Key Points:
- Iron-deficiency is common in heart failure (HF) and associated with increased mortality and hospitalization.
- Previous trials of intravenous (IV) iron in the form of ferric carboxymaltose (FCM) in iron-deficient HF patients have shown improvements in symptoms and quality of life, but effects on clinical events have been unclear.
- This meta-analysis pooled data from three randomized controlled trials (RCTs) – CONFIRM-HF, AFFIRM-HF, and HEART-FID – to assess both a composite endpoint of total CV hospitalizations and death, as well as a composite endpoint of total HF hospitalizations and CV death through 52 weeks.
- In iron-deficient patients with HF with reduced ejection fraction (HFrEF) or HF with mildly reduced ejection fraction (HFmrEF), IV FCM is associated with reduced risk of composite outcome of total cardiovascular (CV) hospitalization and death through 52 weeks compared with placebo.
With a prevalence of 30-80%, iron-deficiency is common in heart failure (HF) and associated with increased mortality and hospitalization. Previous randomized controlled trials (RCTs) of intravenous (IV) iron in iron-deficient HF patients have demonstrated improvements in quality of life, functional capacity, and symptoms, but no clear effects on clinical outcomes. Ponikowski et al present a meta-analysis evaluating the effects of IV iron in the form of IV ferric carboxymaltose (FCM) on hospitalizations and mortality among iron-deficient patients with HF with reduced ejection fraction (HFrEF) or HF with mildly reduced ejection fraction (HFmrEF).
In this meta-analysis, the investigators pooled individual participant data from three placebo-controlled RCTs of IV FCM in adult patients with HF and iron-deficiency with follow-up for at least 52 weeks: CONFIRM-HF, AFFIRM-AHF, and HEART-FID. Among these three trials, 4501 total patients with HFrEF or HFmrEF as well as iron-deficiency were randomly assigned to IV FCM (n=2251) or placebo (n=2250). Mean age of the total population was 69 years, 63% were men, and the mean left ventricular ejection fraction (LVEF) was 32%.
The meta-analysis investigated two primary composite endpoints: 1) total cardiovascular (CV) hospitalizations and CV death, and 2) total HF hospitalizations and CV death. Both endpoints were evaluated through 52 weeks of follow-up. Secondary endpoints were also included, which were the individual components of the composite endpoints.
This meta-analysis found that IV FCM significantly reduced a composite primary endpoint of total CV hospitalization and CV death compared to placebo, with a rate ratio (RR) of 0.86 (95% confidence interval [CI]: 0.75-0.98; p=0.029). There was a trend toward reduction of the other composite primary endpoint of total HF hospitalizations and CV death, though it failed to reach statistical significance, with a RR of 0.87 (95% CI: 0.75-1.01; p=0.076).
In addition, IV FCM was associated with 17% relative rate reduction in total CV hospitalizations (RR 0.83; 95% CI: 0.73-96; p=0.009) and 16% relative rate reduction in total HF hospitalizations (RR 0.84; 95% CI: 0.71-0.98; p=0.025). No effect of FCM on mortality was found. In subgroup analyses, patients in the lowest transferrin saturation (TSAT) tertile (<15%) demonstrated greater benefit from FCM with respect to composite endpoint of total CV hospitalizations or CV death compared to those with higher baseline TSAT (interaction p=0.019). FCM treatment overall appeared to be safe and well-tolerated.
Principal Investigator (PI) Professor Piotr Ponikowski of Wroclaw Medical University remarked: “This was the largest and most up-to-date analysis of the effect of FCM in iron-deficient heart failure patients with reduced or mildly reduced ejection fraction… The findings indicate that intravenous FCM should be considered in iron-deficient patients with heart failure and reduced or mildly reduced ejection fraction to reduce the risk of hospitalization due to heart failure and cardiovascular causes.”
