Elsevier

The Lancet

Volume 396, Issue 10266, 12 December 2020, Pages 1895-1904
The Lancet

Articles
Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial

https://doi.org/10.1016/S0140-6736(20)32339-4Get rights and content

Summary

Background

Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure.

Methods

AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100–299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed.

Findings

Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62–1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64–1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70–1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58–0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66–0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47–0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group.

Interpretation

In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death.

Funding

Vifor Pharma.

Introduction

Iron deficiency is common in patients with heart failure1, 2, 3 and is associated with exercise intolerance, poor quality of life,4, 5 and increased risk for hospitalisation and mortality,2, 3 regardless of the presence or absence of anaemia. Randomised clinical trials have shown that intravenous ferric carboxymaltose improves symptoms, exercise capacity, and quality of life in ambulatory patients with chronic heart failure and left ventricular ejection fraction of 45% or less who have iron deficiency.6, 7 An individual patient data meta-analysis reported that treatment with ferric carboxymaltose was associated with a lower rate of total heart failure hospitalisations or cardiovascular mortality in these patients.8 However, it has never been prospectively investigated whether this therapy could favourably affect outcomes in iron-deficient patients after admission for acute heart failure, when risk of rehospitalisation and mortality is high.

Hospitalisations due to acute heart failure represent a growing health-care problem associated with a high risk of adverse clinical outcomes and a large economic burden.9 Iron deficiency is common in patients with acute heart failure and is associated with poor prognosis.10, 11 Patients with an episode of acute heart failure and concomitant iron deficiency constitute a high-risk target population, in whom treatment of iron deficiency with intravenous iron could translate into a positive effect on outcomes.

AFFIRM-AHF (A Randomised, Double-blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Subjects Admitted for Acute Heart Failure) was designed to evaluate the effect of intravenous ferric carboxymaltose or placebo initiated shortly before hospital discharge in patients with acute heart failure and iron deficiency on total heart failure hospitalisations and cardiovascular death up to 52 weeks after randomisation.

Section snippets

Study design

AFFIRM-AHF was a multicentre, randomised, double-blind, placebo-controlled trial done at 121 sites in Europe, South America, and Singapore (appendix pp 3–8). The study design has been published previously.12 The trial protocol and subsequent amendments and the statistical analysis plan are provided in the appendix (pp 181–607). The protocol and amendments were approved by the institutional review boards at each participating centre. The trial was conducted in accordance with the Declaration of

Results

Between March 21, 2017, and July 30, 2019, 1525 patients at 121 sites in 15 countries were screened. 1132 patients were randomly assigned to receive either ferric carboxymaltose (n=567) or placebo (n=565). Study treatment was started in 1110 patients and at least one post-randomisation value was available for 1108 patients (figure 1). Patient characteristics and medications at baseline were balanced between treatment groups (table 1). At trial closure (July 24, 2020), fatal and non-fatal

Discussion

The findings of AFFIRM-AHF show that, compared with placebo, treatment with ferric carboxymaltose, initiated at hospital discharge in stabilised patients with acute heart failure and concomitant iron deficiency, resulted in an RR for the combined endpoint of total heart failure hospitalisations and cardiovascular death of 0·79 (95% CI 0·62–1·01, p=0·059) which falls just short of conventional 5% statistical significance. The total number of heart failure hospitalisations was significantly lower

Data sharing

Data underlying the findings described in this manuscript may be obtained in accordance with Vifor Pharma's data sharing policy. Enquiries can be made to [email protected].

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    A full list of investigators is provided in the appendix

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