A Trial of Darbepoetin Alfa in Type 2 A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney DiseaseDiabetes and Chronic Kidney Disease

NEJM Volume 361:2019-2032NEJM Volume 361:2019-2032 November 19, 2009 Number 21Number 21

Wafa Badwan, MDWafa Badwan, MD

March 16, 2010March 16, 2010

IntroductionIntroduction Type 2 Diabetes and CKD each increase Type 2 Diabetes and CKD each increase

the risk of cardiovascular events and the risk of cardiovascular events and ESRD.ESRD.

Anemia is considered another biomarker Anemia is considered another biomarker of cardiovascular risk- especially in of cardiovascular risk- especially in diabetic patients.diabetic patients.

Whether the use of ESA’s lowers this Whether the use of ESA’s lowers this cardiac risk by increasing hemoglobin has cardiac risk by increasing hemoglobin has not been studied.not been studied.

IntroductionIntroduction Trial to Reduce Cardiovascular Events Trial to Reduce Cardiovascular Events

with Aranesp Therapy (TREAT)with Aranesp Therapy (TREAT) Goal of the study was to test the Goal of the study was to test the

hypothesis that patients with Type 2 hypothesis that patients with Type 2 diabetes and CKD- not yet dialysis diabetes and CKD- not yet dialysis dependent with anemia by using dependent with anemia by using Darbepoetin, resulting in higher Darbepoetin, resulting in higher hemoglobin levels and therefore would hemoglobin levels and therefore would reduce the rates of death, cardiovascular reduce the rates of death, cardiovascular events and ESRDevents and ESRD

MethodsMethods Randomized, double-blind placebo Randomized, double-blind placebo

controlled trialcontrolled trial 623 sites in 24 countries623 sites in 24 countries All patients provided written informed All patients provided written informed

consentconsent Approved by ethics committee at every Approved by ethics committee at every

site.site. Enrollment from August 25,2004 to Enrollment from August 25,2004 to

December 4, 2007December 4, 2007 Sponspored by AmgenSponspored by Amgen

Study PopulationStudy Population Patients with Type 2 diabetes, CKD with GFR Patients with Type 2 diabetes, CKD with GFR

of 20-60 cc/min with anemia defined as of 20-60 cc/min with anemia defined as hemoglobin less than 11 g/dL and a hemoglobin less than 11 g/dL and a transferrin saturation of 15% or more were transferrin saturation of 15% or more were eligible for enrollment.eligible for enrollment.

Exclusion criteria:Exclusion criteria: uncontrolled hypertension, uncontrolled hypertension, previous kidney transplantation or scheduled previous kidney transplantation or scheduled

receipt of a kidney transplant from a living related receipt of a kidney transplant from a living related donor.donor.

Study PopulationStudy Population Exclusion criteria cont.: Exclusion criteria cont.:

Current use of IV antibiotics, chemotherapy, or radiation Current use of IV antibiotics, chemotherapy, or radiation therapytherapy

Cancer except basal cell or squamous cell cancerCancer except basal cell or squamous cell cancer HIVHIV Active bleedingActive bleeding Hematologic diseaseHematologic disease PregnancyPregnancy Patients who had a cardiovascular event, grand mal seizure, Patients who had a cardiovascular event, grand mal seizure,

had a major surgery.had a major surgery. If they had received an ESA in the 12 weeks before If they had received an ESA in the 12 weeks before

randomization randomization

Study ProceduresStudy Procedures

Prestudy labs were obtainedPrestudy labs were obtained Patients were randomly assigned using a Patients were randomly assigned using a

computer generated design to receive computer generated design to receive darbepoetin alfa or placebo.darbepoetin alfa or placebo.

Randomization was stratified according to Randomization was stratified according to the study site, baseline level of proteinuria, the study site, baseline level of proteinuria, and history of cardiovascular diseaseand history of cardiovascular disease

12 different strengths in prefilled syringes 12 different strengths in prefilled syringes were suppliedwere supplied

Study ProceduresStudy Procedures

An algorithm was designed to adjust the An algorithm was designed to adjust the dose to maintain a hemoglobin of 13.0 dose to maintain a hemoglobin of 13.0 g/dL in those assigned to aranesp.g/dL in those assigned to aranesp.

