Treatment of Anemia Questioned

Discussions for Patients, Family, and Friends PD For Patients
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New York Times

November 30, 2006

Treatment of Anemia Questioned
By ALEX BERENSON

An expert panel of doctors for the National Kidney Foundation plans to assess whether hundreds of thousands of patients with kidney disease are being dangerously overtreated with drugs for anemia.

The decision to convene the panel comes two weeks after studies in The New England Journal of Medicine suggested that kidney patients whose anemia was more aggressively treated were more likely to die or suffer heart problems than those who were allowed to remain more anemic.

As a result, the panel, which will meet early next year, may recommend less aggressive treatment of anemia, potentially hurting sales for Amgen and Johnson & Johnson, which market the drugs, which are among the world’s best-selling prescription medicines.

“There are substantial sums of money involved here,” said Kerry Willis, vice president for medical and scientific activities of the National Kidney Foundation. The foundation, in response to a reporter’s question, confirmed the panel’s plans to meet. The panel’s recommendations would not have the force of law. But they are certain to be closely watched by kidney doctors as well as administrators of the federal Medicare program, which is by far the largest buyer of the drugs worldwide.

Sold under the brand names Epogen, Procrit, and Aranesp, the anemia drugs will reach almost $10 billion in sales worldwide in 2006. Medicare will spend $2 billion on them for kidney dialysis patients alone, and a similar amount for cancer patients and patients with kidney disease not yet on dialysis.

Nearly one million Americans, including 500,000 kidney patients, receive the drugs every year.

But some independent scientists say they believe that kidney patients are receiving too much of the drugs, in part because dialysis clinics make bigger profits for providing higher doses. The clinics make little profit on the actual dialysis services they provide for Medicare enrollees, who are the vast majority of dialysis patients.

The foundation’s panel will probably meet in January or early February and could release new treatment recommendations for public review a few weeks later, the foundation said.

The anemia panel consists of 15 nephrologists who meet under the auspices of the foundation, a private nonprofit group based in New York that provides financing for kidney researchers. The panel is one of several panels sponsored by the foundation that make recommendations about how to improve treatment for kidney patients.

But some scientists complain that Amgen has until now had too much influence on the creation of the foundation’s guidelines. The most recent version of the anemia guidelines, released earlier this year, encourages more aggressive treatment than the Food and Drug Administration recommends.

“The guidelines are funded through the National Kidney Foundation by industry, by and large,” said Dr. Daniel Coyne, professor of medicine at Washington University in St. Louis. “They write guidelines that are opinion-based, by and large, and favor industry or would appear to favor industry.”

While Amgen sponsors the creation of the guidelines and donated $4 million to the foundation last year, both the foundation and the company say that the company does not control which doctors are chosen for the panel or influence their choice of treatment.

Dr. Rob Brenner, senior director of medical affairs at Amgen, said the company had always promoted use of its drugs in accordance with the more cautious F.D.A. label, not the more aggressive guidelines created by the foundation.

The anemia drugs are proteins that stimulate bone marrow cells to produce hemoglobin, the main component of red blood cells. They must be given via injection, either intravenously or through the skin.

The original drug, called epoetin, is made by Amgen, which markets it under the brand name Epogen. Johnson & Johnson sells the identical drug, also produced by Amgen, as Procrit.

The other drug, darbepoetin, is sold under the name Aranesp. It was introduced in 2001 by Amgen and is a slightly modified version of epoetin that can be given less frequently.

Neither the National Kidney Foundation panel nor the F.D.A. suggest how much of the drugs patients should receive. Instead, they have guidelines for hemoglobin targets in the blood.

In general, healthy adults have hemoglobin levels of 14 grams or more per deciliter of blood, while patients are considered to need treatment if their levels are below 10 grams. Severe anemia can be devastating, leaving patients unable to work, walk for more than a few minutes, or even think clearly, while also increasing their risk of infection and heart disease.

But high levels of hemoglobin can cause high blood pressure, strokes and heart attacks, even in healthy adults. Now some scientists say they believe that kidney doctors need to become more conservative about treating anemia, which probably means using less of the drugs.

The prescribing label for Epogen, as approved by the F.D.A., says dialysis patients should have a target hemoglobin level of 10 to 12 grams per deciliter of blood. In its most recent guideline, the panel of doctors overseen by the kidney foundation said a target of 11 to 13 grams was appropriate. It is that target that will now be under review.

In practice, almost all dialysis patients receive the drugs, and almost none have hemoglobin levels below 11 grams after treatment. About half have levels of more than 12 grams, according to data from the United States Renal Data System, a federally sponsored group that monitors kidney patient care. Almost 20 percent of patients have levels above 13 grams.

