Two questions remain to be answered fully:
– In patients with CKD, is it the high Hb that is dangerous or is it the high doses of ESAs?
– What do we do with patients on dialysis who are not even achieving the new lower targets despite escalating doses of an ESA
My personal bias is that it is the ESA that is the problem rather than the Hb dose. Observational studies have shown that patients who achieve high Hb targets without the use of an ESA have no increased risk of CVD. ESAs are known to activate the vasculature and potentially increase the production of profibrotic and prothrombotic circulating factors. Patients who require very high doses of an ESA to achieve a particular Hb target are a high risk group and it may be that the requirement for such high doses is a marker of disease burden.
The Normal Hematocrit Study (NHCT) was published in the NEJM in 1998 and reported that there was a non-significant increase in mortality in patients in the high Hb group. However, there was a benefit in terms of QOL in patients with a higher Hb. This study has been criticized before and further analysis of the outcomes has shown that when the patients were followed for a longer period, there was a statistically significant increase in mortality in the high Hb group. Last year, a paper in KI reanalyzed the results of this study and found that this increase in mortality was evident even earlier that had been reported.
There was another fascinating finding in this report. The original study reported quality of life in patients based on achieved Hb levels. Thus, higher Hb was associated with better QOL irregardless of whether or not the patient was in the high Hb group. There was no difference in QOL between the randomized groups. In other words, it wasn’t the ESA that was making the difference – there was a difference between those patients who had high Hb levels compared to those who did not reach those levels that was not related to the use of an ESA: patients who are healthier and respond better to an ESA have higher QOL scores! There was a misinterpretation of these results to mean that high ESA doses were associated with better QOL which has subsequently been proved wrong.
There was an accompanying editorial with that KI article that is definitely worth a read and advocates for new standards in the reporting of clinical trials.
This is not an argument for new trials. It is an argument for better reporting of trials in the future so that they are not misinterpreted the way that this one was. I don't think anyone would argue at this point that it is a good idea to do further trial of Hb normalization in CKD
Do you really need more trials? If it is daylight outside, you don't do a RCT to prove this
Well done! Thanks for the interesting perspective.
I should add as a postscript to this post that the authors of the original NEJM manuscript replied to Dr. Coyne in KI. Again, a fascinating insight into the editorial process: