Intravenous Iron Reduces HF Readmissions: AFFIRM-AHF

Patrice Wendling

November 13, 2020

Iron supplementation reduces heart failure (HF) readmissions in iron-deficient patients hospitalized for acute HF, according to results of the AFFIRM-AHF trial. 

After 52 weeks, intravenous ferric carboxymaltose (Ferinject) reduced the risk of total HF hospitalizations and cardiovascular (CV) death by 21% compared with placebo (293 vs 372 events; rate ratio [RR] 0.79; 95% CI, 0.62 - 1.01).

Although the composite primary endpoint failed to achieve statistical significance, it was driven by a significant 26% reduction in the risk of total HF hospital readmissions (P = .013) without an effect on CV mortality (P =.809).

Because the management and follow-up of patients was affected by the COVID-19 pandemic, a prespecified sensitivity analysis was performed that censored patients in each country at the date when its first COVID-19 patient was reported, explained principal investigator Piotr Ponikowski, MD, PhD, Wroclaw Medical University, Wroclaw, Poland. 

That analysis revealed a significant 30% reduction in total HF readmissions (P = .005) in patients receiving ferric carboxymaltose (FCM), as well as significant benefits on the primary composite and secondary endpoints.

Notably, 80% of patients required only one or two injections and HF hospitalizations were reduced irrespective of anemia status.

"Iron deficiency should be searched in patients hospitalized with acute heart failure — assessed using a simple blood test — and is now an important therapeutic target," Ponikowski said at the virtual American Heart Association (AHA) Scientific Sessions 2020. 

The results were also published simultaneously in The Lancet.

Iron deficiency is present in up to 70% of patients with acute HF and a predictor of poor outcome, independent of anemia and ejection fraction, he noted.

The FAIR-HF, CONFIRM-HF, and EFFECT-HF trials demonstrated that IV iron supplementation improves exercise capacity, symptoms, and quality of life in iron-deficient HF patients.

However, no such benefit was seen with oral IV in the IRONOUT trial. "So it seems if we are to replace iron, it needs to be done using intravenous therapy," said John McMurray, MD, University of Glasgow, Scotland, who was invited to discuss the results.

He observed that the reduction in HF hospitalizations in AFFIRM-AHF were relatively modest and that the trial was never expected to show a benefit on CV mortality. Also, the COVID-19 sensitivity analysis providing more convincing effects is a valid approach and one recommended by regulators.

Further, the findings are supported by independent evidence in chronic kidney disease, from the PIVOTAL trial, that intravenous iron reduces HF hospitalizations, McMurray said.

"The million-dollar question, of course, is what will the results of this study mean for the guidelines: I think they probably will change the guidelines," he said. "Certainly, 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."

In a class IIb recommendation, the 2017 American College of Cardiology/AHA/Heart Failure Society of America heart failure guidelines say intravenous iron "might be reasonable" to improve functional status and quality of life in New York Heart Association class II and III patients with iron deficiency.

The 2016 European Society of Cardiology guidelines include a class IIa recommendation that IV iron "should be considered" in iron-deficient patients with symptomatic HF with reduced ejection fraction.

"This is the first large-scale [trial] of IV supplementation that could potentially change the way we approach patients, particularly those with hospitalized heart failure," past AHA president Clyde Yancy, MD, MSc, Northwestern University Feinberg School of Medicine in Chicago, said during an earlier press briefing.

He pointed out that clinicians have been circumspect about the early IV iron data. "I have to congratulate you because you've changed the narrative," Yancy said. "We have to start thinking about iron deficiency; we have to think about how we incorporate this in treatment protocols."

Press briefing panelist Marc Pfeffer, MD, PhD, Brigham and Women's Hospital and Harvard Medical School in Boston, acknowledged he was among those circumspect.

"I'm no longer a skeptic and I want to congratulate them for showing it's a risk factor," he said. "It's one thing to have a risk factor; it's another to be a modifiable risk factor and I think that's what's so exciting about this."

The double-blind, phase 4 AFFIRM-AHF trial randomly assigned 1132 patients to receive a bolus injection of ferric carboxymaltose or normal saline before hospital discharge for an acute HF episode. Subsequent treatment was given, as needed, up to 24 weeks post-randomization.

