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without prior lavage period&#58;</p><p class="elsevierStylePara">- Subcutaneous darbepoetin alpha&#58; 2&#44;016 patients&#46; Initially administered every 2 weeks at a dose of 0&#46;75&#181;g&#47;kg and subsequently adjusted to obtain and maintain Hb at 13g&#47;dl&#46; The maximum monthly dose was preset at 600&#181;g&#46; After obtaining Hb of 12-13&#46;5g&#47;dl during two consecutive determinations&#44; a monthly dose of darbepoetin was given&#46;</p><p class="elsevierStylePara">- Placebo&#58; 2&#44;031 patients&#46; For any figure of Hb &#60; 9g&#47;dl&#44; a&#160; single subcutaneous dose of darbepoetin alpha was administered&#44; 0&#46;45&#181;g&#47;kg and subsequently the dose was adjusted every 2 weeks until Hb was &#62;9g&#47;dl&#44; at which point the patient was again given a placebo&#46;</p><p class="elsevierStylePara">Adjustments to the dose were made using an interactive voice response system which&#44; in the case of&#160; the placebo group&#44; simulated the changes that were made in the darbepoetin alpha group&#46; After the adjustment of&#160; the initial dose&#44; visits and Hb determinations were conducted monthly&#44; and other analytic controls every 4 to 6 months&#46; The events analysis was done at weeks 1&#44; 13&#44; 25 and subsequently every 24 weeks&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">Outcome variables</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"></span><span class="elsevierStyleBold">Primary&#58; </span><br></br>- Time to first event&#44; defined as the composite variable of death by any cause or cardiovascular event &#40;MI&#44; heart failure&#44; ACVA or hospitalisation for myocardial ischemia&#41;&#44; or&#58;<br></br>- Time to composite variable of death by any cause or end-stage kidney disease &#40;need for renal replacement treatment&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Secondary&#58;</span><br></br>- Time until death&#46;<br></br>- Cardiovascular mortality&#46;<br></br>- Cardiovascular events&#46; <br></br>- GFR decrease&#46;<br></br>- Changes in two quality of life questionnaires from week 25&#58; FACT-Fatigue &#40;Functional Assessment of Cancer Therapy-Fatigue&#41; and 36-Item Short-Form General Health Survey questionnaire &#40;SF-36&#41;&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">Sample size </span></p><p class="elsevierStylePara">It was calculated that 1203 events would be necessary to detect&#44; with a statistical power of 80&#37;&#44; a 20&#37; risk reduction in the group treated with darbepoetin alpha&#44; assuming an annual event rate of 12&#46;5&#37; in the placebo group&#44; a 15&#37; annual follow-up loss and attenuation in treatment effect due to the early use of erythropoiesis stimulating agents in patients who progressed to terminal renal failure&#46; 0&#46;048 was considered a type I error for the estimation of the sample size and intermediate analyses were made once 20&#44; 40&#44; 60 and 80&#37; of the total expected cardiovascular events were registered&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">Statistical analysis</span></p><p class="elsevierStylePara">Intention to treat Kaplan-Meier curves were used and comparisons based on the log-rank test&#44; stratified in terms of baseline proteinuria and the presence or absence of a history of cardiovascular disease&#46; Hazard ratios and CI 95&#37; were estimated with the stratified Cox proportional hazards model&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">Ethics and registration</span></p><p class="elsevierStylePara">Protocol approved by the ethics committees of each participating centre&#46; Written informed consent was obtained from all patients&#46; The trial was registered at ClinicalTrials&#46;gov with number NCT00093015&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">Promotion</span></p><p class="elsevierStylePara">The trial was financed by Amgen&#46; The authors made a conflict of interest statement&#46; Two of them are employees of Amgen and the rest claim to have received fees for different activities from various pharmaceutical laboratories&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">PRINCIPAL RESULTS</span></p><p class="elsevierStylePara">Nine patients &#40;four in the group treated with darbepoetin alpha and five in the placebo group&#41; were eliminated from the analysis because their centres did not meet the Good Clinical Practice Guidelines&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">BASELINE ANALYSIS OF