Reimbursement Review

Ferric Carboxymaltose (Ferinject)

Sponsor: CSL Vifor

Therapeutic area: Iron deficiency in adult patients with heart failure

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

FCM = ferric carboxymaltose; ID = iron deficiency; NOC = Notice of Compliance; NYHA = New York Heart Association.

Introduction

Heart failure (HF) is a complex and life-threatening syndrome in which abnormal heart function leads to subsequent risk of clinical symptoms and signs of reduced cardiac output and/or pulmonary or systemic congestion at rest or with stress. It is the third leading cause of hospitalization in Canada, with a median length of stay of 7 days, and leads to readmission in 1 of 5 patients within 30 days after discharge.^1,2 This condition is marked by significant morbidity and mortality, reduced functional capacity, and poor quality of life. Patients with chronic HF (CHF) require continuous medical care, frequent monitoring, hospitalizations, and extensive treatment.^3,4

Symptoms of HF are classified using the New York Heart Association (NYHA) functional classes I to IV, which categorize the severity of symptoms ranging from minimal limitations during physical activity (class I) to severe symptoms even at rest (class IV). These symptoms reflect the progressive impact of HF on daily activities and quality of life.⁵

Approximately 60% of patients with HF have anemia and 40% of those without anemia have iron deficiency (ID).^4,6 When iron levels are too low to support adequate hemoglobin synthesis, it can lead to ID anemia (IDA), which impairs the blood's ability to carry oxygen efficiently either due to a reduced number of red blood cells or low Hemoglobinlevels. While anemia can have various causes, ID is the most prevalent.⁷ This condition significantly impacts patient well-being and outcomes^8,9 as iron plays a critical role in oxygen transport and cellular energy metabolism, particularly in tissues demanding high energy like cardiac muscle.^10-12

ID can be characterized in 2 main ways: depleted iron stores due to insufficient dietary intake, impaired absorption, or chronic blood loss (absolute ID); and/or reduced circulating iron linked to chronic inflammation, particularly seen in cardiovascular (CV) diseases (functional ID).^13,14 This inflammation leads to an increased release of hepcidin, a liver-expressed type II acute-phase protein and a major player in iron homeostasis.¹⁵ This mechanism contributes to ID observed in CV diseases. In HF, additional factors such as reduced bowel iron absorption due to generalized edema may also contribute to ID.^16,17 Therefore, hepcidin has been proposed as more a sensitive index to evaluate ID.^6,18,19

The prevalence of ID is 35% to 55% in outpatients with HF and 72% to 83% in patients admitted to hospital due to HF.²⁰ A recent study in Alberta²¹ found that among 17,463 patients with acute HF (AHF), 38.5% had their iron status evaluated within 30 days postindex episode, compared to 34.2% of 11,320 patients with CHF. Of those tested, 72.6% and 73.9% of patients with AHF and CHF, respectively, were found to have ID.

In addition to standard pharmacotherapy for HF with reduced ejection fraction (HFrEF), the Canadian Cardiovascular Society guidelines recommend assessing and treating ID in these patients.^4,22 Specifically, these guidelines advise considering IV iron therapy for patients with HF who meet all of the following criteria: an ejection fraction of 40% or less, and a serum ferritin concentration of less than 100 mcg/L or between 100 mcg/L to 299 mcg/L in combination with a transferrin saturation (TSAT) of less than 20%.^4,23

Ferric carboxymaltose (FCM) is a colloidal dispersion which contains iron in a stable ferric state.²⁴ This complex consists of a polynuclear iron-hydroxide core bound to a carbohydrate ligand. It is specifically formulated to provide easily utilizable iron for the body's iron transport and storage proteins, namely transferrin and ferritin.²⁴

FCM was approved by Health Canada with the following indications:²⁴

• the treatment of IDA in adult and pediatric patients aged 1 year and older when oral iron preparations are not tolerated or are ineffective

• the treatment of ID in adult patients with HF and NYHA class II or class III to improve exercise capacity.

The diagnosis of ID must be based on laboratory tests. The sponsor request for reimbursement is as per the approved Health Canada indication. A Notice of Compliance was issued on March 11, 2024.

The dosage of FCM is expressed as mg of elemental iron, with each mL containing 50 mg of elemental iron.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to the call for input from Canada’s Drug Agency (CDA-AMC) and from the clinical expert consulted by CDA-AMC for the purpose of this review.

Patient Input

No patient group input was submitted.

Clinician Input

Input From Clinical Expert Consulted by CDA-AMC

Treatment of ID with oral iron, although widely available and inexpensive, was described by the expert to be of limited utility due to poor absorption in general, but especially among patients with HF due to a variety of physiological factors specific to HF, such as epithelial dysfunction in the gut because of mucosal edema and reduced intestinal blood flow. The clinical expert indicated that IV iron is currently the preferred and guideline-recommended route for treatment of ID in patients with HF, and the intention of iron supplementation for ID in patients with HF is to improve health-related quality of life (HRQoL), functional capacity, and exercise capacity. The clinical expert described that IV iron formulations typically used in clinical practice include iron sucrose (maximum dose of 200 mg per sitting), ferric derisomaltose (maximum dose of 1,000 mg per injection), or FCM (maximum dose of 1,000 mg per week). Of the IV iron formulations, only FCM has a Health Canada–approved indication specific to the HF subpopulation; however, the other second-generation or third-generation IV iron formulations may also be used in clinical practice in this population.

The expert noted that guidelines^4,25-27 for the treatment of HF recommend all patients with HF should be tested for ID using serum ferritin and TSAT, and Canadian treatment guidelines recommend consideration of IV iron therapy for patients with HF with all of the following: left ventricular ejection fraction (LVEF) of 40% or less, and a serum ferritin of less than 100 mcg/L or between 100 mcg/L to 299 mcg/L in combination with a TSAT of less than 20%. The expert noted that based on Canadian and multiple international treatment guidelines for patients with HF and ID, patients with HF of any NYHA class may potentially be suitable for treatment with IV iron formulations, including FCM.

The clinical expert noted that most patients with HF receiving IV iron supplementation would be expected to continue this therapy for the duration of their lives. So long as guideline criteria for iron replacement therapy remain unchanged, and aside from intolerable adverse events (AEs) or patient or clinician decision or preference, there are no specific reasons to require discontinuation of FCM in a patient with HF and ID. According to the expert, there was no threshold of any laboratory parameter under which the drug should be discontinued due to lack of efficacy, and treatment should be required for as long as dictated by guideline criteria for ID-related IV iron replacement therapy.

IV iron formulations such as FCM are prescribed in hospital and can be ordered by any prescribing clinician managing the patient’s HF and ID in that setting.

Clinician Group Input

A group of 13 independent clinical experts responding to the call for input from CDA-AMC gathered data from product monographs, literature, and personal experience. According to the group, ID is a progressive condition that can lead to IDA if untreated, affecting and impacting patients with HF by worsening disease symptoms and prognosis.

The clinician group emphasized that treatment goals include correcting hemoglobin deficits, replenishing iron stores, and maintaining them over time to alleviate symptoms and enhance HRQoL. While initial therapy often involves oral iron supplements, IV iron is recommended as the first-line treatment for patients with HF due to its rapid efficacy, especially because up to 50% of patients with HF can experience ID, leading to poorer functional capacity and increased hospitalizations and mortality. The clinician group noted that guidelines advocate for initiating IV iron therapy as soon as ID is identified.

The group noted challenges with previous IV iron formulations in Canada, requiring prolonged administration and lacking indications for use in pediatric populations or for the treatment of patients with ID and HF, underscoring the need for more efficient options. Newer products like FCM can deliver high doses (up to 1,000 mg) in a single session, potentially reducing treatment burden and improving adherence.

The clinician group indicated that treatment response is assessed using hematologic and iron parameters, aiming to normalize hemoglobin and ferritin levels. Clinically meaningful outcomes also include reducing the need for blood transfusions, alleviating symptoms, enhancing exercise capacity, improving quality of life, and reducing hospitalizations. Monitoring typically occurs 4 weeks to 8 weeks after completing the initial treatment course to track progress and adjust therapy as needed.

According to the input, factors to consider when deciding to discontinue treatment with FCM include postrepletion assessments of hemoglobin, ferritin, and TSAT levels. Treatment should be immediately discontinued in cases of hypersensitivity reactions or intolerance during administration, and it is contraindicated in patients with iron overload or persistent hypophosphatemia, where re-evaluation of treatment is warranted. FCM is appropriate for treatment in settings equipped to manage anaphylaxis and hypersensitivity reactions. It can also be administered in emergency departments or surgical inpatient units when indicated. While specialists like hematologists and other physicians commonly prescribe FCM, a specialist is not always required for diagnosis, treatment, and monitoring. Family medicine practitioners, as well as specialists in cardiology, gastroenterology, internal medicine, nephrology, and obstetrics and gynecology, among others, may also manage patients requiring IV iron therapy.

Drug Program Input

The drug programs provide input on each drug being reviewed by identifying issues that may affect their ability to implement a recommendation. For the review of FCM in adult patients with HF and ID, the drug plans provided questions or discussion points pertaining to relevant comparators, considerations for initiation, continuation, discontinuation, and prescribing of therapy, care provision issues, and system and economic issues (Table 6).

Clinical Evidence

Systematic Review

Description of Studies

The studies included were the FAIR-HF (N = 459), CONFIRM-HF (N = 304), and HEART-FID (N = 3,065) studies in patients with CHF, and the AFFIRM-AHF study (N = 1,132) in patients with AHF, all 4 of which are placebo-controlled, double-blind, randomized phase III (FAIR-HF and HEART-FID) or phase IV (CONFIRM-HF and AFFIRM-AHF) trials in adults with HF and ID. Of these, 2 studies (FAIR-HF and CONFIRM-HF) were focused primarily on clinical efficacy outcomes such as exercise capacity and NYHA class, while the remaining 2 studies (HEART-FID and AFFIRM-AHF) were focused primarily on composite outcomes related to hospitalizations and deaths. The studies ranged in duration from approximately 6 months (FAIR-HF) to 12 months (CONFIRM-HF, HEART-FID, and AFFIRM-AHF).

The 3 CHF studies each had a maximum allowed LVEF at screening or index visit, although the precise threshold varied: 40% or less (NYHA class II) or LVEF 45% or less (NYHA class III) in the FAIR-HF study, 45% or less in the CONFIRM-HF study, and 40% or less in the HEART-FID study (although historically reduced LVEF was also allowed given specific circumstances). In the AFFIRM-AHF study, the inclusion criteria required that patients had less than 50% LVEF within 12 months before randomization. All 4 included studies required serum ferritin to be less than 100 mcg/mL, or 100 mcg/mL to 299 mcg/mL or 100 mcg/mL to 300 mcg/mL with TSAT less than 20%. At baseline, mean patient ages were approximately 68 years to 71 years across the treatment groups, and the proportion of female patients ranged from 33% to 55%. All 4 studies included adult patients with NYHA class II or class III. Although the HEART-FID study also included NYHA class IV and the AFFIRM-AHF study included NYHA classes I and class IV, the overwhelming majority of patients belonged to NYHA class II or class III, with very few patients belonging to class IV (< 4% in the AFFIRM-AHF study and < 1% in the HEART-FID study) or class I (< 3% in the AFFIRM-AHF study). White race was disproportionately over-represented in all studies; 86% in the HEART-FID study, 95% in the AFFIRM-AHF study, and 99% to 100% in the FAIR-HF and CONFIRM-HF studies. Comorbidities were common, including hypertension, dyslipidemia, diabetes, atrial fibrillation, angina pectoris, and others.

Efficacy Results

NYHA Class

The NYHA functional class system is a subjective but widely used classification used to determine CHF severity based on symptoms, where NYHA class I suggests little to no symptoms of HF and class IV is defined by the inability to carry on any physical activity without discomfort and the presence of symptoms even at rest.

For the outcome of change in NYHA class from baseline, there was a benefit associated with FCM compared to placebo in the FAIR-HF study at week 24 (odds ratio [OR] = 2.400; 95% confidence interval [CI], 1.551 to 3.715; P < 0.001) where an OR of greater than 1 indicates a benefit of FCM, and in the CONFIRM-HF study at week 24 (OR = ████ ████ ███ ████ ██ █████; P = 0 0.004) and week 52 (OR = ████ ████ ███ ████ ██ █████; P < 0.001), where an OR of less than 1 indicates a benefit of FCM compared to placebo. In the AFFIRM-AHF study, although the point estimate suggests benefit associated with FCM at week 52 based on an OR of greater than 1 (OR = ████ ████ ███ ████ ██ █████; P = 0.196), there was insufficient evidence to confirm a difference between the treatment arms because the 95% CI crossed the null. The HEART-FID study did not report this outcome.

6-Minute Walk Test

The 6-minute walk test (6MWT) is a common, validated test that measures the distance a patient can walk on a hard, flat surface over a 6-minute period under clinician supervision, where longer distances represent better exercise capacity. This outcome was assessed in the FAIR-HF, CONFIRM-HF, and HEART-FID studies, but not the AFFIRM-AHF study.

In the FAIR-HF study, the mean change from baseline in 6MWT at 24 weeks was ████ ██████ (standard deviation [SD] █████) in the FCM group compared to ████ ██████ (SD █████) in the placebo group, and the between-group difference was ████ (SD ███) metres (| | █████). Because no 95% CI was presented for the between-group results, additional data were requested from the sponsor, who provided a post hoc analysis of absolute differences on request to inform the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) analysis; according to these additional data, which may not follow the same analysis as described in the study’s Statistical Analysis Plan, the between-group difference was ████████ ███ ████ ██ █████ | | ██████ metres.

In the CONFIRM-HF study primary analysis at week 24, the change from baseline in 6MWT was ████ ███ ██████ ███ ███ ████ ██ █████████ █████ ███ ██████ ███ ███ ██████ ██ █████ metres in the FCM and placebo groups, respectively. The least squares mean between-group difference was ████ ██████ (standard error ██████ ███ ███ ████ ██ ███████.

In the HEART-FID study, as a component of the composite primary outcome, the mean change from baseline to 6 months (i.e., 24 weeks) in 6MWT was 8 metres (SD = 60) and 4 metres (SD = 59), respectively. Because no between-group differences were presented numerically, additional information was requested from the sponsor to support the GRADE analysis, which reported the following: the mean change from baseline to week 24 in 6MWT distance was █████ ███ ██████ metres in the FCM group and █████ ███ ██████ metres in the placebo group, with a between-group difference in change from baseline of █████ ████ ███ ██████ ██ ██████ metres.

In the CONFIRM-HF study secondary analyses at week 52, the least squares mean between-group difference was ████ █ ████ ███ ████ ██ █████ | | ███████ Sensitivity analyses using the per-protocol set (PPS) did not include reporting of between-group differences, but the within-group changes from baseline were similar to that of the full analysis set (FAS) analyses; the treatment benefit was also consistent across preplanned and post hoc subgroup analyses on demographic and disease-related features, and in a supportive analysis without primary imputation for deaths and hospitalizations.

