Abstract 15723: Risk Factors of Fluoropyrimidine Induced Cardiotoxicity Among Cancer Patients: A Systematic Review and Meta-analysis

Introduction: Cancer patients are at increased risk of experiencing cardiotoxicity during their fluoropyrimidine-based chemotherapy. However, risk factors for fluoropyrimidine-induced cardiotoxicity (FIC) are not entirely understood. Methods: We searched PubMed, PsycINFO, IPA, CINAHL, Web of Science and ClinicalTrials.gov for studies published between January 1, 1990 and December 31, 2019, examining risk factors for cardiotoxicity induced by 5-fluorouracil, capecitabine or floxuridine. Two reviewers independently assessed publication quality and extracted study-level data into standardized evidence tables. Review Manager 5 software was used to convert data to risk ratios (RRs) and calculate pooled RRs for meta-analyses using a random-effects method. We conducted a Cochran’s Q test and obtained I 2 index to quantify study heterogeneity in each meta-analysis, with prediction interval (PI) to show the expected range of true effects in future similar studies. Results: Of 690 publications identified for abstract and title screening, 22 unique studies were included in the final review, and 20 of them had sufficient data for meta-analyses. Results indicated that patients undergoing capecitabine-based combination therapy had a higher risk of FIC than those with capecitabine monotherapy (pooled RR=1.61, 95% CI=1.01-2.55, I 2 =0%, 95% PI=0.08-31.71). Also, patients with pre-existing cardiac disease (pooled RR=3.01, 95% CI=2.02-4.49, I 2 =42%, 95% PI=1.03-8.78), hypertension (pooled RR=1.52, 95% CI=1.20-1.93, I 2 =0%, 95% PI=1.08-2.13) or smoking habit (pooled RR=2.22, 95% CI=1.03-4.78, I 2 =39%, 95% PI=0.15-32.46) had a significantly higher risk of FIC than their counterparts, while gender and comorbidities including diabetes, hyperlipidemia, and obesity were not significant risk factors of FIC. Conclusions: Cancer patients with pre-existing cardiac disease, hypertension, and smoking behavior had a higher risk of FIC when they are undergoing fluoropyrimidine-based treatments. Further research is needed to develop risk assessment tools for a risk prediction of FIC among cancer patients, which could advance risk stratification strategies and improve patient outcomes during the application of fluoropyrimidine-based treatments.

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Risk factors for all-cause hospital readmission following exacerbation of COPD: a systematic review and meta-analysis

European Respiratory Review ◽

10.1183/16000617.0166-2019 ◽

2020 ◽

Vol 29 (156) ◽

pp. 190166 ◽

Cited By ~ 6

Author(s):

Jaber S. Alqahtani ◽

Chidiamara M. Njoku ◽

Bonnie Bereznicki ◽

Barbara C. Wimmer ◽

Gregory M. Peterson ◽

...

Keyword(s):

