Interpreting New IV Iron Guidelines, with Muthiah Vaduganathan, MD, MPH

Muthiah Vaduganathan, MD, MPH
Credit: Brigham and Women's Hospital

In recent years, major trials in heart failure have dominated headlines at meetings and been met with calls for updated guidelines to reflect this new information. Although the majority of these trials have pertained to blockbuster agents like SGLT2 inhibitors and, more recently, semaglutide, the role of intravenous iron supplementation in heart failure has become a focal point in research efforts.

At the European Society of Cardiology (ESC) Congress 2023, iron supplementation was in the spotlight, with the debut of new guideline recommendations on the topic and the presentation of results from the HEART-FID trial.

New Iron Supplementation Recommendations:¹

• Intravenous iron supplementation is recommended in symptomatic patients with HFrEF and HFmrEF, and iron deficiency, to alleviate heart failure symptoms and improve quality of life. (Class I, Level A)
• Intravenous iron supplementation with ferric carboxymaltose or ferrite derisomaltose should be considered in symptomatic patients with HFrEF and HFmrEF, and iron deficiency, to reduce the risk of heart failure hospitalization. (Class IIa, Level A)

HEART-FID

Billed as the largest study to assess the long-term safety and efficacy of intravenous ferric carboxymaltose in HFrEF and iron deficiency, the trial’s primary endpoint was a hierarchical composite of 12-month rate of death, hospitalization for worsening heart failure, and the 6-month change in 6-minute walk test distance. The trial randomized 1532 to ferric carboxymaltose and 1533 to placebo therapy.¹

Upon analysis, investigators found the unmatched win ratio for the primary outcome favored the ferric carboxymaltose group did not meet the prespecified significance level (Win Ratio, 1.10; 99% Confidence interval [CI], 0.99-1.23; P = .019). However, investigators pointed out a there was a trend toward benefit for each of the individual outcomes of the composite.²

In a meta-analysis of IV iron trials presented during the same session as HEART-FID at ESC Congress 2023, results indicated use of ferric carboxymaltose was associated with a significant reduction in the coprimary composite endpoint of total cardiovascular hospitalizations and cardiovascular death compared with placebo, (Rate Ratio [RR], 0.86; 95% CI, 0.75-0.98; P = .029). Additionally, investigators observed a trend toward reduction of the coprimary composite endpoint of total heart failure hospitalizations and cardiovascular death but noted it failed to reach statistical significance (RR 0.87; 95% CI, 0.75-1.01; P = .076).¹

At the Heart Failure Society of America (HFSA) 2023 Annual Scientific Meeting, Muthiah Vaduganathan, MD, MPH, codirector of Cardiometabolic Implementation Science at Brigham and Women’s Hospital, led a presentation titled “New ESC Guidelines on management of Iron Deficiency”. As part of our on-site coverage of HFSA 2023, HCPLive Cardiology sat down with Vaduganathan for more perspective on the latest guideline recommendations.

HCPLive Cardiology: In recent years, there has been a renewed emphasis on iron supplementation in heart failure. What do you think is really sort of driven this resurgence of interest in iron supplementation?

Vaduganathan: I think, ultimately, heart failure clinicians are very interested in improving outcomes of interests and that includes preventing hospitalizations, delaying mortality, and improving health status, like health related quality of life of patients. Until recently, we haven't had solid evidence for intravenous iron on multiple of these domains.

We've had early evidence that was fairly compelling around functional capacity, and perhaps even quality of life, but never really would single studies have we seen any shifts in terms of hospitalizations for heart failure or mortality. That is until recently and I think that's why we've seen this resurgence in focus, because clinicians are seeing that a real potential that this therapeutic option can actually improve patient wellbeing.

HCPLive Cardiology: At ESC Congress 2023, updated guidance for iron supplementation was released. Can you discuss the significance of these updated recommendations?

Vaduganathan: I think this ESC guideline takes a number of steps forward or at least a direction we haven't seen before. So, first, is that until now, heart failure guidelines have traditionally not allocated Class 1 recommendations for therapies that do not alter the trajectory of mortality or hospitalization. So, the direction that they're really taking is that this is a therapy that has a strong, strong evidence base for the indication that they've provided, which is improvement in quality of life and symptom burden. That they are saying this is a Class I recommendation is definitely a unique step.

The second fairly unique aspect is that they have now specifically called out 2 different IV iron formulations: ferric, carboxymaltose and ferric derisomaltose. So previously FCM, or ferric carboxymaltose, was the only therapy that was specifically listed. Here, we now have two different options and this was based on the recent clinical trials AFFIRM-HF and IRONMAN. They've called out now the reduction of risk of heart failure hospitalization and with a Class IIA recommendation that can be debated. Both trials actually didn't meet their primary endpoints. They both were influenced by COVID. So, they had some complexities in the data interpretation of the trials.

Then the third and, I think perhaps the most important these guidelines, as with all guidelines, are unfortunately quickly outdated. With an almost simultaneous presentation, we heard the landmark HEART-FID study results, which is the largest trial of an IV iron formulation and this had relatively mixed results. I think the trial did not technically meet its primary endpoint, it had a higher threshold for significance than is traditional. In general, I believe the benefits were driven by improvements in aspects like improvements in functional capacity, which really does substantiate that first recommendation, which is improvement in symptom burden and quality of life.

References:

1. Campbell P. Role of intravenous iron in spotlight at ESC congress 2023. HCP Live. August 27, 2023. Accessed October 9, 2023. https://www.hcplive.com/view/role-of-intravenous-iron-in-spotlight-at-esc-congress-2023.
2. Mentz RJ, Garg J, Rockhold FW, et al. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. N Engl J Med. 2023;389(11):975-986. doi:10.1056/NEJMoa2304968