- Email: [email protected]
Erythropoiesis-Stimulating Agents: Dose and Mortality Risk
ICURT PROCEEDINGS
Erythropoiesis-Stimulating Agents: Dose and Mortality Risk Guido Bellinghieri, MD, Prof,* Carmela Giuseppina Condemi, MD,*,† Salvatore Saitta, MD,* Gianluca Trifiro, MD, Prof,* Sebastiano Gangemi, MD, Prof,* Vincenzo Savica, MD, Prof,* Michele Buemi, MD, Prof,* and Domenico Santoro, MD, Prof* Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality in end-stage renal disease patients. It is not clear if this effect is related to the elevated ESAs dosage for targeting hemoglobin levels or underlying morbid conditions that lead to ESA resistance. We retrospectively evaluated from 2008 to death or December 2011, 28 consecutive incident hemodialysis patients. We identified 2 cohort of patients based on their mean annual ESAs dosage. The correlation between data was evaluated with the Spearman’s rho test. Kaplan–Meier curves were generated to assess survival in subjects with high and low ESAs mean dose. Median ESAs dosage, used as a cutoff point between patients at high and low ESAs dose, was at 11.000 IU/week for epoetin alfa and beta, 55 mcg/week for darbopoietin, and 220 mcg/month for cera. Mean hemoglobin (Hb) level was 10.58 6 0.13 g/dL. Of 28 patients, during follow-up, 6 (21,4%) died of all causes. High-dose ESA therapy was associated with increased all-cause mortality (P 5 .047). Moreover, there was a negative correlation between ESAs dose and Hb levels (rho 5 20.825; P , .001). Higher ESAs dose for the treatment of anemia in incident hemodialysis patients was associated with higher mortality risk. ESAs and Hb serum levels were inversely correlated with mortality. Together, these findings suggest that ESAs dosage and Hb level may play a role through an independent manner or an interactive effect that adversely affects mortality. Ó 2015 by the National Kidney Foundation, Inc. All rights reserved.
A
NEMIA IS A risk factor for cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients1 and is considered a predictor of low quality of life. The introduction of erythropoiesis-stimulating agents (ESAs) for treating anemia in patients with chronic kidney disease (CKD) has been associated with a lower risk of death (20%–70%) and of hospitalization (20%–40%).2 Also, a decrease in hemoglobin (Hb) levels over time has been associated with higher death risk, independent of baseline Hb in hemodialysis patients; falling Hb levels necessitating higher ESA doses were associated with decreased survival.3 The relationship regarding the benefits of treating anemia and decreasing cardiovascular and cerebrovascular mortality derives from observational studies, that simply indicate an association but no causal relationship. Indeed, randomized clinical trials, aimed to achieve Hb targets of 12.0 to 13.5 g/dL compared with Hb levels of 10 to 12 g/dL using different varieties of *
Department of Clinical and Experimental Medicine, University of Messina, Italy. † Unit of Nephrology and Dialysis, San Giovanni XXII Hospital, Bergamo, Italy. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Domenico Santoro, MD, Department of Clinical and Experimental Medicine, University of Messina, Messina 98168, Italy.
E-mail: [email protected] Ó
2015 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.10.012
164
ESAs or without ESA treatment, have consistently shown an increase in adverse vascular events in ESA-treated patients.4-6 A meta-analysis showed that administering ESA to achieve Hb targets .12.5 g/dL led to an increased risk of all-cause mortality (Risk ratio [RR], 1.17; confidence interval [CI] 95%: 1-13.5; P 5.031) compared with administering ESA to achieve Hb targets between 9.0 and 12.0 g/ dL.7 The results of the ‘‘Trial to Reduce Cardiovascular Events with Aranesp Therapy’’ conducted in 4,038 diabetic patients with early CKD not on dialysis showed a significant increase in cerebrovascular events, in patients treated with darbopoietin alfa (RR, 1.92; CI 95%: 1.38-2.68; P , .001) and targeted to reach Hb levels above 12.5 g/ dL, with no significant quality of life advantage.8 A major question that remains to be addressed is whether there is a correlation between dose–response gradient of ESAs and adverse events. To examine this issue, we performed a retrospective exploratory study to evaluate the correlation between ESAs dose and all-cause mortality.
Patients and Methods Study Cohort and Data Collection We studied retrospectively all incident hemodialysis patients of our Academic Unit in Messina University Hospital. Our Institutions Ethics Review Board approved the study. Of 156 incident hemodialysis patients from 2008 to 2011, we selected 28 subjects (17.9%). We considered eligible for the study, only patients who remained in our centre after Journal of Renal Nutrition, Vol 25, No 2 (March), 2015: pp 164-168
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starting hemodialysis, to have their complete follow-up. As a result, the majority of incident patients initiated on dialysis at our unit but discharged to another facility for maintenance dialysis were not enrolled. Additionally, 22 patients (14.1%) with a previous history of high dose (.6,000/IU of epoetin alfa and beta; .30 mcg/week of darbopoetin; .120 mcg of cera/month) of ESA treatment were excluded from the study. Demographic characteristics, CKD and medical history, dialysis and medication prescriptions, and laboratory data were recorded. Diabetes was defined by the use of any hypoglycaemic agents. Hypertension was defined by the use of antihypertensive medication or blood pressure .130/ 85 mm Hg. At follow-up, the occurrence of fatal and nonfatal cardiovascular events, including episodes of acute myocardial infarction (AMI) and acute cerebral ischemia, was abstracted during the period from January 2008 until December 2011 in the medical records. The primary outcome was all-cause mortality rate, and the secondary outcomes were nonfatal cardiovascular and cerebrovascular events. Death events were classified as due to cardiovascular disease (CVD), i.e., myocardial infarction, congestive heart failure, stroke, sudden death, or to nonCVD (infection, malignancy and other, and unknown causes).
