Tag: anemia

Posted on

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
Posted on

Post transplant erythrocytosis

I have a 35 year old patient who recently received his second kidney transplant. He received his first transplant in his 20s in Albania after going into renal failure due to SSG (that’s Some Sort of Glomerulonephritis, a typical diagnosis for a patient who emigrates to the US with a failing transplant and little medical history).

Soon after his transplant his hemoglobin began to rise. We initiated phlebotomy when his hemoglobin rose above 19.

His hemoglobin fell to 17.2 but then increasd up to 18.5.

I started 5 mg of enalepril and it fell to 16.9.

I increased the enalepril to 10 mg and it fell to 16.2 and continued to fall until it is now around 14.

Posted on

Another one bites the dust: TREAT is negative

Darbepoeitin meets a similar fate as epoetin alpha in CKD patients. Here is the press release from the trial onset, a more opportunistic time:

Amgen Inc. (Nasdaq:AMGN), the world’s largest biotechnology company, today announced that the company has initiated a landmark trial to evaluate the impact of treating anemia on cardiovascular outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes. TREAT (Trial to Reduce cardiovascular Events with Aranesp(R) (darbepoetin alfa) Therapy) is one of the largest clinical trials in the company’s 25-year history. The TREAT study design as well as additional Sensipar(R) data was presented at the American Society of Nephrology (ASN) annual meeting in St. Louis.

“Current research suggests that anemia is an augmenter of cardiovascular risk in individuals with CKD and type 2 diabetes,” said TREAT lead investigator Marc Pfeffer, M.D., Ph.D., chief of medicine at Brigham and Women’s Hospital and a professor at Harvard Medical School. “TREAT will be the definitive study to determine if treating anemia with Aranesp does, in fact, lower the risk of death and non-fatal cardiovascular events in individuals with CKD and type 2 diabetes.”

TREAT is an international 4,000 patient, multicenter, randomized, double-blind, placebo-controlled trial. The primary endpoint of TREAT is a composite index of time to mortality or non-fatal cardiovascular event, including myocardial infarction, myocardial ischemia, stroke and heart failure.

The rational for TREAT was published in the American Heart Journal. From the abstract:

BACKGROUND: Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data.

STUDY DESIGN: The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9> or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

This was the last nail in the coffin for use of ESAs to normalize hemoglobin in pre-dialysis CKD. In the years since CHOIR and CREATE one of my partners kept holding out hope for TREAT. He mentioned that TREAT made it through its interim safety monitoring without being stopped so it was unlikely to show the same detrimental findings found in CHOIR.
This data is just preliminary as it was published to satisfy financial requirements. The official results will likely be presented at Renal Week.
Posted on

IV Iron in Hemodialysis

Steven Fishbane, MD from The University of Pennsylvania, came to our fellowship program to discuss Fe and hemodialysis. He began by talking about hepcidin and then went on to discuss the iron targets in light of the DRIVE trial and then touched on IV Fe and proteinuria and finished with a discussion of platelets and mortality and its relationship to recent anemia trials.

He started by talking about why Fe deficiency is so prevelant among CKD and dialysis. As an explanation he did a brief overview of Hepcidin.

Fe is a powerful growth factor for bacteria.
During an infection the body decides to withold Fe.

Inflammation leads to increases in hepcidin which increases ferritin.
Hepcidin decreases intestinal iron absorption and increases Fe sequestration in RE system. The end result is a decrease in serum Fe and TSAT.

DRIVE Study by Daniel Coin and Morin was designed to see if giving Fe in patients with a high ferritin and low TSAT was effective.

Enrollment:

  • Hgb less than 11
  • ESA over 22,500 U/week
  • Ferritin 500-1200

Ave TSAT 18, Ferritin 761, CRP 27, Hgb 10.3, ESA 34,000 U/wk

All patients had their ESA bumped 25% and randomized to either 1g of Fe or placebo.

The primary end-point was a change in hemoglobin over 6 weeks. The hemoglobin rose 10.2 to 11.3 in control and 10.4 to 11.9 in the Fe group over 6 weeks.

47% of the treatment group had an increase in hemoglobin of 2g versus 29% in the control group.

DRIVE-II by Kapoian

6 week follow-up after the randomized trial. Observational
Hgb increase was sustained despite the Fe group getting the Epo cut by 20% with no change in the in the epo dose of the control group.

Ferritin initially rose to 934 from 760+.

No different in responce in the patients with ferritin 500-800 vs 800-1200.

TSAT was not predictive of response low TSAT and high initial TSAT had the same response.

Prospectively studies cannot find link between IV Fe and infection.

Here is some criticism of the DRIVE study by the National Anemia Action Council:

The purpose of the DRIVE study and its six week extension, DRIVE II, was to determine the efficacy and safety of supplemental intravenous iron in anemic hemodialysis patients receiving recombinant erythropoietin who had a transferrin saturation <> 500 ng/mL. The intravenous iron group did increase their hemoglobin levels slightly more than control patients not given intravenous iron without additional toxicity, leading the authors to conclude that intravenous iron in this situation was both safe and effective. Unfortunately, the design and power of both studies were not sufficient for the investigators to reach these conclusions.

