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Iron treatment and the TREAT trial

Iron treatment and the TREAT trial NDT Plus (2011) 4 [Suppl 1]: i3–i5 doi: 10.1093/ndtplus/sfr041 Francesco Locatelli Department of Nephrology, Dialysis and Renal Transplant “Alessandro Manzoni” Hospital, Lecco, Italy Correspondence and offprint requests to: Francesco Locatelli; E-mail: nefrologia@ospedale.lecco.it Abstract ment therapy [1,2] after having ruled out all other causes of anaemia. Dose requirements in achieving anaemia cor- Treatment with erythropoiesis-stimulating agents (ESAs) rection are quite variable and poorly predictable in the in- enables the correction of anaemia in chronic kidney dis- dividual patient. However, a number of patients need a ease (CKD) patients, thus reducing its symptoms and com- greater than usual ESA dose and are defined as hyporespon- plications. Not only is iron therapy aimed at correcting sives. According to the European Best Practice Guidelines iron deficiency, but also it is an adjuvant therapy in (EBPG) [1], resistance to ESA treatment is defined as a con- CKD patients receiving ESAs. Iron stores in CKD patients tinued need for >20 000 IU/week (300 IU/kg/week) of may be near normal, but there may be insufficient imme- rHuEPO administered subcutaneously or 1.5 μg/kg of dar- diately available iron to optimize ESA therapy. In this con- bepoetin alfa (>100 μg/week); this means that resistant pa- text, iron therapy significantly reduces ESA dose tients require more than 2.5 times the average ESA dose. requirements. Erythropoiesis following ESA therapy may The most common cause of incomplete response to precipitate iron deficiency in association with increased ESAs is absolute or functional iron deficiency. According platelet production. In the TREAT trial, the ‘placebo group’ to an Italian cross-sectional study [3], 16% of patients had did not receive a true ‘placebo’since 46% of the patients had a transferrin saturation of <15%, which is considerably at least one dose of ESA and achieved progressively in- below that recommended in the EBPG and in the National creased haemoglobin (Hb) values during follow-up against Kidney Foundation-Kidney Disease Outcomes Quality the common observation. The patients in the ‘placebo’ Initiative (KDOQI) guidelines [1,2]. Angiotensin II- group were treated more frequently with intravenous iron converting enzyme inhibitors and angiotensin II receptor than the darbepoetin group. Given that many patients were blockers, often used in CKD patients for controlling relatively iron deficient at baseline, iron administration was hypertension and possibly slowing down the progression successful in many of them in obtaining and maintaining of CKD, may also play a role. However, compliance partial anaemia correction without the need for ESAs, thus should always be checked in patients self-administering underlining the great importance of iron supplementation in an ESA. correcting anaemia. The upper safety limit for iron adminis- tered to patients in order to minimize, as much as possible, the ESA dose and the upper limit for ESA dosage for main- taining the target Hb range as suggested by the current Iron status guidelines are still open questions. Iron status should be checked every 1–3 months according Keywords: anaemia; CKD; ESA; iron therapy; TREAT trial to clinical needs [1,2]. This information should be evalu- ated together with Hb levels, ESA doses and their trend over time, in order to elucidate the status of both external Anaemia response to erythropoiesis-stimulating (gain or losses) and internal iron balance (distribution of agents iron in stores and erythrocytes) [2]. More widely used iron tests are serum ferritin and trans- Anaemia develops early in the course of chronic kidney ferrin saturation (TSAT) levels. However, these are not op- disease (CKD) and affects a large percentage of CKD pa- timal tests, as they lack accuracy and stability. Indeed, they tients; treatment with erythropoiesis-stimulating agents are greatly influenced by inflammation and malnutrition, (ESAs) enables the correction of anaemia, thus reducing two conditions often affecting CKD patients. its symptoms and complications. ESA therapy should be An ideal marker of functional iron deficiency should be given to treat anaemia in all CKD patients with a haemo- independent of erythropoietic activity. New cell counters globin (Hb) level persistently below 11 g/dL, from patients are able to determine cell volume and Hb concentration in the early stages of CKD to those receiving renal replace- separately on reticulocytes and mature