Laboratory Measurements Blood sampling was performed every month, on a midweek dialysis day. All serum parameters were measured using standard accredited laboratory techniques in our hospital. We included in the analysis of the following laboratory data: hemoglobin, iron status (iron, transferrin, and ferritin), C-reactive protein (CRP), and echocardiography performed in the last 6 months; in particular, we registered the ejection fraction. ESAs, Hb Evaluation, and Iron Status All ESAs used in the present study were epoetin a or epoetin b, darbopoetin, and cera given intravenously at the end of dialysis session. For each patient, we calculated the mean value of ESAs dosage and Hb for each year. Because most studies have examined associations between baseline Hb values and survival and ignored variations in clinical and laboratory measures over time, we decided to correlate the mean annual values, during 4 different years. For methodological reason, we converted ESAs of first (epoietin a and epoetin b) and second (darbopoietin) generation to ESAs of third (metossipolietilenglicole-epoetina beta) generation (mcg/month). We used a conventional ratio of 200-1 to convert from the first to second generation ESAs, according to the data sheet of the drug, and a ratio of 1-4 to convert from the second to third generation ESAs (mcg/month).9 After conversion, we defined ESAs dosage as 2 categories, . or #220 mcg/month, according to the median values in our cohort (interquartile range, 165-324 mcg/month).
The iron status of each patient was ascertained at each monthly visit with ferritin and saturated transferrin (TSAT) levels. All patients received iron supplementation to maintain adequate stores (saturated transferrin .20%).
Statistical Analysis Statistical analysis was performed using SPSS for Windows (version 17.0, SPSS Inc., Chicago, IL.). All continuous variables were expressed as mean 6 standard deviation. Differences between data series were analyzed by the Mann– Whitney test and between categorical groups by the Fisher’s exact test. The correlation between data was evaluated with the Spearman’s rho test. Kaplan–Meier curves were generated to assess survival in subjects with ESAs mean dose above and below 220 mcg (using Gehan-Breslow-Wilcoxon Test). Statistical significance for all tests was set at P , .05.
Results At the end of the observed period (4 years) there were 6 deaths in the 28 incident patients (21.4%). Kaplan–Meier survival curves in patients with ESAs mean dose above and below 220 mcg/month are presented in Figure 1. In subjects with ESAs mean dose above 220 mcg/month, the mortality was higher (P 5 .047). There was no difference between subjects treated with ESAs mean dose above and below 220 mcg, except for Hb (respectively 11.31 6 0.62 vs. 10.34 6 0.53; P 5 .00110 (Table 1). There was a negative correlation between ESAs in mcg and Hb (rho 5 20.825; P , .001; Fig. 2). The mean Hb level was lower in dialysis patients who died compared with survivors (10.16 6 0.52 vs. 11.01 6 0.7 g/dL; P 5.019; Fig. 3). The annual mean value of CRP, at the start of dialysis, was higher in dialysis patients who died compared with survivors (1.2 6 0.17 vs. 0.31 6 0.29 g/dL; P 5.025; Fig. 4). The last recorded ejection fraction was lower in deceased compared with survivors, but the difference was not statistically significant
Figure 1. Kaplan–Meier survival curves in subjects with ESAs mean dose above and below 220 mcg. In subjects with ESAs mean dose above 220 mcg, the mortality increases (P 5 .047; Gehan-Breslow-Wilcoxon Test). ESA, erythropoiesis-stimulating agent.
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Table 1. Differences Between Subjects Treated With ESA Mean Dose Above and Below 220 mcg Parameter
Below 220 mcg
Above 220 mcg
P
Number Gender (M/F) Age (y) Dialytic age (mo) AVF (number) Hb (g/dL mean) CRP (g/dL mean) EF (% last) AMI (number) ACI (number) Heart disease (number, %) Hypertension (number, %) Vascular disease (number, %) HBV (number, %) HCV (number, %) Diabetes (number, %)
14 11/3 64 6 10.92 25.71 6 6.66 1.38 6 0.96 11.31 6 0.62 0.88 6 0.83 54.14 6 11.94 0.43 6 0.65 — 13 (92.86) 12 (85.71) 6 (42.86) 1 (7.14) 2 (14.29) 6 (42.86)
14 6/8 63.29 6 14.4 20.71 6 12.8 1.29 6 0.61 10.34 6 0.53 1.17 6 1.07 56.38 6 6.95 0.36 6 0.63 0.21 6 0.43 10 (71.43) 12 (85.71) 5 (35.71) 1 (7.14) 1 (7.14) 5 (35.71)
— .12 (1) .945 (2) .963 (2) .856 (2) .001 (2) .581 (2) .98 (2) .716 (2) .072 (2) .326 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1)
ACI, acute cerebral ischemia; AMI, acute myocardial infarction; CRP, C-reactive protein; ESA, erythropoiesis-stimulating agent; EF, ejection fraction; Hb, hemoglobin; HBV, hepatitis B virus; HCV, hepatitis C virus; IC, ictus cerebri. For P, (1) the Fisher’s exact test and (2) Mann-Whitney test were used. The differences statistically significant have been bolded.
