Hemoglobin Response Research Articles

Efficacy and Safety of Darbepoetin Alfa (DA) in Patients with Myelodysplastic Syndromes (MDS): A Systematic Review and Meta-Analysis

Introduction: Erythropoiesis-stimulating agents (ESAs) have been used in treating anemic MDS patients to improve erythropoiesis and reduce the risk of red blood cell (RBC) transfusion. Two previous systematic reviews found that ESA use was efficacious, but these reviews focused on short-acting epoetin alfa (EA). Since then, the results of a number of prospective interventional trials of DA have been reported. We present an updated systematic review and meta-analysis to estimate the efficacy of DA in the treatment of MDS-related anemia.Methods: We conducted a systematic review of the medical literature to identify prospective interventional trials of DA in patients with MDS. The main inclusion-exclusion (IE) criteria were: that studies had to be prospective and interventional in nature; have at least 10 adult subjects with MDS reporting either World Health Organization (WHO), French-American-British (FAB) criteria, or International Prognostic Scoring System (IPSS) status; and report results for the pre-specified primary outcome (proportion of patients with erythroid response) or one of the secondary outcomes (which included major hemoglobin response, changes from baseline in hemoglobin levels, transfusion status, and quality of life (QoL) measures). We recorded and collated all reported adverse events. Two independent reviewers identified the studies and abstracted the information and a third reviewer adjudicated. Clinical and methodological heterogeneity across studies were evaluated with respect to the study population and participant selection method (e.g. MDS diagnosis, history of ESA use, baseline erythropoietin (EPO), hemoglobin, and creatinine levels, transfusion status, and other factors), the intervention (e.g. initial and maintenance ESA dose), and the endpoints of interest including the response criteria. Forest plots with formal testing using Cochran's Q-statistic was also used to assess the heterogeneity across the studies. We used random effects methodology to generate combined estimates when warranted by the data. Subgroup analyses and/or meta-regressions were conducted by dose level, ESA-naïve status, baseline EPO level, hemoglobin level, transfusion status, and other factors.Results: Ten studies (9 single-arm, 1 randomized controlled trial [RCT]) with a total of 647 patients were included in the systematic review, with response rates ranging from 38% to 72%, and the median duration of response varying from 5 to 12 months. The overall response rate for the nine studies that used IWG 2000 response criteria could not be evaluated because of heterogeneity. However, among studies that stratified response rates by baseline endogenous EPO levels, patients with EPO <100 IU/L had an overall response of 81% (95% confidence interval [CI]: 73-90%), and on average a 39% [95% CI: 22-56%] better response than patients with EPO >100 IU/L. Across the studies that reported response stratified by prior ESA use, ESA-naïve patients had a median response rate of 75% compared to 53% for patients previously treated with an ESA. Baseline mean hemoglobin was significantly associated with response (p=0.0204), with higher baseline levels associated with improved response. We also found that response tended to improve with dose (p=0.2; Figure 2): the estimated response for a mean initial dose of 150 μg once weekly (QW) was 57% (95% CI: 49-66%) compared to 64% (95% CI: 55-74%) for 300 μg QW. Baseline transfusion independence (6 studies), and low-risk IPSS status (2 studies) were reported to be significantly associated with better response in several studies. Treatment with DA tended to show an improvement in the quality of life (QoL) measures, transfusion rates, and hemoglobin levels, but the number of studies that reported these outcomes was small. Hypertension, thromboembolism, and progression to acute myeloid leukemia were respectively reported in 2%, 1%, and 1% of the patients.Conclusions: Published studies suggest that treatment with DA yielded high hemoglobin response (38-72%) in MDS patients with anemia. The response was strongest in patients with lower baseline serum EPO level, and ESA naïve patients. [Display omitted] [Display omitted] DisclosuresPark:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Mehta:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Callaghan:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Kim:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Tomita:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Xu:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership.

Safety and Efficacy of Rapid (one hour) Single Intravenous Dose Low Molecular Weight Iron Dextran for Treatment of Oral Iron Intolerant Maternal Iron Deficient Anemia

▪ OBJECTIVEDetermine safety and efficacy of rapid (one hour) intravenous infusion of 1,000 mg low molecular weight iron dextran to pregnant women with moderate to severe iron deficient anemia. INTRODUCTIONUp to 70% of pregnant women to whom oral iron is prescribed report significant gastrointestinal side effects. Intravenous iron is an efficient, but often overlooked, therapeutic alternative. METHODSWe conducted an observational treatment study of 1000 mg low molecular weight iron dextran for moderate to severe iron deficient anemia of pregnancy in 189 consecutive, unselected second and third trimester gravidas intolerant of, or unresponsive to, oral iron. All received an intravenous test dose of approximately 25 mg low molecular weight iron dextran. They were then monitored closely for adverse reactions during the balance of a 60 minute infusion. No premedication was administered unless two or more drug allergies or asthma was present in which case prophylactic intravenous methylprednisolone was administered. All subjects were followed through pregnancy and delivery. Monitored parameters included hemoglobin (Hgb), mean corpuscular volume (MCV), serum ferritin, and percent transferrin saturation. RESULTSOne hundred eighty-nine subjects received a single intravenous dose of 1000 mg low molecular weight iron dextran. No first trimester gravidas were treated. No serious adverse events occurred. Minor, self-limited infusion reactions (myalgias or flushing), occurred in 2% of subjects. The mean number of days from treatment to delivery was 58.6 (range 5-190) days. The change in Hgb was positively correlated with the time from treatment to delivery (r2 =0.17, p=0.0039). The initial Hgb was 10.1 g/dl (SD 1.03, SE 0.07) and at delivery 11.5 g/dl (SD=1.04, SE 0.10), with the mean change from diagnosis to delivery of 1.39 g/dl (p<0.0001). An improvement in Hgb was observed in 174 (92% (Figure 1)). In 110 (58%) the observed increment was 1.00-1.99 g/dl (hemoglobin response) and in 45 (24%) ≥ 2.00 g/dl (hematopoietic response). Second trimester treatment was not associated with a greater improvement in Hgb than third trimester treatment. MCV increased by 3.27 femtoliters (fl) for those treated in the second (p<0.0001), and 1.34 in the third(p<0.0001). The mean increment in MCV for those treated in the second trimester was 1.93 fl higher than those treated in the third (p=0.02). Post-partum data were available on 64 (34%). For this subgroup the mean change in Hgb from diagnosis to delivery was 1.48 g/dl, not significantly different than the observed increment for the entire group of 189. From delivery to post-partum follow-up, an additional Hgb increment of 0.66 g/dl was observed (p<0.0001) consistent with sustained iron repletion and post-partum contraction of plasma volume. The increment in Hgb from diagnosis to delivery and diagnosis to post-partum was similar irrespective of trimester of treatment. Anemia resolved in 95%. CONCLUSIONAdministration of a rapid (one hour) single large dose (1000 mg) of intravenous low molecular weight iron dextran is a convenient, effective, well tolerated and safe treatment for maternal iron deficient anemia in women who are intolerant of, or unresponsive to, oral iron. These data are relevant in light of recent publications reporting iron deficient neonates have both delayed growth and development and a statistically significant increment in both cognitive and behavioral abnormalities persisting up to ten years after iron repletion. [Display omitted] DisclosuresOff Label Use: Total dose infusion of low molecular weight iron dextran is off label.

