Trial to Reduce Cardiovascular Events With Aranesp Therapy - TREAT — Presented at AHA 2009

Nov 16, 2009
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Trial Sponsor:
Amgen
Date Published:
01/01/2009
Date Updated:
11/16/2009
Original Posted Date:
11/16/2009
References

Description:

Although erythropoiesis-stimulating agents (ESAs) are widely used in patients with anemia and chronic kidney disease (CKD) who are not on dialysis, randomized data to support this approach are not available. The TREAT trial sought to test the hypothesis that the use of ESAs in patients with diabetes and CKD who were also anemic would be associated with improved outcomes.

Hypothesis:

ESAs would be associated with a lower risk of death, cardiovascular (CV) events, and progression to end-stage renal disease (ESRD) in patients with diabetes, CKD, and anemia.

Study Design

Study Design:

Patients Enrolled: 4,038
Mean Follow Up: Median: 29.1 months
Mean Patient Age: Median: 68 years
Female: 57

Patient Populations:

  • Type 2 diabetes mellitus
  • CKD with eGFR 20-60 ml/min/1.73 m2
  • Hgb <11.0 g/dl
  • Transferrin saturation ≥15%

Exclusions:

  • Uncontrolled hypertension
  • Previous kidney transplant or scheduled receipt of kidney transplant from living donor
  • Current use of intravenous antibiotics
  • Chemotherapy or radiation therapy
  • Cancer
  • Diagnosed HIV infection
  • Active bleeding
  • Hematologic disease
  • Pregnancy
  • CV event, grand mal seizure, major surgery, or ESA use 12 weeks prior to randomization

Primary Endpoints:

  • Time to composite outcome of death from any cause or a CV event (MI, stroke, CHF, hospitalization for myocardial ischemia)
  • Time to ESRD or death

Secondary Endpoints:

  • Time to death
  • Death from CV causes
  • Individual components of the primary endpoints
  • Rate of decline in GFR
  • Change in patient reported outcomes at week 25

Drug/Procedures Used:

Patients were randomized in a 1:1 fashion to receive either darbepoetin alfa or placebo, supplied in matching syringes at 12 different strengths.

Concomitant Medications:

Insulin (49%), angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (80%), beta-blocker (49%), statin (58%), aspirin (42%), oral or intravenous iron (43%)

Principal Findings:

A total of 4,038 patients were randomized, 2,012 to darbopoetin alfa and 2,026 to placebo. Baseline characteristics were fairly similar between the two groups, except for a history of congestive heart failure (CHF), which was lower in the darbepoetin alfa arm (p = 0.01). The median duration of diabetes was about 15.4 years, with a median glycated hemoglobin (HgbA1c) of 7.0%; about 48% had evidence of diabetic neuropathy. The median serum creatinine was 1.8 mg/dl, with a median estimated glomerular filtration rate (eGFR) of 34 ml/min/1.73 m2. Median transferrin saturation was 23%, with a median serum ferritin level of 134 µg/dl. The mean baseline Hgb was 10.4 g/dl.

From 3 months to the end of follow-up, the median Hgb was higher in the darbepoetin alfa arm (12.5 vs. 10.6 g/dl). Over the course of the study, 46% of the patients assigned to placebo received at least one dose of darbepoetin alfa as rescue therapy. Red blood cell transfusion was lower in the darbepoetin alfa arm as compared with placebo (14.8% vs. 24.5%, p < 0.001).

The primary endpoint of death, myocardial infarction (MI), unstable angina, heart failure, or stroke was similar between the darbepoetin alfa and placebo arms (31.4% vs. 29.7%, hazard ratio 1.05, 95% confidence interval 0.94-1.17, p = 0.41). Individual endpoints such as all-cause mortality (20.5% vs. 19.5%, p = 0.48) and MI (6.2% vs. 6.4%, p = 0.73) were similar between the two arms, except stroke (5% vs. 2.6%, p < 0.001), which was higher in the darbepoetin alfa arm. The renal composite endpoint of ESRD or death was similar between the two arms (32.4% vs. 30.5%, p = 0.29). Similarly, the incidence of ESRD was similar between the two arms (16.8% vs. 16.3%, p = 0.83).

Diastolic blood pressure was higher in the darbepoetin alfa arm (median: 73 vs. 71 mm Hg, p < 0.001). There was a trend toward a higher incidence of hypertension in the darbepoetin alfa arm (p = 0.07). Venous (2.0% vs. 1.1%, p = 0.02) and arterial (8.9% vs. 7.1%, p = 0.04) thromboembolic events were more frequent in the darbepoetin alfa arm. There was no difference in the incidence of cancer between the two arms (p = 0.53).

Interpretation:

The results of the large TREAT trial indicate that the routine use of ESAs in patients with diabetes and CKD not on dialysis (who are at a high risk for renal and CV events) and concomitant anemia is not associated with a reduction in renal and CV events over an intermediate period of follow-up. There is a reduction in the need for packed red blood cell transfusion with darbepoetin alfa, but a higher risk of venous and arterial thromboembolic events, as well as stroke, and a trend toward hypertension with the use of darbepoetin alfa. The observed increase in the risk of thromboembolic episodes is consistent with what has been reported earlier in patients with cancer on ESAs. These data are very important, and argue against the routine use of ESAs in patients with diabetes, CKD, and anemia.

References:

Presented by Dr. Mark A. Pfeffer at the American Heart Association Scientific Sessions, Orlando, FL, November 16, 2009.

Pfeffer MA, Burdmann EA, Chen CY, et al., on behalf of the TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-32.

Keywords: Myocardial Infarction, Diabetic Neuropathies, Stroke, Follow-Up Studies, Erythrocyte Transfusion, Kidney Failure, Chronic, Diabetes Mellitus, Type 2, Blood Pressure, Creatinine, Hematinics, Glycated Hemoglobin A, Renal Dialysis, Erythropoietin, Ferritins, Transferrins, Heart Failure, Glomerular Filtration Rate, Confidence Intervals, Hypertension, Renal Insufficiency, Chronic


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