(56.27 6 10.18 vs. 50.6 6 6.27%; P 5 .07), whereas the number of acute cerebral ischemia (0.5 6 0.21 vs. 0.33 6 0.52; P 5 .047) was lower in survivors. All differences between survivors and deceased are shown in Table 2. There was a positive correlation between dialytic age in months and AMI (rho 5 0.41; P 5.01). In 28 dialysis patients, the presence of other pathology (such as heart disease, hypertension, diabetes, vascular disease, hepatitis C virus, and hepatitis B virus) did not affect the number of deceased.
The gold standard for managing anemia of CKD is the use of ESAs; however, targeting higher Hb levels with ESAs has been associated with increased risk of CVD– related morbidity and mortality7,8,11
In our study, we found that higher ESAs dosage was associated with higher all-cause mortality after adjustment for a range of potential confounding factors. Moreover, there was a negative correlation between ESAs mean dosage and Hb mean levels (rho 5 20.825; P , .001). Taken together, these results suggest that higher mortality observed in our patients was related to inadequate ESAs responsiveness as defined by ESAs dosage and Hb level. Understanding the potential role of the ESAs dose versus the target or achieved Hb level is of crucial importance because in some studies, the group of patients targeted to achieve elevated Hb levels, independently of ESAs dosage, had no benefits, with in some cases increased adverse events.4-6,8 Analysis of the Trial to Reduce Cardiovascular Events with Aranesp Therapy study showed a direct correlation between a poor initial hematopoietic response to darbepoetin
Figure 2. Correlation between Hb mean levels and ESAs mean dose in dialysis patients (P , .001, rho 5 20.25; Spearman’s rho test). ESA, erythropoiesis-stimulating agent; Hb, hemoglobin.
Figure 3. Bars represent means 6 standard deviations of Hb mean levels in dialysis patients, in survivors these levels were higher than those in deceased (P 5 .019; Mann–Whitney test). Hb, hemoglobin.
Discussion
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Figure 4. Bars represent means 6 standard deviations of CRP levels at the start of dialysis in dialysis patients; in survivors, these levels were lower than those in deceased (P 5 .025; Mann–Whitney test). CRP, C-reactive protein.
alfa and an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target Hb levels.12 A further analysis did not find a different ESA dose between the groups of patients with or without stroke.13 We found also a positive correlation of CRP with age. This may be the result of aging as reported in the data released from the National Health and Nutrition Examination Survey, 1999 through 2002, which includes a sample of 21,004 people.14 However, inefficient ESAs responsiveness has been associated with poor outcome and this effect correlated also with inflammatory status.15 It was suggested that ESAs dose and Hb level should not be considered separately when evaluating their effects on mortality.16
A recent meta-regression analysis, examined the association of ESAs dose with adverse outcomes independent of target or achieved Hb level. A total of 31 trials (12,956 patients) examined showed that all-cause mortality was associated with higher mean ESAs dose (Incidence rate ratio, 1.09; 95% CI, 1.02-1.18). The authors concluded that in patients with CKD, higher ESAs dose might be associated with all-cause mortality and cardiovascular complications independent of Hb level.17 The progression of cardiac disease with duration of dialysis may also be an important determinant because in our patients, there was a positive correlation between dialytic age in months and AMI (P 5.01; rho 5 0.41). This correlation strongly empathizes the role of vascular calcifications that tend to progress with the age on dialysis as it was demonstrated that end-stage renal disease patients with the progression of vascular calcification have an unfavorable outcome.18 It is well known that the development of vascular calcification plays a pivotal role in CVD and is related to disturbances in calcium–phosphorus metabolism.19-21 Vascular calcification is independently associated with all-cause and cardiovascular mortality in both general population and end-stage renal disease.22 Therefore, identification of mineral metabolism disorder and prevention of vascular calcification may be important for clinicians to manage dialysis patients. The limitations of our study are the small number of patients and the fact that this is a single-center study. Additionally, because patients on hemodialysis have very high cardiovascular risk, increased mortality may be the results of several co-existent factors rather than an effect related to ESAs.
