After 52 weeks, intravenous ferric carboxymaltose (Ferinject) decreased the chance of whole HF hospitalizations and cardiovascular (CV) loss of life by 21% in contrast with placebo (293 vs 372 occasions; charge ratio [RR] 0.79; 95% CI, 0.62 – 1.01).
Though the composite major endpoint failed to attain statistical significance, it was pushed by a major 26% discount within the danger of whole HF hospital readmissions (P = .013) with out an impact on CV mortality (P =.809).
As a result of the administration and follow-up of sufferers was affected by the COVID-19 pandemic, a prespecified sensitivity evaluation was carried out that censored sufferers in every nation on the date when its first COVID-19 affected person was reported, defined principal investigator Piotr Ponikowski, MD, PhD, Wroclaw Medical College, Wroclaw, Poland.
That evaluation revealed a major 30% discount in whole HF readmissions (P = .005) in sufferers receiving ferric carboxymaltose (FCM), in addition to vital advantages on the first composite and secondary endpoints.
Notably, 80% of sufferers required just one or two injections and HF hospitalizations have been decreased no matter anemia standing.
“Iron deficiency must be searched in sufferers hospitalized with acute coronary heart failure — assessed utilizing a easy blood check — and is now an essential therapeutic goal,” Ponikowski mentioned on the digital American Coronary heart Affiliation (AHA) Scientific Periods 2020.
The outcomes have been additionally published simultaneously in The Lancet.
Iron deficiency is current in as much as 70% of sufferers with acute HF and a predictor of poor final result, impartial of anemia and ejection fraction, he famous.
Nonetheless, no such profit was seen with oral IV within the IRONOUT trial. “So it appears if we’re to interchange iron, it must be finished utilizing intravenous remedy,” mentioned John McMurray, MD, College of Glasgow, Scotland, who was invited to debate the outcomes.
He noticed that the discount in HF hospitalizations in AFFIRM-AHF have been comparatively modest and that the trial was by no means anticipated to point out a profit on CV mortality. Additionally, the COVID-19 sensitivity evaluation offering extra convincing results is a legitimate strategy and one really helpful by regulators.
“The million-dollar query, in fact, is what is going to the outcomes of this examine imply for the rules: I feel they most likely will change the rules,” he mentioned. “Definitely, I hope they may change the US pointers, which have actually given a really lukewarm suggestion for intravenous iron and I feel that ought to most likely be stronger.”
In a category IIb suggestion, the 2017 American School of Cardiology/AHA/Coronary heart Failure Society of America coronary heart failure pointers say intravenous iron “is perhaps cheap” to enhance practical standing and high quality of life in New York Coronary heart Affiliation class II and III sufferers with iron deficiency.
The 2016 European Society of Cardiology pointers embody a category IIa suggestion that IV iron “must be thought of” in iron-deficient sufferers with symptomatic HF with decreased ejection fraction.
“That is the primary large-scale [trial] of IV supplementation that would probably change the way in which we strategy sufferers, notably these with hospitalized coronary heart failure,” previous AHA president Clyde Yancy, MD, MSc, Northwestern College Feinberg College of Medication in Chicago, mentioned throughout an earlier press briefing.
He identified that clinicians have been circumspect in regards to the early IV iron information. “I’ve to congratulate you since you’ve modified the narrative,” Yancy mentioned. “We’ve got to start out fascinated about iron deficiency; we have now to consider how we incorporate this in therapy protocols.”
Press briefing panelist Marc Pfeffer, MD, PhD, Brigham and Ladies’s Hospital and Harvard Medical College in Boston, acknowledged he was amongst these circumspect.
“I am not a skeptic and I wish to congratulate them for displaying it is a danger issue,” he mentioned. “It is one factor to have a danger issue; it is one other to be a modifiable danger issue and I feel that is what’s so thrilling about this.”
The double-blind, section 4 AFFIRM-AHF trial randomly assigned 1132 sufferers to obtain a bolus injection of ferric carboxymaltose or regular saline earlier than hospital discharge for an acute HF episode. Subsequent therapy was given, as wanted, as much as 24 weeks post-randomization.
At admission, all sufferers had left ventricular ejection fractions lower 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) evaluation included 558 FCM sufferers and 550 controls in whom examine therapy was began and for whom at the least one post-randomization worth was accessible.
