Hypophosphataemia risk associated with ferric carboxymaltose in heart failure: A pooled analysis of clinical trials.

AIMS: Iron deficiency is a common finding among patients with heart failure (HF) and is associated with adverse outcomes, including decreased quality of life, increased risk of hospitalization, and decreased survival. Intravenous ferric carboxymaltose (FCM) has been shown to improve outcomes among patients with HF and concomitant iron deficiency, but FCM is associated with an increased risk of hypophosphataemia. We aimed to better characterize this risk among HF populations. METHODS AND RESULTS: This pooled analysis examined data from 41 studies of adults with iron deficiency across disease states and therapeutic areas. Among the 7931 patients treated with FCM available for analysis, 14% made up the HF subgroup. Additional subgroups included women's health (36%), non-dialysis-dependent chronic kidney disease (NDD-CKD; 27%), haemodialysis-dependent chronic kidney disease (HD-CKD; 1%), gastrointestinal (10%), neurology (3%), and other (10%). The incidence of post-baseline moderate or severe hypophosphataemia (i.e. serum phosphate [PO4 3- ] level 60 mL/min/1.73 m2 vs. <30 mL/min/1.73 m2 ; odds ratio: 12.2). Among patients in the HF subgroup, the incidence of treatment-emergent adverse events potentially related to hypophosphataemia (e.g. cardiac failure, ventricular tachyarrhythmias, fatigue, muscle weakness, bone pain, neurological symptoms, and muscle pain) was lower among FCM-treated patients than among those receiving placebo, and lower among patients with a post-baseline PO4 3- <2 mg/dL vs. those not meeting such criteria. CONCLUSIONS: The risk of laboratory-assessed hypophosphataemia in HF patients treated with FCM was lower than that seen in patients in other therapeutic areas treated with FCM, and clinical events associated with hypophosphataemia are uncommon with FCM therapy in this population. Appropriate monitoring, particularly soon after administration, will allow for further refinement of management strategies

Clinical and economic impact of ferric carboxymaltose treatment for iron deficiency in patients stabilized following acute heart failure: a multinational study.

OBJECTIVE: To estimate clinical events and evaluate the financial implications of introducing ferric carboxymaltose (FCM) to treat iron deficiency (ID) at discharge in patients hospitalized for acute heart failure (AHF) with left ventricular ejection fraction (LVEF) <50% in the UK, Switzerland and Italy. METHODS: A decision analytic cost-offset model was developed to evaluate the costs associated with introducing FCM for all eligible patients in three countries compared to a world without FCM, over a five-year time horizon. Data from AFFIRM-AHF clinical trial were used to model clinical outcomes, using an established cohort state-transition Markov model. Country-specific prevalence estimates were derived using data from real-world studies to extrapolate number of events and consequent cost totals to the population at risk on a national scale. RESULTS: The cost-offset modeling demonstrated that FCM is projected to be a cost-saving intervention in all three country settings over a five-year time horizon. Savings were driven primarily by reduced hospitalizations and avoided cardiovascular deaths, with net cost savings of -£14,008,238, -CHF25,456,455 and -€105,295,146 incurred to the UK, Switzerland and Italy, respectively. LIMITATIONS: Although AFFIRM-AHF was a multinational trial, efficacy data per country was not sufficiently large to enable country-specific analysis, therefore overall clinical parameters have been assumed to apply to all countries. CONCLUSIONS: This study provides further evidence of the potential cost savings achievable by treating ID with FCM at discharge in patients hospitalized for AHF with LVEF <50%. The value of FCM treatment within the healthcare systems of the UK, Switzerland and Italy was demonstrated even within a limited time frame of one year, with consistent cost savings indicated over a longer term

Ferric carboxymaltose for the treatment of iron deficiency in heart failure: a multinational cost-effectiveness analysis utilising AFFIRM-AHF.

AIMS: Iron deficiency is common in patients with heart failure (HF). In AFFIRM-AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron-deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost-effectiveness of FCM compared with placebo in iron-deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM-AHF trial from Italian, UK, US and Swiss payer perspectives. METHODS AND RESULTS: A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM-AHF trial. Health states were defined using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all-cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM-AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost-effective in Italy [incremental cost-effectiveness ratio (ICER) EUR 1269 per quality-adjusted life-year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43-0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost-effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology. CONCLUSION: Ferric carboxymaltose is estimated to be a highly cost-effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems

Phenotyping heart failure patients for iron deficiency and use of intravenous iron therapy: data from the Swedish Heart Failure Registry.