Patients in the placebo group received Patients in the placebo group received aranesp as “rescue” drug if hemoglobin fell aranesp as “rescue” drug if hemoglobin fell below 9 g/dL and would return to the below 9 g/dL and would return to the placebo drug once hemoglobin returned to placebo drug once hemoglobin returned to 9 or higher.9 or higher.

Study ProceduresStudy Procedures Site investigator had to be notified if the Site investigator had to be notified if the

hemoglobin fell to 7 g/dL or less, or hemoglobin fell to 7 g/dL or less, or

16 g/dL or more, or a decrease of 2.0 g/dL 16 g/dL or more, or a decrease of 2.0 g/dL or more in a 4 week period.or more in a 4 week period.

Measurement of hemoglobin and vital signs Measurement of hemoglobin and vital signs were done every 2 weeks during the study were done every 2 weeks during the study titration period and then monthly.titration period and then monthly.

Transferrin saturation and ferritin levels Transferrin saturation and ferritin levels were measured quarterlywere measured quarterly

Study ProceduresStudy Procedures

Other labs were measured at 24 week Other labs were measured at 24 week intervalsintervals

At each visit information was gathered At each visit information was gathered regarding adverse events, hospitalization, regarding adverse events, hospitalization, transfusions and use of other meds.transfusions and use of other meds.

Evaluation of OutcomesEvaluation of Outcomes Primary endpoints- time to death from any Primary endpoints- time to death from any

cause or a cardiovascular event and time to cause or a cardiovascular event and time to ESRDESRD

Secondary endpoints- time to death, death Secondary endpoints- time to death, death from cardiovascular causes and the from cardiovascular causes and the components of the primary endpoints, rate of components of the primary endpoints, rate of decline in the estimated GFR and changesin decline in the estimated GFR and changesin patient reported outcomes at week 25 using patient reported outcomes at week 25 using the FACT-fatigue and the 36 item short form the FACT-fatigue and the 36 item short form general health survey questionnaire.general health survey questionnaire.

MonitoringMonitoring

Safety reports were reviewed monthlySafety reports were reviewed monthly In 2006, another ESA study- non-placebo In 2006, another ESA study- non-placebo

controlled trial found that higher controlled trial found that higher hemoglobins led to increase rates of hemoglobins led to increase rates of adverse clinical events.adverse clinical events.

Patients all reconsentedPatients all reconsented

Statistical AnalysisStatistical Analysis A total of 1203 cardiovascular events were required to A total of 1203 cardiovascular events were required to

provide 80% statistical power to detect a 20% risk provide 80% statistical power to detect a 20% risk reduction for this event.reduction for this event.

Goal was to enroll ~4000 patientsGoal was to enroll ~4000 patients Assumptions: annual rate of events in the placebo group Assumptions: annual rate of events in the placebo group

to be about 12.5%, 15% loss to followup, and attenuation to be about 12.5%, 15% loss to followup, and attenuation of the treatment effect due to the anticipated use of of the treatment effect due to the anticipated use of ESA’s in patients who had progression to ESRD.ESA’s in patients who had progression to ESRD.

Time to event analysis was used-intention to treat Time to event analysis was used-intention to treat principleprinciple

Patients who discontinued either study drug early were Patients who discontinued either study drug early were followed for study endpoints.followed for study endpoints.

ResultsResults A total of 4047 patients, but a total of 4038 patients were A total of 4047 patients, but a total of 4038 patients were

evaluated due to excluding information on 9 patients evaluated due to excluding information on 9 patients from 2 sites that did not adhere to good clinical practice from 2 sites that did not adhere to good clinical practice guidelines.guidelines.

2012 were assigned to receive darbepoetin alfa and 2012 were assigned to receive darbepoetin alfa and 2026 were assigned to receive placebo.2026 were assigned to receive placebo.

The study was completed on March 28,2009 with a The study was completed on March 28,2009 with a median followup duration of 29.1 months. median followup duration of 29.1 months.

At the time of study completion, 3523 patients were At the time of study completion, 3523 patients were either still being followed for clinical end points or had either still being followed for clinical end points or had died which included 1761 in the darbepoietin group and died which included 1761 in the darbepoietin group and 1762 in the placebo group1762 in the placebo group

ResultsResults Vital status was unknown at the end of study for 153 Vital status was unknown at the end of study for 153

patients in the darbepoietin and 164 patients in the patients in the darbepoietin and 164 patients in the placebo groupplacebo group

The median age was 68 and 57.3% of the patients The median age was 68 and 57.3% of the patients were womenwere women

65.4% of the patients had a history of cardiovascular 65.4% of the patients had a history of cardiovascular disease and about the same percentage had a disease and about the same percentage had a history of coronary artery disease, stroke, peripheral history of coronary artery disease, stroke, peripheral arterial disease and myocardial infarctionarterial disease and myocardial infarction

Imbalance of patients with a history of heart failure, Imbalance of patients with a history of heart failure, 31.5% in the darbepoetin vs 35.2% in the placebo 31.5% in the darbepoetin vs 35.2% in the placebo groupgroup

ResultsResults No clinically baseline imbalances in vital signs, No clinically baseline imbalances in vital signs,

labs, or the use of medications for cardiovascular labs, or the use of medications for cardiovascular disease and diabetesdisease and diabetes

The overall median hemoglobin level at baseline The overall median hemoglobin level at baseline was 10.4 (range 9.8 to 10.9)was 10.4 (range 9.8 to 10.9)

Significant differences in hemoglobins were seen Significant differences in hemoglobins were seen between the two groups starting at one month between the two groups starting at one month after randomizationafter randomization

From 3 months to the end of treatment the median From 3 months to the end of treatment the median achieved hemoglobin was 12.5 in the darbepoietin achieved hemoglobin was 12.5 in the darbepoietin group and 10.6 in the placebo group.group and 10.6 in the placebo group.

ResultsResults 84.6% of patients in the darbepoetin group and 86.9% were 84.6% of patients in the darbepoetin group and 86.9% were

switched to monthly dosing.switched to monthly dosing. Over the course of the study, 46% of the patients assigned Over the course of the study, 46% of the patients assigned

to placebo received at least one dose of darbepoetin as to placebo received at least one dose of darbepoetin as rescue therapy.rescue therapy.

93.9% of the patients in the darbepoetin group and 90.4% 93.9% of the patients in the darbepoetin group and 90.4% in the placebo group were receiving the assigned treatment 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 at 6 months and 87.4% and 83.7% at 1 year and 74.3% and 69.3% respectively at 2 years69.3% respectively at 2 years

No significant difference in the proportions of patients No significant difference in the proportions of patients receiving oral iron therapy but more patients in the placebo receiving oral iron therapy but more patients in the placebo group received IV irongroup received IV iron

Red Cell transfusions were given in 297 patients in the Red Cell transfusions were given in 297 patients in the darbepoietin group and 496 in the placebo group.darbepoietin group and 496 in the placebo group.

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

ResultsResults The primary outcome- cardiovascular event- fatal The primary outcome- cardiovascular event- fatal

and non-fatal occurred in 632 patients in the and non-fatal occurred in 632 patients in the darbepoietin group and 602 patients in the darbepoietin group and 602 patients in the placebo group.placebo group.

It was noted that fatal or nonfatal stroke was It was noted that fatal or nonfatal stroke was more likely to occur in the darbepoetin group (101 more likely to occur in the darbepoetin group (101 vs 53 patients)vs 53 patients)

If the patient had a history of cardiovascular If the patient had a history of cardiovascular disease and proteinuria were considered higher disease and proteinuria were considered higher risk groups.risk groups.

Less cardiac revascularization was noted in the Less cardiac revascularization was noted in the darbepoetin group than the placebo groupdarbepoetin group than the placebo group

ResultsResults

Death or ESRD occurred in 652 patients in the Death or ESRD occurred in 652 patients in the darbepoetin group vs 618 patients in the placebo darbepoetin group vs 618 patients in the placebo group.group.