Risk Factors ◽

Protective Factor ◽

Meta Analysis ◽

Significant Risk ◽

Contributing Factors ◽

Copd Exacerbations ◽

Increased Risk ◽

Newcastle Ottawa Scale ◽

Exacerbation Of Copd ◽

Meta Analyses

BackgroundReadmission rates following hospitalisation for COPD exacerbations are unacceptably high, and the contributing factors are poorly understood. Our objective was to summarise and evaluate the factors associated with 30- and 90-day all-cause readmission following hospitalisation for an exacerbation of COPD.MethodsWe systematically searched electronic databases from inception to 5 November 2019. Data were extracted by two independent authors in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Study quality was assessed using a modified version of the Newcastle–Ottawa Scale. We synthesised a narrative from eligible studies and conducted a meta-analysis where this was possible using a random-effects model.ResultsIn total, 3533 abstracts were screened and 208 full-text manuscripts were reviewed. A total of 32 papers met the inclusion criteria, and 14 studies were included in the meta-analysis. The readmission rate ranged from 8.8–26.0% at 30 days and from 17.5–39.0% at 90 days. Our narrative synthesis showed that comorbidities, previous exacerbations and hospitalisations, and increased length of initial hospital stay were the major risk factors for readmission at 30 and 90 days. Pooled adjusted odds ratios (95% confidence intervals) revealed that heart failure (1.29 (1.22–1.37)), renal failure (1.26 (1.19–1.33)), depression (1.19 (1.05–1.34)) and alcohol use (1.11 (1.07–1.16)) were all associated with an increased risk of 30-day all-cause readmission, whereas being female was a protective factor (0.91 (0.88–0.94)).ConclusionsComorbidities, previous exacerbations and hospitalisation, and increased length of stay were significant risk factors for 30- and 90-day all-cause readmission after an index hospitalisation with an exacerbation of COPD.

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Endemic Cryptosporidium infection and drinking water source: a systematic review and meta-analyses

Water Science & Technology ◽

10.2166/wst.2006.474 ◽

2006 ◽

Vol 54 (3) ◽

pp. 231-238 ◽

Cited By ~ 9

Author(s):

F.A.S. Gualberto ◽

L. Heller

Keyword(s):

Risk Factors ◽

Drinking Water ◽

Meta Analysis ◽

Water Source ◽

Drinking Water Source ◽

Cryptosporidium Infection ◽

Water Users ◽

Increased Risk ◽

Unsafe Water ◽

Meta Analyses

Cryptosporidium is a well-known cause of diarrhoea in humans. Little is known about risk factors associated with endemic cryptosporidiosis, which constitutes the majority of cases. We carried out meta-analyses to verify if drinking water is also associated with endemic infection and to assess the magnitude of the associations. The global meta-analysis suggests that there is an increased risk of Cryptosporidium infection among unsafe water users (OR 1.40 [1.15, 1.72]). Studies were stratified, according to the exposure to different sources of safe drinking water, due to the heterogeneity presented. The consumption of non-well and unboiled water was associated with an increased chance of endemic cryptosporidiosis, though only the latter was significant (OR 1.45 [0.95, 2.20]; OR 1.61 [1.09, 2.38]). Drinking non-bottled water did not present a risk factor associated with endemic cryptosporidiosis (OR 0.87 [0.72, 1.05]). These meta-analyses present results that could be useful to clarify the epidemiology of Cryptosporidium. We recommend that other risk factors could also be studied by this approach.

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Lifestyle and sociodemographic risk factors for gastroschisis: a systematic review and meta-analysis

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-318412 ◽

2020 ◽

Vol 105 (8) ◽

pp. 756-764 ◽

Cited By ~ 2

Author(s):

Silvia Baldacci ◽

Michele Santoro ◽

Alessio Coi ◽

Lorena Mezzasalma ◽

Fabrizio Bianchi ◽

...

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Illicit Drugs ◽

Meta Analysis ◽

Genetic Risk Factors ◽

Epidemiological Studies ◽

Black Mothers ◽

Increased Risk ◽

Sociodemographic Risk ◽

Meta Analyses

BackgroundGastroschisis is strongly associated with young maternal age. This association suggests the need for further investigations on non-genetic risk factors. Identifying these risk factors is a public health priority in order to develop prevention strategies aimed at reducing the prevalence and health consequences in offspring.ObjectiveTo systematically assess and quantitatively synthesise the available epidemiological studies to evaluate the association between non-genetic risk factors and gastroschisis.MethodsLiterature from PubMed, EMBASE and Scopus was searched for the period 1990–2018. Epidemiological studies reporting risk estimates between lifestyle and sociodemographic risk factors and gastroschisis were included. Two pairs of reviewers independently extracted information on study characteristics following Preferred Reporting Items for Systematic Reviews and Meta-Analyses and MOOSE (Meta-analysis Of Oservational Studies in Epidemiology) guidelines. Relative risk (RR) estimates were calculated across the studies and meta-analysis was performed using random-effects model.ResultsWe identified 58 studies. Meta-analyses were conducted on 29 studies. Maternal smoking (RR 1.56, 95% CI 1.40 to 1.74), illicit drug use (RR 2.14, 95% CI 1.48 to 3.07) and alcohol consumption (RR 1.40, 95% CI 1.13 to 1.70) were associated with an increased risk of gastroschisis. A decreased risk among black mothers compared with non-Hispanic white mothers (RR 0.49, 95% CI 0.38 to 0.63) was found. For Hispanic mothers no association was observed.ConclusionsExposure to smoking, illicit drugs and alcohol during pregnancy is associated with an increased risk of gastroschisis. A significantly decreased risk for black mothers was observed. Further epidemiological studies to assess the potential role of other environmental factors are strongly recommended.PROSPERO registration numberCRD42018104284.

