When we last left the anemia wars, the erythropoietin stimulating agents (ESA, which is Epo, Darbe, and CERA) were in full retreat. The ESAs had conquered ESKD and were (and still are) the standard of care to treat anemia. From that position they made a strategic strike on pre-dialysis CKD, targeting anemia in a larger slice of the world. There are 30 million patients with CKD, the market is big but relatively few of them have hemoglobin that is really low. Only 15% of patients with CKD have anemia, and that is using <12 g/dl in woman an < 13 g/dl in men.
One of the prominent theories at the time was to increase the hemoglobin to around 13 to reduce the cardiovascular disease that is so prevalent in CKD (remember the vast majority of these CKD 3 patients will die of heart disease long before they are even smelling a dialysis center).
This strategy was actually not a new idea. We had already tried this is dialysis patients. Besarab’s Normalization of Hematocrit was published in 1998. This showed that bringing the hemoglobin to 13 was bad in hemodialysis. It increased access failure, it nearly increased total mortality, and there was no signal of any benefit.
Despite Besarab’s red flag three randomized controlled trials were done to show that a high hemoglobin was beneficial in CKD, CHOIR, CREATE, and TREAT. All of them failed to show a benefit from the high hemogbin and all of them showed various, and not always consistent safety signals. The bottom line lesson of these three studies (four, if you include Besarab’s) was not to target a high (or even normal) hemoglobin with these drugs. The FDA recommended only using these drugs to avoid transfusions. KDIGO guidelines suggest a hemoglobin from 10 to 11.5 g/dl.
Nobody missed the top line result but the failure of normalization of hemoglobin also shined a light on the remainder of the ESA data. Erythropoietin was approved in the late 80’s for its ability to reduce the need for transfusions. But look as hard as you can you won’t find any data showing that treating anemia improved mortality. This is why the FDA limited use of the drug to prevent transfusion.
Those are quarterly transfusion rates, not annual. 
The transfusion rate fell by two-thirds in the first year of widespread ESA use.
So that is how we left the anemia wars. ESAs retreated back to dialysis and there was a smaller amount of anemia treatment in pre-dialysis CKD to much more modest targets.
Since publishing TREAT and the revised FDA and KDIGO guidelines, anemia has slipped from the forefront of nephrology. The science has continued to mature and there is a new target, HIF-stabilizers (Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors). he HIF-stabilizers have been winding their way from the bench to the bedside for the last 20 years and are currently in the midst of large, long phase three trials. These trials are different than the approval trials for CERA, Darbe and Epo. Those drugs needed to show the ability to correct and maintane a stable hemoglobin. The HIF-stabilizers have to be at least as safe as erythropoietin. Just like diabetes drugs after Rosiglitazone, the FDA is no longer satisfied with an improved number. the drugs need to show cardiovascular safety.
That was the landscape in which two high impact trials on anemia were announced at Kidney Week 2018.
The first was Cardiovascular Safety of Methoxy Polyethylene Glycol-Epoetin Beta in Treatment of Anemia of CKD by Francesco Locatelli. This is a cardiovascular safety study of Mircera. It looks like the same type of trial the HIF-stabilizers are now undergoing to demonstrate CV safety. This is clearly a government request and so my criticism about the study may need to be directed at the FDA/EMA. What makes me uncomfortable with this study is the choice of control. Remember these are cardiovascular safety studies, but the epoetin was originally approved not based on cardiovascular safety but on the ability to avoid transfusion. In the only placebo controlled, cardiovascular trial of ESAs, darbepoetin alfa fell short of placebo.
In this latest Locatelli trial, Mircera was found to be as safe as ESAs that were previously shown to be inferior to placebo (at least at high hemoglobin and in diabetics, with pre-dialysis CKD). It is essential, if we are going to do studies assessing cardiovascular safety that they are compared to appropriate controls.
We should not be having patients spend years in a randomized trial trying to show non-inferiority to a drug that looks pretty inferior.
This is in opposition to the Intravenous Iron in Patients Undergoing Maintenance Hemodialysis study by Iain C. Macdougall. They showed that an aggressive iron schedule resulted in fewer transfusions, no safety signal and some real patient oriented outcome advantages (mainly hospitalization for heart failure and transfusions, which are especially important for patients waiting on a transplant list, i.e. almost everyone on dialysis).
Daniel Coyne, Author of the DRIVE and DRIVE II trials had a nice series of tweets about this trial:
