Intravenous Iron for Patients With Heart Failure? Recent Research Goes Against the Grain.


Injectafer (ferric carboxymaltose injection) was no better than a placebo in a double-blind study of patients with heart failure with reduced ejection fraction. The researchers offered several possible explanations for the unexpected result. Were reduced hospitalizations during the COVID-19 pandemic perhaps a factor?

Iron deficiency is a common problem In patients with heart failure, but what to do about it has been a subject of much debate and extensive research. Findings reported simultaneously in the New England of Medicine and the European Society of Cardiology Congress are likely to muddy the waters rather than clarify them.

Iron pills are still prescribed but are not recommended by guidelines for patients with heart failure with reduced ejection fraction (HFrEF), which is sometimes called systolic heart failure. It occurs when the left ventricle weakens and doesn’t have enough force to push blood out of the heart into the bloodstream.

But it is different story with intravenous iron therapy. Results from large, well-designed studies and meta-analyses have tallied up in favor of using intravenous iron treatment. For example, results of a meta-analysis published earlier this year in the European Journal of Heart Failure showed that intravenous iron therapy reduced a composite endpoint that included recurrent hospitalizations for heart failure and cardiovascular death.

Results from the HEART-FID trial were expected to fall right in line with prior results and bolster rather than undercut the evidence for using intravenous iron therapy. Funded by American Regent, a manufacturer of injectable medicines, included Injectafer (ferric carboxymaltose), an IV iron treatment, the double-blind, randomized trial compared Injectafer with placebo, with 1,532 people with HFrEF (a left ventricular ejection fraction of 40% or less, which is the standard definition) assigned to treatment with Injectafer and 1,533 assigned to be treated with a placebo. The primary endpoint was a hierarchical composite of death within 12 months after randomization; hospitalizations for heart failure, also within 12 months after randomization; or a change in baseline measure of a patient’s walking ability. Hierarchical composites combine and order outcomes and are supposed to capture a complete, and more realistic, picture of an intervention’s effects on people's health than a single outcomes or combined outcomes that aren't weighted.

The results were first reported in late August, and the New England Journal of Medicine published them in its weekly print publication yesterday.

They were a surprise.

Judging by the primary outcome, the hierarchical composite, there was no difference in the outcome between the patients assigned to be treated with Injectafer and those assigned to the placebo.

Robert J. Mentz, M.D., first author of the New England Journal of Medicine paper reporting the results of the HEART-FID study of intravenous iron.

Robert J. Mentz, M.D., first author of the New England Journal of Medicine paper reporting the results of the HEART-FID study of intravenous iron.

“We found that among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite” wrote first author Robert Mentz, M.D., of Duke University School of Medicine and a large team of co-investigators.

Researchers set primary outcomes before a trial starts to preclude sifting through results to identify a positive outcome when the results are otherwise. But secondary outcomes, which may be positive for the intervention when the primary one is not, are also identified and may provide some additional information por nuance about the effects of an intervention. The secondary outcomes of the HEART-FID trial did reveal some differences, including a slightly better results on walking tests among those randomized to Injectafer.

But Mentz and his coauthors said when it came to the main secondary outcome, a composite of cardiovascular deaths or first hospitalization for heart failure, the number of events between the Injectafer and placebo were similar (16.0 events per 100 patient years for the Injectafer v. 17.3 events in the placebo group).

American Regent, which is owned by Daiichi Sankyo Group, a Japanese company, put a positive spin the results in a press release, which highlighted “numerically fewer deaths” in the Injectafer group than in the placebo group (131 vs. 159) and fewer total hospitalizations for heart failure (297 vs. 332).

It remains to be seen how the HEART-FID results will be viewed and how they might influence clinical practice and treatment guidelines.

In the discussion section of the study in the New England Journal of Medicine, Mentz and his colleagues suggest several possible reasons for their results. The patients in their study were drawn from a lower-risk population than the other studies. They also were more like to be taking “evidence-based medications,” said the authors, who specifically mentioned Entresto (sacubitril and valsartan). Another possibility is that criteria used for iron deficiency in HEART-FID skewed the results. Mentz also note that the majority of the study participants were enrolled during the COVID-19 pandemic and that timing may have affected hospitalizations.

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