Assessment of Serum Bioactive Hepcidin-25, Soluble Transferrin Receptor and Their Ratio in Predialysis Patients: Correlation with the Response to Intravenous Ferric Carboxymaltose Administration

Background: No reliable biomarker exists to predict responsiveness to intravenous (IV) iron (Fe) in iron deficient patients with chronic kidney disease (CKD). Our aim was to investigate if Hepcidin-25 (Hepc25) and soluble Transferrin Receptor (sTfR) and their Ratio sTfR/Hepc25 ratio prior to treatment can make a distinction between those predialysis patients with and those without adequate erythropoiesis after administration of IV ferric carboxymaltose (FCM).Patients and methods: In this prospective study we enrolled 78 stable stage III-IV CKD patients with iron deficiency (serum ferritin levels lower than 100µg/L) treated with IV FCM 1000mg/100ml NaCl-0.9% and infused over a period of 20min. Patients were divided in two groups according to hemoglobin (Hb) increase within a month after treatment. The responders (Group R, n=40), showed above 1g/dL increase in Hb concentration. The non-responders (Group NR, n=38) had no such a favorable reaction. Patient data, clinical information and blood samples were collected prior to IV iron administration. Hematologic analysis was performed using a hematogy analyzer. Blood chemistry, including measurements of renal, nutrition and inflammation markers along with measurements of Hepc25, IL-6 and sTfR were performed using appropriate techniques. Receiver Operating Curve (ROC) analysis was applied in order to evaluate the diagnostic potential of Hepc25 and sTfR/Hepc25 ratio and conclusions about the specificity and sensitivity were drawn.Results: As shown in Table 1, there were no significant differences at baseline between responders and non-responders in demographic and clinical parameters. No significant differences were revealed for serum creatinine, e-GFR, folic acid (FA), vitamin B12, hs-CRP and IL-6, with the notable exception of ferritin and Hepc25 levels that were lower and sTfR and sTfR/Hepc25 ratio that were higher in the responders as compared to non-responders (Table 1). Diagnostic efficacy was analyzed by ROC analysis. Cut off point of 1.49 for Hepc25 had sensitivity 84% and specificity 48%, and cut off point of 1.21 for sTfR/Hepc25 ratio had sensitivity 82% and specificity 52% to predict correctly response to Fe therapy (Table 2).Conclusions: These results suggest that lower Hepc25 and ferritin levels, as well as higher sTfR and sTfR/Hepc25 ratio were significant predictors of favorable hemoglobin response within a month after IV administration of FCM in CKD patients. Further in vitro and in vivo experiments and clinical studies in a larger population of patients are needed to better elucidate the role of Hepc25 and sTfR/Hepc25 ratio in iron deficiency anemia in CKD.Table 1Demographic, clinical and biochemical parameters in responders vs non-responders.Group R (n=40Group NR (n=38)Age (years)72.7±11.274.5±10.3NSGender (M /F)27:1325:13NSMedications-RAS inhibitors21(27%)19(24%)NSrh EPO1(27%)20(26%)NSCCB10(13%) )11(14%NSBMI (Κg/m2)25.5±3.325.1±3.4NSComorbidities-Cardiovascular Disease17(22%)15(19%)NS-Μechanical valve heart2(2%)2(2%)NS-Diabetes Mellitus20(26%)17(22%)NS-Polycystic Kidney Disease2(1%)1(1%)NSHemoglobin (g/dL)10.9±1.611.1±1.3NSCreatinine (mg/dL)2.4±1.12.5±1.1NSeGFR(mL/min/1.73 m2)35.2±16.930.0±13.4NSB12 (pg/mL)512.0±369.0655.0±414.0NShs-CRP (mg/L)3.9±5.93.7± 4.9NSIL-6 (pg/mL)6.2±5.35.78±4.5NSsTfR (mg/L)2.27±0.991.76±0.760.014Log (1+Hepc25)0.552±0.3430.728±0.3480.027sTfR/Hepc251.91±1.530.80±0.720.002Table 2Sensitivity and specificity of Hepcidin and sTfR/H as predictors of responsiveness to IV FCMAUC95%C.I.P-valueCut-off PointSensitivitySpecificityHepc250.6480.52-0.770.0251.4984%48%sTfR/Hepc250.6800.56-0.800.0061.2182%52% DisclosuresNo relevant conflicts of interest to declare.