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Prevalence of Asthma and Risk Factors for Asthma-Like Symptoms in Aboriginal and Non-Aboriginal Children in the Northern Territories of Canada

Canadian Respiratory Journal ◽

10.1155/2008/302407 ◽

2008 ◽

Vol 15 (3) ◽

pp. 139-145 ◽

Cited By ~ 14

Author(s):

Zhiwei Gao ◽

Brian H Rowe ◽

Carina Majaesic ◽

Cindy O’Hara ◽

A Senthilselvan

Keyword(s):

Risk Factors ◽

Urban Areas ◽

Smoking Habit ◽

Significant Risk ◽

Daily Smoking ◽

Asthma Prevalence ◽

Infants And Toddlers ◽

Increased Risk ◽

Northern Territories ◽

Aboriginal Children

BACKGROUND: Few studies have investigated the prevalence and risk factors of asthma in Canadian Aboriginal children.OBJECTIVE: To determine the prevalence of asthma and asthma-like symptoms, as well as the risk factors for asthma-like symptoms, in Aboriginal and non-Aboriginal children living in the northern territories of Canada.METHODS: Data on 2404 children, aged between 0 and 11 years, who participated in the North component of the National Longitudinal Survey of Children and Youth were used in the present study. A child was considered to have an asthma-like symptom if there was a report of ever having had asthma, asthma attacks or wheeze in the past 12 months.RESULTS: After excluding 59 children with missing information about race, 1399 children (59.7%) were of Aboriginal ancestry. The prevalence of asthma was significantly lower (P<0.05) in Aboriginal children (5.7%) than non-Aboriginal children (10.0%), while the prevalence of wheeze was similar between Aboriginal (15.0%) and non-Aboriginal (14.5%) children. In Aboriginal children, infants and toddlers had a significantly greater prevalence of asthma-like symptoms (30.0%) than preschool-aged children (21.5%) and school-aged children (11.5%). Childhood allergy and a mother’s daily smoking habit were significant risk factors for asthma-like symptoms in both Aboriginal and non-Aboriginal children. In addition, infants and toddlers were at increased risk of asthma-like symptoms in Aboriginal children. In analyses restricted to specific outcomes, a mother’s daily smoking habit was a significant risk factor for current wheeze in Aboriginal children and for ever having had asthma in non-Aboriginal children.CONCLUSIONS: Asthma prevalence appears to be lower in Aboriginal children than in non-Aboriginal children. The association between daily maternal smoking and asthma-like symptoms, which has been mainly reported for children living in urban areas, was observed in Aboriginal and non-Aboriginal children living in northern and remote communities in Canada.

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Factor V Leiden Is Associated with Premature Myocardial Infarction.

