The D&T Report†

Abstract

As this issue of D&T goes to press, the Centers for Medicare and Medicaid Services (CMS) has just declined to issue a change at this time to its payment policies for erythropoiesis-stimulating agents (ESAs) used to manage anemia in renal patients, citing insufficient data to determine risk of the drugs'usage, although it did find “emerging evidence for harm.” Spurred by several large, rigorous trials published over the past few years that link high hemoglobin levels to an increased risk of cardiovascular events and even mortality, CMS initially questioned whether the agency should subsidize a treatment with such a prominent downside and, if so, for which patients—everyone with renal disease? Dialysis and pre-dialysis patients? Transplant candidates and organ recipients? Currently, CMS coverage policies vary by region, with no national payment policy.The agency'sMarch 16th decision, ifmade final,will keep coverage decisions in the hands of regional contractors. A final decision is expected this June.

Two groups in particular are viewing the deliberations with apprehension. In one arena are the companies that make ESAs, most notably Johnson & Johnson, which makes epoetin alfa (Procrit), and Amgen, which also makes epoetin alfa (Epogen), and darbepoetin alfa (Aranesp). They maintain that ESAs improve patient outcomes and decrease the need for transfu-sions, an important issue for transplant candidates, as this can improve their eligibility for an organ by decreasing antibody production that results from exposure to tissue antigens on transferred cells.1 In 2009, ESAs used in the dialysis setting generated $2.8 billion for Amgen alone, with another $365 million coming from the pre-dialysis sector.And, as one industry observer points out, the pre-dialysis market is growing, while the end-stage renal disease (ESRD) market, which comprises most dialysis patients, is expected to remain flat. So restrictions on the use of ESAs in pre-dialysis settings could potentially have amuch greater impact than itmight at first appear.2

Theotherworriedgroupistherenalpatientsthemselves. ManyofthemviewESAs as essential to a decent quality of life, on or off dialysis, and fear that CMS's decision may interfere with their care. “To say, ‘We are not going to be in favor of any kind of therapy that brings hemoglobin up above a certain level’ is basically inserting a subjective decision into the conversation between the doctor and the patient on the best care,” says Paul Conway, vice president of theAmericanAssociationofKidney Patients(AAKP).Essentially,Conwaytells “The D&T Report,”CMSmay be trying to impose a standard that may not be in the patient's best interest or of the doctor's recommendation.

The use of ESAs has long been controversial. Along with their adverse effects, they are notoriously pricey, and the aggressive promotion of their use by the industry has raised some eyebrows. The National Kidney Foundation (NKF) has acknowledged receiving industry support in the development of theKidneyDiseaseOutcomes Quality Initiative (KDOQI) anemia treatment guideline, but states that “no funds given to NKF have influenced the development of any KDOQI guideline's content. Industry support has not been a factor in any work group's deliberations.”3

Some observers have criticized the evidence presented at that hearing. “We think that some of the major elements of the deliberations are flawed,” says Conway. The AAKP's medical research team believes that much of the data CMS is relying on for its decision is observational research that was conducted before 1992. “We don't believe that the core research that's informing this decision process is relevant, given the changes in technology, medication, availability of organs, and other knowledge that's developed over the past 20 years,” he explains.

MEDCAC panel member Ajay K. Singh, MBBS, points out that the FDA is conducting its own analysis to determine whether it should change the way it regulates ESAs. He believes CMS should take its cue from them. “I think it would be prudent for an organization that reimburses for care to wait until it hears how the FDA feels a drug ought to be used,” he says.

Like Conway, Dr. Singh believes CMS should avoid a one-size-fits-all approach, opting instead for reimbursement strategies that emphasize the importance of individualizing anemia management in patients. “There should be flexibility in how the drug is being used, so the reimbursement system shouldn't be forcing physicians to use the same approach to anemia management in every patient,” says Dr. Singh. “I favor individualizing the use of these drugs, with continued reimbursement as long as it encourages treating physicians to discuss the tradeoffs of their use with the patient.” The panel—Dr. Singh among them—voted that there was indeed insufficient evidence to show any benefit of ESA treatment in prolonging renal graft survival.5

Dr. Singh recommends that the NKF revise its 2007 KDOQI anemia management guidelines to reflect the TREAT data; CKD patients with anemia who are not on dialysis should not be considered candidates for ESA therapy, unless there are extenuating circumstances, and; ESA treatment should be considered for people who are transplant candidates, have severe anemia, or in whom blood transfusions are contraindicated.4 CMS is accepting comments from the nephrology community on their recent no-decision, up until their June final decision.

The phenomenon of racial and ethnic differences in medical care has complex roots. As described in the February issue of D&T, geographic and socioeconomic factors account for much of the disparity.1 But the problem goes much deeper than that. The issue of organ donation and transplantation in particular taps into some profound beliefs involving religion and bodily integrity, as well as themistrust of the American medical system harbored by some minorities in the United States. Further, as three recent studies show, other issues such as degree of assimilation and even genetic factors governing the response to transplantation may help explain why some ethnic groups take a dim viewof organ donation.

