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 | Updating Practices in an Evolving IV Iron and Anemia Environment: Practical Solutions  ANNA 2007 Satellite Symposium A New Anemia Treatment Paradigm in Favor of the Patient |
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00:01
Introduction
Ms. Easom: I'm very happy to have Dr. Amerling with us. He went quite on an adventure to get here, and I'm sure you will enjoy his talk on a new anemia treatment paradigm in favor of the patient.
00:14
A New Anemia Treatment Paradigm in Favor of the Patient
Dr. Amerling: Thank you, Andrea, thanks very much for the introductions, and the great talks! There's a lot of money being made in medicine in general and in dialysis in particular. Unfortunately, we're not making it. We're sort of out of the money stream in medicine in general and in dialysis in particular. Now, I'm not going to get into particulars, but we know that companies are in business to make money, and companies who say that their primary mission is to take care of patients are just not being honest. Their primary mission is to provide value to their shareholders, which means make money, make profit. And believe me, I'm for capitalism, I'm for profit. I think that we need to have companies that make profit or they go out of business. If companies go out of business, they can't provide the products.
Now, in dialysis we have a particular situation where a part of the profit for dialysis comes from the actual sale of drugs, and this is problematic. And you will see in the June issue of Nephrology News and Issues, an editorial by me, and my editor is sitting here and typing furiously, Mark Newman from NNI, dealing with this. And I think that this whole mess that we have encountered now with EPO in the press, lately, has pushed us in a way to get away from that system where entities, doctors also, make money from prescribing, actually selling, drugs themselves. This years ago was banned. The common practice in medicine for many years was for doctors, for country doctors, to mix up their medicines and their potions and sell them to their patients at a profit. And this was felt to present an inherent conflict of interest, and the practice was abandoned in mainstream medicine. There are still practitioners out there who do mix up their own formulas and potions, if you will, and sell herbs and things like that, and I think that is really not good, that is ethically suspect. And I think that the dialysis companies making so much of their money from the sale of drugs is a problem and should be dealt with.
That being said, there are two groups of people whose job truly is to represent the best interest of the patient - you and me. Nurses and physicians are the only groups that are professionally dedicated by their ethical code to put their patients' interests first. So we have to provide a bulwark of defense against the unbridled profit motive that can sort of wreak havoc in our practices.
03:14
Objectives
We're going to talk about current anemia treatment philosophy regarding iron and ESA use. We'll discuss emerging information on iron and ESA therapies that will hopefully change our ideas about this, and perhaps a more appropriate anemia treatment paradigm based on new data, and then we'll review some actual data. And one of the things that is exciting about being here at ANNA is, that you are going to be the first group to see this data that I'm going to present, which will hopefully be at the ASN come next November. New hot data right off of the press.
03:52
Current Anemia Treatment Philosophy
Well, there's a general feeling, or there has been anyway, that increasing hemoglobin levels with ESAs at all doses is relatively safe. In fact, at a recent FMC medical directors meeting which I attended, they did a poll and a lot of the doctors out there still felt that 13 was an appropriate target for hemoglobin. There's also this idea that patients will not respond to IV iron when their serum ferritin is high, and that, of course, has been partially helped by the KDOQI guidelines, that iron use is not safe at higher ferritin levels. So we're going to look at these assumptions now.
04:27
Anemia Management Practices: The KDOQI Influence
Anemia practice, management of anemia in dialysis, has been heavily influenced by KDOQI. And the recent guidelines (2006) that were issued, which actually created the big firestorm, define a lower limit of hemoglobin as 11, and this is based on moderate strength evidence. The evidence here is really very poor. There certainly is no prospective evidence that a hemoglobin of 11 is any better, shall we say, than a hemoglobin of 10.5 or even 10 for that matter. And then the upper limit of hemoglobin—they sort of couched it very cagily, saying that there's insufficient evidence to recommend maintaining hemoglobin over 13; however, you should decrease but not hold the dose when the hemoglobin hits 13 or above. So in other words, it's a tacit increase of the upper target number from 12 to 13, and this caused a huge firestorm, which many of you probably caught in the media, and it's really still going on. This issue is not going away.
05:29
New Studies Raise Concerns on How to Safely Use ESAs
The firestorm came about, because shortly after the release of these guidelines (in 2006), two key studies were published in the New England Journal of Medicine, the CHOIR and the CREATE study. The CHOIR study was 1432 CKD patients not yet on dialysis who were randomly assigned to get erythropoietin, with half the patients targeted to a higher hemoglobin of 13.5 and the other half to a lower, more moderate level of 11.3. The CREATE study was a study done in Europe with 603, also CKD, patients not yet on dialysis, who were randomly assigned to receive EPO; 301 patients to a higher target of 13 to 15 g/dL, and 302 to a lower target of 10.5 to 11.5. I'm not going to get into the details of these studies, but one important difference was, that the CHOIR study had fairly aggressive EPO dosing on the order of 10,000 units a week, whereas the CREATE study used a much more moderate lower dosing regimen, starting out at, I believe, 2,000 units per week.