AIMS: Iron deficiency (ID) is associated with poor prognosis regardless of anaemia. Intravenous iron improves quality of life and outcomes in patients with ID and heart failure (HF) with reduced ejection fraction (HFrEF). In the Swedish HF registry, we assessed (i) frequency and predictors of ID testing; (ii) prevalence and outcomes of ID with/without anaemia; (iii) use of ferric carboxymaltose (FCM) and its predictors in patients with ID. METHODS AND RESULTS: We used multivariable logistic regressions to assess patient characteristics independently associated with ID testing/FCM use, and Cox regressions to assess risk of outcomes associated with ID. Of 21 496 patients with HF and any ejection fraction enrolled in 2017-2018, ID testing was performed in 27%. Of these, 49% had ID and more specifically 36% had ID-/anaemia-, 15% ID-/anaemia+, 29% ID+/anaemia-, and 20% ID+/anaemia+ (48%, 39%, 13%, 30% and 18% in HFrEF, respectively). Risk of recurrent all-cause hospitalizations was higher in patients with ID regardless of anaemia. Of 1959 patients with ID, 19% received FCM (24% in HFrEF). Important independent predictors of ID testing and FCM use were anaemia, higher New York Heart Association class, having HFrEF, and referral to HF specialty care. CONCLUSION: In this nationwide HF registry, ID testing occurred in only about a quarter of the patients. Among tested patients, ID was present in one half, but only one in five patients received FCM indicating low adherence to current guidelines on screening and treatment

Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis.

BACKGROUND: Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. METHODS: AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. RESULTS: Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (Pinteraction=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. CONCLUSIONS: The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02937454

Health status improvement with ferric carboxymaltose in heart failure with reduced ejection fraction and iron deficiency.

AIM: Intravenous ferric carboxymaltose (FCM) has been shown to improve overall quality of life in iron-deficient heart failure with reduced ejection fraction (HFrEF) patients at a trial population level. This FAIR-HF and CONFIRM-HF pooled analysis explored the likelihood of individual improvement or deterioration in Kansas City Cardiomyopathy Questionnaire (KCCQ) domains with FCM versus placebo and evaluated the stability of this response over time. METHODS AND RESULTS: Changes versus baseline in KCCQ overall summary score (OSS), clinical summary score (CSS) and total symptom score (TSS) were assessed at weeks 12 and 24 in FCM and placebo groups. Mean between-group differences were estimated and individual responder analyses and analyses of response stability were performed. Overall, 760 (FCM, n = 454) patients were studied. At week 12, the mean improvement in KCCQ OSS was 10.6 points with FCM versus 4.8 points with placebo (least-square mean difference [95% confidence interval, CI] 4.36 [2.14; 6.59] points). A higher proportion of patients on FCM versus placebo experienced a KCCQ OSS improvement of ≥5 (58.3% vs. 43.5%; odds ratio [95% CI] 1.81 [1.30; 2.51]), ≥10 (42.4% vs. 29.3%; 1.73 [1.23; 2.43]) or ≥15 (32.1% vs. 22.6%; 1.46 [1.02; 2.11]) points. Differences were similar at week 24 and for CSS and TSS domains. Of FCM patients with a ≥5-, ≥10- or ≥15-point improvement in KCCQ OSS at week 12, >75% sustained this improvement at week 24. CONCLUSION: Treatment of iron-deficient HFrEF patients with intravenous FCM conveyed clinically relevant improvements in health status at an individual-patient level; benefits were sustained over time in most patients

Responder analysis for improvement in 6-min walk test with ferric carboxymaltose in patients with heart failure with reduced ejection fraction and iron deficiency

Aim Improving functional capacity is a key goal in heart failure (HF). This pooled analysis of FAIR-HF and CONFIRM-HF assessed the likelihood of improvement or deterioration in 6-min walk test (6MWT) among iron-deficient patients with chronic HF with reduced ejection fraction (HFrEF) receiving ferric carboxymaltose (FCM). Methods and results Data for 760 patients (FCM: n = 454; placebo: n = 306) were analysed. The proportions of patients receiving FCM or placebo who had ≥20, ≥30, and ≥40 m improvements or ≥10 m deterioration in 6MWT at 12 and 24 weeks were assessed. Patients receiving FCM experienced a mean (standard deviation) 31.1 (62.3) m improvement in 6MWT versus 0.1 (77.1) m improvement for placebo at week 12 (difference in mean changes 26.8 [16.6;37.0]). At week 12, the odds [95% confidence interval] of 6MWT improvements of ≥20 m (odds ratio 2.16 [1.57–2.96]; p < 0.0001), ≥30 m (2.00 [1.44–2.78]; p < 0.0001), and ≥40 m (2.29 [1.60–3.27]; p < 0.0001) were greater with FCM versus placebo, while the odds of a deterioration ≥10 m were reduced with FCM versus placebo (0.55 [0.38–0.80]; p = 0.0019). Among patients who experienced 6MWT improvements of ≥20, ≥30, or ≥40 m with FCM at week 12, more than 80% sustained this improvement at week 24. Conclusion Ferric carboxymaltose resulted in a significantly higher likelihood of improvement and a reduced likelihood of deterioration in 6MWT versus placebo among iron-deficient patients with HF. Of the patients experiencing clinically significant improvements at week 12, the majority sustained this improvement at week 24. These results are supportive of FCM to improve exercise capacity in HF

Impact of ischaemic aetiology on the efficacy of intravenous ferric carboxymaltose in patients with iron deficiency and acute heart failure: insights from the AFFIRM-AHF trial.

