Trial to test efficacy of anemia therapy to reduce CV events

TREAT will enroll 4,000 patients with chronic kidney disease and type 2 diabetes.

A randomized controlled trial will assess the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events among patients with chronic kidney disease and type 2 diabetes.

Marc A. Pfeffer, MD, PhD, professor of medicine at Harvard Medical School and cardiologist at the Brigham and Women’s Hospital, said darbepoetin alfa (Aranesp, Amgen Inc.) is already used to improve hemoglobin and quality of life in patients with anemia and chronic kidney disease, “and the renal guidelines say we should already be treating anemia,” he said.

“We’re taking a step back and asking the ‘show-me’ question,” Pfeffer told Cardiology Today. “The ‘show-me’ is not ‘can we raise your hemoglobin?’ or ‘can we improve your quality of life?’ It will be, ‘can we improve cardiovascular outcomes with this agent?’”

Trial design

Pfeffer and colleagues have already enrolled 900 of a planned 4,000 patients from sites in the United States, the European Union, Australia and Canada into TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy).

Researchers will randomize patients to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL, or to placebo (darbepoetin alfa for Hb less than 9 g/dL until Hb is again Hb 9 g/dL). The TREAT follow-up protocol is event driven with a composite primary outcome of time to mortality and nonfatal cardiovascular events, including MI, myocardial ischemia, stroke and heart failure.

Disease burden

Chronic kidney disease is associated with a high cardiovascular disease burden. “Renal doctors are becoming aware that a patient with chronic kidney disease is more likely to die from cardiovascular causes than to ever reach dialysis,” Pfeffer said.

“Then you throw in anemia, and you find that people who have anemia not due to cancer, a malignancy or iron loss have an amplified risk,” Pfeffer said. “We know that we have a therapy that can raise hemoglobin, and the question is should we be doing that?”

Pfeffer said that in patients with type 2 diabetes and advanced nephropathy, anemia is one of the few important risk factors, including serum creatinine, proteinuria and albumin, for hard renal end points such as progression to end stage renal disease. TREAT will also determine whether darbepoetin alfa will reduce risk of progressing to dialysis or dying. According to Pfeffer and colleagues’ paper on the study’s design, published in the American Heart Journal, for every 1 g/dL increase in hemoglobin, the risk of doubling of serum creatinine or progression to end stage renal disease decreases by 11%.

“Further analyses of these data have recently revealed that for every 1 g/dL lower Hb, the risk of ESRD increased by 11%. Finally, these results are corroborated by an analysis of another cohort of patients with type 2 diabetes mellitus, indicating that for every 1 mmol/L higher Hb, the risk of doubling of serum creatinine or ESRD decreased by 25%,” they wrote.

Pfeffer said the effect on hemoglobin has driven the high rate of prescriptions for darbepoetin alfa, but it is still a surrogate outcome. “For me, I’m used to doing trials with cardiologists and you don’t have to convince anybody that surrogates aren’t good enough,” Pfeffer said.

“But in the nephrology community you’ve got people who already believe that [this therapy] is so good why do we need to do a placebo-controlled trial? So the clash of cultures has been very interesting,” he said. “Uncertainty is the best rationale for a randomized controlled trial.” – by Jeremy Moore

For more information:

• Mix TCH, Brenner RM, Cooper ME, et al. Rationale—trial to reduce cardiovascular events with aranesp therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Am Heart J. 2005;149:408-13.