November 6th, 2009

Darbepoetin–Trick or Treat? Part II


(SEE PART 1 OF SERIES) I was amazed by three things when the results from Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) were presented Friday October 30th, 2009 at the American Society of Nephrology Annual Meeting in San Diego:

  • Thousands of atttendees came to hear TREAT presented by Dr M. Pfeffer–The room was tense with anticipation!
  • This is the first time since I joined the NEJM’s editorial board in 2002 that I remember a presentation at ASN being concurrently published in the journal.
  • With some 4000 patients from more than 600 sites across 24 countries, the size of this trial makes me numb. You cardiologists may consider this an average sized study–Poor nephrologists!

Relative to other randomized clinical trials in nephrology, TREAT is unique in that it is refreshingly simple, large and effective. TREAT was designed to determine in patients with CKD, type 2 diabetes mellitus, and moderate anemia whether the treatment of anemia with darbepoetin alfa would reduce the risk of death, major cardiovascular events and renal events. Within weeks the hemoglobin levels for the groups separated. The median achieved hemoglobin concentrations were 12.5 and 10.6 for darbepoetin alfa and placebo, respectively. The authors found no differences in the overall rate of the primary cardiovascular or renal composite endpoints. Of patients assigned to darbepoetin, 101 patients experienced a stroke compared to 53 patients assigned to placebo (hazard ratio 1.92).

The neutral effect on either the primary composite of cardiovascular endpoints and renal endpoints, together with the observed increased rates of stroke, was not predicted. The clinical importance of an increased rate of stroke, clearly a serious adverse event, must be considered in the context of the population studied. Even though the trial excluded patients with a history of a cardiovascular event in the preceding three months, the risk of death or a major cardiovascular event was 31% in the entire cohort over the course of the trial. Such data serves to remind us about the incredible burden of cardiovascular disease in patients with CKD. The authors conclude that the use of darbepoetin alfa in patients with non-dialysis diabetic CKD with moderate anemia did not reduce either the primary composite cardiovascular or renal outcome and was associated with an increased risk of stroke. They also reported change in FACIT fatigue from baseline to week 25, noting the difference between the darbepoetin alfa group and the placebo group was a humble improvement at best. Let us be clear that this trial did not address patients on dialysis. TREAT did not study patients with severe anemia! The study did not confirm CHOIR.

Treating physicians and patients will recognize the need to balance trade-offs—namely the risk of increased risk of stroke, higher rates of venous thromboembolic events, and possibly deaths from cancer versus the perception of improved quality of life.  I am sensitive to the challenge of quality of life versus the quantity of life. Remembering that “the supreme irony of life is that hardly anyone gets out of it alive”, I am also mindful that I will be a patient at some future date. Most of us can empathize with patients on this truly personal measure of one’s own life. Physicians and patients will need to come to terms with this issue.

With all of this in mind, what would we say to a patient who prioritizes quality of life over morbidity risk? How will this influence your treatment choices?  What will you recommend to your next patient with CKD, diabetes and moderate anemia?

4 Responses to “Darbepoetin–Trick or Treat? Part II”

  1. Insightful comments! To the patient who values quality of life, the gamble would likely be between some improvement in fatigue and the possibly devastating disability from stroke — both issues affecting the quality rather than quantity of life. In this regard, is there a working hypothesis as to the mechanisms underlying increased stroke? It seems that this would be key to identifying those at particular risk and informing the degree to which a regular dosing schedule may or may not be more safe.

  2. Two points:

    1. There does not seem to be any stratification of outcome base don Hgb. In other words, are all the events clustered in patients with the highest Hgb?

    2. The mean dose of aranesp was 176 ug per month or 88 ug every 2 weeks. This dose is approximately the mean dose I need to use in my CKD4 patients. It is entirely possible that the effects are dose related not Hgb related. I would be interested to see outcomes stratified by ESA dose as well. Perhaps this could allow us to use a dose cap in our patients to limit harm.

  3. What do you think this means for us as cardiologists, managing patient with cardiac conditions and CKD who are already on epo therapies chronically? Also, what do you think were some of the underlying mechanisms of adverse outcomes were in Treat?

  4. Thomas Kline md, md phd says:

    We American Physicians and practitioners need to be mindful that we
    have a special reputation for over treatment. Why this is is
    unknown, but once something gets into the fabric of things, it tends
    to stay, and tends to be defended without logic.

    Thomas Kline MD