Large clinical trials of intravenous iron for patients with heart failure have studied hospitalized patients immediately prior to discharge (AFFIRM-HF) and outpatients (HEART-FID)^1-3; efficacy might differ by enrolment setting.

IRONMAN (NCT02642562) was a prospective, randomized, open-label, blinded-endpoint trial comparing intravenous ferric derisomaltose (FDI) with usual care in patients with left ventricular ejection fraction (LVEF) ≤45% and either a serum ferritin <100 μg/L or transferrin saturation (TSAT) <20%.^4-6 Patients were grouped according to recruitment settings: (i) hospitalized; (ii) recently hospitalized (within 6 months); and (iii) outpatients without recent hospitalization with elevated plasma concentrations of natriuretic peptides.

The primary outcome was heart failure hospitalization (HFH) (recurrent events) or cardiovascular (CV) death. Secondary outcomes included: (i) HFH (first event) or CV death; (ii) CV death; (iii) myocardial infarction, stroke, HFH (first event) or CV death; (iv) all-cause hospitalization; (v) CV hospitalization; (vi) all-cause death; (vii) unplanned hospitalization or all-cause death; and (viii) hospitalization for infection.

In this pre-specified subgroup analysis, the effect of FDI on the primary and secondary endpoints compared to usual care was investigated according to enrolment setting.

Of 1137 patients randomized, 164 were enrolled in hospital, 208 had been recently hospitalized, and 765 were more stable outpatients. The median follow-up duration was 2.7 years.

Patients enrolled in hospital had lowest concentrations of haemoglobin compared to the other groups (median 11.5 vs. 12.0 and 12.3 g/dL), lowest TSAT (medians 10% vs. 14% and 16%), highest proportion with TSAT <20% (90% vs. 76% and 73%), highest ferritin (median 65 vs. 50 and 47 μg/L), lowest estimated glomerular filtration rate (eGFR) (median 45 vs. 48 and 53 mL/min/1.73 m²), lowest systolic blood pressure (median 113 vs. 117 and 121 mmHg), lowest LVEF (median 30% vs. 32% and 35%), were least likely to have ischaemic aetiology (41% vs. 51% and 62%), least likely to have prior acute coronary syndrome (37% vs. 42% and 56%), and had the worst (highest) Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores (physical score median 30 vs. 24 and 22). Other baseline characteristics, including age and sex were similar across groups.

Patients enrolled in hospital were more likely on loop diuretics and less likely on renin–angiotensin system inhibitors (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, sacubitril/valsartan) at baseline. Similar proportions across groups were on beta-blockers, mineralocorticoid receptor antagonists, sodium–glucose cotransporter 2 (SGLT2) inhibitors, and digoxin. Investigators were encouraged to optimize treatment per international clinical practice guidelines at all visits⁷; therefore, heart failure treatments may have changed over follow-up.

Patients enrolled in hospital in the usual care arm had double the rate of primary endpoints compared to outpatients (rate/100 patient-years of 44 in the hospitalized group vs. 22 in the outpatient group). The effect of FDI on the primary and secondary endpoints was similar, in terms of relative risk, irrespective of enrolment setting (Figure 1).

The effect of FDI on the change in haemoglobin from baseline to month 4 was consistent across different enrolment settings (p_interaction = 0.16).

Enrolment in the outpatient setting was associated with a greater effect of FDI compared to usual care on MLHFQ physical scores at 4 months (difference [95% confidence interval] −3 [−5, −1]) compared to hospitalized (−2 [−6, 2]) and recently hospitalized (2 [−2, 5]) patients (p_interaction = 0.043).

IRONMAN is the first heart failure outcome trial to provide within-trial comparisons on the effect of intravenous iron by enrolment setting. As anticipated, patients enrolled in hospital had a higher risk profile compared to outpatients and generally demonstrated higher rates of primary and secondary endpoints. The consistent benefits, in relative terms, between FDI and usual care regardless of whether treatment was initiated in the inpatient or outpatient setting suggest that intravenous iron therapy may be beneficial for a broad range of patients with heart failure throughout their disease trajectory. Hospital admission provides an opportune window for optimizing medical therapy, including correction of iron deficiency. Indeed, if the relative benefits are the same regardless of risk profile, the absolute benefit will be greater amongst patients at higher risk.