Blood ◽

10.1182/blood.v112.11.1817.1817 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1817-1817

Author(s):

Flora Peyvandi ◽

Marta Spreafico ◽

Luisa Foco ◽

Luisa Bernardinelli ◽

Stefano Duga ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Meta Analysis ◽

Large Population ◽

Factor V Leiden ◽

Coagulation Factor ◽

Factor V ◽

Gain Of Function ◽

Increased Risk ◽

Meta Analyses

Abstract Plasma levels of haemostatic proteins involved in coagulation and fibrinolysis may represent an important intermediate phenotype for cardiovascular diseases (because increased levels of these proteins have been associated with an increased/reduced risk of thrombosis). However, investigation in arterial diseases of gain-of-function polymorphisms of genes encoding coagulation factor V (F5 G1691A) and prothrombin (F2 G20210A), established risk factors for venous thrombosis, have generally indicated weak or no associations in a number of conflicting and inconclusive reports [Ye et al., Lancet2006;367:651–8]. These negative results might be due to the sample size, too small to reliably assess relatively small genetic effects. Recently, a meta-analysis of 4,944 patients and 7,090 controls on the association of the F2 G20210A and ischemic heart disease [Burzotta et al, Heart2004;90:82–6], and a meta-analysis of 66,155 cases and 91,307 controls on the association of haemostatic genetic variants and coronary artery disease (CAD) [Ye et al, Lancet2006;367:651–8], found that either F2 G20210A and F5 G1691A polymorphisms were associated with a moderately increased risk of CAD. Results from these meta-analyses, large but based respectively upon 19 and 100 different studies all of rather small size, should be taken cautiously. Considering that genetic factors play a particularly important role in CAD occurring in the young, with usually less coronary atherosclerosis and a high prevalence of normal or near-normal coronary angiograms, we chose to replicate the meta-analysis results by investigating an adequately large population of 1,864 Italian patients who developed myocardial infarction (MI) before the age of 45 yrs (1,655 men and 209 women) and 1,864 age- and sex-matched controls. Genotyping was performed by Sequenom MassARRAY platform. Statistical analysis was performed fitting a conditional logistic model with STATA 9.2 software. Our results showed that the minor A allele of F5 G1691A (2.6% frequency in cases and 1.7% in controls) was associated with a moderately increased risk of MI (OR:1.59; 95% CI:1.14–2.20; P=0.006). The association remained statistically significant after adjustment for traditional risk factors, including diabetes, smoking, hypertension, and hypercholesterolemia (OR:1.81; 95% CI:1.14–2.87; P=0.012). The minor A allele of F2 G20210A (2.4% frequency in cases and 1.9% in controls) was not associated with the risk of MI (OR:1.27; 95% CI:0.93–1.74; P=0.133), even after adjustment (OR:1.19; 95% CI:0.77–1.85; P=0.429). In conclusion, results of the previous meta-analyses are replicated only partially in this cohort of young MI patients, the largest investigated so far, as only the gain-of-function variant F5 G1691A (but not F2 G20210A) was associated with an increased risk of MI. Our results suggest that anticoagulant drugs might be considered for secondary prophylaxis of MI in patients with the F5 gene variant, who carry a procoagulant phenotype.

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Incident myocardial infarction associated with major types of arthritis in the general population: a systematic review and meta-analysis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-210275 ◽

2017 ◽

Vol 76 (8) ◽

pp. 1396-1404 ◽

Cited By ~ 52

Author(s):

