current global COVID-19 pandemic, the researchers also conducted a pre-COVID sensitivity analysis, which found statistically significant differences in favor of iron replacement for the primary and secondary outcomes, with the exception of CV death. However, Ponikowski said it is plausible that less complete follow-up, fewer hospitalizations, and other factors related to the pandemic could have diluted the ability to observe treatment differences.

IV ferric carboxymaltose was well tolerated, and there were no apparent differences between groups in development of adverse events, he concluded.

Important Endpoint for Patients

In addition to affecting the ability of red blood cells to carry oxygen, Sweitzer said iron deficiency independent of anemia can impair cellular energetics and immunity and that it’s associated with reduced ability to exercise, impaired quality of life, hospitalization, and death.

The study also raises important questions, she added, the key one being how the IV therapy leads to reduction in hospitalization. Additionally, she said subgroup analyses will be important to determine if there is are differential benefits by sex, age, or ischemia status.

Asked how patients would potentially be followed to prevent future occurrences of iron deficiency, Ponikowski said he believes they should have iron status rechecked approximately every 3 or 4 months. Ferric carboxymaltose, he added, is “a very, very simple tool” that can modify risk through the assessment of simple biomarkers.

Clyde Yancy, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), who moderated the press conference, added that AFFIRM-AHF changes the narrative.

“We have to start thinking about iron deficiency,” he said. “We have to think about how we incorporate this in treatment protocols. It really is important to consider that this may be a strategy that we've not explored before.”