Anemia: Fast Facts (Peer reviewed publications)
Darbepoetin appears cost-effective in treating anemia in hepatitis combination therapy
Erythropoietic growth factor, specifically darbepoetin, is cost effective in treating anemia often associated with the combination of ribavirin (RBV) and interferon therapy used to treat Hepatitis C viral genotypes 1, 2, and 3 (HCV), a study found. The reference case was a 45-year-old Caucasian male with HCV.
Reduction of RBV dose has been the standard treatment when anemia develops. Decreasing RBV dose has been demonstrated to significantly lower sustained viral response rates (SVR). Darbepoetin alfa or epoetin alfa is being used more commonly off-label because of studies showing their effectiveness in keeping hemoglobin level at pre-treatment levels and foregoing the need to reduce RBV doses.
Hemolytic anemia is associated with ribavirin. Myelosuppression is an adverse effect of interferon. Anemia of chronic inflammation is another hematologic factor in HCV.
The SVR was 55.6% when hematologic growth factors were used compared to 46.1% for patients undergoing RBV dose reduction in genotype 1 and 83.3% versus 78.6% for genotypes 2 and 3. This resulted in an overall cost of $34,793 per additional quality-adjusted life-year (QALY) for darbepoetin and $60,600/QALY for epoetin. For genotypes 2 and 3, the costs were $33,832/QALY versus $64,311/QALY.
Darbepoetin was cost effective in this model. Recommendations included further studies be done to find more cost-effective therapeutic guidelines by adjusting RBV dose reduction changes, darbepoetin dosing amounts, timing or end of treatment limits, review of sustained viral response rates, patient profiling for quality of life issues, and patient's age at which HCV therapy is begun.
For additional information on this research, please reference the source article:
Del Rio R, Post A, Singer M. Cost-Effectiveness of Hematologic Growth Factors for Anemia Occurring During Hepatitis C Combination Therapy. Hepatology.2006;44(6):1598-1606
Anemia independent factor on in-hospital mortality of patients with heart failure
Several studies have shown anemia to be an independent factor in mortality of patients with heart failure (HF). The design of those studies has had a limited prognostic role in the evaluation of a large patient population with HF who are having worsening symptoms. In the U.S, this constitutes 1 million patients every year.
In this prospective, multivariate analysis study, 303 patients with decompensated HF, consecutively admitted to the ICU of a tertiary care hospital, were evaluated. Anemia was found to be an independent factor for mortality regardless of whether left ventricular ejection fraction (LVEF) was preserved or not. Preserved LVEF was defined as an ejection fraction ≥45% on echocardiography. One hundred and three (34.3% of the patients) had preserved LVEFs.
Anemia was a frequent finding in patients with severe decompensated HF (47.5%) and even more prevalent in those with preserved LVEF than in patients with systolic dysfunction (58.3% versus 42.6%, P=.01). In hospital mortality was 17.3% (52 patients). There was no difference in in-hospital mortality between the preserved and systolic dysfunction groups (18.4% versus 16.8%, P=.71). Anemia on admission was significantly associated with a higher risk for death during hospitalization (24.3% with versus 10.7% without anemia. Relative risk (RR) 2.27, 95% CI 1.33 to 3.88). A positive association between anemia and mortality occurred in the group with systolic dysfunction (RR 2.7) and the group with preserved LVEF (RR 1.6). After adjustment for confounding factors anemia remained independently associated with in-hospital mortality (odds ration 2.7, 95% CI 1.43 to 5.04. P=.002).
For additional information on this research, please reference the source article:
Latado AA, Passos LC, Darzé ES, Lopes AA. Comparison of the Effect of Anemia on In-Hospital Mortality in Patients with Versus Without Preserved Left Ventricular Ejection Fraction. American Journal of Cardiology. 2006;98:1631-1634.
Darbepoetin pharmacokinetics studied in pediatric chemotherapy-induced anemia
Darbepoetin alfa is effective in treating adult chemotherapy-induced anemia (CIA), but few studies show effectiveness in children. Approximately 80% of pediatric cancer patients undergoing chemotherapy develop CIA. Transfusions have been used to quickly correct severe anemia. Mild anemia may go untreated. Therapies that correct anemia without transfusion would benefit pediatric cancer patients.
Epoetin alfa has been shown to raise hemoglobin (Hb) levels in pediatric patients when given 3-5 times a week. Darbepoetin has the potential to reduce the frequency of dosing, but its pharmacokinetics have not been studied.
