Rationale and design of the IRON-HF study: a randomized trial to assess the effects of iron supplementation in heart failure patients with anemia

BackgroundAnemia is a common finding in heart failure (HF) patients and has been associated with increased morbidity and mortality. It is generally denominated as anemia of chronic disease (ACD), but the association with true ferropenic anemia is common. Many studies have investigated the effects of treating anemia in HF patients with either erythropoietin alone or combination of erythropoietin and intravenous iron. However, the effect of iron supplementation alone in HF patients with ACD, ferropenic anemia, or both is unknown.Methods and ResultsIRON-HF study is a multicenter, investigator initiated, randomized, double-blind, placebo controlled trial that will enroll anemic HF patients with relatively preserved renal function, low transferrin saturation, low iron levels, and low to moderately elevated ferritin levels. Interventions are iron sucrose intravenously 200 mg once per week for 5 weeks, ferrous sulfate 200 mg by mouth 3 times per day for 8 weeks, or placebo. The primary objective is to assess the impact of iron supplementation (intravenously or by mouth) compared with placebo in HF patients with anemia from deficient iron availability. The primary end point is variation of peak oxygen consumption assessed by ergospirometry over 3-month follow-up. Secondary end points include functional class, brain natriuretic peptide levels, quality of life scores, left ventricular ejection fraction, adverse events, HF hospitalization, and death.ConclusionsThe results of IRON-HF should help to clarify the potential clinical impact of mild to moderate anemia correction in HF patients.     

Prevalence and spectrum of iron deficiency in heart failure patients in south Rajasthan

ObjectiveTo estimate the prevalence and pattern of iron deficiency (ID) in heart failure (HF) patients with or without anemia.MethodsThis is a single-center observational study, conducted at a tertiary care hospital of south Rajasthan. Patients admitted to hospital with clinical diagnosis of HF based on validated clinical criteria were included in the study. ID was diagnosed based on complete Iron profile, including serum iron, serum ferritin, total iron binding capacity, and transferrin saturation (TSAT). Anemia was defined as hemoglobin (Hb) <13 g/dl for males and <12 g/dl for females, based on World Health Organization definition. Absolute ID was taken as serum ferritin < 100 μg/L and functional ID was defined as normal serum ferritin (100–300 μg/L) with low TSAT (<20%).ResultsA total of 150 patients of HF (68% males and 32% females) were studied. Most of the patients were of high-functional NYHA class (mean NYHA 2.89 ± 0.95). ID was present in 76% patients with 48.7% patients having absolute and 27.3% patients having functional ID. Females were having significantly higher prevalence of ID than males (91.6% vs 68.6%; p = 0.002). Nearly one-fourth of the patients were having ID but without anemia, signifying importance of workup of ID other than Hb.ConclusionOur study highlights the yet underestimated and neglected burden of ID in HF patients in India. This study suggests further large-scale studies to better characterize this easily treatable condition and considering routine testing in future Indian guidelines.     

L-苏糖酸亚铁治疗缺铁性贫血的多中心随机对照研究

目的了解L-苏糖酸亚铁(FL-T)治疗缺铁性贫血(IDA)的疗效及不良反应。方法采用多中心、随机、双盲、双模拟、阳性药物平行对照试验方法,140例就诊于三所医院的IDA患者,按照入选标准,以随机区组的方法随机分入实验组及对照组,分别予以FL-T胶囊4粒 模拟琥珀酸亚铁2片(A组)、琥珀酸亚铁2片 模拟FL-T胶囊4粒(B组),3次/d,口服,8周为1疗程。治疗前、第4周及结束时测定血清铁、总铁结合力、血清铁蛋白等有关铁参数;每2周随访1次,随访血常规、网织红细胞计数及药物的不良反应。结果两种药治疗8周,IDA的完全缓解率分别为89.06%和85.07%,总有效率分别为98.44%和97.01%,两组间差异无统计学意义。两组用药后Hb不断增长,以8周达到最高值(P<0.01)。两种铁剂治疗后铁参数均出现了有意义的变化(P<0.05),表现为血清铁上升,贮存铁及血清铁蛋白增加,总铁结合力下降。不良反应A组13.85%,B组14.71%,两组差异无统计学意义(P>0.05)。结论FL-T治疗IDA起效快、疗效显著、不良反应轻微且发生率低。     

慢性心力衰竭患者中贫血的患病情况

目的研究慢性心力衰竭(心衰)中贫血的患病情况及贫血与心功能的关系。方法183例慢性心衰患者通过临床、实验室评价和心脏超声心动图检查,参照NYHA分级,心功能Ⅰ~Ⅱ级(轻中度心衰组)86例,Ⅲ~Ⅳ级(重度心衰组)97例。比较2组的左室射血分数、左室舒张末期内径、血液学参数、患贫血率和病死率。结果183例慢性心衰患者中贫血(血红蛋白<120g/L)者43例(24.0%),重度心衰组中贫血患者(30.0%)明显多于轻中度心衰组(16.0%),P<0.05。平均随访17个月,轻中度心衰组死亡4例(5.0%),重度心衰组死亡18例(19.0%),2组相比差异有统计学意义(P<0.01)。贫血患者与非贫血患者相比病死率更高,分别为23.0%和9.0%,P<0.01。结论慢性心衰患者常伴有贫血,贫血的程度与心衰的严重程度有关,贫血使心衰患者死亡的危险性增高。     

The missed opportunities to diagnose and treat iron deficiency in patients hospitalized with heart failure

Introduction

Iron Deficiency (ID) is common in heart failure (HF), and is an independent contributor to mortality and morbidity.We examined whether patients with previously known HF who were recently hospitalized, had previous treatment for ID, were investigated for it at the time of hospitalization, and, if ID was found, were prescribed iron on discharge.

Methods

We examined the records of 76 consecutive patients admitted to our hospital medical wards with a primary diagnosis of HF.

Results

Anemia (Hb < 12 g/dl) was found in 42/76 patients (55.3%). In 55/76 patients (72.4%) there was no iron workup, in 6 (7.9%) an incomplete iron workup with serum iron, transferrin or ferritin lacking and in 15/76 (19.7%) a complete iron workup.If ID was defined as either a serum ferritin of < 100 μg/l or a serum ferritin of 100–299 μg/l and a %Transferrin Saturation of < 20% it was found in 12/15 (80%) of those with a complete workup; in 9 of 10 (90%) of the anemic patients and in 3 of 5 (60%) of those non-anemic patients.At discharge 11/15 (73.3%) of those with a complete iron workup were given iron, 10 orally and 1 IV. In those 6 with an incomplete workup 2 were started on oral iron (33.3%) and in those without any workup, 1 of 55 (1.8%) was given oral iron.

In conclusions

ID is common in hospitalized HF patients but is usually not sought after by physicians at the time of admission. However if detected the physicians usually treated it.     

Effect of intravenous iron replacement on recurrent heart failure hospitalizations and cardiovascular mortality in patients with heart failure and iron deficiency: A Bayesian meta-analysis

Aims

Iron deficiency is common in patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron-deficient HFrEF patients using consistent subgroup definitions across trials.

Methods and results

Individual participant data were used from the FAIR-HF (n = 459), CONFIRM-HF (n = 304) and AFFIRM-AHF (n = 1108) trials. These data were re-analysed following as closely as possible the approach taken in the analyses of IRONMAN (n = 1137), for which study level data were used. Definitions of outcomes and subgroups from the FAIR-HF, CONFIRM-HF and AFFIRM-AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin-Wei-Yang-Ying model, and the data were pooled using Bayesian random-effects meta-analysis. Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR 0.73, 95% credible interval [CI] 0.48–0.99; between-trial heterogeneity tau = 0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR] 1.49 [95% CI 0.95–2.37], age <69.4 vs. ≥69.4 years) (RRR 0.68 [0.40–1.15]), ischaemic versus non-ischaemic aetiology of HF (RRR 0.73 [0.42–1.33]), transferrin saturation <20% vs. ≥20% (RRR 0.75 [0.40–1.34]), estimated glomerular filtration rate ≤60 versus >60 ml/min/1.73 m² (RRR 0.97 [0.56–1.68]), haemoglobin <11.8 versus ≥11.8 (RRR 0.95 [0.53–1.60]), ferritin <35 versus ≥35 μg/L (RRR 1.26 [0.72–2.48]) and New York Heart Association class II versus III/IV (RRR 0.91 [0.54–1.56]).

Conclusions

Treatment of iron-deficient HFrEF patients with intravenous iron – namely with ferric carboxymaltose or ferric derisomaltose – results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present.     