Clinico-Pathological Features and Outcomes in Patients with Congenital Sideroblastic Anemias

▪Background: Ring sideroblasts (RS) are erythroid precursors with perinuclear mitochondrial iron accumulation seen in clonal disorders, such as myelodysplastic syndromes (MDS), and non-clonal conditions, including copper deficiency, lead poisoning, and congenital sideroblastic anemias (CSAs). CSAs involve a broad clinical and pathological spectrum related to mutations in ALAS2, ABCB7, etc. or mitochondrial aberrations (Pearson Syndrome; Myopathy, Lactic Acidosis and Sideroblastic Anemia (MLASA); etc.). MDS-RS is often associated with SF3B1 mutations, which have not been reported in other SAs. This study sought to further describe the characteristics and outcomes of patients with CSAs.Methods: After due IRB approval, we retrospectively identified all patients with a CSA diagnosis seen at our institution from 1990-2014. All bone marrow (BM) slides were re-reviewed to confirm the presence of RS. Secondary causes of SA were excluded. Genetic testing on the BM specimen was carried out when possible through research collaborations with the Boston Children's Hospital. Data was retrospectively extracted and is reported in Table 1. Data was analyzed based on the presence or absence of mitochondrial inheritance.Results: Seventeen patients with CSA were identified, 3 (17.6%) with mitochondrial inheritance. In the non-mitochondrial inheritance group, the median age at diagnosis was 29 years (range, 1-61 years). Six (42.9%) were males. At a median follow-up of 119 months (range, 1-401 months), 1 (7.1%) death was documented. The median overall survival (OS) has not been reached. Six of 14 (42.9%) underwent genetic testing, and a mutation was identified in 4 (ALAS -2, FECH -1, and a novel mutation, currently being validated). Six of 6 (100%) samples analyzed for SF3B1 mutations were negative. Median laboratory values at diagnosis included hemoglobin 9.5 g/dL, MCV 85.8, WBC 6.4, and platelets 297,000. Three (21.4%) patients had splenomegaly. Nine (64.3%) had iron overload; 3 (33%) were treated with iron chelation therapy, with only 1 documented response (≥ 500 µg/L reduction in serum ferritin). Twelve (85.7%) were treated with pyridoxine. Outcomes of pyridoxine treatment are described in Table 1. Three of 14 (21.4%) received red blood cell transfusions, and 3 (21.4%) received erythropoiesis stimulating agents (ESA). One (7.1%) patient underwent allogeneic stem cell transplant.Three patients had SAs of mitochondrial inheritance; aberrations were identified in 2 (YARS2 and a 4 kilobase mitochondrial deletion). In this group, the median age at diagnosis was 2 years (range, 1-13 years), and all were males. At a median follow-up of 173 months (range, 119-329 months), 2 (66.7%) deaths were documented. Median laboratory values at diagnosis included hemoglobin 9.0 g/dL, MCV 97.0, WBC 5.2, and platelets 175,000.Conclusions: Congenital SAs are rare, and the majority are of non-mitochondrial inheritance. The molecular basis for disease can be ascertained in less than 50% of patients. Unlike MDS with RS, CSAs are not characterized by the SF3B1 mutation, which may be used to establish clonality. With appropriate supportive care measures, survival for non-mitochondrially inherited CSA remains favorable.Table 1Demographics and Outcomes for 17 Patients with CSAAge at Diagnosis (Years)GenderMolecular MutationAdditional FeaturesPyridoxine ResponseIron OverloadSurvival (Months)OutcomesNon-Mitochondrial Inheritance5MR452H in ALAS2NY2Y173Alive33MMutation being validatedSplenomegalyY2Y254Alive36MUnknown, PTPN11, ALAS 2, ABCB7 negativeSplenomegalyNY137Alive, status-post transplant29FUnknown1NN/AN131Alive341FUnknown1NY2N83Alive440MPromoter mutation in ALAS2SplenomegalyNN106Alive431FUnknown1NNY401Deceased54MUnknown1NLost to follow-upY1Alive33MFECHNN/AN189Alive31FSCAD -VUSNLost to follow-upY13Alive329FUnknown1NNY205Alive358FUnknown1NNY47Alive, unknown transfusion status61FUnknown1NY2Y58Alive323FUnknown1Alpha-thalassemia-2-traitY2N37Alive3Mitochondrial Inheritance13MYARS2MLASANY329Alive42MUnknown, mitochondrial deletions and ABCB7 negativeMyopathy, AtaxiaN/AN173Deceased1M4 kilobase mitochondrial deletionPearson Syndrome, B cell lymphomaY2N119Deceased1No molecular testing performed2Sustained hemoglobin response of ≥ 1 g/dL over baseline for ≥ 12 weeks3Transfusion-independent4Transfusion-dependent DisclosuresSteensma:Incyte: Consultancy; Onconova: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

European Myeloma Network guidelines for the management of multiple myeloma-related complications.

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).

Outcomes of highly active antiretroviral therapy and its predictors: a cohort study focusing on tuberculosis co-infection in South West Ethiopia.