erythrocytes. © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org i4 F. Locatelli Evidence for iron target in CKD patients not on dialysis in patients with a history of malignancies, and venous and is poor; a target of 100–500 ng/mL for serum ferritin le- arterial thromboembolic events in patients randomized to vels should be adequate to ensure effective erythropoiesis the higher Hb target, associated with a significant reduc- with ESA treatment. tion in cardiac revascularization procedures, number of transfusions and a mild improvement in quality of life. The interpretation of the TREAT results is complex [6]. Iron administration The simplest explanation is that higher Hb levels are the cause of increased occurrence of strokes through an The preferred route of iron administration in haemodialy- increase of blood viscosity and perhaps blood pressure sis patients is intravenous (IV); in PD and CKD patients (median diastolic blood pressure was slightly higher in not on dialysis, it can be either IV or oral [1,2]. the darbepoetin alfa group). However, in the Normal Oral iron is best absorbed when given without food; Hematocrit Study [7] and in the Correction of Hemoglobin constipation, diarrhoea, nausea or abdominal pain limits and Outcomes in Renal Insufficiency (CHOIR) trial [8], compliance. higher achieved Hb levels were associated with fewer In CKD patients, not only is iron therapy aimed at cor- cardiovascular events in each study arm. This leads to the recting iron deficiency, but it is also an adjuvant therapy hypothesis that the lower the dose of ESAs, the better the in patients receiving ESAs, to achieve and maintain the outcome [7]. However, the selection bias of survivors may Hb target. In these patients, iron stores may be near normal, have a role: patients achieving higher Hb concentrations but during ESA treatment, there may be insufficient may be healthier and thus more responsive to treatment. A immediately available iron to optimize ESA therapy. In secondary analysis of the CHOIR study [9] clearly pointed this context, iron therapy significantly reduces ESA dose out that high ESA doses may be related to increased cardio- requirements. vascular events not related to high Hb levels. The link between high ESA dose and negative outcomes may be sim- ply explained by the fact that patients with more comorbid- Iron, ESA and Hb target ities or those who are more inflamed are hyporesponsive to ESA treatment. High ESA dose may stimulate EPO recep- One of the hot topics in nephrology recently is the Hb tar- tors other than those controlling erythropoiesis. This could get from treatment with ESAs and/or iron therapy. Given exacerbate some pleiotropic effects of ESAs on endothelial that cardiovascular morbidity and mortality are a major and muscular cells. ESAs cause thrombocytosis in those pa- concern in CKD patients and lower Hb levels have been tients who are iron deficient. Erythropoiesis following ESA associated with poor outcomes, the most important trials therapy may precipitate iron deficiency. This has been asso- in the field have been designed mainly focusing on this ciated with increased platelet production and thus increased primary end point. thrombotic risk. Therefore, high ESA dosage could cause The hypothesis that complete anaemia correction with cardiovascular events not only through high Hb levels. ESAs would reduce the risk of death, cardiovascular and However, we should not misinterpret the association data renal end points among patients with type 2 diabetes and for ESA doses. Using higher ESA dosage for achieving the CKD not undergoing dialysis was the rationale of the last same Hb levels (or even not achieving it) is a marker of trial in the field, the Trial to Reduce cardiovascular Events comorbidities (inflamed patients reach lower Hb levels with Aranesp® Therapy (TREAT) [4]. More than 4000 pa- despite higher ESA dosages). tients were randomized to darbepoetin alfa to achieve an In the TREAT study, the median monthly darbepoetin Hb level of 13 g/dL or to placebo (with rescue darbepoetin dose in the group randomized to darbepoetin and higher alfa for Hb level <9.0 g/dL). Hb level was rather high (176 μg; interquartile range, 104–305) compared to that used in everyday clinical prac- tice in patients not on dialysis. The fact that the drug was Criticisms of the TREAT trial administered once a month in the majority of the patients and above all some of them were not fully iron-replete may The TREAT trial is the best trial in the field of anaemia have contributed to this high dose requirement. In fact, pa- published to date. However, at the early stages of the study, tients with