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Current Medical Research and Opinion Dec 2006The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in... (Review)
Review
OBJECTIVE
The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in chronic kidney disease (CKD) and to identify determinants of the variation in epoetin alfa:darbepoetin alfa dose ratios across studies.
METHODS
A systematic review of the literature for comparative switch and non-switch studies of epoetin alfa and darbepoetin alfa treatments in CKD for the period 2000-2005 was performed. Two reviewers independently assessed the quality of the information. Data on the study design and outcomes were collected for each selected study. The dose ratio from epoetin alfa to darbepoetin alfa was calculated for each study, and the results were reported stratified by study characteristics. To control for differences in study design and characteristics that could explain the variability in the relative dosages of the two agents across studies, multivariate regression analysis was conducted. Based on these results, a dose conversion ratio for Canada was estimated.
RESULTS
A total of 21 studies involving 16 378 patients exposed to epoetin alfa or darbepoetin alfa in CKD were identified. Univariate analysis of the dose ratios indicated a mean dose ratio of 217:1 (IU of epoetin alfa:mug of darbepoetin alfa). Results from the multivariate analysis demonstrated that the study design (i.e., switch study versus straight comparison studies) and geographical coverage (i.e., United States) affected the results. Based on the multivariate analysis, the dose conversion ratio between epoetin alfa and darbepoetin alfa for Canada was 169:1.
CONCLUSIONS
Despite limitations associated with switching studies and the limited total number of studies available, this systematic review based on aggregated results provides further evidence to the clinical community that the dose conversion ratio for epoetin alfa:darbepoetin alfa in CKD patients in Canada is approximately 169:1. At that ratio, treatment with epoetin alfa is 11-18% cheaper than treatment with darbepoetin alfa in Canada.
Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases; Multivariate Analysis; Recombinant Proteins
PubMed: 17257447
DOI: 10.1185/030079906X154024 -
European Journal of Cancer (Oxford,... Jan 2007Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature... (Review)
Review
Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks. We do not recommend the use of higher than standard initial doses of erythropoietic proteins with the aim of producing higher haematological responses, due to the limited body of evidence available. There is Level I evidence that, within reasonable limits of body weight, fixed doses of erythropoietic proteins can be used to treat patients with chemotherapy-induced anaemia. This analysis confirms that there are no baseline predictive factors of response to erythropoietic proteins that can be routinely used in clinical practice if functional iron deficiency or vitamin deficiency is ruled out; a low serum erythropoietin (EPO) level (only in haematological malignancies) appears to be the only predictive factor to be verified in Level I studies. Further studies are needed to investigate the value of hepcidin, c-reactive protein, and other measures as predictive factors. In these updated guidelines, we explored a new question of whether oral or intravenous iron supplementation increases the response rate to erythropoietic proteins. We found no evidence of increased response with the addition of oral iron supplementation, but there is Level II evidence of improved response to erythropoietic proteins with the addition of intravenous iron. However, the doses and schedules for intravenous iron supplementation are not yet well defined, and further studies in this area are warranted. The two major goals of erythropoietic protein therapy are prevention or elimination of transfusions and improvement of QoL. The total body of evidence shows that red blood cell (RBC) transfusion requirements are reduced following treatment with erythropoietic proteins. This analysis also confirms that QoL is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease following erythropoietic protein therapy, with more robust evidence now available that QoL was improved in studies investigating early intervention in cases of chemotherapy- or radiotherapy-induced anaemia. There is only indirect evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase. None of the studies addressed the question in a prospective, randomised fashion, and so the Taskforce does not recommend dose escalation as a general approach in all patients who are not responding. There is still insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. Our analysis of survival endpoints in studies involving patients receiving radio(chemo)therapy found that most studies were inconclusive, with no clear link between the use of erythropoietic proteins and survival. Likewise, we found no clear link between erythropoietic therapy and other endpoints such as local tumour control, time to progression, and progression-free survival. There is no evidence that pure red cell aplasia occurs in cancer patients following treatment with erythropoietic proteins, and the fear of this condition developing should not lead to erythropoietic proteins being withheld in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Additional trials are warranted, especially to define the optimal doses and schedules of intravenous iron supplementation during erythropoietic therapy. While our review did not address cost benefit evaluations in detail, the consensus is that studies taking into account all real determinants of cost and benefit need to be performed prospectively.