Fifteen pediatric patients with CIA were studied for 8 weeks during planned chemotherapy. Darbepoetin alfa was administered at 2.25 mcg/kg beginning the first day of treatment and then weekly beginning 2 weeks after the 1st dose. Doses were withheld when Hb threshold reached (> 13 g/dL males and females 0-11 yrs. old and > 15 g/dL males 12 and older, or >13 females of the same age) and if toxicity levels were reached.
Darbepoetin was slowly absorbed after a single subcutaneous administration. Mean (SD) peak concentration (Cmax) was 10.5 (3) ng/ml and median time to peak concentrations (Tmax) was 71.4 hrs. Darbepoetin also exhibited a long terminal half-life (mean (SD) of 49.4 [32] hrs).
The study showed the absorption of darbepoetin was similar to that of adults, but the terminal half-life was much shorter ( 49.4 versus over 70 hours for adults). The terminal half-life in these cancer patients was similar to that previously reported studies of pediatric patients with chronic kidney disease (42.8 hrs.), although the CKD patients received a lower per kilogram dose of darbepoetin alfa.
The proportion of pediatric cancer patients receiving transfusions was 77% (95% CI 52-100). Only 29% had a Hb response and none had absolute iron deficiency, suggesting that darbepoetin can increase Hb levels in this population. Highly myelosuppressive chemotherapy regimens were used in these patients who may account for the high percentage of transfusions and the low percentage of patient Hb response. The safety profile was consistent with expectations. Fever was the most common adverse event (50% fever and 44% fever with neutropenia). Darbepoetin alfa was well tolerated and was not associated with any safety concerns in this treatment setting.
For additional information on this research, please reference the source article:
Blumer J, Berg S, Adamson P, Loew T, Rossi G, Hastings C. Pharmacokinetic Evaluation of Darbepoetin Alfa for the Treatment of Pediatric Patients with Chemotherapy-Induced Anemia. Pediatric Blood and Cancer. November 21 2006. [Epub ahead of print]
Correction of anemia does not reduce risk of cardiovascular events in CKD (CREATE)
A total of 603 patients were evaluated in 94 centers world-wide in a 3 year, randomly-assigned, 1:1, open-abel, parallel-group study to determine whether correction of hemoglobin (Hb) levels in patients with anemia and stage 3 or 4 chronic kidney disease had improved cardiovascular outcomes; 476 patients completed the study.
Subcutaneous epoetin beta was administered at a starting dose of 2000 IU weekly in group 1. The dosing was adjusted to maintain target Hb at 13.0-15.0 g/dL. Epoetin was given to group 2 only if Hb fell below 10.5 g/dL.
The primary end point was the time to the first cardiovascular event. At the end of the study 105 patients had their first cardiovascular event. There was no significant difference in this outcome (58 in group 1, 47 in group 2. Hazard ratio for Group 2 - 0.78. 95% CI 0.53 to 1.14. Adjusted P=0.20). There was no statistical difference between groups in frequency or incidence of death from any cause (31 versus 21. Hazard ratio for Group 2 0.66. 95% CI .038 to 1.15). It is important to note NAAC experts felt it important to report the inverse of the hazard ratio, which is 1.28 95% CI .88-1.89 for the CV endpoint and 1.52, 95% CI 0.87-2.6 for death, in order to ensure the reader does not misinterpret these results to suggest a benefit with the higher Hb group.
Lack of a beneficial effect of correction of anemia on cardiovascular events was consistent and independent of whether patients had residual kidney function or required dialysis. Death from any cause favored (but not significantly) the group with the lower Hb target range. This is consistent with other studies and confirms guidelines recommending partial correction of anemia and not routine normalization.
For additional information on this research, please reference the source article:
Drüeke TB, Locatelli F, Clyne N, Eckart, K, MacDougall I, Tsakiris D, Burger H, Scherhag A. Normalization of Hemoglobin Levels in Patients with Chronic Kidney Disease and Anemia. The New England Journal of Medicine. 2006;355:2071-84.
Correction of anemia to higher Hb levels increases adverse outcome risk in CKD (CHOIR)
Use of recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with chronic kidney disease (CKD). An optimal level of hemoglobin (Hb) has not been defined.
In a study of 1432 patients with CKD, 715 were randomly assigned to receive epoetin alfa in a dosing regimen to achieve 13.5 g/dL while 717 were assigned to reach a dose target of 11.3 g/dL. The median study time was 16 months. The primary end point was a composite of death, myocardial infarction (MI), hospitalization for congestive heart failure (CHF) and stroke.