a transferrin saturation of even 15% were eli- many criticisms were made regarding its design, either due gible for enrolment, and transferrin saturation and ferritin to ethical issues (a much lower Hb value than recom- levels were measured quarterly; moreover, there was no mended by guidelines was allowed in the control group) protocol for iron administration, and only 43% of the pa- or because it was considered of little informative use tients received iron at baseline and 66.8% (14.8% IV) in (the comparison did not take into account the ‘gold stand- the darbepoetin alfa group and 68.6% (20.4% IV) in the ard’ of treatment, i.e. partial anaemia correction according placebo group, during the follow-up trial. to current guidelines (Hb 11–12 g/dL)) [1–3,5]. This study clearly demonstrated that the use of darbe- Are we going to change the way we treat our poetin alfa in aiming at an Hb target of 13 g/dL in type patients? 2 diabetic patients not undergoing dialysis does not reduce the risk of the two primary composite outcomes. Besides, secondary analyses showed a higher risk of strokes mainly In my opinion, important limitations inherent to the study in patients with a history of strokes and death due to cancer design reduce the general applicability of TREAT results Iron treatment and the TREAT trial i5 and do not support substantial changes in the way we man- ESA dose and the upper limit for ESA dosage for main- age anaemia in our patients. taining the target Hb range as suggested by the current Literally, reading the intention-to-treat analysis of the guidelines are still open questions. Large prospective rando- TREAT, one could draw the misleading conclusion that mized trials are welcome for clarifying this very important we should treat CKD patients with ESA only if they have clinical issue. an Hb level below 9 g/dL that cannot be managed with Conflict of interest statement. F.L. was vice-chairman of the steering com- blood transfusions [10]. This is further supported by the mittee and an author of the CREATE study. He was a Country Principal results of the secondary analyses (lower risk of stroke, Investigator of the TREAT study and a liaison member of anaemia KDOQI thromboembolic events and death from malignancies in guideline group, chairman of anaemia EBPG group, and a member of the the ‘placebo group’ with lower Hb target range). Conversely, executive board of directors of KDIGO. He is a member of the ERBP group, of an advisory board of Affymax, Amgen-Dompé, Gsk, Janssen Roche and much less emphasis has been put on other secondary out- Takeda, and of a safety committee of Sandoz. comes, i.e. a lower risk of transfusions and cardiac revas- cularization and a better quality of life in the patients randomized to the darbepoetin alfa and higher Hb level. References Moreover, the ‘placebo group’ did not receive a true ‘placebo’ since 46% of the patients had at least one dose 1. Locatelli F, Aljama P, Bárány P et al. Revised European best practice guidelines for the management of anaemia in patients with chronic of ESA [10]. Even more importantly, despite a rescue value renal failure. European Best Practice Guidelines Working Group. of 9 g/dL, achieved Hb values progressively increased dur- Nephrol Dial Transplant 2004; 19: ii1–ii47 ing follow-up (from a median value of 10.4 g/dL at baseline 2. KDOQI. Clinical Practice Guidelines and Clinical practice recom- to 11.2 g/dL at the end of the study, with a median value of mendations for anemia in chronic kidney disease: 2007 update of 10.6 g/dL during follow-up). These achieved values are very haemoglobin target. Am J Kidney Dis 2007; 50: 471–530 close to the target range suggested by current guidelines 3. De Nicola L, Conte G, Chiodini P et al. Stability of target hemoglobin [1–3,5]. This positive trend is against the common observa- levels during the first year of epoetin treatment in patients with chronic kidney disease. Clin J Am Soc Nephrol 2007092: 938–946 tion that CKD patients show a decrease in Hb values during 4. Pfeffer MA, Burdmann EA, Chen CY et al. A trial of darbepoetin alfa the course of their disease, and this makes it hard for us to in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; accept the TREAT study as a ‘placebo’ randomized con- 361: 2019–2032 trolled trial [10]. In addition to rescue treatment with darbe- 5. Locatelli F, Covic A, Eckardt KU et al. ERA-EDTA ERBP Advisory poetin alfa, the patients in the ‘placebo’ group were treated Board.Nephrol Dial Transplant. Anaemia management in patients more frequently with IV iron (and blood transfusions) than with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP). Nephrol