Baseline Anemia Research Articles

Short Term Outcome of Percutaneous Coronary Intervention in Anaemic Patients Presenting with Coronary Artery Diseases

Background: Percutaneous coronary intervention (PCI) has been an effective and widely used treatment for patients with coronary artery disease (CAD). The presence of anaemia in critically ill patients undergoing surgical procedures has been associated with worse clinical outcomes.
 Hence, the current study was conducted to assess short term outcome of percutaneous coronary interventions in anaemic patients presenting with coronary artery diseases.
 Methods: This prospective observational study enrolled 200 patients who underwent PCI. Patients were classified into 2 groups: anaemic patients and non-anaemic patients. The anaemic patients were furtherly be classified according to severity of anaemia into 3 grades mild anaemia, moderate anaemia, and severe anaemia.
 All cases were subjected to complete history taking, clinical examination and baseline laboratory tests: including CBC, serum urea and creatinine, cardiac enzymes include serum troponin, CK-MB and standard 12-lead ECG.
 Results: The mean Heart Rate was statistically significantly higher in the anaemic group as compared with the non-anaemic group. The mean Ejection Fraction was statistically significantly lower in the anaemic group as compared with the non-anaemic group. The percentage of LM affection in the anaemic group was statistically significantly higher as compared with the non-anaemic group. The incidence of arrythmia in the anaemic group was statistically significantly higher as compared with the non-anaemic group. Severe anaemic and low EF% patients were associated with higher incidence of stroke and MI.
 Conclusions: Patients with baseline anaemia before PCI have a higher incidence of PCI associated complications. Therefore, anaemia could be a predictor of PCI related complications.

Severity of and Recovery From Anemia After Transcatheter Aortic Valve Replacement: An Analysis of the PARTNER Trials and Registries.

Anemia is associated with increased mortality in patients undergoing transcatheter aortic valve replacement (TAVR); however, data on the effect of the severity of and recovery from anemia on clinical outcomes are limited. This study examined the impact of the severity of and recovery from anemia after TAVR. Patients with symptomatic, severe aortic stenosis across all surgical risk groups from the Placement of Aortic Transcatheter Valves (PARTNER) I, II, and III trials and registries who underwent TAVR were analyzed. Baseline anemia was defined as mild (hemoglobin [Hb] level ≥11.0 g/dL and <13.0 g/dL for men and ≥11.0 g/dL and <12.0 g/dL for women) and moderate-to-severe anemia (Hb level <11.0 g/dL). Recovery from anemia was defined as an increase of ≥1 g/dL in the Hb level. Patients with missing Hb information and major bleeding within 30 days were excluded. The association of the severity of and recovery from anemia with clinical outcomes was analyzed using multivariable Cox proportional hazards regression models. The primary outcome was 1-year all-cause mortality. The Kaplan-Meier estimate for 1-year all-cause mortality was 5.4%, 8.2%, and 14.5% in patients with no, mild, and moderate-to-severe anemia, respectively (P < .001). Recovery from anemia at 30 days occurred in 8.4% (229/2730) of all patients. Compared with those without baseline or 30-day anemia, patients with recovery from anemia had similar 1-year mortality (hazard ratio, 1.02; CI, 0.50-2.08; P = .96), whereas those without recovery from anemia had higher 1-year mortality (hazard ratio, 1.82; CI, 1.17-2.85; P = .009). In patients undergoing TAVR, moderate-to-severe anemia is independently associated with increased 1-year mortality, and recovery from anemia after TAVR is associated with favorable outcomes. Further efforts are needed to determine whether preprocedural correction of anemia improves post-TAVR outcomes.

Predictors of Incomplete Adherence and Immuno-virologic Failure among HIV Infected Patients in Osun State, Nigeria