First, the decision to increase the dose of recombinant erythropoietin in each group by 25 % confuses the response to ESA and iron. In a chronic inflammatory state, such as chronic renal disease, the problem is not impaired iron availability but insufficient erythropoietin, which is required to mobilize iron and upregulate transferrin receptor expression. It is well recognized that erythropoietin trumps hepcidin in this situation and the authors merely confirmed that phenomenon.

Second, in the control groups of both DRIVE and DRIVE II, there were a disproportionate number of women, who are more likely to be iron deficient, and their response to recombinant erythropoietin proved this, reducing the effectiveness of comparisons.

Third, both DRIVE and DRIVE II were open label observational studies and in addition physician discretion was also allowed with respect to erythropoietin dosing and iron administration. This discretion can introduce significant bias, weakening the conclusions of the studies.

Fourth, no attempt to estimate blood loss, iatrogenic or otherwise, was made for either experimental group. Fifth, the difference in the hemoglobin level achieved with supplemental iron was not striking and also pushed the hemoglobin level above that currently recommended for safety reasons. Finally, since the serum ferritin and transferrin saturation increased in the iron-supplemented group, a state of iron overload was achieved that was unnecessary and the 12 week observation period was certainly not long enough to exclude the possibility of iron-induced organ toxicity.

It is clear that more data derived from larger prospective trials that are conducted for longer periods are needed. Until this data becomes available, anemic hemodialysis patients not responding to conventional doses of recombinant erythropoietin, in whom the serum ferritin is greater than 500 ng/mL, should first be evaluated for a source of blood loss or infection. Then the patient should be given a higher dose of recombinant erythropoietin for a minimum of 6 weeks with serial transferrin saturation and ferritin measurements before resorting to intravenous iron supplementation.

Fishbane then spoke about the possibility of proteinuria induced by iron sucrose. He showed the Agarwal data on proteinuria and IV iron. He stated that with out knowing how long the proteinuria lasted it was impossible to guess if this was important clinically.

Platelets in Nephrology

Fe deficiency causes reactive throbocytosis
ESAs raises platelets
ESAs cause fe deficiency

Increased RBC push platelets along the walls of the blood vessel. So treatment may cause a lot of atherothrombotic complications because they have both more platelets and red cells.

In DRIVE 20% drop in platelets with Fe treatment.
Streja Et al. used the Davita retrospective database to show a nice human association of TSAT and platelets with thrombosis. Importantly he showed no increase in mortality for Hgb over 13 when the data was controlled for the platelet count. Dr. Fishbane was unable to suggest a how one could design a prospective RCT to test this theory.

Posted on

Great cases on call

I’m running the on-call gauntlet.

I was on call Sat and Sun December 6,7

Sat December 13

Sat and Sun December 20,21

Thursday through Sunday December 25-28

four straight week-ends, with Christmas thrown in for the Jew. Ughh.

That said this week-end has had a few great cases:
  • IgM Cold-agglutinin hemolytic anemia in need of plasmapheresis.
  • Fluconazole induced hyperkalemia
  • Urinary obstruction induced electrogenic type 1 RTA (Hyperkalemic variety of type 1 RTA)
  • Primary hyperaldosteronism induced hypertensive emergency
I’ll elaborate on some (all) of these cases in the next few days.

Happy holidays
Posted on

My fellow just answered a question I have had for years.

Part of the dogma of evaluating iron deficiency in patients with anemia is that after a transfusion the iron indices are altered. Over and over the question comes up…

How long after a transfusion do you have to wait before checking to see if the patient is iron deficient?

Well Jabri, my current fellow went to the literature and found this reference. It looks like the answer is you should be safe 48 hours after the transfusion. This surprised me, I expected the acute effects of the transfusion to persist longer than that.

Abstract from the paper:

The effect of transfusion of packed red blood cells on serum iron level, total iron-binding capacity, and transferrin saturation was studied. Samples of blood from 37 hemodynamically stable patients were obtained for analysis at various intervals following the transfusion of packed red blood cells. In 10 patients with possible iron deficiency, a significant rise in serum iron level and transferrin saturation occurred during the 24 hours following transfusion, which persisted at a marginally significant level up to 36 hours. In the remaining 27 patients, a significant rise was also noted in serum iron level and transferrin saturation results, but the rise did not persist beyond the 24 hours after transfusion. No change in total iron-binding capacity was noted in either group. These data show that the diagnosis of iron deficiency (based on a transferrin saturation of < 0.16) might be missed if iron studies are performed on patients within 24 hours following packed red blood cell transfusion. Therefore, if serum iron studies are obtained for patients suspected of having iron deficiency anemia, these studies are best done on blood samples obtained before blood transfusion.