the darbepoetin group. Given that many patients were rela- Dial Transplant 2009; 24: 348–354 tively iron deficient at baseline, iron administration had 6. Locatelli F, Aljama P, Canaud B et al. On behalf of the Anaemia been successful in many of them in obtaining and maintain- Working Group of European Renal Best Practice (ERBP). Target ing partial anaemia correction without the need for ESAs. haemoglobin to aim for with erythropoiesis-stimulating agents: a However, transfusions cannot be considered as an alterna- position statement by ERBP following publication of the Trial to tive treatment for anaemia, and iron alone is not enough Reduce Cardiovascular Events with Aranesp(R) Therapy (TREAT) Study. Nephrol Dial Transplant 2010; 25: 2846–2850 in the later stages of CKD, as strongly demonstrated by 7. Besarab A, Bolton WK, Browne JK et al. The effects of normal as the pre-ESA era experience [11]. compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584–590 Conclusions 8. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. NEng JMed 2006; 335: The findings of the TREAT study underline the great 2085–2098 9. Szczech LA, Barnhart HX, Inrig JK et al. Secondary analysis of the importance of iron supplementation in correcting anaemia, CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. although this should be a well-established approach in Kidney Int 2008; 74: 791–798 everyday clinical practice and has already been clearly 10. Locatelli F, Del Vecchio L, Casartelli D. Darbepoetin alfa and chronic indicated by current guidelines [1–3,5]. The risk–benefit kidney disease. N Engl J Med 2010; 362: 654–655 of more transfusions should also be considered carefully, 11. Locatelli F, Del Vecchio L. Debate: CON Position. Should hemoglobin especially for patients who are potential candidates for targets for anemic patients with chronic kidney disease be changed? transplantation. Am J Nephrol 2010; 31: 557–560 Finally, the upper safety limit for iron administered to patients in order to minimize, as much as possible, the Received for publication: 28.3.11; Accepted: 28.3.11 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Iron treatment and the TREAT trial

Locatelli, Francesco
Clinical Kidney Journal , Volume 4 (suppl_1) – Jun 1, 2011
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© The Author [2011]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
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Abstract

NDT Plus (2011) 4 [Suppl 1]: i3–i5 doi: 10.1093/ndtplus/sfr041 Francesco Locatelli Department of Nephrology, Dialysis and Renal Transplant “Alessandro Manzoni” Hospital, Lecco, Italy Correspondence and offprint requests to: Francesco Locatelli; E-mail: nefrologia@ospedale.lecco.it Abstract ment therapy [1,2] after having ruled out all other causes of anaemia. Dose requirements in achieving anaemia cor- Treatment with erythropoiesis-stimulating agents (ESAs) rection are quite variable and poorly predictable in the in- enables the correction of anaemia in chronic kidney dis- dividual patient. However, a number of patients need a ease (CKD) patients, thus reducing its symptoms and com- greater than usual ESA dose and are defined as hyporespon- plications. Not only is iron therapy aimed at correcting sives. According to the European Best Practice Guidelines iron deficiency, but also it is an adjuvant therapy in (EBPG) [1], resistance to ESA treatment is defined as a con- CKD patients receiving ESAs. Iron stores in CKD patients tinued need for >20 000 IU/week (300 IU/kg/week) of may be near normal, but there may be insufficient imme- rHuEPO administered subcutaneously or 1.5 μg/kg of dar- diately available iron to optimize ESA therapy. In this con- bepoetin alfa (>100 μg/week); this means that resistant pa- text, iron therapy significantly reduces ESA dose tients require more than 2.5 times the average ESA dose. requirements. Erythropoiesis following ESA therapy may The most common cause of incomplete response to precipitate iron deficiency in association with increased ESAs is absolute or functional iron deficiency. According platelet production. In the TREAT trial, the ‘placebo group’ to an Italian cross-sectional study [3], 16% of patients had did not receive a true ‘placebo’since 46% of the patients had a transferrin saturation of <15%, which is considerably at least one dose of ESA and achieved progressively in- below that recommended in the EBPG and in the National creased haemoglobin (Hb) values during follow-up against Kidney Foundation-Kidney Disease Outcomes Quality the common observation. The patients in the ‘placebo’ Initiative (KDOQI) guidelines [1,2]. Angiotensin II- group were treated more frequently with intravenous iron converting enzyme inhibitors and angiotensin II receptor than the darbepoetin group. Given that many patients were blockers, often used in CKD patients for controlling relatively iron deficient at baseline, iron administration was hypertension and possibly slowing down the progression successful in many of them in obtaining and maintaining of CKD, may also play a role. However, compliance partial anaemia correction without the need for ESAs, thus should always be checked in patients self-administering underlining the great importance of iron supplementation in an ESA. correcting anaemia. The upper safety limit for iron adminis- tered to patients in order to minimize, as much as possible, the ESA dose and the upper limit for ESA dosage for main- taining the target Hb range as suggested by the current Iron status guidelines are still open questions. Iron status should be checked every 1–3 months according Keywords: anaemia; CKD; ESA; iron therapy; TREAT trial to clinical needs [1,2]. This information should be evalu- ated together with Hb levels, ESA doses and their trend over time, in order to elucidate the status of both external Anaemia response to erythropoiesis-stimulating (gain or losses) and internal iron balance (distribution of agents iron in stores and erythrocytes) [2]. More widely used iron tests are serum ferritin and trans- Anaemia develops early in the course of chronic kidney ferrin saturation (TSAT) levels. However, these are not op- disease (CKD) and affects a large percentage of CKD pa- timal tests, as they lack accuracy and stability. Indeed, they tients; treatment with erythropoiesis-stimulating agents are greatly influenced by inflammation and malnutrition, (ESAs) enables the correction of anaemia, thus reducing two conditions often affecting CKD patients. its symptoms and complications. ESA therapy should be An ideal marker of functional iron deficiency should be given to treat anaemia in all CKD patients with a haemo- independent of erythropoietic activity. New cell counters globin (Hb) level persistently below 11 g/dL, from patients are able to determine cell volume and Hb concentration in the early stages of CKD to those receiving renal replace- separately on reticulocytes and mature erythrocytes. © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org i4 F. Locatelli Evidence for iron target in CKD patients not on dialysis in patients with a history of malignancies, and venous and is poor; a target of 100–500 ng/mL for serum ferritin le- arterial thromboembolic events in patients randomized to vels should be adequate to ensure effective erythropoiesis the higher Hb target, associated with a significant reduc- with ESA treatment. tion in cardiac revascularization procedures, number of transfusions and a mild improvement in quality of life. The interpretation of the TREAT results is complex [6]. Iron administration The simplest explanation is that higher Hb levels are the cause of increased occurrence of strokes through an The preferred route of iron administration in haemodialy- increase of blood viscosity and perhaps blood pressure sis patients is intravenous (IV); in PD and CKD patients (median diastolic blood pressure was slightly higher in not on dialysis, it can be either IV or oral [1,2]. the darbepoetin alfa group). However, in the Normal Oral iron is best absorbed when given without food; Hematocrit Study [7] and in the Correction of Hemoglobin constipation, diarrhoea, nausea or abdominal pain limits and Outcomes in Renal Insufficiency (CHOIR) trial [8], compliance. higher achieved Hb levels were associated with fewer In CKD patients, not only is iron therapy aimed at cor- cardiovascular events in each study arm. This leads to the recting iron deficiency, but it is also an adjuvant therapy hypothesis that the lower the dose of ESAs, the better the in patients receiving ESAs, to achieve and maintain the outcome [7]. However, the selection bias of survivors may Hb target. In these patients, iron stores may be near normal, have a role: patients achieving higher Hb concentrations but during ESA treatment, there may be insufficient may be healthier and thus more responsive to treatment. A immediately available iron to optimize ESA therapy. In secondary analysis of the CHOIR study [9] clearly pointed this context, iron therapy significantly reduces ESA dose out that high ESA doses may be related to increased cardio- requirements. vascular events not related to high Hb levels. The link between high ESA dose and negative outcomes may be sim- ply explained by the fact that