Javed Butler, MD, MPH, MBA, professor of medicine at University of Mississippi, president of the Baylor Scott & White Research Institute, explains how findings from the HEART-FID trial add to the value of ferric carboxymaltose injection.
Javed Butler, MD, MPH, MBA, professor of medicine at University of Mississippi and president of the Baylor Scott & White Research Institute, highlights positive findings from the HEART-FID trial. Although it just missed its prespecified significance level, Butler explains that the trial was the largest of its kind, had stricter criteria than most trials, raised important questions for future research, and led to several positive outcomes—unsurprisingly including improved quality of life—for patients who received intravenous (IV) ferric carboxymaltose.
What lessons were learned from the HEART-FID trial?
HEART-FID was the largest trial done with IV iron therapy in patients with heart failure with reduced ejection fraction; the therapy that was used was ferric carboxymaltose. So why was the trial done in the first place? Well, there are plenty of data that these therapies are associated with improvement in quality of life, so that was not in question. But those were all smaller trials and every trial showed an improvement in hospitalization, but we really needed a large trial primarily powered to look at that. So the primary end point of this trial was all-cause mortality or heart failure hospitalization at 1 year or improvement in 6-minute walk test at 6 months. Because this was a regulatory trial and the idea was that with one trial there would be an indication, the P value for this trial negotiated with the regulators was more stringent than your usual criteria of P value less than .05. With the traditional criteria, the P value was less than .05, but it did not reach the bar of .01 which was set by the regulators, per se.
Overall, all 3 components of the primary end point—mortality, hospitalization, and improvement in 6-minute walk test—directionally were in favor of IV iron therapy, but in magnitude were less than what we were expecting. So why is [this] the case? Well, on one hand, we can say this was the largest trial with the longest follow-up, but we actually learned a lot of lessons, and the lesson that we learned—and this is my opinion, the trial was not designed to look at it like this—is that the short-term trial, when you give IV iron, you're covered for that short-term duration. In the long run, the question we need to contend is "What is optimal IV replacement?" And the majority of these patients did not get recurrent infusions after 1 year. Therefore, the question is, was there an attenuation of benefit in the long run? I think like most good science, you answer some questions but you raise more questions. And I think the question we need to answer now is not whether repleting iron deficiency is important, but what are the standards and for how long should we replete iron on an ongoing basis? I think those are the questions that we will be discussing.
With ferric carboxymaltose already being FDA-approved earlier this year, what do the HEART-FID findings add to the value of the treatment?
What is interesting is that the data [from] multiple trials across different populations, different study centers, and whatnot consistently showed improvement in quality of life, [but] that quality of life was not even assessed in the HEART-FID trial. This was sort of a given. I think the guideline indication and the indication by the FDA for improvement in quality of life or health status, I think that stays intact and I think we should be using this therapy for improvement in quality of life. But this trial did raise the question whether to get clinical benefit in terms of hospitalization or potential mortality, that not only do we need an appropriately powered longer trial, but give frequent recurrent injections over time and not just only in the beginning. That, I think, will be actively discussed and hopefully we will get some of those answers in FAIR-HF2, which is an ongoing trial in Europe.