BackgroundIn this study, we hypothesized that TB co-infection independently increases the risk of poor treatment outcomes in such patients even if they are on antiretroviral therapy (ART). Therefore, this study was aimed at investigating this hypothesis among cohort of adult PLWHs in South West Ethiopia.MethodologyCohort study comparing the immunologic and clinical outcomes of 130 HIV/TB co-infected and 520 only HIV patients starting ART was enrolled. Chi square and student t test were used to compare outcome variables and logistic regression was used to assess the effect of TB on treatment failure.ResultsIn this study, TB co-infection didn’t increase immunologic failure even in univariate analysis at both 6 [OR, 1.10 (0.59–1.69), P = 0.85] and 12 months [OR, 1.06 (0.58–1.93), P = 0.89] of ART initiation. However, it increased the risk of clinical failure at both 6 [Adjusted Odd Ratio (AOR), 2.90 (1.41–6.09), P = 0.028] and 12 months [AOR, 2.93 (1.41–6.09), P = 0.004] of ART initiation.ConclusionThis study showed that TB co-infection didn’t adversely affect the immunologic outcomes, weight and hemoglobin responses even though it increased the risk of clinical failure nearly three times. Therefore, beside the concern given for TB prevention and treatment, several patient and policy related factors need to be addressed to maximally benefit from highly active antiretroviral therapy rollout in resource limited settings.

Burden of Anemia and Hemoglobin Response to Iron Therapy in Adolescent Girls of State of Chhattisgarh

Burden of Anemia and Hemoglobin Response to Iron Therapy in Adolescent Girls of State of Chhattisgarh

Practical Management of HIV-Associated Anemia in Resource-Limited Settings: Prospective Observational Evaluation of a New Mozambican Guideline.

Mozambique's updated guideline for management of HIV-associated anemia prompts clinicians to consider opportunistic conditions, adverse drug reactions, and untreated immunosuppression in addition to iron deficiency, intestinal helminthes, and malaria. We prospectively evaluated this guideline in rural Zambézia Province. Likely cause(s) of anemia were determined through prespecified history, physical examination, and laboratory testing. Diagnoses were "etiologic" if laboratory confirmed (sputum microscopy, blood culture, Plasmodium falciparum malaria rapid test) or "syndromic" if not. To assess hemoglobin response, we used serial point-of-care measurements. We studied 324 ambulatory, anemic (hemoglobin <10 g/dl) HIV-infected adults. Study clinicians treated nearly all [315 (97.2%)] for suspected iron deficiency and/or helminthes; 56 (17.3%) had laboratory-confirmed malaria. Other assigned diagnoses included tuberculosis [30 (9.3%)], adverse drug reactions [26 (8.0%)], and bacteremia [13 (4.1%)]. Etiologic diagnosis was achieved in 79 (24.4%). Of 169 (52.2%) subjects who improved (hemoglobin increase of ≥1 g/dl without indications for hospitalization), only 65 (38.5%) received conventional management (iron supplementation, deworming, and/or antimalarials) alone. Thirty (9.3%) died and/or were hospitalized, and 125 (38.6%) were lost to follow-up. Multivariable linear and logistic regression models described better hemoglobin responses and/or outcomes in subjects with higher CD4(+) T-lymphocyte counts, pre-enrollment antiretroviral therapy and/or co-trimoxazole prophylaxis, discontinuation of zidovudine for suspected adverse reaction, and smear-positive tuberculosis. Adverse outcomes were associated with fever, low body mass index, bacteremia, esophageal candidiasis, and low or missing CD4(+) T cell counts. In this severely resource-limited setting, successful anemia management often required interventions other than conventional presumptive treatment, thus supporting Mozambique's guideline revision.

Role of the GH-IGF-1 system in Atlantic salmon and rainbow trout postsmolts at elevated water temperature

A comparative experiment with Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) postsmolts was conducted over 35days to provide insight into how growth, respiration, energy metabolism and the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) system are regulated at elevated sea temperatures. Rainbow trout grew better than Atlantic salmon, and did not show reduced growth at 19°C. Rainbow trout kept at 19°C had increased blood hemoglobin concentration compared to rainbow trout kept at 13°C, while salmon did not show the same hemoglobin response due to increased temperature. Both species showed reduced length growth and decreased muscle glycogen stores at 19°C. Circulating IGF-1 concentration was higher in rainbow trout than in Atlantic salmon, but was not affected by temperature in either species. Plasma IGF-binding protein 1b (IGFBP-1b) concentration was reduced in Atlantic salmon reared at 19°C after 15days but increased in rainbow trout at 19 °C after 35days. The igfbp1b mRNA level in liver showed a positive correlation to plasma concentrations of glucose and IGFBP-1b, suggesting involvement of this binding protein in carbohydrate metabolism at 19°C. At this temperature muscle igfbp1a mRNA was down-regulated in both species. The muscle expression of this binding protein correlated negatively with muscle igf1 and length growth. The plasma IGFBP-1b concentration and igfbp1b and igfbp1a expression suggests reduced muscle igf1 signaling at elevated temperature leading to glucose allostasis, and that time course is species specific due to higher thermal tolerance in rainbow trout.

Is achlorhydria a cause of iron deficiency anemia?

We re-evaluated the old hypothesis that gastritis-induced achlorhydria is a cause of iron deficiency anemia (IDA) in humans. First, we analyzed the currently available research on the association between achlorhydria and IDA. When gastric acid secretion was measured after maximal stimulation, the frequency of achlorhydria (or severe hypochlorhydria) was 44% in patients with idiopathic IDA and 1.8% in healthy controls. In some patients with pernicious anemia, presumed achlorhydria preceded the development of IDA in time. However, we found no credible evidence that IDA caused gastritis or that IDA preceded the development of achlorhydria. Thus, correlational results favor achlorhydria as the causal factor in the association between achlorhydria and IDA. Second, we sought to determine whether gastritis and achlorhydria cause negative iron balance. When biosynthetic methods were used to isotopically label iron in food, achlorhydric patients were found to have severe malabsorption of nonheme iron, which persisted after the development of IDA. In 1 study, achlorhydria reduced the normal increase in heme-iron absorption from hemoglobin in response to iron deficiency. After an injection of isotopic iron into normal men, the physiologic loss of iron from the body was found to be 1 mg/d. Patients with chronic gastritis had excess fecal loss of isotopically tagged plasma iron. Calculations based on these results indicate that the absorption of iron from a typical Western diet by achlorhydric patients would be less than physiologic iron losses, creating a negative iron balance that could not be overcome by the adaptive increase in duodenal iron absorptive capacity that occurs in response to iron deficiency. The combination of results from these correlational and pathophysiologic studies supports the hypothesis that gastritis-induced achlorhydria can be an independent cause of IDA.

Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis.

BackgroundFree hemoglobin (fHb) may induce vasoconstriction by scavenging nitric oxide. It may increase in older blood units due to storage lesions. This study evaluated whether old red blood cell transfusion increases plasma fHb in sepsis and how the microvascular response may be affected.MethodsThis is a secondary analysis of a randomized study. Twenty adult septic patients received either fresh or old (<10 or >15 days storage, respectively) RBC transfusions. fHb was measured in RBC units and in the plasma before and 1 hour after transfusion. Simultaneously, the sublingual microcirculation was assessed with sidestream-dark field imaging. The perfused boundary region was calculated as an index of glycocalyx damage. Tissue oxygen saturation (StO2) and Hb index (THI) were measured with near-infrared spectroscopy and a vascular occlusion test was performed.ResultsSimilar fHb levels were found in the supernatant of fresh and old RBC units. Despite this, plasma fHb increased in the old RBC group after transfusion (from 0.125 [0.098–0.219] mg/mL to 0.238 [0.163–0.369] mg/mL, p = 0.006). The sublingual microcirculation was unaltered in both groups, while THI increased. The change in plasma fHb was inversely correlated with the changes in total vessel density (r = -0.57 [95% confidence interval -0.82, -0.16], p = 0.008), De Backer score (r = -0.63 [95% confidence interval -0.84, -0.25], p = 0.003) and THI (r = -0.72 [95% confidence interval -0.88, -0.39], p = 0.0003).ConclusionsOld RBC transfusion was associated with an increase in plasma fHb in septic patients. Increasing plasma fHb levels were associated with decreased microvascular density.Trial RegistrationClinicalTrials.gov NCT01584999

Factors precipitating erythropoiesis-stimulating agent responsiveness in a European haemodialysis cohort: case-crossover study.

PurposeHyporesponsiveness to erythropoiesis‐stimulating agents (ESAs) is clinically and economically important in the treatment of anaemia in chronic kidney disease (CKD) patients. Previous studies focused on baseline predictors of ESA hyporesponsiveness, rather than factors associated with the transition to this state. Reversibility of ESA hyporesponsiveness has also not been studied previously.MethodsCase‐crossover methodology was applied to a cohort of 6645 European CKD patients undergoing haemodialysis and prescribed ESAs. Ninety‐day ESA exposure periods were defined, haemoglobin (Hb) response was calculated using the last 30 days of one period and the first 30 days of the next, and periods were classified based on a median ESA dose (80.8 IU/kg/week) and a 10 g/dL Hb threshold. Clinical, dialysis and laboratory data from patients' first hyporesponsive ‘case’ period was compared with the preceding responsive ‘control’ period using conditional logistic regression. A similar approach was applied to hyporesponsiveness reversal.ResultsOf the patients, 672 experienced hyporesponsiveness periods with preceding responsive periods; 711 reversed to normality from hyporesponsiveness periods. Transition to hyporesponsiveness was associated with hospitalization, vascular access changes or worsening inflammation, with these factors accounting for over two‐thirds of transitions. Findings were largely insensitive to alternative ESA doses and Hb thresholds. Continued hospitalization, catheter insertion and uncontrolled secondary hyperparathyroidism were associated with a lack of regain of responsiveness.ConclusionsTransition to hyporesponsiveness is linked to the development of conditions such as hospitalization events, vascular access issues or episodes of systemic inflammation. However, a third of hyporesponsive episodes remain unexplained. © 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.

A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients

ObjectivesTo develop a nomogram for estimating the glycated haemoglobin (HbA1c) response to different dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes.DesignA systematic review and meta-analysis of randomised controlled trials (RCTs)...

Investigation of negative BOLD responses in human brain through NIRS technique. A visual stimulation study

Despite negative blood oxygenation level dependent (BOLD) responses to visual stimuli have recently gained considerable interest, the explanation for their underlying neuronal and vascular mechanisms is still controversial. In the present study, a multimodal experimental approach is presented to shed light on the negative BOLD phenomenon in the human brain. In particular, information from functional magnetic resonance imaging (fMRI) and near infrared spectroscopy (NIRS) was integrated to confirm and gain insight into the phenomenon of negative BOLD responses (NBRs) to unpatterned intermittent photic stimulation (IPS) in healthy subjects. Eight healthy subjects participated in the study. Consistent findings emerged from the activation analysis of fMRI and NIRS data and the comparison of BOLD and hemoglobin responses at the single channel level showed that NBRs are related to a decrease in oxyhemoglobin (HbO) combined with a lower increase in deoxyhemoglobin (HHb), corresponding to a decrease in total hemoglobin (THb) and estimated cerebral blood volume (CBV). The HbO and HHb variations were significant in at least one channel in six subjects out of eight (p<0.05). The NIRS technique allowed obtaining valuable information on the vascular determinants of the NBRs, since the discrimination between HbO, HHb and THb information provided a more comprehensive view of the negative BOLD phenomenon. The within and between subject heterogeneous BOLD-Hb temporal relations pave the way to further investigations into the neurovascular properties of NBRs.

Evaluation of different classification methods for the diagnosis of schizophrenia based on functional near-infrared spectroscopy.

