Initiation of erythropoiesis-stimulating agents and outcomes: a nationwide observational cohort study in anaemic chronic kidney disease patients

Background In 2012, new clinical guidelines were introduced for use of erythropoiesis-stimulating agents (ESA) in chronic kidney disease (CKD) patients, recommending lower haemoglobin (Hb) target levels and thresholds for ESA initiation. These changes resulted in lower blood levels in these patients. However, there is limited evidence on just when ESA should be initiated and the safety of a low Hb initiation policy. Methods In this observational inception cohort study, Swedish, nephology-referred, ESA-naïve CKD patients (n = 6348) were enrolled when their Hb dropped below 12.0 g/L, and they were followed for mortality and cardiovascular events. Four different ESA treatments were evaluated applying dynamic marginal structural models: (i) begin ESA immediately, (ii) begin ESA when Hb <11.0 g/dL, (iii) begin ESA when Hb <10.0 g/dL and (iv) never begin ESA in comparison with 'current practice' [the observed (factual) survival of the entire study cohort]. The adjusted 3-year survival following ESA begun over a range of Hb (from <9.0 to 12.0 g/dL) was evaluated, after adjustment for covariates at baseline and during follow-up. Results Overall, 36% were treated with ESA. Mortality during follow-up was 33.4% of the ESA-treated and 27.9% of the non-treated subjects. The adjusted 3-year survival associated with ESA initiation improved for subjects with initial Hb <9.0 to 11 g/dL and then decreased again for those with Hb above 11.5 g/dL. Initiating ESA at Hb <11.0 g/dL and <10.0 g/dL was associated with improved survival compared with 'current practice' [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.79-0.89 and 0.90; 95% CI 0.86-0.94, respectively] and did not increase the risk of a cardiovascular event (HR 0.93; 95% CI 0.87-1.00). Conclusion In non-dialysis patients with CKD, ESA initiation at Hb < 10.0-11.0 g/dL is associated with improved survival in patients otherwise treated according to guidelines.

[1]  J. Robins,et al.  Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. , 2000, Epidemiology.

[2]  D. Leaf,et al.  Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia. , 2009, Kidney international.

[3]  H. Burger,et al.  Normalization of hemoglobin level in patients with chronic kidney disease and anemia. , 2006, The New England journal of medicine.

[4]  H. Putter,et al.  Treatment with high dose of erythropoiesis‐stimulating agents and mortality: analysis with a sequential Cox approach and a marginal structural model , 2015, Pharmacoepidemiology and drug safety.

[5]  J. Robins,et al.  The International Journal of Biostatistics CAUSAL INFERENCE Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes , Part I : Main Content , 2011 .

[6]  I. Macdougall,et al.  Is early treatment of anaemia with epoetin-alpha beneficial to pre-dialysis chronic kidney disease patients? Results of a multicentre, open-label, prospective, randomized, comparative group trial. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[7]  A R Nissenson,et al.  The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. , 1998, The New England journal of medicine.

[8]  V. Prasad.  Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease , 2007 .

[9]  J. Adamson,et al.  KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease , 2012 .

[10]  J. Robins,et al.  Marginal Structural Models and Causal Inference in Epidemiology , 2000, Epidemiology.

[11]  S. Fishbane,et al.  Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer. , 2014 .

[12]  W. Winkelmayer,et al.  Trends in anemia care in older patients approaching end-stage renal disease in the United States (1995-2010). , 2014, JAMA internal medicine.

[13]  J. Carrero,et al.  Association between the use of fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients with non-ST-segment elevation myocardial infarction. , 2015, JAMA.

[14]  Wim Van Biesen,et al.  Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[15]  Paul W Armstrong,et al.  Anemia Is Common in Heart Failure and Is Associated With Poor Outcomes: Insights From a Cohort of 12 065 Patients With New-Onset Heart Failure , 2003, Circulation.

[16]  H. Morgenstern,et al.  International Comparisons to Assess Effects of Payment and Regulatory Changes in the United States on Anemia Practice in Patients on Hemodialysis: The Dialysis Outcomes and Practice Patterns Study. , 2016, Journal of the American Society of Nephrology : JASN.

[17]  J. Berlin,et al.  Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes , 2010, British Journal of Cancer.

[18]  J. Adamson,et al.  Notice , 2012, Kidney International Supplements.

[19]  Y. Ohashi,et al.  A prospective observational study of early intervention with erythropoietin therapy and renal survival in non-dialysis chronic kidney disease patients with anemia: JET-STREAM Study , 2016, Clinical and Experimental Nephrology.

[20]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.

[21]  R. Foley,et al.  The impact of anemia on cardiomyopathy, morbidity, and and mortality in end-stage renal disease. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[22]  Tom Greene,et al.  Using Standardized Serum Creatinine Values in the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate , 2006, Annals of Internal Medicine.

[23]  S. Shreay,et al.  Red blood cell (RBC) transfusion rates among US chronic dialysis patients during changes to Medicare end-stage renal disease (ESRD) reimbursement systems and erythropoiesis stimulating agent (ESA) labels , 2014, BMC Nephrology.

[24]  A. Kliger,et al.  KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. , 2013, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[25]  S. Fukuhara,et al.  Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan. , 2012, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[26]  R. Califf,et al.  Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. , 2008, Kidney international.

[27]  K Furu,et al.  The Nordic prescription databases as a resource for pharmacoepidemiological research—a literature review , 2013, Pharmacoepidemiology and drug safety.

[28]  A. Collins,et al.  Association of Mean Weekly Epoetin Alfa Dose with Mortality Risk in a Retrospective Cohort Study of Medicare Hemodialysis Patients , 2011, American Journal of Nephrology.

[29]  D. Rubin,et al.  The central role of the propensity score in observational studies for causal effects , 1983 .

[30]  G. Engström,et al.  Anemia in the general population: prevalence, clinical correlates and prognostic impact , 2014, European Journal of Epidemiology.

[31]  F. Port,et al.  The DOPPS practice monitor for U.S. dialysis care: update on trends in anemia management 2 years into the bundle. , 2013, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[32]  H. Feldman,et al.  Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[33]  B. Kanna,et al.  Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) study. , 2007, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[34]  C. Stehman-Breen,et al.  Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[35]  H. Quan,et al.  Coding Algorithms for Defining Comorbidities in ICD-9-CM and ICD-10 Administrative Data , 2005, Medical care.

[36]  M. Stauffer,et al.  Prevalence of Anemia in Chronic Kidney Disease in the United States , 2014, PloS one.

[37]  E. McLean,et al.  Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993–2005 , 2009, Public Health Nutrition.

[38]  J. Craig,et al.  Darbepoetin for the anaemia of chronic kidney disease. , 2014, The Cochrane database of systematic reviews.

[39]  J. Carrero,et al.  Trends in haemoglobin, erythropoietin-stimulating agents and iron use in Swedish chronic kidney disease patients between 2008 and 2013. , 2016, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[40]  Martha J. Radford,et al.  Comorbidity Indices to Predict Mortality From Medicare Data: Results From the National Registry of Atrial Fibrillation , 2005, Medical care.

[41]  S. Solomon,et al.  A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. , 2009, The New England journal of medicine.