In the HEART-FID study secondary analyses at week 52, the mean change was 5 metres (SD = 71) in the FCM group and 4 metres (SD = 72) in the placebo group. Between-group values were not reported numerically, so additional information was requested from the sponsor, in which it was reported that the mean change from baseline to week 52 was █████ ███ ██████ ███ █████ ███ ██████ metres for the FCM and placebo groups, respectively, with a between-arm difference in change from baseline of █████ ████ ███ ██████ ██ ██████ metres.

Kansas City Cardiomyopathy Questionnaire

The Kansas City Cardiomyopathy Questionnaire (KCCQ) was reported in the FAIR-HF study (at 24 weeks), CONFIRM-HF study (at 24 weeks and 52 weeks), and AFFIRM-AHF study (at 24 weeks and 52 weeks) as a secondary outcome in each case. It is a 23-item, self-administered questionnaire that quantifies physical limitation, symptoms (stability, frequency, and burden), self-efficacy, social function, and HRQoL. Scores are transformed to a range of 0 to 100, where higher scores reflect better health status. Although studies have been performed assessing its measurement properties and validity, the KCCQ is primarily a clinical trial tool and is not typically used in real-world clinical practice.

In the FAIR-HF study at week 24, the study treatment effect of FCM was | ██████ ███ ██ greater in change from baseline of KCCQ overall summary score, compared to placebo (P < 0.001). Because there was no 95% CI provided with the point estimate for the FAIR-HF study, additional data were requested from the sponsor, which reported a between-group difference of ███ ██████ ████ ███ ███ ██ █████ | | ██████ favouring FCM.

In the CONFIRM-HF study at week 24, the least squares mean between-group difference was ███ ████ ███ █████ ██ █████ | | █████ points. In the AFFIRM-AHF study, the difference was ███ ████ ███ ███ ██ ████ | | ███████ In the CONFIRM-HF study at week 52, the between-group difference was ███ ████ ███ ████ ██ █████ | | ██████ points, and in the AFFIRM-AHF study it was 1.44 (95% CI, –1.45 to 4.33; P not reported).

Fatigue Score

Only the CONFIRM-HF study assessed the change from baseline in fatigue score, ranked on a visual analogue scale from 0 to 10, where 0 implies no fatigue and 10 represents very severe fatigue. Some assessments of validity exist for this method of measuring fatigue, but there is no established minimal important difference (MID). At week 24 the between-group difference (as least squares mean) in change in fatigue score was ████ ███ █████ ███ ███ █████ ██ ██████ | | ██████, and at week 52 it was ████ ███ █████ ███ ███ █████ ██ ██████ | | ███████.

Serum Ferritin

At baseline, mean serum ferritin values were less than the threshold of 100 mcg/mL that defines ID in the context of HF in all included studies.

At week 24, across all studies, the FCM groups had mean serum ferritin levels of greater than 100 mcg/mL (although note that patients may still have “functional ID” if their TSAT is < 20% and their serum ferritin is 100 mcg/mL to 300 mcg/mL, as previously discussed), while the mean serum ferritin levels in the placebo groups were close to or less than 100 mcg/mL.

In the FAIR-HF study at week 24, the between-group difference in absolute mean serum ferritin was █████ ███ ██████ █████ in the FCM group and ████ ███ █████ █████ in the placebo group (P < 0.0001).

In the CONFIRM-HF study, between-group values were not reported, but the mean serum ferritin at week 24 was ██████ █████ ███ ████████ in the FCM group, representing a mean change from baseline of ██████ █████ ███ ████████, and in the placebo group the mean serum ferritin was █████ █████ ███ ███████ representing a change from baseline of ████ █████ ████████. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ █████████ Numerical values for serum ferritin were not reported in the HEART-FID study, although graphical representation can be found in the supplementary documents. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ ███████ at week 24.

In the AFFIRM-AHF study, at week 24, the mean change from baseline was ██████ █████ █████████ in the FCM group compared to █████ █████ █████████ in the placebo group; no between-group differences were reported. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ ███████ at week 24.

At week 52, the mean serum ferritin levels in the FCM groups of the CONFIRM-HF, HEART-FID, and AFFIRM-AHF studies were all in excess of 100 mcg/mL but were less than 300 mcg/mL. The FAIR-HF study was a 24-week study so there are no 52-week values. In the placebo groups, the levels were close to or less than 100 mcg/mL.

In the CONFIRM-HF study at 52 weeks, between-group values were not reported, but the mean serum ferritin in mcg/mL at week 52 in the FCM group was ██████ █████ █████████ representing a change from baseline of ██████ █████ ██████████ and in the placebo group was █████ █████ █████████ representing a change from baseline of █████ █████ ██████████ Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ ███████ at week 52.

Values for serum ferritin were not reported in the HEART-FID study, although graphical representation can be found in the supplementary documents. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ ███████ at week 52.

In the AFFIRM-AHF study, at week 52, the mean change from baseline was ██████ █████ █████████ in the FCM group compared to █████ █████ █████████ in the placebo group; no between-group differences were reported. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ ███████ ██ █████████.

CV Hospitalizations

De novo analyses of CV hospitalization rate were provided by the sponsor upon request to assist in the review. Through both 26 weeks and 52 weeks, the between-group difference in event rate per 100 patient-years was lower in the FCM groups than the placebo groups. Through 26 weeks, the between-group difference in event rate per 100 patient-years for FCM versus placebo was ██████ ███████ ██ ██████ in the FAIR-HF study | ██████ ███████ ██ █████ in the CONFIRM-HF study, █████ ███████ ██ ██████ in the HEART-FID study, and ██████ ███████ ██ ██████ in the AFFIRM-AHF study. Through week 52, the between-group differences were ██████ ███████ ██ ██████ in the CONFIRM-HF study, █████ ███████ ██ ██████ in the HEART-FID study, and ██████ ███████ ██ ██████ in the AFFIRM-AHF study.

The HEART-FID and AFFIRM-AHF studies both had composite primary efficacy end points that included hospitalization-related outcomes; these will be discussed briefly here.

In the hierarchical composite primary end point of the HEART-FID study, death had occurred in 131 patients (8.6%) in the FCM group and in 158 (10.3%) in the placebo group at 12 months, there were 297 and 332 total hospitalizations for HF by 12 months, respectively, and the mean change in the 6-minute walk distance from baseline to 6 months was 8 metres (SD = 60) and 4 metres (SD = 59), respectively, (overall P = 0.02). The unmatched win ratio for the hierarchical composite outcome in the FCM group as compared with the placebo group was 1.10 (99% CI, 0.99 to 1.23). Results of prespecified sensitivity analyses that included different imputation methods were reported to be consistent with those of the primary analysis. Because more than half the patients underwent randomization after March 2020, the censoring of data after the onset of the COVID-19 pandemic would have excluded the majority of follow-up data from the analyses.

In the primary efficacy end point of the AFFIRM-AHF study, which was a composite of recurrent HF hospitalizations and CV deaths up to 52 weeks after randomization, the annualized event relative risk (RR) for FCM versus placebo was 0.79 (95% CI, 0.62 to 1.01; P = 0.059). In the prespecified COVID-19 sensitivity analysis, the annualized event RR for FCM versus placebo was 0.75 (95% CI, 0.59 to 0.96; P = 0.024).

CV Mortality

De novo analyses of CV mortality were provided by the sponsor upon request to assist in the review. Through both 26 weeks and 52 weeks, minor and inconsistent differences were observed, with 95% CIs that always crossed null. Through 26 weeks, between groups, the risk difference comparing FCM to placebo was █████ ██████ ██ ██████ in the FAIR-HF study, ████ ██████ ██ ██████ in the CONFIRM-HF study, █████ ██████ ██ ██████ in the HEART-FID study, and █████ ███████ ██████ in the AFFIRM-AHF study. Through 52 weeks, the values were █████ ███████ ██████ in CONFIRM-HF, █████ ███████ ██████ in the HEART-FID study, and █████ ███████ ███████.

Harms Results

Adverse Events

In the FAIR-HF study the proportion of patients who experienced at least 1 AE was █████ in the FCM group and █████ in the placebo group, while in the CONFIRM-HF study the values were 79.6% and 75.7%, respectively. Overall AEs of any severity were not reported in the HEART-FID study. In the AFFIRM-AHF study, at least 1 AE was experienced by ███ ███████ patients in the FCM group and ███ ███████ patients in the placebo group.

Common AEs that occurred in at least 5% of any 1 treatment group across the FAIR-HF and CONFIRM-HF studies included cardiac failure, atrial fibrillation, angina pectoris, bronchitis, respiratory tract infection (viral), nasopharyngitis, influenza, increased blood pressure, hypertension, hypotension, headache, dizziness, and skin or subcutaneous tissue disorders. For the most part, the proportion of patients experiencing these events were relatively similar between treatment groups. Cardiac failure (chronic) appeared to be slightly less common in the FCM group than the placebo group (the FAIR-HF study: ████ ███ ████; the CONFIRM-HF study: ████ ███ ████). Common AEs that occurred in at least 5% of either treatment group in the AFFIRM-AHF study included cardiac failure, infections, gastrointestinal (GI) disorders, nervous system disorders, metabolism and nutrition disorders, renal and urinary disorders, vascular disorders, injury, and musculoskeletal disorders.

Serious Adverse Events

In the FAIR-HF study, a total of ██ ████████ ███████ in the FCM group and ██ ████████ █████ in the placebo group reported at least 1 serious AE (SAE). The most common SAEs were cardiac disorders (████ ███ ████ in the FCM and placebo groups, respectively).

In the CONFIRM-HF study, 43 patients (28.3%) in the FCM group and 53 patients (34.9%) in the placebo group reported at least 1 SAE. The most common SAEs were cardiac disorders (█████ ███ █████ in the FCM and placebo groups, respectively).

In the HEART-FID study, SAEs were reported in 581 patients (37.9%) in the FCM group and 537 patients (35.0%) in the placebo group. The most common SAEs during the treatment period were pneumonia, reported in 57 patients (3.7%) in the FCM group and 35 patients (2.3%) in the placebo group; acute kidney injury, reported in 46 patients (3.0%) in the FCM group and 40 patients (2.6%) in the placebo group; and COVID-19, reported in 39 patients (2.5%) in the FCM group and 37 patients (2.4%) in the placebo group. One event in the FCM group was classified as hypophosphatemia. This event resolved and FCM treatment was continued.

In the AFFIRM-AHF study, SAEs occurred in 250 (44.7%) of 559 patients in the FCM group and 282 (51.2%) of 551 patients in the placebo group. The most common were cardiac disorders (█████ ███ █████ in the FCM and placebo groups, respectively), followed by infections and infestations (████ ███ ████ in the FCM and placebo groups, respectively), followed by general disorders and administration site conditions █████ ███ ████ in the FCM and placebo groups, respectively). Other SAEs were less common.

Withdrawals Due to AEs

In the FAIR-HF study, ██ ████████ ██████ in the FCM group and ██ ████████ ██████ in the placebo group withdrew from the study treatment due to AEs; in the CONFIRM-HF study, this occurred among ██ ████████ ██████ in the FCM group and ██ ████████ ███████ in the placebo group; in the HEART-FID study, ██ ███████ and ██ ████████ and in the AFFIRM-AHF study, ██ ███████ ███ ██ ███████, respectively.

Deaths

In the FAIR-HF study, 5 deaths occurred in the FCM group (████) and 4 in the placebo group (██████ During the study period, ███ patients from the FCM group and ███ from the placebo group died. In the FCM group, 3 patients died due to sudden death, ███ due to ischemic stroke, and ███ due to severe anemia after terminating the study early. In the placebo group, █████ patients died due to myocardial infarction, pulmonary edema, and sudden death.

In the CONFIRM-HF study, a total of ██ ████████ ██████ in the FCM group and ██ ████████ ██████ in the placebo group died during the study period. The majority of deaths (| | ██) were related to cardiac disorders and cardiac-related treatment-emergent AEs (TEAEs) in other system organ classes (e.g., sudden cardiac death and cardiac death in the category of general disorders and administration site conditions). Two patients in the placebo group died of noncardiac disorders (staphylococcal sepsis and acute renal failure).

In the HEART-FID study, death from any cause occurred in 361 patients (23.6%) in the FCM group and 376 patients (24.5%) in the placebo group (hazard ratio = 0.90; 95% CI, 0.78 to 1.05). The hazard ratio for death from any cause through month 12 was 0.82 (95% CI, 0.65 to 1.05). It is unknown how many deaths were due to AE.

In the AFFIRM-AHF study, ██ ███████ patients in the FCM group and ██ ███████ in the placebo group had TEAEs resulting in death. The majority of deaths were related to cardiac disorders and cardiac-related TEAEs in other organ classifications (e.g., sudden cardiac death and cardiac death in the category of general disorders and administration site conditions).

Notable Harms

Hypophosphatemia is a notable harm associated with FCM treatment that is not as highly associated with other IV iron formulations.

There were no reported cases of hypophosphatemia as TEAEs in both the FAIR-HF and CONFIRM-HF studies.

In the FAIR-HF study, transient decreases in phosphate levels were observed in the FCM group and this was reported to be most pronounced at week 4, but there were no clinical consequences, sequelae, or interventions associated with this change. Differences between treatment arms were observed in the percentage of patients with values outside the normal range for phosphate during follow-up (██ ███████ in the FCM group versus ██ ███████ in the placebo group placebo; P = 0.008).

In the CONFIRM-HF study, the minimum recorded serum phosphorus value was ████ ██████ █████ ██████ in 2 patients (1 in the FCM group and 1 in the placebo group), where hypophosphatemia is typically defined as less than 2.5 mg/dL. Among all patients, ███ experienced severe hypophosphatemia based on the clinical events classification threshold of 0.3 mmol/L to less than 0.6 mmol/L, although the investigators did not report these as TEAEs.

The overall incidence of hypophosphatemia was not reported in the HEART-FID study, but 1 SAE of hypophosphatemia reportedly occurred in 1 patient in the FCM group and none in the placebo group. This hypophosphatemia event was considered by the investigator to be unrelated to FCM; the event resolved and FCM was continued.

In the AFFIRM-AHF study, there were ███ cases of hypophosphatemia reported, ███ of which was in the FCM group and ███ was in the placebo group.

Critical Appraisal

The overall risk of bias with regards to internal validity was low for the randomization process, allocation concealment, and maintenance of blinding.

Concerns for potentially important missing data were present for most outcomes assessed in at least 1 contributing study.

With regards to the outcomes assessed in this review, the primary efficacy analyses of the FAIR-HF (i.e., NYHA class) and CONFIRM-HF studies (i.e., 6MWT) were adjusted for multiplicity, but other outcomes from these studies were not.

In supportive analyses of the CONFIRM-HF study using the PPS instead of the FAS, the sample size was substantially reduced from the FAS due to a high number of protocol violations, especially in the active treatment arm, which may result in a risk of bias due to deviations from the intended interventions.