At admission, all patients had left ventricular ejection fractions less than 50% and iron deficiency (serum ferritin <100 ng/mL or serum ferritin 100-299 ng/mL if transferrin saturation <20%).

The modified intention-to-treat (mITT) analysis included 558 FCM patients and 550 controls in whom study treatment was started and for whom at least one post-randomization value was available.

Table. Primary and Secondary Outcomes With FCM

mITT Population* RR or HR (95% CI) Pre-COVID Sensitivity analysis, RR or HR (95% CI)
Total HF Hospitalizations and  CV Death RR: 0.79 (0.62-1.01) RR: 0.75 (0.59-0.96)
Total HF Hospitalizations RR: 0.74 (0.58-0.94) RR: 0.70 (0.55-0.90)
CV Death HR: 0.96 (0.70-1.32) HR: 0.94 (0.68-1.29)
First HF Hospitalization or CV Death HR: 0.80 (0.66-0.98) HR: 0.79 (0.65-0.97)
Total CV Hospitalizations and CV Death RR: 0.80 (0.64-1.00) RR: 0.77 (0.62-0.97)

* RR, rate ratio; HR, hazard ratio

Press briefing discussant Nancy Sweitzer, MD, PhD, director of the University of Arizona's Sarver Heart Center in Tucson, said AFFIRM-AHF is an "important trial likely to change guidelines" and "targeted one of the highest risk populations we have in heart failure."

Patients with iron deficiency tend to be elderly with more comorbidities, have longer hospital lengths of stay, and higher readmission rates. "So impacting hospitalizations in this population is incredibly impactful," she said.

"Awareness and assessment of iron deficiency are an important part of inpatient care of patients with ejection fractions less than or equal to 50% and acute decompensated heart failure, and I think all of us in the community need to pay much more attention to this issue."

As with any new therapy, there are implementation challenges such as how to monitor patients and deliver the therapy in a cost-effective way, Sweitzer said.

The trial focused on the most vulnerable period for HF patients, but these patients should be rechecked every 3 to 4 months for iron deficiency, Ponikowski observed during the briefing.

"This is a modifiable risk factor," he said. "We only need to remember, we only need to assess it, and we have a very, very simple tool in our hands. We just need to measure two biomarkers, transferrin saturation and ferritin — that's all."

Unanswered questions include the mechanism behind the reduction in hospitalization, the relationship of benefit to hemoglobin levels, and whether there is a differential benefit based on age, presence of ischemia, or sex, especially as women tend to be more severely affected by iron deficiency, Sweitzer said.

During the formal presentation, Ponikowski said the primary endpoint was consistent in subgroup analyses across baseline hemoglobin, estimated glomerular filtration rate, and N-terminal pro-brain natriuretic peptide levels, HF etiology, ejection fraction, and whether HF was diagnosed prior to the index hospitalization.

Treatment with FCM was safe, with no significant differences between the FCM and placebo groups in serious adverse events (45% vs 51%) or adverse events leading to study discontinuation (18% vs 17%), he reported. The most common adverse events were cardiac disorders (40.1% vs 44.3%) and infections (18.2% vs 22%).

AFFIRM-AHF is the first of three ongoing mortality and morbidity trials in heart failure with intravenous ferric carboxymaltose; the others are FAIR-HF2 and HEART-FID. Additional insights are also expected next year on intravenous iron isomaltoside from the Scottish-based IRONMAN trial in 1300 HF patients with iron deficiency. 

The study was sponsored by Vifor International. Ponikowski has received research grants and personal fees from Vifor Pharma; and personal fees from Amgen, Bayer, Novartis, Abbott Vascular, Boehringer Ingelheim, Merck, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cibiem, Renal Guard Solutions Bristol-Myers Squibb, and Impulse Dynamics.

Pfeffer reported honoraria from AstraZeneca, Corvidia, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Roche, Sanofi, and Servier; other relationships with DalCor and Novo Nordisk; research grants from Novartis; and an ownership interest in DalCor. Sweitzer reported research payments from Merck and Novartis; and consulting fees from Myocardia.

McMurray reported relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, and Servier. Yancy reported a relationship with Abbott and JAMA Network.

Lancet. Published online November 13, 2020. Full text

American Heart Association Scientific Sessions 2020: Presented November 13, 2020.  

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