Topics: Anemia; Antineoplastic Agents; Bone Marrow Transplantation; Chronic Disease; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Iron; Neoplasms; Practice Guidelines as Topic; Radiotherapy; Thromboembolism
PubMed: 17182241
DOI: 10.1016/j.ejca.2006.10.014 -
The Cochrane Database of Systematic... Oct 2006Anaemia affects 60% to 80% of patients with chronic kidney disease (CKD) reduces quality of life and is a risk factor for early death. Treatment options are blood... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Anaemia affects 60% to 80% of patients with chronic kidney disease (CKD) reduces quality of life and is a risk factor for early death. Treatment options are blood transfusion, erythropoietin (EPO) and darbepoetin alfa. Recently higher haemoglobin (Hb) and haematocrit (HCT) targets have been widely advocated because of positive associations with improved survival and quality of life from observational studies.
OBJECTIVES
To assess the benefits and harms of different Hb or HCT targets in CKD patients receiving any treatment for anaemia.
SEARCH STRATEGY
We searched The Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library) MEDLINE (from 1966), EMBASE (from 1980) and reference lists of retrieved articles. Date of most recent search: April 2006
SELECTION CRITERIA
Randomised controlled trials (RCTs) and quasi-RCTs comparing different Hb/HCT targets in patients with the anaemia of CKD.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and results expressed as relative risks (RR) for dichotomous outcomes and weighted mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI).
MAIN RESULTS
Twenty two trials (3707 patients) were included. Hb > or = 133 g/L was not associated with a reduction in the risk of all-cause mortality compared with 120 g/L in dialysis and pre-dialysis patients. In pre-dialysis patients, there was a significantly lower end of treatment creatinine clearance with Hb < 120 g/L compared to > 130 g/L (MD -4.17, 95% CI -6.33 to -2.02) but no significant difference in the risk of end-stage kidney disease (ESKD) (RR 1.05, 95% CI 0.50 to 2.22). Lower Hb targets resulted in an increased risk for seizures (RR 5.25, 95% CI 1.13 to 24.34) and a reduced risk of hypertensive episodes (RR 0.50, 95% CI 0.33 to 0.76). There were no significant differences in the risk of vascular access thrombosis.
AUTHORS' CONCLUSIONS
There was no significant difference in the risk of death for low (< 120 g/L) versus higher Hb targets (>133 g/L). Lower Hb targets were significantly associated with an increased risk for seizures but a reduced risk of hypertension. In general study quality was poor. There is a need for more adequately powered, well-designed and reported trials. Trials should be pragmatic, focusing on hard end-points (mortality, ESKD, major side effects) or outcomes which were previously not studied adequately (e.g. seizures, quality of life).
Topics: Anemia; Erythropoietin; Hematocrit; Hemoglobin A; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Assessment
PubMed: 17054191
DOI: 10.1002/14651858.CD003967.pub2 -
Clinical Therapeutics Jun 2006Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of chemotherapy-induced anemia (CIA). Evidence-based guidelines and systematic reviews of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of chemotherapy-induced anemia (CIA). Evidence-based guidelines and systematic reviews of the management of CIA do not yet include all currently approved ESPs or all of the clinically relevant benefits and risks of ESPs.
OBJECTIVES
The aims of this work were to provide up-to-date assessments of the clinical efficacy and effectiveness (ie, transfusions and quality-of-life [QoL] benefits) and safety (ie, risk of venous thromboembolism [VTE] and all-cause or treatment-associated death) of epoetin-alfa, epoetin-beta, and darbepoetin-alfa for the treatment of CIA in cancer patients with hemoglobin<11 g/dL. We also considered the impact of differences in study design, patients, and treatments on the results.
