Ferric Carboxymaltose in Iron-Deficient Patients with Hospitalized Heart Failure and Reduced Kidney Function.

BACKGROUND: Reduced kidney function is common among patients with heart failure. In patients with heart failure and/or kidney disease, iron deficiency is an independent predictor of adverse outcomes. In the AFFIRM-AHF trial, patients with acute heart failure with iron deficiency treated with intravenous ferric carboxymaltose demonstrated reduced risk of heart failure hospitalization, with improved quality of life. We aimed to further characterize the impact of ferric carboxymaltose among patients with coexisting kidney impairment. METHODS: The double-blind, placebo-controlled AFFIRM-AHF trial randomized 1132 stabilized adults with acute heart failure (left ventricular ejection fraction <50%) and iron deficiency. Patients on dialysis were excluded. The primary end point was a composite of total heart failure hospitalizations and cardiovascular death during the 52-week follow-up period. Additional end points included cardiovascular hospitalizations, total heart failure hospitalizations, and days lost to heart failure hospitalizations or cardiovascular death. For this subgroup analysis, patients were stratified according to baseline eGFR. RESULTS: Overall, 60% of patients had an eGFR <60 ml/min per 1.73 m 2 (the lower eGFR subgroup). These patients were significantly older, more likely to be female and to have ischemic heart failure, and had higher baseline serum phosphate levels and higher rates of anemia. For all end points, event rates were higher in the lower eGFR group. In the lower eGFR group, the annualized event rates for the primary composite outcome were 68.96 and 86.30 per 100 patient-years in the ferric carboxymaltose and placebo arms, respectively (rate ratio, 0.76; 95% confidence interval, 0.54 to 1.06). The treatment effect was similar in the higher eGFR subgroup (rate ratio, 0.65; 95% confidence interval, 0.42 to 1.02; Pinteraction = 0.60). A similar pattern was observed for all end points ( Pinteraction > 0.05). CONCLUSIONS: In a cohort of patients with acute heart failure, left ventricular ejection fraction <50%, and iron deficiency, the safety and efficacy of ferric carboxymaltose were consistent across a range of eGFR values. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency (Affirm-AHF), NCT02937454 .

Iron deficiency and the effectiveness of the BNT162b2 vaccine for SARS-CoV-2 infection: A retrospective, longitudinal analysis of real-world data.

BACKGROUND: Iron plays a key role in human immune responses; however, the influence of iron deficiency on the coronavirus disease 2019 (COVID-19) vaccine effectiveness is unclear. AIM: To assess the effectiveness of the BNT162b2 messenger RNA COVID-19 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and death in individuals with or without iron deficiency. METHODS: This large retrospective, longitudinal cohort study analyzed real-world data from the Maccabi Healthcare Services database (covering 25% of Israeli residents). Eligible adults (aged ≥16 years) received a first BNT162b2 vaccine dose between December 19, 2020, and February 28, 2021, followed by a second dose as per approved vaccine label. Individuals were excluded if they had SARS-CoV-2 infection before vaccination, had hemoglobinopathy, received a cancer diagnosis since January 2020, had been treated with immunosuppressants, or were pregnant at the time of vaccination. Vaccine effectiveness was assessed in terms of incidence rates of SARS-CoV-2 infection confirmed by real-time polymerase chain reaction assay, relative risks of COVID-19-related hospitalization, and mortality in individuals with iron deficiency (ferritin <30 ng/mL or transferrin saturation <20%). The two-dose protection period was Days 7 to 28 after the second vaccination. RESULTS: Data from 184,171 individuals with (mean [standard deviation; SD] age 46.2 [19.6] years; 81.2% female) versus 1,072,019 without (mean [SD] age 46.9 [18.0] years; 46.2% female) known iron deficiency were analyzed. Vaccine effectiveness in the two-dose protection period was 91.9% (95% confidence interval [CI] 83.7-96.0%) and 92.1% (95% CI 84.2-96.1%) for those with versus without iron deficiency (P = 0.96). Of patients with versus without iron deficiency, hospitalizations occurred in 28 and 19 per 100,000 during the reference period (Days 1-7 after the first dose), and in 19 and 7 per 100,000 during the two-dose protection period, respectively. Mortality rates were comparable between study groups: 2.2 per 100,000 (4/181,012) in the population with iron deficiency and 1.8 per 100,000 (19/1,055,298) in those without known iron deficiency. CONCLUSIONS: Results suggest that the BNT162b2 COVID-19 vaccine is >90% effective in preventing SARS-CoV-2 infection in the 3 weeks after the second vaccination, irrespective of iron-deficiency status. These findings support the use of the vaccine in populations with iron deficiency.

Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.

BACKGROUND: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. METHODS: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 µg/L, or 100-299 µg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. FINDINGS: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. INTERPRETATION: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. FUNDING: Vifor Pharma.

Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomised, placebo-controlled trial.

BACKGROUND: The clinical effects of roflumilast, a selective phosphodiesterase-4 inhibitor, are well established, but little is known about the anti-inflammatory mechanisms underlying the drug's efficacy. The aim of the ROflumilast Biopsy European Research Trial (ROBERT) was to assess the anti-inflammatory effects of roflumilast on bronchial mucosal inflammation in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis. METHODS: ROBERT was a randomised, double-blind, placebo-controlled trial done at 18 sites in five countries. Eligible patients were aged 40-80 years, had COPD, and had had a chronic productive cough for 3 months in each of the two previous years. Patients also had to have a post-bronchodilator predicted FEV1 30-80% and a post-bronchodilator FEV1/forced vital capacity ratio of 70% or less. Patients entered a 6-week run-in period before being randomly assigned (1:1) via a computerised central randomisation system to roflumilast 500 µg once daily or placebo for 16 weeks, in addition to bronchodilator therapy (inhaled corticosteroids were not permitted). Randomisation was stratified by concomitant use of long-acting ß agonist. Both participants and investigators were masked to group assignment. Roflumilast and placebo were supplied as identical yellow, triangular tablets. Airway inflammation was assessed by quantification of inflammatory cells in bronchial biopsy samples and induced sputum samples. The primary endpoint was the change in the number of CD8 inflammatory cells in bronchial biopsy submucosa from randomisation to week 16 in the intention-to-treat population. Changes in cell counts of additional inflammatory markers, including eosinophils, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, number NCT01509677, and is closed to new participants, with follow-up completed. FINDINGS: Between Jan 4, 2012, and Feb 11, 2016, 158 patients were randomly assigned: 79 to the roflumilast group, and 79 to the placebo group. At week 16, the change in the number of CD8 cells in the bronchial submucosa did not differ significantly between the roflumilast and placebo groups (treatment ratio 1·03 [95% CI 0·82-1·30]; p=0·79). However, compared with placebo, roflumilast was associated with a significant reduction in eosinophils in bronchial biopsy samples at week 16 (treatment ratio 0·53 [95% CI 0·34-0·82]; p=0·0046). Significant reductions in both absolute (p=0·0042) and differential (p=0·0086) eosinophil cell counts in induced sputum were also noted with roflumilast compared with placebo, but peripheral blood eosinophil counts were not significantly affected. We noted no other significant effects of roflumilast on bronchial mucosal inflammatory cells. The most common (ie, occurring in >5% patients) moderate adverse events were worsening of COPD (three [4%] patients in the roflumilast group vs seven [9%] in the placebo group), cough (six [8%] vs four [5%]), diarrhoea (four [5%] vs three [4%]), and nasopharyngitis (three [4%] vs five [6%]). Severe adverse events included worsening of COPD, which occurred in four (5%) patients in the roflumilast group and two (3%) in the placebo group. No deaths occurred during the study. Serious adverse events occurred in eight (10%) patients in the roflumilast group and five (6%) in the placebo group. INTERPRETATION: 16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo. However, we noted significant reductions in eosinophil cell counts in bronchial biopsy samples and induced sputum, generating the hypothesis that the effect of roflumilast in COPD could be mediated by an effect on lung eosinophils. FUNDING: Takeda and AstraZeneca.