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• W2073613013 abstract "A randomized trial had suggested that high doses of erythropoiesis-stimulating agents (ESAs) might increase the risk of cardiovascular outcomes in predialysis diabetic patients. To evaluate this risk in diabetic patients receiving dialysis, we used data from 35,593 elderly Medicare patients on hemodialysis in the US Renal Data System of whom 19,034 were diabetic. A pooled logistic model was used to estimate the monthly probability of mortality and a composite cardiovascular end point. Inverse probability weighting was used to adjust for measured time-dependent confounding by indication, estimated separately for diabetic and non-diabetic cohorts. The adjusted 9-month mortality risk, significantly different between an ESA dose of 45,000 and 15,000 U/week, was 13% among diabetics and 5% among non-diabetics. In diabetic patients, the hazard ratio (HR) for more than 40,000 U/week was 1.32 for all-cause mortality and 1.26 for a composite end point of death and cardiovascular events compared with patients receiving 20,000 to 30,000 U/week. The corresponding HRs in non-diabetic patients were 1.06 and 1.10, respectively. A smaller effect of dose was found in non-diabetic patients. Thus, higher ESA doses, which are often necessary to achieve high hemoglobin levels, are not beneficial, and possibly harmful, to diabetic patients receiving dialysis. Our findings support a Food and Drug Administration advisory recommending that the lowest possible ESA dose be used to treat hemodialysis patients. A randomized trial had suggested that high doses of erythropoiesis-stimulating agents (ESAs) might increase the risk of cardiovascular outcomes in predialysis diabetic patients. To evaluate this risk in diabetic patients receiving dialysis, we used data from 35,593 elderly Medicare patients on hemodialysis in the US Renal Data System of whom 19,034 were diabetic. A pooled logistic model was used to estimate the monthly probability of mortality and a composite cardiovascular end point. Inverse probability weighting was used to adjust for measured time-dependent confounding by indication, estimated separately for diabetic and non-diabetic cohorts. The adjusted 9-month mortality risk, significantly different between an ESA dose of 45,000 and 15,000 U/week, was 13% among diabetics and 5% among non-diabetics. In diabetic patients, the hazard ratio (HR) for more than 40,000 U/week was 1.32 for all-cause mortality and 1.26 for a composite end point of death and cardiovascular events compared with patients receiving 20,000 to 30,000 U/week. The corresponding HRs in non-diabetic patients were 1.06 and 1.10, respectively. A smaller effect of dose was found in non-diabetic patients. Thus, higher ESA doses, which are often necessary to achieve high hemoglobin levels, are not beneficial, and possibly harmful, to diabetic patients receiving dialysis. Our findings support a Food and Drug Administration advisory recommending that the lowest possible ESA dose be used to treat hemodialysis patients. Chronic kidney disease (CKD) and end-stage renal disease (ESRD) hemodialysis patients assigned to normal hematocrit (Hct) targets receive high doses of erythropoiesis-stimulating agents (ESAs; also referred to as epoetin, epoetin-α, or darbepoetin). Randomized trials have shown increased mortality1.Singh A.K. Szczech L. Tang K.L. et al.CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2280) Google Scholar or no beneficial clinical effects2.Drüeke T.B. Locatelli F. Clyne N. et al.CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1785) Google Scholar among those assigned to normal Hct targets, and observational studies3.Zhang Y. Thamer M. Stefanik K. et al.Epoetin requirements predict mortality in hemodialysis patients.Am J Kidney Dis. 2004; 44: 866-876Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 4.Zhang Y. Thamer M. Cotter D. et al.Estimated effect of epoetin dosage on survival among elderly hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 638-644Crossref PubMed Scopus (42) Google Scholar have found no survival benefits among hemodialysis patients receiving high ESA doses. Nearly half of all CKD and dialysis patients have comorbid diabetes. Compared with CKD patients without diabetes, those with diabetes generally receive higher ESA doses, attain lower Hct levels,5.Khoshdel A. Carney S. Gillies A. et al.Potential roles of erythropoietin in the management of anaemia and other complications diabetes.Diabetes Obes Metab. 