Based on near-infrared spectroscopy (NIRS), recent converging evidence has been observed that patients with schizophrenia exhibit abnormal functional activities in the prefrontal cortex during a verbal fluency task (VFT). Therefore, some studies have attempted to employ NIRS measurements to differentiate schizophrenia patients from healthy controls with different classification methods. However, no systematic evaluation was conducted to compare their respective classification performances on the same study population. In this study, we evaluated the classification performance of four classification methods (including linear discriminant analysis, k-nearest neighbors, Gaussian process classifier, and support vector machines) on an NIRS-aided schizophrenia diagnosis. We recruited a large sample of 120 schizophrenia patients and 120 healthy controls and measured the hemoglobin response in the prefrontal cortex during the VFT using a multichannel NIRS system. Features for classification were extracted from three types of NIRS data in each channel. We subsequently performed a principal component analysis (PCA) for feature selection prior to comparison of the different classification methods. We achieved a maximum accuracy of 85.83% and an overall mean accuracy of 83.37% using a PCA-based feature selection on oxygenated hemoglobin signals and support vector machine classifier. This is the first comprehensive evaluation of different classification methods for the diagnosis of schizophrenia based on different types of NIRS signals. Our results suggested that, using the appropriate classification method, NIRS has the potential capacity to be an effective objective biomarker for the diagnosis of schizophrenia.

Hemoglobin Outcomes during Administration of Continuous Erythropoietin Receptor Activator (C.E.R.A): A Prospective, Observational, Multicenter Study

Objective: To evaluate Hb outcomes in patients with dialysis-dependent or non-dialysis dependent chronic kidney disease (CKD) receiving continuous erythropoietin receptor activator (C.E.R.A.) therapy under routine conditions at specialist nephrology centers in Germany. Methods: In a 12-month, prospective, observational, multicenter study, Hb outcomes were assessed in 1,580 patients with CKD (1,184 dialysis-dependent, 326 non-dialysis dependent) given once-monthly C.E.R.A. under routine conditions. Results: Across the total study population, mean hemoglobin was in the range 11.4–11.6 g/dL at all post-baseline visits. In the 962 patients on hemodialysis who were pretreated with ESA including C.E.R.A., mean (SD) hemoglobin was 11.4 (1.2) g/dL at baseline and 11.5 (1.1) g/dL at month 12; the mean (SD) number of C.E.R.A. dose changes was 3.0 (2.4). For the 227 non-dialysis dependent patients without prior ESA therapy, mean hemoglobin values were 10.6 (1.1) g/dL at baseline and 11.6 (1.3) g/dL at month 12, with a mean of 1.0 (1.4) dose changes. Presence of diabetic nephropathy showed no clinically relevant effect on hemoglobin response in either group. Overall, the proportion of patients with every hemoglobin measurement within narrow (≤ 2 g/dL) pre-specified ranges was low (<10%), but higher for the range 10.0–13.0 g/dL (28.7%), reflecting the known fluctuation in hemoglobin values over time. Patients managed at large centers were more likely to have hemoglobin range in the range 10–13 g/dL throughout the 12-month study, suggesting closer anemia management. In total, five patients (0.3%) discontinued C.E.R.A. due to adverse events. Conclusion: Switching dialysis-dependent patients from more frequent ESA regimens to once-monthly C.E.R.A. therapy or initiating once-monthly C.E.R.A. de novo in predialysis CKD patients appears to be an effective therapeutic strategy regardless of diabetic status.

Poor ESA Responders As Defined By Week 4 Hemoglobin Response Have Greater ESA Dosing but Worse Cardiovascular Outcomes in Patients with Anemia of Chronic Kidney Disease (CKD) Not on Dialysis

Erythropoiesis-stimulating agents (ESAs) reduce transfusion use in patients with anemia of CKD (A-CKD) but ESA use is associated with worse cardiovascular outcomes in all trials to date. Several studies indicate that patients with A-CKD who have initial poor responses to ESAs have even worse cardiovascular outcomes than others. No specific baseline characteristics identify poor ESA responders. If these patients could be identified early in their therapy, their anemia management might be altered to reduce their known greater risks of major adverse cardiovascular events (MACE). A standardized and early definition of poor ESA responders is desirable but has not been established.We analyzed three groups of patients with anemia of CKD not on dialysis (A-CKD-NOD), for their initial response to ESA therapy, ESA dosing over time, and subsequent MACE outcomes. One group consisted of all patients in the TREAT trial receiving darbepoetin alfa (n=1981; New Engl J Med 2009 and 2010). The other two groups consisted of all patients in the phase 3 trials of the ESA peginesatide for A-CKD-NOD (New Engl J Med 2013), based on the ESA to which they were randomized. Patients receiving peginesatide (n=600) comprised one group, and the control group receiving darbepoetin alfa therapy (n=304) comprised the third group (for this group, events are too few for further analysis). In all patients, peginesatide was given once monthly and darbepoetin was given every two weeks, initially at a prespecified dose and then titrated to achieve and maintain target hemoglobin (Hgb) levels of 11-12 g/dL. All analyses used the patient populations with both baseline and week 4-5 Hgb values. Peginesatide was non-inferior to darbepoetin in raising Hgb in the trials. Our analyses compared early Hgb responses at week 4-5 for each patient with later Hgb levels, cumulative ESA dosage, and with primary outcomes of MACE (time to first event of stroke, myocardial infarction, or death) for each group. Patient level data was available for all patients, and all data has been reported publically. All outcomes were assessed by blinded independent review. The relationships between MACE outcomes and the hemoglobin response were assessed using three methods: Kaplan-Meier analysis with log-rank test, adjusted Cox model with model selection, and bootstrap simulations.Results: In all groups, patients’ baseline Hgb was 10-10.5 g/dL. No individual or composite baseline characteristics were predictive for defining a poor responder group. “Poor responders” for each group, identified by week 4-5 Hgb values, remained poor responders at week 12. The average Hgb level after 12 weeks remained marginally lower in the poor responder group. Over time, the poor responder group received more ESA dose yet achieved lower Hgb increments and sustained more MACE events. TableStudy groupsCKD not on dialysisNPoor responder: Hgb increment from baselinen (%)Relative Risk for MACE for poor vs better responderPeginesatide6000.3 g/dL or less112 (19)2.56Darbepoetin (TREAT trial)19810.1 g/dL or less451 (23)1.22In exploratory analyses, patients with little or no increment in Hgb at 4 weeks on ESA therapy, defined by having 0.3 g/dL Hgb increment with peginesatide or 0.1 g/dL or less Hgb increment with darbepoetin, have the greatest risk for MACE outcomes and should be studied prospectively for alternatives to continuing or escalating usual ESA therapy, to determine if the poor responder findings are prognostic or predictive (or both). The risk of a MACE outcome is less common but not eliminated among better responders. In sensitivity analyses, by using additional adverse outcomes (such as onset of heart failure or of hospitalization) in composite models, more events are identified and allow for greater precision for risk estimates but may not be as reliable clinically as are MACE events.This work is independent and does not represent views of any government agency. DisclosuresNo relevant conflicts of interest to declare.