Table 2. Differences Between Survivors and Deceased, Mean 6 SD Parameter Number Gender (M/F) Age (y) Dialytic age (mo) AVF (number) Hb (g/dL mean) ESA (mcg mean) P (mg/dL mean) PTH (mean) CRP (g/dL mean) EF (% last) AMI (number) IC (number) Heart disease (number, %) Hypertension (number, %) Vascular disease (number, %) HBV (number, %) HCV (number, %) Diabetes (number, %)
Survivors
Deceased
P
22 14/8 62.27 6 11.85 27.18 6 10.36 1.38 6 0.86 11 6 0.7 229.74 6 114.55 5.2 6 1 188.62 6 120.37 0.95 6 0.93 56.27 6 10.18 0.32 6 0.57 0.5 6 2.1 19 (86.36) 19 (86.36) 7 (31.81) 2 (9.09) 2 (9.09) 9 (40.91)
6 3/3 68.67 6 14.88 20.33 6 6.77 1.17 6 0.4 10.16 6 0.52 302.33 6 98.36 5.1 6 0.75 117.48 6 72.56 1.27 6 1.09 50.6 6 6.27 0.67 6 0.82 0.33 6 0.52 4 (66.67) 5 (83.33) 4 (66.67) 0 (0) 1 (16.67) 2 (33.33)
— .653 (1) .275 (2) .123 (2) .663 (2) .019 (2) .093 (2) .723 (2) .194 (2) .467 (2) .073 (2) .26 (2) .047 (2) .285 (1) 1 (1) .174 (1) 1 (1) .530 (1) 1 (1)
AMI, acute myocardial infarction; CRP, C-reactive protein; EF, ejection fraction; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HBV, hepatitis B virus; HCV, hepatitis C virus; IC, ictus cerebri, PTH, parathormone; SD, standard deviation. For P, (1) the Fisher’s exact test and (2) Mann–Whitney test were used. The differences statistically significant have been bolded.
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Strength of our study is the number of the variables used for statistical analysis that were not the results of a single value, but rather a mean value of 12-month blood samples. Indeed, for each year, we considered in the analysis, we had a mean values of each variable like Hb and ESAs dose. In addition, the study included only incident patients on hemodialysis, without any prior history of high ESAs dosage. Our study raises the question whether ESAs dose may be considered an independent predictor of mortality and other adverse cardiovascular events in patients with CKD on dialysis in whom the highest ESAs doses are used. Future studies are needed to be focused on the effect of ESAs dose rather than target Hb level on cardiovascular end points. A trial is on going to assess the benefits and harms of a high versus a low fixed ESAs dose for the management of anemia in patients with end-stage kidney disease and to better understand determinants of individual variables for ESAs responsiveness.23 This trial, using an absolute dosing protocol, hopefully would help revise current anemia treatment guidelines in CKD by incorporating not only target Hb level but also the optimal ESAs dose. In conclusion, our retrospective analysis showed that higher ESAs dose for the treatment of anemia in incident hemodialysis patients might be associated with higher mortality risk. Moreover, we showed a negative correlation between ESAs and hemoglobin. Together, these findings suggest that ESAs dosage and Hb level may play a role through an independent manner and an interactive effects on mortality.
References 1. Eckardt KU. Managing a fateful alliance: anaemia and cardiovascular outcomes. Nephrol Dial Transplant. 2005;20(suppl 6):vi16-vi20. 2. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol. 2001;12:2465-2473. 3. Regidor DL, Kopple JD, Kovesdy CP, et al. Association between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. 2006;17:1181-1191. 4. Besarab A, Bolton WK, Browne JK, 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(suppl 9):584-590.5. 5. Singh AK, Szczech L, Tang KL, et al. CHOIR investigators: correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098. 6. Dr€ ueke TB, Locatelli F, Clyne N, et al., CREATE Investigators. Normalization of Hb level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355(suppl 20):2071-2084.
7. Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369: 381-388. 8. Pfeffer MA, Burdmann EA, Chen CY, et al., TREAT Investigators. A trial of darbopoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019-2032. 9. Minutolo R, Zamboli P, Chiodini P, et al. Conversion of darbepoetin to low doses of CERA maintains Hb levels in non-dialysis chronic kidney disease patients. Blood Purif. 2010;30:186-194. 10. De Nicola L, Chiodini P, Zoccali C, et al., SIN-TABLE CKD Study Group. Prognosis of CKD patients receiving outpatient nephrology care in Italy. Clin J Am Soc Nephrol. 2011;6:2421-2428. 11. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010;153:23-33. 12. Solomon SD, Uno H, Lewis EF, 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;363:1146-1155. 13. Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with darboetin alfa: the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) experience. Circulation. 2011;124:2903-2908. 14. Woloshin S, Schwartz LM. Distribution of C-reactive protein values in the United States. N Engl J Med. 2005;352:1611-1613. 15. Panichi V, Rosati A, Bigazzi R, et al., RISCAVID Study Group. Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant. 2011;26:2641-2648. 16. Fukuma S, Yamaguchi T, Hashimoto S, et al. Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan. Am J Kidney Dis. 2012;59:108-116. 17. Koulouridis I, Alfayez M, Trikalinos TA, Balk EM, Jaber BL. Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. Am J Kidney Dis. 2013;61:44-56. 18. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis. 1996;27:394-401. 19. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208-2218. 20. Noordzij M, Cranenburg EM, Engelsman LF, et al., NECOSAD Study Group. Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients. Nephrol Dial Transplant. 2011;26:1662-1669. 21. Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res. 2011;109:697-711. 22. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18:1731-1740. 23. Strippoli GF, Clinical Evaluation of the DOse of Erythropoietins Study Group (C.E. DOSE). Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol. Trials. 2010;11:70.
