Halloween trick: don’t TREAT diabetes with ESAs 3

In the first adequately powered trial of an erythropoiesis-stimulating agent (ESA), darbepoetin alfa (Aranesp, Amgen) failed to reduce major clinical events and was associated with an increased risk of stroke in a population of type 2 diabetics with chronic kidney disease.

The much-anticipated TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) was presented by Marc Pfeffer as a late-breaking clinical trial as part of Renal Week in San Diego, and published simultaneously in the New England Journal of Medicine. The trial randomized 4038 diabetic patients with CKD and anemia to darbepoetin alfa (target hemoglobin level of about 13 g/dl) or placebo (with rescue darbepoetin alfa when hemoglobin dropped below 9 g/dl).

TREAT had two composite primary endpoints: death or a cardiovascular event (nonfatal MI, CHF, stroke, or hospitalization for ischemia) and death or end-stage renal disease. There were no significant differences  in either composite endpoint, though there were more events in the ESA group.

  • Death or CV event: 632 (ESA) vs 602 (placebo)
  • Death or ESRD: 652 (ESA) vs 618 (placebo)

However, the rate of fatal or nonfatal stroke was almost double in the ESA group: 101 events vs 53 events (HR: 1.92; 95% CI: 1.38-2.68; P<0.001). Although ESA treatment did result in a significant reduction in transfusions (297 in the ESA group versus 496 in the placebo group, p< 0.001), the investigators reported “only a modest improvement in patient-reported fatigue” in the ESA group when compared to the placebo group.

Scary Pumpking

There were no significant differences in cancer-related adverse events (6.9% in the ESA group vs 6.4% in the placebo group) or in the number of deaths attributed to cancer (39 in the ESA group vs 25 in the placebo group, P=0.08). There were 60 deaths from any cause in the 188 ESA patients who had cancer at baseline, versus 37 deaths out of 160 placebo patients (P=0.13).  In this subgroup, 14 of the 188 ESA patients died from cancer, compared to 1 of the 160 patients assigned to placebo (P=0.002).

Writing in the NEJM, the TREAT investigators observe that “although ESAs have been available for more than two decades, the hypothesis that this treatment approach would lower the risks associated with anemia and improve the prognosis has not been examined.” In fact, they write, “the presumption of the benefits associated with the use of ESAs was so pervasive that major clinical trials considered the use of placebo unnecessary or even unethical.”

The authors conclude with a strikingly negative statement about ESA’s in this population:

“It is our view that, in many patients with diabetes, chronic kidney disease, and moderate anemia who are not undergoing dialysis, the increased risk of stroke and possibly death among patients with a history of a malignant condition will outweigh any potential benefit of an ESA.”

Pfeffer offered the following comment in a press release from Brigham & Women’s Hospital:

“Although darbepoetin had some benefits in the patients we studied, it also had important risks. Raising hemoglobin did reduce the need for red cell transfusions and led to a statistically significant but rather modest improvement in a measure of fatigue in our patients with chronic kidney disease (not on dialysis) with moderate anemia. However, in my view, for many patients the increased risk of stroke that was uncovered and possibly deaths in those with prior malignancy outweigh the potential benefits of ESA use. The highest goal of a clinical trial is to provide data that improves clinical practice. TREAT meets this objective.”

Harlan Krumholz provided the following comment to CardioBrief:

“A very important article that tests conventional wisdom and provides another example of where an intervention to modify a surrogate endpoint failed to translate into the expected improvement in patient outcome. Even more concerning, the intervention was associated with greater risk of stroke – it is a shame that this information lagged behind the enthusiastic adoption of this treatment strategy. The finding highlights the importance of testing our interventions for their effects on patient outcomes.”

Click here to access the previous publication in AJKD on the baseline characteristics of the TREAT population.

 

Click here to read the Amgen press release.

Here is the press release from Brigham & Women’s Hospital:

Anemia Treatment of Patients with Diabetes and Chronic Kidney Disease is No More Effective Than Placebo and Carries Risks.

Boston, MA.-Researchers from Brigham and Women’s Hospital (BWH) and international collaborators have conducted a major clinical trial of anemia treatment with darbepoetin alfa (Aranesp) in patients with diabetes and chronic kidney disease (not requiring dialysis) and found no significant differences in deaths, heart attacks, heart failure, or need for dialysis compared to placebo. However, researchers found an increased risk of stroke among those assigned to darbepoetin alfa compared to placebo.

The findings will be presented as a Late Breaking Clinical Trial at The Annual Scientific Meeting of The American Society of Nephrology in San Diego, California Friday, October 30, 2009 and will appear concurrently online in The New England Journal of Medicine.

TREAT, (Trial to Reduce cardiovascular Events with Aranesp Therapy) launched in 2004, was a randomized, double-blind placebo-controlled trial of 4038 patients with type 2 diabetes, chronic kidney disease and anemia. It is the largest trial to date to examine the use of erythropoiesis stimulating agents (ESAs), a class of drugs approved to raise hemoglobin levels, and the only study to compare morbidity and mortality outcomes against placebo.

“Chronic kidney disease can be associated with anemia and both of these factors greatly increase the risk of a patient with diabetes having premature adverse cardiovascular events and progressing to dialysis. We tested whether the treatment of anemia with Aranesp would reduce the dreaded complications of diabetes- heart failure, myocardial infarction, stroke, end-stage renal disease (dialysis) and death. Previous trials presumed benefits of ESAs without conducting the most fundamental test against placebo,” said Marc A. Pfeffer M.D., PhD lead investigator of TREAT and Senior Physician in cardiovascular medicine at BWH.

TREAT supplies new data from the most reliable assessment of the risks and benefits of ESA therapy and provides physicians and patients with more accurate information on which to base individual patient care decisions.

Pfeffer, who is also the Dzau Professor of Medicine at Harvard Medical School added,

“Although darbepoetin had some benefits in the patients we studied, it also had important risks. Raising hemoglobin did reduce the need for red cell transfusions and led to a statistically significant but rather modest improvement in a measure of fatigue in our patients with chronic kidney disease (not on dialysis) with moderate anemia. However, in my view, for many patients the increased risk of stroke that was uncovered and possibly deaths in those with prior malignancy outweigh the potential benefits of ESA use. The highest goal of a clinical trial is to provide data that improves clinical practice. TREAT meets this objective.”

The research was supported by and conducted in collaboration with Amgen.

Brigham and Women’s Hospital (BWH) is a 777-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery system. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. In July 2008, the hospital opened the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on a diversity of human diseases and is at the forefront of personalized medicine. BWH has approximately 900 scientific investigators and more than $450 million in research support, more than 50 percent of which comes from the NIH. BWH is also home to major landmark population studies, including the Nurses’ and Physicians’ Health Studies and the Women’s Health Initiative, which have provided important information on diet and lifestyle risk factors for common chronic diseases. For more information about BWH, please visit: http://www.brighamandwomens.org.

3 comments

  1. Pingback: NEJM: FDA to reevaluate ESAs in treatment of anemia « CardioBrief

  2. Pingback: Reevaluating ESAs: too little, too late? « CardioBrief

  3. Pingback: Amgen Pleads Guilty To Misbranding Anemia Drug Aranesp « CardioBrief

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