Out of a total of 222 events, 122 events occurred in the high-Hb group compared to 97 in the low-Hb group (hazard ratio 1.34; 95%CI 1.03-1.74; P=0.03). Hospitalization for CHF accounted for 45.5% of the events with 65 deaths (29.3%), 25 MIs (11.3%) and 23 strokes (10.4%) completing the adverse outcome end points.
Quality of life issues were also measured in both groups using the Linear Analogue Self-Assessment (LASA), the Kidney Disease Questionnaire (KDQ), and the Medical Outcome Study 36-item Short-Form Health Survey (SF-36). For each test, higher scores indicate better function or health.
The score on all 3 tests showed similar levels in improvement over baseline. The one exception was a significantly higher emotional score in the low-Hb group from the SF-36 test (score 57.2 ± 43.6 in the high-Hb. Change in baseline 0.8 ± 48.3 versus 57.4 ± 43.3 in the low-Hb group. Change in baseline 5.9 ± 48.1).
A recommendation was made to utilize a target level of Hb of 11.0 to 12.0 g/dL rather than an 11.0 to 13.0 g/dL target to correct anemia in patients with CKD. There was no significant quality of life benefit and there was a higher adverse event risk in using the higher target. Further, a cost benefit of using less epoetin alfa should be considered. More studies will be required to explore the role of the level of Hb and dose of epoetin alfa as well as the mechanism of the poorer outcome of a high target Hb level.
For additional information on this research, please reference the source article:
Singh A, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D: CHOIR Investigators. Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease. The New England Journal of Medicine 2006;355:2085-2098.
Anemia associated with decline in GFR in adolescents with chronic kidney disease
In a 3 year, longitudinal, prospective cohort investigation of 108 adolescents enrolled in the Functional Outcomes in Adolescent CKD study, 23 patients completed evaluation for rates of kidney function decline and identifiable risk factors for CKD progression which could be modified.
The outcome of interest was the change in glomerular filtration rate (GFR) per year calculated by taking the difference between and adolescent's estimated GFR at successive study visits and divide it by the difference in calendar time between 2 successive visits. Sixty-one percent (14) of the patients were anemic (hematocrit below 36%).
Anemia was associated with an accelerated decline of 7.8 ml/min/1.73 m2 (0.13 ml/s/1.73 m2) (95% CI, 3.3 to 12 [0.055 to 0.20]), along with the diagnosis of hypoalbuminemia. The overall annualized decline was 5.6 ml/min/1.73 m2 (0.093 ml/s/1.73 m2) per year of study follow-up (95% CI, 1.9 to 9.3 [0.032 to 0.16], but only 1 ml/min/1.73 m2 if no anemia (From Table 2).
Decreased oxygen delivery to renal tubules stimulating an extra-cellular matrix production and release of pro-fibrotic cytokinines is the proposed mechanism for accelerated kidney disease progression.
Anemia, hypoalbuminemia, male gender and older age were identified as being independently associated factors of faster decline in GFR in adolescents. Future trials are recommended to verify these observations in younger children. Development of future clinical guidelines that emphasize the treatment of anemia and proteinuria to slow CKD progression in children can then be established.
For additional information on this research, please reference the source article:
Furth S, Cole S, Fadrowski J, Gerson A, Pierce C, Chandra M, Weiss R, Kaskel F. The association of anemia and hypoalbuminemia with accelerated decline in GFR among adolescents with chronic kidney disease. Pediatric Nephrology. November 2006. [Epub ahead of print]
Challenge to RBC transfusion in hemodynamically stable critically ill patients
Until the 1980's red blood cell (RBC) transfusions were considered a safe and effective means of improving oxygen delivery to tissues. From 1942, the general rule followed by physicians was to transfuse when the hemoglobin (Hb) dropped below 10 g/dL and a hematocrit (Hct) of 30%. More recently, guidelines suggest transfusing only for defined physiologic needs.
Almost 95% of ICU patients experience a drop in Hb by day 3. Fifty percent of all patients admitted to the ICU are transfused at least 1 unit RBCs; 85% are transfused if the stay more than 1 week. On average, critically ill patients received 5 RBC units per admission to ICU.
Common causes of anemia in the critically ill without gastrointestinal bleeding include phlebotomy in the ICU setting and the blunted erythropoietin (EPO) response by inhibition of EPO gene by inflammatory inhibitors (anemia of chronic inflammation). Phlebotomy losses in the critically ill of 60-70 ml/day have been reported over the last 2 decades. One large observational study documented a daily average phlebotomy volume of 41 ml which had significant deleterious effect on organ dysfunction.