METHODS
A systematic review of the literature was performed to identify and analyze English-language studies (controlled trials and prospective uncontrolled studies with >or=300 patients) published between 1980 and July 2005. The databases searched were MEDLINE and the Cochrane Library. Relevant abstracts from the last 2 annual meetings of the American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology were also included. Studies were selected, using predefined eligibility criteria. Two reviewers had to agree on all included and excluded studies, and on all data extracted from each accepted study before they were entered into a relational database. Meta-analyses were performed to quantify benefit and risk outcomes.
RESULTS
In total, 40 studies including 21,378 patients were eligible for analysis. Each ESP was found to have efficacy relative to standard care or placebo. The odds ratio (OR) for transfusions in studies of epoetin versus controls was 0.44 (95% CI, 0.35-0.55) and of darbepoetin versus controls was 0.41 (95% CI, 0.31-0.55). Patients receiving ESPs experienced a significant improvement in QoL; the mean difference in Functional Assessment of Cancer Therapy-Fatigue score for ESPs versus controls was 0.23 (95% CI, 0.10-0.36; P=0.001). The frequency of VTE and death was not significantly different between ESPs and control (VTE OR, 1.41 [95% CI, 0.81-2.47]; all-cause mortality OR, 1.00 [95% CI, 0.69-1.44]).
CONCLUSIONS
This analysis of key clinical benefits and risks of epoetin and darbepoetin in the treatment of CIA found no clinically relevant differences between these drugs.
Topics: Adult; Anemia; Antineoplastic Agents; Blood Transfusion; Child; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Quality of Life; Recombinant Proteins; Thromboembolism; Venous Thrombosis
PubMed: 16860166
DOI: 10.1016/j.clinthera.2006.06.003 -
The Cochrane Database of Systematic... Jul 2006Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions.
OBJECTIVES
The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients.
SEARCH STRATEGY
We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies.
SELECTION CRITERIA
Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required.
DATA COLLECTION AND ANALYSIS
Several reviewers independently assessed trial quality and extracted data.
MAIN RESULTS
This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167).
AUTHORS' CONCLUSIONS
There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.
Topics: Anemia; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins
PubMed: 16856007
DOI: 10.1002/14651858.CD003407.pub4 -
Journal of the National Cancer Institute May 2006This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005,... (Meta-Analysis)
Meta-Analysis Review
This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.
Topics: Anemia, Hypochromic; Antineoplastic Agents; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Risk Assessment; Thromboembolism; Treatment Outcome
PubMed: 16705125
DOI: 10.1093/jnci/djj189 -
Annals of Oncology : Official Journal... Oct 2005Anaemia effects up to 90% of cancer patients, with more than 60% requiring blood transfusion during or after treatment. With the advent of recombinant human... (Review)
Review
Anaemia effects up to 90% of cancer patients, with more than 60% requiring blood transfusion during or after treatment. With the advent of recombinant human erythropoietins (rHuEPO), an alternative to red blood cell transfusion has become available. So far, three drugs have been approved for the treatment of anaemia in patients with malignancies (epoetin alfa, epoetin beta and darbepoetin alfa). New concepts for the use of erythropoietin in cancer patients include 3- and 4-weekly dosing, as well as loading-dose concepts. Important factors helping to judge the impact of erythropoietin in cancer treatment include pharmacoeconomics and better predictive factors. Lately, the influence of erythropoietin therapy on survival in cancer patients has been discussed very intensively, because conflicting data have emerged. Studies aimed at correcting anaemia in cancer patients had indicated a possible survival advantage of those patients receiving erythropoietin. In contrast, two recent trials aimed at correction of haemoglobin levels beyond anaemia reported a poorer survival of patients receiving erythropoietin. This might grossly be attributed to a higher risk of thrombosis in these patients. The largest systematic review on the use of erythropoietin in cancer patients undergoing treatment indicates a suggestive but not significant survival advantage of erythropoietin-treated patients. In addition, very recent results of a Food and Drug Administration meeting on safety and survival of patients treated with erythropoietin are presented.