Compared to those enrolled in outpatient settings, hospitalized patients had features of more severe heart failure (including lower eGFR, systolic blood pressure, and LVEF) which itself may underpin the lower haemoglobin. Haemodilution may also contribute. Lower TSAT, indicating worse iron deficiency, may reflect heart failure severity including inflammation, potentially contributing to hospitalization and lower haemoglobin. Higher ferritin levels seen in hospitalized patients are consistent with greater inflammation due to various causes.

In AFFIRM-AHF, intravenous iron was given immediately prior to discharge; in clinical practice it may be challenging to coordinate this. In contrast, in IRONMAN, patients could receive intravenous iron at any time during the inpatient stay, which allows resources to be used more flexibly, helping to mitigate ‘therapeutic inertia’ and potential delays in treatment initiation. Reassuringly, there was no suggestion of an increased rate of severe infection or an increase in other hazards in patients enrolled in hospital settings. In IRONMAN, there was no difference in the risk of hospitalization due to infection across the three enrolment settings (Figure 1).

SGLT2 inhibitors are foundational therapy for heart failure, necessitating understanding their interactions with intravenous iron. In a post-hoc analysis of IRONMAN, there was a trend towards greater increase in haemoglobin with FDI in iron-deficient patients on SGLT2 inhibitors at baseline compared to those not on one.⁸

This analysis has several limitations that should be acknowledged. The trial was not powered to investigate the effects of treatment in subgroups. Patient characteristics differed in many ways according to recruitment context, which may account for any observed trends or lack thereof. Patients were enrolled solely in the UK, and most were White and men, therefore the results should be extrapolated to other populations with caution.

In conclusion, hospitalized patients exhibited a higher rate of the primary outcome compared to outpatients, but the relative risk reduction of FDI was consistent regardless of whether patients were enrolled in hospital wards or outpatient clinics. These findings suggest that intravenous iron therapy may offer benefits across the breadth of clinical settings in the management of heart failure.

对心力衰竭患者静脉注射铁剂的大型临床试验研究了出院前即刻住院患者 （AFFIRM-HF） 和门诊患者 （HEART-FID）^1-3;疗效可能因入组环境而异。

IRONMAN （NCT02642562） 是一项前瞻性、随机、开放标签、盲法终点试验，在左心室射血分数 （LVEF） ≤45% 和血清铁蛋白 <100 μg/L 或转铁蛋白饱和度 （TSAT） <20% 的患者中，比较静脉注射去铁麦芽糖铁 （FDI） 与常规护理。^4-6 名患者根据招募环境分组： （i） 住院;（ii） 最近住院（6 个月内）;（iii） 近期未住院且血浆利钠肽浓度升高的门诊患者。

主要结局是心力衰竭住院 （HFH） （复发事件） 或心血管 （CV） 死亡。次要结局包括：（i） HFH （首次事件） 或 CV 死亡;（ii） CV 死亡;（iii） 心肌梗死、中风、HFH（首次事件）或 CV 死亡;（iv） 全因住院;（v） CV 住院;（vi） 全因死亡;（vii） 意外住院或全因死亡;（viii） 因感染住院。

在这个预先指定的亚组分析中，根据入组环境调查了与常规护理相比，FDI 对主要和次要终点的影响。

在随机分配的 1137 例患者中，164 例入组，208 例近期住院，765 例为更稳定的门诊患者。中位随访时间为 2.7 年。

与其他组相比，入院患者的血红蛋白浓度最低（中位数 11.5 vs. 12.0 和 12.3 g/dL），最低的 TSAT（中位数 10% vs. 14% 和 16%），TSAT <20% 的比例最高（90% vs. 76% 和 73%），铁蛋白最高（中位数 65 vs. 50 和 47 μg/L），最低的估计肾小球滤过率 （eGFR）（中位数 45 vs. 48 和 53 mL/min/1.73 m²）、收缩压最低（中位数 113 vs. 117 和 121 mmHg）、最低 LVEF（中位数 30% vs. 32% 和 35%），最不可能有缺血性病因（41% vs. 51% 和 62%），最不可能既往患有急性冠脉综合征（37% vs. 42% 和 56%），并且明尼苏达心力衰竭患者生活问卷 （MLHFQ） 评分最差（最高）（体格评分中位数 30 vs. 24 和 22）。其他基线特征，包括年龄和性别，在不同组之间相似。