Orit Schieir ◽

Cedomir Tosevski ◽

Richard H Glazier ◽

Sheilah Hogg-Johnson ◽

Elizabeth M Badley

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Meta Analysis ◽

Population Based ◽

Case Control Studies ◽

Increased Risk ◽

Traditional Risk Factors ◽

Meta Analyses ◽

Review Criteria ◽

Age And Sex

ObjectiveTo synthesise, quantify and compare risks for incident myocardial infarction (MI) across five major types of arthritis in population-based studies.MethodsA systematic search was performed in MEDLINE, EMBASE and CINAHL databases with additional manual/hand searches for population-based cohort or case-control studies published in English of French between January 1980 and January 2015 with a measure of effect and variance for associations between incident MI and five major types of arthritis: rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), gout or osteoarthritis (OA), adjusted for at least age and sex. All search screening, data abstraction quality appraisals were performed independently by two reviewers. Where appropriate, random-effects meta-analysis was used to pool results from studies with a minimum of 10 events.ResultsWe identified a total of 4, 285 articles; 27 met review criteria and 25 criteria for meta-analyses. In studies adjusting for age and sex, MI risk was significantly increased in RA (pooled relative risk (RR): 1.69, 95% CI 1.50 to 1.90), gout (pooled RR: 1.47, 95% CI 1.24 to 1.73), PsA (pooled RR: 1.41, 95% CI 1.17 to 1.69), OA (pooled RR: 1.31, 95% CI 1.01 to 1.71) and tended towards increased risk in AS (pooled RR: 1.24, 95% CI 0.93 to 1.65). Traditional risk factors were more prevalent in all types of arthritis. MI risk was attenuated for each type of arthritis in studies adjusting for traditional risk factors and remained significantly increased in RA, PsA and gout.ConclusionsMI risk was consistently increased in multiple types of arthritis in population-based studies, and was partially explained by a higher prevalence of traditional risk factors in all types of arthritis. Findings support more integrated cardiovascular (CV) prevention strategies for arthritis populations that target both reducing inflammation and enhancing management of traditional CV risk factors.

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TP53 codon 72 polymorphisms and breast carcinoma susceptibility: A meta-analysis

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22171 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22171-e22171

Author(s):

B. Zhu ◽

W. Zhuo ◽

Z. Chen

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Breast Carcinoma ◽

Meta Analysis ◽

Inclusion Criteria ◽

Codon 72 ◽

Knowledge Infrastructure ◽

Increased Risk ◽

Meta Analyses ◽

Chinese National Knowledge Infrastructure

e22171 Background: Previously, TP53 codon 72 polymorphisms have been implicated as risk factors for various cancers. Several studies have conducted on the association of TP53 codon 72 polymorphisms with susceptibility to breast carcinoma and have yielded inconclusive results. The aim of the present study was to assess possible associations of breast cancer risk with TP53 codon 72 polymorphisms. Methods: We conducted a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to Dec 2008. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. Results: Consequently, fifteen studies, including 3436 cases and 4394 controls, met the included criteria and thus were selected. Ultimately, the relevant data were extracted and further analyzed using systematic meta- analyses. The results showed that individuals carrying homozygote Arg/Arg genotype have a significant increased risk of breast cancer compared with those carrying Pro/Pro genotype (OR: 1.58, 95%CI:1.10–2.28). For Arg allele, no evidence indicated that individuals with Arg/Arg genotype have an increased risk of breast cancer compared with those with a combined Pro genotype (Arg/Pro+Pro/Pro) (OR: 1.68, 95%CI:1.24–2.29). For Pro allele, individuals with homozygote Pro/Pro genotype have a marked decreased susceptibility to breast cancer relative to those with a combined Arg genotype (Arg/Pro+Arg/Arg) (OR: 0.84, 95%CI:0.73–0.98). Conclusions: The results of the present study suggest that TP53 codon 72 polymorphisms might be a risk factor for breast cancer. Homozygote Arg allele genotype could significantly increase susceptibility to breast cancer, while Pro/Pro allele markedly decreases breast risk. No significant financial relationships to disclose.

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Risk factors for infectiousness of patients with tuberculosis: a systematic review and meta-analysis

Epidemiology and Infection ◽

10.1017/s0950268817003041 ◽

2018 ◽

Vol 146 (3) ◽

pp. 345-353 ◽

Cited By ~ 15

Author(s):

Y.A. Melsew ◽

T.N. Doan ◽

M. Gambhir ◽

A.C. Cheng ◽

E. McBryde ◽

...

