Effect of intravenous ferric carboxymaltose on exercise capacity in symptomatic patients with heart failure and a preserved ejection fraction with iron deficiency with and without anaemia

Abstract

The invention relates to an iron carbohydrate complex for use in the treatment of a patient suffering from heart failure (HF) with preserved ejection fraction (HFpEF), wherein the iron carbohydrate complex is selected from the group of ferric carboxymaltose, iron isomaltoside 1000, iron derisomaltose and ferumoxytoL The administration of the iron carbohydrate complex improves the clinical health status of the patient comprising the exercise capacity, reduced aerobic capacity, and / or reduced endurance of the patient, wherein the exercise capacity of the patient is measured as a 6-minute walk test distance (6MWTD) compared to the patient's exercise capacity prior to initiation of treatment with the iron complex.

Description

[0001] Effect of intravenous ferric carboxymaltose on exercise capacity in symptomatic patients with heart failure and a preserved ejection fraction with iron deficiency with and without anaemia Iron deficiency affects approximately half of all patients with heart failure. Its presence is linked to diminished quality of life, decreased exercise capacity, and elevated rates of hospitalization and mortality. Clinical effects of treating iron deficiency in patients with heart failure with preserved ejection fraction (HFpEF) have not been studied in prospective trials so far. In chronic heart failure (HF), iron deficiency (ID) is prevalent in up to 50% of all patients, with even higher rates during cardiac decompensation.1,2,3As a very frequent comorbidity in HF, ID has garnered significant research attention in recent years. This has led to the conduct of several large- scale trials,4–6such as FAIR-HF4, AFFIRM-AHF5and IRONMAN6reinforcing that correcting ID improves quality of life (QoL), enhances exercise capacity, and reduces HF hospitalization rates in patients with HF with reduced ejection fraction (HFrEF) or mildly reduced ejection fraction (HFmrEF), leading to guideline recommendations for the use of ferric carboxymaltose (FCM) and ferric derisomaltose exclusively in these populations.7,8Despite guidelines from the European Society of Cardiology (ESC)7and joint guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Failure Society of America (HFSA)8advocating for ID screening in all patients with HF, a treatment gap persists for patients with HF with preserved ejection fraction (HFpEF), and it has thus not been demonstrated whether recommended diagnostic criteria apply in this cohort of patients. This point is important, because besides the use of diuretics and the recently introduced successful treatment with sodium–glucose co-transporter 2 (SGLT2) inhibitors,9the treatment of comorbidities such as coronary artery disease, atrial fibrillation (AF), arterial hypertension, chronic ob-structive pulmonary disease, or obesity remains the mainstay of therapy in HFpEF.10,11With guideline-recommended threshold values for detecting ID in patients with HF set at serum ferritin < 100 ng / mL or serum ferritin 100–299 ng / mL with transferrin saturation (TSAT) < 20%, recent meta-analysis data from 15 studiessuggest that the prevalence of ID in patients with HFpEF reaches 59%.12 Taking into account boththe symptomatic burden experienced by patients and these prevalence statistics, the multi-center, double-blind, randomized FAIR-HFpEF trial was designed to evaluate the effectiveness of FCM in patients with HFpEF and ID on exercise capacity as assessed by the 6-minute walking test distance (6MWTD). Background of the inventionHeart failure (HF) affects millions of patients worldwide and is a major cause of death in the elderly.1,2Comorbidies are numerous and have relevant impact on symptoms, quality of life and outcomes. Iron deficiency affects approximately half of all patients with heart failure. Its presence is linked to diminished quality of life, decreased exercise capacity, and elevated rates of hospitalization and mortality. Clinical effects of treating iron deficiency in patients with heart failure with preserved ejection fraction (HFpEF) have not been studied in prospective trials so far. Following the large FAIR-HF and ConFIR-HF trials, the European Society of cardiology (ESC) and other international bodies recommend the treatment of iron deficiency (ID) intravenously using ferric carboxymaltose (FCM) in symptomatic patients with HF with reduced ejection fraction (HFrEF) and ID (defined as serum ferrin <100 ng / mL or serum ferrin 100-299 ng / mL with transferrin saturation (TSAT) < 20%) to alleviate HF symptoms, improve exercise ca­pacity and quality of life. Most recent evidence for this group of patients has been added by publication of the IRONMAN trial in late 2022 using ferric derisomaltose in patients with HFrEF and ID. The AFIRM-AHF trial has helped to extend recommendation for the use of FCM to symptomatic HF patients recently hospitalized for worsening HF with either reduced or mildly reduced ejection fraction (HFmrEF) with left ventricular ejection fraction (LVEF) 50% and ID. Altogether, treatment of ID using FCM has been deemed safe and cost-effective.6ESC and the joint guideline of the American Heart and the Heart failure Association of America recommend to diagnose ID using the aforementioned cut­off values for ferritin and TSAT in all patients with HF across the entire spectrum of LVEF.2,7Apart from high prevalence values of ID in patients with HFrEF and HFmrEF, several analyses have shown similar trends for patients with HF with preserved ejection fraction (HFpEF). A recent meta­analysis of 15 studies has shown an ID prevalence of 59% among these patients.8The presence of ID in patients with HFpEF leads to reduced exercise capacity as evidenced by a lower peak oxygen consumption during exercise, by reduced 6­minute walk test distance (6MWTD), reduced health­related quality of life, or reduced functional status as determined by dyspnea class.9In this meta­analysis, the authors failed to detect an impact of ID on death or hospitalization rates.8No clinical trial has validated the applicability of the ESC criteria of ID so far in patients with HFpEF using intravenous iron. Heart Failure Heart failure (HF) is a complex clinical syndrome that results from a structural or functional impairment of contraction or filling of the heart. It is a very common condition: 1–3% of the adult population has HF, and the prevalence rises with age (Dunlay et al., 2017). The chief symptoms of HF are exercise intolerance and dyspnea on exertion. Fatigue, peripheral edema, orthopnea, paroxysmal nocturnal dyspnea, loss of appetite, and nycturia are other possible signs and symptoms. Current guidelines divide HF patients according to left ventricular (LV) ejection fraction (defined as LV stroke volume over LV end-diastolic volume) (Yancy et al., 2013; Ponikowski et al., 2016). Signs and symptoms are equal in those with reduced and preserved ejection fraction, but there are differences in pathophysiology and treatment. Patients with HF and reduced ejection fraction (HFrEF) have a prominent LV contraction problem. Fatigue and exercise intolerance are directly caused by the reduced systolic function as the low cardiac output is insufficient to meet the body’s demands. Congestion is also directly caused by the reduced contractility: blood accumulating in the LV causes end-diastolic pressure to rise. This higher pressure is transferred to the pulmonary, portal, and peripheral circulation, where extravasation of fluid causes lung, splanchnic, and peripheral edema. HF is a heterogeneous condition and is categorised into three groups based on ejection fraction (EF): 1. those with HF and a reduced EF (HFrEF where left ventricular EF [LVEF] is <40%) 2. those with HF and a mid-range EF (HFmrEF where LVEF is 40–50%) 3. those with HF and a preserved or normal EF (HFpEF where LVEF is ≥50%). Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide. It is the commonest cause of hospitalisation in individuals above the age of 65 years and contributes to one in nine deaths. Patients with this diagnosis have a reduction in both quality of life and life expectancy (50% of patients with the diagnosis are not expected to survive more than 5 years).2Actually, there are limited treatment options available to either improve survival or reduce HF hospitalisations for patients with HF and a preserved EF. In patients with HF and preserved ejection fraction (HFpEF), LV ejection fraction is normal, although contractile dysfunction is often present and only detected with advanced imaging techniques. End-diastolic pressure elevation and congestion are as severe as in HFrEF (Van Aelst et al., 2018). In HFpEF, the rise in end-diastolic pressure is caused by a complex interplay between diastolic dysfunction, subtle systolic dysfunction, atrial and LV stiffness, and reduced arterial compliance. The LV, the left atrium, the aorta, and peripheral arteries all participate (Borlaug, 2014). HF symptoms are more subtle in HFpEF than in HFrEF and often only present on exertion, a fact that often delays diagnosis. Prognosis is, however, equally grim as in HFrEF: 5-year mortality is around 75%, which is worse than most cancers (Shah et al., 2017). Neurohumoral drugs, device therapy, and cardiac rehabilitation have improved survival rates in HFrEF, but not a single treatment has been able to consistently improve prognosis in HFpEF. Guidelines currently advise to treat symptoms with diuretics, and to control comorbidities such as hypertension and diabetes tightly (Yancy et al., 2013; Ponikowski et al., 2016). In HFrEF (also called systolic HF), global LV systolic dysfunction predominates. The LV contracts poorly and empties inadequately, leading to an increased diastolic volume and pressure and a decreased ejection fraction (≤ 40%). Many defects in energy utilization, energy supply, electrophysiologic functions, and contractile element interaction occur, with abnormalities in intracellular calcium modulation and cAMP production. Predominant systolic dysfunction is common in heat failure due to myocardial infarction, myocarditis, and dilated cardiomyopathy. Systolic dysfunction may affect primarily the LV or the right ventricle (RV); LV failure often leads to RV failure. In HFpEF (also called diastolic heart failure), LV filling is impaired, resulting in an increased LV end-diastolic pressure at rest or during exertion and usually, normal LV end-diastolic volume. The global contractility and hence ejection fraction remain normal (≥ 50%). However, in some patients, marked restriction to LV filling can cause inappropriately low LV end- diastolic volume and thus cause low CO (cardiac output) and systemic symptoms. Elevated left atrial pressures can cause pulmonary hypertension and pulmonary congestion. Diastolic dysfunction usually results from impaired ventricular relaxation (an active process), increased ventricular stiffness, valvular disease, or constrictive pericarditis. Acute myocardial ischemia is also a cause of diastolic dysfunction. Resistance to filling increases with age, reflecting both cardiomyocyte dysfunction and cardiomyocyte loss, and increased interstitial collagen deposition; thus, diastolic dysfunction is particularly common among older adults. Diastolic dysfunction predominates in hypertrophic cardiomyopathy, other disorders with ventricular hypertrophy (eg, hypertension, significant aortic stenosis), and amyloid infiltration of the myocardium. LV filling and function may also be impaired if marked increases in RV pressure shift the interventricular septum to the left. Diastolic dysfunction has increasingly been recognized as a cause of HF. Estimates vary, but about 50% of patients with heart failure have HFpEF; the prevalence increases with age and in patients with diabetes. It is now known that HFpEF is a complex, heterogenous, multiorgan, systemic syndrome, often with multiple concomitant pathophysiologies. Current data suggest that multiple comorbidities (eg, obesity, hypertension, diabetes, chronic kidney disease) lead to systemic inflammation, widespread endothelial dysfunction, cardiac microvascular dysfunction, and, ultimately, molecular changes in the heart that cause increased myocardial fibrosis and ventricular stiffening. Thus, although HFrEF is typically associated with primary myocardial injury, HFpEF may be associated with secondary myocardial injury due to abnormalities in the periphery. At a cellular level, cardiac myocytes in patients with HFpEF are thicker and shorter than normal myocytes, and collagen content is increased. Histologic studies have shown reductions in myocardial capillary density that may contribute. At the organ level, affected individuals may have concentric remodeling with or without hypertrophy, although many people have normal ventricular geometry. Increases in myocyte stiffness are mediated in part by relative hypophosphorylation of the sarcomeric molecule titin, due to cyclic guanosine monophosphate (cGMP) deficiency thought to arise primarily as a consequence of increased nitroso-oxidative stress induced by comorbid conditions such as obesity, metabolic syndrome and aging. Cellular and tissue characteristics may become more pronounced as the disease progresses. Treatment of HFpEF With regard to the treatment of HFpEF, there are no disease-modifying therapies for HFpEF or HFmrEF that improve outcomes compared to HFrEF agents. Efficacious therapies for HFrEF have failed to demonstrate a benefit for HFpEF, and more research is required to evaluate them in HFmrEF.[1] Spironolactone has been shown to reduce HF hospitalization rates in HFpEF, but no treatment has demonstrated improved survival. Treatment focuses on controlling BP using beta-blockers, ACEi or ARBs is reasonable to control BP in patients with HFpEF (class IIA), diuretics to relieve symptoms of volume overload, and to address the risk factors and comorbidities. There are no studies to determine the impact of revascularization on symptoms or outcomes, specifically in patients with HFpEF. Iron deficiency in HF Iron deficiency (ID) impairs the body’s ability to produce hemoglobin, the key oxygen transporter, and impairs the function of key energy (ATP) producing enzymes. Symptoms consequently include fatigue and other signs of energy deprivation such as rapid heartbeat, shortness of breath, and chest pain. ID has serious consequences. In chronic heart failure (CHF) patients, the risk of death or hospitalization has been reported to be increased in patients with ID relative to patients with normal iron status. Quality of life (QoL) is severely affected and improves rapidly upon restoration of iron stores. The gathered experimental and clinical evidence provided the basis to consider ID as a potential therapeutic target in patients with chronic heart failure (chronic HF). Indeed, in recent years, several studies have investigated the effects of intravenous iron therapy in iron- deficient patients with chronic HF, including the FAIR-HF trial (ferric carboxymaltose assessment in patients with iron deficiency and chronic heart failure; see also Anker et al., 2009) and the CONFIRM-HF trial (ferric carboxymaltose evaluation on performance in patients with iron deficiency in combination with chronic heart failure; see also Ponikowski et al., 2015) encompassing > 450 and > 300 patients, respectively. Based on an aggregate data meta- analysis of five randomized controlled trials that evaluated the effects of intravenous iron therapy (using iron sucrose or ferric carboxymaltose) in iron-deficient patients with systolic HF (HFrEF), Jankowska et al., 2016 state that there is evidence that indicates that intravenous iron therapy in iron-deficient patients with systolic HF improves outcomes, alleviates HF symptoms, improves exercise capacity and quality of life, and reduces the risk of HF hospitalization. However, the number of deaths and the incidence of adverse events (AE) were similar in the five studies meta- analyzed. Since none of the intravenous iron trials in the beginning were powered to test for an effect on major cardiovascular outcomes, the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure therefore conclude that the effect of treating iron deficiency in HFpEF / HFmrEF is unknown. Based on the findings from FAIR-HF and CONFIRM-HF, the European Society of Cardiology (ESC) guidelines recommend that intravenous ferric carboxymaltose should be considered in patients with iron deficiency (serum ferritin < 100 pg / L, or ferritin between 100-299 pg / L and transferrin saturation < 20%) in order to alleviate HF symptoms, and improve exercise capacity and quality of life. Ponikowski et al., 2016. Likewise, the American College of Cardiology (ACC), the American Heart Association (AHA) Task Force on Clinical Practice Guidelines and the Heart Failure Society of America (HSFA) recommend that in patients with New York Heart Association (NYHA) class II and III HF and iron deficiency (ferritin < 100 ng / mL or 100 to 300 ng / mL if transferrin saturation is < 20%), intravenous iron replacement might be reasonable to improve functional status and QoL. (Yancy et al., 2017). However, there is no mention or recommendation in this Guidelines for patients with HFpEF for providing methods of treating iron deficiency that provide benefit to patients with HFpEF (“2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure”, developed by the task force for the diagnosis and treatment of acute and chronis heart failure of the ESC and contribution of the Heart failure Association of the ESC). Hence, patients with HFpEF need a different approach to management than patients with HFrEF. Summary of the Invention In light of the prior art the technical problem underlying the present invention is to provide alternative and / or improved means for the treatment of patients suffering from heart failure (HF) with preserved rejection fraction (HFpEF). The technical problem may also be viewed as the provision of alternative and / or improved means for the prevention and / or treatment of comorbidities occurring with HFpEF. This problem is solved by the features of the independent claims. Preferred embodiments of the present invention are provided by the dependent claims.Subject-matter of the present invention relates to an iron carbohydrate complex for usein the treatment of a patient suffering from heart failure (HF) with preserved rejection fraction (HFpEF) or in a patient being at risk of developing heart failure. The diagnosis of HF is based on clinical signs and symptoms, laboratory workup, and echocardiogram. In order to evaluate patients with HFpEF, one or more of the following tests and examinations are necessary: • Complete blood count to rule out anemia as a possible cause of patients' symptoms. Besides, anemia is associated with higher HF severity, and intravenous iron replacement is important to improve functional status and quality of life if ferritin is under 100 ng / ml or 100 to 300 ng / ml if transferrin saturation is below 20%. • Determination of serum electrolytes (including calcium and magnesium levels) and kidney functions (blood urea nitrogen and serum creatinine): serum creatinine and blood urea are prognostic factors in hospitalized patients with HF, and hyponatremia plays a prognostic factor role in chronic patients with HF. Besides, some HF medications can cause electrolyte abnormalities and kidney dysfunction (like spironolactone, angiotensin- converting enzyme inhibitor (ACEi), and furosemide). • Measurement of B-type Natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) is helpful to support the clinical diagnosis of HF in the ambulatory setting and to support the diagnosis of acutely decompensated HF in hospitalized / ER patients. Measurement of natriuretic peptides (NPs) like BNP / NT-proBNP is also helpful in supporting the diagnosis in ambulatory and inpatient settings. BNP has 70% sensitivity and 99% specificity for HF diagnosis, and NT-proBNP has 99% sensitivity and 85% specificity. • Other laboratory workups include glucose, fasting lipid profile, liver function tests, and thyroid-stimulating hormone. • EKG is necessary for all patients with suspected HF, and it helps rule out HF if completely normal, with a sensitivity of 89% but low specificity.

[0022] Abnormal EKG increases the likelihood of HF diagnosis. It also can provide information on etiology (e.g., history of previous myocardial infarction makes CAD a possible cause of HF, arrhythmia as a potential cause of tachycardia-mediated cardiomyopathy HF, LV hypertrophy indicates hypertension-induced HF, widened QRS complex / left bundle branch block may suggest idiopathic dilated cardiomyopathy, and heart blocks as seen in patients with cardiac sarcoidosis) and provide indications for therapy (anticoagulation if atrial fibrillation, pacemaker in some bradycardia, and cardiac resynchronization therapy (CRT) if broadened QRS). • Chest X-ray is also useful and may show pleural effusions secondary to volume overload, cardiomegaly, and Kerley B-lines (interstitial edema). • Transthoracic echocardiogram (TTE) is the most useful test that helps establish the diagnosis of HF and classify it as HFrEF, HFmrEF, or HFpEF. Abnormal parameters in HFrEF that can be measured by echocardiogram include increased end-diastolic diameter and volume (LV diameter over 60 mm or 32 mm / m with LV volume exceeding 97 mL / m) and end-systolic diameter and volume (LV diameter greater than 45 mm or 25 mm / m with LV volume over 43 mL / m). Echocardiogram also helps to assess LVEF in HFrEF to guide evidence-based medical and device therapies (implantable cardioverter- defibrillator (ICD) and CRT), evaluate the valves, provide information on ventricular wall thickness, and it is vital in the risk stratification of patients with HF. • Genetic testing: some CMP can be genetic, especially DCM, HCM, and autosomal dominant ARVD / C, and screening the family members may be important in family-based management. • Computed tomography (CT) scanning or cardiac magnetic resonance imaging (cMR): neither are routinely indicated in the diagnosis and management of HF, and the role of imaging modalities other than TTE was restricted in the 2106 ESC guidelines. Cardiac CT can help to evaluate the coronary arteries in patients with HF with low to intermediate pretest probability of CAD. They provide information about cardiac function and have a high anatomical resolution of all aspects of the heart and surrounding structures (ventricular mass, chamber size, heart valves, and pericardium and wall motion). • Cardiac MRI assesses LV volume, LVEF, myocardial perfusion, viability, and fibrosis and helps identify HF etiology (ischemic versus non-ischemic disease, infiltrative disease, and hypertrophic disease) and assess prognosis. CMR can determine viability, help the success of revascularization in patients with low EF, and is the gold standard for evaluating RV function. However, cMR is costly and cannot be performed with implantable defibrillators all the time (some of the defibrillators as MRI-compatible these days). Also, both cardiac CT and cMR have low accuracy in patients with high heart rates. • Left heart catheterization or coronary angiography is indicated in patients with HF and angina symptoms or ischemic changes by ECG or noninvasive testing. Indications also include worsening HF symptoms without a clear cause, when the pretest probability of underlying ICMP is high, before cardiac transplantation or LVAD, and in post-infarction mechanical complications like a ventricular aneurysm. It may be useful in patients with HF without angina but with LV dysfunction. In patients without CAD, CAD should be considered as a potential etiology of HF and impaired LV function and should be excluded whenever possible. It is only necessary if patients are potentially eligible for revascularization. • Nuclear imaging or echocardiography may be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina unless they are ineligible for revascularization. In a preferred embodiment, the iron carbohydrate complex is selected from the group comprising iron monosaccharide, iron disaccharide or iron polysaccharide, such as iron carboxymaltose complex, iron mannitol complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, an iron polyglucose sorbitol carboxymethyl ether complex, or an iron hydrogenated dextran complex. In another preferred embodiment, the iron carbohydrate complex is selected from the group of ferric carboxymaltose, iron isomaltoside 1000, iron derisomaltose and ferumoxytol. In a preferred embodiment, the iron carbohydrate complex is ferric carboxymaltose. Another embodiment of the present invention relates to the iron carbohydrate complex for use in the treatment of a patient suffering from heart failure with preserved rejection fraction (HFpEF) and iron deficiency (ID). In one embodiment of the present invention the patient is suffering from heart failure with preserved rejection fraction and aneamia or the patient being anaemic and at risk of developing heart failure. In another embodiment of the present invention, the patient is suffering from heart failure with preserved rejection fraction and aneamia. In embodiments of the present invention, the heart failure is either chronic or acute heart failure. In one embodiment of the present invention, the heart failure is diastolic. In another embodiment, the preserved ejection fraction is characterized by high left ventricular (LV) filling pressure and a LV ejection fraction which is equal or above 50%, as measured by echocardiographic or magnetic resonance imaging. In another embodiment the patient is also administered at least one standard of care HF agent. In the context of the present application, standard of care HF agents are selected from the groupcomprising Angiotensin-converting enzyme (ACE) inhibitors, Angiotensin II receptor blockers(ARBs), Angiotensin receptor plus neprilysin inhibitors (ARNIs), Beta blockers and / or diuretics.In another embodiment of the present invention said use of the iron carbohydrate complex further improves heart failure symptoms. In another preferred embodiment of the invention, the improvement in heart failure symptoms and / or quality of life is measured by a patient's higher score on the KCCQ Overall Summary Score (OSS) compared to the patient's score prior to initiation of treatment with a therapeutically effective amount of an iron carbohydrate complex. In another embodiment of the invention, the higher score on the KCCQ OSS is at least 5 points higher than the score prior to administration with a therapeutically effective amount of an iron carbohydrate complex. In one embodiment of the invention the higher score on the KCCQ OSS is at least 10 points higher than the score prior to administration with a therapeutically effective amount of iron carbohydrate complex. In another embodiment of the invention, the higher score on the KCCQ OSS is at least 15 points higher than the score prior to administration with therapeutically effective amount of iron carbohydrate complex. In another preferred embodiment of the invention, the improvement in heart failure symptoms is measured by a patient's lower deterioration in score on the KCCQ OSS relative to an administration regimen where the patient receives at least one standard of care HF agent alone. In another preferred embodiment of the invention, the patient is 18 years or older, wherein the patient does exhibit any one of the following criteria selected from the group comprising of chronic HFpEF, reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, New York Heart Association functional class II-III symptoms, receiving treatment with a diuretic, raised natriuretic peptide levels (BNP ≥35 pg / mL or NT­proBNP level ≥125 pg / mL) or a history of hospitalization with a diagnosis of HF within 12 months prior to the beginning of treatment with the iron complex, an LVEF ≥45% as measured by echocardiographic or magnetic resonance imaging within 6 months prior to treatment with the iron complex, wherein the reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, at baseline is measured as a 6- minute walk test distance (6MWTD), after an assessment of medical history, a physical examination and an electrocardiogram reading of the patient. In another embodiment of the invention, the patient is 18 years or older, wherein the patient does exhibit any one of the following criteria selected from the group comprising of chronic HF with LVEF ≥45% as measured by echocardiographic or magnetic resonance imaging within 6 months prior to treatment, stable ambulatory (≥ 7 days) with NYHA II / III class II­III symptoms, receiving treatment with a diuretic, raised natriuretic peptide levels (BNP >100 pg / mL or NT-proBNP level >300 pg / mL if in sinus rhythm; BNP >200 pg / mL or NT-proBNP level > 600 pg / mL if in AF), a history of hospitalization with a diagnosis of HF within 12 months prior to the beginning of treatment with the iron complex, a 6-minute walk test distance (6MWTD) of less than 450 m, Haemoglobin level > 9.0 and ≤14.0 g / dL and a presence of an iron deficiency (ferritin < 100 ng / mL or serum ferritin < 300 ng / mL and TSAT < 20 %). In other embodiments, the overall doses of the iron carbohydrate complex per patient vary between 1000 mg to 5000 mg per year, preferably 1500 mg to 3000 mg per year, more preferably 1000 mg to 2000 mg per year, most preferably 500 mg to 1500 mg per year, depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured. In another embodiment of the invention, initial doses of the iron carbohydrate complex for correcting the ID vary between 500 mg and 2000 mg provided in up to 2 administration sessions which are 7-14 days apart, and dosed depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured. In another embodiment of the present invention, the iron carbohydrate complex is administered intravenously. In another preferred embodiment of the invention, initial doses of the iron carbohydrate complex for correcting the ID are administered in in 1-2 sessions (baseline), which is followed by an additional repeat dose applications after year 1 every 3-6 months, and after 16±1 weeks, 24±1 weeks and 32±2 weeks, and where treatment in the second and subsequent years is repeated as in year 1 as long as a treatment need is diagnosed. In one embodiment of the invention, administration of the iron carbohydrate complex is repeated for as long as heart failure with iron deficiency persists. In preferred embodiments, the administration occurs on the first day of treatment (baseline) and after 24 hours and after 5-11 days and after 16±1 week and after 24±1 week and after 32±2 weeks and after 52±2 weeks. In another embodiment of the invention, the treatment need of the patient is considered present, when iron deficiency is still present in year 2 and subsequent years. In a further embodiment of the invention, administration of the iron carbohydrate complex is repeated for as long as heart failure with iron deficiency or a risk of developing heart failure persists. In another embodiment of the invention, the patient is suffering from at least one of the diseases selected from the group comprising obesity, cachexia, sarcopenia, frailty, COPD, atrial fibrillation, diabetes, and / or stroke. In another preferred embodiment of the invention, the patient is suffering from obesity. In another embodiment of the invention, the patient is suffering from sarcopenia. In another embodiment of the invention, the patient is suffering from COPD. In another embodiment of the invention, the patient is suffering from cachexia. In another embodiment of the invention, the patient is suffering from diabetes. In another embodiment of the invention, the patient is suffering from frailty. In another embodiment of the invention, the patient is suffering from stroke. In one embodiment of the invention, the patient is suffering from atrial fibrillation. In another preferred embodiment of the invention, the patient is suffering from anaemia. In one embodiment of the invention, the patient is suffering from at least one of the diseases selected from the group comprising obesity, cachexia, sarcopenia, frailty, COPD, atrial fibrillation, diabetes, and / or stroke, wherein the patient is not suffering from HF or HFpEF. In another preferred embodiment of the invention, the patient is suffering from obesity, wherein the patient is not suffering from HF or HFpEF. In another embodiment of the invention, the patient is suffering from sarcopenia, wherein the patient is not suffering from HF or HFpEF. In another embodiment of the invention, the patient is suffering from COPD, wherein the patient is not suffering from HF or HFpEF. In another embodiment of the invention, the patient is suffering from cachexia, wherein the patient is not suffering from HF or HFpEF. In another embodiment of the invention, the patient is suffering from diabetes, wherein the patient is not suffering from HF or HFpEF. In another embodiment of the invention, the patient is suffering from frailty, wherein the patient is not suffering from HF or HFpEF. In one embodiment of the invention, the patient is suffering from atrial fibrillation, wherein the patient is not suffering from HF or HFpEF. In one embodiment of the invention, the patient is suffering from stroke, wherein the patient is not suffering from HF or HFpEF. In another preferred embodiment of the invention, the patient is suffering from anaemia, wherein the patient is not suffering from HF or HFpEF. Anemia is usually not a disease in its own right, but a symptom of multifactorial genesis that can be observed across all medical disciplines. Specifically, anemia is defined as a reduced hemoglobin (Hb) concentration in the blood or a reduced hematocrit (Hk). According to the definition of the World Health Organization (WHO), anemia is present when the hemoglobin concentration (Hb value) falls below 13 g / dl (8.07 mmol / l) in men and 12 g / dl (7.45 mmol / l) in women. In up to 80 % of cases, iron deficiency is the cause of anemia. It is estimated that around 600 million people worldwide suffer from iron deficiency. In Europe, the prevalence is 5-10%, in women of childbearing age around 20%. Anemia can have serious consequences for oncology and cardiology patients (especially those with heart failure), but also for patients undergoing surgery or interventions. It must be clarified aetiologically and, ideally, a treatment should be attempted. Anemia should be corrected on the basis of an evidence-based, multimodal patient blood management (PBM) concept, which is based on a rational indication for the choice of therapy in line with the guidelines. Iron deficiency without anaemia is also common. Patients may present with unexplained, non- specific symptoms. Iron studies will usually show a low ferritin and / or low transferrin saturation with a normal haemoglobin concentration. The cause of the iron deficiency of the patient should be identified and managed. A further embodiment of the present invention relates to the iron carbohydrate complex for use in the treatment of a patient suffering from heart failure with preserved rejection fraction (HFpEF) and anaemia or the patient being is anaemic and at risk of developing heart failure. In the context of the invention, the patient may or may not have anemia. In embodiments of the invention, the patient has one or more comorbidities. The term “comorbidity” in the context of the present invention refers to any further pathology or disease of the patient of the invention that may be present in addition to a suspected infection or sepsis. Such comorbidities may comprise, without limitation, cardiovascular disease, atrial fibrillation, flutter, congestive heart failure, COPD, asthma, lung fibrosis, metabolic disorder (obesity), diabetes, renal disease, hypertension, stroke, transient ischemic attack (TIA), dementia, anemia, thrombosis. In preferred embodiments, the one or more comorbidities is / are selected from the group comprising cachexia, sarcopenia, frailty, COPD, coronary artery disease, valvular heart disease, chronic kidney disease, hypertension, atrial fibrillation, obesity, diabetes and / or stroke. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and obesity. In the context of the present invention and according to the WHO, overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. Adults are classified as obese when their body mass index(BMI)—a person's weight divided by the square of the person's height—is over 30 / m2; the range 25–30 kg / m2is defined as overweight. The U.S. Centers for Disease Control and Prevention (CDC) further subdivides obesity based on BMI: A BMI 30 to 34.9 is called class 1 obesity; a BMI 35 to 39.9 as class 2 obesity; and a BMI equal and larger than 40, class 3 obesity. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and obesity, but the patient is not suffering from heart failure with reduced rejection fraction (HFrEF) or with mildly reduced ejection fraction (HFmEF). In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and COPD. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and Diabetes mellitus. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and coronary artery disease. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and ischemic aetiology. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and non-ischemic aetiology. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and atrial fibrillation. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and patients are classified as NYHA III. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and Cachexia / Sarcopenia. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and obesity (BMI < 25) and Cachexia / Sarcopenia. In another preferred embodiment, the patient is suffering from heart failure (HF) with preserved rejection fraction (HFpEF) and Cachexia / Sarcopenia and patients are classified as NYHA III. In other embodiments of the present invention, the iron deficiency is defined as either a serum ferritin level below 100 ng / mL or the serum ferritin level is between 100-299 ng / mL with transferrin saturation [TSAT] below 20%. In embodiments, the administration of the iron complex improves the clinical health status of the patient comprising the exercise capacity, reduced aerobic capacity, and / or reduced endurance, of the patient which is measured by 6min-walking test distance, symptoms of heart failure which is classified by NYHA functional class, cardiac function which is determined by measuring cardiac biomarker (NT-BNP) levels and comparison to baseline, inflammatory status by measuring inflammatory biomarker levels (CRP, PCT) and quality of life by determining KCCQ OSS . The inventors have surprisingly found that patients treated with FCM significantly increased the walking distance in the 6min-walking test, which even improved with longer treatment periods. The skilled person in the art could not have been expected such strong improvements for the HFpEF patients being treated with FCM. Statistical significance levels reported herein may not necessarily correlate directly with the clinical efficacy of the treatment. Non-significant results can have clinical relevance and contribute to patient improvements as disclosed herein. Therefore, the determination of a significance level is also to be considered independently from the clinical relevance, clinical efficacy and effectiveness of the treatment. This understanding allows for a more nuanced interpretation of data, recognizing that even outcomes not meeting thresholds of significance, known by the skilled person in the art, can have meaningful impacts on patient care and therapeutic advancements. In the context of the present application, the Kansas City Cardiomyopathy Questionnaire (KCCQ) in heart failure has been qualified by the U.S. Food and Drug Administration as a Clinical Outcome Assessment and recommended as a performance measure for quantifying the quality of care. By systematically asking the same questions reproducibly over time, the KCCQ can validly and sensitively capture the impact of heart failure on patients’ lives and is strongly associated with clinical events over time. The KCCQ has a 2-week recall period (given the day-to-day variability in heart failure symptoms) and includes 12 (KCCQ-12) or 23 (KCCQ-23) items that map to 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations;; and self-efficacy (the patient’s understanding of how to manage their heart failure). The KCCQ-12 is a validated health status measure for patients with HF. It contains four subdomains: Physical Limitation, Symptom Frequency, Quality of Life, and Social Limitations. Each subdomain provides an individual score from 0 to 100, with 0 denoting the worst and 100 the best0 possible health status. The mean of the four subdomain scores are presented as a summary score, with differences of 5 points or greater considered to be clinically important. Correlation of changes in the KCCQ and Patient Global Assessment (PGA) in patients with HF with preserved ejection fraction (HFpEF) can be used determine minimal clinically important differences. Patient-reported outcomes (PROs) are increasingly recognized for their value in providing the patient’s perspective on aspects of their condition or their overall health status. Patient global assessment (PGA) is one of the most widely used PROs in medical practice and research and is included in several composite scores such as the 28-joint Disease Activity Score (DAS28). PGA is often assessed by a single question with a 0–10 or 0–100 response. The content can vary and relates either to global health (e.g., how is your health overall) or to disease activity. The wordings used as anchors, i.e., for the score of 0, 10, or 100 according to the scale used, and the timing (i.e., this day or this week) also vary. The different possible ways of measuring PGA translate into variations in its interpretation and reporting and may impact on measures of disease activity and consequently achievement of treat-to-target goals. Furthermore, although PGA is associated with objective measures of disease activity, it is also associated with other aspects of health, such as comorbidities (Nikiphorou et al. Oct 2016; “Patient global assessment in measuring disease activity in rheumatoid arthritis: a review of the literature”). In the context of the present invention, when evaluating the KCCQ Overall Summary Score, an average improvement of more than 3 points is considered good, any improvement of more than 5 points is considered clinically relevant and any average improvement of more than 8-10 points is considered extremely good.In preferred embodiments, even changes smaller than the traditional 5-point improvements inKCCQ OSS may be clinically meaningful.In more preferred embodiments, even patients with changes which are above the standard valuein KCCQ OSS or PGA may be clinically meaningful. In embodiments, the administration of the iron carbohydrate complex improves the exercise capacity, reduced aerobic capacity, and / or reduced endurance of the patient, wherein the exercise capacity of the patient is measured as a 6-minute walk test distance (6MWTD) compared to the patient's exercise capacity prior to initiation of treatment with the iron complex. In embodiments of the invention, the administration of the iron carbohydrate complex improves the exercise capacity, wherein the improvement of the exercise capacity of the patient is measured as a 6-minute walk test distance (6MWTD) compared to the patient's exercise capacity prior to initiation of treatment with the iron complex. Another subject-matter of the present invention relates to a method of treatment of heart failure in a patient suffering from heart failure with preserved rejection fraction or being at risk of developing heart failure, wherein an intravenously administered iron carbohydrate complex is administered to the patient. In another embodiment, for the method of treatment the iron carbohydrate complex is selected from the group comprising iron monosaccharide, iron disaccharide or iron polysaccharide, such as iron carboxymaltose complex, iron mannitol complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, an iron polyglucose sorbitol carboxymethyl ether complex, or an iron hydrogenated dextran complex. In another preferred embodiment, for the method of treatment the iron carbohydrate complex is selected from the group of ferric carboxymaltose, iron isomaltoside 1000, iron derisomaltose and ferumoxytol. In a preferred embodiment, for the method of treatment patient is suffering from heart failure with preserved rejection fraction (HFpEF) and iron deficiency (ID). In one embodiment for the method of treatment, heart failure is either chronic or acute heart failure. In another preferred embodiment, for the method of treatment, the patient is suffering from heart failure with preserved rejection fraction and aneamia. In another embodiment, for the method of treatment the heart failure is diastolic. In another embodiment, for the method of treatment, the preserved ejection fraction is characterized by high left ventricular (LV) filling pressure and a LV ejection fraction which is equal or above 50%, as measured by echocardiographic or magnetic resonance imaging. In another embodiment, for the method of treatment the patient is also administered at least one standard of care HF agent. In another embodiment of the present invention for the method of treatment, said use of the iron carbohydrate complex further improves heart failure symptoms. In another preferred embodiment of the invention, for the method of treatment, the improvement in heart failure symptoms and / or quality of life is measured by a patient's higher score on the KCCQ Overall Summary Score (OSS) compared to the patient's score prior to initiation of treatment with a therapeutically effective amount of an iron carbohydrate complex. In other embodiments, for the method of treatment, the overall doses of the iron carbohydrate complex per patient vary between 1000 mg to 5000 mg per year, preferably 1500 mg to 3000 mg per year, more preferably 1000 mg to 2000 mg per year, most preferably 500 mg to 1500 mg per year, depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured. In another embodiment for the method of treatment, the initial doses of the iron carbohydrate complex for correcting the ID vary between 500 mg and 2000 mg provided in up to 2 administration sessions which are 7-14 days apart, and dosed depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured. In another preferred embodiment for the method of treatment, initial doses of the iron carbohydrate complex for correcting the ID are administered in in 1-2 sessions (baseline), which is followed by an additional repeat dose applications after year 1 every 3-6 months, and after 16±1 weeks, 24±1 weeks and 32±2 weeks, and where treatment in the second and subsequent years is repeated as in year 1 as long as a treatment need is diagnosed. In one embodiment for the method of treatment, the administration of the iron carbohydrate complex is repeated for as long as heart failure with iron deficiency persists. In preferred embodiments for the method of treatment, the administration occurs on the first day of treatment (baseline) and after 24 hours and after 5-11 days and after 16±1 week and after 24±1 week and after 32±2 weeks and after 52±2 weeks. In another embodiment for the method of treatment, the treatment need of the patient is considered present, when iron deficiency is still present in year 2 and subsequent years. In a further embodiment for the method of treatment, administration of the iron carbohydrate complex is repeated for as long as heart failure with iron deficiency or a risk of developing heart failure persists. In another embodiment for the method of treatment, the patient is suffering from at least one of the diseases selected from the group comprising obesity, cachexia, sarcopenia, frailty, COPD, atrial fibrillation, obesity, diabetes, and / or stroke. In one embodiment of the invention for the method of treatment, the patient is suffering from at least one of the diseases selected from the group comprising obesity, cachexia, sarcopenia, frailty, COPD, atrial fibrillation, obesity, diabetes, and / or stroke, wherein the patient is not suffering from HF or HFpEF. In one embodiment for the method of treatment, the patient is 18 years or older, wherein the patient does exhibit any one of the following criteria selected from the group comprising of chronic HFpEF, reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, New York Heart Association functional class II-III symptoms, receiving treatment with a diuretic, raised natriuretic peptide levels (BNP ≥35 pg / mL or NT­proBNP level ≥125 pg / mL) or a history of hospitalization with a diagnosis of HF within 12 months prior to the beginning of treatment with the iron complex, an LVEF ≥45% as measured by echocardiographic or magnetic resonance imaging within 6 months prior to treatment with the iron complex, wherein the reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, at baseline is measured as a 6- minute walk test distance (6MWTD), after an assessment of medical history, a physical examination and an electrocardiogram reading of the patient. In a preferred embodiment, for the method of treatment, the overall doses of the iron complex per patient vary between 2000 mg to 3000 mg, preferably 1000 mg to 2000 mg, more preferably 500 to 1000 mg depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured. In embodiments for the method of treatment, administration occurs on the first day of treatment (baseline) and after 24 hours and after 5-11 days and after 16±1 week and after 24±1 week and after 32±2 weeks and after 52±2 weeks. In one embodiment for the method of treatment, the patient has one or more comorbidities. In a preferred embodiment for the method of treatment, the one or more comorbidities is selected from the group comprising cachexia, sarcopenia, frailty, COPD, coronary artery disease, valvular heart disease, chronic kidney disease, hypertension, atrial fibrillation, obesity, diabetes and / or stroke. In embodiments for the method of treatment, the iron deficiency is defined either as a serum ferritin level below 100 ng / mL or the serum ferritin level is between 100-299 ng / mL with transferrin saturation (TSAT) below 20%. In a preferred embodiment for the method of treatment, the administration of the iron carbohydrate complex improves the clinical health status of the patient comprising the exercise capacity, reduced aerobic capacity, and / or reduced endurance, of the patient which is measured by 6min-walking test distance, symptoms of heart failure which is classified by NYHA functional class, cardiac function which is determined