The cost-effectiveness of treatment with erythropoietin compared to red blood cell transfusions for patients with chemotherapy induced anaemia: a Markov model.

BACKGROUND: Anaemia is a common complication of chemotherapy. As anaemia can lead to e.g. fatigue, depression, social isolation and chest pain it diminishes physical capacity and quality of life. It is generally accepted that symptomatic anaemia should be corrected. Treatment options include red blood cell transfusion (RBCT), erythropoietin (EPO) administration or a combination of both. OBJECTIVE: The objective of this study was to carry out a cost-effectiveness analysis of treatment with EPO (epoetin alfa), compared to treatment with RBCT for patients with chemotherapy-induced anaemia in Sweden from a health care perspective. METHOD: A model was developed for estimating incremental costs and QALY gains associated with EPO treatment compared to treatment with RBCTs, based on a model commissioned by the UK National Institute for Health and Clinical Excellence and adjusted to reflect Swedish treatment practice. Data regarding patient characteristics, response rates, and RBCT was derived from a Swedish observational study of EPO treatment in cancer patients with chemotherapy related anaemia. Swedish guidelines and unit costs were used throughout the study. A systematic review of EPO for treatment of anaemia associated with cancer was used to estimate QALY gains associated with changes in Hb-concentrations in our model. RESULTS: The model's results validate well to real world data from three major hospitals in Sweden. The cost per QALY gained from administration of EPO was estimated at EUR 24,700 in the base case analysis. Practicing an EPO treatment target Hb-level of 12 g/dl yields a cost per QALY about 40% lower than practicing a Hb-target level of 13 g/dl, which is in agreement with updated recommendations of using a 12 g/dl target. CONCLUSION: The estimated cost per QALY falls well within the range acceptable in Sweden when practicing a Hb-target level of 12 g/dl. The incremental cost of elevating Hb-levels above 13 g/dl is very high in relation to the incremental QALY gain achieved.

[Economic assessment of iron deficiency. Replacement of ferritin and serum iron by other parameters]. / Mise en évidence économique d'une déficience en fer. Relève de la ferritine et du fer sérique par d'autres paramètres.

Economic assessment of iron deficiency. Replacement of serum iron and ferritin by other parameters. Serum iron and ferritin are still widely used parameters for the assessment of iron deficiency, in spite of their poor diagnostic performance. Compared to the combined use of ferritin, zinc protoporphyrin and soluble transferrin receptors an increase of the percentage of hypochromic erythrocytes (PEH) was found to be highly sensitive and specific for iron deficiency. We suggest to use it in a two phase strategy. Normal PEH excludes iron deficiency. Increased PEH may be confirmed by zinc protoporphyrin and/or soluble transferrin receptors.

Assessment of cardiac index in anemic patients.

STUDY OBJECTIVES: During isovolemic hemodilution, healthy individuals maintain oxygen consumption VO2 by identical increases in cardiac index (CI) and oxygen extraction ratio (O(2)ER). In critically ill patients, the relationship between CI and O(2)ER may be different. Patients with an altered cardiac function may have a decreased CI/O(2)ER ratio, whereas patients with sepsis may have an increased CI/O(2)ER ratio. We hypothesized that the analysis of the CI-O(2)ER relationship could help us to assess the adequacy of cardiac function in critically ill patients with anemia. DESIGN: Prospective, observational study. SETTING: Thirty-one-bed medicosurgical ICU of a university hospital. PATIENTS: Sixty patients equipped with arterial and Swan-Ganz catheters presenting with anemia, which was defined as a hemoglobin level < or = 10 g/dL in the absence of active bleeding. Patients were classified into those with compromised cardiac function (group 1; n = 40), and those with normal cardiac function (group 2; n = 20). MEASUREMENTS AND RESULTS: In addition to the pertinent clinical data, initial hemodynamic measurements, including pulmonary artery occlusion pressure (PAOP), CI, and O(2)ER, were collected in all patients at the onset of anemia. As anticipated, group 1 patients (n = 40) had lower CIs, higher O(2)ER levels, and lower CI/O(2)ER ratios than group 2 patients. However, there was no significant difference in PAOP values between the groups. The CI/O(2)ER ratio was < 10 in 27 of 40 group 1 patients but only in 4 of 20 group 2 patients. Of these latter four patients, three were found to be hypovolemic, and one patient with sepsis had severe myocardial depression. There was no statistically significant difference in PAOP in group 2 patients with or without hypovolemia ([mean +/- SD] 12.3+/-2.1 mm Hg) vs 13.7+/-4.3 mm Hg; p = 0.21). In group 1, survivors had a higher CI and CI/O(2)ER ratio than nonsurvivors. In group 2, however, such a relationship did not reach statistical significance. CONCLUSIONS: The relationship between CI and O(2)ER level can help interpret the CI in anemic patients. In anemic patients with no cardiac history, a low CI/O(2)ER ratio (< 10) suggests hypovolemia even when CI is not depressed.

