This study tested whether treating anemia in patients with type 2 diabetes and chronic kidney disease using darbepoetin alfa would reduce rates of death and cardiovascular events compared to a placebo. Over 4,000 patients were randomized to receive darbepoetin alfa or placebo, with the goal of maintaining a hemoglobin level of 13.0 g/dL in the treatment group. The study found no significant difference in rates of death, cardiovascular events, or end-stage renal disease between the groups. However, there was an increase in stroke risk observed with darbepoetin alfa treatment.

1. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease NEJM Volume 361:2019-2032 November 19, 2009 Number 21 Wafa Badwan, MD March 16, 2010

2. Introduction Type 2 Diabetes and CKD each increase the risk of cardiovascular events and ESRD. Anemia is considered another biomarker of cardiovascular risk- especially in diabetic patients. Whether the use of ESA’s lowers this cardiac risk by increasing hemoglobin has not been studied.

3. Introduction Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Goal of the study was to test the hypothesis that patients with Type 2 diabetes and CKD- not yet dialysis dependent with anemia by using Darbepoetin, resulting in higher hemoglobin levels and therefore would reduce the rates of death, cardiovascular events and ESRD

4. Methods Randomized, double-blind placebo controlled trial 623 sites in 24 countries All patients provided written informed consent Approved by ethics committee at every site. Enrollment from August 25,2004 to December 4, 2007 Sponspored by Amgen

5. Study Population Patients with Type 2 diabetes, CKD with GFR of 20-60 cc/min with anemia defined as hemoglobin less than 11 g/dL and a transferrin saturation of 15% or more were eligible for enrollment. Exclusion criteria: uncontrolled hypertension, previous kidney transplantation or scheduled receipt of a kidney transplant from a living related donor.

6. Study Population Exclusion criteria cont.: Current use of IV antibiotics, chemotherapy, or radiation therapy Cancer except basal cell or squamous cell cancer HIV Active bleeding Hematologic disease Pregnancy Patients who had a cardiovascular event, grand mal seizure, had a major surgery. If they had received an ESA in the 12 weeks before randomization

7. Study Procedures Prestudy labs were obtained Patients were randomly assigned using a computer generated design to receive darbepoetin alfa or placebo. Randomization was stratified according to the study site, baseline level of proteinuria, and history of cardiovascular disease 12 different strengths in prefilled syringes were supplied

8. Study Procedures An algorithm was designed to adjust the dose to maintain a hemoglobin of 13.0 g/dL in those assigned to aranesp. Patients in the placebo group received aranesp as “rescue” drug if hemoglobin fell below 9 g/dL and would return to the placebo drug once hemoglobin returned to 9 or higher.

9. Study Procedures Site investigator had to be notified if the hemoglobin fell to 7 g/dL or less, or 16 g/dL or more, or a decrease of 2.0 g/dL or more in a 4 week period. Measurement of hemoglobin and vital signs were done every 2 weeks during the study titration period and then monthly. Transferrin saturation and ferritin levels were measured quarterly

10. Study Procedures Other labs were measured at 24 week intervals At each visit information was gathered regarding adverse events, hospitalization, transfusions and use of other meds.

11. Evaluation of Outcomes Primary endpoints- time to death from any cause or a cardiovascular event and time to ESRD Secondary endpoints- time to death, death from cardiovascular causes and the components of the primary endpoints, rate of decline in the estimated GFR and changesin patient reported outcomes at week 25 using the FACT-fatigue and the 36 item short form general health survey questionnaire.

12. Monitoring Safety reports were reviewed monthly In 2006, another ESA study- non-placebo controlled trial found that higher hemoglobins led to increase rates of adverse clinical events. Patients all reconsented

13. Statistical Analysis A total of 1203 cardiovascular events were required to provide 80% statistical power to detect a 20% risk reduction for this event. Goal was to enroll ~4000 patients Assumptions: annual rate of events in the placebo group to be about 12.5%, 15% loss to followup, and attenuation of the treatment effect due to the anticipated use of ESA’s in patients who had progression to ESRD. Time to event analysis was used-intention to treat principle Patients who discontinued either study drug early were followed for study endpoints.