by measuring cardiac biomarker (NT-BNP) levels and comparison to baseline, inflammatory status by measuring inflammatory biomarker levels (CRP, PCT) and quality of life by determining KCCQ . In other embodiments for the method of treatment, the administration of the iron carbohydrate complex improves the exercise capacity, reduced aerobic capacity, and / or reduced endurance of the patient, wherein the exercise capacity of the patient is measured as a 6-minute walk test distance (6MWTD) compared to the patient's exercise capacity prior to initiation of treatment with the iron complex. Another subject-matter of the present application relates to a pharmaceutical composition comprising one or more iron carbohydrate complexes for use in the treatment of a patient suffering from heart failure (HF) with preserved rejection fraction (HFpEF) or a patient being at risk of developing heart failure. In embodiments, the pharmaceutical composition is administered to the patient intravenously. In some embodiments, the iron carbohydrate complex is selected from the group comprising iron monosaccharide, iron disaccharide or iron polysaccharide, such as iron carboxymaltose complex, iron mannitol complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, an iron polyglucose sorbitol carboxymethyl ether complex, or an iron hydrogenated dextran complex. The invention further relates to a pharmaceutical composition comprising one or more iron carbohydrate complexes for use in the treatment of a patient with one or more comorbidities, wherein the one or more comorbidities is selected from the group comprising cachexia, sarcopenia, frailty, COPD, coronary artery disease, valvular heart disease, chronic kidney disease, hypertension, atrial fibrillation, obesity, diabetes and / or stroke. All preferred embodiments and advantages of the methods of the present invention disclosed herein also apply to the pharmaceutical composition of the present invention. This also applies the other way around for the preferred embodiments and advantages of the pharmaceutical composition of the invention. DETAILED DESCRIPTION OF THE INVENTION All cited documents of the patent and non-patent literature are hereby incorporated by reference in their entirety. In order that the present description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description. "Treatment" or "therapy" of a patient refers to any type of intervention or process performed on, or the administration of an active agent to, the patient with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down, or preventing the onset, progression, development, severity, or recurrence of a symptom, complication, condition, or biochemical indicia associated with a disease. A “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. For the purpose of this disclosure, when specifying a dose in mg or g of an iron carbohydrate complex, consistent with the practice in the literature, the value refers to the amount of elemental iron provided in mg or g. This invention is to be understood expressly in the context of heart failure with preserved ejection fraction (HFpEF). This invention is not to be understood as being related to heart failure with reduced ejection fraction (HFrEF). The invention dislosed herein is exclusively related to uses, methods, substances, and compositions for the prevention, treatment, management, or monitoring of heart failure with preserved ejection fraction (HFpEF). It is expressly noted that this application does not cover or claim any inventions related to heart failure with reduced ejection fraction (HFrEF ), which is characterized by a left ventricular ejection fraction (LVEF) of less than 40%. The scope of this application is limited to HFpEF, where the LVEF is 50% or greater. Any reference to "heart failure" within this document should be understood as referring specifically to HFpEF unless otherwise explicitly stated. No claims are made regarding therapeutic or diagnostic approaches for HFrEF, and no efficacy or applicability of the described innovations for HFrEF should be inferred. This disclaimer serves to clarify the intended exclusion of HFrEF from the scope of the current patent application and to prevent any ambiguity concerning the population targeted by the proposed inventions. A particular group of patients having iron deficiency as disclosed herein is characterized as being at risk of developing heart failure and / or at risk of a cardiovascular adverse event. A patient being at risk of a cardiovascular adverse event is a subject having a risk for heart failure, in particular one or more events selected from the group consisting of events that affect the heart (cardiac adverse events), such as congestive heart failure (CHF), in particular CHF requiring hospitalization or medical intervention, myocardial infarction, unstable angina, in particular angina requiring hospitalization, or arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events), such as hypertension and hypotension; events that affect the cerebral vasculature (cerebrovascular adverse events), such as stroke; and / or general adverse events, such as death. Cardiovascular disease Cardiovascular disease comprises a large class of diseases that affect the heart or blood vessels (arteries and veins). Cardiovascular diseases include arrhythmias, vascular disease, myocardial infarction, heart failure, myocarditis, atherosclerosis, restenosis, coronary heart disease, coronary artery disease, atherosclerotic cardiovascular disease, arterial hypertension, cardiac fibrosis, stroke, sudden cardiac death syndrome, heart failure, ischemic cardiomyopathy, myocardial infarction, coronary artery calcification. These diseases have similar causes, mechanisms, and treatments. Most cardiovascular diseases have common risk factors, including inflammation, fibrosis, diabetes, cholesterol, and vascular deposits. Heart failure Heart failure (HF) is a chronic or acute, progressive condition in which the heart muscle is unable to pump enough blood to sufficiently supply the body with blood and oxygen. This inability may result from structural or functional heart abnormalities that affect the ability of the heart chambers to fill with blood or to eject blood. Symptoms of heart failure typically include shortness of breath, persistent coughing or wheezing, accumulation of excess fluid in the body tissues (edema), fatigue, and decreased exercise capacity. Ejection fraction and heart failure Heart failure is often categorized by ejection fraction. Ejection fraction refers to the percentage of blood that leaves the heart during each contraction. Heart failure with reduced ejection fraction (HFrEF) occurs when the heart's ability to contract is impaired, resulting in a low ejection fraction. In heart failure with preserved ejection fraction (HFpEF), the ejection fraction is normal or near normal, meaning the heart's pumping function remains intact. In HFpEF, however, the heart muscle becomes stiff and less compliant, making it difficult to fill the heart chambers with blood - a problem primarily associated with diastolic dysfunction. Patients with HFpEF may present with symptoms similar to those of HFrEF, but require different treatment approaches due to the different pathophysiological mechanisms. The prevalence of HFpEF is increasing compared to HFrEF, especially in older adults and in patients with multiple comorbidities such as hypertension, obesity and diabetes mellitus. Therefore, understanding and treating HFpEF has become an important focus of cardiovascular care. Heart failure with preserved ejection fraction Heart failure is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and / or functional cardiac abnormality, resulting in a reduced cardiac output and / or elevated intracardiac pressures at rest or during stress. Thus, the current definition of HF restricts itself to stages at which clinical symptoms are apparent. Before clinical symptoms become apparent, subjects can present with asymptomatic structural or functional cardiac abnormalities, such as systolic or diastolic left ventricular (LV) dysfunction, which are precursors of HF. Recognition of these precursors is important because they are related to poor outcomes, and starting treatment at the precursor stage may reduce mortality in subjects with asymptomatic systolic LV dysfunction. Heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure, is a clinical syndrome characterized by the typical symptoms of heart failure, such as dyspnea (shortness of breath), fatigue, and fluid retention, in the presence of a preserved left ventricular ejection fraction (LVEF). The term "preserved ejection fraction" implies that the percentage of blood ejected from the left ventricle during systole (the contraction phase of the cardiac cycle) is within normal limits, typically defined as an LVEF greater than or equal to 50%. Despite a normal or near-normal ejection fraction, patients with HFpEF experience impaired relaxation and / or increased stiffness of the left ventricle, which leads to elevated filling pressures in the heart during diastole (the relaxation phase of the cardiac cycle). This diastolic dysfunction hampers the efficient filling of the ventricles and contributes to the accumulation of fluid in the lungs and other tissues. The pathophysiology of HFpEF is complex and multifactorial, involving connected mechanisms such as systemic inflammation, endothelial dysfunction, abnormal myocardial remodelling, and neurohormonal activation. These underlying processes result in structural changes within the myocardium and alterations in ventricular-vascular coupling, which lead to compromised cardiac output during physical exertion despite a preserved ejection fraction at rest. Congestive Heart Failure (CHF) “Congestive HF” is a term that is used to describe chronic heart failure, in particular if there is evidence of volume overload, most often displayed as peripheral or pulmonary edema. In a particular embodiment of the invention, the congestive heart failure (CHF) is heart failure with reduced ejection fraction, LVEF <40% (HFrEF). Diagnosis HFpEF Diagnosis of HFpEF requires documentation of normal or mildly abnormal LVEF and also evidence of diastolic dysfunction obtained through comprehensive echocardiographic assessment or elevated levels of natriuretic peptides (e.g., B-type natriuretic peptide [BNP] or N- terminal pro-BNP [NT-proBNP]) in conjunction with clinical signs and symptoms indicative of heart failure. HFpEF represents a at least one heart failure case and poses unique challenges in terms of management and treatment. Unlike heart failure with reduced ejection fraction (HFrEF), where several evidence-based therapies have been shown to improve outcomes, effective treatments for HFpEF are limited, highlighting an area of substantial unmet medical need. HFpEF is also based on established diagnostic criteria, such as clinical presentation, echocardiographic parameters demonstrating diastolic dysfunction or elevated filling pressures, and LVEF measurements. These criteria are met to distinguish HFpEF from other forms of heart failure and to guide appropriate management strategies. Clinical criteria Patients with HFpEF typically clinically present with signs and symptoms consistent with heart failure, which may include exertional dyspnea, fatigue, reduced exercise tolerance, and fluid retention manifesting as peripheral edema or pulmonary congestion. These symptoms are often precipitated by physical activity, stress, or other conditions that increase the demand on the heart. Additionally, patients may have a history of atrial fibrillation or hypertension, which are common comorbidities associated with HFpEF. Echocardiographic Parameters Echocardiographic Parameters for Diastolic Dysfunction, as used herein, is the preferred primary imaging modality used to assess diastolic function in patients suspected of having HFpEF. Key echocardiographic indicators of diastolic dysfunction include an elevated E / e' ratio (the ratio of early mitral inflow velocity to mitral annular early diastolic velocity), a decreased e' velocity (indicating impaired relaxation of the left ventricle), prolonged deceleration time of early mitral inflow, and an increased left atrial volume index. These parameters suggest impaired left ventricular relaxation and increased stiffness, leading to elevated filling pressures during diastole. Elevated Filling Pressures Elevated Filling Pressures for HFpEF, as used herein, is another evidence of diastolic dysfunction in addition to echocardiographic. The direct or indirect indicators of elevated left ventricular filling pressures can support the diagnosis of HFpEF. This may include elevated levels of natriuretic peptides such as BNP or NT-proBNP, which are released in response to myocardial wall stress due to high filling pressures. Invasive hemodynamic measurements obtained via cardiac catheterization can also provide definitive evidence of increased left ventricular end-diastolic pressure (LVEDP), although this invasive procedure is less commonly used in routine clinical practice. LVEF Measurements for HFpEF, as used herein, is preferably measured using echocardiography or other cardiac imaging techniques such as cardiac magnetic resonance imaging (MRI). A preserved ejection fraction is a hallmark feature of HFpEF. For the diagnosis of HFpEF, LVEF should be greater than or equal to 50%, indicating that the systolic function of the heart is within normal limits despite the presence of clinical symptoms and signs indicative of heart failure. Comorbidities of HFpEF Comorbidity refers to the simultaneous presence of two or more diseases or medical conditions in a patient. Several Comorbidities for HFpEF are known and are expected to impact the pathophysiology of HFpEF. HFpEF patients are generally older, more often female and have a high prevalence of cardiovascular and non-cardiovascular comorbidities, such as obesity, metabolic syndrome, diabetes mellitus type 2, salt-sensitive hypertension, atrial fibrillation (AF), chronic obstructive pulmonary disease, anaemia and renal dysfunction. The associated increase in comorbidities in patients with chronic heart failure leads to a less favorable prognosis for survival. Treatment recommendations based on comorbidity-specific guidelines are recommended by current guidelines (McDonagh TA et al (2022) 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 24(1):4–131). Hypertension Hypertension refers to a chronic medical condition in which the blood pressure in the arteries is persistently elevated. Hypertension is defined as an increase in systolic blood pressure > 20 mm Hg that results in a value > 180 mm Hg or an increase in diastolic blood pressure > 15 mm Hg that results in a value > 105 mm Hg. Long-standing high blood pressure can lead to changes in the heart's structure and function, contributing to HFpEF. Obesity Obesity refers to a condition characterized by excessive body fat accumulation that presents a risk to health. Obesity can lead to metabolic changes, increased cardiac workload, and inflammation, all of which may contribute to HFpEF. “Obesity” is a condition characterized by excessive body weight to the extent when the body mass index (BMI), a measurement obtained by dividing a person's weight by the square of the person's height, is over 30 kg / m2. Having a BMI of greater than 30 kg / m2, i.e. being obese, there is serious risk for developing hypertension (e.g., due to intra-abdominal fat), diabetes and atherosclerosis which are risk factors for a cardiovascular adverse event. Diabetes Mellitus Diabetes mellitus refers to a metabolic disorder where there is high blood sugar over a prolonged period due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced. Diabetes is associated with increased risk of cardiovascular disease and can worsen outcomes in HFpEF. Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Type 1 diabetes, once known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin. Different factors, including genetics and some viruses, may contribute to type 1 diabetes. Although type 1 diabetes usually appears during childhood or adolescence, it can develop in adults. Despite active research, type 1 diabetes has no cure. Treatment focuses on managing blood sugar levels with insulin, diet and lifestyle to prevent complications. Having diabetes increases the risk for a cardiovascular adverse event two to four times compared to people without diabetes. Cardiovascular adverse event are the leading cause of mortality for people with diabetes. This is in particular due to hypertension, abnormal blood lipids and obesity, all risk factors for cardiovascular adverse events. Coronary Artery Disease (CAD) Coronary artery disease (CAD) refers to a disease marked by the narrowing or blockage of coronary arteries due to plaque buildup, which can reduce blood flow to the heart muscle and lead to myocardial ischemia. CAD can coexist with HFpEF and exacerbate its symptoms. Atrial Fibrillation Atrial fibrillation refers to an irregular and often rapid heart rate that can increase the risk of stroke, heart failure, and other heart-related complications. Atrial fibrillation is common in patients with HFpEF and can complicate its management. Chronic Kidney Disease (CKD) Chronic Kidney Disease (CKD) also refers to a long-term condition where the kidneys do not work as well as they should to filter waste products from the blood. CKD can affect cardiovascular health and is frequently found in patients with HFpEF. Subjects with a glomerular filtration rate (GFR) < 60 ml / min / 1.73 m2for 3 months are classified as having CKD, irrespective of the presence or absence of kidney damage. Those subjects with CKD who require either dialysis or kidney transplantation are typically referred to as end-stage renal disease (ESRD) subjects. Chronic Obstructive Pulmonary Disease (COPD) Chronic Obstructive Pulmonary Disease (COPD) refers to a group of lung diseases that block airflow and make it difficult to breathe. COPD may lead to low oxygen levels and increased pulmonary pressures, which can impact cardiac function in HFpEF. Sleep Apnea Sleep apnea refers to a sleep disorder characterized by pauses in breathing or periods of shallow breathing during sleep. Sleep apnea can cause intermittent hypoxia and increased sympathetic activity, both of which may contribute to cardiovascular dysfunction seen in HFpEF. Anemia Anemia also refers to a condition in which there is a deficiency of red blood cells or hemoglobin in the blood, leading to reduced oxygen transport capacity. Anemia can worsen symptoms of fatigue and exercise intolerance in patients with HFpEF. Valvular Heart Disease Valvular Heart Disease also refers to disease processes involving one or more valves of the heart (e.g., aortic stenosis, mitral regurgitation) that affects the flow of blood within the heart. Valvular abnormalities can increase cardiac workload and contribute to HFpEF development. Stroke Stroke is classically characterized as a neurological deficit attributed to an acute focal injury of the central nervous system by a vascular cause, including cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage. Subjects having a history in stroke, i.e. subjects who have suffered a stroke, remain at a high risk for further cardiovascular adverse event, in particular for a further stroke. 6-minute walking test The term “6-minute walking test” or “6-minute walk test” (6MWT) refers to a functional exercise test that measures the distance an individual can walk on a flat, hard surface in a period of six minutes. The test is used to assess aerobic capacity or exercise capacity and endurance in various patient populations, particularly those with cardiopulmonary conditions such as heart failure, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, and interstitial lung disease. It is widely used in clinical trials and in practice to measure the cardiopulmonary performance of patients with various diseases such as heart failure, chronic obstructive pulmonary disease (COPD) and other chronic diseases. During the 6MWT, the individual is instructed to walk at their own pace, but to cover as much ground as possible within the allotted time. The objective is to walk for as long and consistently as one can over the six-minute duration. The test is self-paced and reflects the functional exercise level for daily physical activities. The total distance walked (in meters) is recorded at the end of the six minutes and serves as the primary outcome measure of the test. Standardized encouragement is provided at specified intervals throughout the test to ensure consistency across administrations. The 6MWT is simple to administer, does not require advanced exercise testing equipment. In addition to measuring walking distance, other parameters may be monitored during the 6MWT, including heart rate, oxygen saturation, perceived exertion using scales like the Borg scale, and symptoms such as dyspnea and fatigue. These additional measurements can provide insight into an individual's exercise tolerance and physiological response to exertion. The 6MWT has been widely validated and is considered a reliable indicator of functional status in patients with cardiovascular and pulmonary diseases. It has been accepted as a quantitative measure by approval authorities, such as the European Medicines Agency (EMA). It also serves as a prognostic tool for predicting morbidity and mortality in these populations. Furthermore, it can be used to monitor disease progression over time or to evaluate the response to therapeutic interventions aimed at improving exercise capacity. Normal values for the 6MWT may vary because they depend on several factors, including age, gender, height, weight, walking underground, and general health. An often-cited source of normative values is a 1998 study by Enright and Sherrill, which provides reference equations for healthy adults between the ages of 40 and 80, and is incorporated herein by reference. These equations take gender, age and height into account. For example, the expected walking distance for a healthy middle-aged man may be approximately 576 meters plus 7 meters for each inch of height over 5 feet. Clinical trials preferably examine specific cohorts, so separate normative values or baseline data for these populations may be established. In one embodiment, the normative values for HFpEF are above 250 m. The results of the 6MWT are preferably used to assess changes over time or in response to treatment. In one embodiment, the baseline values of the 6MWT of the HFpEF patient have been assessed at time point zero which refers to the time point before treatment disclosed herein has been initiated. Aerobic Capacity: The term “aerobic capacity” or also termed as “maximal oxygen uptake (VO2 max)” or “cardiorespiratory fitness”, as used herein, also refers to the maximum rate at which an individual can consume oxygen during intense or maximal exercise. It is a measure of the cardiovascular and respiratory systems' ability to deliver oxygen to working muscles and the muscles' efficiency in using that oxygen to produce energy through aerobic metabolism. The maximal oxygen uptake (VO2 max) refers to the maximum amount of oxygen the body can utilize during intense exercise. Aerobic capacity is typically expressed in milliliters of oxygen consumed per kilogram of body weight per minute (ml / kg / min). It is widely recognized as the gold standard for assessing an individual's cardiorespiratory fitness level and can be influenced by factors such as age, sex, genetics, training status, and health. Norm values for aerobic capacity vary greatly depending on age, gender, fitness level and population. In general, average values apply for VO2 max for young adult men between 45-55 ml / kg / min and young adult women between 35-45 ml / kg / min. These values decrease with age. For example, normal VO2 max values for people over the age of 60 could be around 10-20% lower than the above values. Therefore, reduced aerobic capacity or reduced cardiorespiratory fitness, preferably refers to a lower than normal ability of the cardiovascular and respiratory systems to supply oxygen to the muscles during sustained physical activity and is characterized by a decreased VO2max. Individuals with reduced aerobic capacity experience limitations in performing activities that require endurance, such as walking, running, or cycling, and may fatigue more quickly due to the inefficiency of their oxygen transport and utilization systems. Reduced aerobic capacity can result from sedentary lifestyles, aging, chronic diseases, or other factors that impair the heart, lungs, blood vessels, or muscles. Exercise Capacity The term “exercise capacity”, as used herein, also refers to the maximum physical exertion that an individual can sustain. It encompasses the cardiorespiratory system's function and includes muscular strength, endurance, and flexibility. Exercise capacity can be indirectly assessed through various performance tests, such as the 6-Minute Walk Test, treadmill stress testing, or cycle ergometry, where individuals perform a specific activity until exhaustion. Outcome measures may include distance traveled, duration, work performed or performance. Physical performance is an important indicator of a person's functional status and their ability to perform daily activities without excessive fatigue. It is also used clinically to assess the impact of disease on physical function and to monitor the effectiveness of therapeutic interventions to improve or maintain physical performance. Normal values are usually based on age, gender and sometimes height and weight. An example of a normal value for the 6MWT could be for healthy adult males between 400 m and 700 m and for healthy adult females between 300 m and 600 m. Reduced exercise capacity is therefore preferably a condition where a patient’s ability to perform physical activity is lower than what would be expected for their age, sex, and physical condition. This limitation can occur as decreased strength, endurance, or overall performance during training. It may result from various factors such as cardiovascular or pulmonary diseases, COPD, anaemia, musculoskeletal disorders, chronic fatigue, or deconditioning. Reduced exercise capacity often leads to difficulties in performing daily activities and can significantly impact the quality of life. Endurance The term "endurance" refers to a patient's ability to sustain prolonged physical activity over a period of time. It is the ability of the muscles, cardiovascular system and respiratory system to work together efficiently to maintain exercise intensity and resist fatigue. Endurance can be divided into two main types: cardiovascular endurance and muscular endurance. Cardiovascular endurance, or aerobic endurance, refers to the ability of the heart and lungs to deliver oxygen to the body's tissues during continuous and rhythmic activities such as walking, running, swimming, or cycling. Muscular endurance refers to the ability of a0 muscle group to perform repeated contractions over time without fatigue. It is often measured by how many repetitions of a particular exercise a patient can perform in a given time. Reduced endurance therefore refers to a reduced ability to sustain physical activity over a prolonged period of time. Patients with reduced endurance fatigue more quickly during physical exertion or routine tasks and are unable to maintain a certain level of activity for as long as they used to be able to or as would be considered normal for their individual profile. This decline may be due to respiratory or cardiovascular limitations. Reduced stamina can affect a person's activities of daily living and independence. Endurance is also a measure of risks for developing chronic diseases, mental well-being, and quality of life. The New York Heart Association (NYHA) Classification classifies patients in one of four categories based on how much they are limited during physical activity. Patients having no symptoms and no limitation such as undue fatigue, palpitation, or dyspnea (shortness of breath), in ordinary physical activity, e.g. walking, climbing stairs etc., are assigned to NYHA class I. Patients with mild symptoms (mild shortness of breath and / or angina) and slight limitation of physical activity are assigned to NYHA class II. Patients having a marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances of 20 to 100 m, and which are comfortable only at rest are assigned to NYHA class III. Patient who experience symptoms even while being at rest and are unable to carry on any physical activity without discomfort are assigned to NYHA class IV. In a particular embodiment of the invention, the congestive heart failure (CHF) is congestive heart failure in NYHA class II-IV. Individuals with iron deficiency first deplete the stored iron in the body. Because most of the iron utilized by the body is required for hemoglobin, iron-deficiency anemia is the primary clinical manifestation of iron deficiency. Oxygen transport to tissues including organs is vital and severe anemia is harmful and potentially fatal due to systemic lack of oxygen. Iron-deficient subjects will suffer, and in some instances may die, from organ damage caused by oxygen depletion well before cells run out of the iron needed for intracellular processes. There are several markers of systemic iron status that may be measured to determine whether a subject has sufficient iron stores to maintain adequate health. These markers may be circulating iron stores, iron stored in iron-binding complexes, or both, and are also typically referred to as iron storage parameters. Iron storage parameters can include, for example, hematocrit, hemoglobin concentration (Hb), total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum iron levels, liver iron levels, spleen iron levels, and serum ferritin levels. Of these, the hematocrit, hemoglobin concentration (Hb), total iron binding capacity (TIBC), transferrin saturation (TSAT) and serum iron levels are commonly known as circulating iron stores. The liver iron levels, spleen iron levels, and serum ferritin levels are commonly referred to as stored iron or iron stored in iron-binding complexes. It is noted that while the above blood parameters are determined in serum, they can likewise be determined in plasma. Serum and plasma levels correlate and can be converted into each other. In one embodiment, the at least one iron storage parameter is hemoglobin concentration, and improving