Trials have shown that while critically ill patients transfused to a Hct ≥30% may feel better, they may be harmed by the increase. In a randomized controlled trial by the Canadian Critical Care Trials Group (TRICC) transfusions given to obtain Hb levels from 10-12 g/dL (transfusion trigger =10 g/dL trigger) were compared to a restrictive strategy of 7-9 g/dL (transfusion trigger =7.0 g/dL). There was a trend toward better outcome measures such as the 30-day mortality rate in the patients in the restrictive category. Other studies, some using a slightly higher trigger, have indicated the tolerance for lower Hb levels and a decrease in possible harm.
Epoetin replacement has been shown to reduce RBC transfusions in several studies. In one randomized placebo-controlled trial of 160 patients, recombinant human erythropoietin (rHuEPO) administration resulted in a 50% reduction of transfusions. A larger study showed a 10% reduction. In another study, 86 patients admitted to a long-term care facility received 4,000 IU rHuEPO for up to 12 weeks. The total reduction in RBCs transfused was 73 units versus 113 units in the placebo group. Sixty-one percent of the placebo group versus 31% of rHuEPO group were likely to be transfused (P=.006. odds ratio 0.28, 95% CI 0.12-0.69).
No data presently support the use of routine RBC transfusion to treat anemia in hemodynamically stable, critically ill patients without evidence of acute bleeding. Hb levels of 7-9 g/dL are well tolerated making a transfusion threshold of 7 g/dL appropriate. Controversy still exists for some critically ill patients with ischemic heart disease and resuscitation of the patient in septic shock. A threshold of 8-10 g/dL is reasonable for acute coronary syndromes and septic shock until further evidence becomes available. Clinical recommendations suggest administering 1 unit at a time and re-measuring Hb concentrations after each RBC unit.
For additional information on these guidelines, please reference the source article:
Corwin HL. Anemia and Red Blood Cell Transfusion in the Critically Ill. Seminars in Dialysis. November-December 2006;19(6):513-516
Intravenous iron correction of anemia in CKD increases oxidative stress complications
In a small study of nine, non-dialysis patients with chronic kidney disease (CKD), correction of anemia by intravenous iron supplementation to improve ferrous stores can cause oxidative stress, a component of tissue and organ damage at the cellular level.
Oxidative stress can be considered an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms. Atherosclerosis is associated with an exaggerated production of ROS. A fraction of metabolized oxygen from mitochondria can leak through the electron transport chain and form oxygen intermediates and radicals that may be harmful. Ferric iron, for instance, when reduced to the ferrous form via the Fenton reaction can produce the hydroxyl radical, one of the most potent ROS.
Measuring the antioxidant defense enzyme ratio between glutathione (GSH) and its oxidized, disulfide form GSSG, the study demonstrated the potential for damage by NADPH oxidase, a ROS important in damaging endothelial and phagocytic cells. Using this ratio also showed how correction of the oxidative stress occurs with the addition of subcutaneous darbepoetin alfa.
Administration of intravenous iron elevated malondialdehyde levels, an index of lipid peroxidation. The erythrocyte GSH/GSSG ratio decreased because of a decrease in GSH rather than a change in GSSG. Subcutaneous treatment with darbepoetin alfa returned malondialdehyde levels to those comparable to before iron supplementation and markedly increased the GSH/GSSG ratio.
This study supports the clinical benefits of anemia correction with erythropoiesis-stimulating agents in patients who have CKD and receive intravenous iron supplementation that can cause oxidative stress on vascular and other organ tissues.
For additional information on this research, please reference the source article:
Laher V, Goicoechea M, de Vinuesa S, Oubiña P, Cachofeiro V, Gómez-Campderá F, Amann R, Luño José. Oxidative Stress in Uremia: The Role of Anemia Correction. Journal of the American Society of Nephrology. 2006;17:S174-S177
Anemia is risk factor in patients with ileal pouch-anal anastomoses
Anemia is frequently observed in patients who have ileal pouch-anal anastomoses (IPAA). Restorative proctocolectomy with IPAA is a surgical procedure often used to treat medically refractory ulcerative colitis and most patients with familial adenomatous polyposis who require surgery. The procedure improves the quality of life of the patient but complications can occur. Some of these can be surgically related, inflammatory, such as Crohn's disease or pouchitis, functional disorders, cancer, and systemic or metabolic disorders such as persistent anemia. This study sought to define an etiology of the anemia.