促红细胞生成素联合铁剂辅助治疗慢性充血性心力衰竭合并贫血临床观察

目的:观察在慢性充血性心力衰竭(CHF)合并贫血时,标准治疗基础上加用促红细胞生成素(EPO)联合铁剂的临床疗效。方法:40例CHF合并贫血的患者,随机分为治疗组(20例)和对照组(20例)。对照组给予CHF常规治疗,用血管紧张素转换酶抑制剂(ACEI)或血管紧张素受体拮抗剂(ARB)、洋地黄毒苷、利尿剂、美托洛尔等内科常规治疗,治疗组给予CHF的标准治疗基础上加用EPO及铁剂(EPO 2000IU/次,2～3次∕w,皮下注射至患者血红蛋白浓度在120 g/L稍高水平后,间断给药维持;同时予硫酸亚铁口服,3次∕d),观察并比较2组治疗3个月前后血红蛋白(Hb)、6min步行距离、心功能分级及左心室射血分数(LVEF)。结果:Hb、6min步行距离、心功能分级及LVEF较治疗前差异有统计学意义(P<0.05)。结论:EPO联合铁剂辅助治疗CHF合并贫血患者有效,能改善患者心功能指标,提高患者的生活质量。     

Cardiovascular effects of hemoglobin response in patients receiving epoetin alfa and oral iron in heart failure with a preserved ejection fraction

Background Previous data from a recently conducted prospective, single blind randomized clinical trial among community dwelling older patients with heart failure with a preserved ejection fraction （HFPEF） and anemia randomized to treatment with epoetin alfa （erythro-poiesis-stimulating agents, ESA） vs. placebo did not demonstrate significant benefits of therapy regarding left ventricular （LV） structure, functional capacity, or quality of life （QOL）. However, several patients randomized to the treatment arm were non-responders with a subop-timal increase in hemoglobin. All patients in the trial also received oral ferrous gluconate, which could have contributed to increases in he-moglobin observed in those receiving placebo. Accordingly, we performed an analysis separating patients into responders vs. non-responders in order to determine if measured improvement in anemia would have any effect on clinical endpoints. Methods A total of 56 patients （age 77 ± 11 years, 68%female） were recruited who had anemia defined as a hemoglobin of≤12 g/dL （average, 10.4 ± 1 g/dL） with HFPEF defined as having NHANES-CHF （National Health And Nutrition Examination Survey：Congestive Heart Failure） criteria score of≥3 and an ejection fraction of＆gt;40%（average EF=63%±15%）. Patients were randomly allocated to receive either ESA and ferrous gluconate or ferrous gluconate only. In this analysis, a responder was defined as a patient with an increase of 1 g/dL in the first 4 weeks of the trial. Re-sults Nineteen subjects were classified as responders compared to 33 non-responders. While the average hemoglobin increased signifi-cantly at the end of 6 months for responders （1.8 ± 0.3 vs. 0.8 ± 0.2 g/dL, P = 0.004）, 50% of the subjects assigned to ESA were non-responders. Left ventricular function including ejection fraction （P=0.32） and end diastolic volume （P=0.59） was unchanged in res-ponders compared to non-responders. Responders also showed no significant improvements in New York Heart Association （NYHA） class, Six Minute Walk Test （6 MWT） and peak VO2. Though QOL improved significantly within each group, there was no difference between the two. Conclusions A significant hemoglobin response to anemia treatment with ESA and oral iron does not lead to differences in LV re-modeling, functional status, or QOL. Additionally, a significant percent of older adults with HFPEF and anemia do not respond to ESA ther-apy. Given the results of this small trial, it appears as though using objective improvements in anemia as a marker in older adult subjects with HFPEF does not have significant clinical utility.     

贫血治疗对改善慢性心力衰竭预后的价值

目的:探讨低剂量重组人促红细胞生成素(rhEPO)加铁剂治疗重症慢性充血性心力衰竭合并贫血的临床安全性以及对临床预后的影响。方法:入选慢性心力衰竭纽约心功能分级Ⅲ级以上、左心室射血分数(LVEF)<0.4且血红蛋白<100 g/L的患者共128例,随机分为贫血治疗组(n=66)和对照组(n=62)。随访12个月,记录2组无事件生存时间、主要终点事件(心衰恶化住院、心衰死亡)、次要终点事件(非心衰死亡、猝死、心肌梗死、不稳定性心绞痛、卒中、动脉栓塞、药物不良反应导致停药)。比较两组存活患者治疗前后的LVEF、左心室室壁应力(MWS)、左心室质量指数(LVMI)以及肿瘤坏死因子-α(TNF-α)、高敏C反应蛋白(hsCRP)和B型利钠肽(BNP)水平。结果:与对照组比较,治疗组无事件生存时间延长,但心衰死亡和心衰恶化住院率无显著性差异;非心衰心血管事件治疗组未增加。治疗组MWS和LVMI在治疗后显著降低,与对照组差异显著,而LVEF、BNP、TNF-α以及hsCRP水平两组无差异。结论:低剂量rhEPO加用铁剂治疗可安全用于重症充血性心力衰竭合并贫血患者,能延长生存时间和改善左心室功能,但不降低心衰病死率和心衰恶化入院率。     

