Background

For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure.

Methods

IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562.

Findings

Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016).

Interpretation

For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population.

Funding

British Heart Foundation and Pharmacosmos.

中文翻译：

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英国心力衰竭和缺铁患者静脉注射脱异麦芽糖铁 (IRONMAN)：一项研究者发起的、前瞻性、随机化、开放标签、盲法终点试验

背景

对于心力衰竭、左心室射血分数降低和缺铁的患者，静脉内给予羧基麦芽糖铁可改善短期生活质量和运动能力，并减少长达 1 年的心力衰竭住院率。我们的目的是评估静脉注射脱异麦芽糖铁对心力衰竭患者心血管事件的长期影响。

方法

IRONMAN 是一项在英国 70 家医院进行的前瞻性、随机、开放标签、盲法终点试验。18 岁或以上心力衰竭（左心室射血分数≤45%）且转铁蛋白饱和度低于 20% 或血清铁蛋白低于 100 μg/L 的患者符合入组条件。使用基于网络的系统将参与者随机分配 (1:1) 接受静脉注射脱异麦芽糖铁或常规护理，按招募背景和试验地点分层。该试验是开放标签的，对结果进行隐蔽裁决。静脉注射脱异麦芽糖铁的剂量由患者体重和血红蛋白浓度决定。主要结局是因心力衰竭和心血管死亡而再次入院，在所有有效随机分配的患者中进行评估。对所有接受至少一次输注的去异麦芽糖铁治疗的患者和接受常规治疗的所有患者都进行了安全性评估。预先指定了 2020 年 9 月 30 日审查后续行动的 COVID-19 敏感性分析。IRONMAN 已在 ClinicalTrials.gov 注册，NCT02642562。

发现

2016 年 8 月 25 日至 2021 年 10 月 15 日期间，对 1869 名患者进行了资格筛选，其中 1137 名患者被随机分配接受静脉内异麦芽糖铁铁 (n=569) 或常规治疗 (n=568)。中位随访时间为 2·7 年 (IQR 1·8–3·6)。336 个主要终点（22·4/100 患者年）发生在脱异麦芽糖铁组，411（27·5/100 患者年）发生在常规治疗组（率比 [RR] 0·82 [95% CI 0·66 至 1·02]；p=0·070）。在 COVID-19 分析中，去异麦芽糖铁组发生了 210 次主要终点（每 100 患者年 22·3），而常规治疗组发生了 280 次（每 100 患者年 29·3）（RR 0·76 [ 95% CI 0·58 至 1·00]；p=0·047）。未观察到因感染导致的死亡或住院率存在组间差异。

解释

对于范围广泛的心力衰竭、左心室射血分数降低和缺铁的患者，静脉内给予去异麦芽糖铁与心力衰竭和心血管死亡的住院风险较低相关，进一步支持补铁对这一人群的益处。

资金

英国心脏基金会和 Pharmacosmos。