Almost half of heart failure patients have low iron levels. Having insufficient means to transport oxygen due to iron deficiency is the last thing a patient with reduced heart function needs.
It therefore seems pointless to replace something as essential as iron when its levels are low.
The IRONMAN process
Yet at the American Heart Association (AHA) 2022 Scientific Sessions, a large randomized controlled trial with the best acronym ever, the IRONMAN trial, failed to confirm what makes perfect sense.
IRONMAN studied a new intravenous iron replacement agent called ferric derisomaltose. Patients who had heart failure and left ventricular ejection fraction less than 45% and proven iron deficiency were randomly assigned to receive intravenous iron infusions or usual care.
Unlike the previous iron replacement trial, AFFIRM-AHF, which randomized patients to short-term iron infusions (or none), the IRONMAN trial enrolled mostly ambulatory patients and scheduled repeated iron infusions to maintain normal iron levels.
The primary endpoint in IRONMAN was death from cardiovascular (CVD) causes or re-hospitalization for heart failure.
As is common in recent years, the pandemic affected the court. IRONMAN was carried out in the National Health System in the UK and the lockdown prevented some patients from coming in for repeat infusions. Only 60% of patients in the active arm received more than one infusion. About 17% of patients in 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 derisomaltosis group compared with the usual care group (27.5 per 100 patient-years).
This almost reached statistical significance (rate ratio [RR]0.82; 95% CI, 0.66 – 1.02; P = 0.070). Hospitalizations for heart failure caused the decrease. Deaths from CV causes, all-cause mortality, and total hospitalizations were not significantly different.
After 4 months, patients in the iron infusion arm had better quality of life and physical domain scores than the control group. After 20 months, these scores were no longer significantly different between the two treatment groups. Serious adverse events were also not different.
IRONMAN enrolled patients from August 2016 to September 2021. A sensitivity analysis was performed to minimize the effect of the pandemic, using September 30, 2020 as the censoring date. This analysis included 91% of all randomized patients and found a 24% reduction in the primary endpoint, which met statistical significance (RR, 0.76; 95% CI, 0.58 – 1.00; P = 0.047). This was again due to fewer hospitalizations for heart failure, without a significant reduction in CV or all-cause death.
Comments
I will address three issues with iron infusions in patients with heart failure.
1. Is IRONMAN a positive or negative test?
The point estimate of the relative risk reduction of the primary endpoint has an upper limit of 95% CI of 1.02 and P a value of 0.07. This does not meet our arbitrary threshold for statistical significance.
But that doesn’t mean they don’t provide iron infusions some advantage. The lower bound of the same CI includes a 34% reduction in the primary endpoint, and most of the CI includes a benefit.
Moreover, this degree of relative risk reduction corresponded well with the AFFIRM-AHF grade (RR, 0.79; 95% CI, 0.62 – 1.01; P = 0.06), who also found lower hospitalizations for heart failure in the iron group and no significant reduction in CV death.
The likelihood of a small benefit from iron infusion seems much more likely than noise. Which brings me to the second problem.
2. Do iron infusions have a clinically significant benefit?
In the IRONMAN study, the primary endpoint was a lower rate of heart failure hospitalizations in the active arm. More important endpoints such as CV death, all-cause death, and all-cause hospitalization were not significantly different. That’s a negative.
Almost a quarter of patients died of cardiovascular causes during the study. So it seems that the problem is not too few events. You would want a heart failure intervention to do more than just reduce one type of hospitalization.
Proponents of iron replacement can point to data showing it reduces exercise time and quality of life. Therapies that make patients feel better are important. But that brings me to the third problem.
3. Are iron infusions worth the trouble—for both patients and payers?
At the AHA, I spoke with Ricky Turgeon, PharmD, of the University of British Columbia, about the logistics of administering iron infusions to outpatients. His simple message: It was tough in Canada. Hard on the system and hard on the patient. I strongly suspect that it is not easy to get patients into IV centers in any system.
We should always remember that heart failure patients are already under a significant burden. They often visit the doctor’s office and have to take many medications. They both wasted time that could have been spent living.
Conclusion
Adding outpatient visits for intravenous infusions would be fine if there were clinically strong and statistically strong benefits. But I don’t think we’ve seen that with this data.
The weakness of the data also informs whether systems should cover the cost of iron infusions. If there were unlimited budgets, then it would be fine. But it’s definitely not like that.
This is a difficult area in which there may be little benefit. More exams are coming up. Hopefully they will add clarity.
For now, please tell me in the comments if you agree or disagree with my position.
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