Procrit, Anemia, Payoffs, and Problems!

[SierraJim]

Not that I wanted to get all serious on everyone, but this is an important issue.  Recent articles in the New England Journal of Medicine (NEJM 11/16/2006) concluded that correction of anemia with Procrit not only does not reduce the risk of cardiovascular events, it increases it.  I was startled to read these results, since I thought that the use of Procrit was well documented.  I was also surprised to learn that in Europe, less Procrit is used, and fewer patients suffer from complications associated with Procrit, namely congestive heart failure, myocardial infarctions, and strokes. There are three articles in that issue, titled respectively "Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease," "Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia," and an editorial titled "Correction of Anemia -- Payoffs and Problems."  In both trials, high target hemoglobin levels increased the risk of congestive heart failure and stroke.  They conclude that caution in the full correction of anemia in patients with chronic kidney disease be observed.  In other words, be careful with the Procrit! 

Another factor in all this is that Procrit is damned expensive.  6ml of 20000 unit per ml Procrit costs $1,640.43.  This is approximately a one-month supply.  Dialysis centers are marketers of this drug, and every unit that they sell to us represents a substantial profit to them.  Fact is that without the sale of Procrit, dialysis centers would not be economically viable.  This should change!  I don't want my dialysis center to be dependent upon the sale of a drug with side effects that include heart failure and stroke.  But the fact is that they are.  Of course, this is my opinion, but I don't think I'm wrong.

If any of you would like to see the original studies, please write to me and I'll email a reply.  I truly believe that we all need to be educated regarding these issues.

[kitkatz]

We do need to be educated, but most of us are stuck in a system that sucks.

[jbeany]

Are the studies only for Procrit?  What about other forms of epo, like Aranesp?  And how do you weigh an increased risk of stroke against life without epo?  My hemoglobin was on a downward spiral before my doc put me on it years ago.  Life with a hemoglobin at 6 and dropping is no way to live.  I'd like to get a transplant, so constant transfusions are a bad idea, not that they aren't without risks beyond messing up your antibodies.  I spent a long time with undertreated anemia and I do not want to go back to that!  I've rather gotten used to walking from one side of the room to other without pausing to catch my breath. . .

[SierraJim]

Perhaps I was using the brand name "Procrit" too loosely.  I should have used the term epoetin beta or erythropoietin.  Procrit is a brand name for this.  I'm definitely not advocating that anyone tell their physician to stop prescribing erythropoietin!  I believe that would be suicidal.  I am suggesting though that too much is prescribed and I'm decrying the fact that there is a financial incentive to prescribe it.  My personal physician has assured me that he is prescribing as low a dose as possible, given that my system would require transfusions if I didn't have it.

Jim 

[BigSky]

This has been discussed in a couple of other threads.

The erythropoietin class of drugs are over prescribed in some units for profit.  However when that class of drugs is used as per FDA guidelines in dialysis patients there are few problems.  Medicare only pays for a 10-12 range which is what the FDA suggests  being optimal for patients.  When patients go over the 13 range the risk for clots increases, at that point Medicare will still pay for the drug but it needs to be cut by 25% until it falls back into the ideal range prescribed by the FDA.

IMO many other factors also play into what happens.  That mainly being many on dialysis are older and the dialysis population as a whole tends not to be as active.

As to the NEJM, if that is the same one I am thinking of they did not actually do the study on dialysis patients,  it was performed on non dialysis patients in which a hemoglobin target of 13.5 was reached.  This is far  higher that what is recommended by the FDA and Amgen.  It was when that level was reached that problems and dangers occurred.  This news is not really new as it has been part of the pharmacological information of the Epo and Aranesp and this information of problems has been out for roughly 8-10 years now.

[Rerun]

I don't think an FDA approved range of 10-12 with stroke at 13 is good enough.  I think it should be a range of 8-10 with stroke at 13 for a "little" bit of a buffer!  My dialysis center isn't that in tune to my charts and my doctor isn't that consistant on looking at my charts to notice that I'm at 13 for a month! 

It is not going to KILL you to be a little anemic.   

[renal30yrs]

Procrit is known to cause aplastic anemia and red cell aplasia in small cases.  It still beats getting transfused every 2 weeks.

[jbeany]

It is not going to KILL you to be a little anemic.

Unless I fall asleep driving my car. . .

Anything below 10 and I can't stay awake more than a few hours a day.  8 might work for you, rerun, but I hate having no life, and refuse to spend my days in a complete fog. 

[stauffenberg]

The fact that all forms of erythropoeitin increase the risk of stroke, clotting, and heart attack has been well known since the mid 1980s.  The risk greatly increases, however, the closer the patient's blood count is raised to normal, so the usual solution has been to give dialysis patients so little Epo that they are severely anemic and totally exhausted all the time.  Keep in mind that the normal hemoglobin level for men ranges from 170 to 140 (or 17 to 14 on another version of the 'system international' units), and that values in the low 130s or high 120s are considered symptomatic of serious anemia requiring immediate correction -- in healthy people, that is.  For women the normal value ranges from 140 to 120, so again, their hemoglobin levels on dialysis are also being kept artificially low out of fear of what an adequate amount of Epo would do to them.  Until they find a way for dialysis patients to make their own red blood cells in normal amounts, the choice will be between giving them enough Epo to give them normal strength but probably killing them in the process from Epo's side effects, or giving so little Epo as to keep them perpetually exhausted!

[SierraJim]

I feel that this issue is important enough that everyone on dialysis ought to read this article, which I am quoting in full from the New England Journal of Medicine.  The full site is: Volume 356:4-6         January 4, 2007         Number 1.  If anyone wants a copy of the full article including the figure, email me and I'll send you a copy.

Medicare and Erythropoietin
Robert Steinbrook, M.D.   


Since Medicare coverage of care for end-stage renal disease (ESRD) was implemented in 1973, dialysis treatments paid for by the federal government have extended the lives of hundreds of thousands of people. For nearly two decades, one of the most important services has been the administration of recombinant human erythropoietin, or epoetin, the mainstay of the treatment of anemia associated with chronic renal failure. In 2005, the ESRD program covered about 390,000 beneficiaries and spent $7.9 billion for dialysis services, including $2.9 billion for medications that are reimbursed separately. Epoetin alfa accounted for $2 billion of this spending and was the highest-expenditure drug in all of Medicare Part B.1

Dialysis facilities can make more money from administering epoietin than from dialysis and related routine services, which Medicare has reimbursed at a composite rate since 1983.1,2 Monthly spending per patient for epoetin has soared to about half that for dialysis, which has remained relatively flat (see graph).3 Expenditures for injectable iron and vitamin D are increasing rapidly as well. In 2007, Congress may consider whether to eliminate financial incentives that may lead to the overuse of epoetin and other separately billable drugs by establishing a combined payment system for all ESRD services, as was recently recommended by the Government Accountability Office (GAO)1 and discussed at a December 2006 hearing of the House Committee on Ways and Means. In a November 2006 letter to the Centers for Medicare and Medicaid Services (CMS), Representative Bill Thomas (R-CA), then the committee chairman, and Representative Pete Stark (D-CA), then the ranking member of the subcommittee on health, wrote, "We are deeply concerned that the current CMS policy is not aggressive enough to stem the systemic abuse of [epoetin alfa], resulting in costs to taxpayers and potential health dangers to patients." At the hearing, Thomas told CMS officials, "You seriously need to consider that your payment policy is killing people." If it enacts reforms, however, Congress could inadvertently create new incentives that encourage inadequate treatment.

Figure 1
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     Monthly Spending per Patient for Clinical Dialysis Services in the Medicare Program.

Erythropoiesis-stimulating agents are epoetin alfa and darbepoetin alfa. Other separately billable medications include injectable iron and vitamin D, which account for most of the spending in this category. Data are from the U.S. Renal Data System.3

 
Erythropoietin has an essential role in improving the quality of life of patients undergoing dialysis and reducing their need for blood transfusions. Administration of fewer transfusions reduces the frequency of sensitization, thereby increasing the likelihood of some patients' receiving a kidney transplant, and lowering the risk, albeit small, of infectious diseases. Medicare's current cost-containment efforts have slowed — but not reversed — the growth in epoetin use.1 Three erythropoietin products are marketed in the United States: epoetin alfa, which is manufactured by Amgen and is marketed by Amgen as Epogen and by Ortho Biotech as Procrit, and darbepoetin alfa, a longer-acting agent that is manufactured by Amgen and marketed as Aranesp. Epogen accounts for about 95% percent of the epoetin used in patients with ESRD in the United States, and Aranesp accounts for the rest; Procrit is marketed for patients with chronic kidney disease but not for those undergoing dialysis. Because Amgen has a monopoly, there is no price competition. The company has held seven patents on Epogen, the last of which expires in 2015, and has prevented the marketing of competing products.1 In April 2006, Roche applied for approval from the Food and Drug Administration (FDA) to market such an agent — a continuous erythropoietin-receptor activator, or CERA, which has a longer duration of action than either epoetin or darbepoetin. Although the FDA has not announced a decision, Amgen has sued Roche for patent infringement.

With regard to patient safety, recent data indicate that about half of patients undergoing dialysis in the United States have their hemoglobin levels maintained at values above the maximum target (12 g per deciliter) specified in the product labeling for erythropoiesis-stimulating agents.2,3 Maintaining higher hemoglobin levels may benefit patients' quality of life but requires substantially more medication and increases their risk of serious and life-threatening cardiovascular complications, including death. This was demonstrated by the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study.4 That study found that targeting a hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) in patients with chronic kidney disease who did not yet need dialysis was associated with a significantly increased risk of a composite end point of death, myocardial infarction, hospitalization for congestive heart failure (without renal-replacement therapy), and stroke. On November 16, 2006, the day the CHOIR study was published, the FDA issued a public health advisory to "underscore the importance of following the currently approved prescribing information" by raising hemoglobin levels no higher than 12 g per deciliter.5