patients with more comorbid- Iron, ESA and Hb target ities or those who are more inflamed are hyporesponsive to ESA treatment. High ESA dose may stimulate EPO recep- One of the hot topics in nephrology recently is the Hb tar- tors other than those controlling erythropoiesis. This could get from treatment with ESAs and/or iron therapy. Given exacerbate some pleiotropic effects of ESAs on endothelial that cardiovascular morbidity and mortality are a major and muscular cells. ESAs cause thrombocytosis in those pa- concern in CKD patients and lower Hb levels have been tients who are iron deficient. Erythropoiesis following ESA associated with poor outcomes, the most important trials therapy may precipitate iron deficiency. This has been asso- in the field have been designed mainly focusing on this ciated with increased platelet production and thus increased primary end point. thrombotic risk. Therefore, high ESA dosage could cause The hypothesis that complete anaemia correction with cardiovascular events not only through high Hb levels. ESAs would reduce the risk of death, cardiovascular and However, we should not misinterpret the association data renal end points among patients with type 2 diabetes and for ESA doses. Using higher ESA dosage for achieving the CKD not undergoing dialysis was the rationale of the last same Hb levels (or even not achieving it) is a marker of trial in the field, the Trial to Reduce cardiovascular Events comorbidities (inflamed patients reach lower Hb levels with Aranesp® Therapy (TREAT) [4]. More than 4000 pa- despite higher ESA dosages). tients were randomized to darbepoetin alfa to achieve an In the TREAT study, the median monthly darbepoetin Hb level of 13 g/dL or to placebo (with rescue darbepoetin dose in the group randomized to darbepoetin and higher alfa for Hb level <9.0 g/dL). Hb level was rather high (176 μg; interquartile range, 104–305) compared to that used in everyday clinical prac- tice in patients not on dialysis. The fact that the drug was Criticisms of the TREAT trial administered once a month in the majority of the patients and above all some of them were not fully iron-replete may The TREAT trial is the best trial in the field of anaemia have contributed to this high dose requirement. In fact, pa- published to date. However, at the early stages of the study, tients with a transferrin saturation of even 15% were eli- many criticisms were made regarding its design, either due gible for enrolment, and transferrin saturation and ferritin to ethical issues (a much lower Hb value than recom- levels were measured quarterly; moreover, there was no mended by guidelines was allowed in the control group) protocol for iron administration, and only 43% of the pa- or because it was considered of little informative use tients received iron at baseline and 66.8% (14.8% IV) in (the comparison did not take into account the ‘gold stand- the darbepoetin alfa group and 68.6% (20.4% IV) in the ard’ of treatment, i.e. partial anaemia correction according placebo group, during the follow-up trial. to current guidelines (Hb 11–12 g/dL)) [1–3,5]. This study clearly demonstrated that the use of darbe- Are we going to change the way we treat our poetin alfa in aiming at an Hb target of 13 g/dL in type patients? 2 diabetic patients not undergoing dialysis does not reduce the risk of the two primary composite outcomes. Besides, secondary analyses showed a higher risk of strokes mainly In my opinion, important limitations inherent to the study in patients with a history of strokes and death due to cancer design reduce the general applicability of TREAT results Iron treatment and the TREAT trial i5 and do not support substantial changes in the way we man- ESA dose and the upper limit for ESA dosage for main- age anaemia in our patients. taining the target Hb range as suggested by the current Literally, reading the intention-to-treat analysis of the guidelines are still open questions. Large prospective rando- TREAT, one could draw the misleading conclusion that mized trials are welcome for clarifying this very important we should treat CKD patients with ESA only if they have clinical issue. an Hb level below 9 g/dL that cannot be managed with Conflict of interest statement. F.L. was vice-chairman of the steering com- blood transfusions [10]. This is further supported by the mittee and an author of the CREATE study. He was a Country Principal results of the secondary analyses (lower risk of stroke, Investigator of the TREAT study and a liaison member of anaemia KDOQI thromboembolic events and death from malignancies in guideline group, chairman of anaemia EBPG group, and