GROUPS</span></p><p class="elsevierStylePara">The two groups had similar baseline characteristics&#46; The mean age was 68 years&#44; with 57&#46;3&#37; women&#46; The median known duration time of diabetes was 15&#46;4 years&#46; 65&#46;4&#37; had previous cardiovascular disease&#46;</p><p class="elsevierStylePara">The darbepoetin group had a lower proportion of heart failure than the control group &#40;31&#46;5 against 35&#46;2&#37;&#59; p &#61; 0&#46;01&#41;&#46; There were no differences in the remaining demographic&#44; clinical or laboratory variables&#46;</p><p class="elsevierStylePara">The median baseline Hb was 10&#46;4g&#47;dl &#40;interquartile interval &#91;IQ&#93;&#58; 9&#46;8-10&#46;9&#41;&#44; transferrin saturation was 23&#37; in both groups and ferritin 131 against 137&#181;g&#47;l&#46; 41&#46;8&#37; against 42&#46;7&#37; received oral iron supplements&#44; 1&#46;4&#37; against 1&#46;6&#37; intravenous iron and 8&#46;8&#37; against 10&#46;2&#37; had previously received an erythropoietin stimulating factor &#40;darbepoetin group with respect to control group&#41;&#46;</p><p class="elsevierStylePara">At the close of the database&#44; there had been a follow-up loss of 153 patients &#40;7&#46;6&#37;&#41; from the darbepoetin group and 164 &#40;8&#46;1&#37;&#41; of the placebo group&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">PRIMARY AND SECONDARY VARIABLES</span> &#40;table 1&#41;</p><p class="elsevierStylePara">History of cardiovascular disease &#40;RR 1&#46;32&#59; CI&#58; 1&#46;20-1-45&#41; and proteinuria &#62; 1mg&#47;mg &#40;protein quotient&#47;creatinine in isolated urine sample&#41; &#40;RR 2&#46;03&#59; CI&#58; 1&#46;20-1&#46;45&#41; or of a first cardiovascular event&#44; identified a population at greater risk of death&#44; independently of the assigned group&#44; treatment or placebo&#46; Absence of treatment effect with darbepoetin was observed in each prespecified subgroup&#44; with no significant interactions with age&#44; sex&#44; ethnic group&#44; region or baseline GF&#46;</p><p class="elsevierStylePara">In the follow-up of the groups&#58;</p><p class="elsevierStylePara">1&#46; The median Hb from the third month to end of study was 12&#46;5g&#47;dl &#40;IQ&#58; 12&#46;0-12&#46;8&#41; in the darbepoetin group and&#160; 10&#46;6g&#47;dl &#40;IQ&#58; 9&#46;9-11&#46;3&#41; in the placebo group&#46; <br></br>2&#46; The median monthly dose of darbepoetin in both groups was 176 &#181;g &#40;CI&#58; 104-305&#41; and 0 &#40;IQ&#58; 0-5&#41;&#46; <br></br>3&#46; 46&#37; of patients assigned a placebo received at least one dose of darbepoetin as rescue therapy&#46; <br></br>4&#46; The placebo group received more intravenous iron &#40;20&#46;4 against 14&#46;8&#37;&#59; p &#60; 0&#46;001&#41;&#46; There were no differences in the proportion of patients who received oral iron &#40;66&#46;8 against 68&#46;6&#37;&#59; p &#61; 0&#46;25&#41;&#46; <br></br>5&#46; The placebo group required more transfusions&#58; 496 &#40;24&#46;5&#37;&#41; against 297 &#40;14&#46;8&#37;&#41;&#59; HR&#58; darbepoetin against placebo&#58; 0&#46;56&#59; &#40;CI&#58; 49-0&#46;65&#41;&#59; p &#60; 0&#46;001&#46; <br></br>6&#46; Diastolic blood pressure was higher in those treated with darbepoetin&#46; Mean&#58; 73mmHg &#40;IQ&#58; 67-78&#41; against 71mmHg &#40;65-77&#41;&#59; p &#60; 0&#46;001&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">SECONDARY EFFECTS</span></p><p class="elsevierStylePara">The main differences between the two groups were a higher rate of venous and arterial thrombosis in the darbepoetin group and a greater mortality from cancer in those patients treated with darbepoetin with history of neoplasia &#40;Table 2&#41;&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">AUTHORS CONCLUSIONS</span></p><p class="elsevierStylePara">Treatment with darbepoetin alpha in patients with diabetes&#44; with CKD and not on dialysis and with moderate anaemia does not reduce the combined risk of death and presentation of a cardiovascular event&#44; or death and inclusion in renal replacement treatment&#44; but is associated with an increased risk of ictus&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">REVIEWERS COMMENTS</span></p><p class="elsevierStylePara">The TREAT trial is a multicentre&#44; randomised&#44; double-blind study with rigorous methodology&#44; that shows the absence of benefits from treatment with darbepoetin alpha&#44; in terms of mortality&#44; cardiovascular events and progression to end-stage kidney disease in the study population&#58; diabetics with