The differences may seem small, but one of the studies published in The New England Journal found that patients treated to an average hemoglobin level of 12.6 grams had a 34 percent higher risk of death or serious heart problems than those treated to a level of 11.3 grams.

And the average patient at the higher level required about twice as much of the anemia drug to get to that level.

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Truth be told, noone really knows just yet what the correct range should be - it’s a relatively new drug - out since 1989 - but it has made a world of difference for treating anemia associated with ESRD. At least it is very good that panels are formed to discuss these issues as they arise.

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I think it’s odd that research finds that a “normal” level of Hgb is somehow harmful in people with kidney failure. Even assuming that the studies were well done and the findings are correct, though (keep in mind who funded them–two companies that have competing products in the pipeline), to me this is a classic trade-off between possible quantity (length) of life and quality of life. This type of trade-off is made every day in many other illnesses, like cancer, but for some reason in ESRD, doctors and Medicare seem to believe that they can or should make medical decisions for prople.

How do you feel when your Hgb is higher vs. when it drops lower? Do you want decisions about your quality of life and energy level made by policymakers–or by YOU in consultation wtth your doctor? If people who are affected by these issues don’t speak up, decisions will be made without your input, and policymakers are not the ones who will suffer if the pendulum swings too far the other way–toward a repeat of the payment policies that were very punitive if a patient’s Hgb edged even a tiny bit above the upper end of the target range. To be sure they would never lose money on EPO, dialysis providers would quickly cut off the dose when folks got close to the upper end, causing a “roller coaster” effect that was very hard to live with. Beth and I wrote an article on this phenomenon for Nephrology News & Issues that came out in Nov. '04.

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But Dori they just don’t know. Say for instance the increased viscosity of a normal hemoglobin in a dialysis patient whose blood is outside their body in an extracorporeal circuit at least three times weekly that may require more heparin to keep the circuit from clotting and that could possibly lead to heparin induced secondary thrombocytopenia. Or increased viscosity in already compromised coronary or peripheral vessels causing more stress - as those with renal disease already have some sort of cardiovascular compromise due to hypertension or calcylphaxis? I think your statement on “feeling better” vs quality and quantity of life is alittle too generalized. There are too many if’s and unknowns here. The drug is certainly too new to tell. And also remember years ago buttonholes were abandoned because of the increase in infections in these accesses. From the posts on this board it appears infection with buttonholes is indeed raging it’s ugly head again. I personally cringe when I hear that a patient has to remove an old scab prior to reinsertion - the skin and scabs are a natural mechanism of defense. It appears to me if those old scabs are not removed routinely with a sterile object and albeit carefully at that this is a tragedy waiting to occur. Sometimes I think just a regular well developed fistula or graft that the patient can rotate sites on and that the patient can be taught to cannulate at home would be better. All my home dialysis patients had a fistula or graft and were pretty good at self-cannulation. But then I have been out of the loop with home hemo since the program closed b/o lack of patient interest - now I exclusively teach PD. This of course is just my opinion, and I learn more everyday from this site and other professional reading.

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Increased blood viscocity is exactly why I suspect that a “normal” Hgb can’t be tolerated in people on 3x/week in-center HD. And, why I wonder if it might be tolerated in people on PD or other forms of home HD where their blood doesn’t ever get as dehydrated. In-center HD is just not a physiologic treatment. As far as the tradeoff between improved QOL and a possible increased risk of reduced longevity, I stand by my statement that educated patients are the only ones who have any business making this choice–it’s their lives.

The drug is certainly too new to tell.

Epogen? It’s been in clinical use for almost 20 years–patented in 1989. That’s not a new drug.

And also remember years ago buttonholes were abandoned because of the increase in infections in these accesses.

I’ve never heard this before. My sense was that buttonholes never caught on the US–quite possibly because fistulas have never really caught on the way they should in the US. The very limited literature on the buttonhole technique suggests less infection, not more.

It appears to me if those old scabs are not removed routinely with a sterile object and albeit carefully at that this is a tragedy waiting to occur.

I do believe you’re right about this–people have been too cavalier about removing the scabs with any old thing, and this is definitely proving to be dangerous.

Sometimes I think just a regular well developed fistula or graft that the patient can rotate sites on and that the patient can be taught to cannulate at home would be better.

If it were me, I’d choose the buttonhole because those large needles ARE painful (and buttonhole cannulations are much less so), and because over time, fistulas that are cannulated using the rope ladder technique seem to be more likely to develop disfiguring and dangerous aneurysms. IMHO, the key is to teach correct technique–e.g., sterile tweezers–for the buttonhole, not to take away patients’ choices. Fistulas cannulated by the rope ladder technique also develop infection–it’s always a risk no matter what form of access (or cannulation) is used.