Erythropoiesis-Stimulating Agents: Dose and Mortality Risk Guido Bellinghieri, MD, Prof,* Carmela Giuseppina Condemi, MD,*,† Salvatore Saitta, MD,* Gianluca Trifiro, MD, Prof,* Sebastiano Gangemi, MD, Prof,* Vincenzo Savica, MD, Prof,* Michele Buemi, MD, Prof,* and Domenico Santoro, MD, Prof* Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality in end-stage renal disease patients. It is not clear if this effect is related to the elevated ESAs dosage for targeting hemoglobin levels or underlying morbid conditions that lead to ESA resistance. We retrospectively evaluated from 2008 to death or December 2011, 28 consecutive incident hemodialysis patients. We identified 2 cohort of patients based on their mean annual ESAs dosage. The correlation between data was evaluated with the Spearman’s rho test. Kaplan–Meier curves were generated to assess survival in subjects with high and low ESAs mean dose. Median ESAs dosage, used as a cutoff point between patients at high and low ESAs dose, was at 11.000 IU/week for epoetin alfa and beta, 55 mcg/week for darbopoietin, and 220 mcg/month for cera. Mean hemoglobin (Hb) level was 10.58 6 0.13 g/dL. Of 28 patients, during follow-up, 6 (21,4%) died of all causes. High-dose ESA therapy was associated with increased all-cause mortality (P 5 .047). Moreover, there was a negative correlation between ESAs dose and Hb levels (rho 5 20.825; P , .001). Higher ESAs dose for the treatment of anemia in incident hemodialysis patients was associated with higher mortality risk. ESAs and Hb serum levels were inversely correlated with mortality. Together, these findings suggest that ESAs dosage and Hb level may play a role through an independent manner or an interactive effect that adversely affects mortality. Ó 2015 by the National Kidney Foundation, Inc. All rights reserved.
A
NEMIA IS A risk factor for cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients1 and is considered a predictor of low quality of life. The introduction of erythropoiesis-stimulating agents (ESAs) for treating anemia in patients with chronic kidney disease (CKD) has been associated with a lower risk of death (20%–70%) and of hospitalization (20%–40%).2 Also, a decrease in hemoglobin (Hb) levels over time has been associated with higher death risk, independent of baseline Hb in hemodialysis patients; falling Hb levels necessitating higher ESA doses were associated with decreased survival.3 The relationship regarding the benefits of treating anemia and decreasing cardiovascular and cerebrovascular mortality derives from observational studies, that simply indicate an association but no causal relationship. Indeed, randomized clinical trials, aimed to achieve Hb targets of 12.0 to 13.5 g/dL compared with Hb levels of 10 to 12 g/dL using different varieties of *
Department of Clinical and Experimental Medicine, University of Messina, Italy. † Unit of Nephrology and Dialysis, San Giovanni XXII Hospital, Bergamo, Italy. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Domenico Santoro, MD, Department of Clinical and Experimental Medicine, University of Messina, Messina 98168, Italy.
E-mail: [email protected] Ó
2015 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.10.012
164
ESAs or without ESA treatment, have consistently shown an increase in adverse vascular events in ESA-treated patients.4-6 A meta-analysis showed that administering ESA to achieve Hb targets .12.5 g/dL led to an increased risk of all-cause mortality (Risk ratio [RR], 1.17; confidence interval [CI] 95%: 1-13.5; P 5.031) compared with administering ESA to achieve Hb targets between 9.0 and 12.0 g/ dL.7 The results of the ‘‘Trial to Reduce Cardiovascular Events with Aranesp Therapy’’ conducted in 4,038 diabetic patients with early CKD not on dialysis showed a significant increase in cerebrovascular events, in patients treated with darbopoietin alfa (RR, 1.92; CI 95%: 1.38-2.68; P , .001) and targeted to reach Hb levels above 12.5 g/ dL, with no significant quality of life advantage.8 A major question that remains to be addressed is whether there is a correlation between dose–response gradient of ESAs and adverse events. To examine this issue, we performed a retrospective exploratory study to evaluate the correlation between ESAs dose and all-cause mortality.
Patients and Methods Study Cohort and Data Collection We studied retrospectively all incident hemodialysis patients of our Academic Unit in Messina University Hospital. Our Institutions Ethics Review Board approved the study. Of 156 incident hemodialysis patients from 2008 to 2011, we selected 28 subjects (17.9%). We considered eligible for the study, only patients who remained in our centre after Journal of Renal Nutrition, Vol 25, No 2 (March), 2015: pp 164-168
165
ESA DOSE AND MORTALITY
starting hemodialysis, to have their complete follow-up. As a result, the majority of incident patients initiated on dialysis at our unit but discharged to another facility for maintenance dialysis were not enrolled. Additionally, 22 patients (14.1%) with a previous history of high dose (.6,000/IU of epoetin alfa and beta; .30 mcg/week of darbopoetin; .120 mcg of cera/month) of ESA treatment were excluded from the study. Demographic characteristics, CKD and medical history, dialysis and medication prescriptions, and laboratory data were recorded. Diabetes was defined by the use of any hypoglycaemic agents. Hypertension was defined by the use of antihypertensive medication or blood pressure .130/ 85 mm Hg. At follow-up, the occurrence of fatal and nonfatal cardiovascular events, including episodes of acute myocardial infarction (AMI) and acute cerebral ischemia, was abstracted during the period from January 2008 until December 2011 in the medical records. The primary outcome was all-cause mortality rate, and the secondary outcomes were nonfatal cardiovascular and cerebrovascular events. Death events were classified as due to cardiovascular disease (CVD), i.e., myocardial infarction, congestive heart failure, stroke, sudden death, or to nonCVD (infection, malignancy and other, and unknown causes).