2008; 10: 1-9PubMed Google Scholar, 6.Vlagopoulos P.T. Tighiouart H. Weiner D.E. et al.Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease.J Am Soc Nephrol. 2005; 16: 3403-3410Crossref PubMed Scopus (232) Google Scholar, 7.Tong P.C.Y. Kong A.P.S. So W.-Y. et al.Hematocrit, independent of chronic kidney disease, predicts adverse cardiovascular outcomes in Chinese patients with type 2 diabetes.Diabetes Care. 2006; 29: 2439-2444Crossref PubMed Scopus (56) Google Scholar have a higher mortality rate, and experience more cardiovascular events.8.US Renal Data System Excerpts from the United States Renal Data System 2005 Annual Data Report.Am J Kidney Dis. 2006; 47: S1PubMed Google Scholar A recent randomized trial (Trial to Reduce Cardiovascular Events with Aranesp Therapy; TREAT) was restricted to diabetic CKD predialysis patients9.Pfeffer M. Burdmann E.A. Cooper D.E. et al.A trial of darbepoetin-alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 1-14Crossref PubMed Scopus (1649) Google Scholar and found no cardiovascular or renal benefits and an increased risk for stroke for those assigned to darbepoetin treatment targeting hemoglobin levels >13 g/dl compared with those assigned placebo treatment with rescue treatment with darbepoetin for hemoglobin levels <9 g/dl. It is therefore possible that the apparent lack of a beneficial effect for those targeted to higher hemoglobins in all previous randomized controlled trials as well as in observational studies could be due to the mixing of diabetic and non-diabetic patients in their study groups. Whether the adverse effects of targeting normal hemoglobins is due to the hemoglobin level or other factors remains controversial. To achieve higher hemoglobin levels, most patients require higher ESA doses. The adverse effects of higher hemoglobin targets might be due to the higher ESA doses, particularly in patients who might be ESA hyporesponsive. In fact, a recent post hoc analysis of the TREAT Study found that patients who had poor initial hematopoietic response to darbepoetin were at greater risk for cardiovascular adverse events and death.10.Solomon S.D. Uno H. Lewis E.F. et al.Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes.N Engl J Med. 2010; 363: 1146-1155Crossref PubMed Scopus (375) Google Scholar The authors could not determine whether the initial poor response identified a patient at greater risk or whether the increased risk was attributable to the higher doses of darbepoetin they received. We designed an observational study to estimate the effect of ESA exposure (epoetin-α) on mortality and cardiovascular outcomes among elderly hemodialysis patients with and without diabetes. Figure 1 depicts the selection process for patients included in the analysis. The analysis for the death-only outcome included 35,593 patients, of whom 19,034 (53%) were diabetic. During the follow-up period, 8238 (23%) of the patients were censored and 7179 (20%) died. The analysis for the composite outcome included 32,534 patients (after 3059 patients were excluded for having had a stroke, myocardial infarction (MI), or congestive heart failure (CHF) during the study baseline period), of whom 17,387 (53%) were diabetic. A total of 6933 patients (21%) were censored; 8512 (26%) had a composite event including 4868 deaths (57%) and 3644 (43%) cardiovascular events. Of the 3,644 cardiovascular hospitalization events, 2117 (24.7%) were for CHF, 726 (8.5%) were for stroke, and 801 (9.5%) were for an MI. The event rates for diabetics and non-diabetics were similar for both mortality and composite outcomes (data not shown). Compared with non-diabetics, diabetics were younger, more likely to be male and black, had a more severe comorbidity burden (higher Charlson score) with almost three times as many cardiovascular comorbidities, and had an increased likelihood of being hospitalized and for longer periods of