Topics: Anemia; Economics, Pharmaceutical; Erythropoietin; Humans; Neoplasms; Prognosis; Recombinant Proteins; Risk Factors; Survival; Thrombosis
PubMed: 15958437
DOI: 10.1093/annonc/mdi307 -
The Cochrane Database of Systematic... 2003Anaemia affects 60-80% of patients with renal impairment, reduces quality of life and is a risk factor for early death. Treatment options are blood transfusion,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Anaemia affects 60-80% of patients with renal impairment, reduces quality of life and is a risk factor for early death. Treatment options are blood transfusion, erythropoietin (EPO) alpha or beta and darbepoetin alfa. Recently higher haemoglobin (Hb) and haematocrit targets have been widely advocated because of positive data from observational studies. However, higher targets may lead to access thrombosis and hypertension and are costly.
OBJECTIVES
This review assesses the benefits and harms of low (Hb = 100 g/L or HCT = 30%) and high (Hb > 100 g/L or HCT > 30%) targets in pre- and post-dialysis patients receiving any treatment for anaemia.
SEARCH STRATEGY
We searched The Cochrane Renal Group specialised register (September 2002), Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002) MEDLINE (1966 - September 2002), EMBASE (1988 - September 2002) and reference lists of retrieved articles.
SELECTION CRITERIA
Randomised controlled trials (RCTs) and quasi-RCTs comparing low Hb/HCT targets (Hb- 100 g/L) with high Hb/HCT targets (Hb > 100 g/dL) in patients with anaemia of chronic renal disease.
DATA COLLECTION AND ANALYSIS
Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes, with 95% confidence intervals (95% CI).
MAIN RESULTS
Fifteen trials were identified in which 2096 patients were included. Twelve trials (673 patients) compared placebo with EPO and three trials (1423 patients) compared two doses of EPO. Hb values of 100 g/L (obtained with low EPO doses) were associated with lower mortality compared to Hb values of 140 g/L or more (obtained with high EPO doses) in the population with chronic renal disease and cardiovascular impairment (two trials, 1379 patients: RR 0.82; 95% CI 0.68 to 0.99). Lower targets obtained with a placebo resulted in an increased risk for seizures (four trials, 219 patients: RR 5.25; 95% CI 1.13 to 24.34) as compared to higher targets reached with EPO treatment. Finally, there was a reduced risk for hypertensive episodes with lower Hb targets reached with a placebo as compared to higher targets reached with EPO (six trials, 387 patients: RR 0.50; 95% CI 0.33 to 0.76). Quality of life was not adequately evaluated in the studies.
REVIEWER'S CONCLUSIONS
Lower Hb targets of 100 g/L were associated with a lower risk of death in the population with cardiovascular impairment and chronic renal disease as compared to Hb 140 g/L. Lower Hb targets (Hb < 100 g/L) were also significantly associated with an increased risk for seizures and a reduced risk of hypertension compared to Hb > 100 g/L. There is a need of more adequately powered, well-designed and reported trials in this area. In particular, randomised controlled trials comparing the benefits and harms of low (Hb < 100 g/L) versus intermediate (Hb 130 g/L) and high (Hb 140 g/L) targets in the pre-dialysis population with chronic renal disease are necessary. In fact, there is a large deficiency of trials in the pre-dialysis population. The new trials should focus on hard outcomes and also look at outcomes which were previously not studied adequately, such as seizures and quality of life, which is to be assessed with validated measures.
Topics: Anemia; Erythropoietin; Hematocrit; Hemoglobin A; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Assessment
PubMed: 12535495
DOI: 10.1002/14651858.CD003967