TREAT or don’t treat? Future goals of anemia treatment…

Historically - before CHOIR and CREATE – Goals for anemia management were

• Hb level of 11-13 g/dl
• Iron saturation > 20%
• Ferritin >200.

CREATE changed the tide which was followed by CHOIR. CREATE (Epo-β) had intent to treat with two groups, 13-15 vs. 10.5-11.5 g/dl. Six hundred and three CKD patients participated (301 vs. 302) with eGFR of 15-35 ml/min. The weekly Epo Dose used was 5000 vs. 2000 Units. After duration of three years there were no effects on first cardiovascular events (58 vs. 47, p=0.20). However 127 vs. 111 (p=0.03) reached ESRD in the high Hb/Epo group . There was also more HTN (89 vs. 59, p=0.005), however general health and physical function were improved.

CHOIR (Epo-α) had also intent to treat (13.5 vs. 11.3 g/dl). A total of 1432 CKD patients (715 vs. 717) were included. Approximately 50% of patients were diabetics. The weekly Epo dose used was 11000 vs. 6300 Units. The duration was 16 months and composite events were 125 vs. 97 (p=0.03) and included death, MI, CHF and stroke in the high Epo group. There was no change in quality of life.

After these two studies the goals of anemia treatment changed and aimed for lower Hb levels. During my clinic fellow year in 2007 at the BWH, I learned them to be as follows:

• The goal for Hb was reduced to 11-12 g/dl (NKF) and 10-12 g/dl (FDA) and ESAs were minimized.
  
• Latter was mainly accomplished by aiming towards high Iron saturations (sat>50%)
• Ferritin levels (> 500-800; some even advocating Ferritin > 1000).

Last year at the ASN meeting in San Diego the TREAT study came out (see ref. below). This was the first large placebo-controlled study, and compared to the previous two it was larger and all (!) patients were diabetics. It was a randomized and double-blind study with two groups. The intervention group (N=2012) had a Hb goal of 13 g/dl and was treated with Darbopoetin. The placebo group (N=2026) had a goal to maintain a Hb > 9 g/dl and received rescue doses of Darbopoetin or blood transfusions. All patients were type 2 diabetics and there eGFR ranged from 20-60 ml/min. The targets of the study were not completely achieved (Hb 12.5 vs. 10.5 g/dl). There was no difference in composite events (632 vs. 602, p=0.41) except for increased stroke events (101 vs. 53, P<0.001) p="0.002).">

• many of my colleagues tolerate lower Hb levels (9-12 g/dl).
  
• With this change, more iron infusions are necessary to target higher Ferritin levels (800-1000).
  
• ESAs (or blood transfusions) are used to rescue patients who drop with Hb levels <9-10>

We all are awaiting new guidelines (by FDA, NKF and KDIGO) confirming this approach to renal anemia. Some issues will remain the same though, e.g. Hb variability is associated with mortality in CKD/ESRD and we don’t know if it’s a marker or maker. Also, high ESA dosing (when necessary) and its safety remains a problem. It may affect only a subgroup of our CKD/ESRD patient population, the hyporesponders to ESAs. This subgroup actually may be especially receptive to stroke (Marc Pfeffer, TREAT study, BWH renal grand rounds 3/2010). The definition is unclear, however these are patients requiring high Epo dosing and have poor response. The causes remain unclear but could include inflammation, infection (HIV), malignancy, aluminium toxicity, antibodies, high PTH levels and ACE inhibitors. In conclusion, what did TREAT teach us? Well, as long patients are asymptomatic or “feeling well” despite anemia below current goals, they may be better off with restriction of (high dose) Epo and tolerating “lower” Hb levels.

However, if patients are complaining about “not feeling good”, we probably still treat them with caution. If uremia and low iron stores or other causes are ruled out, they need either ESAs or blood transfusion for (rescue) management of renal anemia. The active issues of ESA dose changing are the management of undertreated (?Hb<10>12 g/dl) and frequency of monitoring. Once a month, as recommended by the NKF, is probably not enough…


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