The external validity and applicability of the results of this review are limited by the absence of any direct or indirect evidence comparing FCM with other IV iron formulations, which are its direct comparators in patients with HF and ID despite having no specific indication in the HF population in Canada at this time. No conclusions can be drawn from any of the submitted evidence on the relative efficacy or safety of FCM with any other available IV iron formulation in patients with HF and ID. Additionally, there may be generalizability concerns regarding the demographics of the studies. The proportion of patients identified as white race was disproportionately high across the trials, particularly in the FAIR-HF and CONFIRM-HF studies (98% to 100% across the treatment arms) but this was also generally true in the other 2 studies (85% and 95%). The trials were primarily conducted in countries other than Canada, and so demographic features as well as clinical practice related to both ID and HF individually and together may differ. The HEART-FID study included US sites, but the other 3 included studies were conducted primarily in Eastern Europe with some sites in Western Europe, Oceania, Asia, and/or South America, and so the clinical practices and patient characteristics may differ from those in Canada. Additionally, the HEART-FID study was the most recently conducted study and had the most inconsistent results, especially with regards to 6MWT, when compared to the other included studies; the reason for this inconsistency is not certain, but it may be related to changes in clinical practice and standard of care over time.

The proposed reimbursement request in HF is specific to patients of NYHA class II or class III. However, this does not reflect the treatment guidelines, which do not specify any particular NYHA class in its recommendations for IV iron repletion therapies. The AFFIRM-AHF study enrolled patients with a broader range of NYHA classes (I to IV inclusive), and the HEART-FID study in patients with CHF also enrolled patients with NYHA class IV. However, the number of patients with NYHA class I and/or class IV was proportionally very low in both studies.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• HF disease severity as measured by NYHA score

• exercise capacity as measured by change in 6MWT from baseline

• HRQoL as measured using change from baseline in KCCQ

• fatigue score

• change from baseline in serum ferritin

• CV hospitalization rate

• CV mortality risk.

Table 2: Summary of Findings for FCM vs. PBO for Patients With CHF and ID

6MWT = 6-minute walk test; CHF = chronic heart failure; CI = confidence interval; CV = cardiovascular; FCM = ferric carboxymaltose; HF = heart failure; HRQoL = health-related quality of life; KCCQ = Kansas City Cardiomyopathy Questionnaire; LSM = least squares mean; MID = minimal important difference; NYHA = New York Heart Association; OR = odds ratio; PBO = placebo; RCT = randomized controlled trial; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aThis outcome is subjective, but there was no suspected risk of bias due to adequate maintenance of blinding.

^bNo known MID so the target of certainty appraisal was any effect.

^cOnly the FAIR-HF study adjusted for multiplicity for this outcome (NYHA). With that exception noted, no studies adjusted for multiplicity for this or any other outcome in this table.

^dRated down 1 level for risk of bias due to missing data.

^eThis value was provided by the sponsor upon request to assist in the interpretation of the evidence. Note that the analysis is post hoc and not necessarily represented in the Statistical Analysis Plan of the relevant study.

^fRated down 2 levels for very serious inconsistency due to differences in magnitude of effect between the studies, wherein the 95% CIs of some studies are minimally overlapping or not overlapping.

^gRated down 1 level for serious imprecision. CI crosses thresholds between 1 set of: harm, no difference, or benefit.

^hAlthough the CI could be rated down twice, it was judged to be a narrow CI and not a sufficient cause for concern.

ⁱThe total number of events for all patients in the treatment group was divided by the total patient-years of follow-up in that treatment group multiplied by 100. Follow-up duration is equal to time on study. Time on study (weeks) = (last known date – randomization date + 1)/7.

^jRisk difference is FCM – placebo with 95% Miettinen-Nurminen CI.

^kRated down 1 level for indirectness. Based on clinical expert opinion, the duration of assessment is likely insufficient to identify a difference between treatment groups for this outcome.

Sources: Additional information request for absolute differences results data,²⁸ Clinical Study Reports for the FAIR-HF²⁹ and CONFIRM-HF studies,³⁰ and publication and supplementary appendix of the HEART-FID study.³¹

Table 3: Summary of Findings for FCM vs. PBO for Patients With AHF and ID

6MWT = 6-minute walk test; AHF = acute heart failure; CI = confidence interval; CV = cardiovascular; FCM = ferric carboxymaltose; HF = heart failure; HRQoL = health-related quality of life; ID = iron deficiency; KCCQ = Kansas City Cardiomyopathy Questionnaire; MID = minimal important difference; NA = not applicable; NYHA = New York Heart Association; OR = odds ratio; PBO = placebo; RCT = randomized controlled trial; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 for serious risk of bias caused by a high proportion of potentially important missing data.

^bThis outcome was not adjusted for multiplicity.

^cNo known MID so the target of certainty appraisal was any effect.

^dRated down 1 level for risk of bias due to missing data.

^eThis value was provided by the sponsor upon request to assist in the interpretation of the evidence. If this value represents an analysis outcome, note that the analysis is post hoc and not necessarily represented in the Statistical Analysis Plan of the relevant study.

^fRated down 1 level for serious imprecision. No known MID so target of certainty appraisal was any effect.

^gThe total number of events for all patients in the treatment group was divided by the total patient-years of follow-up in that treatment group multiplied by 100. Follow-up duration is equal to time on study. Time on study (weeks) = (last known date – randomization date + 1)/7.

^hRisk difference is FCM – placebo with 95% Miettinen-Nurminen CI.

ⁱRated down 1 level for indirectness. Based on clinical expert opinion, the duration of assessment is likely insufficient to identify a difference between treatment groups for this outcome.

^jAlthough the CI includes possibility of both benefit and arm, the CI is relatively narrow around the null, so it was subjectively judged that this was not imprecise enough to warrant rating down a second time for imprecision.

Sources: Additional information request for absolute differences results data,²⁸ and Clinical Study Report of the AFFIRM-AHF study.³²

Long-Term Extension Studies

No long-term extension studies were submitted for this indication.

Indirect Comparisons

No indirect comparisons were submitted for this indication.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the evidence were summarized from the systematic review for this indication. The characteristics of some additional studies are briefly summarized in Appendix 1 as they were considered unlikely to impact the conclusions of the review, but are relevant to the indication under consideration. The sponsor also submitted a meta-analysis by Ponikowski and colleagues (2023)³³ which is summarized and critically appraised in the following.

Summary and Critical Appraisal of Meta-Analysis by Ponikowski and Colleagues (2023)³³

Objective

The objective of the meta-analysis was to evaluate the effects of FCM treatment on clinical events, such as hospitalizations and mortality, in patients with HF and ID using patient-level data from randomized, placebo-controlled trials of FCM that enrolled adults with HF and ID.

Methods

Inclusion Criteria

Ponikowski and colleagues performed a pooled analysis of patient-level data from trials that met the following criteria: studied adult patients with HF and ID (defined as ferritin < 100 mcg/mL or ferritin 100 mcg/mL to 300 mcg/mL and TSAT < 20%); used FCM as an active treatment for ID; were double-blind, randomized, and placebo-controlled; had at least 52 weeks of follow-up; and prospectively recorded clinical outcomes (e.g., first and recurrent HF and CV hospitalizations, CV death, and all-cause death).

Included Studies

The meta-analysis ultimately included the CONFIRM-HF, AFFIRM-AHF, and HEART-FID studies. Searches were conducted to identify any additional studies, but none were added per the eligibility criteria. The authors were able to access individual patient data for the included studies.

End Points

The prespecified co-primary efficacy end points were:

• a composite of recurrent (total) CV hospitalizations and death for any CV reason (CV death)

• a composite of recurrent (total) HF hospitalizations and CV death.

All of these outcomes were based on events adjudicated independently by blinded event committees. All 3 FCM trials used consistent criteria for adjudication, which were prespecified in each trial.

The key secondary efficacy end points were: time to first CV hospitalization or CV death, time to first HF hospitalization or CV death, rate of total HF hospitalizations, time to first HF hospitalization, time to CV death, time to all-cause death, total CV hospitalizations, time to CV death, time to all-cause death, total CV hospitalizations, time to first CV hospitalization, and total all-cause hospitalizations.

All primary and key secondary end points were examined through 52 weeks of follow-up (primary end points were set with a time window up to 408 days).

Data Analysis

Efficacy analyses were conducted on the full analysis population defined as all randomly assigned patients who received at least 1 dose of study medication and had at least 1 postbaseline efficacy assessment. The safety population comprised all patients who were randomly assigned and received at least 1 dose of study medication, and was used to assess baseline characteristics and analyze the frequency of AEs.

A negative binomial regression model was used to analyze event rates, including recurrent hospitalizations. The models were adjusted for baseline hemoglobin and region as fixed effects. Study was included as a random effect. The between-trial heterogeneity was explored by including a treatment by study interaction and a Cochrane Q test. Time-to-event outcomes used Cox proportional hazard analyses and the models were adjusted for hemoglobin at baseline and region. To explore between-trial heterogeneity, the study effect was included as a fixed effect.

Several preplanned subgroup analyses and sensitivity analyses were conducted. As the purpose of the sponsor presenting this meta-analysis was in part to discuss the impact of TSAT on efficacy results, the TSAT subgroup will be discussed briefly in this subgroup, but other subgroups will not be.

A sensitivity analysis incorporating the IRONMAN trial (which did not include FCM) was also conducted to evaluate IV iron formulations versus placebo, which will not be discussed in depth here. An additional sensitivity analysis was also conducted using all available follow-up data (i.e., beyond 52 weeks).

Results

Efficacy

The results were in favour of FCM without the 95% CI overlapping null for the co-primary composite end point of CV death and total CV hospitalizations (rate ratio = 0.86; 95% CI, 0.75 to 0.98; P = 0.029). Similarly FCM was associated with a 17% relative rate reduction in total CV hospitalizations (rate ratio = 0.83; 95% CI, 0.73 to 0.96; P = 0.009) and a 16% relative rate reduction in total HF hospitalizations (rate ratio = 0.84; 95% CI, 0.71 to 0.98; P = 0.025). For the outcome of total HF hospitalizations and CV death, the result was in favour of FCM; however, the 95% CI overlapped null (0.75 to 1.01). For the outcome of time to CV death, the 95% CI also crossed null, indicating that there was no statistically significant difference between the treatment arms. Similarly, there was no statistically significant difference for time to all-cause death. Rate reductions in the primary composite end points were mainly driven by the treatment effect on HF hospitalizations and CV hospitalizations, with no apparent effect on CV or all-cause mortality.

In terms of subgroup results, there was a significant interaction effect identified between TSAT tertile and the composite of CV hospitalization and CV death (interaction P = 0.019) and between TSAT tertile and CV death (interaction P = 0.035), where patients in a lower TSAT tertile were more likely to see treatment benefit than those in a higher TSAT tertile. Although not statistically significant, a similar pattern was observed for the effect of TSAT on total HF hospitalizations and CV death (interaction P = 0.095). There were some other subgroups identified regarding “numerically” different treatment effects by subgroup (e.g., across hemoglobin tertiles and HF etiology); other than these, the effects of FCM therapy on both of the primary efficacy end points, CV death and all-cause death, were similar across other subgroups examined.

Safety

The incidences of investigator-reported serious TEAEs, serious TEAEs leading to death, and serious TEAEs leading to study discontinuation were similar across treatment groups through week 52. No deaths were judged to be the cause of serious treatment-related TEAEs. The rate of serious treatment-emergent infections was 9.9 per 100 patient-years and 9.6 per 100 patient-years in the FCM and placebo groups, respectively. Treatment appeared to be safe and well tolerated.

Critical Appraisal

The meta-analysis appears to be conducted appropriately. All of the included trials were placebo-controlled, double-blind, randomized phase III or phase IV trials in adults with HF and ID. The CONFIRM-HF study was focused on clinical efficacy outcomes such as exercise capacity and NYHA class, although the study did report survival and HF or CV-related outcomes as well. The AFFIRM-AHF and HEART-FID studies were focused primarily on composite outcomes related to hospitalizations and death. All 3 trials were at least 12 months in duration. The studies differed in minor ways with regards to inclusion criteria, such as whether NYHA class I or class IV was included; in the CONFIRM-HF study, only class II and class III were included, while the HEART-FID study additionally included class IV and the AFFIRM-AHF study did not specify any exclusions based on NYHA class. This was not expected to represent an important difference in patient populations, in part because prescription of IV iron is not dependent on NYHA class and in part because very few patients outside of class II and class III were included in any study overall. There were also minor differences with regards to the upper limit of LVEF and the range of included hemoglobin levels, but altogether these were considered very similar. The definitions of ID were the same across the studies.

A key difference in study design is that the AFFIRM-AHF study required patients to be hospitalized for AHF during enrolment, while the CONFIRM-HF and HEART-FID studies required a hospitalization within the prior year (or, in the case of the HEART-FID study, hospitalization within the prior 12 months or elevated N-terminal pro-brain natriuretic peptide within 90 days of randomization). These differences are important to consider when interpreting the results but were not expected to pose a concern with regards to conducting a meta-analysis such as that presented in Ponikowski and colleagues (2023), and all of the studies do represent the patient population in question. The inclusion of the AFFIRM-AHF study, which involves hospitalized patients with AHF, introduces a significant between-trial difference in design and patient population. However, the HEART-FID study is a substantially larger trial, so any skewing of results due to the more at-risk population in the AFFIRM-AHF study may not be substantial. A sensitivity analysis excluding the AFFIRM-AHF study could have been useful to address this difference in patient population. Despite this minor concern, the treatment effect in the AFFIRM-AHF study was not consistently the highest in magnitude. In fact, the CONFIRM-HF study generally showed the largest treatment effect but also had the widest 95% CIs across all co-primary composite outcomes and their components. Further exploration into this observation may be warranted, but it does not discredit the meta-analysis results. In the publication, between-trial heterogeneity in treatment effect was explored and models were adjusted for baseline hemoglobin and region, which was considered appropriate. The study authors state that there was no identified heterogeneity between the trials for any primary or key secondary outcomes, and that the treatment arms appeared to be balanced by demographics.

Conclusions

Findings from 3 randomized controlled trials (RCTs) in CHF and 1 RCT in AHF demonstrated potential benefit of FCM compared to placebo in patients with HF and ID based on 24-week and 52-week outcomes. Evidence from 3 CHF studies, considered together, demonstrated that treatment with FCM likely results in an improvement in NYHA class at 24 weeks and 52 weeks, KCCQ at 52 weeks, fatigue score at 24 weeks and 52 weeks, and serum ferritin at 24 weeks and 52 weeks. There is uncertainty regarding whether the magnitude of benefit is clinically meaningful for all of the aforementioned outcomes. Treatment with FCM in patients with CHF may also result in an improvement in KCCQ at 24 weeks but the certainty was lower at this time point due to imprecision. In CHF, the evidence was very uncertain with regards to the effect of FCM on 6MWT at 24 weeks or 52 weeks due to inconsistency, imprecision, and missing data; notably, older studies (FAIR-HF and CONFIRM-HF) showed likely clinically meaningful benefit while a more recent and larger study (HEART-FID) did not show an important benefit, and the reason for this discrepancy is not fully clear. FCM may result in little to no difference in CV mortality when compared to placebo at 26 weeks or 52 weeks, but the duration of follow-up may be inadequate and studies may be inadequately powered to assess this outcome fully.

