Rationale and design of the IRON‐CRT trial: effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy

Abstract

Aims Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF). In patients with cardiac resynchronization therapy (CRT), it is associated with a diminished reverse remodelling response and poor functional improvement. The latter is partially related to a loss in contractile force at higher heart rates (negative force-frequency relationship). Methods and resultsThe effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy (IRON-CRT) trial is a multicentre, prospective, randomized, double-blind controlled trial in HFrEF patients who experienced incomplete reverse remodelling (defined as a left ventricular ejection fraction below <45%) at least 6 months after CRT. Additionally, patients need to have iron deficiency defined as a ferritin below 100 μg/L irrespective of transferrin saturation or a ferritin between 100 and 300 μg/L with a transferrin saturation <20%. Patients will be randomized to either intravenous ferric carboxymaltose (dose based according to Summary of Product Characteristics) or intravenous placebo. The primary objective is to evaluate the effect of ferric carboxymaltose on metrics of cardiac reverse remodelling and contractility, measured by the primary endpoint, change in left ventricular ejection fraction assessed by three-dimensional (3D) echo from baseline to 3 month follow-up and the secondary endpoints change in left ventricular end-systolic and enddiastolic volume. The secondary objective is to determine if ferric carboxymaltose is capable of improving cardiac contractility in vivo, by assessing the force-frequency relationship through incremental biventricular pacing. A total of 100 patients will be randomized in a 1:1 fashion. Conclusions The IRON-CRT trial will determine the effect of ferric carboxymaltose on cardiac reverse remodelling and ratedependent cardiac contractility in HFrEF patients.

Short‐term changes in left and right systolic function following ferric carboxymaltose: a substudy of the Myocardial‐IRON trial

“…However, further research will be necessary to provide definite answers. For instance, the IRON‐CRT trial is currently evaluating whether FCM is capable of improving LVEF and cardiac remodelling in patients with HF and reduced ejection fraction with an incomplete response to cardiac resynchronization therapy 23 . A planned echocardiographic substudy of the EFFECT‐HF study will also provide valuable information on this topic 24 .…”

Noncardiovascular comorbidities in patients with heart failure and their impact on prognosis

“…iron in HF patients with ID. The IRON-CRT trial [93] will determine the effect of FCM on cardiac reverse remodelling and cardiac contractility in HFrEF patients. Furthermore, ongoing FAIR-HFpEF trial (ClinicalTrials.gov Identifier: NCT03074591) will verify any benefits of i.v.…”

Optimized implementation of cardiac resynchronization therapy: a call for action for referral and optimization of care

“…Furthermore, while renal disease was an exclusion criteria in the major CRT trials and early observational data suggested less reverse remodelling in patients with chronic kidney disease stage IV and V, 1,3–6,47 more recent data indicate that patients with chronic kidney disease derive similar mortality benefit from lesser reverse remodelling 31,45 . Iron deficiency, which is common in CRT recipients (around 55%), might be associated with less functional improvement and less reverse remodelling following CRT, 85 possibly due to the role of iron as an essential co‐factor for protein synthesis and normal cell functioning 86 …”

“…31,45 Iron deficiency, which is common in CRT recipients (around 55%), might be associated with less functional improvement and less reverse remodelling following CRT, 85 possibly due to the role of iron as an essential co-factor for protein synthesis and normal cell functioning. 86 In conclusion, CRT selection and optimization must occur in the context of other heart failure interventions and other comorbidities. With a growing heart failure treatment armamentarium, this is becoming increasingly challenging for the cardiologist, highlighting the need for early referral to a heart failure management team.…”