A sample of 195 patients were taken from a prospective study of patients who had IPAA between 1998 and 2005 found a 19% prevalence rate of anemia in males and 15% in females. Patients with ulcerative colitis had a 17% prevalence rate and those with familial adenomatous polyposis had a rate of 26% (P=0.27). Sixty-seven patients with anemia were compared with a second group of 128 patients with IPAA and no anemia. Anemia was defined as a hemoglobin (Hb) of < 13.5 g/dL in males and <12 g/dL in females. Eighty-two percent of the patients were determined to have mild anemia (≥ 10 g/dL).
At least one obvious etiologic factor could be found in the majority of patients in the anemia group. In 16 patients, the etiology was unclear (24%). Univariate and multivariate analysis was performed on demographic and clinical parameters.
In the univariate model malignancy or desmoids tumors, use of myelosuppressive medications and renal insufficiency were significantly associated with anemia. Patients on myelosuppressive drugs were 2.84 times more likely to have anemia (95% CI level 1.17-6.88).
Multivariate analysis identified malignancy or desmoids tumors at occurring 19.6 times in the anemic group (95% CI 1.3-209.36. P=.014). Because only 1 patient without anemia had a malignancy or desmoids tumor, this estimate of tumor association with anemia is highly imprecise. The type of pouch at the anastamoses indicated that those patients with an S-type pouch were 5 times more likely to have anemia than those with a J-type (95% CI 1.04-23.81. P=.044). Evidence suggested that renal insufficiency is associated with anemia in this group but adjustment in the multivariate was confounded because none of the patients in the control group had renal insufficiency.
This study did not investigate any adverse consequences of anemia or the management options used to treat it. Since more than 1 in 6 patients develops anemia with IPAA, regular laboratory evaluation for anemia should be part of the follow up regimen.
For additional information on this research, please reference the source article:
Oikonomou I, Fazio V, Remzi F, Lopez R, Lashner B, Shen B. Risk Factors for Anemia in Patients with Ileal Pouch-Anal Anastomosis. Diseases of the Colon and Rectum. 2006;50:1-6
Anemia risk tool developed for chemotherapy treated nonsmall cell lung cancer
Nonsmall cell lung cancer (NSCLC) compromises about 80% of lung cancer, the most common of lethal malignancies worldwide. About 40% of these patients have "distant" disease and are classified as advanced along with the patients with metastases. These patients require some form of palliation to diminish symptoms and modestly extend survival (about 6 months on supportive care alone). These benefits are traded off against toxicity risks, inconvenience, and costs.
Some toxicities are preemptively managed prophylactically. Anemia is not usually managed until advanced. This study was done to develop a prediction tool for clinicians to evaluate which patients would be at risk for developing anemia. Prophylactically treating patients with erythropoiesis-stimulating agents who do not need treatment (Hb <120 g/l) can increase risk and be very expensive.
Data was collected from 536 patients undergoing prospective study as part of the European Cancer Anemia Survey. A second sample of 76 patients treated between 2004 and 2005 at the Toronto Sunnybrook Regional Cancer Center in Toronto, Canada.
Using univariate and multivariate techniques, 8 variables were found to be of use as predictors (P≤.05): before chemotherapy cycle Hb, age, body surface area (BSA), World Health Organization (WHO) patient performance status, disease status, and the use of platinum-based chemotherapy or gemcitabine. There was no significant interaction between platinum-based chemotherapy and gemcitabine. The most important predictor was pre-treatment cycle Hb where 1 g/l drop was associated with a relative increase in risk (odds ratio 1.09. 95% CI 1.07-1.11. P<.001). This factor translated into an impact on anemia risk of 8% increase per 1 g/l drop. Other risk factors associated with increased risk in the multivariate model were age >68 (1.5 times), body surface area <1.97 (5.6 times), platinum-based (2.6 times) or gemcitabine treatment (1.7 times), lower physical function, and recurrent/persistent lung cancer.
The current anemia model and other risk models are available for clinicians to enter in relevant risk factor information for a particular patient and then receive a model-calculated probability of an event occurring in "real time." The website is http://www.PredictPatientEvents.com. The anemia risk tool should not be applied to patients who are already receiving recombinant erythropoietin therapy because reliability was not established. Response to epoetin was beyond the scope of this study.
For additional information on this research, please reference the source article:
Vincent M, Dranitsaris G, Verma S, Lau C, Gascon P, Van Belle S, Ludwig H. The development and validation of a prediction tool for chemotherapy-induced anemia in patients with advanced nonsmall cell lung cancer receiving palliative therapy. Supportive Care I Cancer. November 21, 2006; [Epub ahead of print]
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