Prevalência de anemia ferropriva e marcadores de risco associados em crianças entre 12 e 18 meses de idade atendidas nos Ambulatórios do Instituto de Puericultura e Pediatria Martagäo Gesteira / Prevalence of iron deficiency anemia and risk indicators in children from 12 to 18 months attended at the outpatient clinic of Instituto de Puericultura e Pediatria Martagäo Gesteira

Objetivo: Estudar a prevalência de anemia ferropriva em crianças entre 12 a 18 meses nos ambulatórios do IPPMG e os marcadores de risco a ela associados, no intuito de avaliar e monitorizar o serviço. Métodos: Trata-se de um estudo descritivo de corte transversal. Foram incluídas 288 crianças atendidas no ambulatório do IPPMG, de janeiro a dezembro de 1993. A anemia foi diagnosticada através da dosagem de hemoglobina sérica. Os marcadores de risco estudados foram: realizaçäo de pré-natal, peso ao nascer, acompanhamento pediátrico, características sócio-econômicas, padräo de amamentaçäo, estado nutricional e prescriçäo de ferro. Os dados foram computados e analisados pelos programas EPI-INFO e EGRET...

Iron deficiency: assessment during pregnancy and its importance in pregnant adolescents.

The assessment of iron deficiency in pregnancy requires the accurate determination of indicators that have significant within-subject variability. For instance, serum ferritin concentrations may vary by as much as 25% from one day to the next. Added to this uncertainty about biological variability is the influence of plasma volume expansion on concentration-dependent indexes such as ferritin, plasma iron, and hemoglobin. Multiple measurements of iron status are suggested, and, if this is not possible, within-subject variability needs to be included in the confidence of assigning individuals to iron-status groups. An example of this former approach is shown for a group of pregnant adolescents with a very high prevalence of iron deficiency. Although the assessment of iron status in human populations is advanced compared with that of other nutrients, there is still a large uncertainty about absolute diagnosis during pregnancy.

PIP: Precise determination of indicators that have considerable within-subject variability is needed to assess iron deficiency in pregnant women. Within-subject day-to-day variation of serum ferritin levels may fluctuate as much as 25%. The uncertainty of biological variability is accompanied by the uncertainty of concentration-dependent indexes (e.g., ferritin, plasma iron, and hemoglobin) caused by plasma volume expansion. Physicians should take several measurements to determine iron status in pregnant women. If they cannot do this, they should incorporate confidence limits around measurements of women assigned to iron-sufficient or iron-deficient groups. In central Pennsylvania, health workers determined the iron status of 88 pregnant adolescents attending the prenatal clinic at Altoona Hospital or the Allegheny Family Physicians Group in Altoona to examine within-subject variability of iron status and the prevalence of iron deficiency in this group. At entry into the pilot study, about 70% of the pregnant teenagers had depleted iron stores. Even though the women were prescribed an iron supplement, depleted iron stores continued throughout pregnancy. Iron deficiency anemia was found in 7.4% at the end of the 1st trimester of pregnancy. Another 3.6% had anemia but not iron deficiency. At 2 weeks postpartum, 55% had iron deficiency anemia. About 20% had anemia with no signs of iron deficiency. When the researchers considered daily variability, the prevalence of depleted iron stores rose to 80% from 69%. All low birth weight infants (born to 8% of subjects) were born to mothers who were iron deficient at 11-16 weeks of pregnancy. There is considerable doubt about an absolute diagnosis of iron status during pregnancy.

Iron disorders can mimic anything, so always test for them.

