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
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.
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.
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.
Figure 1- Mean Hemoglobin levels through 48 months among patients who were assigned to receive Darbepoetin Alfa or placebo
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
Figure 2 Kaplan-Meier Estimates of the Probability of the Primary and Secondary End Points
Figure 3- Kaplan Meier Estimates of the Probability of Renal Outcomes
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.
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.