入院患者在基线时更可能使用袢利尿剂，而不太可能使用肾素-血管紧张素系统抑制剂 （血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂、沙库巴曲/缬沙坦）。各组服用 β 受体阻滞剂、盐皮质激素受体拮抗剂、钠-葡萄糖协同转运蛋白 2 （SGLT2） 抑制剂和地高辛的比例相似。鼓励研究人员在所有访视时根据国际临床实践指南优化治疗⁷;因此，心力衰竭的治疗可能在随访期间发生了变化。

与门诊患者相比，常规护理组入院患者的主要终点发生率是门诊患者的两倍（住院组为 44 例/100 患者年，门诊组为 22 例）。就相对风险而言，FDI 对主要和次要终点的影响相似，与入组环境无关（图 1）。

FDI 对血红蛋白从基线到第 4 个月变化的影响在不同的入组环境中是一致的 （p_交互作用 = 0.16）。

与常规护理相比，门诊入组与 FDI 对 4 个月时 MLHFQ 身体评分的更大影响相关 （差异 [95% 置信区间] -3 [-5， -1]） 与住院 （-2 [-6， 2]） 和最近住院 （2 [-2， 5]） 患者 （p_交互 = 0.043）。

IRONMAN 是第一个通过入组环境对静脉注射铁剂效果进行试验内比较的心力衰竭结局试验。正如预期的那样，与门诊患者相比，入院患者的风险更高，并且通常表现出更高的主要和次要终点发生率。相对而言，无论治疗是在住院还是门诊开始，FDI 和常规护理之间的一致益处表明，静脉铁剂治疗可能对整个疾病轨迹中的广大心力衰竭患者有益。入院为优化药物治疗（包括纠正铁缺乏）提供了合适的窗口。事实上，如果无论风险状况如何，相对获益都相同，则风险较高的患者的绝对获益会更大。

与门诊患者相比，住院患者具有更严重的心力衰竭特征（包括较低的 eGFR、收缩压和 LVEF），这本身可能是降低血红蛋白的基础。血液稀释也可能起作用。较低的 TSAT 表明铁缺乏更严重，可能反映了心力衰竭的严重程度，包括炎症，可能导致住院和血红蛋白降低。住院患者体内较高的铁蛋白水平与各种原因导致的炎症加剧一致。

在 AFFIRM-AHF 中，出院前立即静脉注射铁剂;在临床实践中，协调这一点可能具有挑战性。相比之下，在 IRONMAN 中，患者可以在住院期间的任何时间接受静脉注射铁剂，这使得资源可以更灵活地使用，有助于减轻“治疗惰性”和治疗开始的潜在延迟。令人欣慰的是，没有迹象表明在医院环境中入组的患者严重感染率增加或其他危害增加。在 IRONMAN 中，三种入组环境中因感染而住院的风险没有差异（图 1）。

SGLT2 抑制剂是心力衰竭的基础疗法，需要了解它们与静脉注射铁剂的相互作用。在 IRONMAN 的事后分析中，与未使用 SGLT2 抑制剂的患者相比，基线时接受 SGLT2 抑制剂治疗的缺铁患者 FDI 的血红蛋白增加幅度更大。⁸

这种分析有几个应该承认的局限性。该试验没有把握度来调查亚组治疗的效果。根据招募情况，患者特征在许多方面有所不同，这可能是观察到任何趋势或缺乏趋势的原因。患者仅在英国入组，大多数是白人和男性，因此应谨慎将结果外推到其他人群。

总之，与门诊患者相比，住院患者表现出更高的主要结局发生率，但无论患者是在医院病房还是门诊就诊，FDI 的相对风险降低都是一致的。这些发现表明，静脉铁剂治疗可能在心力衰竭的管理中为广泛的临床环境带来益处。