comprises increasing the hemoglobin concentration of the subject. In other embodiments, the at least one iron storage parameter is transferrin saturation, and improving comprises increasing the transferrin saturation of the subject. In yet other embodiments, the at least one iron storage parameter is serum ferritin levels, and improving comprises increasing the serum ferritin levels of the subject. In a healthy subject, a normal ferritin blood serum level, sometimes referred to as the reference interval, is usually between 30-300 ng / ml for males, and 15-200 ng / ml for females. In patients at risk of cardiovascular adverse events, normal ferritin blood serum level is usually above 100 ng / mL. In an iron-deficient subject, however, serum ferritin levels are typically markedly reduced as the amount of iron available to be bound by ferritin and stored in the liver is decreased, which occurs as the body loses its ability to absorb and store iron. The term “serum ferritin” (5-ferritin) as used herein refers to the level of ferritin in blood serum as measured using a two-site immunoenzymatic (“sandwich”) assay. Ferritin is the major iron storage protein for the body. The concentration of ferritin is directly proportional to the total iron stores of the body, resulting in serum ferritin levels becoming a common diagnostic tool in the evaluation of iron status. Subjects with iron-deficiency anemia have serum ferritin levels approximately one tenth of normal subjects, while subjects with iron overload (hemochromatosis, hemosiderosis) have serum ferritin level much higher than normal. Ferritin levels also provide a sensitive means of detecting iron deficiency at an early stage. In both adults and children, chronic inflammation results in a disproportionate increase in ferritin levels in relation to iron reserves. Elevated ferritin levels also are observed in acute and chronic liver disease, chronic renal failure and in some types of neoplastic disease. In some embodiments, subjects treated according to the methods disclosed herein experience an increase in serum ferritin levels. In addition to stored iron, a small amount of iron, typically about 3 to 4 mg, circulates through the blood plasma bound to a protein called transferrin. Therefore, serum iron (5-iron) levels can be represented by the amount of iron circulating in the blood that is bound to the protein transferrin. Transferrin is a glycoprotein produced by the liver that can bind one or two ferric iron (iron(III) or Fe3+) ions. It is the most prevalent and dynamic carrier of iron in the blood, and therefore is an essential component of the body's ability to transport stored iron for use throughout the body. Transferrin saturation (or TSAT) is measured as a percentage and is calculated as the ratio of serum iron and total iron-binding capacity, multiplied by 100. This value tells a clinician how much serum iron is actually bound to the total amount of transferrin that is available to bind iron. For instance, a TSAT value of 35% means that 35% of the available iron-binding sites of transferrin in a blood sample are occupied by iron. In a healthy subject, typical TSAT values are approximately 15-50% for males and 12-45% for females. In patients at risk of cardiovascular adverse events, normal TSAT values are typically above 20%. In an iron-deficient subject, however, TSAT values are typically markedly reduced as the amount of iron available to be bound by transferrin is decreased, which occurs as the body loses its ability to absorb and store iron. In some embodiments, the TSAT value is below 20% and / or the ferritin concentration is < 100 pg / L. Symptoms of iron deficiency can include, for example, fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer- Vinson syndrome (painful atrophy of the mucous membrane covering the tongue, pharynx and esophagus), impaired immune function, pagophagia, and restless legs syndrome, among others. In some embodiments, the iron deficiency is iron-deficiency anemia. Iron-deficiency anemia is characterized by low levels of circulating red blood cells and can be caused by insufficient dietary intake, absorption and / or storage of iron. Red blood cells, which contain iron bound in hemoglobin proteins, and are typically not formed when the amount of iron in the body is deficient. Iron- deficiency anemia is typically characterized by pallor (pale color resulting from reduced oxyhemoglobin in the skin and mucous membranes), fatigue, lightheadedness, and weakness. However, signs of iron-deficiency anemia can vary between subjects. Herein a patient’ may be a vertebrate, preferably a mammal, more preferably a human subject or patient. In the context of the present invention, the term "subject" or “patient” includes both humans and animals, particularly mammals, more particularly humans, and other organisms. As used herein, the term “sample” is a biological sample that is obtained or isolated from the patient or subject. A sample may, for example, refer to a biopsy sample, a sample of bodily fluid or tissue obtained for the purpose of diagnosis, prognosis, or evaluation of a subject of interest, such as a patient. In embodiments, the sample is a tissue sample, a tissue biopsy, a sample of a bodily fluid, such as blood, serum, plasma, cerebrospinal fluid, urine, pleural effusions, cells, a cellular extract, and the like. Particularly, the sample is blood, or blood plasma, blood serum. In embodiments “pharmaceutical compositions” provided for administration to a subject and which include a “therapeutically effective amount” of one or more of the iron carbohydrate complexes disclosed herein. The therapeutically effective amount of the disclosed composition will depend on the route of administration and the physical characteristics of the patient being treated. Specific factors that can be taken into account include disease severity and stage, weight, diet and concurrent medications. The relationship of these factors to determining a therapeutically effective amount of the disclosed composition is understood by those of skill in the art. Accordance to the treatment methods according to the invention, the compositions can be delivered to a subject in a manner consistent with conventional methodologies associated with management of the disorder for which treatment or prevention is sought. In accordance with the disclosure herein, a prophylactically or therapeutically effective amount of the composition and / or other biologically active agents is administered to a subject in need of such treatment for a time and under conditions sufficient to prevent, inhibit, and / or ameliorate a selected disease or condition or one or more symptom(s) thereof. "Administration of and "administering" the iron complex or a composition should be understood to mean providing said complex or a pharmaceutical composition as described herein. The composition(s) can be administered by another person to the patient (e.g., intravenously). Dosage can be varied by the attending clinician to maintain a desired concentration at a target site (for example, the kidney, bladder, lungs or systemic circulation). Higher or lower concentrations can be selected based on the mode of delivery, for example, intravenous, delivery, or any other suitable route of delivery. Dosage can also be adjusted based on the release rate of the administered formulation, for example, of an intravenous versus injected delivery formulations, and so forth. The present invention also relates to a method of treatment of patients suffering from heart failure as disclosed herein. The method of treatment comprises preferably the administration of a therapeutically effective amount of an iron carbohydrate complex disclosed herein to a patient in need thereof. The composition described herein may comprise different types of carriers depending on whether it is to be administered in liquid form, and whether it need to be sterile for such routes of administration as injection. The composition of the present invention can be administered intravenously and is known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference). Additionally, such compositions can comprise pharmaceutically acceptable carriers that can be aqueous or non-aqueous solutions, suspensions, and emulsions, most preferably aqueous solutions or solid formulations of various types known in the art. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions and suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as Ringer's dextrose, those based on Ringer's dextrose, and the like. Fluids used commonly for i.v. administration are found, for example, in Remington: The Science and Practice of Pharmacy, 20th Ed., p.808, Lippincott Williams S- Wilkins (2000). Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like. Pharmaceutical compositions for administration to a patient can comprise at least one additional pharmaceutically acceptable additive such as carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. In embodiments pharmaceutical compositions can also comprise one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents and the like. Pharmaceutically acceptable carriers useful for such formulations are conventional. Formulations suitable for pharmaceutical delivery of the cells and T cells described herein are described in Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995). In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. As used herein, the term "approximately" or “about” is used to describe and account for small variations. For example, the term may refer to less than or equal to 10, such as less than or equal down to 1, when appropriate, also the term may refer to more than or equal to 10, such as more than or equal up to 100 or more, when appropriate. It is to be understood that range format is used for the sake of simplicity and brevity and is to be flexibly understood to include numeric values expressly stated as boundaries of a range, encompassing each numeric value and sub- ranges. The given definitions and explanations also apply mutatis mutandis to the following embodiments. The present invention also relates to the following embodiments: 1. An iron carbohydrate complex for use in the treatment of a patient suffering from heart failure (HF) with preserved rejection fraction (HFpEF) or in a patient being at risk of developing heart failure. 2. The iron carbohydrate complex for use according to embodiment 1, wherein the iron carbohydrate complex is selected from the group comprising iron monosaccharide, iron disaccharide or iron polysaccharide, such as iron carboxymaltose complex, iron mannitol complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, an iron polyglucose sorbitol carboxymethyl ether complex, or an iron hydrogenated dextran complex. 3. The iron carbohydrate complex for use according to embodiment 1 and 2, wherein theiron carbohydrate complex is selected from the group of ferric carboxymaltose, iron isomaltoside1000, iron derisomaltose and ferumoxytol. 4. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the patient is suffering from heart failure with preserved rejection fraction (HFpEF) and iron deficiency (ID) 5. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the patient is suffering from heart failure with preserved rejection fraction (HFpEF) and aneamia or the patient being anaemic and at risk of developing heart failure. 6. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein heart failure is either chronic or acute heart failure. 7. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein heart failure is diastolic. 8. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the preserved ejection fraction (HFpEF) is characterized by high left ventricular (LV) filling pressure and a LV ejection fraction which is equal or above 50%, as measured by echocardiographic or magnetic resonance imaging. 9. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the patient is also administered at least one standard of care HF agent. 10. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein said use further improves heart failure symptoms. 11. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the improvement in heart failure symptoms and / or quality of life is measured by a patient's higher score on the KCCQ Overall Summary Score (OSS) compared to the patient's score prior to initiation of treatment with a therapeutically effective amount of an iron carbohydrate complex. 12. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the higher score on the KCCQ OSS is at least 5 points higher than the score prior to administration with a therapeutically effective amount of an iron carbohydrate complex. 13. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the higher score on the KCCQ OSS is at least 10 points higher than the score prior to administration with a therapeutically effective amount of iron carbohydrate complex. 14. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the higher score on the KCCQ OSS is at least 15 points higher than the score prior to administration with therapeutically effective amount of iron carbohydrate complex. 15. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the improvement in heart failure symptoms is measured by a patient's lower deterioration in score on the KCCQ OSS relative to an administration regimen where the patient receives at least one standard of care HF agent alone. 16. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the patient is 18 years or older, wherein the patient does exhibit any one of the following criteria selected from the group comprising of chronic HFpEF, reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, New York Heart Association functional class IIIII symptoms, receiving treatment with a diuretic, raised natriuretic peptide levels (BNP ≥35 pg / mL or NT­proBNP level ≥125 pg / mL) or a history of hospitalization with a diagnosis of HF within 12 months prior to the beginning of treatment with the iron complex, an LVEF ≥45% as measured by echocardiographic or magnetic resonance imaging within 6 months prior to treatment with the iron complex, wherein the reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, at baseline is measured as a 6-minute walk test distance (6MWTD), after an assessment of medical history, a physical examination and an electrocardiogram reading of the patient. 17. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the overall doses of the iron complex per patient vary between 1000 mg to 5000 mg per year, preferably 1500 mg to 3000 mg per year, more preferably 1000 mg to 2000 mg per year, most preferably 500 mg to 1500 mg per year. 18. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein initial doses of the iron complex for correcting the ID vary between 500 mg and 2000 mg provided in up to 2 administration sessions which are 7-14 days apart, and dosed depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured. 19. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein said iron complex is administered intravenously. 20. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein initial doses of the iron carbohydrate complex for correcting the ID are administered in in 1-2 sessions (baseline), which is followed by an additional repeat dose applications after year 1 every 3-6 months, and after 16±1 weeks, 24±1 weeks and 32±2 weeks, and where treatment in the second and subsequent years is repeated as in year 1 as long as a treatment need is diagnosed. 21. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the treatment need is considered present, when iron deficiency is still present in year 2 and subsequent years. 22. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein administration is repeated for as long as heart failure with iron deficiency or a risk of developing heart failure persists. 23. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the patients is suffering from at least one of the diseases selected from the group comprising cachexia, sarcopenia, frailty, COPD, atrial fibrillation, obesity, diabetes, and / or stroke. 24. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the patient has one or more comorbidities. 25. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the one or more comorbidities is selected from the group comprising cachexia, sarcopenia, frailty, COPD, coronary artery disease, valvular heart disease, chronic kidney disease, hypertension, atrial fibrillation, obesity, diabetes, and / or stroke. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the iron deficiency is defined as a either a serum ferritin level below 100 ng / mL or the serum ferritin level is between 100-299 ng / mL with transferrin saturation (TSAT) below 20%. 26. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the administration of the iron carbohydrate complex improves the clinical health status of the patient comprising the exercise capacity, reduced aerobic capacity, and / or reduced endurance, of the patient which is measured by 6min-walking test distance, symptoms of heart failure which is classified by NYHA functional class, cardiac function which is determined by measuring cardiac biomarker (NT-BNP) levels and comparison to baseline, inflammatory status by measuring inflammatory biomarker levels (CRP, PCT) and quality of life by determining KCCQ. 27. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the administration of the iron complex improves the exercise capacity, reduced aerobic capacity, and / or reduced endurance of the patient, wherein the exercise capacity of the patient is measured as a 6-minute walk test distance (6MWTD) compared to the patient's exercise capacity prior to initiation of treatment with the iron complex. 28. The iron carbohydrate complex for use according to any of the preceding embodiments, wherein the administration of the iron carbohydrate complex improves the exercise capacity. 29. A method of treatment of heart failure in a patient suffering from heart failure with preserved rejection fraction or being at risk of developing heart failure, wherein an intravenously administered iron carbohydrate complex is administered to the patient. 30. The method of treatment of heart failure according to embodiment 30, wherein the iron carbohydrate complex is selected from the group comprising iron monosaccharide, iron disaccharide or iron polysaccharide, such as iron carboxymaltose complex, iron mannitol complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, an iron polyglucose sorbitol carboxymethyl ether complex, or an iron hydrogenated dextran complex. 31. The method of treatment of heart failure according to embodiment 30 and 31, wherein theiron carbohydrate complex is selected from the group of ferric carboxymaltose, iron isomaltoside1000, iron derisomaltose and ferumoxytol. 32. The method of treatment of heart failure according to embodiments 30 to 32, wherein patient is suffering from heart failure with preserved rejection fraction (HFpEF) and iron deficiency (ID) or being iron deficient and at risk of developing heart failure. 33. The method of treatment of heart failure according to embodiments 30-33, wherein heart failure is either chronic or acute heart failure. 34. The method of treatment of heart failure according to embodiments 30- 34, wherein heart failure is diastolic. 35. The method of treatment of heart failure according to embodiments 30-35, wherein the preserved ejection fraction (HFpEF) is characterized by high left ventricular (LV) filling pressure and a LV ejection fraction which is equal or above 50%, as measured by echocardiographic or magnetic resonance imaging. 36. The method of treatment of heart failure according to embodiments 30-36, wherein the patient is 18 years or older, wherein the patient does exhibit any one of the following criteria selected from the group comprising of chronic HFpEF, reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, New York Heart Association functional class IIIII symptoms, receiving treatment with a diuretic, raised natriuretic peptide levels (BNP ≥35 pg / mL or NT­proBNP level ≥125 pg / mL) or a history of hospitalization with a diagnosis of HF within 12 months prior to the beginning of treatment with the iron complex, an LVEF ≥45% as measured by echocardiographic or magnetic resonance imaging within 6 months prior to treatment with the iron complex, wherein the reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, at baseline is measured as a 6-minute walk test distance (6MWTD), after an assessment of medical history, a physical examination and an electrocardiogram reading of the patient. 37. The method of treatment of heart failure according to embodiments 30-37, wherein the overall doses of the iron complex per patient vary between 2000 mg to 3000 mg, preferably 1000 mg to 2000 mg, more preferably 500 to 1000 mg depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured. 38. The method of treatment of heart failure according to embodiments 30-38, wherein said iron complex is administered intravenously. 39. The method of treatment of heart failure according to embodiments 30-39, wherein administration occurs on the first day of treatment (baseline) and after 24 hours and after 5-11 days and after 16±1 week and after 24±1 week and after 32±2 weeks and after 52±2 weeks. 40. The method of treatment of heart failure according to embodiments 30-40, wherein administration is repeated for as long as heart failure with iron deficiency or a risk of developing heart failure persists. 41. The method of treatment of heart failure according to embodiments 30-41, wherein the patient has one or more comorbidities. 42. The method of treatment of heart failure according to embodiments 30-42, wherein the one or more comorbidities is selected from the group comprising cachexia, sarcopenia, frailty, COPD, coronary artery disease, valvular heart disease, chronic kidney disease, hypertension, atrial fibrillation, obesity, diabetes, anaemia and / or stroke. 43. The method of treatment of heart failure according to embodiments 30-43, wherein the iron deficiency is defined as a serum ferritin level below 100 ng / mL or the serum ferritin level is between 100-299 ng / mL with transferrin saturation (TSAT) below 20%. 44. The method of treatment of heart failure according to embodiments 30-44, wherein the administration of the iron complex improves the clinical health status of the patient comprising the exercise capacity, reduced aerobic capacity, and / or reduced endurance, of the patient which is measured by 6-min-walking test distance, symptoms of heart failure which is classified by NYHA functional class, cardiac function which is determined by measuring cardiac biomarker (NT-BNP) levels and comparison to baseline, inflammatory status by measuring inflammatory biomarker levels (CRP, PCT) and quality of life by determining KCCQ . 45. The method of treatment of heart failure according to embodiments 30-45, wherein the administration of the iron carbohydrate complex improves the exercise capacity, reduced aerobic capacity, and / or reduced endurance of the patient, wherein the exercise capacity of the patient is measured as a 6-minute walk test distance (6MWTD) compared to the patient's exercise capacity prior to initiation of treatment with the iron complex. 46. Pharmaceutical composition comprising one or more iron carbohydrate complexes for use in the treatment of a patient suffering from heart failure (HF) with preserved rejection fraction (HFpEF) or a patient being at risk of developing heart failure. 47. Pharmaceutical composition for use in the treatment according to the preceding embodiments, wherein an iron carbohydrate complex is administered to the patient intravenously. 48. Pharmaceutical composition for use as a medicament according to the preceding embodiments, wherein the iron carbohydrate complex is selected from the group comprising iron monosaccharide, iron disaccharide or iron polysaccharide, such as iron carboxymaltose complex, iron mannitol complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, an iron polyglucose sorbitol carboxymethyl ether complex, or an iron hydrogenated dextran complex. 49. Pharmaceutical composition comprising one or more iron carbohydrate complexes for use in the treatment of a patient with at least one of the diseases, selected from the group comprising cachexia, sarcopenia, frailty, COPD, atrial fibrillation, obesity, diabetes, and / or stroke. 50. Pharmaceutical composition for use as a medicament according to the preceding embodiments, wherein the patient has or has not also anemia. Figures The invention is further described by the following figures. These are not intended to limit the scope of the invention, but represent preferred embodiments of aspects of the invention provided for greater illustration of the invention described herein. Brief description of the figures Figure 1: Design of the FAIR­HFpEF trialFigure 2 Flow chart showing the number of patients fulfilling the criteria and those included inthe studyFigure 3 Detailed results on changes in 6min-walking test distanceA) Results over time until week 52 for the whole population (arrows indicate dosing visits) B) Individual data (baseline to week 24) for patients with Hgb<12.0 g / dL (…..) or ≤12.0 g / dL (–)Figure 4 Changes in 6min-walking test distance from baseline to 24 weeks for 8prespecified subgroupsFigure 5 Results for Patient Global Assessment over time for (A) KCCQ, (B) EQ-5D, and(C) NYHA class Detailed description of the figures Figure 1: Design of the FAIR­HFpEF trial. Patients will be seen at the clinic within two weeks prior to the first dose of study drug to determine eligibility for the study. Before receiving the first dose of study medication, patients will undergo a screening process within two weeks to assess their eligibility, including signing informed consent and having laboratory data no older than 7 days. Eligible patients will then be randomized to receive either intravenous FCM or placebo / saline in a double-blind manner, with unblinded personnel handling drug administration and monitoring for elevated iron or hemoglobin levels. Study assessments, including the 6MWT, quality of life questionnaires, and blood samples for cardiovascular and neurohormonal markers, will occur at baseline and several follow-up visits over a 52-week period. If iron overload or severe anemia occurs, FCM treatment will be adjusted or discontinued according to specific criteria, but patients will remain in the study for its full duration. [AF, atrial fibrillation; BNP, B­type natriuretic peptide; HF, heart failure; LVEF, left ventricular ejection fraction; NT­probnp, N­terminal pro B­type natriuretic peptide; MR­proanp, mid­regional pro atrial natriuretic peptide; NYHA, New York Heart Association; TSAT, transferrin saturation. Since a single dose of FCM must not exceed 1000 mg, visit 2B is a dosing visit for patients who require more than 1000 mg of FCM for iron store repletion. A sy­ ringe symbol marks a dosing visit.]Figure 2: Flow chart showing the number of patients fulfilling the criteria and those included inthe study. A total of 74 patients with HFpEF, reduced exercise capacity and ID were screened at 7 centers. Of these, 42 patients were eligible for randomization, three of whom were excluded for one patient’s personal reasons and two for the occurrence of exclusion criteria after enrolment and conduct of the screening visit. The final analysis was therefore performed in 39 patients in a modified intention-to-treat analysis per statistical analysis plan, 18 of whom received FCM, 21 received placebo / saline. The two groups were similar with regards to age, sex, haemoglobin, serum ferritin, TSAT, other laboratory characteristics, and use of cardiovascular medications and 6MWTD at baseline.Figure 3A and B: Detailed results on changes in 6min-walking test distanceA) Results over time until week 52 for the whole population (arrows indicate dosing visits). The 6MWTD improved in the FCM group from 284.6 ± 112.0 at baseline to 350.2 ± 117.2 m at week 24 (p<0.01) with a change of 45 ± 62 m. The respective values in the placebo / saline group were 306.3 ± 67.5 at baseline and 309.6 ± 65.8 at week 24 with a change of -8 ± 61 m. The difference in least square means between the two groups at 24 weeks was 49.1 ± 22.1 m (95% confidence interval, 5.1–93.0, p=0.0292). Detailed data are provided in Figure 3A and Table 3, which also shows that the efficacy was best at week 32 (treatment effect between groups: 65±22 m, p=0.005) and then almost completely lost at week 52 weeks (treatment effect 13±23 m, p=0.57), i.e.20 weeks after intravenous iron administration was performed for the last time. Arrow indicates a treatment application. B) Individual data (baseline to week 24) for patients with Haemoglobin (Hgb) <12.0 g / dL or ≥ 12.0 g / dL. Improvements in 6MWTD were similar in patients with and without anemia (i.e. haemoglobin values of <12.0 or ≥12.0 g / dL) at baseline Figure 4: Effect of treatment of FCM on 6-minute walk distance stratified by subgroups. Data are presented as mean values with 95% CI. All P values are for interactions and are 2-sided with no adjustments made for multiple comparisons. Transferrin saturation, TSAT; GFR, glomerular filtration rate; NYHA, New York Heart Association. Scale for Estimate (meters). Figure 5: Results for Patient Global Assessment over time for (A) KCCQ, (B) EQ-5D, and(C) NYHA class. By week 24, five of 17 patients in the group receiving FCM reported moderateor much improvement in the PGA with no statistically different difference compared to the group that received placebo / saline where 8 of 18 patients reported little or moderate improvement (p=0.20). At baseline, 11 (61.1%) of 18 patients treated with FCM were in NYHA class II, 7 (38.9%) in NYHA class III. In week 24, 11 (64.7%) of 17 patients were in NYHA class II, 6 (35.3%) in NYHA class III. For patients receiving placebo / saline, the respective numbers at baseline were 10 (47.6%) of 21 patients in NYHA class II and 11 (52.4%) in NYHA class III. Like in the FCM group, values were essentially unchanged in week 24 with 9 (50%) of 18 patients in NYHA class II and 9 (50%) patients in NYHA class III. Between baseline and week 24 or other time points, no significant difference was noted between FCM and placebo / saline with regards to changes in the values of the EQ-5D, KCCQ or PGA (see Figure 5A to 5C) or serum values in creatinine, estimated glomerular filtration rate, bilirubin, blood urea nitrogen, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl-transferase (gGT), or C-reactive protein (CRP, all p>0.05).