Laboratory Measurements Blood sampling was performed every month, on a midweek dialysis day. All serum parameters were measured using standard accredited laboratory techniques in our hospital. We included in the analysis of the following laboratory data: hemoglobin, iron status (iron, transferrin, and ferritin), C-reactive protein (CRP), and echocardiography performed in the last 6 months; in particular, we registered the ejection fraction. ESAs, Hb Evaluation, and Iron Status All ESAs used in the present study were epoetin a or epoetin b, darbopoetin, and cera given intravenously at the end of dialysis session. For each patient, we calculated the mean value of ESAs dosage and Hb for each year. Because most studies have examined associations between baseline Hb values and survival and ignored variations in clinical and laboratory measures over time, we decided to correlate the mean annual values, during 4 different years. For methodological reason, we converted ESAs of first (epoietin a and epoetin b) and second (darbopoietin) generation to ESAs of third (metossipolietilenglicole-epoetina beta) generation (mcg/month). We used a conventional ratio of 200-1 to convert from the first to second generation ESAs, according to the data sheet of the drug, and a ratio of 1-4 to convert from the second to third generation ESAs (mcg/month).9 After conversion, we defined ESAs dosage as 2 categories, . or #220 mcg/month, according to the median values in our cohort (interquartile range, 165-324 mcg/month).
The iron status of each patient was ascertained at each monthly visit with ferritin and saturated transferrin (TSAT) levels. All patients received iron supplementation to maintain adequate stores (saturated transferrin .20%).
Statistical Analysis Statistical analysis was performed using SPSS for Windows (version 17.0, SPSS Inc., Chicago, IL.). All continuous variables were expressed as mean 6 standard deviation. Differences between data series were analyzed by the Mann– Whitney test and between categorical groups by the Fisher’s exact test. The correlation between data was evaluated with the Spearman’s rho test. Kaplan–Meier curves were generated to assess survival in subjects with ESAs mean dose above and below 220 mcg (using Gehan-Breslow-Wilcoxon Test). Statistical significance for all tests was set at P , .05.
Results At the end of the observed period (4 years) there were 6 deaths in the 28 incident patients (21.4%). Kaplan–Meier survival curves in patients with ESAs mean dose above and below 220 mcg/month are presented in Figure 1. In subjects with ESAs mean dose above 220 mcg/month, the mortality was higher (P 5 .047). There was no difference between subjects treated with ESAs mean dose above and below 220 mcg, except for Hb (respectively 11.31 6 0.62 vs. 10.34 6 0.53; P 5 .00110 (Table 1). There was a negative correlation between ESAs in mcg and Hb (rho 5 20.825; P , .001; Fig. 2). The mean Hb level was lower in dialysis patients who died compared with survivors (10.16 6 0.52 vs. 11.01 6 0.7 g/dL; P 5.019; Fig. 3). The annual mean value of CRP, at the start of dialysis, was higher in dialysis patients who died compared with survivors (1.2 6 0.17 vs. 0.31 6 0.29 g/dL; P 5.025; Fig. 4). The last recorded ejection fraction was lower in deceased compared with survivors, but the difference was not statistically significant
Figure 1. Kaplan–Meier survival curves in subjects with ESAs mean dose above and below 220 mcg. In subjects with ESAs mean dose above 220 mcg, the mortality increases (P 5 .047; Gehan-Breslow-Wilcoxon Test). ESA, erythropoiesis-stimulating agent.
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Table 1. Differences Between Subjects Treated With ESA Mean Dose Above and Below 220 mcg Parameter
Below 220 mcg
Above 220 mcg
P
Number Gender (M/F) Age (y) Dialytic age (mo) AVF (number) Hb (g/dL mean) CRP (g/dL mean) EF (% last) AMI (number) ACI (number) Heart disease (number, %) Hypertension (number, %) Vascular disease (number, %) HBV (number, %) HCV (number, %) Diabetes (number, %)
14 11/3 64 6 10.92 25.71 6 6.66 1.38 6 0.96 11.31 6 0.62 0.88 6 0.83 54.14 6 11.94 0.43 6 0.65 — 13 (92.86) 12 (85.71) 6 (42.86) 1 (7.14) 2 (14.29) 6 (42.86)
14 6/8 63.29 6 14.4 20.71 6 12.8 1.29 6 0.61 10.34 6 0.53 1.17 6 1.07 56.38 6 6.95 0.36 6 0.63 0.21 6 0.43 10 (71.43) 12 (85.71) 5 (35.71) 1 (7.14) 1 (7.14) 5 (35.71)
— .12 (1) .945 (2) .963 (2) .856 (2) .001 (2) .581 (2) .98 (2) .716 (2) .072 (2) .326 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1)
ACI, acute cerebral ischemia; AMI, acute myocardial infarction; CRP, C-reactive protein; ESA, erythropoiesis-stimulating agent; EF, ejection fraction; Hb, hemoglobin; HBV, hepatitis B virus; HCV, hepatitis C virus; IC, ictus cerebri. For P, (1) the Fisher’s exact test and (2) Mann-Whitney test were used. The differences statistically significant have been bolded.