Evidence from 1 AHF study demonstrated that FCM likely results in an improvement in NYHA class at 24 weeks and 52 weeks, KCCQ at 24 weeks, and serum ferritin at 24 weeks and 52 weeks, CV hospitalization rate at 24 weeks and 52 weeks, and may result in little to no difference in CV mortality at 24 weeks or 52 weeks. There was uncertainty regarding whether the magnitude of effect observed was clinically meaningful for all of the aforementioned outcomes. There were no data available to inform the effect of FCM on 6MWT or fatigue in patients with AHF.

FCM was well tolerated in all included studies. The frequency of AEs was generally similar between treatment groups within each included study, where reported. These trends align with the expected pathophysiology of HF and ID and the expected treatment effect and side effects of iron supplementation. There were slightly more patients who experienced SAEs in the placebo groups than the FCM groups, and these were most commonly cardiac disorders. FCM is associated with a risk of hypophosphatemia, as detailed in the product monograph, and these events appeared relatively uncommon in the included studies in all treatment groups.

Other IV formulations of iron supplementation exist and are used in clinical practice to treat patients with HF and ID, albeit without a specific indication for this population. There is a lack of direct or indirect evidence comparing FCM to other third-generation or second-generation IV iron formulations, which represent the direct comparators of FCM. According to clinical practice guidelines in Canada and around the world, as well as clinical expert input, IV iron is standard of care for patients with HF and ID to improve exercise capacity and symptoms. The treatment goal of IV iron is not necessarily to improve hospitalization and mortality directly as these are likely more strongly driven by the patient’s underlying HF, which is not modified by iron supplementation. Although FCM was demonstrated to be reasonably effective and safe compared to placebo, no conclusions can be drawn regarding the relative efficacy and safety of FCM with other commonly used IV iron formulations such as iron sucrose or ferric derisomaltose in the HF population.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of FCM for IV administration in the treatment of ID in adult patients with HF to improve exercise capacity.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CDA-AMC review team.

HF is a complex and life-threatening syndrome in which abnormal heart function leads to or increases clinical symptoms and signs of reduced cardiac output and/or pulmonary or systemic congestion at rest or with stress. It is the third leading cause of hospitalization in Canada, with a median length of stay of 7 days, and leads to readmission in 1 in 5 patients within 30 days after discharge.^1,2 This condition is marked by significant morbidity and mortality, reduced functional capacity, and poor quality of life. Patients with CHF require continuous medical care, frequent monitoring, hospitalizations, and extensive treatment.^3,4

Symptoms of HF are classified using the NYHA functional classes I to IV, which categorize the severity of symptoms ranging from minimal limitations during physical activity (class I) to severe symptoms even at rest (class IV). These symptoms include fatigue, shortness of breath, swelling (edema), and reduced exercise tolerance, reflecting the progressive impact of HF on daily activities and quality of life.⁵

Approximately 60% of patients with HF have anemia and 40% of those without anemia have ID.^4,6 This condition significantly impacts patient well-being^8,9 as iron plays a critical role in oxygen transport and cellular energy metabolism, particularly in tissues demanding high energy like cardiac muscle.^10-12

ID can be characterized in 2 main ways: depleted iron stores due to insufficient dietary intake, impaired absorption, or chronic blood loss (absolute ID); and/or reduced circulating iron linked to chronic inflammation, particularly seen in CV diseases (functional ID).^13,14 This inflammation leads to an increased release of hepcidin, a liver-expressed type II acute-phase protein and a major player in iron homeostasis by inhibiting iron absorption in the intestines and iron release from macrophages in the liver and spleen.¹⁵ This mechanism contributes to ID observed in CV diseases. In HF, additional factors such as reduced bowel iron absorption due to generalized edema may also contribute to ID.^16,17 Ferritin levels can be artificially elevated in patients with CHF due to chronic inflammation.³⁴ Therefore, hepcidin has been proposed as a more sensitive index to evaluate ID.^6,18,19

When iron levels are too low to support adequate hemoglobin synthesis, it can lead to IDA, which impairs the blood's ability to carry oxygen efficiently either due to a reduced number of red blood cells or low hemoglobin levels. While anemia can have various causes, ID is the most prevalent.⁷

According to European data, the prevalence of ID (with or without anemia) is 35% to 55% in outpatients with HF and 72% to 83% in patients admitted for HF.²⁰ A recent study in Alberta²¹ used population-level data that included adult patients with HF between 2012 and 2019, to examine the prevalence of ID and IDA among patients with AHF and CHF. Among 17,463 patients with AHF, 38.5% had their iron status evaluated within 30 days postindex episode, compared to 34.2% of 11,320 patients with CHF. Of those tested, 72.6% and 73.9% of patients with AHF and CHF, respectively, were found to have ID, and 51.4% and 49.0% had IDA, respectively.

In addition to standard pharmacotherapy for HFrEF, the Canadian Cardiovascular Society guidelines⁴ recommend assessing and treating ID in these patients. This approach aims to enhance exercise tolerance, improve quality of life, and reduce hospitalizations due to HF, supported by strong recommendations and moderate-quality evidence.^4,22

As with the use of other HF treatments, management of ID in HF is suboptimal. TSAT is an important marker in these patients, with a value of less than 20% indicative of low plasma iron availability to tissues in patients with both absolute and functional ID. Canadian Cardiovascular Society guidelines⁴ recommend consideration of IV iron therapy for patients with HF with all of the following: ejection fraction of 40% or less, and serum ferritin concentration of less than 100 mcg/L or between 100 mcg/L to 299 mcg/L in combination with a TSAT of less than 20%.^23,24

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CDA-AMC review team.

The key goals in the treatment of ID and IDA are the correction of the hemoglobin deficit and repletion of iron stores (the correction phase), and maintenance of iron levels over time (the maintenance phase).^35,36

Oral iron, often in the form of ferrous sulphate, is the first-line therapy for most cases of ID and IDA and is relatively safe, effective, and inexpensive. Some patients may be unable to absorb ferrous sulphate adequately due to impaired intestinal uptake resulting from GI disease or clinical conditions such as chronic inflammation, which may in turn lead to elevated levels of hepcidin.^37-39 In other instances, the rate of absorption of even high-dose oral ferrous sulphate is insufficient to correct the anemia and blood transfusion may be indicated.^37,40

ID among patients with HF is known to be particularly recalcitrant to oral iron therapy, necessitating IV iron supplementation.^4,41 Because ID is an independent predictor of reduced functional capacity, increased hospitalization, and increased mortality for patients with HF, guidelines from the Canadian Cardiovascular Society, the Heart Failure Society of America, and the European Society of Cardiology all recommend starting patients who have ID with IV iron in preference to oral formulations, regardless of whether anemia is present.^{4,26,27,41,42} The recently updated European Society of Cardiology guideline for the diagnosis and treatment of CHF and AHF recommends FCM or ferric derisomaltose as a treatment for symptomatic patients with HF with ID.²⁷ Similarly, recent guidelines from the American College of Cardiology recommend that in patients with HFrEF and ID with or without anemia, IV iron replacement is reasonable to improve functional status and quality of life.²⁵ Oral iron supplements are associated with GI side effects, which can have a detrimental impact on patient adherence to treatment.^35,36 A systematic review and meta-analysis of RCTs found an increased risk of GI side effects (OR = 2.32; 95% CI, 1.74 to 3.08; P < 0.0001), particularly constipation, nausea, and diarrhea.⁴³

There is also a need to deliver iron rapidly in certain clinical situations including, for example, when a patient with ID requires an urgent surgery with risk of blood loss.⁴⁴ While repletion of iron stores with oral iron may require administration over several months, the correction of iron stores following IV iron administration occurs within a few weeks.^36,40 IV iron supplementation can, therefore, be an important treatment option in patients unable to absorb sufficient iron via the GI tract, unable to tolerate the required amounts of ferrous sulphate, and/or who require a rapid replenishment of stores. The IV route of iron administration can also benefit patients with poor adherence to other forms of treatment, chronic iron losses exceeding the rate of replacement possible with oral supplementation, and/or taking erythropoiesis-stimulating agent (ESA) treatment leading to increased demands. In patients taking ESAs, IV iron might significantly reduce ESA requirements and treatment costs.⁴⁰

The earliest IV iron preparations were associated with acute toxicity resulting from the release of bioactive labile iron. Subsequent iron formulations (referred to as “second generation”) were complexes with nondextran carbohydrates, which release iron more slowly, such as iron sucrose and iron gluconate. Third-generation IV iron products, such as FCM and ferric derisomaltose, are formulated to be given in larger doses over a shorter period.⁴⁰

In addition to FCM, there are currently 4 other IV iron products approved in Canada, albeit none are indicated specifically for patients with HF: Ferrlecit (sodium ferric gluconate complex in sucrose, 12.5 mg/mL), Monoferric (ferric derisomaltose, 100 mg/mL), Venofer (iron sucrose, 20 mg/mL), and pms-Iron Sucrose (iron sucrose injection, 20 mg/mL). Of these products, none are indicated for use in pediatric populations.

Drug Under Review

FCM is a colloidal dispersion which contains iron in a stable ferric state.²⁴ This complex consists of a polynuclear iron-hydroxide core bound to a carbohydrate ligand. It is specifically formulated to provide easily utilizable iron for the body's iron transport and storage proteins, namely transferrin and ferritin.²⁴

FCM was approved by Health Canada with the following indications:²⁴

• the treatment of IDA in adult and pediatric patients aged 1 year and older when oral iron preparations are not tolerated or are ineffective

• the treatment of ID in adult patients with HF and NYHA class II or class III to improve exercise capacity.

The diagnosis of ID must be based on laboratory tests. The sponsor request for reimbursement is as per Health Canada indication for HF. A Notice of Compliance was issued on March 11, 2024.

The dosage of FCM is expressed as mg of elemental iron, with each mL containing 50 mg of elemental iron. The recommended dosing of FCM for adult patients follows a stepwise approach by first determining the individual iron need for repletion based on the patient’s body weight and hemoglobin level (Table 4).

Table 4: Determination of the Total Iron Need in Adults (Aged ≥ 18 Years)

Source: Product monograph for Ferinject.²⁴

The maximum recommended cumulative dose of FCM is 1,000 mg of iron (20 mL FCM) per week. If the total iron need is higher, then the administration of an additional dose should be a minimum of 7 days apart from the first dose. A single FCM administration should not exceed either 15 mg iron/kg body weight, or 1,000 mg iron (20 mL FCM). Reassessment should be performed by the clinician based on the individual patient’s condition. The hemoglobin level should be reassessed no earlier than 4 weeks after final FCM administration to allow adequate time for erythropoiesis and iron utilization. In the event the patient requires further iron repletion, the iron need should be recalculated.

Key characteristics of FCM are summarized in Table 5 with off-label IV treatments for ID in patients with HF. Sodium ferric gluconate (Ferrlecit), an IV iron formulation approved in Canada, is not represented here because of clinical expert input that this is not a comparator of interest in this population and may only be used in very uncommon, niche clinical circumstances among patients with kidney failure requiring other specific interventions.

Table 5: Key Characteristics of FCM, FD, and IS

FCM = ferric carboxymaltose; FD = ferric derisomaltose; HDD-CKD = hemodialysis-dependent chronic kidney disease; ID = iron deficiency; IS = iron sucrose; NDD-CKD = non–dialysis-dependent chronic kidney disease; NYHA = New York Heart Association; PDD-CKD = peritoneal dialysis–dependent chronic kidney disease.

^aHealth Canada–approved indication.

Sources: Product monographs for ferric carboxymaltose,²⁴ ferric derisomaltose,⁴⁵ and iron sucrose.⁴⁶

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received by CDA-AMC are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups.

No patient group input was submitted.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of ID in patients with HF.

Unmet Needs

Although widely available and inexpensive, treatment of ID with oral iron was described by the expert to be of limited utility due to poor absorption in general, but especially among patients with HF due to a variety of physiological factors specific to HF, such as epithelial dysfunction in the gut because of mucosal edema and reduced intestinal blood flow. Oral iron is also associated with GI side effects that, as described by the clinical expert, can often lead to poor adherence. Oral iron is also limited in the dosage that can be consumed, which, compounded with the low rate of absorption, can result in very slow repletion. The expert also noted that oral administration of iron supplementation can interfere with the administration of other therapies, which can cause issues in a patient with HF who requires a concurrent cocktail of other medications to manage their underlying HF and improve their HRQoL.

The clinical expert indicated that IV iron is currently the preferred route for treatment of ID in patients with HF, and the intention of iron supplementation for ID in patients with HF is to improve HRQoL, functional capacity, and exercise capacity. According to the clinical expert, iron repletion is not in itself necessarily expected or intended to directly or immediately impact outcomes such as mortality because iron replenishment is not directly affecting the disease process causing the HF. Rather, the effects of ID are the worsening of HRQoL, functional capacity, and exercise capacity, which IV iron treatment has shown clearly to benefit. These are also symptoms of HF and thus are particularly severe in patients with both ID and HF. Consequently, according to the clinical expert, treatment of ID associated with HF would be expected to provide particular benefit with regards to these effects.

Place in Therapy

European,^26,27 Canadian,⁴ and American guidelines²⁵ for the management of ID in the setting of HF all recommend against oral iron and state preference for IV iron for repletion. The clinical expert described that IV iron preparations typically used in clinical practice include iron sucrose (maximum dose of 200 mg per sitting), ferric derisomaltose (maximum dose of 1,000 mg per injection), or FCM (maximum dose of 1,000 mg per week). Iron sucrose is a second-generation IV iron formulation, in contrast to ferric derisomaltose and FCM which are third generation, and according to the clinical expert are more thermodynamically stable and are designed to permit higher doses to be administered than previous generations. According to the clinical expert, first-generation IV iron formulations such as iron dextran are not used due to higher risks of anaphylaxis. Of the IV iron formulations, only FCM has a Health Canada–approved indication specific to the HF subpopulation; however, the other second-generation or third-generation IV iron preparations may also be used in clinical practice in this population.

Patient Population

The clinical expert described that ID is highly prevalent in patients with HF and is an independent predictor of worse functional capacity and outcome. Risk factors for ID according to the clinical expert include female sex, advanced HF, higher levels of N-terminal pro-brain natriuretic peptide and C-reactive protein. The expert noted that guidelines for the treatment of HF recommend all patients with HF should be tested for ID using serum ferritin and TSAT, and treatment with IV iron over oral iron is recommended for patients with ID and HF who meet other qualifying features that vary by regional guideline.

The expert highlighted that Canadian guidelines recommend consideration of IV iron therapy for patients with HF with all of the following: LVEF of 40% or less, and serum ferritin less than 100 mcg/L or between 100 mcg/L to 299 mcg/L with a TSAT less than 20%.