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Meta Analysis ◽

Random Effect ◽

Significant Risk ◽

Sputum Smear ◽

Targeted Interventions ◽

Related Risk ◽

Cavitary Disease ◽

Meta Analyses

AbstractWe performed a systematic review and meta-analyses of studies assessing tuberculosis (TB) patient-related risk factors for transmission of Mycobacterium tuberculosis infection. Meta-analyses were conducted for sputum smear-positivity, lung cavitation and HIV seropositivity of index patients with both crude and adjusted odds ratios (AORs) pooled using random effect models. Thirty-seven studies were included in the review. We found that demographic characteristics such as age and sex were not significant risk factors, while behaviours such as smoking and alcohol intake were associated with infectiousness although inconsistently. Treatment delay of >28 days was a significant predictor of greater infectiousness. Contacts of sputum smear-positive index patients were found to be more likely to be infected than contacts of sputum smear-negative patients, with a pooled AOR of 2.15 (95% confidence interval (CI) 1.47–3.17, I2 = 38%). Similarly, contacts of patients with the cavitary disease were around twice as likely to be infected as contacts of patients without cavitation (pooled AOR 1.9, 95% CI 1.26–2.84, I2 = 63%). In contrast, HIV seropositive patients were associated with few contact infections than HIV seronegative patients (AOR 0.45, 95% CI 0.26–0.80, I2 = 52%). In conclusion, behavioural and clinical characteristics of TB patients can be used to identify highly infectious patients for targeted interventions.

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Systematic Review and Meta-Analysis of Psychosocial Risk Factors for Stroke

Seminars in Neurology ◽

10.1055/s-0037-1603758 ◽

2017 ◽

Vol 37 (03) ◽

pp. 294-306 ◽

Cited By ~ 9

Author(s):

Andrew Clegg ◽

Kulsum Patel ◽

Julie Lucas ◽

Hannah Storey ◽

Maree Hackett ◽

...

Keyword(s):

Risk Factors ◽

Meta Analysis ◽

Case Control ◽

Psychosocial Risk Factors ◽

Psychosocial Risk ◽

Systemic Review ◽

Case Control Studies ◽

Cochrane Database ◽

Increased Risk ◽

Meta Analyses

AbstractSeveral studies have assessed the link between psychosocial risk factors and stroke; however, the results were inconsistent. We have conducted a systemic review and meta-analysis of cohort or case-control studies to ascertain the association between psychosocial risk factors (psychological, vocational, behavioral, interpersonal, and neuropsychological) and the risk of stroke. Systematic searches were undertaken in MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Database of Systematic Reviews between 2000 and January 2017. Two reviewers independently screened titles, abstracts, and full texts. One reviewer assessed quality and extracted data, which was checked by a second reviewer. For studies that reported risk estimates, a meta-analysis was performed. We identified 41 cohort studies and 5 case-control studies. No neuropsychological papers were found. Overall, pooled adjusted estimates showed that all other psychosocial risk factors were independent risk factors for stroke. Psychological factors increased the risk of stroke by 39% (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.27–1.51), vocational by 35% (HR, 1.35; 95% CI, 1.20–1.51), and interpersonal by 16% (HR, 1.16; 95% CI, 1.03–1.31), and the effects of behavioral factors were equivocal (HR, 0.94; 95% CI, 0.20–4.31). The meta-analyses were affected by heterogeneity. Psychosocial risk factors are associated with an increased risk of stroke.

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Erythropoiesis Stimulating Agent (ESA) Use for Anemic Cancer and Chronic Kidney Disease (CKD) Patients in 2008: Advocacy for Conservative Use

Blood ◽

10.1182/blood.v112.11.4680.4680 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4680-4680

Author(s):

Charles L. Bennett ◽

Benjamin Kim ◽

Athena T Samaras ◽

Allen R Nissenson ◽

A. Oliver Sartor ◽

...