time (Table 1). Although diabetic patients were more likely to receive predialysis epoetin therapy, they received similar amounts of epoetin during the baseline period and achieved similar Hct levels at the end of baseline when compared with non-diabetic patients.Table 1Characteristics of study population (N=35,593)DiabeticsNon-diabeticsN19,03415,559Patient demographics Race (%) White67.974.7 Black26.121.1 Other/unknown6.04.2 Mean age (years)74.177.2 Male sex (%)53.146.9Facility characteristics Region Northeast (networks 1–5)23.826.2 Southeast (networks 6–8, 13, 14)35.833.1 Midwest (networks 9–12)23.524.6 West (networks 15–18)16.916.1Chain membership (%) Chain 132.431.1 Chain 214.114.1 Chain 316.917.1 Chain 49.910.4 Chain 53.94.0 Chain 61.01.0 Small chain/non-chain21.822.4Patient clinical history Cause of ESRD (%) Diabetes86.3NA Hypertension9.766.5 Glomerulonephritis1.19.0 Cystic kidney0.12.1 Other2.922.5 Body weight (Kg) <6116.729.9 61 to <7222.927.6 72 to 8425.323.5 ≥8435.219.0 Charlson index scoreaFirst 3 months of dialysis therapy. <36.630.3 3 to <627.529.3 6 to <826.015.2 ≥839.925.2 Hospitalization (days)aFirst 3 months of dialysis therapy. 056.757.7 <511.311.8 5 to <1012.512.2 ≥1019.518.3Cardiovascular comorbidities (%)49.134.8Non-cardiovascular comorbidities (%)67.611.4Anemia management practicesReceipt of predialysis epoetin (%)36.733.7Hematocrit level at end of month 3 (%) <30%5.15.3 30 to <33%9.08.9 33 to <36%19.119.4 36 to <39%27.026.9 ≥39%39.839.4Epoetin dose (U/week)aFirst 3 months of dialysis therapy. <10,0009.29.8 10,000 to <20,00029.630.2 20,000 to <30,00029.328.4 30,000 to <40,00016.816.3 ≥40,00015.115.3Average iron (U/month)aFirst 3 months of dialysis therapy. <45018.120.2 450 to <80019.719.6 800 to <1,20026.826.5 ≥1,20035.433.6Abbreviation: ESRD, end-stage renal disease.Note: Diabetics defined as patients with diabetes as primary cause of ESRD. Non-diabetics defined as other primary cause of ESRD.a First 3 months of dialysis therapy. Open table in a new tab Abbreviation: ESRD, end-stage renal disease. Note: Diabetics defined as patients with diabetes as primary cause of ESRD. Non-diabetics defined as other primary cause of ESRD. Figure 2 shows the adjusted survival curves under three hypothetical epoetin dose levels: 15,000, 30,000, and 45,000 U/week throughout the entire follow-up period and for each outcome separately (Figure 2a shows death-only and Figure 2b shows the composite outcome). The survival decreased with increasing doses. For the lowest epoetin doses of 15,000 U/week, the 9-month risk of death was 20% (28% for composite endpoint) among diabetics and 24% (31%) among non-diabetics. The difference in mortality risk between 30,000 and 15,000 U/week was 9% (95% confidence interval (CI): 7 and 11%) among diabetics and 5% (95% CI: 2 and 7%) among non-diabetics (P-value for heterogeneity=0.04). The difference in mortality risk between 45,000 and 15,000 U/week was 13% (95% CI: 10 and 16%) among diabetics compared with 5% (95% CI: 2 and 9%) among non-diabetics (P-value=0.002). Table 2 presents the estimated average hazard ratios (HRs) for both mortality and the composite outcome. The estimates were consistent with the findings from the survival curves. Among both diabetics and non-diabetics, lower epoetin dose levels (<20,000 U/week) were associated with lower risk for both mortality and composite outcomes. In diabetic patients, the HR (95% CI) for >40,000 U/week was 1.32 (1.11, 1.58) for all-cause mortality and 1.26 (1.07, 1.50) for the composite end point of death and cardiovascular events compared with a dose of 20,000–30,000 U/week. The corresponding HRs (95% CI) in non-diabetic patients were 1.06 (0.88 and 1.28) and 1.10 (0.92 and 1.32), respectively. Results for HRs estimated using the first dose level (<10,000 U/week) as the reference group are shown in the Supplementary Appendix Table S3 online.Table 2Cumulative average epoetin dose and HRs based on IP weightingDeath onlyCompositeaComposite outcome is death or hospitalization for MI, stroke, or CHF.Epoetin doseDiabeticNon-diabeticDiabeticNon-diabeticU/weekHR95% CIHR95% CIHR95% CIHR95% CI<10,0000.690.570.830.710.570.880.800.670.940.690.570.8210,000 to <20,0000.700.600.810.860.721.020.860.750.990.890.761.0420,000 to <30,000 (reference group)Ref.Ref.Ref.Ref.30,000 to <40,0001.210.981.511.120.911.381.211.001.471.140.941.39≥40,0001.321.111.581.060.881.281.261.071.501.100.921.32Abbreviations: CHF, congestive heart failure; CI, confidence interval; HR, hazard ratio, IP, inverse probability; MI, myocardial infarction; ref., reference.a Composite outcome is death or hospitalization for MI, stroke, or CHF. Open table in a new tab Download .doc (.18 MB) Help with doc files Supplementary Appendix Figure and Tables Abbreviations: CHF, congestive heart failure; CI, confidence interval; HR, hazard ratio, IP, inverse probability; MI, myocardial infarction; ref., reference. In secondary analyses, the estimates were similar when we made different assumptions about the amount of epoetin used during hospitalizations (Supplementary Appendix Figure S1 online). Our estimates did not materially change when we used other summaries of epoetin use (that is, total cumulative dosage from start of follow-up, recent, and past cumulative average dosage) in the logistic model, cubic splines with knots at different locations, inverse probability (IP) weights that were not truncated (Supplementary Appendix Table S2 online), IP weights estimated under a gamma distribution for the log of epoetin dosage, alternative categorizations of Hct values, expanded billable service (or claims) gap definition from 30 to 60 days, censoring that did not include change of provider, and censoring criteria that included reduced dialysis sessions. Our findings suggest that high ESA doses are associated with a greater risk of death and cardiovascular outcomes. In diabetic patients, the adjusted 9-month risk of death increased from 20% for a dose of 15,000 U/week to 33% for 45,000 U/week. The corresponding increase in non-diabetic patients was smaller (from 24 to 30%). Four randomized trials—CREATE, 2 CHOIR, 1 NHT,11.Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1883) and TREAT10—had previously found no survival or cardiovascular benefits among those targeted to higher Hcts and therefore exposed to higher ESA doses. In contrast to our findings, a post hoc analysis of the CHOIR Trial12.Szczech L.A. Barnhart H.X. Sapp S. et al.A secondary analysis of CHOIR shows that comorbid conditions differentially affect outcomes during anemia treatment.Kidney Int. 2010; 77: 239-246Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar found that non-diabetic, but not diabetic, CKD patients assigned to the higher target group (who received higher doses on average) had an increased risk of 70%. This finding, however, is hard to interpret because in the CHOIR Trial diabetics and non-diabetics assigned to low hemoglobin targets had similar event rates, and non-diabetics had higher event rates than diabetics assigned to the high hemoglobin target. Finding similar or higher event rates in non-diabetics than diabetics is somewhat surprising and might reflect unique features of their study population or random variability. The authors of the CHOIR secondary analysis reported that the relationship between epoetin dose and outcomes could not be assessed in diabetics because of small sample size. Our results support a harmful effect of receiving high epoetin doses, which might explain the higher risk found in the TREAT Trial among patients who were initially hyporesponsive to ESA therapy and who subsequently received the higher doses of darbepoetin-α and were at highest risk for adverse outcomes.10.Solomon S.D. Uno H. Lewis E.F. et al.Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes.N Engl J Med. 2010; 363: 1146-1155Crossref PubMed Scopus (375) Google Scholar There are several pathways through which higher epoetin exposures could be detrimental, including an increased risk of hypertension and thrombosis. According to Vaziri et al.13.Vaziri N.D. Cardiovascular effects of erythropoietin and anemia correction.Curr Opin Nephrol Hypertens. 