BACKGROUND: To identify and address modifiable baseline clinical and non- clinical predictors related to negative outcomes, and identify high risk patients who need priority attention in order to prevent future failure of treatment in HIV patients. METHODS: The study was a longitudinal clinical based cohort study of One hundred and forty (140) HIV infected adults who were initially ART naive and commenced ART in June- July 2013 were followed up to June 2014. Three out of the participants were lost to follow up, one participant died and 1 participant was transferred to another treatment centre, while a total of one hundred and thirty-five (135) patients were finally included in the immuno-virologic analysis. Adherence was assessed using both self-report questionnaire and measurement of Mean Cell Volume (MCV) which was obtained using automated haematology analyzer. CD4 counts were analyzed using flow cytometry method and HIV-RNA levels were measured by using the RT-Polymerase Chain Reaction technique. RESULTS: Incomplete adherence was recorded in 28 (20.7%) of the study participants, immunologic failure (decline in CD4 count to or below baseline or CD4 count change &lt; 50 cells/ul at 12 months) was observed in 39 (28.8%) of the participants. Virologic failure rate (viral load &gt; 400 copies/ml) was 27.4% and immuno-virologic failure rate was 31.9%. Using logistic regression model, immunologic failure was associated with male gender (OR=1.29; p=0.008), non-disclosure of status (OR=1.24; p=0.01), baseline anaemia (OR=1.15; p=0.009) and incomplete adherence by self-report (OR=3.28; p=0.001). Virologic failure was associated with no formal education (OR=2.29; p=0.01), non-disclosure of status (OR=1.04; p = &lt; 0.01), non-adherence (OR=2.74; p=0.015), being unemployed (OR=0.57; p=0.04). CONCLUSIONS: The study observed that immunologic recovery and virologic suppression rate within the first year of treatment was significant, although the rate of incomplete adherence obtained still needs improvement. Effort to promote social coping particularly to patients who were unemployed, re-strategizing on improving patient education and counseling especially to patients with no formal education, focusing on campaigns against stigmatization will help in addressing predictors of negative immuno-virologic outcomes. Baseline HIV-RNA level should also be considered in addition to CD4 testing in order to identify virological failure and thus preventing the emergence of drug resistance in HIV/AIDS management.

Benefits of pre-operative oral Sucrosomial® iron supplementation in cardiac surgery: influence of patient's baseline hemoglobin and gender.

The prevalence of low pre-operative hemoglobin (Hb) among cardiac surgery patients is high. As iron homeostasis is often impaired in these patients, restoration of iron availability might over-ride iron-restricted erythropoiesis. This post-hoc analysis of a previously published, large, randomized clinical trial (ClincalTrials.gov NCT03560687; n=1,000) assesses which sub-cohort of patients benefits the most from pre-operative Hb optimization with oral Sucrosomial® iron. Patients without baseline Hb (n=349) or receiving >5 red blood cell units (n=57) were excluded from the study. Data from the remaining 594 were reanalyzed according to treatment, baseline anemia (Hb <13 g/dL) or gender. Patients (pt) received a one-month course of 60 mg/day Sucrosomial® iron (Iron group, n=309) or routine care (Control group, n=285) prior to elective cardiac surgery. Main end-point variables were increase in Hb from randomization to hospital admission, transfusion requirements, and cost-effectiveness of Sucrosomial® iron administration. At hospital admission, Hb had increased 0.7 g/dL and 0.1 g/dL, for Iron and Control groups, respectively (p<0.001), with no gender-related differences, leading to a decrease in transfusion rate (30 vs 59%, respectively; p<0.001) and transfusion index (0.5 units/patient vs 1.2 units/pt, respectively; p<0.001). Sucrosomial® iron administration was well-tolerated, and yielded cost-savings of €92/pt (p<0.001), particularly in those presenting with baseline Hb <13 g/dL. This post-hoc analysis confirms pre-operative Sucrosomial® iron administration is a safe and cost-effective strategy to increase preoperative Hb and decrease transfusion requirements in elective cardiac surgery, especially in those anemic at baseline.

Canakinumab Effects on Erythropoiesis, Cardiovascular Risk, and Clonal Hematopoiesis: Proteogenomic Analysis of the Cantos Randomized Clinical Trial

Canakinumab is a monoclonal antibody that directly neutralizes interleukin (IL)-1β. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) - a randomized, double-blind, placebo-controlled trial that enrolled 10,061 patients with previous myocardial infarction and high-sensitivity C-reactive protein (hsCRP) levels ≥2 mg/L - canakinumab prevented recurrent cardiovascular (CV) events (Ridker et al. NEJM 2017). Anemia of inflammation (AI) presents with mild to moderate anemia in the setting of systemic inflammatory conditions. The pathogenesis of AI involves deregulation of iron homeostasis via hepcidin and inflammatory cytokines such as IL-1β, IL-6, and TNF-α, resulting in skewed myeloid differentiation and decreased erythrocyte lifespan via enhanced erythrophagocytosis (Ganz et al. NEJM 2019). A CANTOS exploratory study revealed that canakinumab reduces the incidence of anemia and improves hemoglobin levels (Vallurupalli et al. Ann Intern Med. 2020). Among mutations associated with clonal hematopoiesis (CH), patients with TET2 variants had fewer major adverse CV events than those without CH mutations (Svensson et al. JAMA Cardiol. 2022). CH mutations in TET2 were associated with higher IL-1β levels (Bick et al. Nature 2020), generating the hypothesis that inhibition of IL-1β may provide preferential benefits to patients with CH mutations. To determine the association between CH mutations and clinical response to canakinumab and evaluate the underlying molecular mechanisms of anemia response, a proteogenomic study was performed in 13080 plasma samples from 4595 CANTOS participants, including highly multiplexed proteomics (4785 proteins) and targeted deep sequencing of CH mutations with variant allele fraction≥ 2% (Figure A). Longitudinal and cross-sectional analyses were performed in pre- and post-treatment samples from patients with at least one pre-treatment sample (baseline). CH mutations were associated with older age, anemia at baseline, and higher baseline IL-6 and TNF-α levels (all OR's >1.4 and p<0.003). Among patients without baseline anemia, canakinumab treatment prevented incidental anemia, compared to those treated with a placebo (without CH mutation: HR=0.72; 95% CI=0.61-0.84; P < 0.001, with CH mutations: HR=0.77; 95% CI=0.49-1.19; P =0.24). In individuals treated with canakinumab, however, those with CH mutations were more likely to develop incidental anemia compared to patients without CH mutations (HR=1.56; 95% CI=1.18-2.07; P=0.002). Conversely, among patients with baseline anemia, canakinumab treatment significantly improved hemoglobin levels in patients with CH mutations compared to a placebo (P< 0.001), whereas a significant difference was not found in hemoglobin levels of patients without CH mutations (Figure B). Enhanced hemoglobin response over time to canakinumab was observed in patients with concurrent baseline anemia and CH mutations, particularly in DNMT3A and TET2, compared to no CH mutations (all CH mutations, DNMT3A and TET2,P = 0.022, 0.004, 0.078 respectively). We observed that canakinumab treatment reversed multiple nodes of abnormal erythropoiesis associated with AI. Canakinumab treatment was associated with lower hepcidin and inflammatory cytokines (IL-6 and TNF-α) and down-regulation of pathways for complement activation and phagocytosis, which may prolong RBC lifespan and promote erythropoiesis. Higher odds of having both an increase in hemoglobin and a decrease in hepcidin (OR=1.88; 95% CI=1.62 - 2.17; P<0.001 ) and both an increase in hemoglobin and a decrease in IL-6 (OR=3.46; 95%CI=3.00 - 4.00; P<0.001) were observed with canakinumab treatment compared to placebo. The characterization of proteomic profiles in patients with CH mutations revealed novel biological links in dysregulation of RBC homeostasis, cardiovascular risk biomarkers, inhibitory immune molecules, and bone morphogenetic protein antagonists, which were reversed by canakinumab treatment more significantly in patients with TET2 mutations. Collectively this data provides direct clinical evidence that patients with concurrent anemia and CH mutations can benefit from canakinumab treatment by suppressing CH-mediated activation of the IL-1β/IL-6 axis and reversing ineffective erythropoiesis via multiple mechanisms, and the type of CH mutations may be associated with distinct clinical and biological response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Iron Supplementation May Selectively Reprofile the Gut Microbiome in Iron-Deficient Bangladeshi Infants

Children in low- and middle-income countries (LMICs) have a high burden of anemia, much of which is attributable to iron deficiency. The World Health Organization (WHO) recommends universal iron interventions in preschool-aged children in countries where there is a high anemia prevalence. However, oral iron supplementation is associated with increased risks of infection, including diarrhea. In small studies in Africa, iron has been shown to reprofile the intestinal microbiota leading to a reduction in commensal bacteria and an increase in pathogenic taxa. Gut dysbiosis has been implicated in the pathogenesis of gastrointestinal, autoimmune and inflammatory disease. The BRISC (Benefits and Risks of Iron Interventions in Children) trial was a double-blind, placebo-controlled randomized controlled trial of oral iron supplementation in 3,300 infants in Bangladesh. Children were randomized to receive one of iron syrup, iron-containing multiple micronutrient powder (MNP) or placebo daily for three months. The primary outcome of the trial was child cognitive development. Key findings from the trial were an improvement in hematological indices with iron but no effect on the functional outcomes assessed (Pasricha et al New Engl J Med 2021). We aimed to study the effect of iron on microbiome composition, diversity and function in the BRISC participants. To achieve this aim we undertook a substudy in which we collected stool samples from 925 children at the three time points of the main BRISC trial: at recruitment, end of intervention and at nine-month follow up. DNA was extracted and analyzed by 16S ribosomal RNA gene (rRNA) amplicon sequencing (2,339 samples across three timepoints) and shotgun metagenomics (965 samples across three timepoints). Episodes of infection were documented as per the main BRISC trial and included diarrhea, respiratory symptoms, antibiotic use, and clinic/hospital visits. The V4 hypervariable region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq instrument together with negative and positive controls. Demultiplexed forward and reverse FASTQ files for each sample were trimmed and processed using the DADA2 package in RStudio, and taxonomy was assigned using the SILVA 138 SSU Ref NR 99 reference database. Control samples and samples with fewer than 500 reads were removed (2,284 samples met this minimum read threshold). Taxonomic, alpha diversity and beta diversity measures were conducted using phyloseq and microbiomeSeq packages in RStudio. Differential abundance was calculated by two separate methods: i. limma voom (using trimmed mean of M values [TMM] normalization and log transformation) and ii. ANCOM-BC (using additive log-ratio transformation). Prior to implementing differential abundance methods a filter was applied such that operational taxonomic units (OTUs) found in under 10% of samples were pruned from the samples. As previously reported, there was no overall significant increase in diarrhea incidence among participants receiving iron compared to those given placebo among BRISC trial participants. Baseline iron deficiency, anemia and iron deficiency anemia prevalence among substudy participants was 33%, 42% and 26% respectively. 16S rRNA analysis demonstrated that recent antibiotic (12% of children at end of intervention) was associated with a significant reduction in alpha diversity. Accordingly, analysis was conducted to exclude recent antibiotic use from analysis by intervention arm. Using this analysis, there were no significant differences in alpha or beta diversity between trial intervention groups at the end of intervention (alpha diversity by Shannon index shown in Figure 1). Members of Ruminococcus torques group (limma voom and ANCOM-BC) and Leuconostoc (limma voom only) were more abundant in the intestinal microbiota of children randomized to iron, but no genus was found to be differentially abundant when controlling for multiple comparisons. However, several bacterial genera were differentially abundant in children who were iron deficient at baseline who received iron. Two forms of analyses (Limma voom and ANCOM-BC) showed agreement in finding a reduction in Sutterella and Lactococcus species in iron deficient children receiving iron. These results are shown in Table 1. These data indicate that reprofiling of the intestinal microbiota in response to iron supplementation is dependent on baseline host iron status. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Randomised Controlled Trial of Intravenous Iron (ferric carboxymaltose) for Second Trimester Anaemia in Malawian Pregnant Women (REVAMP)