06:31
CHOIR: Trends Towards Higher Risk with ESA in High-Hb Group
The CHOIR study showed a significant trend towards higher risk in the group given erythropoietin therapy at the higher hemoglobin target, in terms of a composite endpoint the included death, stroke, MI, and CHF. The relative risk of having that was much higher, 34% higher, significant at the 0.03 level, in the higher hemoglobin level target group. The risk of death did not quite reach statistical significance, but clearly was higher in the higher Hb target group. The risk of hospitalization for CHF, also, while it did not reach the 0.05 significance level, came pretty close, and was also higher in the higher hemoglobin target group.
07:09
CHOIR: Increased AEs in the High-Hb Group
There were also increased adverse events with erythropoietin therapy in the high target Hb group - serious adverse events of 10 versus 3, with a P value of 0.05; heart failure, 77 versus cases versus 51 cases in the low Hb target group, which also was statistically significant.
07:27
CREATE: Increased AE and Progression to Dialysis with ESA in High-Hb Group
The CREATE study had a higher incidence of adverse events and progression to dialysis, in the patients who were treated to the higher hemoglobin targets. You see here the numbers. Vascular disorders in particular were more common, and hypertension or worsened hypertension also was more common in the higher hemoglobin group. And progression to dialysis occurred more frequently in patients treated to the higher hemoglobin level. These two studies were published in November, and the KDOQI guidelines, I believe, came out in August of 2006. And the firestorm was created because the panelists had been informed of the imminent publication of these studies and yet went ahead with their, I think, cavalier, implicit raising of the Hb target to 13, and there were stories in the major news media. And, as I said, this has not died down.
08:16
FDA Update on ESA Use
The FDA, responding to this data appropriately, really recommends using the lowest ESA dose possible to increase hemoglobin concentration and to avoid the need for transfusion, measuring hemoglobin twice a week—I think that is a little excessive and I think that is impractical, we actually do not do that—and to withhold the ESA dose if hemoglobin exceeds 12 g/dL or rises by 1 g/dL in 2 weeks. So I think that they're telling us now, that we have to really cut back heavily on EPO dosing, and I'm very concerned now about, also, the trial lawyers milling around this, and I think that they smell lots of money. And once again we're not going to get any of it, so don't even think about that.
09:04
Anemia Management Practices: The KDOQI Influence
Here is again the KDOQI influence on iron management, recommending a TSAT of over 20%, reticulocyte hemoglobin of over 29 pg/cell, and a serum ferritin over 200 mg/L—this is considered to be sufficient iron during erythropoietin therapy. And at a serum ferritin of over 500—now this is a reduction of the previously accepted 800 value, and by the way that wasn't based on any evidence either—but at over 500, they just say that there's insufficient data to recommend routine IV iron, that one should weigh the response, in another words, individualized treatment. So there's no formal recommendation to withhold IV iron at a ferritin level over 500, although many practitioners see that number and they don't see any further, and they turn that into a protocol, and that's what they do. They hold it over 500, and as I will show you, I think that's very wrong.
09:58
DRIVE Trial
Another study that was recently published, and it also was known, I believe, by the KDOQI panelists, that this was coming out shortly, was the DRIVE study - Dialysis Patient Response to IV Iron with Elevated Ferritin. This was to investigate whether IV iron is effective and safe in improving anemia in dialysis patients with high ferritins, ferritins over 500. Then there was a follow-up trial or DRIVE II, which was to look at the effect of IV iron on ESA dose in patients with ferritin over 500.
10:36
Study Design
The patients were randomized to receive either a full loading dose, 1 g of ferric gluconate over eight sessions, or no IV iron, and all patients during this period had a 25% increase in ESA dose beginning at week 1. And then there was no change in the ESA dose, except occasionally for safety issues. The study was headed up by Dan Coyne, by the way.
11:01
DRIVE Results: Change in Hb
Here are the results, primary results - changes in hemoglobin. You see a much larger rise in hemoglobin in the ferric gluconate treated group, going up to almost 12 as opposed to 11.3 in the patients just given the 25% increase in ESA.
11:16
Percentage of Responders
The percentage of responders also was increased, almost 50% in the ferric gluconate treated group, versus only 30% in the control group.
11:25
Change in TSAT and Serum Ferritin
TSAT went up and ferritin went up in the ferric gluconate treated group. The ferritin actually went down in the ESA only group, which is not unexpected.
11:36
Change in Median CRP
There was no difference in C-reactive protein, suggesting that the administration of Ferrlecit® (ferric gluconate) certainly did not increase the inflammatory state in these patients.
11:47
Adverse Events
Adverse events were also similar in both groups.
11:53
TSAT Is a Poor Predictor of Hb Response to IV Iron
One of the things that came out in a subsequent analysis by Singh and his colleagues was, that neither the TSAT nor the serum ferritin level predicts response (in Hb) to an IV iron bolus.
12:06
Serum Ferritin Is a Poor Predictor of Hb Response to IV Iron
They both really were of no help in terms of saying who would respond to this treatment, ...
12:12
Lower Baseline CRP Predicted Likelihood of Hb Response to IV Iron
...whereas patients who had a low C-reactive protein do respond better, clearly, to IV iron.
12:19
Case Study
Now what did we do? Now, I do believe that we should base our practice on good evidence. The problem is, that there is not much good evidence, or I just presented you a couple of prospective studies, randomized studies, that constitute in my view good evidence. So following on this, we decided to look at our patients and see who would benefit from aggressive iron therapy.
12:41
Evolving Practice Model
We identified almost 90 dialysis patients, and we gave them each 1 g of iron over eight treatments based on having a TSAT under 30%. Serum ferritin ranged from 100 to 1500 and the hemoglobin was 8 to 15 before the administration of this big bolus of iron. By the way, our patient population is about 180; so it's almost half of our patient population. 70% of the patients had no ESA dose change, 16% had an increase, and 14% had a decrease, in the ESA dose. This was before we gave them this treatment.
13:17
Results: Hb Response
(Here is) the hemoglobin response, 11.8 to 12.5, after 10 weeks.
13:33
Results: Change in TSAT and Serum Ferritin
The TSAT and ferritin levels both went up, as you could imagine. The ferritin level went from 689 up to 1089, and the mean values are shown here.
13:47
Results: Change in Mean ESA Dose
The EPO dose went down - went from a mean of 10,650 units per treatment down to 7600 per treatment. Now this is across the entire unit. These are not just the responders. Individual responders had much more dramatic effects. And I will show you a couple of cases that illustrate this.
14:05
IV Iron Therapy: ESA Sparing Effects
Here is a patient who had a decent hemoglobin, and serum ferritin was 663. Then in February, this is very recent as you see, his TSAT was down at 26. Well, we gave this patient a bolus of Ferrlecit, and after a couple of weeks really, the hemoglobin was good but we were able to decrease the EPO dose 3000, 3000, and finally just a few weeks ago, down to 2000. While continuing maintenance iron, serum ferritin increased and transferin saturation also was restored.
14:40
IV Iron Therapy: ESA Sparing Effects
Here is another patient. This patient is clearly anemic, 9.9 hemoglobin, ferritin of 565, TSAT of 23%. Now this is a patient who is also getting 10,000 units of EPO 3 times a week, whom you would normally probably not use aggressive iron therapy on, but based on the results of the DRIVE study, we decided to give this patient 1 gram of ferric gluconate. And the hemoglobin really rocketed up, hitting 14.4 by March. We were able to cut the EPO dose considerably, in half now, from 10,000 down to 5000.
15:17
Overcoming Iron-Restricted Erythropoiesis Due to ESA Dosing
Here is another example of iron-restricted erythropoiesis because of ESA dosing. A patient with a decent hemoglobin, serum ferritin which would be considered to be normal, and ESA dose of 10,000. He was given a bolus of ferric gluconate, which got the ESA dose down to 7000, increasing the ferritin, and maintaining stable, or perhaps increasing somewhat, the hemoglobin. So these are really typical responses that we saw.
15:48
Conclusions
Let me conclude by saying that the recent ESA studies really show that higher hemoglobin levels probably are harmful. Some people say that CHOIR and CREATE, since they were in CKD patients and not dialysis patients, do not apply to the dialysis population. I think that they do in spades because the CKD patients have stable hemoglobin. The dialysis patients do not. In dialysis patients we're measuring their hemoglobin at the lowest point, and if you look at the postdialysis hemoglobin in some of these patients, you will be pretty scared at the numbers you get.
So I think that the DRIVE study demonstrated that iron therapy is effective, and I'm talking about aggressive bolus therapy, effective in anemia in dialysis patients with serum ferritins in the 500 to 1200 range, TSATs less than 25%, and who were on adequate doses of ESA. And you are able to reduce ESA dosing in this patient population extremely well. One of the things that I don't have a slide for is the percent of our patients who were under 10 g/dL of hemoglobin, which I consider to be our EPO-resistant, nonresponder type patients, and who always hovered between 10% and 15%. And this was really sort of a thorn in our side. After 3 months of this (more aggressive IV iron dosing), this group is down to under 5%. So we have been able to reduce this percent of nonresponders or resistant patients, and lower ESA dose across the board.
So once again, let me applaud you for taking on anemia management. Those of you who are anemia managers, I would encourage you to, as Peter says, "Bring other players, other people into anemia management." I've been involved in anemia management for the past year and I can tell you it's really fun. I'm enjoying going there with my red pen saying "cut EPO, cut down to 3000, down to 1500, off, DC (discontinue) EPO." It's a wonderful feeling. It's really very satisfying. So I encourage you to bring your doctors into this. They will enjoy it and you will appreciate it.
Thanks very much.
References
- Coyne DW, Kapoian T, Suki W, Singh AK, Moran JE, Dahl NV, Rizkala AR, DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients J Am Soc Nephrol. 2007 Mar;18(3):975-84.
- Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A, CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84.
- KDOQI, National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006 May;47(5 Suppl 3):S11-145.
- Singh AK, Coyne DW, Shapiro W, Rizkala AR, DRIVE Study Group. Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation. Kidney Int. 2007 Jun;71(11):1163-71.
- Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98.
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