2001; 10: 633-637Crossref PubMed Scopus (73) Google Scholar and others,14.Sasaki N. Ando Y. Kusano E. et al.A case of erythropoietin induced hypertension in a bilaterally nephrectomized patient.ASAIO J. 2003; 49: 131-135Crossref PubMed Scopus (4) Google Scholar, 15.Sunder-Plassmann G. Horl W.H. Effect of erythropoietin on cardiovascular diseases.Am J Kidney Dis. 2001; 38: S20-S25Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar chronic erythropoietin administration results in a Hct-independent, elevated vasoconstriction-dependent hypertension. Observational studies have shown that diabetes is associated with increased mortality in anemic CKD patients6.Vlagopoulos P.T. Tighiouart H. Weiner D.E. et al.Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease.J Am Soc Nephrol. 2005; 16: 3403-3410Crossref PubMed Scopus (232) Google Scholar and that anemia is associated with an increased risk of cardiovascular events in CKD patients with diabetes.6.Vlagopoulos P.T. Tighiouart H. Weiner D.E. et al.Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease.J Am Soc Nephrol. 2005; 16: 3403-3410Crossref PubMed Scopus (232) Google Scholar, 7.Tong P.C.Y. Kong A.P.S. So W.-Y. et al.Hematocrit, independent of chronic kidney disease, predicts adverse cardiovascular outcomes in Chinese patients with type 2 diabetes.Diabetes Care. 2006; 29: 2439-2444Crossref PubMed Scopus (56) Google Scholar At high ESA levels, diabetic hemodialysis patients could be at a higher risk for adverse outcomes when compared with their non-diabetic counterparts due to the increased presence of hypertension in this group.16.Suh D.C. Kim C.M. Choi I.S. et al.Trends in blood pressure control and treatment among type 2 diabetes with comorbid hypertension in the United States: 1988–2004.J Hypertens. 2009; 27: 1908-1916Crossref PubMed Scopus (74) Google Scholar Extra-hematopoietic effects of epoetin use, particularly worsening of hypertension, should be explored to determine whether it contributes to an increase in mortality and cardiovascular events among hemodialysis diabetic patients who are exposed to high ESA doses. Residual confounding might also partly explain our findings. Similar to previous observational studies,17.Bradbury B.D. Do T.P. Winkelmayer W.C. et al.Greater epoetin alfa (EPO) doses and short-term mortality risk among hemodialysis patients with hemoglobin levels less than 11 g/dl.Pharmacoepidemiol Drug Saf. 2009; 18: 932-940Crossref PubMed Scopus (24) Google Scholar, 18.Zhang Y. Thamer M. Stefanik K. et al.Epoetin requirements predict mortality in hemodialysis patients.Am J Kidney Dis. 2004; 44: 866-876Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 19.Zhang Y. Thamer M. Cotter D. et al.The estimated effect of epoetin dose on survival among elderly hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 638-644Crossref PubMed Scopus (36) Google Scholar, 20.Szczech L.A. Barnhart H.X. Sapp S. et al.A secondary analysis of CHOIR shows that comorbid conditions differentially affect outcomes during anemia treatment.Kidney Int. 2010; 77: 239-246Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar ours found a strong association between dose and mortality when not adjusting for the measured confounders or when using standard adjustment methods (Supplementary Appendix Table S1 online). Confounding adjustment via IP weighting—a theoretically correct method—brought the HRs closer to the null. A similar trend was reported in other observational studies that adjusted for confounding via IP weighting19.Zhang Y. Thamer M. Cotter D. et al.The estimated effect of epoetin dose on survival among elderly hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 638-644Crossref PubMed Scopus (36) Google Scholar, 21.Wang O. Kilpatrich R.D. Critchlow C.W. et al.Relationship between epoetin alfa dose and mortality: findings from a marginal structural model.Clin J Am Soc Nephrol. 