Routinely measuring iron status is necessary because not only are about 6% of Americans in significant negative iron balance, but about 1% have iron overload. Serum ferritin is in equilibrium with body iron stores, and is the only blood test that measures them. Barring inflammation, each one ng (0.0179 pmol) ferritin/ml of serum indicates approximately 10 mg (0.179 mmol) of body iron stores. Very early Stage I positive balance is best recognized by measuring saturation of iron binding capacity. Conversely, serum ferritin best recognizes early (Stage I and II) negative balance. Deviations from normal are: 1. Both stages of iron depletion (i.e. low stores, no dysfunction). Negative iron balance Stage I is reduced iron absorption producing moderately depleted iron stores. Stage II is severely depleted stores, without dysfunction. These stages include over half of all cases of negative iron balance. Treated with iron, they never progress to dysfunction, i.e. to disease. 2. Both stages of iron deficiency. Deficiency is inadequate iron for normal function, i.e. dysfunction, disease. Negative balance Stage III is dysfunction without anemia; Stage IV is with anemia. 3. Positive iron balance: Stage I is a multi-year period without dysfunction. Supplements of iron and/or vitamin C promote progression to dysfunction (disease). Iron removal prevents progression. Stage II is iron overload disease, encompassing years of insidiously progressive damage to tissues and organs from iron overload. Iron removal arrests progression.

Clinical assessment of the knowledge base of an expert system for data analysis in laboratory medicine.

Despite the apparent demand for a consultation system, only a few expert systems have been developed for laboratory medicine. Some studies on the diagnostic precision of such systems have been reported, but the efficiency of their knowledge bases has not yet been investigated. An expert system, named BLOOD, for data analysis in a hematology laboratory, which is written in C-Prolog and runs on VAX-station, has already been reported to have excellent diagnostic reliability and ability to cope with the fuzziness involved in clinical diagnostic procedures. A quantitative examination of the knowledge base of BLOOD using real laboratory data from 58 patients diagnosed as having iron deficiency anemia clearly revealed the verbosity of the knowledge base, and proved that it was effective for obtaining a group of essential diagnostic rules.

The non-iron-deficiency-related difference in hemoglobin concentration distribution between blacks and whites and between men and women.

The relation of hemoglobin concentration to transferrin saturation had two distinct phases in the data of adult men and women (aged 18-44 years) collected in the first National Health and Nutrition Examination Survey (NHANES I): 1) a stable, linear phase of hemoglobin concentration in the range of normal transferrin saturation, and 2) a dramatic fall in hemoglobin concentration as the degree of transferrin saturation decreased below the linear range. This study confirmed that over the linear range of the hemoglobin concentration-transferrin saturation curve, where subjects were adequately iron-nourished, whites had systematically higher hemoglobin concentration values than blacks (0.61 g/dl); also, males had higher values than females (1.895 g/dl). The effects of race and sex on hemoglobin concentration were additive. The variance of the hemoglobin distribution in blacks was also greater than that in whites. Socioeconomic status and smoking status could not explain the above race and sex differences. The impact on the prevalence estimate of reducing the hemoglobin cut-off by 0.5 g/dl is substantial enough to justify a separate standard for blacks.

Assessment of iron availability using stable 54Fe.

This paper describes a method of quantitatively assaying the bioavailability of orally administered iron in order to promote haemoglobin synthesis in iron deficiency anaemia. The non-radioactive tracer substance 54Fe was employed. An experimental iron deficiency model was tested in 18 healthy male volunteers. The trial design made it possible to assess intestinal absorption and efficacy of iron substitution. The iron deficiency was experimentally induced by weekly phlebotomy. Two commercially available iron preparations with different rates of iron release were investigated at a dosage of 150 and 160 mg Fe2+ daily, respectively. In the first seven days of treatment, both preparations were administered in 54Fe-labelled form. Afterwards, iron substitution was given with the commercially available preparations. Measurements were made of erythrocyte utilization of 54Fe and plasma iron tolerance curves at the beginning of the periods in which the 54Fe-labelled product and the commercially available preparation were administered, and of haemoglobin and serum ferritin concentration curves over three months. The mean utilization of the iron administered was virtually identical for the two preparations (23 and 22%, respectively). Likewise, there was no difference with respect to the average daily increase in haemoglobin concentration in the blood (1.5 g 1-1). There was also no significant difference with respect to serum ferritin concentration curves. In contrast, the two preparations differed markedly with respect to the plasma iron tolerance curves. This suggests that evaluation of plasma iron tolerance curves alone is not suitable for comparative assessment of the therapeutic value of orally administered iron preparations.

Detection of two-component mixtures of lognormal distributions in grouped, doubly truncated data: analysis of red blood cell volume distributions.

We have examined the statistical requirements for the detection of mixtures of two lognormal distributions in doubly truncated data when the sample size is large. The expectation-maximization algorithm was used for parameter estimation. A bootstrap approach was used to test for a mixture of distributions using the likelihood ratio statistic. Analysis of computer simulated mixtures showed that as the ratio of the difference between the means to the minimum standard deviation increases, the power for detection also increases and the accuracy of parameter estimates improves. These procedures were used to examine the distribution of red blood cell volume in blood samples. Each distribution was doubly truncated to eliminate artifactual frequency counts and tested for best fit to a single lognormal distribution or a mixture of two lognormal distributions. A single population was found in samples obtained from 60 healthy individuals. Two subpopulations of cells were detected in 25 of 27 mixtures of blood prepared in vitro. Analyses of mixtures of blood from 40 patients treated for iron-deficiency anemia showed that subpopulations could be detected in all by 6 weeks after onset of treatment. To determine if two-component mixtures could be detected, distributions were examined from untransfused patients with refractory anemia. In two patients with inherited sideroblastic anemia a mixture of microcytic and normocytic cells was found, while in the third patient a single population of microcytic cells was identified. In two family members previously identified as carriers of inherited sideroblastic anemia, mixtures of microcytic and normocytic subpopulations were found. Twenty-five patients with acquired myelodysplastic anemia were examined. A good fit to a mixture of subpopulations containing abnormal microcytic or macrocytic cells was found in two. We have demonstrated that with large sample sizes, mixtures of distributions can be detected even when distributions appear to be unimodal. These statistical techniques provide a means to characterize and quantify alterations in erythrocyte subpopulations in anemia but could also be applied to any set of grouped, doubly truncated data to test for the presence of a mixture of two lognormal distributions.

[The value of erythrocytic protoporphyrin measurement for screening blood donors for iron deficiency: a decision analysis]. / Intérêt de la mesure de la protoporphyrine érythrocytaire pour le dépistage de la carence en fer chez le donneur de sang: analyse de la décision.

Blood donors are considered as a group with increased risk of iron deficiency. Therefore it seems particularly useful to have a simple screening test at one's disposal in blood centers to detect easily early iron deficiency. Erythrocyte protoporphyrin assay on an hematofluorometer is very easy and of a low cost. So we studied its diagnostic value on a sample of 285 blood donors (131 men and 154 women). Prevalence of iron deficiency, defined by the coexistence of, at least, two abnormal indicators (serum ferritin, transferrin saturation, erythrocyte protoporphyrin, mean corpuscular volume), was 5.6% in this sample; sensitivity of erythrocyte protoporphyrin used alone was 75% and its specificity was 91.5%. We used a decision analysis to evaluate the opportunity of screening with this test, accompanied where indicated by iron supplements. The results, though preliminary, suggest that erythrocyte protoporphyrin measurement could be of interest in screening blood donors for iron deficiency.

[Evaluation of a clinical sign in predicting iron deficiency in women: the blue sclera]. / Valoración de un signo clínico en la predicción del déficit de hierro en la mujer: las escleróticas azules.

The purpose of this study was to calculate the predictive value (PV) of blue sclera (BS) in iron deficiency in women. The presence of this clinical sign was evaluated in 498 female patients at an urban primary care centre. Three observers independently evaluated the existence of BS on a scale of 0 to 3 in all female patients visited over a period of 35 weeks. Twenty eight cases of BS were detected over this period, of which 16 had ferropenia and 21 had anemia or iron deficiency. The positive predictive value of the clinical sign was 57.14%, 95% within the confidence interval of 52.77-61.51. The presence of BS was not affected by age or eye color. BS appears to be a good indicator of iron deficiency in our medium and, if confirmed by other studies, should be considered in the every-day clinical examination.

Assessment of iron status of Filipino pregnant women.

Plasma ferritin (PF), erythrocyte protoporphyrin (EP) and hemoglobin (Hb) were used to assess the iron status of 158 Filipino pregnant women included as subjects in the third national nutrition survey conducted by the Food and Nutrition Research Institute in 1987. The prevalence of iron depletion was 39.9% based on PF (less than 12 ng/ml). Iron deficient erythropoiesis was present in 36.1% based on EP of greater than 28 micrograms/dl whole blood and 40.5% based on EP/Hb ratio of greater than 2.4. When the criterion of iron deficiency was that both PF and EP were abnormal, the prevalence of deficiency was lower and only 16.4%. Iron deficiency anemia was present in 14.6% based on Hb less than 11 g/dl in addition to abnormal PF and EP. Significantly lower mean values for PF were obtained in women on the 2nd and 3rd trimesters of pregnancy indicating decreasing iron stores and the need for iron therapy to prevent anemia during those periods. The iron status of 38 women who reported taking iron supplements was not significantly different from those who did not take supplements.

