Is Iron Replacement in Heart Failure Worth the Trouble?

Medscape

John M. Mandrola, MD

November 07, 2022

Nearly half of patients with heart failure have low iron levels. Having inadequate means to transport oxygen due to iron deficiency is the last thing a patient with reduced cardiac function needs.

It therefore seems like a no-brainer to replace something as essential as iron when levels are low.

The IRONMAN Trial

Yet at the American Heart Association (AHA) Scientific Sessions 2022, a large randomized controlled trial, with the best acronym ever, the IRONMAN trial, failed to confirm that which makes perfect sense.

IRONMAN studied a novel intravenous iron replacement agent called ferric derisomaltose. Patients who had heart failure and a left ventricular ejection fraction of less than 45% and evidence of iron deficiency were randomly assigned to intravenous iron infusions or usual care.

Unlike the previous iron replacement trial, AFFIRM-AHF, which randomized hospitalized patients to short-term use of iron infusions (or none), IRONMAN trialists enrolled mostly outpatients and planned repeated iron infusions to maintain normal iron levels.

The primary endpoint in IRONMAN was death due to cardiovascular (CV) causes or recurrent hospital admissions for heart failure.
As is common in recent years, the pandemic influenced the trial.

IRONMAN was carried out in the National Health System in the United Kingdom, and lockdowns prevented some patients from coming in for repeat infusions. Only 60% of those assigned to the active arm received more than one infusion. About 17% of those in the usual care received one or more iron infusions.

At a median follow-up of 2.7 years, the primary outcome was reduced by 18% (22.4 per 100 patient-years) in the ferric derisomaltose group compared with the usual care group (27.5 per 100 patient-years).

This nearly made statistical significance (rate ratio [RR], 0.82; 95% CI, 0.66 – 1.02; P = .070). Hospitalizations for heart failure drove the reduction. Death due to CV causes, all cause mortality, and total hospitalizations did not differ significantly.

At 4 months, patients in the iron infusion arm had better quality of life and physical domain scores than the control group. By 20 months, these scores no longer differed significantly between the two treatment groups. Serious adverse events also did not differ.
IRONMAN enrolled patients from August 2016 to September of 2021. A sensitivity analysis was done to minimize the effect of the pandemic, using September 30, 2020, as

a censoring date. This analysis included 91% of all randomly assigned patients and found a 24% reduction in the primary endpoint that met statistical significance (RR, 0.76; 95% CI, 0.58 – 1.00; P = .047).

This was again driven by lower hospitalizations for heart failure, with no significant reductions in CV death or all-cause death.

I will address three issues with iron infusions in patients with heart failure.

1. Is IRONMAN a positive or negative trial?

The point estimate of the relative risk reduction of the primary endpoint has an upper bound of the 95% CI of 1.02 and a P value of .07. That does not meet our arbitrary threshold of statistical significance.

But this does not mean that iron infusions do not provide some benefit. The lower bound of that same CI includes a 34% reduction of the primary endpoint, and most of the CI includes a benefit.

What’s more, this degree of relative risk reduction aligns well with that of AFFIRM-AHF (RR, 0.79; 95% CI, 0.62 – 1.01; P = .06), which also found lower hospitalizations for heart failure in the iron group and no significant reduction in CV death.

The probability of a small benefit from iron infusion seems far more likely than it being noise. Which brings me to the second issue.

2. Do iron infusions have a clinically meaningful benefit?

In IRONMAN, the lower rate of heart failure hospitalizations in the active arm drove the primary endpoint. More important endpoints, such as

CV death, all-cause death, and all cause hospitalization, did not differ significantly. That’s a negative.

Nearly a quarter of the patients died of CV causes over the span of the trial. So, the problem seems not to be too few events. You’d want a heart failure intervention to do more than just reduce one kind of hospitalization.

Proponents of iron replacement can point to data that show it improves exercise time and quality of life. Therapies that make patients feel better are important. But that brings me to the third issue.

3. Are iron infusions worth the trouble—for patients and payers alike?

At AHA, I spoke with Ricky Turgeon, PharmD, from the University of British Columbia, about the logistics of giving iron infusions to outpatients.

His simple message: In Canada, it was hard. Hard on the system and hard on the patient. I strongly suspect it’s not easy to get patients to centres for intravenous infusions in any system.

We should always remember that patients with heart failure already incur a significant burden. They attend frequent office visits, and they must take many medications. Both burn up time they could spend living life.

Conclusion

Adding outpatient visits for intravenous infusions would be fine if there were clinically strong and statistically robust benefits. But I don’t think we’ve seen that with these data.

The weakness of the data also informs the matter of whether systems should cover the costs of iron infusions. If there were unlimited budgets, then it would be fine. But that is surely not the case.

This is a tough area in which there may be some small benefit. There are more trials coming. Perhaps they will add clarity.