The clinical expert noted that there has been no assessment for the role of IV iron for anemia in patients with HF with preserved ejection fraction (HFpEF), a subgroup with poor prognosis and few condition-specific treatments impacting on survival. This is in contrast to patients HFrEF, for whom the Canadian guidelines do recommend IV iron supplementation if presenting with ID.

The clinical expert highlighted that the treatment guidelines do not delineate between NYHA classes with regards to treatment and rather determine who should receive which treatment based on clinical and objective factors such as ejection fraction, serum ferritin, and TSAT. Therefore, based on Canadian and multiple international treatment guidelines for patients with HF and ID, patients with any NYHA class may potentially be suitable for treatment with IV iron formulations, including FCM.

Assessing the Response Treatment

The clinical expert consulted by CDA-AMC noted that assessing response should follow the treatment guidelines and product monographs, which lay out objective metrics for determining a patient’s iron need and suitability for IV iron based on metrics such as ejection fraction (related to the patient’s HF), serum ferritin, and TSAT. The clinical expert noted that, adverse reactions to treatment aside, there might be circumstances in which a patient could stop therapy, but this would depend on the etiology of their ID and therefore this should be identified in the event that it could be otherwise managed (e.g., GI-related blood loss). However, the clinical expert suggested that many patients would be expected to continue IV iron life-long given that HF is a chronic disease and any HF-related ID is unlikely to resolve spontaneously. The clinical expert did not feel that there was any evidence to suggest a generalized reason (e.g., a threshold of inadequate response) to stop therapy prematurely. Evidence of persisting ID requiring IV iron treatment per guidelines should, in their opinion, be the only determinant for coverage. Put differently, the only reason to discontinue treatment would be evidence that iron stores became consistently repleted such that guidelines no longer supported ongoing IV iron administration.

Discontinuing Treatment

The clinical expert stated that the majority of patients receiving IV iron supplementation would be expected to continue this therapy for the duration of their lives. Aside from intolerance or contraindication, there are no specific reasons to necessarily discontinue treatment with FCM in this population. The clinical expert highlighted that in patients with HF and ID, the ID is generally not expected to spontaneously resolve. The clinical expert also noted there is no circumstance in which a patient with HF and ID would be recommended to switch to oral iron supplementation rather than IV iron, although switching to a different IV formulation may be done based on physician discretion and patient preference.

Prescribing Considerations

IV iron formulations such as FCM are prescribed in hospital and can be ordered by any prescribing clinician managing the patient’s HF and ID in that setting.

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by clinician groups.

A diverse group of clinical experts responding to CDA-AMC call for input from clinician groups comprised 13 independent clinicians spanning multiple specialties. They gathered information from product monographs, published literature, and their extensive personal experiences.

According to the group, ID is a progressive condition that can lead to IDA if untreated, affecting various patient populations, including those with HF. For patients with comorbidities like HF, ID exacerbates symptoms, accelerates disease progression, and worsens prognosis. ID correlates with poorer functional capacity, increased hospitalizations, and increased mortality.

The clinician group emphasized that treatment goals include correcting hemoglobin deficits, replenishing iron stores, and maintaining them over time to alleviate symptoms and enhance HRQoL. While initial therapy often involves oral iron supplements, IV iron is recommended as the first-line treatment for patients with HF due to its rapid efficacy in iron repletion and its ability to improve outcomes. Guidelines advocate for initiating IV iron therapy as soon as ID is identified, regardless of anemia status. This strategy is especially beneficial for patients who cannot adequately absorb oral iron, experience intolerable GI side effects, or require higher rates of iron replacement, such as those receiving ESAs.

The clinician group noted that while IV iron formulations in Canada offer flexible dosing options to meet individual patient needs effectively, previous IV iron products posed significant challenges. These included requiring long administration periods or multiple sessions to achieve a cumulative dose of 1,000 mg. Additionally, none were indicated for use in pediatric populations or for the treatment of patients with ID and HF. This underscores the necessity for more efficient and versatile IV iron therapies capable of effectively addressing these treatment gaps. Newer IV iron products in Canada, like FCM, can deliver high doses (up to 1,000 mg) in a single injection or short infusion, which may reduce treatment burden, enhance convenience, and improve adherence, leading to faster symptom relief and better outcomes.

According to the clinician group, patients with HF and ID are particularly suitable for treatment with FCM. The clinician group indicated that treatment response is assessed using hematologic measures and iron parameters (ferritin and TSAT) to gauge improvements. Ideally, clinicians aim for normalization of hemoglobin levels and increased ferritin levels exceeding those indicating ID. Response evaluation should consider individual variations and potential challenges like ongoing blood loss or underlying health conditions. Clinically meaningful outcomes also include reducing the need for blood transfusions, symptom alleviation, enhanced exercise capacity, improved quality of life, and fewer hospitalizations. Monitoring typically occurs 4 weeks to 8 weeks after completing the initial treatment course to track progress and adjust therapy as needed.

According to the input, factors to consider when deciding to discontinue treatment with FCM include postrepletion assessments of hemoglobin, ferritin, and TSAT levels. Reassessment should occur no earlier than 4 weeks after the final dose to allow for adequate time for erythropoiesis and iron utilization. Treatment should be immediately discontinued in cases of hypersensitivity reactions or intolerance during administration, and it is contraindicated in patients with iron overload or persistent hypophosphatemia, where re-evaluation of treatment is warranted. FCM is appropriate for treatment in settings equipped to manage anaphylaxis and hypersensitivity reactions. It can also be administered in emergency departments or surgical inpatient units when indicated. While specialists like hematologists and other physicians commonly prescribe FCM, a specialist is not always required for diagnosis, treatment, and monitoring. Family medicine practitioners, as well as specialists in cardiology, gastroenterology, internal medicine, nephrology, and obstetrics and gynecology, among others, may also manage patients requiring IV iron therapy.

Drug Program Input

The drug programs provide input on each drug being reviewed through the CDA-AMC Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 6.

Table 6: Summary of Drug Plan Input and Clinical Expert Response

AE = adverse event; AHF = acute heart failure; CDEC = Canadian Drug Expert Committee; CHF = chronic heart failure; GI = gastrointestinal; HF = heart failure; ID = iron deficiency; IDA = iron deficiency anemia.

Clinical Evidence

The objective of this CDA-AMC Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of Ferinject (ferric carboxymaltose) for the treatment of ID in adult patients with HF and NYHA class II or class III to improve exercise capacity. The focus will be placed on comparing FCM to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of FCM is presented in 4 sections with the CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence uses the GRADE approach and follows the critical appraisal of the evidence. Subsequent sections would detail long-term extension studies, indirect evidence, and studies addressing gaps in the evidence, but there were no studies of interest submitted for this indication.

Included Studies

Clinical evidence from the following are included in the CDA-AMC review and appraised in this document:

• 4 pivotal studies or RCTs identified in systematic review.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CDA-AMC review team.

Description of Studies

Characteristics of the included studies are summarized in Table 7. Ideally, studies of interest would compare FCM to other IV infusion formulations of iron supplementation; however, no such studies exist to our knowledge. The studies included were the FAIR-HF study (N = 459), CONFIRM-HF study (N = 304), and HEART-FID (N = 3,065) study in patients with CHF, and the AFFIRM-AHF study (N = 1,132) in patients with AHF, all 4 of which are placebo-controlled, double-blind, randomized phase III (FAIR-HF and HEART-FID) or phase IV (CONFIRM-HF and AFFIRM-AHF) trials in adults with HF and ID. Of these, 2 studies (FAIR-HF and CONFIRM-HF) were focused primarily on clinical efficacy outcomes such as exercise capacity and NYHA class, while the remaining 2 studies (HEART-FID and AFFIRM-AHF) were focused primarily on composite outcomes related to hospitalizations and deaths (the HEART-FID study also included the 6MWT in their composite primary outcome). The studies ranged in duration from approximately 6 months (the FAIR-HF study) to 12 months (the CONFIRM-HF, HEART-FID, and AFFIRM-AHF studies).

Some studies of adults with HF and ID were excluded from consideration in this review. Studies that compared to oral iron were not considered to be of interest because oral iron has been demonstrated to be ineffective in iron repletion in this population, is not recommended in this population by Canadian⁴ and international^25-27 treatment guidelines for the management of HF, and was confirmed by the clinical expert consulted by CDA-AMC to be an inappropriate choice of treatment among patients with HF because of physiological consequences of HF that lower the ability of the body to absorb iron administered orally. One study that was potentially of interest, the EFFECT-HF study (N = 174), was excluded because the comparator arm was standard of care and 29 of 86 patients in the standard of care treatment group were receiving oral iron.

Other studies with similar populations were excluded due to small sample sizes and because it was not believed they would contribute to the overall conclusions of this review to an important degree (the Caravita et al.,⁷⁰ Martens et al.,⁷¹ Nunez et al.,⁷² and FER-CARS-01 studies⁷³). The characteristics of these studies, in addition to the EFFECT-HF study, are summarized briefly in Appendix 1.

Table 7: Details of Studies Included in the Systematic Review

6MWT = 6-minute walk test; AE = adverse event; AHF = acute heart failure; ALT = alanine transaminase; AST = aspartate transferase; BNP = brain natriuretic peptide; CHF = chronic heart failure; CV = cardiovascular; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; FCM = ferric carboxymaltose; HF = heart failure; HRQoL = health-related quality of life; KCCQ = Kansas City Cardiomyopathy Questionnaire; LV = left ventricle; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NYHA = New York Heart Association; NR = not reported; PGA = Physician’s Global Assessment; TIA = transient ischemic attack; TSAT = transferrin saturation; w/v = weight per volume.

^aIn general, optimal pharmacological treatment which includes a diuretic, a beta-blocker, and/or an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker as determined by the investigator, unless contraindicated or not tolerated.

^bIron deficit (mg) = body weight (kg) × (150 – actual hemoglobin [g/L]) × 0.24 + 500 mg (depot iron). In patients with a body mass index > 25 kg/m², a normalized weight will be used to calculate the iron deficit. Body mass index is calculated as weight (kg)/(height [m] x height [m]) and normalized weight (kg) is calculated as 25 × height (m) × height (m). The factor of 0.24 in the calculation of iron deficit is calculated as: 0.0034 (as iron content of hemoglobin = 0.34%) × 0.07 (as blood volume = 7% of body weight) × 1,000 (conversion of g to mg).

^cFerinject was administered in doses of 200 mg (4 mL) weekly up to iron repletion (correction phase of variable duration depending on individual iron deficit). The calculated dose was rounded to the next 100 mg of iron, (i.e., the final dose may be 100 mg of iron depending on the individual iron deficit). After the correction phase, FCM was given monthly in doses of 200 mg until the 24th week (maintenance phase). Total dose required was calculated using the Ganzoni formula (and administered in first 12 weeks) with a maintenance dose administered from week 12 at 200 mg every 4 weeks until week 24. If ferritin was > 800 mcg/L or > 500 mcg/L when TSAT was > 50%, or hemoglobin was > 16.0 g/dL at any stage of treatment, iron treatment was discontinued and placebo was administered instead.

Sources: Clinical Study Reports, Statistical Analysis Plans, and Protocols for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies;³² publication, supplementary appendix, and protocol of the HEART-FID study.³¹

Populations

Inclusion and Exclusion Criteria

All 4 studies included adult patients with NYHA class II or class III, although the HEART-FID study also included class IV, and the AFFIRM-AHF study also included both class I and class IV. The 3 CHF studies had a maximum allowed LVEF at screening or index visit, although the precise threshold varied: 40% or less (NYHA class II) or LVEF of 45% or less (NYHA class III) in the FAIR-HF study, 45% or less in the CONFIRM-HF study, and 40% or less in the HEART-FID study (although historically reduced LVEF was also allowed given specific circumstances). In the AFFIRM-AHF study, the inclusion criteria required that patients had a LVEF of less than 50% within 12 months before randomization. All 4 included studies required a serum ferritin of less than 100 mcg/mL, or 100 mcg/mL to 299 mcg/mL or 100 mcg/mL to 300 mcg/mL with a TSAT of less than 20%. The exclusion criteria were relatively similar across trials with no notable concerns for interpretation of the evidence.

Interventions

All 4 studies compared FCM (5% weight by volume in water for injection) to placebo.

In the FAIR-HF study, the dosage form was 2 mL vials containing 100 mg of iron per vial, in a 5% weight by volume solution. Placebo was in the form of 5 mL containers of normal saline at a concentration of 0.9% weight by volume. Because these appear visually different, preparation and administration of the solutions for injection was completed by an unblinded study person using black syringes, with recommendations for steps to maintain blinding of the patient and outcome assessors. Dosing was divided between a “correction phase” and “maintenance phase.” Each injection of either FCM or placebo was given in a volume of 4 mL (corresponding to 200 mg iron in the FCM group), with the exception of the last injection of the correction phase, which could be 2 mL (100 mg iron in the FCM group). Total iron dosing for repletion was calculated using the Ganzoni formula. The correction phase included weekly doses of 200 mg iron (or corresponding volume of placebo [4 mL saline]) until iron repletion was achieved, rounded to the next 100 mg. After the correction phase, doses were given on a monthly basis in a volume of 4 mL (i.e., 200 mg iron in the FCM group) until week 24. In terms of concomitant medications, patients were not allowed to participate in the trial if they were on immunosuppressive therapy, had a previous heart transplant, or were on renal dialysis. Prescription or administration of erythropoietin, IV or oral iron therapy, and blood transfusion concomitantly with study treatment was not allowed, because these agents can induce an increase of iron blood parameters and overlap the effect of IV iron therapy, hence mislead the evaluation of efficacy and safety of IV iron therapy in patients with CHF.

In the CONFIRM-HF study, the dosage form was 10 mL vials containing 500 mg iron per vial. Placebo was in the form of a 5 mL, 0.9% weight by volume sodium chloride solution in water for injection. Because these appear visually different, preparation and administration of the solutions for injection was completed by an unblinded study person using black syringes, with recommendations for steps to maintain blinding of the patient and outcome assessors. Unlike the FAIR-HF study, the CONFIRM-HF study did not use the Ganzoni formula for calculating iron need; instead, the regimen was simplified based on screening weight and hemoglobin levels. Correction of ID was done with a cumulative dose of 500 mg to 2,000 mg of iron, with up to 3 additional maintenance doses of 500 mg thereafter. On day 0, patients receiving FCM received an initial single dose of 1,000 mg, or 500 mg for those with hemoglobin greater than 14 g/dL; patients allocated to placebo instead received 4 vials of saline to match the volume. At week 6, patients received an additional dose based on weight and hemoglobin: patients weighing less than 70 kg at screening and with hemoglobin of less than 10 g/dL at week 6 received 10 mL (500 mg) or 2 vials of saline; patients with a screening weight of 70 kg or greater received either 20 mL corresponding to 1,000 mg of FCM (or 4 vials saline) if their hemoglobin was less than 10 g/dL or 10 mL corresponding to 500 mg of FCM (or 2 vials saline) if their hemoglobin was between 10 g/dL to 14 g/dL. No dose was given to patients who either weighed less than 70 kg and had a hemoglobin reading of 10 g/dL to 14 g/dL, or weighed 70 kg or greater and had a hemoglobin greater than 14 g/dL. At weeks 12, 24, and 36, as maintenance dosing, patients could receive 10 mL (500 mg) of FCM (or 2 vials of saline) if their serum ferritin was still less than 100 mcg/mL or was between 100 mcg/mL to 300 mcg/mL and their TSAT was less than 20%. In terms of concomitant therapy, prohibited therapies during the study included other parenteral iron therapy, oral iron therapy (albeit ongoing use of multivitamins containing < 75 mg/day of iron was permitted), red cell transfusions, or ESAs.

