Friday, June 10, 2011

Epo, anemia and the lack of placebo controlled trials

By a mistake of communication I was scheduled to give the anemia talk at a recent chronic kidney disease symposium. I would have never selected this topic on my own. I work with Robert Provenzano, one of the Gods of Anemia. Fortunately, this was a happy accident. I loved researching and writing this presentation. The whole experience was an important lesson on the value of working out of your comfort areas.

The anemia saga is well known to all nephrologists and is covered in depth in my presentation but let me recap my version of the story.

Life before Epo was pretty bad. the average dialysis patient received a transfusion more years than not. On the Eve of Epo the transfusion was rate was 16% per quarter!
After the release of Epo, the transfusion rate plummets. It falls by two thirds in a year and continues to fall so that the current rate of 0.3% per quarter is a 98% reduction in transfusions. Revolutionary. And this doesn't even begin to address the quality of life brought to dialysis patients by higher hemoglobins.

I was in college when this happened and it's a little hard to imagine how exciting that must have been.  The introduction of Epo launched a million observational trials that all pointed in the same direction: 

Where you found higher hemoglobins you found better patient outcomes. 

It almost didn't matter what outcome you were interested in: hospitalizations, mortality, regression of left ventricular hypertrophy, quality of life, fatigue score. It didn't matter, everything was better with higher hemoglobins. I suspect the community was seduced by the observational results but for what ever reason the amount of randomized controlled trial data that emerged was laughably small. By 2007, Epo was eating up 1.8 billion Medicare dollars. It should have been the best studied drug and instead it was among the least studied.
I tried to find Henry Paulson's signature but had to settle for George Bush's.
Here is the table from K/DOQI anemia recommendations where they summarized all of the RCT data from the birth of Epo through May 2006 (apparently it omits a single 2005 study).

8 Epo vs Epo studies and 3 placebo controlled trials, 1 placebo controlled trials in pediatrics

The paucity of placebo controlled trials is shocking. No one demonstrated that higher hemoglobin targets had a mortality benefit or regressed LVH compared to placebo. This would not be so problematic if the Epo vs Epo studies had been positive, but those too were negative trials. So we are in the awkward position, a quarter century after the introduction of EPO we cannot conclusively state that the drug does any more than reduce transfusions and improve quality of life. All the mortality reductions, cardiovascular disease protection amount to observational-backed hype (one small rct (N=38) study did show a reduction in LVH).
Favorite slide from the deck

Part of me is outraged but another part understands how difficult it would be randomize dialysis patients to placebo. I couldn't, in good faith, expose trial subjects to the transfusions, fatigue and weakness that being randomized to the placebo-arm would entail. It fails my personal "Grandma test" (i.e. Would you feel comfortable enrolling your grandma in a placebo controlled trial of Epo? No). I understand that and forgive the dialysis researchers; however I am a little disturbed to witness how in the pre-dialysis CKD population the same pattern of relying on observational data. In CKD these is no transfusion epidemic that needed to be derailed, there is no profound fatigue turning patients to zombies. We had an opportunity to do the right studies to figure out if this expensive Nectar of Thousand Oaks really helped. The paucity of placebo controlled and randomized controlled trials in pre-dialysis patients is embarrassing.

Reading this editorial by Marc Pfeffer crystalized this critical mistake. I spent a fair proportion of the presentation laying out how statins evolved from being used in only the sickest patients to larger and larger populations and how at each step placebo controlled trials were used to prove efficacy. Not every step was a win, statins for heart failure failed, but the key is that cardiologists know that statins don't improve heart failure because they tested it with two (1, 2) placebo-controlled trials.

Why is nephrology lacking the randomized controlled trials that have defined the huge advancement in cardiovascular disease over the last 25 years?

  • It isn't due to the severity of illness, the first placebo controlled trial of ACEi in heart failure used a cohort with 40% mortality at 6 months. 
  • It isn't timing, ACEi for heart failure was developed and proven at the same time as the introduction of Epo.
I don't know the why but I have a couple of theories. One is the richness of the retrospective data in nephrology, brought to us by the USRDS, blinds us to the importance of prospective data. This could explain why are repeatedly burned by observational studies, see: kT/V, vitamin D, and binders.

The other theory is that, unlike statins and ACEi where there are many vendors producing drugs in the class of interest, there is a total monopoly in the field of ESA. You want to increase the hemoglobin you need to buy Epogen. No generic, no competing ESA. In the ACEi market, having enalepril as the drug studied in the CONSENSUS and SOLVD trials paid huge dividends to Merck. Having in-class competition lead to commercial support of critical research. Amgen had no need for this because the US Patent Office gave them a monopoly. A monopoly that seems to last forever. Why is it that every other drug from the late 80's is generic: omeprazole, captopril, enalepril, benazepril, metformin, simvastatin, etc. Even drugs from the 90's are now generic: losartan, lansoprazole. 

Epogen stands alone without generic competition. And unfortunately, largely without placebo controlled trials to back-up mountains of hype.

The deck can be found here: Keynote | PDF
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