Introduction Anemia affects 46% of pregnancies in Africa. WHO estimates 50% of anaemia in pregnancy (44% in Africa) is responsive to iron; other causes of anaemia in Africa include infection (e.g. P. falciparum). Antenatal oral iron supplementation improves maternal anaemia and birthweight, but adherence may be suboptimal. Ferric carboxymaltose (FCM) is a modern intravenous iron formulation which enables provision of 1000mg (or 20mg/kg) in one 15 minute infusion. We reasoned FCM is an option to treat antenatal anaemia in low income primary-care settings, but the feasibility, efficacy and safety of this approach is unproven. Methods REVAMP was an open label, individually randomised controlled trial set in Malawi, sub-Saharan Africa, a low income setting where anaemia, malaria and other infections (including HIV) are common. Women were screened at antenatal clinics and were eligible if they met criteria including capillary haemoglobin (Hb) <10.0g/dL, negative Plasmodium rapid diagnostic test, and ultrasound-confirmed singleton pregnancy of 13 to 26 weeks gestation. HIV positivity was not an exclusion. Women were randomly assigned 1:1 to the intervention arm (FCM 20mg/kg, up to 1000mg, once at enrolment) or standard of care (SOC, 60mg elemental iron b.d for 90 days, in alignment with local practice). All women received IPTp with Suphadoxine-Pyrimethamine at enrolment and 28 days. The primary maternal outcome was anaemia at 36 weeks gestation. Secondary maternal outcomes included anaemia at other timepoints (28 days post infusion, during delivery and 28 days post-partum), and Hb, iron deficiency (ID) and iron deficiency anaemia (IDA) at each timepoint. The primary neonatal outcome was birthweight. Subgroup analyses (e.g. by baseline anaemia severity, ID, IDA, HIV status) were prespecified. Safety outcomes included incidence of adverse events (AEs) during infusion, and all AEs from randomisation to 4 weeks postpartum, including serious AEs (SAEs): unplanned hospitalisation or death including pregnancy loss and neonatal death. Results We screened 21258 women and randomised 862. Baseline characteristics, including anaemia severity and prevalence of iron deficiency, inflammation, and HIV were similar between arms. Compared with SOC, FCM reduced the prevalence of anaemia at 28 days post infusion (PR 0.91 95% CI 0.85 to 0.97, P=0.007) but did not statistically significantly decrease anaemia prevalence at the primary timepoint of 36 weeks gestation (52.5% vs 56.8%, prevalence ratio (PR) 0.92, 95% CI 0.81 to 1.06, P=0.27), or at delivery or 28 days postpartum (Table 1). Hb concentrations increased from baseline to 28 days post partum in both arms and were greater in women randomised to FCM 28 days post infusion (1.3 vs 1.1 g/dL, difference 0.19 [0.06-0.33]) and at 28 days postpartum (3.1 vs 2.9 g/dL, difference 0.25 [0.06-0.45]). IDA prevalence was reduced at each timepoint, including at 36 weeks gestation (PR 0.29 [0.20 to 0.43], P<0.001). ID prevalence was also reduced at all timepoints. Birthweight did not differ between FCM and SOC. Adverse reactions during FCM administration were reported by 26/430 (6.0%) women; there were no infusion-related SAEs. There was no clinically relevant difference in AEs by any systemic organ class, including infection (including malaria), and SAEs in women and neonates (Table 2). Hypophosphataemia (PO4<0.080mmol/L) at 28 days post infusion was seen in 22/403 (5.5%) women randomised to FCM compared to 8/382 (2.0%) with SOC. There was no difference in pregnancy loss or stillbirth between arms. Conclusions In this low-income, malaria endemic setting, treatment of anaemic pregnant women in the second trimester with FCM worked faster than SOC to resolve anaemia but benefit was not evident by 36 weeks. However FCM reduced ID and IDA at every timepoint. Administration of FCM was feasible and safe. Extended follow-up of mothers and babies is underway. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 13642: Post-Operative Bleeding Risk in TAVR Patients With Atrial Fibrillation