Intravenous iron in patients with heart failure and iron deficiency: an updated meta-analysis

Aims

For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta-analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF.

Methods and results

We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all-cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval [CI] 0.61–0.93; p < 0.01) and first HHF or CVD (odds ratio [OR] 0.72, 95% CI 0.53–0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70–1.05; p = 0.14) and all-cause mortality (OR 0.93, 95% CI 0.78–1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow-up, which was less disrupted by the COVID-19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49–0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74–1.30) (heterogeneity p = 0.07).

Conclusion

In patients with HF and ID, this meta-analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all-cause mortality remains inconclusive.     

Association of renal tubular damage with cardio-renal anemia syndrome in patients with heart failure

Background

Cardio-renal anemia syndrome (CRAS) has begun to gather attention as a vicious circle since chronic heart failure (CHF), chronic kidney disease (CKD), and anemia are all able to be caused and exacerbated by each other. However, it remains unclear whether renal tubular damage (RTD), another type of kidney dysfunction, is associated with this vicious circle. The aim of the present study was to assess the association of RTD with CRAS in patients with CHF.

Methods and results

We included 300 consecutive patients with CHF. RTD was defined as a urinary β₂-microglobulin to creatinine ratio ≥ 300 μg/g. Patients with RTD had lower serum iron and higher levels of high sensitivity C-reactive protein than those without it. Multivariate logistic analysis showed that RTD was closely associated with anemia in patients with CHF, after adjustment for confounding factors. During a median period of 1098 days, there were 86 cardiac events, including 14 cardiac deaths and 72 re-hospitalizations for worsening heart failure. Net reclassification improvement was significantly improved by addition of RTD to the model including age, New York Heart Association functional class, brain natriuretic peptide, anemia, and CKD. All patients were divided into 3 groups: CRAS + RTD group, CRAS group, and control group. Kaplan–Meier analysis demonstrated that CRAS + RTD had the greatest risk in patients with CHF.

Conclusions

RTD was associated with normocytic anemia, accompanying iron deficiency and inflammation. RTD added prognostic information to conventional CRAS, suggesting the importance of RTD in cardio-renal anemia interaction.     

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health‐related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two‐day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run‐in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.     

Pilates in heart failure patients: a randomized controlled pilot trial

Background: Conventional cardiac rehabilitation program consist of 15 min of warm-up, 30 min of aerobic exercise and followed by 15 min calisthenics exercise. The Pilates method has been increasingly applied for its therapeutic benefits, however little scientific evidence supports or rebukes its use as a treatment in patients with heart failure (HF). Purpose: Investigate the effects of Pilates on exercise capacity variables in HF. Methods: Sixteen pts with HF, left ventricular ejection fraction 27 ± 14%, NYHA class I-II were randomly assigned to conventional cardiac rehabilitation program (n = 8) or mat Pilates training (n = 8) for 16 weeks of 30 min of aerobic exercise followed by 20 min of the specific program. Results: At 16 weeks, pts in the mat Pilates group and conventional group showed significantly increase on exercise time 11.9 ± 2.5 to 17.8 ± 4 and 11.7 ± 3.9 to 14.2 ± 4 min, respectively. However, only the Pilates group increased significantly the ventilation (from 56 ± 20 to 69 ± 17 L/min, P= 0.02), peak VO(2) (from 20.9 ± 6 to 24.8 ± 6 mL/kg/min, P= 0.01), and O(2) pulse (from 11.9 ± 2 to 13.8 ± 3 mL/bpm, P= 0.003). The Pilates group showed significantly increase in peak VO(2) when compared with conventional group (24.8 ± 6 vs. 18.3 ± 4, P= 0.02). Conclusions: The result suggests that the Pilates method may be a beneficial adjunctive treatment that enhances functional capacity in patients with HF who are already receiving standard medical therapy.