Guidelines on heart failure (HF) define iron deficiency (ID) as a serum ferritin <100 ng/mL or, when 100-299 ng/mL, a transferrin saturation (TSAT) <20%. Inflammation (common in HF) may hinder ...interpretation of serum ferritin.
This study sought to investigate how different definitions of ID affect its prevalence and relationship to prognosis in ambulatory patients with chronic HF.
Prevalence, relationship with patients' characteristics, and outcomes of various ID definitions were evaluated among patients with HF referred to a regional clinic (Hull LifeLab) from 2001 to 2019.
Of 4,422 patients with HF (median age 75 years range: 68-82 years, 60% men, 32% with reduced left ventricular ejection fraction), 46% had TSAT <20%, 48% had serum iron ≤13 μmol/L, 57% had serum ferritin <100 ng/mL, and 68% fulfilled current guideline criteria for ID, of whom 35% had a TSAT >20%. Irrespective of definition, ID was more common in women and those with more severe symptoms, anemia, or preserved ejection fraction. TSAT <20% and serum iron ≤13 μmol/L, but not guideline criteria, were associated with higher 5-year mortality (HR: 1.27; 95% CI: 1.14-1.43; P < 0.001; and HR: 1.37; 95% CI: 1.22-1.54; P < 0.001, respectively). Serum ferritin <100 ng/mL tended to be associated with lower mortality (HR: 0.91; 95% CI: 0.81-1.01; P = 0.09).
Different definitions of ID provide discordant results for prevalence and prognosis. Definitions lacking specificity may attenuate the benefits of intravenous iron observed in trials while definitions lacking sensitivity may exclude patients who should receive intravenous iron. Prespecified subgroup analyses of ongoing randomized trials should address this issue.
Aims
For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about ...the effects in subgroups and the impact on mortality. We conducted a meta‐analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF.
Methods and results
We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all‐cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval CI 0.61–0.93; p < 0.01) and first HHF or CVD (odds ratio OR 0.72, 95% CI 0.53–0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70–1.05; p = 0.14) and all‐cause mortality (OR 0.93, 95% CI 0.78–1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow‐up, which was less disrupted by the COVID‐19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49–0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74–1.30) (heterogeneity p = 0.07).
Conclusion
In patients with HF and ID, this meta‐analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all‐cause mortality remains inconclusive.
In a meta‐analysis of ten randomized controlled trials (RCTs) including AFFIRM‐AHF and IRONMAN of over 3000 patients with heart failure (HF) and iron deficiency (ID), compared to standard care/placebo, intravenous (IV) iron reduced the primary outcome of recurrent hospitalisations for heart failure (HHF) and cardiovascular mortality (CVM) by 25%. The effect was mainly driven by a reduction in HHF with the effect on CVM being inconconclusive. Created in BioRender.com. Additional icons provided from
http://icon‐library.com/icon/heart‐disease‐icon‐3.html.html Heart Disease Icon #293840. CI, confidence interval; CVM, cardiovascular mortality; HF, heart failure; HHF, hospitalization for heart failure; I, iron deficiency; IV, intravenous/interval variable; OR, odds ratio; RCT, randomized controlled trial; RR, risk rate; SE, standard error; SoC, standard of care.
Aims
Iron deficiency (ID) and anaemia are common in heart failure; less is known about changes over time.
Methods and results
We investigated prevalence, incidence and resolution of ID and anaemia in ...906 patients with chronic heart failure (median age 73 (65–79) years, 70% men, 51% with heart failure with reduced ejection fraction) 1 year apart. ID was defined as serum iron ≤13 µmol/L and anaemia as haemoglobin <13.0 g/dL for men or <12.0 g/dL for women. FAIR‐HF criteria for ID were also considered. At baseline, 10% had anaemia without ID, 23% had ID without anaemia, 20% had both, and 47% had neither. Percentages changed little over 1 year, but 157 (30%) patients had new‐onset ID, 104 (16%) new‐onset anaemia, whilst ID resolved in 173 (44%) and anaemia in 63 (23%). Compared to those who remained iron replete (iron >13 µmol/L), mortality was higher in those with persistent or incident ID at 1 year hazard ratio (HR) 1.81 (1.23–2.67), and HR 1.40 (0.91–2.14), respectively in multivariable models (P = 0.02). Compared to persistent ID, resolution of ID was associated with a lower mortality HR 0.61 (0.44–0.86); P = 0.004. Changes in ID defined by FAIR‐HF criteria were not similarly associated with mortality. Anaemia was associated with a poor outcome even if it resolved.
Conclusions
The prevalence and incidence of ID and anaemia are high in chronic heart failure but so is the rate of resolution. Persistent or incident ID, defined by a serum iron ≤13 µmol/L, is associated with higher mortality and resolution of ID with lower mortality.
Longitudinal data from 906 patients with chronic heart failure. Over 1 year most patients (70%) have or develop iron deficiency (ID), anaemia or both. Compared to those with either persistent ID or anaemia, only those who recovered from ID (achieving a serum iron >13 µmol/L) had lower all‐cause mortality at 4 years, with transferrin saturation (TSAT) showing a similar trend. CI, confidence interval; HR, hazard ratio.