(56.27 6 10.18 vs. 50.6 6 6.27%; P 5 .07), whereas the number of acute cerebral ischemia (0.5 6 0.21 vs. 0.33 6 0.52; P 5 .047) was lower in survivors. All differences between survivors and deceased are shown in Table 2. There was a positive correlation between dialytic age in months and AMI (rho 5 0.41; P 5.01). In 28 dialysis patients, the presence of other pathology (such as heart disease, hypertension, diabetes, vascular disease, hepatitis C virus, and hepatitis B virus) did not affect the number of deceased.
The gold standard for managing anemia of CKD is the use of ESAs; however, targeting higher Hb levels with ESAs has been associated with increased risk of CVD– related morbidity and mortality7,8,11
In our study, we found that higher ESAs dosage was associated with higher all-cause mortality after adjustment for a range of potential confounding factors. Moreover, there was a negative correlation between ESAs mean dosage and Hb mean levels (rho 5 20.825; P , .001). Taken together, these results suggest that higher mortality observed in our patients was related to inadequate ESAs responsiveness as defined by ESAs dosage and Hb level. Understanding the potential role of the ESAs dose versus the target or achieved Hb level is of crucial importance because in some studies, the group of patients targeted to achieve elevated Hb levels, independently of ESAs dosage, had no benefits, with in some cases increased adverse events.4-6,8 Analysis of the Trial to Reduce Cardiovascular Events with Aranesp Therapy study showed a direct correlation between a poor initial hematopoietic response to darbepoetin
Figure 2. Correlation between Hb mean levels and ESAs mean dose in dialysis patients (P , .001, rho 5 20.25; Spearman’s rho test). ESA, erythropoiesis-stimulating agent; Hb, hemoglobin.
Figure 3. Bars represent means 6 standard deviations of Hb mean levels in dialysis patients, in survivors these levels were higher than those in deceased (P 5 .019; Mann–Whitney test). Hb, hemoglobin.
Discussion
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Figure 4. Bars represent means 6 standard deviations of CRP levels at the start of dialysis in dialysis patients; in survivors, these levels were lower than those in deceased (P 5 .025; Mann–Whitney test). CRP, C-reactive protein.
alfa and an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target Hb levels.12 A further analysis did not find a different ESA dose between the groups of patients with or without stroke.13 We found also a positive correlation of CRP with age. This may be the result of aging as reported in the data released from the National Health and Nutrition Examination Survey, 1999 through 2002, which includes a sample of 21,004 people.14 However, inefficient ESAs responsiveness has been associated with poor outcome and this effect correlated also with inflammatory status.15 It was suggested that ESAs dose and Hb level should not be considered separately when evaluating their effects on mortality.16
A recent meta-regression analysis, examined the association of ESAs dose with adverse outcomes independent of target or achieved Hb level. A total of 31 trials (12,956 patients) examined showed that all-cause mortality was associated with higher mean ESAs dose (Incidence rate ratio, 1.09; 95% CI, 1.02-1.18). The authors concluded that in patients with CKD, higher ESAs dose might be associated with all-cause mortality and cardiovascular complications independent of Hb level.17 The progression of cardiac disease with duration of dialysis may also be an important determinant because in our patients, there was a positive correlation between dialytic age in months and AMI (P 5.01; rho 5 0.41). This correlation strongly empathizes the role of vascular calcifications that tend to progress with the age on dialysis as it was demonstrated that end-stage renal disease patients with the progression of vascular calcification have an unfavorable outcome.18 It is well known that the development of vascular calcification plays a pivotal role in CVD and is related to disturbances in calcium–phosphorus metabolism.19-21 Vascular calcification is independently associated with all-cause and cardiovascular mortality in both general population and end-stage renal disease.22 Therefore, identification of mineral metabolism disorder and prevention of vascular calcification may be important for clinicians to manage dialysis patients. The limitations of our study are the small number of patients and the fact that this is a single-center study. Additionally, because patients on hemodialysis have very high cardiovascular risk, increased mortality may be the results of several co-existent factors rather than an effect related to ESAs.