Chronic Administration of Hydroxyurea (HU) and Outcomes in Patients with Sickle Cell Disease (SCD) at a Single Referral Institution

Introduction: Since HU has been FDA-approved for patients with SCD, it is not clear what proportion are taking a therapeutic dose (≥15mg/kg/day). There is also inadequate reporting of the frequency of HU dose modification during follow-up, or whether those who were treated with subtherapeutic doses (<15mg/kg/day) benefit from HU. We conducted this analysis to answer these important questions in a single center in Palermo, Italy.Methods: Patients were enrolled at the Haematology Department of Ospedale V. Cervello between January 2000 and April 2014. Laboratory parameters and frequency of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) were recorded. Blood counts, fetal hemoglobin (HbF) response, and changes in SCD complications were compared between the first and last visits to the clinic and across these 3 groups: patients who never took HU were combined with those who suspended HU before the last visit (no HU group, n=50, 36%); HU <15mg/kg (n=30, 21%); or HU ≥15mg/kg (n=60, 43%).Results: There were a total of 140 patients: 25 HbSS, 54 HbSβ0thal, and 61 HbSβ+thal. Median follow-up was 6.6 years. The median age was 35 years (range 0.4-61 years). 28% of patients never took HU, and 8% suspended HU treatment during the follow-up. Among patients taking <15mg/kg HU at first visit, about half stayed in the same dose range (<15mg/Kg/day) and half increased to the ≥15mg/kg dose range. Among patient taking ≥15 mg/kg, 17% decreased to <15mg/Kg/day due to cytopenia; 83% stayed on the ≥15 mg/kg. White blood cell (WBC) counts were lower in both HU groups, but comparing first and last visits, the change in WBC within each group was insignificant (P all >0.05, Table 1). Similarly, the change in total hemoglobin levels within each group was also insignificant (P all >0.05). HbF decreased in the no HU group, likely due to maturing age of 2 young children included in this group. Both HU treatment groups had modest increases in HbF (P=0.004, 0.001).With respect to SCD complications, the no HU group had less severe disease at the first visit, with lower percent of subjects with and fewer episodes of VOC and ACS (Table 2). While there was an increase in both VOC and ACS with time, this increase was not statistically significant. Both HU treatment groups had a significant reduction in both complications (p<0.0001 in both), and the magnitude of reduction was similar. The pattern of reduction appeared to be similar in all SCD phenotypes, but the small sample size precluded subtype analysis. Comparing changes in laboratory markers of liver and kidney function as well as TRV and ejection fraction between the first and last visit showed no significant differences.Conclusions: About one third of patients with SCD never took or discontinued HU. While these patients may have less severe disease initially, their rates of complications increased during follow-up. Among those taking HU, dose adjustment was common. HU increased HbF and is associated with reducing VOC and ACS. Since the increase in HbF and changes in HU dosing parameters were only modest in patients even on the highest HU doses, titrating HU to the maximum HbF response should be explored in order to improve markers of organ function.Table 1:Hematologic parameters based on HU statusFirst VisitLast VisitNO HUHU <15mg/kgHU >15mg/kgNO HUHU <15mg/kgHU >15mg/kgWBC (k/uL)11.28.74*10.910.77.8*8.3*Hgb (g/dL)10.010.210.010.29.79.9HbF (%)11.9**9.4*10.7*7.711.7*12.8**P<0.05 compared to no HU group**includes 4 subjects with hereditary persistent of HbF and 2 children aged 3 months.Table 2:SCD complications based on HU statusVOCACS% of subjectsCrisis per patient per year% of subjectsMean episodes per patientF VL VF VL VF VL VF VL VNo HU607022.522280.20.28HU<15mg/kg9056.64.3*1.2*50200.7*0.23HU>15mg/kg96.6604.1*1.1*51251.1*0.32FV, first visit; LV, last visit*P<0.05 compared to no HU group DisclosuresNo relevant conflicts of interest to declare.