The prevalence of anaemia and iron deficiency and their prognostic association with cardiovascular disease have rarely been explored at population level.
National Health Service records of the ...Greater Glasgow region for patients aged ≥50 years with a broad range of cardiovascular diagnoses were obtained. During 2013/14, prevalent disease was identified and results of investigations collated. Anaemia was defined as haemoglobin <13 g/dL for men or <12 g/dL for women. Incident heart failure, cancer and death between 2015 and 2018 were identified.
The 2013/14 dataset comprised 197 152 patients, including 14 335 (7%) with heart failure. Most (78%) patients had haemoglobin measured, especially those with heart failure (90%). Of those tested, anaemia was common both in patients without (29%) and with heart failure (prevalent cases in 2013/14: 46%; incident cases during 2013/14: 57%). Ferritin was usually measured only when haemoglobin was markedly depressed; transferrin saturation (TSAT) even less often. Incidence rates for heart failure and cancer during 2015-18 were inversely related to nadir haemoglobin in 2013/14. A haemoglobin of 13-15 g/dL for women and 14-16 g/dL for men was associated with the lowest mortality. Low ferritin was associated with a better prognosis and low TSAT with a worse prognosis.
In patients with a broad range of cardiovascular disorders, haemoglobin is often measured but, unless anaemia is severe, markers of iron deficiency are usually not. Low haemoglobin and TSAT, but not low ferritin, are associated with a worse prognosis. The nadir of risk occurs at haemoglobin 1-3 g/dL above the WHO definition of anaemia.
A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the ...hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na(+) excretion and further Na(+) loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.
Background
The recent AFFIRM-AHF trial assessing the effect of intravenous (IV) iron on outcomes in patients hospitalised with worsening heart failure who had iron deficiency (ID) narrowly missed its ...primary efficacy endpoint of recurrent hospitalisations for heart failure (HHF) or cardiovascular (CV) death. We conducted a meta-analysis to determine whether these results were consistent with previous trials.
Methods
We searched for randomised trials of patients with heart failure investigating the effect of IV iron vs placebo/control groups that reported HHF and CV mortality from 1st January 2000 to 5th December 2020. Seven trials were identified and included in this analysis. A fixed effect model was applied to assess the effects of IV iron on the composite of first HHF or CV mortality and individual components of these.
Results
Altogether, 2,166 patients were included (
n
= 1168 assigned to IV iron;
n
= 998 assigned to control). IV iron reduced the composite of HHF or CV mortality substantially OR 0.73; (95% confidence interval 0.59–0.90);
p
= 0.003. Outcomes were consistent for the pooled trials prior to AFFIRM-AHF. Whereas first HHF were reduced substantially OR 0.67; (0.54–0.85);
p
= 0.0007, the effect on CV mortality was uncertain but appeared smaller OR 0.89; (0.66–1.21);
p
= 0.47.
Conclusion
Administration of IV iron to patients with heart failure and ID reduces the risk of the composite outcome of first heart failure hospitalisation or cardiovascular mortality, but this outcome may be driven predominantly by an effect on HHF. At least three more substantial trials of intravenous iron are underway.
Graphic abstract
Abstract Background and Aims Many patients are prescribed loop diuretics without a diagnostic record of heart failure. Little is known about their characteristics and prognosis. Methods Glasgow ...regional health records (2009–16) were obtained for adults with cardiovascular disease or taking loop diuretics. Outcomes were investigated using Cox models with hazard ratios adjusted for age, sex, socioeconomic deprivation, and comorbid disease (adjHR). Results Of 198 898 patients (median age 65 years; 55% women), 161 935 (81%) neither took loop diuretics nor had a diagnostic record of heart failure (reference group), 23 963 (12%) were taking loop diuretics but had no heart failure recorded, 7844 (4%) had heart failure recorded and took loop diuretics, and 5156 (3%) had heart failure recorded but were not receiving loop diuretics. Compared to the reference group, five-year mortality was only slightly higher for heart failure in the absence of loop diuretics 22%; adjHR 1.2 (95% CI 1.1–1.3), substantially higher for those taking loop diuretics with no record of heart failure 40%; adjHR 1.8 (95% CI 1.7–1.8), and highest for heart failure treated with loop diuretics 52%; adjHR 2.2 (95% CI 2.0–2.2). Conclusions For patients with cardiovascular disease, many are prescribed loop diuretics without a recorded diagnosis of heart failure. Mortality is more strongly associated with loop diuretic use than with a record of heart failure. The diagnosis of heart failure may be often missed, or loop diuretic use is associated with other conditions with a prognosis similar to heart failure, or inappropriate loop diuretic use increases mortality; all might be true.
Aim
To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide.
Methods and results
...In this randomized, double‐blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT‐proBNP at baseline was 1487 (interquartile range: 847–2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post‐furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion.
Conclusions
For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload.
Trial design and summary results. BP, blood pressure; CO, cardiac output; CPI, cardiac power index; Hct, haematocrit; IV, intravenous; Na+, sodium; PV, plasma volume; TBW, total body water; TPR, total peripheral resistance; Vol., volume.
PDF