14. Results A total of 4047 patients, but a total of 4038 patients were evaluated due to excluding information on 9 patients from 2 sites that did not adhere to good clinical practice guidelines. 2012 were assigned to receive darbepoetin alfa and 2026 were assigned to receive placebo. The study was completed on March 28,2009 with a median followup duration of 29.1 months. At the time of study completion, 3523 patients were either still being followed for clinical end points or had died which included 1761 in the darbepoietin group and 1762 in the placebo group

15. Results Vital status was unknown at the end of study for 153 patients in the darbepoietin and 164 patients in the placebo group The median age was 68 and 57.3% of the patients were women 65.4% of the patients had a history of cardiovascular disease and about the same percentage had a history of coronary artery disease, stroke, peripheral arterial disease and myocardial infarction Imbalance of patients with a history of heart failure, 31.5% in the darbepoetin vs 35.2% in the placebo group

16. Results No clinically baseline imbalances in vital signs, labs, or the use of medications for cardiovascular disease and diabetes The overall median hemoglobin level at baseline was 10.4 (range 9.8 to 10.9) Significant differences in hemoglobins were seen between the two groups starting at one month after randomization From 3 months to the end of treatment the median achieved hemoglobin was 12.5 in the darbepoietin group and 10.6 in the placebo group.

17. Results 84.6% of patients in the darbepoetin group and 86.9% were switched to monthly dosing. Over the course of the study, 46% of the patients assigned to placebo received at least one dose of darbepoetin as rescue therapy. 93.9% of the patients in the darbepoetin group and 90.4% in the placebo group were receiving the assigned treatment at 6 months and 87.4% and 83.7% at 1 year and 74.3% and 69.3% respectively at 2 years No significant difference in the proportions of patients receiving oral iron therapy but more patients in the placebo group received IV iron Red Cell transfusions were given in 297 patients in the darbepoietin group and 496 in the placebo group.

18. Figure 1- Mean Hemoglobin levels through 48 months among patients who were assigned to receive Darbepoetin Alfa or placebo

19. Results The primary outcome- cardiovascular event- fatal and non-fatal occurred in 632 patients in the darbepoietin group and 602 patients in the placebo group. It was noted that fatal or nonfatal stroke was more likely to occur in the darbepoetin group (101 vs 53 patients) If the patient had a history of cardiovascular disease and proteinuria were considered higher risk groups. Less cardiac revascularization was noted in the darbepoetin group than the placebo group

20. Results Death or ESRD occurred in 652 patients in the darbepoetin group vs 618 patients in the placebo group. ESRD- 338 in darbepoetin and 330 in placebo groups The primary prespecified analysis of patients reported outcomes was the change from baseline to 25 weeks in the FACT-Fatigue score- improvement was shown in the darbepoetin group to a higher rate than the placebo

21. Figure 2 Kaplan-Meier Estimates of the Probability of the Primary and Secondary End Points

22. Figure 3- Kaplan Meier Estimates of the Probability of Renal Outcomes

23. Table 2

24. Results No difference in systolic blood pressure between the two groups. Diastolic blood pressure was higher in the darbepoetin than placebo group Hypertension occurred in 491 patients in darbepoetin group and 446 in the placebo group Convulsions occurred in 9 patients in darbepoetin group and 4 in placebo No cases of antibody mediated red cell aplasia in either group Venous Thromboembolic events were reported in 41 patients in darbepoetin group and 23 in placebo group. Arterial Thromboembolic events were also more common in darbepoetin group.

25. Results No significant difference between the groups in the number of cancer events: 139 in darbepoetin and 130 in placebo group. 39 deaths were attributed to cancer in 2012 patients in the darbepoetin group and 25 deaths from cancer in placebo group.

26. Summary The TREAT trial was done to determine if treatment of a low hemoglobin with darbepoetin alfa would reduce the risk of death, heart failure, myocardial infarction, admission for myocardial ischemia or ESRD in patients with type 2 diabetes, CKD, and anemia. This study showed that there was no significant difference in the overall rates between the two groups.

27. Summary There was an increase in the incidence of stroke in the darbepoetin and there was not an increase in systolic blood pressure in these patients. This study did show the relationship between the use of ESA’s and stroke and thromboembolic events. The CHOIR study was the next largest study done using epoetin alfa in CKD patients.- this study showed a higher rate of cardovascular events in the group that had a target hemoglobin level of 13.5 g/dL than the group assigned to a target level of 11.3 g/dL. The cardiovascular events in the CHOIR study led to more death and heart failure events and because of this in the TREAT trial updated consent form to reflect the results of the CHOIR study and informed consent was again obtained.

28. Summary In patients who developed cancer during the trial the drug was discontinued to the suggestion of increased mortality in patients receiving ESA’s who had an active malignancy.