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.

Keywords: Cardiac remodelling; Contractility; Heart failure; Iron deficiency; Randomized controlled trials.

Overview of study design and main findings.

Figure 1

CONSORT flow chart of patients screened, randomized and followed up. A total of 221 met the inclusion criteria (numbers 1–6) mentioned in the Methods section and were screened for the presence of iron deficiency, which was present in 48%. Exclusion criteria included haemoglobin >15 g/dL, C-reactive protein >20 mg/L, insufficient image quality to assure three-dimensional echocardiography, and active inclusion in another randomized controlled trial or recent (<30 days) completion of another randomized controlled trial.

Figure 2

Change in primary and secondary endpoints. Change at 3 months in (A) left ventricular ejection fraction, (B) left ventricular end-systolic volume, and (C) left ventricular end-diastolic volume. FCM, ferric carboxymaltose; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; SOC, standard of care. P-values are from an ANCOVA (analysis of covariance) model with correction for baseline values.

Figure 3

Effect on the cardiac force-frequency relationship. (A) Difference in cardiac contractility index slope between ferric carboxymaltose and standard of care at follow-up. (B) Cardiac contractility index slope at baseline and follow-up in the ferric carboxymaltose group. (C) Cardiac contractility index slope at baseline and follow-up in the standard of care group. Slope evaluation was analysed using linear mixed models as described in the statistics section. FCM, ferric carboxymaltose; CCI, cardiac contractility index; CI, confidence interval; SOC, standard of care.

Figure 4

Change in tertiary endpoints. Change at 3 months in (A) peak VO₂, (B) V_E/V_CO2 ratio, (C) Kansas City Cardiomyopathy Questionnaire, and (D) N-terminal pro B-type natriuretic peptide. P-values are from an ANCOVA model with correction for baseline values. FCM, ferric carboxymaltose; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; NT-proBNP, N-terminal pro B-type natriuretic peptide; SOC, standard of care; V_E/V_CO2, slope of minute ventilation/carbon dioxide production; VO₂, oxygen consumption.

Figure 5

Forest plot of subgroup analysis for the effect of ferric carboxymaltose on the primary endpoint. FCM, ferric carboxymaltose; Hb, haemoglobin; LVEF, left ventricular ejection fraction; SOC, standard of care; TSAT, transferrin saturation.