Introduction: Antithrombotic medications are the subject of multiple transcatheter aortic valve replacement (TAVR) randomized control trials. Pragmatically, decisions are complicated by conditions such as atrial fibrillation (AF) that also require lifetime anticoagulation. Our study examines antithrombotic medications in a real-world cohort to identify risk factors for bleeding by 1-year post-TAVR. Methods: This retrospective study includes 844 patients undergoing transfemoral TAVR between 2015 and 2020. Pre- and post-operative medications, comorbidities, and 1-year outcomes were recorded based on review of the medical record. Antithrombotic regiment decisions were made on a case-by-case basis. Bleeding classification followed VARC2 definitions. Patients were stratified into two groups based on history of AF. Multivariable logistic regression was used to determine independent predictors of bleeding. Results: Among the 844 patients, 290 had comorbid AF (34%). Patients with AF were older (80.3 vs 77.8 years; p&lt;0.001), more frequently had cardiovascular comorbidities, and had lower LVEF (52.4% vs 56.8%; p&lt;0.001). Patients with AF were more likely to experience major or life-threatening bleeding (10% vs 5%; p&lt;0.001), but there were no differences in rates of myocardial infarction, cerebrovascular accident, nor death by 1-year follow-up. After controlling for risk factors including anticoagulation and increases to antithrombotic regiment post-operatively, the independent risk predictors of major or life-threatening bleed included female sex [OR 1.522 (1.118-1.741); p=0.018], severe baseline anemia [2.938 (1.146-7.533); p=0.025], and atrial fibrillation [2.195 (1.206-3.997); p=0.010]. Conclusions: Female sex, severe baseline anemia, and comorbid atrial fibrillation are predictors of major or life-threatening bleed by 1 year in patients undergoing transfemoral TAVR, independent of antithrombotic regiment.

Real-world experience of intravenous ferric derisomaltose evaluated through safety and efficacy reporting in the UK

Ferric derisomaltose (FDI; Monofer) is used in clinical practice to treat iron deficiency, but the safety and efficacy of FDI has not been robustly evaluated in a large real-world study. This retrospective, multicentre, audit-based, observational study provides pragmatic information about safety and clinical responses with FDI across therapy areas and patient populations, helping to facilitate treatment decisions. Participating sites provided data from the medical records of adults who had received ≥ 1 FDI infusion. The primary outcome was the incidence of adverse reactions within 24 hours of the FDI infusion. Secondary outcomes included the change from baseline in haemoglobin and ferritin up to 12 months post infusion. In total, 19 sites provided data for a total of 7354 FDI-treated patients; 64.3% of patients were female, and 42.2% were aged ≥ 70 years. Surgery was the main hospital specialty (34.5%). The incidence of any recorded adverse reactions, hypersensitivity reactions, and anaphylaxis were 1.7%, 0.4%, and < 0.1%, respectively, regardless of baseline anaemia status. Statistically significant increases in haemoglobin and ferritin were observed between baseline and Month 4 following FDI treatment (p < 0.0001). Improvements in haemoglobin were more pronounced for hospital specialties where operative blood loss is expected (surgery/obstetrics) compared with those where blood loss is not expected. This study provides real-world clinical evidence for the low risk of adverse reactions with FDI across diverse patient populations, providing reassurance that intravenous iron is not associated with serious toxicity. These findings may inform changes in intravenous iron delivery to provide effective therapy to more patients in need.

Baseline anemia predicts a poor prognosis in patients with non-small cell lung cancer with epidermal growth factor receptor mutations: a retrospective study

BackgroundAnemia is relatively common in cancer patients, and baseline anemia is associated with poor survival in patients with non-small cell lung cancer (NSCLC). However, there is a lack of large-sample studies of patients with NSCLC with epidermal growth factor receptor (EGFR) mutations.MethodsWe retrospectively analyzed anemia‑related data for patients with NSCLC and EGFR mutations who were admitted to Zhejiang Cancer Hospital from January 2013 to June 2019 and treated with targeted therapy. The patients’ clinicopathological features were evaluated by χ2 tests and the relationships between clinical characteristics and prognosis were investigated using Kaplan–Meier and multivariate Cox regression analyses.ResultsA total of 2,029 patients treated with EGFR-tyrosine kinase inhibitors (TKIs) were finally enrolled in this study, of whom 24.6% had baseline anemia. Patients without baseline anemia had longer median overall survival (OS) than patients with baseline anemia (36.10 vs. 29.10 months, P = 0.001), and patients with grade < 2 anemia had longer median OS than those with grade ≥ 2 anemia (35.00 vs. 25.10 months, P < 0.001). Multivariate analyses identified baseline anemia as a factor predicting a poor prognosis in terms of OS in patients with EGFR mutations.ConclusionsBaseline anemia is a significant factor predicting a poor prognosis in terms of OS in patients with NSCLC and EGFR mutations treated with targeted therapy. A higher grade of baseline anemia may also be related to shorter OS. And a higher risk of EGFR-mutated patients who had received targeted therapy could also be observed.

PREVALENCE OF ANEMIA IN CARDIAC AMYLOIDOSIS AND ASSOCIATION WITH CLINICAL FACTORS AND OUTCOMES

PREVALENCE OF ANEMIA IN CARDIAC AMYLOIDOSIS AND ASSOCIATION WITH CLINICAL FACTORS AND OUTCOMES

Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data

BackgroundIn 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns.MethodsA systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models.ResultsData comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17–0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19–0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms.ConclusionsOur results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients.Trial registrationPROSPERO, CRD42019128185

Incidence, kinetics, and risk factors for intra- and extracranial cerebral arteriopathies in a newborn sickle cell disease cohort early assessed by transcranial and cervical color Doppler ultrasound.

The risk of stroke in children with sickle cell disease (SCD) is detected by abnormal intracranial arterial time-averaged mean of maximum velocities (TAMVs ≥200 cm/s). Recently, extracranial internal carotid artery (eICA) arteriopathy has been reported, and a cross-sectional study showed that eICA-TAMVs ≥160 cm/s are significantly associated with eICA kinkings and stenosis. The cumulative incidence of and predictive risk factors for intracranial arteriopathy are well described in sickle cell anemia (SCA=SS/Sβ0) but are lacking for SC/Sβ+ children, as is the cumulative incidence of eICA arteriopathy. We report a prospective longitudinal cohort study including 493 children with SCD (398 SCA, 95 SC/Sβ+), all assessed by transcranial and cervical color Doppler ultrasound. Cerebral MRI/MRA data were available in 375 children with SCD and neck MRA in 365 children. eICA kinkings were defined as eICA tortuosities on neck MRA, with an internal acute angle between the two adjacent segments <90°. The median follow-up was 10.6 years. The cumulative incidence of kinkings was significantly lower in SC/Sβ+ children than in children with SCA, and no SC/Sβ+ child developed intra- or extracranial stenotic arteriopathy. The 10-year KM estimate of cumulative incidence (95% CI) for eICA-TAMVs ≥160 cm/s revealed its development in the 2nd year of life in children with SCA, reaching a plateau of 17.4% (13.2–21.6%) by about 10 years of age, while the plateau for eICA stenosis was 12.3% (8.3–16.3%). eICA assessment identified 13.5% (9.3–17.7%) patients at risk of stroke who were not detected by transcranial color Doppler ultrasound. We also show, for the first time, that in addition to a congenital origin, eICA kinkings sin patients with SCD can develop progressively with aging as a function of eICA-TAMVs, themselves related to anemia severity. Ongoing hydroxyurea treatment was significantly associated with a lower risk of abnormal intracranial arteriopathy and eICA kinkings. After adjustment with hydroxyurea, baseline low hemoglobin, high reticulocyte, and WBC counts remained independent risk factors for intracranial arteriopathy, while low hemoglobin and SEN β-haplotype number were independent risk factors for extracranial arteriopathy. The association between extracranial arteriopathy and SEN β-haplotype number suggested a genetic link between the ethnic origin and incidence of eICA kinkings. This prospective cohort study shows the importance of systematically assessing the eICA and of recording biological parameters during the 2nd year of life before any intensive therapy to predict the risk of cerebral arteriopathy and treat patients with severe baseline anemia.

Effects on Mortality and Major Bleeding of Radial Versus Femoral Artery Access for Coronary Angiography or Percutaneous Coronary Intervention: Meta-Analysis of Individual Patient Data From 7 Multicenter Randomized Clinical Trials

In some randomized clinical trials, transradial access (TRA) compared with transfemoral access (TFA) was associated with lower mortality in patients with coronary artery disease undergoing invasive management. We analyzed the effects of TRA versus TFA across multicenter randomized clinical trials and whether these associations are modified by patient or procedural characteristics. We performed an individual patient data meta-analysis of multicenter randomized clinical trials comparing TRA with TFA among patients undergoing coronary angiography with or without percutaneous coronary intervention. The primary outcome was all-cause mortality and the co-primary outcome was major bleeding at 30 days. The primary analysis was conducted by 1-stage mixed-effects models on the basis of the intention-to-treat cohort. The effect of access site on mortality and major bleeding was assessed further by multivariable analysis. The relationship among access site, bleeding, and mortality was investigated by natural effect model mediation analysis with multivariable adjustment. A total of 21 600 patients (10 775 TRA, 10 825 TFA) from 7 randomized clinical trials were included. The median age was 63.9 years, 31.9% were women, 95% presented with acute coronary syndrome, and 75.2% underwent percutaneous coronary intervention. All-cause mortality (1.6% versus 2.1%; hazard ratio, 0.77 [95% CI, 0.63-0.95]; P=0.012) and major bleeding (1.5% versus 2.7%; odds ratio, 0.55 [95% CI, 0.45-0.67]; P<0.001) were lower with TRA. Subgroup analyses for mortality showed consistent results, except for baseline hemoglobin level (Pinteraction=0.003), indicating that the benefit of TRA was substantial in patients with moderate or severe anemia, whereas it was not significant in patients with milder or no baseline anemia. After adjustment, TRA remained associated with 24% and 51% relative risk reduction of all-cause mortality and major bleeding, respectively. A mediation analysis showed that the benefit of TRA on mortality was only partially driven by major bleeding prevention and ancillary mechanisms are required to fully explain the causal association. TRA is associated with lower all-cause mortality and major bleeding at 30 days compared with TFA. The effect on mortality was driven by patients with anemia. The reduction in major bleeding only partially explains the mortality benefit. URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42018109664.

Iron Deficiency and Incident Infections among Community-Dwelling Adults Age 70 Years and Older: Results from the DO-HEALTH Study.

To assess if baseline iron deficiency, with or without anemia, is associated with incident infections over 3 years among community-dwelling older adults. Prospective secondary analysis of DO-HEALTH, a 3-year randomized, double-blind controlled trial. 2157 community-dwelling adults age 70+ from 5 European countries with good cognitive function and mobility and no major health events in the 5 years prior to enrollment Measurements: Incident infections, their severity and type were recorded every 3 months throughout the 3-year follow-up. Iron deficiency was defined as soluble transferrin receptor (sTfR) levels > 28.1 nmol/l and anemia as hemoglobin levels < 120 g/l for women and 130 g/l for men. We applied negative binomial mixed effects regression models with random effects for countries, and controlling for treatment allocation, age, sex, body mass index, polypharmacy, number of comorbidities, smoking status, living situation, alcohol intake, frailty status, and physical activity levels. A pre-defined stratified analysis was performed to explore if the associations between iron deficiency and infections were consistent by baseline anemia status. In total, 2141 participants were included in the analyses (mean age 74.9 years, 61.5% of women, 26.8% with iron deficiency). Across all participants, baseline iron deficiency was not associated with incident overall infections, but was associated with a 63% greater rate of incident severe infections requiring hospitalization (incidence rate ratio [IRR] 1.63, 95% Confidence Interval [CI] 1.11-2.41, p=0.01). This association was more pronounced among the 2000 participants who did not have anemia at baseline (IRR=1.80, 95% CI 1.20-2.69, p=0.005). Based on this prospective study among generally healthy European community-dwelling older adults, iron deficiency was not associated with the incidence rate of overall infections but may increase the incidence of severe infections. Intervention studies are needed to prove the causality of this observation.

Clinical Outcomes after Transcatheter Aortic Valve Replacement Stratified by Hemoglobin Levels

Background: Anemia is a prevalent comorbidity in patients undergoing aortic valve replacement. Objectives: The objectives of this study were to define baseline parameters of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) to determine procedural risk and mortality outcomes stratified by hemoglobin (Hb) levels. Methods: Retrospective study of a population of patients with severe AS undergoing TAVR with the Edwards SAPIEN 3 valve between 2018 and 2021 at Sabah Al-Ahmad Cardiac Centre, Al Amiri Hospital, Kuwait. Two cohorts were identified based on Hb level: Hb &lt;13 and Hb ≥13 g/dl. Results: A total of 61 patients were included. The mean age was 73.5 ± 9.0 years, with a higher prevalence of females. The cohort with lower Hb had lower body surface area (2.0 ± 0.1 vs. 1.8 ± 0.2, P = 0.035) and bioprosthesis size (26.5 ± 1.8 vs. 24.4 ± 1.8, P = 0.001). Based on echocardiography, patients with higher Hb levels had a higher prevalence of aortic regurgitation in addition to stenosis (P = 0.029). Conclusions: Baseline anemia is a common comorbidity in patients with severe AS undergoing TAVR. However, in terms of procedural outcomes and mortality, Hb levels were not a predictor of post-TAVR complications or in-hospital death.

Development and Validation of a Nomogram for the Prediction of Unfavorable Treatment Outcome Among Multi-Drug Resistant Tuberculosis Patients in North West Ethiopia: An Application of Prediction Modelling.

BackgroundMultidrug-resistant tuberculosis (MDR-TB) is a global problem and a health security threat, which makes “Ending the global TB epidemic in 2035” unachievable. Globally, the unfavourable treatment outcome remains unacceptably high. Therefore, this study aimed to develop a risk prediction model for unfavorable treatment outcomes in MDR-TB patients, which can be used by clinicians as a simple clinical tool in their decision-making.ObjectiveThe objective of this study was to develop and validate a risk prediction model for the prediction of unfavorable treatment outcomes among MDR-TB patients in North-West Ethiopia.MethodsWe used MDR-TB data collected from the University of Gondar and Debre Markos referral hospitals. A retrospective follow-up study was conducted and a total of 517 patients were included in the study. STATA version 16 statistical software and R version 4.0.5 were used for the analysis. Descriptive statistics were carried out. A multivariable model was fitted using all potent predictors selected by the lasso regression method. A simplified risk prediction model (nomogram) was developed based on the binomial logit-based model, and its performance was described by assessing its discriminatory power and calibration. Finally, decision curve analysis (DCA) was done to evaluate the clinical and public health impact of the developed model.ResultsThe developed nomogram comprised six predictors: baseline anemia, major adverse event, comorbidity, age, marital status, and treatment supporter. The model has a discriminatory power of 0.753 (95% CI: 0.708, 0.798) and calibration test of (P-value = 0.695). It was internally validated by bootstrapping method, and it has a relatively corrected discrimination performance (AUC = 0.744, 95CI: 0.699, 0.788). The optimism coefficient was found to be 0.009. The decision curve analysis showed the net benefit of the model as threshold probabilities varied.ConclusionThe developed nomogram can be used for individualized prediction of unfavorable treatment outcomes in MDR-TB patients for it has a satisfactory level of accuracy and good calibration. The model is clinically interpretable and was found to have added benefits in clinical practice.

Cetuximab and anemia prevention in head and neck cancer patients undergoing radiotherapy

BackgroundEpidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia.MethodsWe queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared.ResultsA total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068).ConclusionsIn contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia.

Incidence, Prediction, and Outcomes of Major Bleeding After Percutaneous Coronary Intervention in Chinese Patients.

The patterns of late major bleeding (MB) after percutaneous coronary intervention (PCI) remain unknown in Chinese patients. This study sought to determine the incidence, prediction, and long-term outcomes of late MB in Chinese patients. This was a retrospective cohort study from 14 hospitals in Hong Kong. Participants were patients undergoing first-time PCI without MB within 30days or death within 1 year. Patients were stratified by the presence of late MB, defined as MB between 30 and 365days. The primary endpoint was all-cause mortality. The secondary endpoints were major adverse cardiac events (MACE). A total of 32,057 patients were analyzed. After adjustment for baseline characteristics, periprocedural characteristics, and medications on discharge, the risks of all-cause mortality at 5 years were significantly higher with late MB (HR: 2.15; 95%CI: 1.92-2.41; P< 0.001). Late MB was also associated with a higher risk of MACE (HR: 1.57; 95%CI: 1.03-1.50; P< 0.001), myocardial infarction (HR: 1.25; 95%CI: 1.04-1.52; P = 0.02), and stroke (HR: 1.38; 95%CI: 1.09-1.73; P = 0.006). The CARDIAC (anti-Coagulation therapy, Age, Renal insufficiency, Drop In hemoglobin, baseline Anemia in Chinese patients) score had a good discriminating power for prediction of MB within 365days (area under the receiver-operating characteristic curve: 0.76). Late MB was independently associated with a higher risk of mortality, MACE, myocardial infarction, and stroke in patients undergoing PCI. The CARDIAC score is a simple model that can predict MB after PCI. Prevention of MB represents an important strategy to optimize cardiovascular outcomes for patients undergoing PCI.

Momelotinib for the treatment of myelofibrosis with anemia.

Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, debilitating constitutional symptomsand bone marrow failure. Disease-related anemia is common and associated with an inferior quality of life and survival. Unfortunately, few therapies exist to improve hemoglobin in myelofibrosis patients. Momelotinib is a JAK1/JAK2 inhibitor that also antagonizes ACVR1, leading to downregulation of hepcidin expression and increased availability of iron for erythropoiesis. In clinical testing, momelotinib has demonstrated a unique ability to improve hemoglobin and reduce transfusion burden in myelofibrosis patients with baseline anemia, while producing reductions in spleen size and symptom burden. This review explores the preclinical rationale, clinical trial dataand future role of momelotinib in the evolving therapeutic landscape of myelofibrosis.