Table 2. Differences Between Survivors and Deceased, Mean 6 SD Parameter Number Gender (M/F) Age (y) Dialytic age (mo) AVF (number) Hb (g/dL mean) ESA (mcg mean) P (mg/dL mean) PTH (mean) CRP (g/dL mean) EF (% last) AMI (number) IC (number) Heart disease (number, %) Hypertension (number, %) Vascular disease (number, %) HBV (number, %) HCV (number, %) Diabetes (number, %)
Survivors
Deceased
P
22 14/8 62.27 6 11.85 27.18 6 10.36 1.38 6 0.86 11 6 0.7 229.74 6 114.55 5.2 6 1 188.62 6 120.37 0.95 6 0.93 56.27 6 10.18 0.32 6 0.57 0.5 6 2.1 19 (86.36) 19 (86.36) 7 (31.81) 2 (9.09) 2 (9.09) 9 (40.91)
6 3/3 68.67 6 14.88 20.33 6 6.77 1.17 6 0.4 10.16 6 0.52 302.33 6 98.36 5.1 6 0.75 117.48 6 72.56 1.27 6 1.09 50.6 6 6.27 0.67 6 0.82 0.33 6 0.52 4 (66.67) 5 (83.33) 4 (66.67) 0 (0) 1 (16.67) 2 (33.33)
— .653 (1) .275 (2) .123 (2) .663 (2) .019 (2) .093 (2) .723 (2) .194 (2) .467 (2) .073 (2) .26 (2) .047 (2) .285 (1) 1 (1) .174 (1) 1 (1) .530 (1) 1 (1)
AMI, acute myocardial infarction; CRP, C-reactive protein; EF, ejection fraction; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HBV, hepatitis B virus; HCV, hepatitis C virus; IC, ictus cerebri, PTH, parathormone; SD, standard deviation. For P, (1) the Fisher’s exact test and (2) Mann–Whitney test were used. The differences statistically significant have been bolded.
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Strength of our study is the number of the variables used for statistical analysis that were not the results of a single value, but rather a mean value of 12-month blood samples. Indeed, for each year, we considered in the analysis, we had a mean values of each variable like Hb and ESAs dose. In addition, the study included only incident patients on hemodialysis, without any prior history of high ESAs dosage. Our study raises the question whether ESAs dose may be considered an independent predictor of mortality and other adverse cardiovascular events in patients with CKD on dialysis in whom the highest ESAs doses are used. Future studies are needed to be focused on the effect of ESAs dose rather than target Hb level on cardiovascular end points. A trial is on going to assess the benefits and harms of a high versus a low fixed ESAs dose for the management of anemia in patients with end-stage kidney disease and to better understand determinants of individual variables for ESAs responsiveness.23 This trial, using an absolute dosing protocol, hopefully would help revise current anemia treatment guidelines in CKD by incorporating not only target Hb level but also the optimal ESAs dose. In conclusion, our retrospective analysis showed that higher ESAs dose for the treatment of anemia in incident hemodialysis patients might be associated with higher mortality risk. Moreover, we showed a negative correlation between ESAs and hemoglobin. Together, these findings suggest that ESAs dosage and Hb level may play a role through an independent manner and an interactive effects on mortality.
References 1. Eckardt KU. Managing a fateful alliance: anaemia and cardiovascular outcomes. Nephrol Dial Transplant. 2005;20(suppl 6):vi16-vi20. 2. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol. 2001;12:2465-2473. 3. Regidor DL, Kopple JD, Kovesdy CP, et al. Association between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. 2006;17:1181-1191. 4. Besarab A, Bolton WK, Browne JK, 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(suppl 9):584-590.5. 5. Singh AK, Szczech L, Tang KL, et al. CHOIR investigators: correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098. 6. Dr€ ueke TB, Locatelli F, Clyne N, et al., CREATE Investigators. Normalization of Hb level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355(suppl 20):2071-2084.
7. Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369: 381-388. 8. Pfeffer MA, Burdmann EA, Chen CY, et al., TREAT Investigators. A trial of darbopoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019-2032. 9. Minutolo R, Zamboli P, Chiodini P, et al. Conversion of darbepoetin to low doses of CERA maintains Hb levels in non-dialysis chronic kidney disease patients. Blood Purif. 2010;30:186-194. 10. De Nicola L, Chiodini P, Zoccali C, et al., SIN-TABLE CKD Study Group. Prognosis of CKD patients receiving outpatient nephrology care in Italy. Clin J Am Soc Nephrol. 2011;6:2421-2428. 11. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010;153:23-33. 12. Solomon SD, Uno H, Lewis EF, 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;363:1146-1155. 13. Skali H, Parving HH, Parfrey PS, et al. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with darboetin alfa: the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) experience. Circulation. 2011;124:2903-2908. 14. Woloshin S, Schwartz LM. Distribution of C-reactive protein values in the United States. N Engl J Med. 2005;352:1611-1613. 15. Panichi V, Rosati A, Bigazzi R, et al., RISCAVID Study Group. Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant. 2011;26:2641-2648. 16. Fukuma S, Yamaguchi T, Hashimoto S, et al. Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan. Am J Kidney Dis. 2012;59:108-116. 17. Koulouridis I, Alfayez M, Trikalinos TA, Balk EM, Jaber BL. Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. Am J Kidney Dis. 2013;61:44-56. 18. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis. 1996;27:394-401. 19. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208-2218. 20. Noordzij M, Cranenburg EM, Engelsman LF, et al., NECOSAD Study Group. Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients. Nephrol Dial Transplant. 2011;26:1662-1669. 21. Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res. 2011;109:697-711. 22. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18:1731-1740. 23. Strippoli GF, Clinical Evaluation of the DOse of Erythropoietins Study Group (C.E. DOSE). Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol. Trials. 2010;11:70.