In the HEART-FID study, FCM was available in 15 mL vials containing 750 mg and administered as either a continuous infusion or a slow IV injection at a rate of 2 mL (100 mg) per minute for a total dose of 750 mg per injection for patients weighing greater than 50 kg. For patients weighing less than 50 kg, the dose was adjusted to 15 mg/kg per injection. Patients received 2 doses separated by 7 (± 2) days. The Ganzoni formula was not used to calculate iron need, based on the justification that the US label (at the time approved for IDA) outlined dosing as previously described based on whether patients weigh at least 50 kg or not, and that the Ganzoni formula is theoretical and may not be applicable to all disease states or clinical scenarios (according to the study protocol publication). Placebo (normal saline) dosing volume was adjusted for weight to maintain blinding. Blinding of patients was maintained using blindfolds or curtains so that they could not see the vials being injected. Blinded study personnel were blinded to posttreatment iron indices and serum phosphorous laboratory results due to the potential for these to break the blind. Patients could receive additional doses of study drug every 6 months; patients in the FCM group were dosed based on hemoglobin levels (< 13.5 g/dL in females or < 15.0 g/dL in males) and iron studies (ferritin < than 100 mcg/mL, or between 100 mcg/mL to 300 mcg/mL with TSAT < 20%), while patients in the placebo group received matching volumes of placebo based on these parameters. Blinded staff administered assessments such as the 6MWT and other examinations. The HEART-FID study disallowed patients who had recently received (within 3 months) ESA, IV iron therapy, or blood transfusion; with current or planned mechanical circulatory support or heart transplant; and with hemodialysis or peritoneal dialysis currently or planned within 6 months.

In the AFFIRM-AHF study, the dosage form was the same as in the CONFIRM-HF study (i.e., 10 mL vials containing 500 mg iron per vial, a concentration of 5% weight by volume). Similar to both the FAIR-HF and CONFIRM-HF studies, due to this solution being dark brown and the saline (0.9% weight by volume, 10 mL vial) solution being clear, preparation was completed using black syringes with steps taken to maintain blinding of study patients and blinded personnel performing study assessments. Calculation of total iron need was done in a similar manner to the CONFIRM-HF study (i.e., a simplified algorithm not using the Ganzoni formula). Administration of study drug or placebo was done in 10 mL volumes (i.e., 500 mg iron in the FCM group) at each injection. At week 0, all patients received 10 mL of either FCM or placebo solution. At week 6, patients received an injection of 10 mL if they had either a hemoglobin level of less than 10 g/dL (received 10 mL if < 70 kg or 20 mL if ≥ 70 kg), or if they weighed 70 kg or greater and had a hemoglobin level of 10 g/dL to 14 g/dL, inclusive (received 10 mL). Patients outside of these parameters (i.e., higher hemoglobin level) did not receive a week 6 dose. At week 12 and week 24, patients could receive a 10 mL dose (i.e., 500 mg iron) if ID persisted, which was defined as serum ferritin of 100 mcg/mL, or serum ferritin of 100 mcg/mL to 299 mcg/mL inclusive if TSAT was less 20%. As an aside, in the Netherlands, Spain, and Singapore, patients with a hemoglobin level less than 10 g/dL were withdrawn from further study dosing due to differences in the eligibility criteria in those countries. In terms of concomitant medications, the following therapies were disallowed, and if required then the patient was to withdraw from the study treatment: immunosuppressive or myelosuppressive therapy, erythropoietin, oral or IV iron therapy other than study medication (albeit ongoing use of multivitamins containing < 75 mg/day of iron was permitted), blood transfusion, surgery that could result in significant blood loss, renal dialysis, or heart transplant.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 8, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical expert consulted by CDA-AMC and input from clinician groups and public drug plans. Patient group input would normally be considered but none was submitted. Using the same considerations, the review team selected end points that were considered to be most relevant to inform Canadian Drug Expert Committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Where outcomes of interest were reported as components of composite outcomes in some trials, these composites were descriptively summarized but not assessed using GRADE.

Table 8: Outcomes Summarized From the Studies Included in the Systematic Review

6MWT = 6-minute walk test; CHF = chronic heart failure; CV = cardiovascular; KCCQ = Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; NR = not reported.

^aThese analyses were uncontrolled for multiplicity, so there is an increased risk of erroneously rejecting the null hypothesis.

Sources: Clinical Study Reports, Statistical Analysis Plans, and Protocols for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies;³² publication, supplementary appendix, and protocol of the HEART-FID study.³¹

NYHA Class

Change in NYHA class was a co-primary end point (at 24 weeks) in the FAIR-HF study, a secondary end point in the CONFIRM-HF study (24 weeks and 52 weeks), and “other” end point in the AFFIRM-AHF study (24 weeks and 52 weeks).

The NYHA functional class system is a subjective but widely used classification used to determine CHF severity based on symptoms, as follows. This particular verbiage is from the protocols of the FAIR-HF and CONFIRM-HF studies, but is generally consistent across included studies and is standardized.⁵³

• Class I: Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.

• Class II: Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.

• Class III: Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain.

• Class IV: Patients have cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

6MWT

The 6MWT was the primary end point of the CONFIRM-HF study at 24 weeks and a secondary end point in the CONFIRM-HF study at 52 weeks and was also a secondary end point in the FAIR-HF study (at 24 weeks) and the HEART-FID study (as a component of the composite primary end point, evaluated at 24 weeks, and as a secondary end point at 52 weeks). Additional time points were also recorded at every visit, although are not reported herein as only the 24-week and 52-week end points were considered to be of interest for this review. The 6MWT is a test of exercise capacity, validated among patients with CHF, that assesses how far a patient can walk along the length of a hard, flat course at their own pace while attempting to cover as much ground as possible in 6 minutes, which was recorded to the nearest metre. According to the protocols of the FAIR-HF and CONFIRM-HF studies, patients were allowed to rest on chairs during the test but were encouraged to resume walking as soon as they felt physically able and were instructed not to perform vigorous activity for 2 hours before the test. In the FAIR-HF and CONFIRM-HF studies, it was specified that every effort was to be made to ensure the test was performed by the same clinic personnel for the duration of the trial for any 1 patient. These additional details were not available in the publications for the HEART-FID study but given that this is a common, simple, and validated assessment, there were no particular concerns that the methodology would greatly vary. The 6MWT was not assessed in the AFFIRM-AHF study.

KCCQ

The KCCQ was reported by the FAIR-HF study (24 weeks), CONFIRM-HF study (24 weeks and 52 weeks), and AFFIRM-AHF study (24 weeks and 52 weeks) as a secondary end point in each case. The KCCQ was not reported in the HEART-FID study. It is a 23-item, self-administered questionnaire that quantifies physical limitation, symptoms (stability, frequency, and burden), self-efficacy, social function, and HRQoL. Scores are transformed to a range of 0 to 100, where higher scores reflect better health status. This outcome was selected with assistance from clinical expert input because it is a disease-specific HRQoL metric. Some studies also reported a generic HRQoL metric, the EQ-5D, which is not detailed here.

Fatigue Score

The change in baseline of self-reported fatigue score was assessed as a secondary end point in the CONFIRM-HF study (24 weeks and 52 weeks) only and was assessed at every visit before patients began the 6MWT assessment. The fatigue score was assessed using a 10-point visual analogue fatigue scale, ranging from 1 for “no fatigue” to 10 for “very severe fatigue.” This outcome was selected for this review with assistance from clinical expert input and because fatigue is a major symptom of HF and ID and can have a substantial impact on patients’ HRQoL.

Serum Ferritin

Serum ferritin was a key factor considered in dosing of FCM in the CONFIRM-HF, HEART-FID, and AFFIRM-AHF studies, and the change in serum ferritin from baseline is available from all 4 included studies at week 24 and/or week 52, depending on study duration. Importantly, serum ferritin is a defining metric of ID, and in the context of HF in particular, ID has been defined as serum ferritin of less than 100 mcg/mL (absolute ID) or less than 300 mcg/mL with TSAT of less than 20% (functional ID).

Hospitalization and Mortality Rate Due to Any CV Reason

Although the treatment goal of FCM in patients with HF and ID is to improve exercise capacity, hospitalizations and mortality due to CV reasons were selected for this review because objective outcomes relating to resource use and mortality are of interest to the committee for deliberation and for the pharmacoeconomic review of FCM. All studies reported some metrics related to hospitalizations and mortality, but rates of hospitalization and death specific to CV reasons were provided by the sponsor at the request of CDA-AMC to facilitate this review, as the preplanned analyses differed in each study. The primary outcome of the HEART-FID study was a hierarchical composite comprising death at 12 months, number of hospitalizations for HF at 12 months, and change from baseline in 6MWT at 6 months; the primary outcome of the AFFIRM-AHF study was the composite of recurrent HF hospitalizations and CV death up to 52 weeks after randomization. These are both described briefly in the hospitalizations section of the results of this report.

Table 9: Summary of Outcome Measures and Their Measurement Properties

6MWD = 6-minute walk distance; 6MWT = 6-minute walk test; CI = confidence interval; CSS = Clinical Summary Score; FCM = ferric carboxymaltose; HF = heart failure; HRQoL = health-related quality of life; ICC = intraclass correlation coefficient; KCCQ = Kansas City Cardiomyopathy Questionnaire; MID = minimal important difference; NYHA = New York Heart Association; OSS = overall summary score; TSS = Total Symptom Score; vs. = versus.

Statistical Analysis

Sample Size and Power Calculation

FAIR-HF

Sample size calculations were based on the Physician’s Global Assessment (PGA) score and change in NYHA class 24 weeks after start of iron repletion. A 2-group t test with a 0.025 two-sided significance level had 90% power to detect a difference in PGA score means of 0.900, assuming that the common SD was 2.407, when the sample sizes in the 2 groups were 134 and 268 (a total sample size of 402). A 2-group t test with a 0.025 two-sided significance level had 90% power to detect a difference in NYHA class means of 0.500, assuming that the common SD was 1.337, when the sample sizes in the 2 groups were 134 and 268 (a total sample size of 402). With an estimated rate of 30% of patients who do not have a week 24 assessment while taking an investigational drug, 576 patients had to be included in the study.

CONFIRM-HF

Using the data reported in the FAIR-HF study, the mean difference in the 6MWT to week 24 was assumed to be 29.1 metres with a SD of 71.8 metres. Based on these assumptions, a sample size of 130 patients per group (260 total) was needed for 90% power using an alpha of 0.05 (2-sided) to detect mean treatment effect of at least 29.1 metres at week 24. The sample size was rounded up to 150 patients per group (300 total) to allow for some loss of information due to early discontinuations.

HEART-FID

With 3,014 patients (1,507 per arm) and 2.5% annual loss to follow-up for clinical outcomes and 15% of individuals with missing 6MWT at 6 months (unable to perform or lost to follow-up), projected simulations estimated 90% power at an overall 2-sided significance level of 0.01 for the primary end point, accounting for 1 interim analysis. Considerations for time to CV death or hospitalization for HF were also included in the power calculations, although will not be detailed here as these time-to-event outcomes were not selected to be of interest.

AFFIRM-AHF

It was anticipated that approximately 35% of patients would sustain either a CV death or at least 1 HF hospitalization, and that 12% of patients would sustain a CV death. It was assumed that the rate ratio between FCM and placebo for the composite of recurrent HF hospitalizations and CV deaths would be approximately 25%, with an assumed dispersion factor (K) of 1. The sample size calculation was done using the formula proposed in the study by Zhu and Lakkis.⁶⁵ Assuming a rate of recurrent HF hospitalization and CV death of 0.7 events/year in the placebo group, 1,000 patients (500 per study treatment group) would be required to demonstrate a statistically significant rate ratio of 0.75 with a power of 80% and a 2-sided alpha of 0.05. Taking into account 9% loss to follow-up, a sample size of 1,100 patients (550 per treatment group) was planned.

Statistical Testing

The statistical testing methods as well as covariates and/or baseline values that were included in the statistical models for each outcome are provided in Table 10.

FAIR-HF

In the FAIR-HF study, the co-primary end points were change in NYHA class and change in PGA from baseline to week 24. However, PGA was not selected for this review and so will not be detailed further. For all outcomes assessed at 24 weeks, only the closest assessment obtained within the allowed time window of the week 24 visit was to be used.

The FAIR-HF study tested the overall effect of treatment on NYHA class adjusted for baseline by ordered polytomous regression using treatment and baseline NYHA class (separated into 3 dummy binary variables with NYHA class III being the reference) as covariates. Alpha adjustment was planned using the method of Benjamini-Hochberg. The P values for the 2 tests (P value of the treatment covariate in the ordered polytomous regression for the PGA and NYHA values) were to be ordered in size (p1 ≤ p2, where p1 is the P value of the treatment covariate in the ordered polytomous regression for PGA values, and p2 for NYHA values). p2 would be compared to a significance level of 5%. If p2 was 5% or less, both alternative hypotheses would be proven (represented by H₁ and H₂). If p2 was greater than 5% and p1 was 2.5% or less, the corresponding alternative hypothesis of the smaller P value (H₁) would be proven. Other end points were not adjusted for multiplicity. Details on imputation of missing values can be found in Table 10.

For the secondary end point of 6MWT, the analysis of treatment difference was to be done by comparing the model-adjusted means of the corresponding visit based on a model for repeated measures including terms for treatment, baseline, time, and treatment by time with an unstructured covariance matrix to model the within-patient variability. The method of imputation of missing values for 6MWT differed from NYHA because the intervals for assessment for 6MWT were significantly longer (6-week to 12-week intervals), during which time a patient’s health status could change considerably; therefore, a more conservative approach was selected for imputation for patients who had missing values due to hospitalization or death (refer to Table 10). No multiplicity adjustment was described for any secondary outcomes, including 6MWT.

The KCCQ and continuous laboratory metrics were analyzed in the same manner as 6MWT.

CONFIRM-HF

The primary efficacy analyses of the change in 6MWT from baseline to week 24 were conducted using an analysis of covariance, with adjustment for baseline 6MWT distance, hemoglobin level at screening (< 12 g/dL and ≥ 12 g/dL), and pooled country (Russia, Ukraine, Poland, and pooled C [other European countries: Austria, Italy, Portugal, Spain, Sweden, and the UK]). A second analysis of covariance was run to examine the terms of interaction between pooled country and treatment group as well as between hemoglobin level at screening and treatment group. No multiplicity adjustment was described for any primary or secondary outcomes.

