Iron substitution improves LVEF in intensively treated CRT patients with iron deficiency

Therapy with ferric carboxymaltose (FCM) improved cardiac performance in intensively treated cardiac resynchronisation therapy (CRT) patients with persistently reduced left ventricular ejection fraction (LVEF). This was demonstrated in the randomised, multicentre, phase 4 IRON-CRT trial.

Iron deficiency is a frequent comorbidity in heart failure with reduced ejection fraction (HFrEF), affecting approximately 50% of patients. Iron deficiency aggravates both functional status and clinical outcomes of patients with heart failure [1]. Progression of iron deficiency parallels an increased risk of worsening heart failure. FCM has been shown to reduce the risk for heart failure admission. Yet, the cardiac effects are relatively unknown. From a cardiac perspective, iron deficiency is associated with progressive cardiac remodelling, diminished cardiac/cardiomyocyte contractility, and reduced cardiac energy reserve. “The myocardium requires a lot of energy, for which you need iron,” Dr Pieter Martens (Hospital Oost-Limburg, Belgium) explained (see Figure) [2]. One of the operating mechanisms is the force-frequency relationship. In contrast to healthy controls, a reduced contractility is seen in HFrEF patients with increasing heart rate. “This energetic deficit worsens with iron deficiency,” Dr Martens added.

Figure: Iron deficiency and energy/contractility. Modified from [3,4]

CK, creatine kinase; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle.

The rationale of the multicentre, randomised, double-blind, phase 4 IRON-CRT trial (NCT03380520) was to determine whether FCM induces incremental reverse remodelling in patients undergoing CRT with a persistently reduced LVEF and iron deficiency [2,5]. Moreover, the study assessed whether FCM could improve the force-frequency relationship in HFrEF. CRT patients were chosen specifically to perform a validated force-frequency pacing protocol.

The trial included adult patients with stable HFrEF and a CRT implant more than 6 months (n=75). All patients had a persistently reduced LVEF (<45%) and iron deficiency (ferritin <100 ng/mL or between 100-300 ng/mL if transferrin saturation was <20%). “Our patients were intensively treated: 50% of them received an angiotensin receptor neprilysin inhibitor on top of device therapy,” Dr Martens said. They were treated with either standard of care (n=37) or FCM (n=38). The primary endpoint was change in LVEF from baseline to 3 months. Change in left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) were assessed as secondary endpoints.

 

Significant improvement in primary and secondary endpoints
After 3 months, LVEF in the FCM group improved significantly compared with the standard-of-care group (P<0.001). LVEF increased in the FCM group by 4.22% (95% CI 3.05–5.38) compared with a decrease of 0.23% (95% CI -1.44 to 0.97) in the standard-of-care group. “We noticed an absolute improvement of about 4%,” Dr Martens said. The positive treatment effect of FCM was also noted in the secondary endpoints. LVESV was significantly decreased in the FCM group with 9.72 mL (95% CI -13.5 to -5.93) compared with a 1.83 mL decrease (95% CI -5.7 to 2.1) in the standard-of-care group (P=0.001). In addition, the force-frequency relationship changed from negative to positive. Therapy with FCM also improved maximal exercise capacity as measured by Peak VO₂. A predefined subgroup analysis revealed that patients had a consistent beneficial treatment effect independent of their LVEF, haemoglobin, or transferrin saturation at baseline.

“We did not observe more adverse events in the FCM groups compared with placebo,” Dr Martens said. Therefore, he concluded that therapy with FCM in HF patients with persistently reduced LVEF despite optimal medical therapy and CRT over 3 months resulted in cardiac reverse remodelling (documented by a change in LVEF and LVESV) and an improvement in cardiac performance. Thus, the IRON-CRT trial further expands knowledge on the mode-of-action of FCM in HFrEF.

1. 
   
   1. Martens P, et al. Acta Cardiol 2018:73(2):115-23.
   2. Martens P, et al. The effect of intravenous ferric-carboxymaltose on cardiac reverse remodeling following cardiac resynchronization therapy – The IRON CRT trial. LBT 1, Heart Failure and World Congress on Acute Heart Failure 2021, 29 June–1 July.
   3. Martens P, et al. Eur J Heart Fail 2018;20(5):920-2.
   4. Martens P, et al. Eur J Heart Fail 2018;20(4):806-8.
   5. Martens P, et al. Eur. Heart J. 2021. DOI: 1093/eurheartj/ehab411.

 

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Posted on 19 August, 202120 August, 2021