CKD and anaemia &#40;Hb &#60; 11g&#47;dl&#41; and with an elevated rate of cardiovascular morbidity and mortality &#40;30&#37; in 29 months of follow-up&#41;&#44; which corresponds to that estimated in the calculation of sample size&#46; It also casts serious doubts on the appropriateness of normalising Hb in this population since it increases the risk of ictus&#44; thrombotic phenomena and&#44; in those patients with history of neoplasias&#44; the risk of mortality from cancer&#46;</p><p class="elsevierStylePara">The TREAT trial confirms the findings of other non-blind studies such as the CREATE and the CHOIR&#46; In these studies&#44; erythropoiesis stimulating agents were used on CKD patients to obtain two treatment targets&#44; Hb&#58; 11 or 13-15g&#47;dl and also showed no benefits in terms of lesser risk of mortality or cardiovascular events&#46; Specifically&#44; the CHOIR reported a greater cardiovascular morbidity and mortality in the high Hb group&#46; In these two clinical trials&#44; the highest Hb groups had received more iron supplements&#44; suggesting that the treatment with iron could have been a confusing factor in the results&#46; However&#44; in the TREAT study&#44; the group with the lowest Hb received more iron supplements&#44; which would not support that hypothesis&#46;</p><p class="elsevierStylePara">The benefits demonstrated in the TREAT study in the intervention group &#40;lesser risk of receiving transfusions&#44; lesser rate of coronary revascularisation and a slight increase in the score in one of the quality of life questionnaires&#41;&#44; and the allogeneic sensitisation in potential renal transplant recipients because of the greater number of transfusions in the control group&#44; compares unfavourably with the secondary effects described &#40;greater risk of ictus and thrombotic phenomena&#44; greater mortality from cancer if there is a history of neoplasias&#41;&#46; This unfavourable safety profile coincides with the findings in other clinical trials in other populations&#44; especially oncological&#46;</p><p class="elsevierStylePara">However&#44; some issues of the TREAT study should be taken into account&#46; The first refers to the evolution of anaemia in the placebo group&#44; with a median of 10&#46;4g&#47;dl and which increased to 10&#46;6g&#47;dl in the follow-up&#44; implying that many patients in the placebo group would not have had anaemia secondary to treatment with erythropoiesis stimulating agents&#44; in accordance with the current recommendations of the clinical practice guidelines&#46; The study does not describe &#40;it was not one of its objectives&#41; whether the patients in the placebo group with persistently low haemoglobin&#44; and which are those who&#44; in clinical practice&#44; suggest the appropriateness of intervention&#44; had better or worse evolution than the treated group&#46;</p><p class="elsevierStylePara">The second aspect is related to the dose of darbepoetin used in the intervention group&#44; 176&#181;g&#47;month &#40;IQ&#58; 104-305&#41;&#44; which indicates that many patients received higher doses than typically used in CKD patients not on dialysis&#46; Observational studies and the subanalysis of studies like the CHOIR indicate that the higher the dose of epoetin required to obtain target Hb&#44; the greater the risk of complications&#46; Whether this tendency also applies to patients in the TREAT study&#44; is not addressed and will probably be the focus of analysis in other studies&#46;</p><p class="elsevierStylePara">¿ <span class="elsevierStyleBold">REVIEWERS COMMENTS</span></p><p class="elsevierStylePara">This study&#44; along with the available evidence&#44; shows that treatment with erythropoiesis stimulating factors in an attempt to normalise Hb levels in diabetic patients with CKD not on dialysis&#44; does not provide benefits in terms of morbidity and mortality and raises doubts about the safety of this strategy&#46;</p><p class="elsevierStylePara"><a href="grande&#47;1003518078&#95;t1&#95;pag116&#46;jpg" class="elsevierStyleCrossRefs"><img src="1003518078_t1_pag116.jpg" alt="PRIMARY AND SECONDARY VARIABLES"></img></a></p><p class="elsevierStylePara">Table 1&#46; PRIMARY AND SECONDARY VARIABLES</p><p class="elsevierStylePara"><a href="grande&#47;1003518078&#95;t2&#95;pag117&#46;jpg" class="elsevierStyleCrossRefs"><img src="1003518078_t2_pag117.jpg" alt="SECONDARY EFFECTS"></img></a></p><p class="elsevierStylePara">Table 2&#46; SECONDARY EFFECTS</p>"
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