Noninvasive assessment of tissue iron stores.

Multivariate regression methods were used to create two equations for calculation of the "iron index," a predictor of bone marrow iron scores. With the use of the most efficient cut-off point, approximately 90% of 210 patients could be diagnosed correctly. Selection of a criterion that minimizes false negatives (missed iron deficiency) would increase the number of unnecessary bone marrow aspirations, but, even then, more than a third of such tests could be avoided. Rapid turnaround time would be desirable for all measurements used to calculate the iron index, although it is recognized that for most hospitalized patients the length of hospital stay is determined by severity of an underlying disease, not the presence of anemia.

Carbonyl iron therapy for iron deficiency anemia.

To determine if elemental carbonyl iron powder is safe and effective therapy for iron deficiency anemia, 20 nonanemic and 32 anemic volunteers were studied. Single doses of 1,000 to 10,000 mg of carbonyl iron (15 to 150 times the 65 mg of iron in the usual dose of ferrous sulfate) were tolerated by nonanemic volunteers with no evidence of toxicity and only minor gastrointestinal side effects. Anemic volunteers (menstruating women who had previously donated blood) were treated with several regimens providing 1,000 to 3,000 mg of carbonyl iron daily in one to three doses for 8 to 28 days. After 12 weeks anemia was corrected in 29 of 32 patients, and serum ferritin was greater than 12 micrograms/L in 14. Hemoglobin regeneration proceeded at a rate similar to that described for therapy with oral iron salts and parenteral iron dextran. There was no evidence of hematologic, hepatic, or renal toxicity, but mild gastrointestinal side effects occurred in a majority of anemic volunteers. Carbonyl iron is an effective, inexpensive treatment for iron deficiency anemia, is accompanied by tolerable side effects and may have an advantage over therapy with iron salts by substantially reducing or eliminating the risk of iron poisoning in children.

Impact of the WIC program on the iron status of infants.

The WIC Program (Special Supplemental Food Program for Women, Infants and Children) was initiated in the early 1970s to improve the nutritional status of pregnant women, lactating women, and children from birth to 5 years of age who were at risk for nutritionally related health problems. Better hematologic status of a group of preschool-aged infants who were enrolled in the WIC Program from birth, as compared with another group of similar age and socioeconomic status from the pre-WIC Program era, suggests that participation in the WIC Program will help limit the development of iron depletion or iron deficiency anemia in young children, an important consideration in view of the deleterious hematologic and nonhematologic effects that have been attributed to those conditions.

Serum iron and total iron-binding capacity compared with serum ferritin in assessment of iron deficiency.

Ferritin values for 250 selected sera were compared with values for iron, total iron-binding capacity (TIBC), and transferrin saturation, to assess the potential of the ferritin assay for the detection of latent iron deficiency. The specimens were grouped (50 in each group) according to their values for iron and TIBC. In Group 1 (low iron, high TIBC) the saturation and ferritin values both indicated iron deficiency in all but one. In the 100 specimens of Groups 2 (normal iron, high TIBC) and 4 (normal iron, high normal TIBC), the saturation values revealed 16 iron-deficient cases, the ferritin test 55. For Groups 3 (low iron, normal TIBC) and 5 (low iron, low TIBC), the ferritin test revealed fewer cases of iron deficiency than did the saturation values (37 cases vs 51 cases, in the 100 specimens). Evidently the ferritin test detects iron deficiency in many cases for whom the serum iron and TIBC tests are not positively indicative. The correlation of serum ferritin with iron, TIBC, and transferrin saturation in the five groups was good only in the case of specimens for which the TIBC was normal; if it was abnormal the correlation was very poor.

Serum ferritin estimation in the assessment of iron stores in severe iron deficiency anaemia in pregnancy and the response to treatment.

Serum ferritin estimation was used to determine the iron stores in 55 patients with severe iron deficiency anaemia in pregnancy. The response to oral or intravenous iron therapy was monitored in 18 of these patients. The results in all cases indicated deficient iron stores. Replenishment of iron stores was significantly greater in those patients treated with parenteral iron. This may be the treatment of choice for severe iron deficiency anaemia during pregnancy.