The protocol describes that, to account for any potential bias introduced in favour of FCM using the imputation for hospitalizations and deaths (refer to Table 10), the analysis of the 6MWT was repeated using observed cases only. Because there had been a previous incidence of AEs leading to hospitalization in the FCM group of the FAIR-HF study (compared to placebo), assuming this held true in the CONFIRM-HF study, any treatment effect of FCM could be artificially inflated by using the worst nonnull imputation (as it would be disproportionately applied to the placebo arm due to patients missing the 6MWT due to hospitalization). Therefore, for the CONFIRM-HF study, the potential for bias was addressed by analysis of observed cases. Observed cases were also analyzed using last observation carried forward (LOCF) at week 24 and week 52 to demonstrate whether any observed treatment benefit of FCM was driven by patients who withdrew before these time points. These considerations were not applied for other efficacy variables.

For NYHA, analysis of covariance repeated measure models were used for the analysis of the continuous secondary end point variables, and repeated measures polytomous regression for the noncontinuous variables analysis. Time-to-event analyses for outcome-related end points (adjudicated hospitalizations and deaths) were conducted using Kaplan-Meier estimators and log-rank tests. Hazard ratios and corresponding 95% CIs were obtained from the proportional hazard ratio models. For safety outcomes, missing and/or incomplete dates or times for AEs were imputed only for determination of treatment emergence and time of event relative to the first administration of study medication. A worst-case approach was followed in the event of missing severity or causality data.

HEART-FID

The primary outcome follows a hierarchical scale of clinical severity comprising death at 12 months, number of hospitalizations for HF at 12 months, or change from baseline in 6MWT distance at 6 months, and the main comparison was conducted using the Wilcoxon-Mann-Whitney test for the null hypothesis that a randomly chosen patient in the FCM group is equally likely to be ranked better or worse than a randomly chosen patient in the control group. However, the outcomes assessed in this report were provided by the sponsor as absolute between-arm differences upon request and are not subject to this statistical methodology.

With respect to the outcomes assessed in this review, no adjustments for multiplicity were reported in the protocol.

AFFIRM-AHF

The primary outcome was the composite of recurrent HF hospitalizations and CV death up to 52 weeks after randomization, which was assessed using a rate ratio analyzed using a negative binomial model. This was selected over the Poisson distribution because it allows for different individual tendencies with respect to their risks of repeat hospitalizations, according to the trial protocol.

With regards to the secondary outcomes (refer to Table 10), Hochberg procedure was used to control the overall type I error for the evaluation of the secondary end points on FAS at the 2-sided alpha of 5%. All secondary end point P values were sorted from the smallest to the largest and compared with Hochberg critical values. The highest P value with lower value than the Hochberg critical value was chosen. This P value and all lower P values were considered statistically significant at an overall 2-sided level of 5%.

Other end points not listed as secondary end points were not adjusted for multiplicity, such as the change from baseline in NYHA functional class, KCCQ, safety end points, and laboratory values.

In general, there was no replacement for missing data with some exceptions, such as to impute missing date values for time-to-event calculations and for assigning missing dates to AEs and concomitant medications. However, there was otherwise no imputation for missing outcomes data.

Due to the COVID-19 pandemic, sensitivity analyses were to be performed for the primary and secondary end points on the FAS censoring patients at index date. The index date was given by country and corresponds with the first reported patient with COVID-19 in the country. All events after the index date were to be excluded and patient’s follow-up time was considered only up to the index date.

Subgroup Analyses

Both the FAIR-HF and CONFIRM-HF studies conducted subgroup analyses on their primary end points across a wide range of baseline demographic and disease-related characteristics. The main purpose of the subgroup analyses was to evaluate the consistency of the treatment effects across the different populations and subgroups. As no subgroups were identified to be of special interest, these will not be described in detail in this report.

In the HEART-FID study, no prespecified subgroup analyses were detailed.

In the AFFIRM-AHF study, no prespecified subgroups were detailed, although additional exploratory analyses of subgroups by baseline characteristics were permitted by the protocol and were conducted for several demographic and disease-related characteristics according to the Statistical Analysis Plan and Clinical Study Report.

Table 10: Statistical Analysis of Efficacy End Points

6MWT = 6-minute walk test; AE = adverse event; ANCOVA = analysis of covariance; CEC = clinical events classification; CHF = chronic heart failure; CI = confidence interval; CV = cardiovascular; FAS = full analysis set; HF = heart failure; HR = hazard ratio; KCCQ = Kansas City Cardiomyopathy Questionnaire; LOCF = last observation carried forward; NR = not reported; NYHA = New York Heart Association; PP = per protocol; PY = patient-years.

Source: Clinical Study Reports, Statistical Analysis Plans and Protocols for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies;³² publication, supplementary appendix, and protocol of the HEART-FID study.³¹

Analysis Populations

The analysis populations of each study are summarized in Table 11. The FAIR-HF and CONFIRM-HF studies are summarized together because their study designs were similar in terms of analysis populations.

Table 11: Analysis Populations of Included Studies

FAS = full analysis set; ITT = intent to treat; PP = per protocol; PPP = per-protocol population; PPS = per-protocol set; SAF = safety; SS = safety set.

Source: Clinical Study Reports, Statistical Analysis Plans, and Protocols for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies;³² publication, supplementary appendix, and protocol of the HEART-FID study.³¹

Results

Patient Disposition

The disposition of patients screened and randomized in each study is summarized in Table 12. There were high proportions of screening failures in the FAIR-HF (51.8%), CONFIRM-HF (48.4%), and HEART-FID (62.6%) studies, primarily due to failing eligibility criteria. At least 70% of enrolled patients completed the study in each case. Discontinuation due to AE was generally uncommon. The PPS in the CONFIRM-HF study was notably smaller than the FAS due to a large number of protocol violations.

Baseline Characteristics

The baseline characteristics outlined in Table 13 (CHF) and Table 14 (AHF) are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

The mean age across studies and treatment arms ranged from approximately 67 years to 69 years in the CHF studies and was slightly higher in the AFFIRM-AHF study (71 years in the FCM group and 70 years in the placebo group). The proportion of female patients was 44% to 45% in the AFFIRM-AHF study, 45% to 49% in the CONFIRM-HF study, 52% to 55% in the FAIR-HF study, and 33% to 35% in the HEART-FID study in the FCM group and the placebo group, respectively. In all cases, the populations were disproportionately white race, especially in the FAIR-HF study (99.7% and 100% in the FCM group and the placebo group, respectively) and the CONFIRM-HF study (99% and 99% in the FCM group and the placebo group, respectively). In terms of the distribution of NYHA classes, the FAIR-HF study mostly included patients in NYHA class III (> 80% while the remainder were class II at baseline), while in the CONFIRM-HF, HEART-FID, and AFFIRM-AHF studies, the balance was closer to even between class II and class III. The HEART-FID study also included NYHA class IV, and the AFFIRM-AHF study also included class I and class IV, but the proportion of each of these were very low in the respective studies (i.e., ≤ 3%). Comorbidities were common, where reported, especially hypertension, dyslipidemia, diabetes mellitus, and other CV conditions such as atrial fibrillation and history of myocardial infarction.

Table 12: Summary of Patient Disposition

FAS = full analysis set; FCM = ferric carboxymaltose; NR = not reported; PPS = per-protocol set.

^aScreened in error.

^bIn the FAIR-HF study, the adverse events category was defined as “development of an intolerable AE or pregnancy.”

Sources: Clinical Study Reports, Statistical Analysis Plans, and Protocols for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies;³² publication, supplementary appendix, and protocol of the HEART-FID study.³¹

Table 13: Summary of Baseline Characteristics From Studies Included in the Systematic Review — Chronic Heart Failure

AF = atrial fibrillation; ALT = alanine transaminase; AST = aspartate transferase; BNP = brain natriuretic peptide; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; FCM = ferric carboxymaltose; LVEF = left ventricular ejection fraction; MCV = mean corpuscular volume; MI = myocardial infarction; NA = not applicable; NR = not reported; NT pro-BNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; SD = standard deviation; TSAT = transferrin saturation.

^aMedian = 1,485.5 pg/mL (interquartile range, 727.1 pg/mL to 3,044.5 pg/mL) from 1,518 patients.

^bMedian = 1,423.6 pg/mL (interquartile range, 710.0 pg/mL to 2,883.8 pg/mL) from 1,526 patients.

Sources: Clinical Study Reports, Statistical Analysis Plans, and Protocols for the FAIR-HF²⁹ and CONFIRM-HF studies;³⁰ publication, supplementary appendix, and protocol of the HEART-FID study.³¹

Table 14: Summary of Baseline Characteristics From Studies Included in the Systematic Review — Acute Heart Failure

BNP = brain natriuretic peptide; eGFR = estimated glomerular filtration rate; FCM = ferric carboxymaltose; IQR = interquartile range; LVEF = left ventricular ejection fraction; NT pro-BNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; SD = standard deviation; TSAT = transferrin saturation.

Sources: Clinical Study Report, Statistical Analysis Plan, and Protocol for the AFFIRM-AHF study.³²

Concomitant medications are detailed for the CHF studies in Table 15 and for the AHF study in Table 16. The studies differed greatly in the selection of concomitant medications reported, which may reflect the different times in which they were conducted. Where reported, use of diuretics and use of beta-blockers were both common (at least 80% across all studies that reported these). The HEART-FID study uniquely reported use of sacubitril-valsartan (approximately 30%) and sodium-glucose cotransporter-2 inhibitors (approximately 8%), and both the HEART-FID and AFFIRM-AHF studies reported use of mineralocorticoid receptor antagonists (approximately 56% and 66%, respectively), while the FAIR-HF and CONFIRM-HF studies did not.

Table 15: Summary of Concomitant Medications From Studies Included in the Systematic Review — Chronic Heart Failure

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; FCM = ferric carboxymaltose; NR = not reported; SGLT2 = sodium-glucose cotransporter-2.

Sources: Clinical Study Reports, Statistical Analysis Plans, and Protocols for the FAIR-HF²⁹ and CONFIRM-HF studies;³⁰ publication, supplementary appendix, and protocol of the HEART-FID study.³¹

Table 16: Summary of Concomitant Medications From Studies Included in the Systematic Review — Acute Heart Failure

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; FCM = ferric carboxymaltose.

Sources: Clinical Study Report, Statistical Analysis Plan, and Protocol for the AFFIRM-AHF study.³²

Exposure to Study Treatments

Patient exposure to study treatments is summarized in Table 17. The format of reporting differed by study. Mean doses received in the placebo arms of the CONFIRM-HF and AFFIRM-AHF studies were higher than mean doses in the corresponding FCM arm, presumably because dosing is based on current iron need and patients assigned to the placebo group would typically not be seeing iron repletion as the study went on. In the CONFIRM-HF study, patients had up to 5 administration of study drug or placebo, while in the AFFIRM-AHF study, it was up to 4; these data were not reported in the FAIR-HF or HEART-FID studies, although the median number of administrations in the HEART-FID study was 6. In both the CONFIRM-HF and AFFIRM-AHF studies, which reported these types of data, a much higher proportion of patients assigned to placebo had higher numbers of injections (e.g., 3 injections to 5 injections) compared to patients assigned to FCM, again likely because this was determined based on iron need.

In the HEART-FID study, data were generally not presented in the same format, and so will be summarized here. Overall, ||| patients in the FCM group and | | patient in the placebo group did not receive the assigned drug. Dose interruptions (i.e., missed injections) occurred in ███ ████████ ███████— ███ ████████ in the FCM group and ███ in the placebo group. The median number of injections during follow-up was | ███████████████ ██████ █ ██ ███ and was the same in both groups. At the day 180 visit, ████ ██ ████ ████████ ███████ in the FCM group who had received the trial drug did not require additional iron replacement therapy at this visit owing to adequate iron indexes and hemoglobin values. Use of IV iron outside the trial protocol occurred in ██ ████████ in the FCM group and ███ ████████ in the placebo group.

No subsequent therapies were given in any included study.

Table 17: Patient Exposure in Included Studies

FCM = ferric carboxymaltose; IQR = interquartile range; NR = not reported; SAS = safety analysis set; SD = standard deviation.

Sources: Clinical Study Reports, Statistical Analysis Plans, and Protocols for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies;³² publication, supplementary appendix, and protocol of the HEART-FID study.³¹

Efficacy

NYHA Class

For the FAIR-HF, CONFIRM-HF, and AFFIRM-AHF studies, the distribution of NYHA class at baseline, week 24, and (where applicable) week 56 are reported in Table 18 by treatment group, along with between-treatment ORs for change in NYHA class from baseline. Note that the direction of the ORs varies by study according to how the analysis was performed.

Among patients with CHF, there was an increased odds of being in a lower (better) NYHA class with FCM compared to placebo in both the FAIR-HF and CONFIRM-HF studies at week 24. In the FAIR-HF study, the OR was 2.400 (95% CI, 1.551 to 3.715; P < 0.001) where an OR of greater than 1 indicates a benefit of FCM, and in the CONFIRM-HF study, the OR was ████ ████ ███ ████ ██ █████ | | | █████ where an OR of less than 1 indicates a benefit of FCM.

At week 52, in the CONFIRM-HF study there was an increased odds of being in a lower NYHA class with FCM compared to placebo ████ ████ ████ ███ ████ ██ ██████ | | ███████ where an OR of less than 1 indicates a benefit of FCM compared to placebo.

Among patients with AHF, in the AFFIRM-AHF study, there was insufficient evidence to confirm a difference between the treatment groups at week 52 ████ ████ ████ ███ ████ ██ ██████ | | ███████.

Sensitivity analyses for NYHA class were conducted in the FAIR-HF and CONFIRM-HF studies by repeating the analysis using the PPS, and the results generally aligned with the FAS analyses presented here in terms of direction and approximate magnitude. Subgroup analyses in the FAIR-HF study based on demographic and disease characteristics were also generally consistent.

Table 18: Efficacy Results — NYHA Class at Week 24 and Week 52

CI = confidence interval; FAS = full analysis set; FCM = ferric carboxymaltose; HF = heart failure; LOCF = last observation carried forward; NA = not applicable; NR = not reported; NYHA = New York Heart Association; PPS = per-protocol set; vs. = versus.

^aIn the FAIR-HF study, odds ratios and P values for the treatment difference were ordered polytomous regression using treatment and baseline NYHA class (separated into 3 dummy binary variables). Odds ratio > 1 implies a better response for the FCM group.

^bIn the CONFIRM-HF study, the change in NYHA classification at each time point was analyzed using repeated measures polytomous regression as described for noncontinuous variables. Treatment, visit, sex, age, pooled country, baseline score, and hemoglobin level at screening (< 12 g/dL or ≥ 12 g/dL) were included as covariates in the model; a term of interaction between visit and treatment was also included (FAS, PPS). For the analysis of the week 52 end point (using LOCF), the change in NYHA was analyzed with a logistic regression including the same covariates as previously described. Missing NYHA class values were imputed if a patient was hospitalized or had died: a patient was considered as NYHA class IV if the patient was hospitalized at the time of the planned assessment and as NYHA class V if the patient had died. Odds ratio < 1 implies a better response for the FCM group.