[0002] EXAMPLES The invention is further described by the following examples. These are not intended to limit the scope of the invention, but represent preferred embodiments of aspects of the invention provided for greater illustration of the invention described herein. The examples are to be considered as providing a non-limiting illustration and technical support for carrying out the invention. The examples below present: - Trial design of the underlying clinical trial FAIR-HFpEF - The clinical efficacy of treating iron deficiency in patients with heart failure with preserved ejection fraction Example 1: FAIR-HFpEF trial design Background: Iron deficiency is highly prevalent in patients with heart failure and has well established diagnostic criteria. Its occurrence is associated with reduced quality of life, exercise capacity and increased hospitalization rates and mortality. The clinical efficacy of treating iron deficiency has not been tested in patients with heart failure with preserved ejection fraction (HFpEF). Methods: Trial structure The FAIRHFpEF trial is a prospective, multicenter, 1:1 randomized, double-blind, parallel, placebo-controlled trial investigating the effects of intravenous FCM compared to placebo (saline) designed to study the effect on exercise tolerance, symptoms and quality of life in patients with HFpEF and ID (defined as ferritin < 100 ng / mL or ferritin 100–299 ng / mL plus TSAT < 20%), with or without anemia. A detailed trial protocol has been previously published (von Haehling S, Doehner W, Evertz R, Garfias-Veitl T, Diek M, Karakas M, et al. Iron deficiency in heart failure with preserved ejecton fraction: rationale and design of the FAIR-HFpEF trial. Glob Cardiol 2023;1:39–46). The trial is conducted as an investigator-initiated trial in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice. An independent ethics committee approved the protocol at every participating center. All subjects provide written informed consent. The trial is registered at clinicaltrials.gov (NCT03074591). The FAIR­HFpEF trial is designed to investigate the effect of intravenous iron repletion in iron deficient patients with HFpEF using FCM. The primary endpoint is the change in exercise capacity from baseline to week 24 as assessed in a 6­min­walking test. The 6­min­walking test measures the distance an individual is able to walk, in meters, over a total of six minutes on a hard, fiat surface. The goal is to walk as far as possible in six minutes to give an assessment of exercise tolerability. The individual is allowed to self­pace and rest as needed as they traverse back and forth along a marked walkway (e.g. hospital corridor). The 6MWTD provides an information about a patient’s exercise ca­pacity during usual daytime (submaximal) activities and thus provides a different measure than the peak oxygen consump­tion measured during spiroergometry, which assesses exercise capacity during maximal effort. Study participants The FAIRHFpEF trial aims to recruit men and women aged ≥18 years who have chronic HFpEF and reduced exercise capacity, New York Heart Association functional class IIIII symptoms, treatment with a diuretic, raised natriuretic peptide levels or a history of hospitalization with a diagnosis of HF within 12 months prior to randomization, and an LVEF ≥45% as measured by echocardiographic or magnetic resonance imaging within 6 months prior to randomization. Reduced exercise capacity at baseline is defined as a 6MWTD <450 m, measured as average of the last 2 documented tests within 8 weeks prior to planned randomization that also need to be within 20% of each other. Subjects are required to have ID at screening, defined as ferritin <100 ng / mL or ferritin 100-300 ng / ml with transferrin saturation (TSAT) <20%. At randomization, patients are required to have evidence of diastolic dysfunction as assessed using echocardiography. The full list of inclusion criteria is provided in Table 1. The target number of patients to be randomized given the original protocol was 100 anemic and 100 nonanemic patients with HFpEF, i.e.200 patients in total. Table 1: Obligatory inclusion criteria Patient is to and written informed consent Age ≥18 years Clinical diagnosis of HFpEF with LVEF ≥45% at screening or within 6 months prior to planned randomization (assessed by echocardiography or magnetic resonance imaging) Ambulatory for at least 7 days with NYHA class II or III at time of randomization (the screening visit can take place at the end of a hospitalization) Treated with a diuretic Presence of AF is allowed in 2 out of 4 patients (calculated per center) At screening or randomization, presence of one of the following criteria: a) hospitalization with a diagnosis of HF within 12 months prior to planned randomization b) raised plasma levels of natriuretic peptides in a patient with sinus rhythm (i.e. in patients without AF: NTproBNP >300 pg / mL or BNP >100 pg / mL or MRproANP >120 pmol / L; in patients with AF: NTproBNP >600 pg / mL or BNP >200 pg / mL or MRproANP >250 pmol / L) Evidence of diastolic at or defined as: Hemoglobin >9.0 g / dL and ≤14.0 g / dL (at screening) ID with ferritin <100 ng / mL or ferritin 100299 ng / mL plus TSAT <20 % (at screening); 6MWTD at baseline <450 m (average of the last 2 documented tests within 8 weeks prior to planned randomization that also need to be within 20% of each other) HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; AF, atrial fibrillation; HF, heart failure; LA, left atrium; ID, iron deficiency; TSAT, transferrin saturation; 6MWTD, 6­minute walk test distance. Major exclusion criteria embrace any prior echo LVEF measurement <40%, clinical signs of infection or the use of intravenous iron, erythropoietin or blood transfusions within 60 days prior to enrolment. A complete list of exclusion criteria is provided in Table 2. Table 2: Exclusion criteria Unable to sign informed consent Any prior echocardiography measurement of LVEF <40% Clinical signs and symptoms of infection including fever >38°C Use of intravenous iron, erythropoietin, or blood transfusions within the previous 60 days Use of concurrent immunosuppressive therapy History of acquired iron overload or haemochromatosis (or a first relative with haemochromatosis) Known hypersensitivity to FCM or any other intravenous iron product Known bleeding or hemolytic anemia Presence of any condition that precludes exercise testing, such as decompensated HF, significant musculoskeletal disease, unstable angina pectoris, obstructive cardiomyopathy, severe uncorrected valvular disease, or uncontrolled bradyarrhythmias or tachyarrhythmias Probable alternative diagnoses that in the opinion of the investigator could account for the patient’s HF symptoms such as severe obesity, primary pulmonary hypertension, or COPD; hence, patients with the following are excluded: a) severe COPD, i.e. with known FEV1<50%, requiring home oxygen therapy, or on chronic oral steroid therapy Presence of uncontrolled atrial fibrillation with resting heart rate >110 / min Presence of uncontrolled hypertension with blood pressure >160 / 100 mm Hg Renal replacement therapy Concurrent therapy with an erythropoiesis stimulating agent Known active malignancy Known HIV or active hepatitis infection Pregnancy Patients, who may be dependent on the sponsor, the investigator or the trial sites, have to be excluded from the trial Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial Participation in another clinical trial within previous 30 days and / or anticipated participation in another trial during this study Inability to fully comprehend and / or perform study procedures in the investigator’s opinion Persons staying at an institution due to order by a national body or a court of law LVEF, left ventricular ejection fraction; FMC, ferric carboxymaltose; HF, heart failure; COPD, chronic obstructive pulmonary disease. Study visits and follow-up Patients will attend clinic within two weeks prior to the first dose of study medication to evaluate their eligibility for the study (Figure 1). Laboratory data used for determination of eligibility at the baseline visit must not be older than 7 days. Patients will sign the informed consent document before any study-specific procedures are performed. After this enrolment, blood samples will be taken. The results of these evaluations will be checked at the baseline visit to confirm eligibility according to the inclusion and exclusion criteria. Table 3 provides the full list of assessments performed during screening. Table 3: Procedures performed during the first screening visit. Assignment of subject identification number - Conformance with inclusion / exclusion criteria (blood samples will be taken, for evaluation at the baseline visit before randomization) - At least two hemoglobin values are to be obtained on site during the screening period. The mean of two values will be used for determination of eligibility and iron deficit. The time between these hemoglobin analyses can be 2 to 7 days. The later of the two hemoglobin values may not be older than 7 days at the baseline visit; it can also be obtained on the day of the baseline visit - Recording of demographic data and baseline characteristics (year of birth, height, race and gender). In addition, socioeconomic data (employment status, reason for unemployment, health insurance status) will be recorded - Medical and surgical history (past five years or onset of chronic HF, whichever is longer) Prior medication history during the 12 weeks before screening - Vital signs (blood pressure, pulse rate, body weight and waisthip ratio) - Clinical chemistry - Hematology - Vitamin B12 and serum folate status. In case of deficiencies, the patient is to receive substitution with preparations of Vitamin B12 and / or folate. In this case the patient can be rescreened using the same subject identification number - Iron status - Neurohormonal and inflammatory markers Urine pregnancy test (for female patients of childbearing potential) - NYHA classification HF, heart failure; NYHA, New York Heart Association. After baseline assessments, eligible patients will be randomized in a 1:1 ratio to receive intravenous FCM or placebo / saline (normal saline: 0.9% w / v NaCl) by unblinded investigators. In the FCM group, FCM will be administered according to the dosing schedule detailed in Table 4. In the placebo / saline group, patients will receive the equivalent number of normal saline infusions. Table 4: Dosing schedule in the FAIR­HFpEF trial. Visit (week) Total ferric carboxymaltose in mg Weight <70 kg Weight ≥70 kgHb <10 g / dL ≥10 g / dL Hb , ≤14 g / dL Hb <10 g / dL ≥10 g / dL Hb ≤14 g / dL 2A (baseline) 1000 1000 1000 1000 2B (week 1) 500 ­ 1000 500 3 (week 8) ­ ­ ­ ­ 4 (week 16) If required* If required* If required* If required* 500* 500* 500* 500* 5 (week 24) ­ ­ ­ ­ 6 (week 32) If required* If required* If required* If required* 500* 500* 500* 500* 7 (week 52 ­ ­ ­ ­ HB, hemoglobin. *If required, i.e. if serum ferritin <300 ng / mL. Study related assessments (including 6MWT, patient global assessment, quality of life questionnaires and NYHA class) will be performed by blinded investigators at baseline (visit 2), and visits 3 (week 8±3 days), 4 (week 16±1 week), 5 (week 24±1 week), 6 (week 32±2 weeks), and 7 (week 52±2 weeks). At assessment visits, a clinical examination and study related tests will be performed. Blood samples will be taken and stored for later assessment of cardiovascular and neurohormonal blood markers as well as characteristics of iron metabolism and immune status [baseline (visit 2), and visits 3, 4, 5, 6, and 7]. To keep the study doubleblind (FCM is a dark brown solution), certain study procedures are to be performed by unblinded independent personnel at the site. The unblinded study personnel will perform the following study procedures: i. Drug accountability ii. Prepare and administer infusions (in black syringe and behind curtain to keep patient blinded). iii. Monitor patients for elevated iron parameters or hemoglobin levels and proceed according to stopping rule below. Procedures are decided by the unblinded physician. In case of elevated levels of ferritin >800 ng / mL, or ferritin >500 ng / mL when TSAT is >50%, or hemoglobin >16 g / dL at any stage, FCM treatment has to be discontinued and placebo / saline is to be given instead. In this case, ferritin, TSAT and hemoglobin should be rechecked at the next visit, and these visits should coincide with planned dosing visits and / or assessment visits. Once ferritin has dropped to <400 ng / mL,and TSAT to <45%, and hemoglobin to <16 g / dL, treatment with FCM is to be reinstituted. In case severe anemia develops (i.e. hemoglobin ≤9 g / dL), the patient is to discontinue treatment but remain in the study and further management of anemia is at the investigator’s discretion. The study duration for all patients enrolled is 52 weeks (including followup for adverse events). All patients will be followed according to protocol and will receive doubleblind iron repletion therapy or placebo / saline. Primary and secondary endpoints The primary endpoint is the change in exercise capacity from baseline (visit 1 to visit 5 (week 24±1 week) as assessed by the change in 6MWTD. This change will be assessed as the difference of the 6MWTD in meters from baseline to visit 5. Secondary endpoints include the change in 6MWTD from baseline (visit 2) to visits 3, 4, 6, and 7 and the change in PGA, NYHA class, blood parameters of kidney function and inflammation, and HRQoL from baseline (visit 2) to visit 3, 4, 5, 6, and 7, and the rate of recurrent cardiovascular hospitalizations and death. As a tertiary endpoint, resource use and costs associated with the treatment with intravenous FCM compared with placebo / saline were assessed as were safety endpoints detailed elsewhere.Fehler!Textmarke nicht definiert..For each subject the 6MWTD will be assessed by the same assessor throughout the study whenever possible. Health-related quality of life (HRQoL) will be assessed using the HRQoL questionnaire which combines the European Quality of Life 5 Dimensions (EQ5D) questionnaire as a generic instrument with a diseasespecific cardiology instrument: the Kansas City Cardiomyopathy Questionnaire (KCCQ). A complete list of endpoints is given in Table 5. Table 5: Complete list of endpoints in the FAIR­HFpEF trial. Primary endpoint Change in exercise capacity from baseline (visit 2A) to visit 5 as assessed by the 6MWTD Secondary Change in 6MWTD (in meters) from baseline (visit 2A) to visit 3, 4, 6, and 7, endpoints respectively PGA assessment at visit 3, 4, 5, 6, and 7; Change in NYHA functional class from baseline (visit 2A) to visit 3, 4, 5, 6, and 7, respectively Change in plasma levels of blood parameters of kidney function and inflammation between baseline (visit 2A) and visits 3, 4, 5, 6, and 7 Change in quality-of-life assessments (EQ-5D, KCCQ) from baseline (visit 2A) to the respective assessment timepoint at visit 3, 4, 5, 6, and 7 Rate of recurrent HF hospitalizations and death* Tertiary endpoints Resource use and costs associated with the treatment with intravenous FCM compared with placebo / saline: a. *medication, generic name (date of prescription, dose); b. ambulatory care contacts (not exclusively study related); c. examinations and procedures performed; d. emergency room visits / day clinic visits; e. hospitalizations (number, duration, reason); f. other health care services; g. days of work lost. Safety endpoints Frequency, severity, and relationship to treatment for all adverse and serious adverse events (including deaths and hospitalizations with date-change – all to be adjudicated) Observation of episodes of anaphylactoid reactions or symptomatic hypotension after IV iron infusion Differences in vital signs (systolic and diastolic blood pressure, heart rate), body weight, waist-to-hip-ratio, alanine transaminase, urea, eGFR and creatinine from baseline to visit 7 Number and duration of hospitalizations (total, for cardiovascular conditions, for worsening HF) 6MWTD, 6­minute walking test; PGA, patient global assessment; NYHA, New York Heart Association; HF, heart failure; FCM, ferric carboxymaltose; IV, intravenous; eGFR, estimated glomerular filtration rate. *Given the lower than planned number of enrolled patients, these endpoints are considered exploratory and, as applicable, for safety considerations only. Sample size calculation and statistical analysis A sample size of 86 patients per group gives a power of 90% for a two­sample t­test at the usual one­sided level of 2.5% if the standardized mean difference (Cohen’s d) is 0.50. Accounting for 10% dropout (which is supported by findings in the FAIR­HF and CONFIRM­HF trials) theaim is to recruit 100 patients per group (i.e.200 patients in total). The sample size calculation was carried out using nQuery Advisor 7.0 (Statisti­ cal Solutions Ltd., Cork, Ireland) The primary endpoint (change in the 6MWTD from base­ line to visit 5) will be analyzed using a mixed model repeated measures approach adjusted presence of atrial fibrillation, anemia, visit and baseline 6MWTD. Standard procedures for reporting of adverse events will be used. Adverse events will be summarized as frequencies and percentages by intervention or treatment group. Event rates were compared using negative binomial regression accounting for over-dispersion. All analyses were carried out using the statistical software R (version 4.3.1). Secondary endpoints: The analyses of continuous secondary endpoints will follow the same lines as the analysis of the primary endpoint. Patient global assessment scores at all visits will be compared between both groups using chi­ square tests or Fisher’s exact tests, when appropriate. Mixed effects proportional odds models will be used to adjust patient global assessment scores at all visits and NYHA class change from baseline to all visits for covariates. Taken together: The FAIR-HFpEF trial aims to explore the impact of intravenous iron supplementation using Ferric Carboxymaltose (FCM) on iron-deficient patients with Heart Failure with preserved Ejection Fraction (HFpEF). The primary measure of effectiveness is the change in a patient's ability to exercise, as determined by the 6-minute walking test (6MWTD), from the start of the study to week 24. This test assesses submaximal exercise capacity, which is distinct from peak oxygen consumption measured during maximal effort tests. Previous studies have shown that most medications recommended for Heart Failure with reduced Ejection Fraction (HFrEF) do not improve exercise capacity, with ivabradine being an exception. In contrast, exercise training has been effective in enhancing exercise capacity in both HFrEF and HFpEF. While improving Health-Related Quality of Life (HRQoL) has seen some success with certain drugs in HFrEF, results in HFpEF are less conclusive, and HRQoL assessments like KCCQ and EQ-5D are commonly used in clinical trials to measure this outcome. Example 2: Clinical efficacy of treating iron deficiency in patients with heart failure with preserved ejection fraction The clinical efficacy of treating iron deficiency has not been tested in patients with heart failure with preserved ejection fraction (HFpEF). Iron deficiency is highly prevalent in patients with heart failure and has well established diagnostic criteria. Its occurrence is associated with reduced quality of life, exercise capacity and increased hospitalization rates and mortality. The FAIR- HFpEF trial reports the effect of intravenous iron repletion in iron deficient patients with HFpEF using FCM. Methods: Patients attended clinic within two weeks prior to the first dose of study medication to evaluate their eligibility for the study (Figure 1). The FAIR-HFpEF trial screened 74 patients with HFpEF, reduced exercise capacity and iron deficiency (defined as serum ferritin <100 ng / mL or serum ferritin 100-299 ng / mL with transferrin saturation [TSAT] <20%), of whom 42 were eligible for randomization. Patients baseline characteristics were as follows: age 77.6±7.8 years, 62% female, haemoglobin 12.0±1.4 g / dl, serum ferritin 63.5±47.6 µmol / l, TSAT 18.0±7.5%, NT-proBNP 1246±1620 ng / l, 6-minute walk test (6-MWT) 299±91 m. Patients were treated in a multi-center, double-blind, randomized clinical trial with intravenous ferric carboxymaltose (FCM) at doses aimed to replenish iron stores vs. placebo (Figure). The primary endpoint is the difference in exercise capacity from baseline to week 24 as assessed by the 6-MWT. Secondary endpoints include health-related quality of life assessments like the Kansas City Cardiomyopathy Questionnaire (KCCQ), the European Quality of Life – 5 Dimensions (EQ-5D) questionnaire and global function tests. Treatment was provided at baseline in 1-2 sessions (1000-2000 mg FCM or saline), as well as at week 16 (500-1000 mg) and at week 32 (500-1000 mg), always in a setting that kept the blinding. Treatment according to randomisation was continued at week 16 and 32 unless ferritin was >800 ng / mL, or when ferritin was >500 ng / mL with TSAT >50%, or when haemoglobin was >16.0 g / dL at any stage during follow-up (in which case saline had to be given). These stopping rules are identical to that of FAIR-HF and almost as liberal as in FAIR-HF214. Randomisation in FAIR-HFpEF included stratification by the presence of atrial fibrillation (AF) at baseline and by screening haemoglobin (Hb). The trial enrolled men and women aged ≥18 years with chronic HFpEF and diminished exercise capacity (defined as a 6MWTD <450 m, averaged from the last two documented tests within 8 weeks prior to planned randomization), New York Heart Association (NYHA) class II–III symptoms, treated with a diuretic, elevated natriuretic peptide levels or a history of HF-related hospitalization within 12 months prior to randomization, and a left ventricular ejection fraction (LVEF) ≥45%. All procedures were conducted in accordance with the principles of the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice. An independent ethics committee approved the protocol at all participating centers, and all subjects provided written informed consent. The trial was registered at clinicaltrials.gov (NCT03074591). The original protocol aimed to randomize a total of 200 patients, evenly split between those with and without anaemia. However, enrolment proved to be more challenging than anticipated, compounded by the impact of the COVID-19 pandemic. As a result, enrolment was halted after recruiting 42 patients. Trial procedures With FCM being a brown substance and normal saline serving a comparator, the trial was conducted by unblinded and blinded investigators. Following screening (visit 1), study-related assessments, including the 6MWTD, patient global assessment (PGA), quality of life questionnaires, and NYHA class, were performed by blinded investigators at baseline (visit 2) and after visits 3 (week 8±3 days), visit 4 (week 16±1 week), visit 5 (week 24±1 week), visit 6 (week 32±2 weeks), and visit 7 (week 52±2 weeks ). Health-related quality of life (HRQoL) was evaluated using the ‘HRQoL questionnaire,’ which integrates the European Quality of Life – 5 Dimensions (EQ-5D) questionnaire as a generic instrument with a disease-specific cardiology tool, the ‘Kansas City Cardiomyopathy Questionnaire’ (KCCQ). During all assessment visits, a clinical examination and relevant study-related tests were conducted. Unblinded investigators performed infusions of intravenous placebo (normal saline) or FCM according to the dosing regimen in Table 6 as well as certain trial-related procedures (e.g., drug accountability, monitoring patients for elevated iron parameters or haemoglobin levels). Table 6. Dosing schedule in the FAIR-HFpEF trial. TOTAL MG FCM Visit (week) Weight <70 kg Weight ≥70 kg Hb <10 g / dL Hb ≥10 g / dL Hb <10 g / dL Hb ≥10 g / dL ≤14 g / dL ≤14 g / dL 2A (baseline) 1000 mg 1000 mg 1000 mg 1000 mg 2B (week 1) 500 mg - 1000 mg 500 mg 3 (week 8) - - - - 4 (week 16) If required* If required* If required* If required* 500 mg 500 mg 500 mg 500 mg 5 (week 24) - - - - 6 (week 32) If required* If required* If required* If required* 500 mg 500 mg 500 mg 500 mg 7 (week 52) - - - - *if serum ferritin <300 ng / mL. Primary and secondary endpoints The primary endpoint of the trial is the change in 6MWTD from baseline (visit 2) to visit 5 (week 24±1 week), assessed in meters. Secondary endpoints include the change in 6MWTD from baseline (visit 2) to visits 3, 4, 6, and 7 and the change in PGA, NYHA class, blood parameters of kidney function and inflammation, and HRQoL from baseline (visit 2) to visit 3, 4, 5, 6, and 7, and the rate of recurrent H cardiovascular hospitalizations and death. As a tertiary endpoint, resource use and costs associated with the treatment with intravenous FCM compared with placebo / saline were assessed as were safety endpoints detailed elsewhere.Fehler! Textmarke nicht definiert.Statistical analysis A sample size of 86 patients per group gives a power of 90% for a two­sample t­test at the usual one­sided level of 2.5% if the standardized mean difference (Cohen’s d) is 0.50. Accounting for 10% dropout the original aim was to recruit 100 patients per group. Enrolment, however, proved to be more difficult than expected and was hampered by the COVID-19 pandemic that led to termination of enrolment in November 2022 after 42 patients. A sample size of 21 patients per group yields a power of at least 80% at a one-sided level of 2.5% as long as the mean difference is at least 0.89. The primary analysis was based on the modified intention to treat (mITT) population including all randomized patients who received at least one dose of study medication and have at least one post-baseline assessment of the primary endpoint; they are analyzed in the group they are randomized to. The primary endpoint was analyzed using a mixed model repeated measures (MMRM) approach adjusted for the presence of atrialfibrillation, anaemia, age at baseline, visit and baseline 6MWTD; visit by treatment interactions are also included. Least square group differences are reported with standard errors, 95% confidence intervals (CIs) and p-values testing the null hypothesis of no intervention effect using all available data without any imputation method.. The analyses of continuous secondary endpoints followed the same lines as the analysis of the primary endpoint. PGA at all visits wascompared between both groups using Fisher’s exact tests. To adjust for covariates, a mixed-effects proportional odds model including a random intercept for subject and the main effects for treatment, visit, treatment-visit interaction, presence of atrial fibrillation at baseline, haemoglobin status at baseline, age at baseline, and LVEF at baseline as fixed effects was calculated. The change in NYHA class from baseline to the respective visit in the FCM group was tested using the Bowker symmetry test. Between groups the NYHA class was compared using the Wilcoxon­Mann­Whitney test. As with PGA, mixed effects proportional odds models were used for adjusted analyses. Time to event outcomes are displayed by Kaplan-Meier curves and analyzed using Cox regression. Recurrent events are modelled by negative binomial regression. Adverse events were summarized as frequencies and percentages by treatment group. Event rates were compared using negative binomial regression accounting for over-dispersion. All analyses were carried out using the statistical software R (version 4.2.2 or higher). RESULTS A total of 74 patients with HFpEF, reduced exercise capacity and ID were screened at 7 centers. Of them, 42 patients were eligible for randomization, three of whom were excluded for one patient’s personal reasons and two for the occurrence of exclusion