Experience of a Single Latin-American Institution Using a Colloidal Iron Oxide Coated with a Semisynthetic Carbohydrate (ferumoxytol) for Iron Deficiency Anemia (IDA) in Patients with Intolerance or Treatment Failure with Oral Iron

Tolerance to oral iron and low percentage of absorption in the gut has provoked the Iron Deficiency Anemia patients (IDA) fail to treatment or they have symptoms of anemia even more than 12 weeks until recovery. Intravenous iron is an alternative to minimize risk and treatment-related adverse effects and maximize profits in the short and long term. The number of patients who have access to ferumoxytol is reduced in developing countries, therefore experience in the treatment with this type of iron is limited. Patients received ferumoxytol 1020mg (two 510mg 8 days apart) and the response at 4 weeks of treatment by raising hemoglobin and clinical response was evaluated without transfusion support. From a total of 30 patients 76.6% (19) were women of whom 36.8% (7) were postmenopausal. The average age was 45.3 years (range 21-76 years). Before starting treatment, the mean serum iron, ferritin and rate of transferrin saturation was 35.6 mcg (range 8–174 mcg/dL), 13.8 ng/mL (range 1.6–60 ng/mL), 10.8% (range 2-58%) respectively. The mean initial hemoglobin was 10.5 g / dL (range 7.1-13.7g/dL), reaching an average of 13.03 g dL (range 9.4 - 16 _g/dL) at 4 weeks, raising 2.52 g dL (0.3 - 5.4g / _ g/dL) in 28 days. The percentage of patients who achieved an increase of > 2 g/dL of hemoglobin was 70% (21). The initial symptoms attributed to anemia disappeared in 66.6% within the first 2 weeks and the rest in 4-5 weeks. Adverse effects more frequently than 2%: fatigue 16.6% (5), headache 10% (3), nausea and dizziness 10% (3), peripheral edema 6.6% (2) and hypersensitivity 3.3% (1). All previous were easily controlled with medications. Despite the low number of patients treated due to the difficult accessibility of the drug in our population, ferumoxytol was shown to be an attractive option that rapidly improves symptoms with a satisfactory safety profile. DisclosuresNo relevant conflicts of interest to declare.

Clinical Criteria for Transitioning from Oral to IV Iron Replacement Therapy in Patients with Iron Deficiency Anemia

▪Introduction: Oral iron supplementation is an effective means of iron replacement. Nevertheless, there is a frequent need to transition patients with iron deficiency anemia (IDA) from oral to intravenous (IV) iron therapy for inadequate response. No definitive guidance on the optimal timing for this change in therapy exists. Serum hepcidin may be a marker in predicting response to oral iron therapy, but currently, hepcidin assays are not commercially available. We evaluated the ability of various early response characteristics to accurately predict for an overall hemoglobin (Hb) response to oral iron. Our objective was to identify an early predictor of overall Hb response in patients on oral iron treatment as a guide to the decision to switch from oral to IV iron in patients unlikely to benefit from continued oral iron.Methods: Proprietary datasets from 6 published randomized studies in which oral iron (325 mg of ferrous sulfate containing 65 mg of elemental iron, t.i.d.[4 studies], 304.3 mg capsules containing 100 mg bivalent iron b.i.d [1 study] and as prescribed by the investigator [1 study]) was used as a comparator to ferric carboxymaltose were analyzed. Five studies were pooled into one primary analysis dataset and one study was analyzed separately due to differences in study design that precluded pooling. Patients were grouped by the underlying etiology of their IDA (postpartum, heavy uterine bleeding, gastrointestinal, and others) and stratified by those who had ≥ 1 g/dL Hb change after 14 days of oral iron therapy (responders) and those who did not (non-responders). Further analyses evaluated Hb response at various time points based on initial 14 day Hb response (≥ 1 g/dL change vs < 1 g/dL). We systemically evaluated changes in hemoglobin, absolute reticulocyte count, % reticulocyte count, ferritin, and transferrin saturation at specific time points to determine their ability to predict overall Hb response.Results: A total of 738 patients who were randomized to oral iron were included in the pooled study analysis. In the separate study, a total of 253 patients, all non-responders, were included. The mean baseline values for the 6 studies were Hb 9.9 g/dL, ferritin 19.9 ng/mL, and TSAT 16.9%. The vast majority of patients (96%) were females with a mean age of 36 years. In the pooled analysis, by day 14 of oral iron treatment, 27.2% (201/738) of patients had a Hb increase of < 1 g/dL (non-responders). Of these 201 patients, less than half (46.8%, 94/201) achieved an increase in Hb ≥ 1 g/dL from baseline after 2 additional weeks of oral iron (by day 28) and only 63.2% (127/201) had an increase in Hb ≥ 1g/dL from baseline after 6 to 8 weeks of oral iron (42 to 56 days). Furthermore, only 27.4% (55/201) and 5.5% (11/201) had an increase in Hb of 2 or 3 g/dL respectively at the Day 42 or 56 measurement. In comparison, responders (those who had a Hb increase ≥ 1 g/dL by 14 days of treatment) sustained a robust Hb response with continued dosing of oral iron. After 4 weeks of oral iron (28 days), 84.9% of the responders had a ≥ 2 g/dL increase in Hb from baseline. After 6 to 8 weeks of oral iron (42 or 56 days), 92.9% of the patients had ≥ 2 g/dL Hb increase from baseline, significantly different from non-responders (p < 0.0001). Patients with etiology of postpartum anemia had the most robust Hb response to oral iron. Results observed in the sixth study were similar to the pooled analysis. Only 10.2% (17/167) of non-responders who continued oral iron after day 14 achieved a Hb ≥ 2g/dL by Day 35, whereas 38.8% (57/147) who were switched to IV ferric carboxymaltose achieved a Hb > 2/dL by Day 35 (p =0.0001). Hb response after 14 days of oral iron was a strong predictor of overall response (sensitivity = 90.1%, specificity = 79.3%, positive predictive value = 92.9%, negative predictive value= 72.7%), surpassing other parameters evaluated in this study.Conclusion: In the absence of significant continuous blood loss, Hb measurements taken 14 days after initiation of oral iron therapy can reliably predict overall response in Hb to oral iron therapy. Accordingly, day 14 Hb may be a useful tool for clinicians in determining when to switch patients from oral to IV iron. DisclosuresKoch:Luitpold Pharmaceuticals: Employment.