Wednesday, September 22, 2010

Epo: The honeymoon is not over

Having just returned from my own honeymoon, I was taken by this recent hypothesis-piece by Fishbane et al. They have made some observations on the natural history of untreated renal anemia from examining the placebo arm of the recent TREAT RCT. Briefly, placebo-treated patients in TREAT received rescue therapy with Epo only if their Hgb levels fell to less than 9.0 g/dl; Epo was discontinued and patients returned to placebo as soon as their Hgb levels rose above this level. By this design, the placebo arm of TREAT sheds light on a very conservative approach to anemia management in pre-dialysis CKD.
Interestingly, analogous to patients with newly diagnosed type 1 DM who commonly experience a sharp reduction in their insulin requirement after initial presentation, there appears to be a similar “honeymoon period” after initial presentation with renal anemia, during which the hematocrit stabilizes or even increases (see figure) without treatment. An explanation may be that CKD patients presenting with an acute event such as infection may experience an abrupt, transient, decline in serum erythropoietin levels, and worsening of anemia. As they recover from the presenting event, serum erythropoietin levels and Hgb may also improve. However, this improvement would be masked in patients already initiated on maintenance outpatient Epo.


Many Nephrologists feel as though they are stuck between a rock and a hard place when it comes to Epo administration post-TREAT. This observation may encourage them to hold their nerve in CKD patients who initially appear to require Epo, as the anemia may well improve given time, at least in the short term. Of course, most patients with progressive CKD (save those perhaps with APCKD) will ultimately develop intractable anemia. A further RCT is required to know how to treat them, perhaps with a “TREAT placebo arm” vs. “no Epo at all” design. Perhaps, it could be called the DIVORCE trial (Darbepoetin Intermittently Vs Observation in Renal anemia of CKD).

6 comments:

abraham said...

Interesting post .Congrats for the mariage ...

amrut24 said...

Congrats on your marriage.
Interesting that ur proposing DIVORCE TRIAL soon after the marriage !!

Trampy said...

congrats... do you think your idea is ethically okay? you'll have to treat that anemia at some time point...

Conall O' Seaghdha said...

Thanks for the kind wishes and feedback Trampy! Personally, I don't see any ethical conflict. Patients in the treatment arm of TREAT on average derived no symptomatic benefit from Epo anyway, and TREAT is the best Epo trial we have.
I should point out that I will still treat very symptomatic anemia with Epo after counselling the patient on the CV risks. However, this has now become an evidence-free zone and I think a trial along the lines I have suggested will be necessary to give us some evidence-based guidance. I'm v. interested to hear your thoughts - it's feedback makes running the site worthwhile!

Trampy said...

Conall-
Thank you for your response. Generally spoken, I agree with you.

But then, we will have the placebo arm (give ESA with Hb of 9) and an arm where you give ESA when the anemia becomes severe... Maybe I don't get the point, but the second arm will most likely have a much worse outcome and life quality (e.g. fatigue...).

I think the idea of the TREAT study was to see whether aiming for a Hb of ~13 is favourable to a Hb of ~9-10 (moderate anemia)? Or do you think this study challenges the use of ESA in CKD in general because of the CV events, even in patients with severe anemia?

I am excited for your response :-)

Conall O' Seaghdha said...

Thanks Trampy,

Exactly! I think that, as it stands, TREAT challenges the very use of Epo in CKD. However, as untreated renal anemia is also independently associated with CV events, I personally believe there is a safe range of use - we just don't know what it is! I think we will need to thrash this issue out much like was done to determine a safe INR for CVA prevention in A. fib. Although you say you don't see the point of such a trial, Nephrologist's instincts have been wrong every time on this issue (Anemia-normalization, CHOIR, TREAT...) and i think further RCTs are the only way to proceed.

It is very hard to know how to proceed in the interim (primum non nocerere) - that's why I currently will only l treat very symptomatic anemia, after first counselling the patient on the risk of CVA.

Looking forward to your future comments!