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20 years is relatively new to me. In the beginning we were quite concerned about the possible increase in blood pressure - paranoid about it - but that only occured in a low number of patients. We were worried about the increase of stroke and increasing anticoagulation to prevent a circuit from clotting due the potential increase in red blood cells. That didn’t happen much either. No one yet quite knows definitively about the long terms effects of EPO, sorry to disagree with you. What I can say with great certainty is that it definitely improves the quality of life in dialysis patients. It was like the TUMS issue - for many years patients were encouraged to take TUMs as an affordable phosphorus binders. Patients were taking 10-20 TUMS a day! Then calciphylaxis became an issue. Now we know how tragic the effects of calciphylaxis can be. Fact is, until the creation of the first DOQI council there were practically no standards or guidelines on which to base adequacy of dialysis. Few knew or understood URR or the concept of KT/V. Standards of care in dialysis are realtively new and still evolving.
As far as the frequency of infections from buttonholes, I do think that was an issue several years back. I do not have any data at my fingertips presently to give you. Ask a few of your old time nephrology/surgeon contacts.

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Even before TUMs the bigger problem was aluminum-based binders that caused an aluminum build-up in the brain. <Sigh> The vessel calcification issue is a very serious one–whenever we play around with the balance of substances in the body, we always need to be very careful. But Epogen is a bioengineered form of a substance the body already produces. The data seem to indicate that raising the Hgb up to a “normal” level isn’t tolerated well (in terms of longevity) by people with ESRD. But there’s certainly nearly two decades of data suggesting that if you keep levels within the target range set by the FDA submission that it is safe and well-tolerated. I don’t believe the calciphylaxis argument really fits here.

Fact is, until the creation of the first DOQI council there were practically no standards or guidelines on which to base adequacy of dialysis. Few knew or understood URR or the concept of KT/V. Standards of care in dialysis are realtively new and still evolving.

Good thing!–I hope they’ll continue to evolve away from the use of small molecule clearance as the sole indicator of adequacy. It’s better to measure something than nothing, I suppose, but there was a very interesting article on this topic just last year. Here’s the abstract (emphasis is mine):

Semin Dial. 2005 May-Jun;18(3):203-11
Uremic toxins: a new focus on an old subject.

Yavuz A, Tetta C, Ersoy FF, D’intini V, Ratanarat R, De Cal M, Bonello M, Bordoni V, Salvatori G,Andrikos E, Yakupoglu G, Levin NW, Ronco C.
Division of Nephrology and Transplantation, Akdeniz University, Antalya, Turkey.

The uremic syndrome is characterized by an accumulation of uremic toxins due to inadequate kidney function. [b]The European Uremic Toxin (EUTox) Work Group has listed 90 compounds considered to be uremic toxins. Sixty-eight have a molecular weight less than 500 Da, 12 exceed 12,000 Da, and 10 have a molecular weight between 500 and 12,000 Da.[b] Twenty-five solutes (28%) are protein bound. The kinetics of urea removal is not representative of other molecules such as protein-bound solutes or the middle molecules, making Kt/V misleading. Clearances of urea, even in well-dialyzed patients, amount to only one-sixth of physiological clearance. In contrast to native kidney function, the removal of uremic toxins in dialysis is achieved by a one-step membrane-based process and is intermittent. The resulting sawtooth plasma concentrations of uremic toxins contrast with the continuous function of native kidneys, which provides constant solute clearances and mass removal rates. Our increasing knowledge of uremic toxins will help guide future treatment strategies to remove them.

To me, this article suggests that A). Our reliance on urea as a molecule to measure as a “surrogate” for other molecules removed in dialysis is sadly misplaced, and B). The more continuous the therapy, the more physiologic it is. So, short daily and long nocturnal HD and PD are considerably better-tolerated than short, thrice-weekly in-center HD–which paradoxically is the most costly.

As far as the frequency of infections from buttonholes, I do think that was an issue several years back. I do not have any data at my fingertips presently to give you. Ask a few of your old time nephrology/surgeon contacts.

I’ll ask around. :slight_smile:

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Thank you, my dear. Whomever you serve in your area is very lucky to have you looking out for them. You always provide great insight and experience. I have been doing this a very long time too - 24 years - and love to come here to this site because you always get my brain working and thinking of better ways to deliver care. Have a good one!

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You’re VERY welcome, Jerseygirl! We really welcome your posts and your expertise and willingness to keep learning so you can help your patients do better. They’re lucky to have you! :slight_smile: