The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy—the IRON-CRT trial

Abstract

Aims Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF. Methods and results Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF <45%) at least 6 months after cardiac resynchronization therapy (CRT) implant were prospectively randomized to FCM or standard of care (SOC) in a double-blind manner. The primary endpoint was the change in LVEF from baseline to 3-month follow-up assessed by three-dimensional echocardiography. Secondary endpoints included the change in left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) from baseline to 3-month follow-up. Cardiac performance was evaluated by the force–frequency relationship as assessed by the slope change of the cardiac contractility index (CCI = systolic blood pressure/LVESV index) at 70, 90, and 110 beats of biventricular pacing. A total of 75 patients were randomized to FCM (n = 37) or SOC (n = 38). At baseline, both treatment groups were well matched including baseline LVEF (34 ± 7 vs. 33 ± 8, P = 0.411). After 3 months, the change in LVEF was significantly higher in the FMC group [+4.22%, 95% confidence interval (CI) +3.05%; +5.38%] than in the SOC group (−0.23%, 95% CI −1.44%; +0.97%; P < 0.001). Similarly, LVESV (−9.72 mL, 95% CI −13.5 mL; −5.93 mL vs. −1.83 mL, 95% CI −5.7 mL; 2.1 mL; P = 0.001), but not LVEDV (P = 0.748), improved in the FCM vs. the SOC group. At baseline, both treatment groups demonstrated a negative force–frequency relationship, as defined by a decrease in CCI at higher heart rates (negative slope). FCM resulted in an improvement in the CCI slope during incremental biventricular pacing, with a positive force–frequency relationship at 3 months. Functional status and exercise capacity, as measured by the Kansas City Cardiomyopathy Questionnaire and peak oxygen consumption, were improved by FCM. Conclusions Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force–frequency relationship.

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

“…Remarkably, in HFrEF patients receiving cardiac resynchronisation therapy (CRT), the presence of ID is associated with diminished reverse remodelling and lesser likelihood of functional improvement after CRT implementation, suggesting that adequate myocardial iron content is a prerequisite to derive optimal benefits from CRT implantation with respect to reverse cardiac remodelling and improved cardiac function [ 226 , 227 ]. In line with these findings, the recent IRON-CRT trial showed that IV iron repletion reverses myocardial remodelling and boosts cardiac performance and contractility in patients receiving CRT, which were also accompanied by improvements in quality of life and exercise capacity [ 62 ]. These results demonstrate the incremental potential of IV iron in reverse cardiac remodelling in addition to guideline-directed therapies that induce reverse remodelling [ 228 ].…”

“…Additionally, subgroup analysis of individual patient data meta-analysis ( n = 839) pooled from four double-blind, randomised controlled trials (RCTs) showed that although intravenous ferric carboxymaltose (FCM) generally reduces recurrent cardiovascular hospitalisations and cardiovascular mortality, patients with TSAT <20.1% benefit more from FCM iron than those with TSAT >20.1% even if ferritin levels were low [ 61 ]. Similarly, in the IRON-CRT trial, it was found that HF patients with TSAT <20% benefit more from FCM iron than if TSAT was >20% in terms of cardiac contractility and left ventricular ejection fraction (LVEF) [ 62 ]. However, similar interaction was not found in the AFFIRM-AHF trial [ 27 ].…”

The Effect of Iron Deficiency on Cardiac Function and Structure in Heart Failure with Reduced Ejection Fraction

“…Additionally, the change in LVESV from baseline to follow-up was more pronounced in the ferric carboxymaltose group versus the standard of care group (−9.72 ml, 95% CI [−13.5, 5.93] versus −1.83 ml, 95% CI [−5.7, 2.1], p=0.001) However, the change in LVEDV was not different between the two treatment groups (ferric carboxymaltose: −2.5 ml, 95% CI [−5.3, 0.3] versus −1.9 ml, 95% CI [−4.7, 1.0], p=0.784). [ 43 ] Additionally, treatment with ferric carboxymaltose was capable of improving the force-frequency relationship as documented in Figure 5 . In patients treated with ferric carboxymaltose the negative force-frequency relationship was transformed into a positive force-frequency relationship.…”

“…Patients were randomised in a double-blind fashion to either standard of care (IV placebo) or ferric carboxymaltose. [ 43 ]…”

Intravenous iron in heart failure with reduced ejection fraction: just about right

“…The main results of the IRON-CRT trial demonstrated that FCM improved LVEF, functional status, and exercise capacity in patients. 14 Of the 75 patients enrolled in the IRON-CRT trial, almost three out of four had RV dysfunction at baseline and over two thirds had RV dilatation. RV function was assessed via the RV fractional area change (RV FAC), tricuspid annular plane systolic excursion (TAPSE), and the pulsed tissue Doppler peak velocity at the RV lateral annulus (RV S ′ ).…”