2010; 5: 182-188Crossref PubMed Scopus (32) Google Scholar or instrumental variable estimation.17.Bradbury B.D. Do T.P. Winkelmayer W.C. et al.Greater epoetin alfa (EPO) doses and short-term mortality risk among hemodialysis patients with hemoglobin levels less than 11 g/dl.Pharmacoepidemiol Drug Saf. 2009; 18: 932-940Crossref PubMed Scopus (24) Google Scholar It is possible that further adjustment for factors that were unavailable (for example, use of insulin, β-blockers, and other drugs) could further attenuate the estimated risk at elevated dose levels. Interestingly, none of the published observational studies found a lower risk among those receiving higher epoetin doses. Our analysis has several limitations. First, the diagnosis of diabetes might be underreported in the United States Renal Data System (USRDS), and thus the differences we found between diabetics and non-diabetics might be attenuated. Second, the diagnosis of cardiovascular disease might also be imperfect because Medicare claims data were collected primarily for the purposes of billing for healthcare services. To limit the number of false positives for cardiovascular disease (which were identified by using International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes in our study), we used only the primary reason (diagnosis) for hospitalization, that is, CHF, or MI, or stroke. Third, use of iron might be overstated because of Medicare billing peculiarities dictating that providers’ bill for iron in vial size amounts (for example, 100 mg/vial) as opposed to billing for the actual amount administered to the patient. In conclusion, our findings suggest that using higher ESA doses as would be needed to achieve higher hemoglobin levels is not beneficial, and is possibly harmful, for diabetic patients. A smaller effect of dose was found in non-diabetic patients. Our results are consistent with Food and Drug Administration's (FDA’s) recent advisories that recommend the lowest possible ESA dose be used when treating hemodialysis patients. The USRDS is the national source for demographic and clinical data regarding ESRD patients and their institutional providers of dialysis treatment. Medicare coverage is provided for 93% of US dialysis patients. The USRDS Medicare claims database includes the monthly Hct and epoetin dose administered to Medicare dialysis patients. The ‘Researcher’s Guide to the USRDS Database’, available from http://www.usrds.org, describes variables, data sources, collection methods, and validation studies. We merged the USRDS standard analytic files for the calendar years 2004–2006 with the USRDS core CD files that contained variables from patient, medical evidence, facility, and physician/supplier data files. We identified incident hemodialysis patients who were 65 years and older, received their first ESRD service between 2004 and 2005, received their first outpatient dialysis service within the first 90 days after being certified as ESRD, did not have missing claims data during the 90-day baseline period, and had Medicare as their primary payer. These inclusions ensure that we had the complete Medicare (parts A and B) claims treatment history for our study group. Patients treated in hospital-based dialysis facilities have more comorbidities and a higher mortality rate when compared with those treated in freestanding dialysis facilities;22.US Renal Data System USRDS 2007 Annual Data Report: Atlas of End-stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD2007: 221Google Scholar hence, we restricted our study population to patients treated in freestanding facilities. We also excluded patients with a history of HIV or cancer as these patients might respond differently to epoetin therapy compared with the ESRD population at large.23.Henke M. Laszig R. Rube C. et al.Erythropoietin to treat head and neck cancer patients with anemia undergoing radiotherapy.Lancet. 2003; 362: 1255-1260Abstract Full Text Full Text PDF PubMed Scopus (1160) Google Scholar, 24.Leyland-Jones B. BEST investigators Breast cancer trial with erythropoietin terminated unexpectedly.Lancet. 2003; 4: 459-460http://oncology.thelancet.comAbstract Full Text Full Text PDF PubMed Scopus (471) Google Scholar, 25.Ifudu O. Mathew J.J. Mayers J.D. et al.Severity of AIDS and response to epoetin in uremia.Am J Kidney Dis. 1997; 30: 28-35Abstract Full Text PDF PubMed Scopus (18) Google Scholar Patients who received darbepoetin (0.9%) were excluded from the study. Finally, we classified a patient as diabetic if diabetes was reported to be the primary cause of renal failure and/or diabetes was listed as a comorbid condition on the Medical Evidence Form 2728, which is completed when a patient enrolls in the Medicare ESRD program (Figure 1). The two end points of interest were all-cause