EBM 11/6/09

A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease(TREAT)
Pfeffer M. A., Burdmann E. A., Chen C.-Y. et al. N Engl J Med 2009

BACKGROUND: Anemia has been associated with poorer outcomes in those patients with CKD with some observational studies suggesting lower Hgb is associated with increased rate of cardiovascular and renal events. Interestingly, pay for performance fees in ESRD include a quality measure of hematocrit >33. ESAs or erythropoiesis stimulating agents,are effective in increasing hemoglobin levels however the effect in clinical outcomes is questionable. Earlier, small, observational studies using ESAs to treat severe anemia showed reduced requirement for blood transfusions and improved quality of life assessments. However larger more recent trials including the CREATE and CHOIR trials did not support these previous findings. The CREATE trial involved 603 patients w/ anemia & CKD who were treated with epo to target levels of 13-15 in one group compared to 10.5-11.5 in comparison group, there was no difference in rate of cardiovascular events, progression to ESRD, quality of life. The CHOIR trial involved 1432 patients with CKD & anemia who were treated with epo to target 13.5 versus 11.3. The CHOIR trial was stopped prematurely due to increased risk of composite endpoint of death, MI, stroke, and hospitalization for CHF. The TREAT trialbegan enrolling subjects in 2004 as the only placebo controlled, randomized, double blind study to look at the hypothesis that in patients with CKD (not on dialysis), DM2, and anemia increasing Hgb levels with ESA (darbepoetin) would lower the rates of death, cardiovascular events, & ESRD. Interestingly, the results of the CHOIR trial were published during the ongoing TREAT trial, however there was no recommendation to stop the TREAT trial due to the fact that the TREAT trial had already gathered data showing more clinical events than had been published in the other trials.

METHODS: 4038 patient’s were randomized to placebo vsdarbepoetin use to goal Hgb >13, the placebo group were planned to receive darbepoetin as rescue if Hgb <9, with 2012 in the darbepoetin group and 2026 in the placebo group. Baseline Hgb 10.4 at the beginning of the study, significant difference between groupHgb was seen by 1 month with average Hgb 12.5 in treatment group, and 10.6 in placebo group

INCLUSION/EXCLUSION CRITERIA:

Study Population: DM2, CKD (GFR 20-60 ml/min by MDRD), anemia (Hgb <11), transferrin sat >15%

Exclusions: Uncontrolled HTN, prior kidney tx or scheduled tx from living donor, current IV abx, chemotx, radiation rx, cancer (except basal-fell, or squamous cell), HIV, active bleed, hematologic disease, pregnancy, & if they had any of the following within 12 weeks prior to randomization: CV event, grand mal seizure, major surgery, received ESA.

ARE THE RESULTS VALID?

Was the assignment of patients to treatments randomized? Yes. Computer generated 1:1 randomization to placebo versus darbepoetin group.

Was follow up sufficiently long and complete? Median follow up was 29.1 months with 3523 (87.2%) still being followed or had died

Were all patient’s analyzed in the groups to which they were randomized? Yes

Were the patients and clinicians kept “blind” to treatment? Yes, the patient’s received matching pre-filled syringes at 12 different strengths; third party monitored Hgb and computer assigned doses according algorithm (to keep Hgb >13 in darbepoetingrp)

Were the groups treated equally, apart from the experimental treatment? Yes however it is interesting to note that 46% of patients in the placebo group received at least one rescue darbepoetin shot

Were the groups similar at the start of the trial? Yes they were relatively well matched with regard to medications, diabetes control, and comorbidities with the exception of heart failure, with more subjects with CHF in the placebo group when compared with the treatment group

WHAT ARE THE RESULTS?

-No significant difference in cardiovascular composite endpoint including death from any cause, MI, stroke, CHF, & myocardial ischemia

-When considering the above individually there was a significant difference in fatal or nonfatal stroke with increased # strokes in darbepoetin group

-No significant difference in renal composite endpoint (ESRD or death)

-Increase in thromboembolic events including both venous and arterial thrombosis in darbepoetin treated group versus placebo

-Significantly more PRBC transfusions were given in the placebo group versus the treatment group

-Improved FACT-fatigue score in the treatment group when compared to placebo

APPLICATION: This was a fairly well designed trial with negative outcome which supports previous reports that use of ESAs to increase Hgb does not lower the rate of death or cardiovascular events. In fact, it increases the risk of thromboembolic events, including strokes as suggested in the current study. The study population despite multiple co-morbidities had relatively well controlled DM2, and HTN suggesting that with poorly controlled co-morbidities these events would likely be even higher. It is interesting that patients in the placebo group did receive at least one rescue dose of darbepoetin but differences in level of Hgb remained significant. Conclusion from this study more solidly shows that use of ESAs to raise Hgb to level of 12-13 is not advised. The study also raises the question of whether ESAs should be used at all, or merely as a rescue agent for lower hemoglobins. This leads to further questions regarding what goal Hgb is safe and what threshold of Hgb should be tolerated before initiating treatment.