In 2006, Medicare's composite base rate for reimbursement for dialysis was about $130 for free-standing facilities; coverage is limited to three treatments per week.1 Medicare's spending on epoetin reflects the reimbursement rate, the frequency of administration, the dose, and the monitoring policy for epoetin use, which the CMS revised in 2006. Also in 2006, the CMS set payment levels for drugs that are billable separately under Medicare Part B, which covers physician services and hospital outpatient services, at the average sales price plus 6%. In October 2006, the reimbursement rate for epoetin was $9.45 per 1000 units.1 Patients undergoing dialysis typically receive injections at nearly every treatment; Medicare beneficiaries who required dialysis averaged about 10.5 administrations per month in the first half of 2006, and the average dose was about 7500 units.1 According to House testimony by David Walker, the comptroller general of the GAO, as long as dialysis facilities "receive a separate payment for each administration of each [separately billable] drug and the payment exceeds the costs of acquiring the drug, an incentive remains to use more of these drugs than necessary."

Under its monitoring policy, Medicare expects that providers, in addition to following the FDA label instructions for epoetin, will reduce the dose by 25% if the patient's hematocrit exceeds 39.0 (a hemoglobin level of 13.0 g per deciliter). Even if the dose is not reduced, CMS decreases the payment. This payment-reduction threshold recognizes clinical variability in maintaining hemoglobin levels in individual patients. Nonetheless, the House Committee on Ways and Means and others have criticized the CMS policy because the level that triggers a reduction in payment is higher than the FDA's maximum target level for patient care.

Medicare uses a bundled-payment approach to pay for most services. According to the GAO, extending this approach to all ESRD services would make treatment choices "payment neutral" and encourage "providers to operate efficiently, as they retain the difference if Medicare's payment exceeds the costs they incur to provide the services."1 For example, providers might administer epoetin to more patients subcutaneously, which requires considerably less drug than intravenous administration to achieve the same effect. Of course, the success of a global, prospectively set rate depends on the design of the implementation strategy. In addition to avoiding incentives for undertreating, critical issues include the reimbursement rate, how it is updated to reflect changes in costs and medical practice, and how Medicare adjusts payments to account for the distribution among centers of patients whose care is more or less expensive. Moreover, in the case of epoetin, other approaches to cost reduction could complement efforts to control utilization. Examples include a lower reimbursement rate, price competition with other medications, and legislation to provide Medicare with the authority to negotiate lower drug prices.

Under the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Congress required CMS to submit, in October 2005, a report on how a bundled-payment system for ESRD would be designed and to start a 3-year bundling demonstration in January 2006.1 In her testimony at the December hearings, Leslie Norwalk, the acting CMS administrator, said that the agency generally supports shifting to such a system but wants to finalize the details first. The CMS report, however, has yet to be submitted, and the demonstration project has not started. Congress will have to decide whether to wait at least several more years for the results or to create a bundled-payment system before they become available.


Source Information

Dr. Steinbrook (rsteinbrook@attglobal.net) is a national correspondent for the Journal.

References

   1. Report to the Chairman, Committee on Ways and Means, House of Representatives. End-stage renal disease: bundling of Medicare's payment for drugs with payment for all ESRD services would promote efficiency and clinical flexibility. Washington, DC: Government Accountability Office, November 2006. (GAO-07-77.) (Accessed December 12, 2006, at http://www.gao.gov/cgi-bin/getrpt?GAO-07-77.)
   2. Steinbrook R. Haemoglobin concentrations in chronic kidney disease. Lancet. Published online November 17, 2006 (DOI:10.1016-S0140-6736(06)69707-9).
   3. USRDS 2006 annual data report: atlas of end-stage renal disease in the United States. Minneapolis: U.S. Renal Data System, 2006. (Accessed December 12, 2006 at http://www.usrds.org/adr.htm.)
   4. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098. [Free Full Text]
   5. FDA Public Health Advisory. Epoetin alfa (marketed as Procrit, Epogen); darbepoetin alfa (marketed as Aranesp). Rockville, MD: Food and Drug Administration, November 16, 2006. (Accessed December 12, 2006, at http://www.fda.gov/cder/drug/advisory/RHE.htm.)

[stauffenberg]

I find that remark about "avoiding incentives for undertreating" to be fascinating, since Congress, as ever more interested in protecting profits for companies than people, deliberately encourages undertreatment among private dialysis providers, simply by underfunding the monitoring program for compliance with medicare's minimum guidelines.  Some clinics haven't been checked in five years!  And if a private clinic is caught cheating, which the medicare funding system of paying a set fee per treatment and then allowing the companies to make their profits by performing the least service possible for that set fee, it gets a mere slap on the wrist!  No wonder the death rate in US dialysis centers is the same as it is in the industrialized world only at the few not-for-profit dialysis clinics, but much worse at all the for-profit clinics.

A factor which Congress seems to be forgetting, at least as far as I can judge from this brief report, is that the rate at which diabetic complications develop is accelerated by low hemoglobin levels, which might encourage a clinical decision in some cases to prefer a higher hemoglobin level despite the risks of stroke and cardiac arrest.