^cNot adjusted for multiple comparisons; there is an increased risk of a false-positive result.

^dIn the AFFIRM-AHF study, odds ratio from the marginal model of ordinal response using the generalized estimating equations method. The following variables are included in the model: treatment, visit, baseline NYHA class, sex, age, HF etiology, HF duration, and country. An independent working correlation structure is used. The odds ratio indicates that the odds of FCM being in lower response. Lower response categories are better for NYHA score. Class V was imputed for patients who died. If the patient was hospitalized during a visit window, class IV was imputed if no other assessment available in the visit window. The odds ratio for FCM vs. placebo for analysis without imputation of missing NYHA classes was █████ ███ ███ ████ ██ █████ | | █████ ██ ███ ███.

Sources: Clinical Study Reports for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies.³²

6-Minute Walk Test

Results for the change in 6MWT from baseline among patients with CHF are reported in Table 19 for the FAIR-HF study (week 24 only, secondary end point), the CONFIRM-HF study (week 24 [primary end point] and week 52 [secondary end point]), and the HEART-FID study (week 24 [third component of hierarchical composite primary end point] and week 52 [secondary end point]).

Week 24

In the FAIR-HF study, the mean change from baseline in 6MWT at 24 weeks was ████ ██████ ███ ██████ in the FCM group compared to ████ ██████ ███ ██████ in the placebo group, and the between-group difference was 34.9 metres (SD = 7.8) (P < 0.001). Because no 95% CI was presented for the between-group results, additional data were requested from the sponsor, who provided a post hoc analysis of absolute differences on request to inform the GRADE analysis; according to these additional data, the within-group differences were ████ ███ ██████ and ████ ███ ██████ metres, respectively, and the between-group difference was ████ ████ ███ ████ ██ █████ | | ██████ ██████.

In the CONFIRM-HF study primary analysis at week 24, the change from baseline in 6MWT was ████ ███ ██████ ███ ███ ████ ████████ and █████ ███ ██████ ███ ███ ██████ ██ █████ metres in the FCM and placebo groups, respectively. The least squares mean between-group difference was ████ ██████ ███ ██████ ███ ███ ████ ██ ███████.

In the HEART-FID study, as a component of the composite primary outcome, the mean change from baseline to 6 months (i.e., 24 weeks) in 6MWT was | ███ ███ and | ███ ███ respectively. The least squares mean difference between groups was | ████ ███ ██ ██ ███ In the FAIR-HF and CONFIRM-HF studies, sensitivity analyses using the PPS did not include reporting of between-group differences, but the within-group changes from baseline were similar to that of the FAS analyses. In the CONFIRM-HF study, the treatment benefit was also consistent across preplanned and post hoc subgroup analyses on demographic and disease-related features, and in a supportive analysis without primary imputation for deaths and hospitalizations. To our knowledge, no sensitivity or subgroup analyses are available from the HEART-FID study specific to the outcomes presented herein.

Week 52

In the CONFIRM-HF study secondary analyses at week 52, the least squares mean between-group difference was ████████████████ ██ █████ | | ██████. Sensitivity analyses using the PPS did not include reporting of between-group differences, but the within-group changes from baseline were similar to that of the FAS analyses; the treatment benefit was also consistent across preplanned and post hoc subgroup analyses on demographic and disease-related features, and in a supportive analysis without primary imputation for deaths and hospitalizations.

In the HEART-FID study secondary analyses at week 52, the mean change | ██████ ███ ███ in the FCM group and || ██████ ███ ███ in the placebo group. Between-group values were not reported numerically, so additional information was requested from the sponsor, in which it was reported that the mean change from baseline to week 52 was █████ ███ ██████ and █████ ███ ██████ metres for the FCM and placebo groups, respectively, with a between-arm difference in change from baseline of █████ ████ ███ ██████ ██ ██████ metres.

Table 19: Efficacy Results — Change From Baseline in 6MWT

6MWT = 6-minute walk test; ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; FCM = ferric carboxymaltose; GRADE = Grading of Recommendations, Assessment, Development and Evaluations; NA = not applicable; NR = not reported; SD = standard deviation.

^aSD = 7.8.

^bBecause there was either no numerical point estimate reported, and/or no 95% CI presented with the point estimate for this outcome, additional data were provided by the sponsor upon request to facilitate the GRADE analysis (refer to Table 2 and Table 3 for GRADE analyses and associated data).

^cNot adjusted for multiplicity.

^dLeast squares mean. Primary analysis of covariance analysis using imputation for hospitalizations and deaths, using pooled country, baseline 6MWT score, and hemoglobin level at screening (< 12 g/dL or ≥ 12 g/dL) as covariates.

Sources: Clinical Study Reports for the FAIR-HF²⁹ and CONFIRM-HF studies.³⁰ Publication and supplementary appendix of the HEART-FID study.³¹

Kansas City Cardiomyopathy Questionnaire

Results for the KCCQ overall summary score (range, 0 to 100, where 100 is a better HRQoL) are reported in Table 20 for the FAIR-HF study (for 24 weeks only), and the CONFIRM-HF and AFFIRM-AHF studies at week 24 and week 52.

Week 24

In the FAIR-HF study at week 24, the study treatment effect of FCM was 7 points (SD = 2) greater in change from baseline of KCCQ overall summary score, compared to placebo (P < 0.001). Because there was no 95% CI provided with the point estimate for the FAIR-HF study, additional data were requested from the sponsor, which reported a between-group difference of ███ ██████ ████ ███ ███ ██ █████ | | ██████ favouring FCM.

In the CONFIRM-HF study at week 24, the least squares mean between-group difference was 1.3 points (95% CI, –1.88 points to 4.57 points; P = 0.41). In the AFFIRM-AHF study, the difference was ███ ████ ███ ███ ██ ████ | | ███████.

Week 52

In the CONFIRM-HF study at week 52, the between-group difference was 4.5 points (95% CI, 1.07 points to 7.94 points; P = 0.010), and in the AFFIRM-AHF study, it was 1.44 points (95% CI, –1.45 points to 4.33 points; P = 0.33).

Table 20: Efficacy Results — Change From Baseline in KCCQ (Overall Summary Score, Range, 0 to 100)

ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; FCM = ferric carboxymaltose; GRADE = Grading of Recommendations, Assessment, Development and Evaluations; KCCQ = Kansas City Cardiomyopathy Questionnaire; NA = not applicable; NR = not reported; SD = standard deviation.

^aSD = 2.

^bBecause there was either no numerical point estimate reported, and/or no 95% CI was presented with the point estimate for this outcome, additional data were provided by the sponsor upon request to facilitate the GRADE analysis (refer to Table 2 and Table 3 for GRADE analyses and associated data).

^cNot adjusted for multiplicity.

^dDifference in least squares mean from ANCOVA with repeated measures model with treatment, visit, sex, age, pooled country, baseline value, and hemoglobin level at screening (< 12 g/dL or ≥ 12 g/dL) as covariates.

^eDifference in adjusted mean change. Estimates are from analysis based on mixed-effect model of repeated measures using unstructured covariance matrix: change score = baseline score + treatment + visit + treatment × visit + baseline covariates.

^fP values for treatment difference at each visit were calculated from the repeated measures analysis model with fixed effects for treatment, time, and treatment by time interaction, baseline as a covariate, using an unstructured covariance matrix to model the within-patient variability, using contrasts.

Sources: Clinical Study Reports for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies.³²

Fatigue Score

Only the CONFIRM-HF study assessed the change from baseline in fatigue score, ranked on a visual analogue scale from 0 to 10, where 0 implies no fatigue and 10 represents very severe fatigue (refer to Table 21).

Week 24

At week 24, the between-group difference (as least squares mean) in change in fatigue score was –0.6 (standard error = 0.20; 95% CI, –1.00 to –0.23; P = 0.002).

Week 52

At week 52, the between-group difference (as least squares mean) in change in fatigue score was –0.7 (standard error = 0.21; 95% CI, –1.07 to –0.25; P = 0.002).

Table 21: Efficacy Results — Change from Baseline in Fatigue Score (Range, 0 to 10 on VAS)

ANCOVA = analysis of covariance; CI = confidence interval; FAS = full analysis set; FCM = ferric carboxymaltose; NA = not applicable; NR = not reported; SD = standard deviation; VAS = visual analogue scale.

^aLeast squares means are from an ANCOVA with repeated measures model with treatment, visit, sex, age, pooled country, baseline value, hemoglobin level at screening (< 12 g/dL, ≥ 12 g/dL), and interaction between visit and treatment. The following correction was applied for the sites in Spain due to use of different VAS scale (0 to 10, instead of 1 to 10): corrected fatigue score = (0.9 × case report form value) + 1. For sites not in Spain, if the fatigue score was < 1 or > 10, the value was set to missing for the analysis.

Source: Clinical Study Report for the CONFIRM-HF study.³⁰

Serum Ferritin

Results for serum ferritin at baseline, week 24, and week 52 are reported for all 4 included studies in Table 22 based on the analyses requested to inform GRADE. No P values were reported.

At baseline, mean serum ferritin values were less than the threshold of 100 mcg/mL that defines ID in the context of HF.

Week 24

At week 24, across all studies, the FCM groups had mean serum ferritin levels of greater than 100 (although note that patients may still have “functional ID” if their TSAT is < 20% and their serum ferritin is 100 mcg/mL to 300 mcg/mL, as previously discussed), while the mean serum ferritin levels in the placebo groups were close to or less than 100 mcg/mL.

In the FAIR-HF study, at week 24, the between-group difference in absolute mean serum ferritin was 311.7 mcg/mL (██ █████) in the FCM group and 74.2 mcg/mL (██ ████) at in the placebo group (P < 0.0001).

In the CONFIRM-HF study, between-group values were not reported, but the mean serum ferritin at week 24 was ██████ █████ ███ ████████ in the FCM group, representing a mean change from baseline of ██████ █████ ███ █████████ and in the placebo group the mean serum ferritin was █████ █████ ███ ███████ representing a change from baseline of ████ █████ █████████ . Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ █████████. Numerical values for serum ferritin were not reported in the HEART-FID study, although graphical representation can be found in the supplementary documents. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ ███████ at week 24.

In the AFFIRM-AHF study, at week 24, the mean change from baseline was ██████ █████ █████████ in the FCM group compared to █████ █████ █████████ in the placebo group; no between-group differences were reported. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was 264.59 mcg/mL ███████ ██ ███████ at week 24.

Week 52

At week 52, the mean serum ferritin levels in the FCM groups of the CONFIRM-HF, HEART-FID, and AFFIRM-AHF studies were all in excess of 100 mcg/mL but were lower than 300 mcg/mL. The FAIR-HF study was a 24-week study so there are no 52-week values. In the placebo groups, the levels were close to or less than 100 mcg/mL.

In the CONFIRM-HF study, at 52 weeks, between-group values were not reported, but the mean serum ferritin (mcg/mL) at week 52 in the FCM group was ██████ █████ █████████ representing a change from baseline of ██████ █████ ██████████ and in the placebo group was █████ █████ █████████ representing a change from baseline of █████ █████ ██████████ Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ ███████ at week 52.

Values for serum ferritin were not reported in the HEART-FID study, although graphical representation can be found in the supplementary documents. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ █████ ███████ ██ ███████ at week 52.

In the AFFIRM-AHF study, at week 52, the mean change from baseline was ██████ █████ █████████ in the FCM group compared to █████ █████ █████████ in the placebo group; no between-group differences were reported. Additional data were provided by the sponsor upon request, in which it was reported that the between-group difference in change from baseline was ██████ ███████ ██ █████████.

Table 22: Efficacy Results — Change From Baseline in Serum Ferritin (mcg/L)

CI = confidence interval; FAS = full analysis set; FCM = ferric carboxymaltose; NA = not applicable; NR = not reported; SAS = safety analysis set; SD = standard deviation.

Note: No outcomes in this table were adjusted for multiplicity.

^aAll data from the HEART-FID study for this end point were provided by the sponsor in response to an additional information request to assist in interpretation of the data.²⁸

^bAll between-group differences were provided by the sponsor in response to an additional information request to assist in interpretation of the data.²⁸ No P values were reported.

Sources: Clinical Study Reports for the FAIR-HF,²⁹ CONFIRM-HF,³⁰ and AFFIRM-AHF studies.³² Publication and supplementary appendix of the HEART-FID study.³¹ Additional information request for absolute differences results data.²⁸

Hospitalization Rate Due to Any CV Reasons

The event rate per 100 patient-years and differences in CV hospitalizations comparing FCM and placebo are presented in Table 23 based on data provided by the sponsor on request for the purpose of this review. Through both 26 weeks and 52 weeks, the between-group difference in event rate per 100 patient-years was lower in the FCM groups than the placebo groups. At week 26, the 95% CI of the CONFIRM-HF study crossed null, but no other 95% CIs did. Up to 26 weeks, the between-group difference in event rate per 100 patient-years for FCM versus placebo was ██████ ███████ ████████ in the FAIR-HF study, ██████ ███████ ██ █████ in the CONFIRM-HF study █████ ███████ ██ ██████ in the HEART-FID study, and ██████ ███████ ██ ██████ in the AFFIRM-AHF study. Up to week 52, the values were ██████ ███████ ██ ██████ in the CONFIRM-HF study, █████ ███████ ██ ██████ in the HEART-FID study, and ██████ ███████ ██ ██████ in the AFFIRM-AHF study.

As the analysis of these data was a de novo analysis requested for this review, and the primary outcomes of the HEART-FID and AFFIRM-AHF studies were both composite outcomes including hospitalization-related and death-related components, the preplanned analyses of the primary end points for these 2 studies will be briefly recapped in the following.

In the hierarchical composite primary end point of the HEART-FID study, death had occurred in 131 patients (8.6%) in the FCM group and in 158 (10.3%) in the placebo group at 12 months, there were 297 and 332 total hospitalizations for HF by 12 months in the FCM and placebo groups, respectively, and the mean change in the 6-minute walk distance from baseline to 6 months was 8 metres (SD = 60) and 4 metres (SD = 59), in the FCM and placebo groups, respectively. The unmatched win ratio for the hierarchical composite outcome in the FCM group compared with the placebo group was 1.10 (99% CI, 0.99 to 1.23; P = 0.02). Results of prespecified sensitivity analyses that included different imputation methods was reported to be consistent with those of the primary analysis. Because more than half the patients underwent randomization after March 2020, the censoring of data after the onset of the COVID-19 pandemic would have excluded the majority of follow-up data from the analyses.

In the primary efficacy end point of the AFFIRM-AHF study, which was a composite of recurrent HF hospitalizations and CV deaths up to 52 weeks after randomization, the annualized event RR for FCM versus placebo was 0.79 (95% CI, 0.62 to 1.01; P = 0.059). In the prespecified COVID-19 sensitivity analysis, the annualized event RR for FCM versus placebo was 0.75 (95% CI, 0.59 to 0.96; P = 0.024).

Table 23: Efficacy Results — CV Hospitalizations (FAS)