Desk. Main and Secondary Outcomes With FCM
|mITT Inhabitants* RR or HR (95% CI)||Pre-COVID Sensitivity evaluation, RR or HR (95% CI)|
|Complete HF Hospitalizations and CV Dying||RR: 0.79 (0.62-1.01)||RR: 0.75 (0.59-0.96)|
|Complete HF Hospitalizations||RR: 0.74 (0.58-0.94)||RR: 0.70 (0.55-0.90)|
|CV Dying||HR: 0.96 (0.70-1.32)||HR: 0.94 (0.68-1.29)|
|First HF Hospitalization or CV Dying||HR: 0.80 (0.66-0.98)||HR: 0.79 (0.65-0.97)|
|Complete CV Hospitalizations and CV Dying||RR: 0.80 (0.64-1.00)||RR: 0.77 (0.62-0.97)|
* RR, charge ratio; HR, hazard ratio
Press briefing discussant Nancy Sweitzer, MD, PhD, director of the College of Arizona’s Sarver Coronary heart Middle in Tucson, mentioned AFFIRM-AHF is an “essential trial more likely to change pointers” and “focused one of many highest danger populations we have now in coronary heart failure.”
Sufferers with iron deficiency are usually aged with extra comorbidities, have longer hospital lengths of keep, and better readmission charges. “So impacting hospitalizations on this inhabitants is extremely impactful,” she mentioned.
“Consciousness and evaluation of iron deficiency are an essential a part of inpatient care of sufferers with ejection fractions lower than or equal to 50% and acute decompensated coronary heart failure, and I feel all of us locally must pay rather more consideration to this subject.”
As with every new remedy, there are implementation challenges akin to find out how to monitor sufferers and ship the remedy in an economical method, Sweitzer mentioned.
The trial targeted on probably the most susceptible interval for HF sufferers, however these sufferers must be rechecked each 3 to 4 months for iron deficiency, Ponikowski noticed through the briefing.
“This can be a modifiable danger issue,” he mentioned. “We solely want to recollect, we solely must assess it, and we have now a really, quite simple instrument in our palms. We simply must measure two biomarkers, transferrin saturation and ferritin — that is all.”
Unanswered questions embody the mechanism behind the discount in hospitalization, the connection of profit to hemoglobin ranges, and whether or not there’s a differential profit primarily based on age, presence of ischemia, or intercourse, particularly as girls are usually extra severely affected by iron deficiency, Sweitzer mentioned.
Throughout the formal presentation, Ponikowski mentioned the first endpoint was constant in subgroup analyses throughout baseline hemoglobin, estimated glomerular filtration charge, and N-terminal pro-brain natriuretic peptide ranges, HF etiology, ejection fraction, and whether or not HF was recognized previous to the index hospitalization.
Therapy with FCM was secure, with no vital variations between the FCM and placebo teams in critical antagonistic occasions (45% vs 51%) or antagonistic occasions main to review discontinuation (18% vs 17%), he reported. The commonest antagonistic occasions have been cardiac issues (40.1% vs 44.3%) and infections (18.2% vs 22%).
AFFIRM-AHF is the primary of three ongoing mortality and morbidity trials in coronary heart failure with intravenous ferric carboxymaltose; the others are FAIR-HF2 and HEART-FID. Further insights are additionally anticipated subsequent 12 months on intravenous iron isomaltoside from the Scottish-based IRONMAN trial in 1300 HF sufferers with iron deficiency.
The examine was sponsored by Vifor Worldwide. Ponikowski has acquired analysis grants and private charges from Vifor Pharma; and private charges from Amgen, Bayer, Novartis, Abbott Vascular, Boehringer Ingelheim, Merck, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cibiem, Renal Guard Options Bristol-Myers Squibb, and Impulse Dynamics.
Pfeffer reported honoraria from AstraZeneca, Corvidia, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Roche, Sanofi, and Servier; different relationships with DalCor and Novo Nordisk; analysis grants from Novartis; and an possession curiosity in DalCor. Sweitzer reported analysis funds from Merck and Novartis; and consulting charges from Myocardia.
McMurray reported relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, and Servier. Yancy reported a relationship with Abbott and JAMA Community.
Lancet. Printed on-line November 13, 2020. Full text
American Coronary heart Affiliation Scientific Periods 2020: Introduced November 13, 2020.