AIMS: In AFFIRM‐AHF, intravenous ferric carboxymaltose (FCM) reduced heart failure (HF) hospitalisations and improved quality of life versus placebo in iron‐deficient patients stabilised after an acute HF episode. This analysis explored the effects of FCM versus placebo in patients with ischaemic and non‐ischaemic HF aetiology. METHODS AND RESULTS: We included 1082 patients from AFFIRM‐AHF: 590 with ischaemic HF (defined as investigator‐reported ischaemic HF aetiology and/or prior acute myocardial infarction and/or prior coronary revascularisation) and 492 with non‐ischaemic HF. The prevalences of male sex, comorbidities, and history of HF were higher in the ischaemic versus non‐ischaemic HF subgroup. Annualised event rates for the primary composite outcome of total HF hospitalisations and cardiovascular death with FCM versus placebo were 65.3 versus 100.6 per 100 patient‐years in the ischaemic HF subgroup (rate ratio [RR] 0.65, 95% confidence interval [CI] 0.47–0.89, p = 0.007) and 58.3 versus 52.5 in the non‐ischaemic HF subgroup (RR 1.11, 95% CI 0.75–1.66, p = 0.60) (p (interaction) = 0.039). An interaction between HF aetiology and treatment effect was also observed for the secondary outcome of total HF hospitalisations (p (interaction) = 0.038). A nominal increase in quality of life, assessed using the 12‐item Kansas City Cardiomyopathy Questionnaire, was observed with FCM versus placebo, within each subgroup. CONCLUSIONS: Heart failure hospitalisations and cardiovascular deaths occurred at a higher rate in patients with ishaemic versus those with non‐ischaemic HF and were reduced by FCM versus placebo only in ischaemic patients. Further studies are needed to assess the role of aetiology in FCM efficacy

High Serum Uric Acid Increases the Risk for Nonalcoholic Fatty Liver Disease: A Prospective Observational Study

Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease, and serum uric acid is observed to be significantly elevated in NAFLD patients. However, whether this elevation is causal, a bystander, or a consequence of NAFLD remains unclear. We performed a population-based prospective study among the employees of Zhenhai Refining & Chemical Company Ltd., Ningbo, China to investigate whether the elevation of serum uric acid has a casual role for NAFLD. A total of 6890 initially NAFLD-free subjects were followed up for 3 years. Overall, 11.80% (813/6890) subjects developed NAFLD over 3 years of follow-up. The cumulative incidence of NAFLD increased with progressively higher baseline serum uric acid levels (the cumulative incidence was 7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5, respectively; P value for trend <0.001). Cox proportional hazards regression analyses showed that serum uric acid levels were independently and positively associated with the risk for incident NAFLD; the age-, gender- and metabolic syndrome adjusted hazard ratio (95% CI) for the subjects in quintile 2, 3, 4 and 5 versus quintile 1 was 1.18 (0.91–1.54), 1.32 (1.03–1.70), 1.39 (1.09–1.78) and 1.50 (1.18–1.92), respectively. Taken together, our prospective observational study showed that elevation of serum uric acid levels independently predicts increase risk for incident NAFLD

Risk factors for bone mineral density at the calcaneus in 40–59 year-old male workers: A cross-sectional study in Korea

<p>Abstract</p> <p>Background</p> <p>Few epidemiologic studies have attempted to investigate the prevalence and risk factors for osteopenia and osteoporosis in middle-aged Asian men. We performed this study to determine the prevalence and risk factors of osteopenia and osteoporosis in this population.</p> <p>Methods</p> <p>This cross-sectional study was conducted from March to July, 2004. The subjects were 2,073 males aged from 40 to 59 years in the KHNP (Korea Hydro & Nuclear Power) workplace-based cohort. Bone mineral density (BMD) was measured by peripheral, dual-energy, X-ray absorptiometry (DXA) at the calcaneus. Anthropometric and lifestyle factors were investigated using a standard, self-reported questionnaire.</p> <p>Results</p> <p>BMD was 0.60 ± 0.09 g/cm²(mean ± standard deviation) and was negatively correlated with age (r = -0.18, <it>P </it>< 0.001), but positively correlated with waist-to-hip ratio (WHR; r = 0.15, <it>P </it>< 0.001), body fat (r = 0.10, <it>P </it>< 0.001), BMI (r = 0.35, <it>P </it>< 0.001), height (r = 0.26, <it>P </it>< 0.001), and weight (r = 0.43, <it>P </it>< 0.001).</p> <p>In multiple linear regression analysis, the independent determinants associated with BMD were increasing age (coefficient = -0.002, <it>P </it>< 0.001), physical activity (≤ 2/week vs. ≥ 3/week; coefficient = 0.017, <it>P </it>< 0.001), WHR (coefficient = -0.796, <it>P </it>< 0.001), body mass index (BMI; coefficient = 0.023, <it>P </it>< 0.001) and smoking status (never vs. ever; coefficient = -0.018, <it>P </it>< 0.001).</p> <p>Conclusion</p> <p>We suggest that BMD of the calcaneus is correlated negatively with exposure to smoke and increased WHR, but positively with regular exercise and increased BMI.</p