a member of the the ‘placebo group’ with lower Hb target range). Conversely, executive board of directors of KDIGO. He is a member of the ERBP group, of an advisory board of Affymax, Amgen-Dompé, Gsk, Janssen Roche and much less emphasis has been put on other secondary out- Takeda, and of a safety committee of Sandoz. comes, i.e. a lower risk of transfusions and cardiac revas- cularization and a better quality of life in the patients randomized to the darbepoetin alfa and higher Hb level. References Moreover, the ‘placebo group’ did not receive a true ‘placebo’ since 46% of the patients had at least one dose 1. Locatelli F, Aljama P, Bárány P et al. Revised European best practice guidelines for the management of anaemia in patients with chronic of ESA [10]. Even more importantly, despite a rescue value renal failure. European Best Practice Guidelines Working Group. of 9 g/dL, achieved Hb values progressively increased dur- Nephrol Dial Transplant 2004; 19: ii1–ii47 ing follow-up (from a median value of 10.4 g/dL at baseline 2. KDOQI. Clinical Practice Guidelines and Clinical practice recom- to 11.2 g/dL at the end of the study, with a median value of mendations for anemia in chronic kidney disease: 2007 update of 10.6 g/dL during follow-up). These achieved values are very haemoglobin target. Am J Kidney Dis 2007; 50: 471–530 close to the target range suggested by current guidelines 3. De Nicola L, Conte G, Chiodini P et al. Stability of target hemoglobin [1–3,5]. This positive trend is against the common observa- levels during the first year of epoetin treatment in patients with chronic kidney disease. Clin J Am Soc Nephrol 2007092: 938–946 tion that CKD patients show a decrease in Hb values during 4. Pfeffer MA, Burdmann EA, Chen CY et al. A trial of darbepoetin alfa the course of their disease, and this makes it hard for us to in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; accept the TREAT study as a ‘placebo’ randomized con- 361: 2019–2032 trolled trial [10]. In addition to rescue treatment with darbe- 5. Locatelli F, Covic A, Eckardt KU et al. ERA-EDTA ERBP Advisory poetin alfa, the patients in the ‘placebo’ group were treated Board.Nephrol Dial Transplant. Anaemia management in patients more frequently with IV iron (and blood transfusions) than with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP). Nephrol the darbepoetin group. Given that many patients were rela- Dial Transplant 2009; 24: 348–354 tively iron deficient at baseline, iron administration had 6. Locatelli F, Aljama P, Canaud B et al. On behalf of the Anaemia been successful in many of them in obtaining and maintain- Working Group of European Renal Best Practice (ERBP). Target ing partial anaemia correction without the need for ESAs. haemoglobin to aim for with erythropoiesis-stimulating agents: a However, transfusions cannot be considered as an alterna- position statement by ERBP following publication of the Trial to tive treatment for anaemia, and iron alone is not enough Reduce Cardiovascular Events with Aranesp(R) Therapy (TREAT) Study. Nephrol Dial Transplant 2010; 25: 2846–2850 in the later stages of CKD, as strongly demonstrated by 7. Besarab A, Bolton WK, Browne JK et al. The effects of normal as the pre-ESA era experience [11]. compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584–590 Conclusions 8. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. NEng JMed 2006; 335: The findings of the TREAT study underline the great 2085–2098 9. Szczech LA, Barnhart HX, Inrig JK et al. Secondary analysis of the importance of iron supplementation in correcting anaemia, CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. although this should be a well-established approach in Kidney Int 2008; 74: 791–798 everyday clinical practice and has already been clearly 10. Locatelli F, Del Vecchio L, Casartelli D. Darbepoetin alfa and chronic indicated by current guidelines [1–3,5]. The risk–benefit kidney disease. N Engl J Med 2010; 362: 654–655 of more transfusions should also be considered carefully, 11. Locatelli F, Del Vecchio L. Debate: CON Position. Should hemoglobin especially for patients who are potential candidates for targets for anemic patients with chronic kidney disease be changed? transplantation. Am J Nephrol 2010; 31: 557–560 Finally, the upper safety limit for iron administered to patients in order to minimize, as much as possible, the Received for publication: 28.3.11; Accepted: 28.3.11

Journal

Clinical Kidney Journal – Oxford University Press

Published: Jun 1, 2011

Keywords: Keywords anaemia CKD ESA guidelines iron therapy TREAT trial

There are no references for this article.