mortality and a composite outcome including death and hospitalization for MI, stroke, or CHF. The composite outcome was similar to the one used in two recent ESA randomized trials.1.Singh A.K. Szczech L. Tang K.L. et al.CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2280) Google Scholar, 9.Pfeffer M. Burdmann E.A. Cooper D.E. et al.A trial of darbepoetin-alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 1-14Crossref PubMed Scopus (1649) Google Scholar We defined the cardiovascular events included in the composite outcome measure by using the following ICD-9-CM codes: MI: codes 410.xx (except 410.x2); CHF: codes 402.x1, 425.xx, 428.xx, 518.4, and 398.91; and stroke: codes 430.xx, 431.xx, 432.xx, 433.xx, and 434.xx. Using these ICD-9 codes found on Medicare hospital claims, we determined the primary reason for hospitalization and identified those patients who experienced an event of interest. Once the initial 3 months of outpatient dialysis treatment had passed, patient follow-up began. The observation period ended 9 months later, or at death, or at a censoring event, whichever happened the earliest. The censoring events included: a change of dialysis modality; receipt of a kidney transplant; at 60 days after change of dialysis provider, or when a 30-day gap in outpatient dialysis services occurred. Patients who had experienced any of these censoring events during the first 3 months on dialysis were also excluded from the analysis. For each patient and each month of follow-up, we calculated the cumulative average dose of epoetin as the cumulative dose received since the start of follow-up divided by the time of follow-up. Epoetin administered during hospitalization is not available on Medicare claims data, although it is likely that hemodialysis patients with longer hospital stays would have received some epoetin. As in our previous study,4.Zhang Y. Thamer M. Cotter D. et al.Estimated effect of epoetin dosage on survival among elderly hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 638-644Crossref PubMed Scopus (42) Google Scholar we assumed that patients receive epoetin from day 5 of hospitalization onward at the same dose level (dose per administration) as they received during their immediate pre-hospitalization outpatient dialysis period. We also conducted a sensitivity analysis where we assumed that the same pre-hospitalization epoetin dose was given throughout the hospital stay. We fit a pooled logistic model to estimate the monthly probability of the outcome as a function of cumulative average log epoetin dose (cubic splines with knots located at 5th, 25th, 75th, and 95th percentiles of dose before that month), baseline covariates measured at the start of the follow-up, and cubic splines of follow-up (months). Our model also included product (‘interaction’) terms between cumulative average log epoetin dose and the month variables. As higher epoetin doses are more likely to be prescribed to patients with lower Hcts who also might be at higher mortality and cardiovascular risk, the estimates from our model needed to be adjusted for the effect of time-dependent confounding by indication.26.Hernán M.A. Hernandez-Diaz S. Robins J.M. A structural approach to selection bias.Epidemiology. 2004; 15: 615-625Crossref PubMed Scopus (1645) Google Scholar As previously described,27.Robins J.M. Hernán M.A. Brumback B. Marginal structural models and causal inference in epidemiology.Epidemiology. 2000; 11: 550-560Crossref PubMed Scopus (3379) Google Scholar we used IP weighting to adjust for time-dependent confounding by measured time-varying covariates, including Hct, iron treatment, and hospitalization. When the outcome of interest was death only, we also adjusted the model for hospitalization due to CHF, MI, and stroke. Each patient received a time-varying weight inversely proportional to the estimated probability of having his/her own observed epoetin dose history, as described elsewhere.4.Zhang Y. Thamer M. Cotter D. et al.Estimated effect of epoetin dosage on survival among elderly hemodialysis patients in the United States.Clin J Am Soc Nephrol. 2009; 4: 638-644Crossref PubMed Scopus (42) Google Scholar Briefly, the IP weights were estimated by fitting two nested models: (1) a logistic regression model to estimate each patient's probability of not receiving epoetin at any given month (7% of the patient-months had zero dose) and (2) a linear regression model to estimate each patient's density (assumed to be normal) of the log epoetin dose among those patients with non-zero dose in that month. Both models included the baseline covariates and time-varying covariates listed above plus the following product terms: between Hct and log epoetin dose; between Hct and hospitalization; and between chains and both baseline epoetin dose and time-varying epoetin dose (because chain characteristics are associated with epoetin dosing patterns28.Thamer M. Zhang Y. Kaufman J. et al.Dialysis facility ownership and epoetin dosing in patients receiving hemodialysis.JAMA. 2007; 297: 1667-1674Crossref PubMed Scopus (99) Google Scholar). IP weights were also estimated to adjust for potential selection bias because of censoring. Both the epoetin dose and censoring weights were stabilized and the product (of these weights) was used to fit the weighted regression model. The mean of estimated epoetin treatment weights was 1.02, and the 99th percentile was 5.80. The mean of the estimated censoring weights was 0.99, and the 99th percentile was 1.07. We truncated the IP weights to a maximum of 20 and used those observations in the primary analyses. Truncation did not materially affect the point estimates. All models were fit separately for diabetic and non-diabetic patients. We then applied the weighted logistic model to estimate the survival curve under three hypothetical scenarios: all patients exposed to a cumulative average dose of (1) 15,000 U/week, (2) 30,000U/week, and (3) 45,000 /week. These dose levels were selected to approximate low, average, and high exposure to epoetin. Point-wise 95% confidence intervals for the survival model were calculated via percentile-based non-parametric bootstrap based on 200 full samples. For comparison with previous analyses, we also estimated average HRs over the entire follow-up. We fitted the weighted logistic model for this outcome without product terms between epoetin dose and other variables, and with epoetin dose replaced by a categorical variable at five dose levels: 0 to <10,000; 10,000 to <20,000; 20,000 to <30,000; 30,000 to <40,000; and ≥40,000 U/week. The reference group, chosen to represent FDA-recommended dosage levels, was 20,000–30,000 U/week. To assess potential effect modification by diabetic status, we estimated the 9-month survivals separately in diabetics and non-diabetics and used bootstrapping (200 samples) to test whether the differences were equal to zero. All analyses were conducted with SAS 9.1 (SAS Institute, Cary, NC). The study was supported by the US National Institutes of Health Grants R01-DK066011-01A2 and R01-HL080644-01, and the US Agency for Healthcare Research and Quality Grant R21-HS19513-01. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as the official policy or interpretation of the US government. Figure S1. (A) Survival probabilities for three selected dosage regimens: Low dosage (15,000 U/week), medium dosage (30,000 U/week), and high dosage (45,000 U/week), based on the secondary analysis which inputs epoetin throughout the duration of the hospital stay. (B) Composite outcome defined as death or hospitalization for myocardial infarction, stroke, or congestive heart failure. Table S1. Cumulative average epoetin dose and hazard ratios (HR) based on standard models (controlling for baseline variables only). Table S2. Cumulative average epoetin dosage and hazard ratios (HR) for weighted regression models based on untruncated weights. Table S3. Cumulative average epoetin dose and hazard ratios (HR) based on inverse probability weighting using lowest dose level as the reference. Supplementary material is linked to the online version of the paper at http://www.nature.com/ki" @default.
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• W2073613013 title "High doses of epoetin do not lower mortality and cardiovascular risk among elderly hemodialysis patients with diabetes" @default.
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