ESRD- 338 in darbepoetin and 330 in placebo ESRD- 338 in darbepoetin and 330 in placebo groupsgroups

The primary prespecified analysis of patients The primary prespecified analysis of patients reported outcomes was the change from reported outcomes was the change from baseline to 25 weeks in the FACT-Fatigue score- baseline to 25 weeks in the FACT-Fatigue score- improvement was shown in the darbepoetin improvement was shown in the darbepoetin group to a higher rate than the placebogroup to a higher rate than the placebo

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

Figure 3- Kaplan Meier Estimates of the Figure 3- Kaplan Meier Estimates of the Probability of Renal OutcomesProbability of Renal Outcomes

Table 2Table 2

ResultsResults No difference in systolic blood pressure between the two No difference in systolic blood pressure between the two

groups. groups. Diastolic blood pressure was higher in the darbepoetin than Diastolic blood pressure was higher in the darbepoetin than

placebo groupplacebo group Hypertension occurred in 491 patients in darbepoetin group Hypertension occurred in 491 patients in darbepoetin group

and 446 in the placebo groupand 446 in the placebo group Convulsions occurred in 9 patients in darbepoetin group Convulsions occurred in 9 patients in darbepoetin group

and 4 in placeboand 4 in placebo No cases of antibody mediated red cell aplasia in either No cases of antibody mediated red cell aplasia in either

groupgroup Venous Thromboembolic events were reported in 41 Venous Thromboembolic events were reported in 41

patients in darbepoetin group and 23 in placebo group.patients in darbepoetin group and 23 in placebo group. Arterial Thromboembolic events were also more common in Arterial Thromboembolic events were also more common in

darbepoetin group.darbepoetin group.

ResultsResults

No significant difference between the No significant difference between the groups in the number of cancer events: groups in the number of cancer events: 139 in darbepoetin and 130 in placebo 139 in darbepoetin and 130 in placebo group.group.

39 deaths were attributed to cancer in 39 deaths were attributed to cancer in 2012 patients in the darbepoetin group 2012 patients in the darbepoetin group and 25 deaths from cancer in placebo and 25 deaths from cancer in placebo group.group.

SummarySummary

The TREAT trial was done to determine if The TREAT trial was done to determine if treatment of a low hemoglobin with treatment of a low hemoglobin with darbepoetin alfa would reduce the risk of darbepoetin alfa would reduce the risk of death, heart failure, myocardial infarction, death, heart failure, myocardial infarction, admission for myocardial ischemia or ESRD in admission for myocardial ischemia or ESRD in patients with type 2 diabetes, CKD, and patients with type 2 diabetes, CKD, and anemia.anemia.

This study showed that there was no This study showed that there was no significant difference in the overall rates significant difference in the overall rates between the two groups.between the two groups.

SummarySummary There was an increase in the incidence of stroke in the There was an increase in the incidence of stroke in the

darbepoetin and there was not an increase in systolic blood darbepoetin and there was not an increase in systolic blood pressure in these patients.pressure in these patients.

This study did show the relationship between the use of This study did show the relationship between the use of ESA’s and stroke and thromboembolic events.ESA’s and stroke and thromboembolic events.

The CHOIR study was the next largest study done using The CHOIR study was the next largest study done using epoetin alfa in CKD patients.- this study showed a higher epoetin alfa in CKD patients.- this study showed a higher rate of cardovascular events in the group that had a target rate of cardovascular events in the group that had a target hemoglobin level of 13.5 g/dL than the group assigned to a hemoglobin level of 13.5 g/dL than the group assigned to a target level of 11.3 g/dL.target level of 11.3 g/dL.

The cardiovascular events in the CHOIR study led to more The cardiovascular events in the CHOIR study led to more death and heart failure events and because of this in the death and heart failure events and because of this in the TREAT trial updated consent form to reflect the results of the TREAT trial updated consent form to reflect the results of the CHOIR study and informed consent was again obtained.CHOIR study and informed consent was again obtained.

SummarySummary

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