Keyword(s):

Clinical Trials ◽

Kidney Disease ◽

Cancer Patients ◽

Basic Science ◽

Meta Analysis ◽

Cardiovascular Risks ◽

Increased Risk ◽

American Society ◽

Meta Analyses ◽

Patient At Risk

Abstract The ESAs epoetin and darbepoetin were approved for treatment of chemotherapy-associated anemia in 1993 and 2002 and CKD-associated anemia in 1989 and 2001, respectively. In 2006, ESAs were the largest single pharmaceutical expenditure by the Center for Medicare and Medicaid Studies (CMS). Recently, a series of preclinical experiments, clinical trials, and meta-analyses of ESAs have been reported. The Food and Drug Administration (FDA), National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO), and Kidney Disease Outcomes Quality Improvement (KDOQI) have issued guideline statements for ESAs, and CMS has implemented an ESA Monitoring Policy (EMP) to help ensure appropriate ESA claims. Herein, we analyze these actions and usage trends of ESAs for anemic cancer and CKD patients. Data sources included basic science studies, clinical trials, meta-analyses, notifications from CMS, ESA manufacturers, and the FDA, guidelines from the NCCN, ASH/ASCO, and KDOQI, and published reports regarding ESA usage reported between 2006 and 2008. Search terms included erythropoietin, darbepoetin, anemia, neoplasm, and CKD. Results from eight recent clinical trials and one 2008 meta-analysis for anemic cancer patients identified tumor progression and mortality risks with ESA versus placebo/control use. Analyses from one clinical trial and one 2008 meta-analysis for CKD patients identified mortality and cardiovascular risks when high hemoglobin levels were targeted. Guidelines, manufacturer notifications, and reimbursement policies have become increasingly conservative. ESA administration to anemic cancer and CKD patients has decreased. Among anemic cancer patients, red blood cell transfusions are increasing and ESA use is decreasing. Among anemic CKD patients, target and achieved hemoglobin levels and ESA doses have decreased. Regulatory, clinical and professional communities now advocate for conservative use of ESAs for anemic patients with cancer or CKD. Chemotherapy-associated anemia CKD-associated anemia Basic Science ESAs may be harmful: Erythropoietin receptors have been identified in tumor cells and have demonstrated downstream cellular effects including proliferation, anti-apoptosis, invasion, and chemotherapy resistance. ESAs may be beneficial: Studies have identified neurotrophic and neuroprotective effects of erythropoietin. Also, erythropoietin protects against hypoxia-induced apoptosis, ischemia-reperfusion injury, and promotes ventricular modeling. Clinical Trials and Meta-analyses Eight clinical trials and one meta-analysis have identified increased risk of mortality and/or tumor progression associated with ESA use. Two meta-analyses have identified significantly increased risk of VTE and seven trials reported four-fold or greater increased risk of VTE. One trial and one meta-analysis have identified mortality and cardiovascular risks when ESAs were targeted to higher versus lower hemoglobin levels. A second trial did not identify clinical benefits with ESA administration targeted to normal versus lower hemoglobin levels. Guidelines NCCN and ASH/ASCO guidelines support ESA administration targeted to between 10 and 12 g/dl and a trigger hemoglobin level to initiate ESA use at 10 g/dl. KDOQI supports hemoglobin levels targeted to between 11 and 12 g/dl and avoiding levels > 13 g/dl. Recent Manufacturer Notifications The FDA mandated that product labels state that ESAs are not indicated for patients receiving myelosuppressive therapy with curative intent, the trigger hemoglobin should be <10 g/dl, and ESAs should be withheld if the hemoglobin exceeds a level necessary to avoid transfusion. Revised labels indicated hemoglobin levels should be targeted to between 10 and 12 g/dl and that high ESA doses should be avoided. Reimbursement Policies Target and trigger hemoglobin levels of < 10 g/dl and a maximum duration of 8 weeks of treatment are supported by CMS. Target hemoglobin levels < 13 g/dl are supported by CMS. Reimbursement is reduced when hemoglobin levels > 13 g/dl are recorded for 3 or more consecutive billing cycles. Usage Trend Between November 2006 and October 2007, usage of ESAs declined from 42% to 15% per patient at risk while transfusions increased from 24% to 28% per patient at risk. ESA use among CKD patients not on hemodialysis decreased from 54% to 42% from 2007 to 2008.

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