criteria after enrolment and conduct of the screening visit. The final analysis was therefore performed in 39 patients in a modified intention- to-treat analysis per statistical analysis plan, 18 of whom received FCM, 21 received placebo / saline. The two groups were similar with regards to age, sex, haemoglobin, serum ferritin, TSAT, other laboratory characteristics, and use of cardiovascular medications and 6MWTD at baseline. Detailed clinical characteristics are presented in Table 7. For the overall cohort, the median age was 80 years [inter-quartile range (IQR): 75–84], 62% were women, haemoglobin was 12.5 g / dL (IQR: 11.4–13.1), serum ferritin was 49.0 ng / mL (IQR: 24.7–91.0), TSAT was 17.0% (IQR: 13.7–22.6), and median N-terminal pro-B-type natriuret-ic peptide was 772 pg / mL (IQR: 342–1499). Seven of 39 patients had an LVEF of <50%. The two treatment groups were similar with regard to age, sex, haemoglobin, serum ferritin, TSAT, other laboratory characteris-tics, and use of cardiovascular medications and 6MWTD at baseline (all P > 0.05). Detailed clinical characteristicsare presented in Table 7. The data obtained was statistically analyzed in two ways, therefore 2 valuesare given for some characteristics. Table 7: Baseline characteristics of patients included in Fair-HFpEF Placebo / saline FCM p-value (n=21) (n=18) Sex (female) 14 (66.7%) 10 (55.6%) 0.48 Weight (kg) 82.1 ± 10.1; 83.0 (75.0-90.0) 84.4 ± 15.3; 83.0 0.83 (75.8-87.8) BMI (kg / m2) 29.5 ± 3.8; 29.8 (26.1-32.5) 29.3 ± 4.4; 28.9 0.74 (26.3-32.4) BMI ≥30 kg / m210 (47.6%) 6 (33.3%) 0.37 Age Mean (SD) 78.86 ± 7.03 76.44 ± 8.88 0.41 Median (Q1-Q3) 80.0 (77.0 – 84.0) 79.3 (72.3 – 82.8) 0.41 LVEF Mean (SD) 54.1 ± 6.7; 55.1 ± 7.8 55.6 ± 6.7; 55.3 ± 0.55 6.5 Median (Q1-Q3) 55 (50-56) 55 (50-60) NYHA class II 10 (47.6%) 11 (61.1%) 0.52 III 11 (52.4%) 7 (38.9%) Cause of heart failure Ischaemic 14 (66.7%) 9 (50.0%) 0.29 Non-ischaemic 7 (33.3%) 9 (50.0%) Haemodynamics Heart rate (bpm) 69.7 ± 11.8; 68 (61-80) 66.7 ± 8.3; 68 (60- 0.58 71) Systolic blood pressure 124.0 ± 17.5; 125 (111-136) 130.8 ± 23.8; 127 0.39 (mmHg) (113-151) Diastolic blood pressure 66.7 ± 8.1; 67 (62-729) 72.4 ± 14.2; 75 (63- 0.13 (mmHg) 80) Laboratory results Haemoglobin (g / dL) 11.9 ± 1.3; 12.0 (11.4-12.8) 12.2 ± 1.6; 12.9 0.28 (11.7-13.2) Serum ferritin (µmol / L) 63.1 ± 46.5; 50 (25-94) 57.0 ± 39.4; 44 (23- 0.76 72) Serum ferritin < 100 17 (81%) 15 (83%) ng / mL TSAT (%) 17.1 ± 7.2; 16.0 (14.0-21.0) 19.1 ± 7.4; 19.9 0.34 (13.8-24.8) TSAT < 20% 14 (67%) 9 (50%) Creatinine (mg / dL) 1.1 (0.8-1.5) 1.1 (0.8-1.5) 0.06 eGFR (mL / min / 1.73 m2) 55.6 ± 21.1; 59 (36-76) 46.5 ± 19.3; 40 (32- 0.25 66) (n= 17) Bilirubin (mg / dL) 1.30 ± 1.81; 1.95 ± 3.68; 0.52 0.7 (0.5-0.9) (n=10) 0.5 (0.4-0.6) (n=7) Blood urea nitrogen 15.1 ± 14.0; 10 (8-18) 16.3 ± 11.6; 19 (10- 0.77 (mg / dL) (n=9) 33)(n=6) ASAT (U / L) 25.4 ± 9.4; 24 (22-27) 23.1 ± 7.7; 25 (22- 0.74 38) ALAT (U / L) 19.4 ± 9.5; 19 (15-24) 17.5 ± 9.0; 16 (14- 0.40 22) γ-GT (U / L) 40.0 ± 36.2; 27(17-46) 37.7 ± 33.6; 31 (19- 0.97 53) (n= 17) CRP (mg / L) 7.5 ± 16.2; 2.9 (1.4-6.0) 24.7 ± 75.9; 2.1 0.87 (1.8-5.0) NT-proBNP (pg / mL) 826 ± 567; 490 (343-1331) 1902 ± 2559; 1129 0.39 (407-2293) Medical history Previous Hospitalization 26.3%; 5 (24%) 52.9%; 9 (50%) 0.10 for HF Atrial fibrillation / flutter 10 (47.6%) 10 (55.6%) 0.62 Diabetes mellitus 8 (38.1%) 10 (55.6%) 0.28 Hypertension 19 (90.5%) 16 (88.9%) 1.00 Dyslipidaemia 14 (66.7%) 10 (55.6%) 0.48 Coronary artery disease 14 (66.7%) 9 (52.9%), (50%) 0.39 Previous myocardial 50.0%; 7 (33 %) 11.1%, 1 (6%) 0.09 infarction Previous CABG 14.3%; 2 (10%) 22.2%; 2 (11%) 1.00 Previous PCI 85.7%; 12 (57%) 66.7%; 6 (33%) 0.34 Valvular heart disease 12 (57.1%) 11 (61.1%) 0.80 (deemed clinically meaningful) Treatment ACE inhibitor 13 (61.9%) 6 (35.3%) (33%) 0.19 ARB 6 (28.6%) 5 (29.4%) (28%) 1.00 ARNi 0 (0 %) 2 (11.8%) 0.19 Beta-blocker 16 (76.2%) 76.5%, 13 (72%) 1.00 Calcium antagonist 7 (33.3%) 3 (17.6%) 0.46 MRA 7 (33.3%) 2 (11.8%) 0.15 SGLT2 inhibitor 4 (19.0%) 1 (5.9%) 0.36 Any other anti-diabetic 7 (33.3%) 35.3%, 6 (33%) 1.00 Loop diuretic 14 (66.7%) 88.2%, 15 (83%) 0.15 Insulin 3 (14.3%) 3 (17.6%) 1.00 Any other diuretic 6 (28.6%) 23.5%, 4 (22%) 1.00 Allopurinol 5 (23.8%) 47.1%, 8 (44%) 0.18 Proton-pump inhibitor 11 (52.4%) 41.2%, 7 (39%) 0.15 Cholesterol-lowering 16 (76.2%) 10 (58.8%) 0.31 drug Any anti-platelet 10 (47.6%) 52.9%, 7 (39%) 1.00 Any anticoagulant 10 (47.6%) 52.9%; 9 (50%) 1.00 Previous ICD 1 (4.8%) 1 (5.6%) 1.00 Previous CRT 3 (14.3%) 0 (0%) 0.24 ALAT, alanine aminotransferase; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor- neprilysin inhibitor; ASAT, aspartate aminotransferase; CABG, coronary artery bypass graft; eGFR, estimated glomerular filtration rate; ICD, implantable cardioverter defibrillator; MRA, mineralocorticoid receptor antagonist; γ­GT, γ­glutamyltransferase. Follow-up Of the 18 patients assigned to receive FCM, one did not complete the 24 weeks and the 52 weeks of follow-up. Of the 21 patients assigned to receive placebo / saline, three did not complete the 24 weeks and four did not complete the 52 weeks of follow-up. Primary and secondary end points The 6MWTD improved in the FCM group from 284.6 ± 112.0 at baseline to 350.2 ± 117.2 m at week 24 (p<0.01) with a change of 45 ± 62 m compared to baseline (p= 0.14), or in other words the 6MWTD improved in the FCM group from a median of 308 m (IQR: 198–378) at baseline to 403 m (IQR: 306–416) at week 24, with a change of 45 ± 62 m compared to baseline (P = 0.014) The respective values in the placebo / saline group were 306.3 ± 67.5 (or 325 m (IQR: 250–342)) at baseline and 309.6 ± 65.8 (or 308 m (IQR: 285–354)) at week 24 (p>0.2) with a change of -8 ± 61 m vs. base-line (P = 0.62). The difference in least square means between the two groups at 24 weeks was 49.1 ± 22.1 m (mean ± SEM, 95% confidence interval, 5.1–93.0, p=0.0292). Of note, in total, 31 patients performed 6MWTD at week 24 (FCM: 15, placebo 16; see Tables 8 and 9), but all 39 randomized patients contributed data to the result in the MMRM analysis for this endpoint. Detailed data are provided in Figure 3A and Table 10, which also shows that the efficacy was somewhat further enhanced or best at week 32 (treatment effect between groups: 65±22 m, p=0.005) and then mostly or almost completely lost at 52 weeks (treatment effect 13±23 m, p=0.57), i.e.20 weeks after intravenous iron administration was performed for the last time. Improvements in 6MWTD were similar in patients with and without anemia (i.e. haemoglobin values of <12.0 or ≥12.0 g / dL) at baseline (Figure 3B). When key subgroups were considered (including sex, ischaemic aetiology of HF, NYHA class, glomerular filtration rate (GFR) and haematinics at baseline), no significant interaction was found for subgroup of HFpEF patients to respond differently to FCM vs placebo with regards to changes in 6MWTD between baseline and 24 weeks (all p>0.3, Figure 4), however, all subgroups were small. Due to these small subgroup sizes, the absence of interaction should not be considered as evidence of no interaction. By week 24, 5 of 17 patients in the group receiving FCM reported moderate or much improvement in the PGA with no statistically different or significant difference compared to the group that received placebo / saline where 8 of 18 patients reported little or moderate improvement (in the FCM group 5 of 17, p=0.20) (see Fig.5C). At baseline, 11 (61.1%) of 18 patients treated with FCM were in NYHA class II, 7 (38.9%) in NYHA class III. In week 24, 11 (64.7%) of 17 patients were in NYHA class II, 6 (35.3%) in NYHA class III. For patients receiving placebo / saline, the respective numbers at baseline were 10 (47.6%) of 21 patients in NYHA class II and 11 (52.4%) in NYHA class III. Like in the FCM group, values were essentially unchanged in week 24 with 9 (50%) of 18 patients in NYHA class II and 9 (50%) patients in NYHA class III. Between baseline and week 24 or other time points, no significant difference was noted between FCM and placebo / saline with regards to changes in the values of the EQ-5D, KCCQ or PGA (see Figure 5A to 5C) or serum values in creatinine, estimated glomerular filtration rate, bilirubin, blood urea nitrogen, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl-transferase (gGT), or C-reactive protein (CRP, all p>0.05). Significant increases were noted from baseline to week 24 in patients treated with FCM vs. placebo / saline for haemoglobin (P = 0.028), ferritin (P ≤ 0.001), and TSAT levels (P ≤ 0.001) (see Table 10). Serum levels of creatinine, estimated glomerular filtration rate, bilirubin, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, or C- reactive protein were not different between treatment groups at week 24 (all P > 0.05). The data obtained was statistically analyzed in two ways and therefore 2 values are given for some key results presented in Table 10. Table 8: Completeness of visits and data for the primary endpoint assessment: Patient retention across visits for the mITT population. Overall Placebo / Saline Ferric Characteristic (N=39)1(N=21)1Carboxymaltose(N=18)1Performed visit 1 (Screening) 39 (100%) 21 (100%) 18 (100%)Performed visit 2a (Baseline) 39 (100%) 21 (100%) 18 (100%)Performed visit 2b (Week 1; if35 (95%) 18 (95%) 17 (94%)required) Performed visit 3 (Week 8) 38 (97%) 21 (100%) 17 (94%)Performed visit 4 (Week 16) 37 (95%) 19 (90%) 18 (100%)Performed visit 5 (Week 24) 35 (95%) 18 (95%) 17 (94%)Performed visit 6 (Week 32) 34 (92%) 18 (95%) 16 (89%)Performed visit 7 (Week 52) 34 (92%) 17 (89%) 17 (94%)1n (%)Table 9: Completeness of visits and data for the primary endpoint assessment: 6MWTperformed in visits (in the mITT population). Overall Placebo / Saline Ferric Characteristic (N=39)1(N=21)1Carboxymaltose(N=18)16MWT performed visit 2a39 (100%) 21 (100%) 18 (100%)(Baseline) 6MWT performed visit 3 (Week35 (90%) 20 (95%) 15 (83%)8) 6MWT performed visit 4 (Week31 (84%) 16 (84%) 15 (83%)16) 6MWT performed visit 5 (Week31 (86%) 16 (84%) 15 (88%)24) 6MWT performed visit 6 (Week31 (89%) 17 (89%) 14 (88%)32) 6MWT performed visit 7 (Week26 (76%) 12 (71%) 14 (82%)52) 1n (%) Table 10 Key results Baseline Week 24 Treatment p-value effect with 95% CI (or OR) (at week 24) Placebo FCM Placebo FCM (n=21) (n=18) (n=18) (n=17) Primary endpoint 6-minute walk 306.3±67.5; 284.6±112.0; 309.6±65.8; 350.2±117.2; 49.0±22.1 0.029 test distance 325 (250- 308 (198- 308 (285- 403 (306- (m) 342 378) 354) 416) Change from Change from BL to w24: BL to w24: -7.8±60.6 44.9±61.9 Secondary endpoints Patient global - - Much Much worse:0 OR 0.924 0.91 assessment worse:1 Worse: 1 (0.24, 3.51) Worse:1 Little worse:2 Little worse:2 Unchanged:9 Unchanged:6 Litlle Litlle improved:0 improved:5 Improved:4 Improved:3 Much Much improved:1 improved:0 NYHA class 2.52±0.51 2.38±0.50 2.50±0.51 2.35±0.49 -0.03±0.15; 0.83; II: 10 II: 11 II: 9 II: 11 (-0.32, 0.26) 0.63 III: 11 III: 7 III: 9 III: 6 EQ-5D-3L 0.65±0.18; 0.68± 0.22; 0.60±0.23; 0.64±0.23; -0.028 0.21 0.68 (0.59- 0.62 (0.50- 0.69 (0.60- 0.68 (0.50- ±0.057; -0.03 0.76) 0.71) 0.78) 0.78) (-0.14, 0.09) KCCQ Overall 63.9±21.3; 63.4±23.0; 52.4±19.2; 70 64.8±16.6; 60 6.5±5.1 0.21 Summary 72 (50-77) 50 (36-66) (54-82) (56-81) (-3.8, 16.7) Score Change from Change from BL to w24: BL to w24: 0.49 ± 14.81 12.41 ± 11.53 eGFR 55.6±21.1; 46.5±19.3; 51.7±19.3; 49.0±16.4; 0.27±3.72 0.94 (mL / min / 1.73 59 (36-76) 40 (32-66) 50 (35-72) 47 (38-63) (-7.16, 7.70) m2) CRP (mg / L) 8±16; 25±76; 4±3; 6±9; -8.2±12.1; 0.50 2.9 (1.3-6.7) 2.1 (1.8-6.1) 2.5 (0.8-5.0) 2.3 (1.5-8.3) (-32.6, 16.2) Other endpoints and biomarker assessments Haemoglobin 11.9±1.3; 12.5±1.1; 12.0±1.2; 13.6±0.9; 0.93±0.41 0.028 (g / dL) 12.0 (11.4- 12.9 (11.7- 12.1 (11.2- 13.8 (13.4- (0.10, 1.76) 12.8) 13.2) 13.1) 14.2) Ferritin 63.1±46.5; 57.0±39.4; 56.4±36.8; 306.9±137.2; 215.2±37.2; <0.001 (µmol / L) 50 (25-94) 44 (23-72) 46 (29-78) 326 (238- (141, 289) 402) TSAT (%) 17.1±7.2; 19.0±7.4; 19.0±6.6; 31.2±11.1; 9.7±2.9; 0.001 16.0 (14.0- 19.9 (13.8- 19.0 (13.5- 30.0 (24.5- (3.9, 15.5) 21.0) 24.8) 23.0) 35.6) Systolic blood 124±18; 130±23; 126±20; 126±14; 1±6; 0.84 pressure 125 (111- 127 (113- 130 (113- 127 (118- (-10.3, 12.6) (mmHg) 136) 151) 135) 139) Diastolic blood 67±8; 70±14; 71±9; 71±11; -4±3 0.282 pressure 67 (62-72) 75 (63-81) 71 (64-77) 71 (63-79) (-10.3, 3.0) (mmHg) Heart rate 70±12; 66±9; 72±12; 67±15; -4±4 0.257 (bpm) 68 (61-80) 68 (60-71) 74 (64-82) 66 (60-67) (-12, 33) ASAT (U / L) 26±8; 25±5; 25±7; 25±5; -0.22±4.3 0.96 24 (22-27) 25 (22-28) 24 (21-31) 26 (23-27) (-8.3, 8.7) ALAT (U / L) 19±9; 23±10; 16 18±8; 20 (17- 23±9; 22 (17- 2.4±2.8 0.38 19 (15-24) (14-22) (n= 25) 28) (n= 16) (-3.0, 7.8) 17) γ-GT (U / L) 41±35; 27 41±32; 31 42±39; 30 72±51; 54 21±14; (-5.4, 0.12 (17-46) (19-53) (n= (16-52) (33-105) (n= 48.3) 17) 16) Creatinine 1.17±0.45; 1.56±0.75; 1.27±0.45; 1.1 1.37±0.51; -0.09±0.14; 0.53 (mg / dL) 1.1 (0.8-1.5) 1.3 (1.0-1.6) (09-1.5) 1.2 (1.1-1.6) (-0.23, 0.16) Blood urea 24.1±30.8; 24.8±20.9; 16.7±12.9; 31.4±27.5; 0.13±5.4; 0.98 nitrogen 9.8 (7.5- 18.9 (9.7- 11.8 (9.7- 19.2 (10.3- (-10.8, 11.1) (mg / dL) 18.2) (n= 9) 32.8) (n= 6) 15.6) (n= 6) 45.7) (n= 9) BL, baseline; OR, odds ratio Safety Survival status was available for all patients through week 52 with no patient having died during the conduct of the trial. A total of 5 of 21 patients receiving placebo / saline and 1 of 18 patients receiving FCM were hospitalized for cardiovascular reasons during the conduct of the trial, —in total 8 vs.2 cardiovascular hospitalization events were observed in the two treatment groups, respectively (P = 0.045). Nine patients in the placebo group and 3 patients in the FCM group reported at least one serious adverse event (P = 0.085). The total number of adverse events (76 vs.114) and serious adverse events (5 vs.19) was lower in patients treated with FCM compared to placebo. To account for the number of events and observation time per patient, we used a negative binomial regression showing a rate ratio of 0.38 (95% CI: 0.17, 0.88; P = 0.023) for the number of adverse events and of 0.27 (95%CI: 0.07, 0.96; P = 0.043) for the number of serious adverse events. The incidence serious adverseevents was significantly higher in patients on placebo / saline than on FCM (19 vs 5 SAEs, p=0.04), primarily driven by serious adverse events that required hospitalization or prolongation of an existing hospitalization (16 vs 4 events) and by events that were deemed life threatening (3 vs none) (Table 11). No significant difference was detected for the occurrence of adverse events, which were numerically higher for cardiovascular, musculoskeletal, and renal events in the placebo / saline group than in the FCM group. Data on serious and nonserious adverse events are also shown in Table 11. Between baseline and week 24 or other time points, no significant difference was noted between FCM and placebo / saline with regards to changes in the serum values of creatinine, estimated glomerular filtration rate, bilirubin, blood urea nitrogen, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl-transferase (gGT), or C-reactive protein (CRP, all p>0.05). The study treatment was stopped prematurely in 3 of the 18 patients assigned to receive FCM and in 1 of the 21 patients assigned to receive placebo. No severe allergic reactions related to the study treatment were reported. Table 11. Safety data Placebo / saline FCM p-value Safety Event (n=21) (n=18) Number of Patients with at least17 (81%) 16 (88%) 1.000one AE, n (%) Number of Patients with at least9 (43%) 3 (17%) 0.085one SAE, n (%) Serious adverse events 19 5 0.043 Results in death 0 0 Life threatening 3 0 Requires inpatient hospitalization 16 4 or prolongation of existing hospitalization Other medically important 0 1 Adverse events 114 76 Cardiovascular 30 16 0.62 Cognitive 1 0 Dermatological 3 2 Gastrointestinal 4 2 Haematological 1 0 Infectiological 0 3 Metabolic 1 0 Musculoskeletal 7 2 Nephrotoxic 1 0 Neurological 1 2 Renal 4 2 Respiratory 5 5 Other 56 42 Actions No Action taken 80 67 0.004 Dose adjusted / temporary 4 0 0.15 interruption of study drug Permanent discontinuation 1 3 0.30 Hospitalization 16 2 0.009 Other action 19 4 0.018 * The SAEs that were classified as “Requires inpatient hospitalisation or prolongation of existing hospitalisation” were sub-classified as follows: • Cardiovascular: 8 (Placebo: 6, FCM: 2) • Cognitive: 1 (Placebo) • Dermatologic: 2 (Placebo) • Muskuloskeletal: 2 (Placebo) • Respiratory: 1 (Placebo) • Other: 6 (placebo: 4, FCM: 2) DISCUSSION The results of the trial show for the first time that FCM improves exercise capacity as assessed by the 6MWTD in patients with HFpEF and ID as defined using standard criteria for the diagnosis of ID proposed in the guidelines of the ESC and American College of Cardiology (ACC) / American Heart Association (AHA) / Heart Failure Society of America (HFSA). The change in 6MWTD with FCM vs placebo by week 24 in the FAIR-HFpEF trial—even though being based on a small number of subjects—suggests presence of a meaningful change that is at least as big or may even gobeyond what was seen in the FAIR-HF trial. The change in 6MWTD with FCM vs. placebo by week24, the primary endpoint of the trial, was 49 ± 22m with a 95% CI of 5 to 93 m (p<0.03) and provides evidence of a meaningful change that goes beyond what was seen in the FAIR-HF trial, the first large-scale trial in patients with HFrEF and ID published some 15 years ago, in which the increase was 35 ± 8 m by week 24 in the group that received FCM.Fehler! Textmarke nicht definiert.No significant changes, however, were noted for self-reported patient global assessment of well- being, HRQoL assessments or NYHA functional class. Importantly, no significant differences were noted for changes in laboratory markers including creatinine, estimated glomerular filtration rate, bilirubin, blood urea nitrogen, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl-transferase (gGT), or C-reactive protein between patients receiving FCM and placebo / saline, buttressing the safety of FCM application. FCM slightly increase haemoglobin values and corrected measures of iron deficiency as expected. It is crucial to recognize two key points: firstly, the standard criteria for diagnosing ID are applicable in patients with HFpEF, and the treatment of patients with ID using these criteria yields clinical improvement. Secondly, the potential improvement in 6MWTD achieved through FCM treatment clearly surpasses the threshold of clinical relevance that is needed to establish to consider medical progress being made, and is estimated at approximately 25–35 meters with HF or other cardio- pulmonary diseases like pulmonary hypertension15,16. Notably, a study by Täger et al., drawing on data from over 970 patients suggested that the minimal important difference before and after an intervention should surpass this level. This reflects a 10% enhancement in 6MWTD, particularly noteworthy for individuals with severely limited baseline distances below 400 meters17, just like in our study cohort of comparatively old subjects whose median age was 80 years, highlighting the importance of treatment effects also for geriatric populations. Some other points are important in this context: A recently published systematic review has underscored our challenges in enhancing exercise capacity among patients with HF.iIn those with HFrEF, many guideline-recommended therapies, including inhibitors of the angiotensin converting enzyme (ACE), sacubitril / valsartan, beta-blockers, mineralocorticoid-receptor antagonists, and SGLT2 inhibitors like dapagliflozin and empagliflozin, have shown limited efficacy in increasing 6MWTD or peak oxygen consumption. Only ivabradine has demonstrated notable benefits in thisrealm.i,ii The situation is similar in HFpEF, where trials of ACE inhibitors and other frequently utilizedmedications have failed to improve exercise capacity. While the PEP-CHF trial suggested improvements with perindopril in HFpEF patients, it fell short of its primary endpoint, complicatingthe analysis of secondary outcomes.iii Dapagliflozin has shown some modest improvement in6MWTD (mean effect size of 20.1 m), but similar effects have not been consistently observed with empagliflozin.21,22Similarly, semaglutide has shown modest improvement in 6MWTD of 14.3 and21.5 m in patients with HFpEF and obesity, with and without diabetes, respectively..23 Hence, thesignificance of enhancing exercise capacity by replenishing iron stores in HFpEF cannot be overstated and appears to be a promising therapeutic approach. The loss of a significant treatment effect at 52 weeks may, on the one hand, be related to the reduced number of patients investigated at that time (14 on FCM vs 12 on placebo) compared to week 24 (15 on FCM vs 16 on placebo) – which in part is due to the hospitalisation events observed mostly in the placebo group and with this overall small study cohort easily could impact overall results – but on the other hand, may also underscore the need for sufficient, repeat iron administration to achieve clinical impact. In this regard, the distance of 20 weeks from last administration of FCM at 32 weeks to 52 weeks may be too long and the cumulative dose of at most 500 mg FCM in the last 6 months prior to the assessment at week 52 too little. In contrast, at the 24 weeks time-point (used for the primary endpoint assessment), the last administration of FCM was only 8 weeks prior to the assessment time (i.e. at week 16) and the cumulative dose FCM in the 6 months prior was 4-5 times higher (i.e.1500-2500 mg). The only other consistently effective strategy for improving exercise capacity in both HFrEF and HFpEF patients remains exercise training, which is supported by numerous intervention trials utilizing various protocols.24,25,26,27,28The pathophysiological improvements associated with ID treatment in HF extend well beyond the established efficacy of treating anaemia. Indeed, iron is an essential component of mitochondrial enzymes involved in generating cellular energy in the form of adenosine triphosphate and phosphocreatine in skeletal muscle. Charles-Edwards et al.ivhave provided mechanistic insights suggesting that iron repletion therapy improves the phosphocreatine recovery half-time in skeletal muscle of iron-deficient patients with HFrEF. This observation is significant not only for iron- deficient patients, but potentially also for those with sarcopenia, a muscle-wasting syndrome frequently encountered in elderly populations and in patients with HF, likewise contributing to reduced exercise capacity30,31,32Lastly, statistically significant and clinically meaningful improvements in 6MWTD were detected, but not in measures of HRQoL. The KCCQ overall summary score we found a numerical change of 6.5±5.1 points at week 24 (p=0.21). Applicants consider these results as promising, but also as requiring validation. In FAIR-HF, in patients with HFrEF, the same endpoint showed an increase of 7±2 points (p<0.001). The trial had a more than 10 times greater number of patients included, and hence much more power to detect such a change reliably. Various HRQoL assessment tools are commonly employed in HF clinical trials. The KCCQ is a self-administered, disease-specific questionnaire capturing physical function, symptoms, social function, self-efficacy, and quality of life. In HFpEF, there is limited experience with therapies that can positively impact KCCQ. In PARAGON-HF, it was demonstrated that sacubitril / valsartan can somewhat reduce the decline in KCCQ scores over time (1.0 points treatment difference at 12 months). For SGLT2 inhibitors in HFpEF, in the DELIVER and EMPEROR-Preserved studies with dapagliflozin and empagliflozin respectively, KCCQ results improved by 1-2 points over 8 to 12 months.11,33Much more meaningful results were achieved in the recent STEP-HFpEF trials in obese HFpEF patients with and without diabetes, where weight loss of on average 8.4% induced by semaglutide vs placebo resulted in a change from baseline to week 52 in KCCQ overall summary score of 7.5 points within 12 months(95%CI 5.2–9.6, p<0.0001).34 Future studies need to validate, whether the present results – whichappear to be in that range – can be validated to this end. Hence, largers trial in iron deficient patients with HFpEF are needed. They also should be longer in duration to test the intriguing, but very preliminary safety results seen here, suggesting that serious adverse events – and namely hospitalisation rates – may be reduced by medically correcting iron deficiency in HFpEF patients. Example 3: Subgroup analysis – Treatment with FCM in patients suffering from heart failure and HFpEF with comorbidities In the Fair-HFpEF study population baseline data (like on BMI and QoL questionnaires and some blood markers) allows us to characterise patients also for one or more comorbidities comprising cachexia, sarcopenia, frailty, COPD, coronary artery disease, valvular heart disease, chronic kidney disease, hypertension, atrial fibrillation, obesity, diabetes, anaemia and / or stroke The benefits of FCM in subgroups of such patients are explored by subgroup analyses. These results exemplify clinical benefits with regards to a) exercise capacity (i.e.6min-walking test distance), symptoms (i.e. NYHA functional class), cardiac function (NT-BNP levels), inflammatory status (CRP levels) and quality of life (KCCQ overall or subdomains). Example 4: Analysis of exercise capacity measured by 6-min-walking test distance with patients suffering from heart failure and HFpEF and at least one other comorbidity after treatment with iron carbohydrate complex A responder analysis was performed to analyse the effect of treatment with an iron carbohydrate complex associated with clinically meaningful improvement of exercise capacity in 6-minute walk test (6MWT) distance among patients randomized to 24 weeks (part A) and 32 weeks (part B) of FCM versus placebo in the double-blind FAIR-HFpEF trial. The primary endpoint of the clinical trial is the change in 6min-walking distance after 24 weeks (part A) and 32 weeks (part B) of double-blind treatment with ferric carboxymaltose (FCM) vs placebo. In group 1, patients received placebo, in group 2 patients were administered FCM. The improvement in quality of life as determined by the KCCQ Overall Summary Score was also analyzed and is presented in the following Tables. In addition to the data for both the 6MWTD analysis and the KCCQ score analysis, the patient characteristics regarding age, gender and distribution of NHY classes 2 / 3 are presented.Furthermore, results are shown for patients with obesity, patients with coronary artery disease ,patients with ischemic aetiology, patients with non-ischemic aetiology, patients with Diabetesmellitus, patients with atrial fibrillation and patients classified in NYHA class III.In addition, results are shown for the analysis of change in 6MWTD from baseline to Week 32 for patients suffering from cachexia / sarcopenia and with a BMI <= 25. Part A: Analysis of the change in 6MWTD from baseline to Week 24 1. Subgroup patients with obesity: BMI < 25Table 12: Analysis of change in 6MWTD from baseline to Week 24 for patients with obesity: BMI < 25. In group 1, patients received placebo, in group 2 patients were administered FCM.Group N Obs N Mean Std Dev Minimum Maximum1 3 2 16.0000000 48.0832611 -18.0000000 50.0000000 2 3 3 55.6666667 35.0190424 20.0000000 90.0000000 Table 13: Baseline patient characteristics for patients with obesity: BMI < 25 on age and improvement in quality of life determined by KCCQ with regard to the 6MWTD-analysis Table 14: Baseline patient characteristics for patients with obesity: BMI < 25 on distribution NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis

[0003] Table 15: Statistical analysis of change in KCCQ Overall Summary Score (KCCQ OSS) from baseline to Week 24 for patients with obesity: BMI < 25. Group N Obs N Mean Std Dev Minimum Maximum1 3 1 -6.5104167 . -6.5104167 -6.51041672 3 3 16.2326389 11.1989260 4.9479167 27.3437500Difference +21.7 In favor of FCM: Table 16: Statistical analysis of baseline patient characteristics for patients with obesity: BMI < 25 on age and improvement in quality of life determined by KCCQ OSS

[0004] Table 17: Statistical analysis of baseline patient characteristics for patients with obesity: BMI < 25 on distribution NYHA class 2 / 3 and gender with regard to KCCQ-OSS analysis 2. Subgroup: Patients with obesity: BMI > 30Table 18: Analysis of change in 6MWTD from baseline to week 24 for patients with obesity: BMI > 30 Group N Obs N Mean Std Dev Minimum Maximum 1 10 9 25.6666667 72.5861 137.0000000 83.0000000 557 2 6 5 93.8000000 63.7706 19.0000000 190.0000000 829 Table 19: Baseline patient characteristics for patients with obesity: BMI > 30 on age regard to the 6MWTD-analysis Group N Obs Variable N Mean Std Dev Minimum Maximum19Age9 74.7777778 8.2124567 60.0000000 84.0000000 BMI 9 32.8144444 2.4960524 30.4800000 38.7900000 6MWTD 9 319.5555556 64.5428368 185.0000000 400.0000000 25Age5 67.0000000 10.6770783 54.0000000 82.0000000 BMI 5 34.5320000 2.7760800 32.3700000 38.8600000 6MWTD 5 297.6000000 99.3166653 160.0000000 425.0000000 Table 20: Baseline patient characteristics for patients with obesity: BMI > 30 on age and improvement in quality of life determined by KCCQ OSS with regard to the 6MWTD-analysis Table 21: Baseline patient characteristics for patients with obesity: BMI > 30 on distribution NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis

[0005] Table 22: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients with obesity BMI > 30 Group N Obs N Mean Std Dev Minimum Maximum1 10 9 1.7361111 18.6398130 -32.2916667 33.59375002 6 6 12.9774306 9.8110633 -3.6458333 23.4375000Difference +11.2 In favor of FCM:

[0006] Table 23: Statistical analysis of baseline patient characteristics for patients with obesity: BMI > 30 on age and improvement in quality of life determined by KCCQ OSS

[0007] Table 24: Analysis of change in 6MWTD from baseline to Week 24 for patients with obesity: BMI> 35 Group N Obs N Mean Minimum Maximum1 1 1 -1372 22 +6719 115 Difference +204m In favor of FCM: Wherein Group 1 comprises : age: 79 – male:1, female: 0 Wherein Group 2 comprises: age: 54 & 61, – male:1, female: 1 Table 25: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients with obesity: BMI > 35 Group N Obs N Mean Minimum Maximum1 1 1 -7.032 2 2 +10.94 8.33 13.54Difference +11.2 In favor of FCM: Table 26: Analysis of change in 6MWTD from baseline to Week 24 for patients with obesity: Subgroup: BMI > 38 Group N Obs N Mean Minimum Maximum1 1 1 -1372 11 +19Difference +156m In favor of FCM: Table 27: Analysis of change in 6MWTD from baseline to Week 24 for patients with coronary artery disease Group N Obs N Mean Std Dev Minimum Maximum1 7 5 10.8000000 44.8296777 -28.0000000 83.00000002 8 6 82.8333333 58.7449289 13.0000000 190.0000000Difference +72mGroup N Obs N Mean Std Dev Minimum MaximumIn favor of FCM: Table 28: Baseline patient characteristics for patients with coronary artery disease on age and improvement in quality of life determined by KCCQ OSS with regard to the 6MWTD-analysis Table 29: Baseline patient characteristics for patients coronary artery disease on distribution NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis

[0008] Table 30: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients with patients with coronary artery disease Group N Obs N Mean Std Dev Minimum Maximum1 7 5 11.7187500 15.4537052 -5.7291667 33.59375002 8 7 17.4107143 14.6694418 -3.6458333 37.7604167Difference +5.7 In favor of FCM: Table 31: Statistical analysis of baseline patient characteristics for patients with with coronary artery disease on age and improvement in quality of life determined by KCCQ OSS

[0009] Table 32: Statistical analysis of baseline patient characteristics for patients with with coronary artery disease on distribution NYHA class 2 / 3 and gender with regard to KCCQ OSS analysis Subgroup: Ischemic aetiology Table 33: Analysis of change in 6MWTD from baseline to Week 24 for patients with ischemic aetiology Group N Obs N Mean Std Dev Minimum Maximum1 14 11 -16.2727273 66.7009609 -137.0000000 50.00000002 9 8 19.7500000 56.0350656 -63.0000000 115.0000000 Table 34: Baseline patient characteristics for patients with with ischemic aetiology on age and improvement in quality of life determined by KCCQ OSS with regard to the 6MWTD-analysis Table 35: Baseline patient characteristics for patients with ischemic aetiology on distribution NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis

[0010] Table 36: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients with ischemic aetiology Group N Obs N Mean Std Dev Minimum Maximum1 14 12 -4.1883681 12.2818009 -32.2916667 16.92708332 9 9 8.3912037 8.0189495 -2.6041667 25.0000000 Difference +12.2 In favor of FCM: Table 37: Statistical analysis of baseline patient characteristics for patients with ischemic aetiology on age and improvement in quality of life determined by KCCQ OSS Table 38: Statistical analysis of baseline patient characteristics for patients with ischemic aetiology on distribution NYHA class 2 / 3 and gender with regard to KCCQ OSS analysis

[0011] Subgroup: Non-ischemic aetiology Table 39: Analysis of change in 6MWTD from baseline to Week 24 for patients with non- ischemic aetiology Group N Obs N Mean Std Dev Minimum Maximum1 7 5 10.8000000 44.8296777 -28.0000000 83.00000002 9 7 73.7142857 58.8039519 13.0000000 190.0000000Difference +63m In favor of FCM: Table 40: Baseline patient characteristics for patients with with non-ischemic aetiology on age and improvement in quality of life determined by KCCQ-OSS with regard to the 6MWTD-analysis

[0012] Table 41: Baseline patient characteristics for patients with non-ischemic aetiology on distribution on NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis Table 42: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients with non-ischemic aetiology Group N Obs N Mean Std Dev Minimum Maximum1 7 5 11.7187500 15.4537052 -5.7291667 33.59375002 9 8 16.9270833 13.6499789 -3.6458333 37.7604167Difference +5.2 In favor of FCM: Table 43: Statistical analysis of baseline patient characteristics for patients with non-ischemic aetiology on age and improvement in quality of life determined by KCCQ-OSS Table 44: Statistical analysis of baseline patient characteristics for patients with non-ischemic aetiology on distribution NYHA class 2 / 3 and gender with regard to KCCQ OSS analysis

[0013] Subgroup: Diabetes mellitus Table 45: Analysis of change in 6MWTD from baseline to Week 24 for patients with Diabetes mellitus Group N Obs N Mean Std Dev Minimum Maximum 113 9 -10.2222222 60.0370256 -137.0000000 50.00000002 8 7 57.7142857 70.9171213 -32.0000000 190.0000000Difference +67.5m Group N Obs N Mean Std Dev Minimum Maximum in favor of FCM: Table 46: Baseline patient characteristics for patients with Diabetes mellitus on age and improvement in quality of life determined by KCCQ OSS with regard to the 6MWTD-analysis Table 47: Baseline patient characteristics for patients with Diabetes mellitus on distribution NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis

[0014] Table 48: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients with Diabetes mellitus Group N Obs N Mean Std Dev Minimum Maximum1 13 11 -2.1306818 8.6533744 -16.6666667 15.10416672 8 8 13.1510417 11.2165024 -2.6041667 27.3437500Difference +15 In favor of FCM: Table 49: Statistical analysis of baseline patient characteristics for patients with Diabetes mellitus on age and improvement in quality of life determined by KCCQ OSS Table 50: Statistical analysis of baseline patient characteristics for patients with Diabetes mellitus on distribution NYHA class 2 / 3 and gender with regard to KCCQ OSS analysis

[0015] Subgroup: Atrial fibrillation Table 51: Analysis of change in 6MWTD from baseline to Week 24 for patients with Atrial fibrillation group N Obs N Mean Std Dev Minimum Maximum1 11 11 -8.0909091 52.1813272 -137.0000000 50.00000002 8 6 35.5000000 30.3364467 13.0000000 90.0000000Difference +43.5m In favor of FCM: Table 52: Baseline patient characteristics for patients with Atrial fibrillation on age and improvement in quality of life determined by KCCQ OSS with regard to the 6MWTD-analysis Table 53: Baseline patient characteristics for patients with Atrial fibrillation on distribution NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis

[0016] Table 54: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients with atrial fibrillation Group N Obs N Mean Std Dev Minimum Maximum1 11 10 -0.5989583 10.8878184 -16.6666667 16.92708332 8 7 13.6532738 10.0644187 0.7812500 27.3437500Difference +14 In favor of FCM: Table 55: Statistical analysis of baseline patient characteristics for patients with atrial fibrillation on age and improvement in quality of life determined by KCCQ OSS Table 56: Baseline patient characteristics for patients with Atrial fibrillation on distribution NYHA class 2 / 3 and gender with regard to the KCCQ OSS analysis

[0017] Subgroup: NYHA III Table 57: Analysis of change in 6MWTD from baseline to Week 24 for patients which are classified as NYHA III Group N Obs N Mean Std Dev Minimum Maximum 111 8 10.0000000 66.0173137 -129.0000000 83.00000002 7 6 75.0000000 71.2853421 -10.0000000 190.0000000Difference +65m Group N Obs N Mean Std Dev Minimum Maximum In favor of FCM: Table 58: Baseline patient characteristics for patients which are classified as NYHA III on age and improvement in quality of life determined by KCCQ OSS with regard to the 6MWTD-analysis Table 59: Statistical analysis of change in KCCQ OSS from baseline to Week 24 for patients which are classified as NYHA III Group N Obs N Mean Std Dev Minimum Maximum1 11 10 2.7083333 17.3273108 -32.2916667 33.59375002 7 7 11.3839286 10.0282558 -3.6458333 25.0000000Difference +9.5 In favor of FCM: Table 60: Statistical analysis of baseline patient characteristics for patients which are classified as NYHA III on age and improvement in quality of life determined by KCCQ OSS Table 61: Baseline patient characteristics for patients which are classified as NYHA III on and gender with regard to the KCCQ-analysis PART B.) Change in 6MWTD from baseline to week 32 Table 62: Analysis of change in 6MWTD from baseline to Week 32 for patients with obesity: BMI < 25 group N Obs N Mean Std Dev Minimum Maximum1 3 2 -0.5000000 92.6309883 -66.0000000 65.00000002 3 2 109.5000000 41.7193001 80.0000000 139.0000000Table 63: Baseline patient characteristics for patients with obesity: BMI < 25 on age and improvement in quality of life determined by KCCQ OSS with regard to the 6MWTD-analysis (from baseline to weeks 32)

[0018] Table 64: Baseline patient characteristics for patients with obesity: BMI < 25 on distribution NYHA class 2 / 3 and gender with regard to the 6MWTD-analysis (from baseline to week 32) Table 65: Statistical analysis of change in KCCQ OSS from baseline to week 32 for patients with obesity: BMI < 25 group N Obs N Mean Std Dev Minimum Maximum1 3 2 -11.0677083 3.1304206 -13.2812500 -8.85416672 3 3 10.9375000 10.1895821 -0.7812500 17.7083333Difference +21 In favor of FCM: Table 66: Statistical analysis of baseline patient characteristics for patients with obesity: BMI < 25 on age and improvement in quality of life determined by KCCQ OSS(from baseline to week 32) Table 67: Baseline patient characteristics for patients with obesity: BMI < 25 on age and improvement in quality of life determined by KCCQ with regard to the KCCQ OSS analysis (from baseline to 32 week)

[0019] Subgroup: BMI <= 25 (for Cachexia / Sarcopenia) Table 68: Analysis of change in 6MWTD from baseline to week 32 for patients with Cachexia / Sarcopenia Group N Obs N Mean Std Dev Minimum Maximum1 3 2 -0.5000000 92.6309883 -66.0000000 65.00000002 4 3 77.3333333 63.0423138 13.0000000 139.0000000Difference +78m In favor of FCM: Table 69: Analysis of change in 6MWTD from baseline to week 32 for patients with obesity: BMI <25 and which are classified as NYHA class 3 (for Cachexia / Sarcopenia) Group N Obs N Mean1 1 1 +65 2 1 1 +139 Difference +74m In favor of FCM: Results: 6min-walking distance was significantly improved after 24 weeks. References 1. Rocha BML, Cunha GJL, Menezes Falcão LF. The Burden of Iron Deficiency in Heart Failure: Therapeutic Approach. J Am Coll Cardiol.2018;71:782-793. doi: 10.1016 / j.jacc.2017.12.027. PMID: 29447741. 2.1Savarese G, von Haehling S, Butler J, Cleland JGF, Ponikowski P, Anker SD. Iron deficiency and cardiovascular disease. 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Eur J Heart Fail 2020;22:92-102. McDonagh TA, Metra M, Adamo M, et al.2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: de­veloped by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2022;24:4-131. nker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436-48. Ponikowski P, van Veldhuisen DJ, Comin­Colet J, et al. Beneficial ef­fects of long­term intravenous iron therapy with ferric carboxymal­tose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015;36:657-68. Kalra PR, Cleland JGF, Petrie MC, et al. Intravenous ferric derisoma­ltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator­initiated, prospective, randomised, open­label, blinded­endpoint trial. Lancet 2022;400:2199-209. cEwan P, Harrison C, Binnie R, et al. Impact of ferric carboxymal­tose for iron deficiency at discharge after heart failure hospitalisa­tion: a European multinational economic evaluation. Eur J Heart Fail 2023;25:389-98. eidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA / ACC / HFSA guideline for the management of heart failure: a report of the American College of Cardiology / American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol 2022;79:e263- 421. Beale AL, Warren JL, Roberts N, Meyer P, Townsend NP, Kaye D. Iron deficiency in heart failure with preserved ejection fraction: a sys­tematic review and meta­analysis. Open Heart 2019;6:e001012 Bekfani T, Pellicori P, Morris D, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2019;108:203-11. on Haehling S, Arzt M, Doehner W, et al. Improving exercise ca­pacity and quality of life using non­invasive heart failure treatments evidence from clinical trials. Eur J Heart Fail 2021;23:92-113. Volterrani M, Cice G, Caminiti G, et al. Effect of carvedilol, ivabra­dine or their combination on exercise capacity in patients with heart failure (the CARVIVA HF trial). Int J Cardiol 2011;151:218-24. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, PEP­CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP­CHF) study. Eur Heart J 2006:2338-45. Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor da­pagliflozin in heart failure with preserved ejection fraction: a mul­ticenter randomized trial. Nat Med 2021;27:1954-60. Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of em­pagliflozin on exercise ability and symptoms in heart failure pa­tients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J 2021;42:700-10. AstraZeneca. DETERMINE­preserved. Dapagliflozin effect on exer­cise capacity using a 6­minute walk test in patients with heart fail­ure with preserved ejection fraction. Available from: https: / / clinicaltrials.gov / ct2 / show / results / NCT03877224. Accessed on: 24 February 2023. AstraZeneca. DETERMINE­reduced. Dapagliflozin effect on exercise capacity using a 6­minute walk test in patients with heart failure with reduced ejection fraction. Available from: https: / / clinicaltri­als.gov / ct2 / show / results / NCT03877237. Accessed on: 24 February 2023. Kitzman DW, Brubaker PH, Morgan TM, Stewart KP, Little WC. Ex­ercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single­blind trial. Circ Heart Fail 2010;3:659-67. Edelmann F, Gelbrich G, Düngen HD, et al. Exercise training im­proves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex­DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 2011;58:1780-91. Smart NA, Haluska B, Jeffriess L, Leung D. Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity. Con­gest Heart Fail 2012;18:295-301. Kitzman DW, Brubaker PH, Herrington DM, et al. Effect of en­durance exercise training on endothelial function and arterial stiff­ness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single­blind trial. J Am Coll Car­diol 2013;62:584-92. Kitzman DW, Brubaker P, Morgan T, et al. Effect of caloric restric­tion or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with pre­served ejection fraction: a randomized clinical trial. JAMA 2016;315:36-46. McMurray JJ, Packer M, Desai AS, et al. Angiotensin­neprilysin in­hibition versus enalapril in heart failure. N Engl J Med 2014;371: 993-1004. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin­neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609-20. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City cardiomyopathy questionnaire: a new health status measure for heart failure. J Am Coll Cardiol 2000;35:1245-55. Salah HM, Savarese G, Rosano GMC, Ambrosy AP, Mentz RJ, Fudim M. Intravenous iron infusion in patients with heart failure: a sys­tematic review and study­level meta­analysis. ESC Heart Fail 2023;10:1473-80 Sindone A, Doehner W, Comin­Colet J. Systematic review and meta­analysis of intravenous iron­carbohydrate complexes in HFrEF pa­tients with iron deficiency. ESC Heart Fail 2023;10:44-56 Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron reple­tion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 2017;317:1958-66. Erratum in: JAMA 2017; 317:2453 von Haehling S, Doehner W, Evertz R. et al. Ferric carboxymaltose and exercise capacity in heart failure with preserved ejection fraction and iron deficiency: the FAIR-HFpEF trial. Eur Heart J.2024 Oct 5;45(37):3789-3800. doi: 10.1093 / eurheartj / ehae479.

Claims

Claims 1. An iron carbohydrate complex for use in the treatment of a patient suffering from heart failure (HF) with preserved rejection fraction (HFpEF) or in a patient being at risk of developing heart failure.

2. The iron carbohydrate complex for use according to claim 1, wherein the iron carbohydrate complex is selected from the group comprising iron monosaccharide, iron disaccharide or iron polysaccharide, such as iron carboxymaltose complex, iron mannitol complex, iron polyisomaltose complex, iron polymaltose complex, iron gluconate complex, iron sorbitol complex, iron polyglucose sorbitol carboxymethyl ether complex, or iron hydrogenated dextran complex.

3. The iron carbohydrate complex for use according to claim 1 and 2, wherein the iron carbohydrate complex is selected from the group of ferric carboxymaltose, ironisomaltoside 1000, iron derisomaltose and ferumoxytol.

4. The iron carbohydrate complex for use according to any of the preceding claims, wherein the patient is suffering from heart failure with preserved rejection fraction (HFpEF) and iron deficiency (ID) 5. The iron carbohydrate complex for use according to any of the preceding claims, wherein heart failure is either chronic or acute heart failure.

6. The iron carbohydrate complex for use according to any of the preceding claims, wherein said use further improves heart failure symptoms, wherein the improvement in heart failure symptoms and / or quality of life is measured by a patient's higher score on the KCCQ Overall Summary Score (OSS) compared to the patient's score prior to initiation of treatment with a therapeutically effective amount of an iron carbohydrate complex.

7. The iron carbohydrate complex for use according to any of the preceding claims, wherein the patient is 18 years or older, wherein the patient does exhibit any one of the following criteria selected from the group comprising of chronic HFpEF, reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, New York Heart Association functional class IIIII symptoms, receiving treatment with a diuretic, raised natriuretic peptide levels (BNP ≥35 pg / mL or NT­proBNP level ≥125 pg / mL) or a history of hospitalization with a diagnosis of HF within 12 months prior to the beginning of treatment with the iron complex, an LVEF ≥45% as measured by echocardiographic or magnetic resonance imaging within 6 months prior to treatment with the iron complex, wherein the reduced exercise capacity, reduced aerobic capacity, and / or reduced endurance, at baseline is measured as a 6-minute walk test distance (6MWTD), after an assessment of medical history, a physical examination and an electrocardiogram reading of the patient.

8. The iron carbohydrate complex for use according to any of the preceding claims, wherein the overall doses of the iron complex per patient vary between 1000 mg to 5000 mg per year, preferably 1500 mg to 3000 mg per year, more preferably 1000 mg to 2000 mg per year, most preferably 500 mg to 1500 mg per year.

9. The iron carbohydrate complex for use according to any of the preceding claims, wherein initial doses of the iron complex for correcting the ID vary between 500 mg and 2000 mg provided in up to 2 administration sessions which are 7-14 days apart, and dosed depending on the body weight (kg) of the patient and their Hb levels (g / dL) measured.

10. The iron carbohydrate complex for use according to any of the preceding claims, wherein said iron complex is administered intravenously.

11. The iron carbohydrate complex for use according to any of the preceding claims, wherein the patients is suffering from at least one of the diseases selected from the group comprising cachexia, sarcopenia, frailty, COPD, atrial fibrillation, obesity, diabetes, and / or stroke.

12. The iron carbohydrate complex for use according to any of the preceding claims, wherein the patient has one or more comorbidities, wherein the one or more comorbidities is selected from the group comprising cachexia, sarcopenia, frailty, COPD, coronary artery disease, valvular heart disease, chronic kidney disease, hypertension, atrial fibrillation, obesity, diabetes, and / or stroke.

13. The iron carbohydrate complex for use according to any of the preceding claims, wherein the administration of the iron carbohydrate complex improves the clinical health status of the patient comprising the exercise capacity, reduced aerobic capacity, and / or reduced endurance, of the patient which is measured by 6-min-walking test distance, symptoms of heart failure which is classified by NYHA functional class, cardiac function which is determined by measuring cardiac biomarker (NT-BNP) levels and comparison to baseline, inflammatory status by measuring inflammatory biomarker levels (CRP, PCT) and quality of life by determining KCCQ .

14. The iron carbohydrate complex for use according to any of the preceding claims, wherein the administration of the iron complex improves the exercise capacity, reduced aerobic capacity, and / or reduced endurance of the patient, wherein the exercise capacity of the patient is measured as a 6-minute walk test distance (6MWTD) compared to the patient's exercise capacity prior to initiation of treatment with the iron complex.

15. Pharmaceutical composition comprising one or more iron carbohydrate complexes for use in the treatment of a patient suffering from heart failure (HF) with preserved rejection fraction, wherein the iron carbohydrate complex is administered to the patient intravenously.

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