In the first study, lead author Aasim I. Padela, MD, and colleagues at the University of Michigan explored attitudes toward organ donation in the Arab-American community through a 2003 survey administered to 1,016Arab-American adults living in the Greater Detroit area. Their overall findings: Christians were more likely than Muslims, and women more likely than men, to consider organ donation after death justifiable. Higher income and educational attainment and a greater degree of acculturation into American life also were correlated with an endorsement of organ donation. The authors recommended that local religious and civic leaders be recruited to increase awareness of organ donation options in this community, along with greater use of Arab-languagemedia.2, 3

In a study of 864 kidney recipients, lead author G.V. Ramesh Prasad, MD, and colleagues at the University of Toronto found that people from South Asia (India, Pakistan, Sri Lanka, Nepal, and Bangladesh) were more likely than black,white, or EastAsian patients to experience a major cardiac event after their transplant. They concluded that South Asian ethnicity is an independent risk factor for adverse cardiac events posttransplant, which raises the question of possible genetic variations in risk among different ethnic groups.4

Most recently,Yoshio N. Hall,MD, and coauthors at the University of Washington found that, when compared in terms of time spent on the waiting list, American Indians and Alaska natives were least likely to undergo deceaseddonor renal transplantation, followed by blacks, Pacific Islanders, and Hispanics. Whites and Asians were most likely to receive kidneys. “Area-based efforts targeted to address racial- and ethnic-specific delays in transplantation may help to reduce overall disparities in deceased donor kidney transplantation in the United States,” the authors concluded.5

The study by Padela and colleagues shows the influence of religion in organ donation, independent of ethnicity. “There aremultiple views of organ donation within Islam,” Dr. Padela tells “The D&T Report.” “While many authorities allow organ donation, there are some who feel this is not within the Islamic faith. So, for those who are religiously inclined, there may be some ambiguity about whether this is permissible or not, and therefore would be less likely to have a positive attitude about organ donation.”

These sentiments are echoed in a 2006 survey of attitudes on organ donation and transplantation among various ethnic groups in the U.K. by Myfanwy Morgan, PhD, professor of medical sociology at Kings College London, and colleagues. They found thatMuslims weremore likely than members of other religions to express concerns about organ donation, “despite the declaration by leaders from all the major faith groups in the U.K. that there are no religious prohibitions against organ donation.” They speculated that the survey respondents may not have been aware of those declarations, and noted that many Muslims view cadaveric donation as disrupting their honoring of the dead.The issue may not be simply a question of faith: “The significant association of belief in the need for an intact body with membership of an ethnic minority held after adjusting for religion, suggesting that religion is only one of several influences,” the authors report in the study findings.6

Still, “there are some religions where organ donation runs counter to the teaching,” saysClarence Spigner, DrPH, MPH, professor of Health Services at the University of Washington. There is the notion of wanting to be buried whole, and it may be unacceptable to possess the organ of a dead person, says Spigner.

As shown in the study by Prasad and colleagues, biologic factors may also enter into the equation, be they in the formof a higher risk of adverse events after transplant, or of differences in HLA antigens that make it harder to get a match if the donor and recipient are of different races.7 If information trickles down among certain ethnic groups that its members fare poorly after undergoing an organ transplant, it's not hard to see how, over time, that population will start to take a skeptical viewof the process.

Persuading more members of ethnic minority groups inWestern countries of the benefits of organ donation and transplantation will involve reaching out to them in ways they can understand, saysDr. Padela. “We need culturally sensitive organ donation messages within the Arab community, which means information should be available in their language, and using their news media. Local community organizations can partner with academic ones to deliver these sorts of messages.” Religious and civic leaders can help refine themessage even more.

In addition, says Dr. Spigner, the medical community must become more diverse. “It is a major contradiction for a predominantly white establishment to expect any population, and especiallyAfricanAmericans, to hand over their bodies to be organ donors,” he says. “When people see themselves represented among those doing the asking, organ donation is much more persuasive.”

Teleflex Incorporated, a provider of medical technology products, has received market clearance from the U.S. Food and Drug Administration (FDA) for itsArrow NextStepAntegrade Chronic Hemodialysis Catheter. The catheter is designed to attain long-term vascular access for hemodialysis and apheresis, and indicated for use in adult patients. Teleflex expects to launch the product in theUnited States later this year.

The catheter includes a step-tip catheter's ease of insertion and a split-tip catheter's sustained high flow. Compared with traditional chronic hemodialysis catheters, the ports are reversed to match the heart's natural blood-flow dynamics. The venous port releases blood into the superior vena cava.The arterial port draws blood from the right atrium. Side holes on the tip of the catheter are designed to pull blood from all sides of the catheter. The ports are significantly separated to enhance flow andminimize recirculation.

Satellite Laboratory Services, a clinical services and electronic solutions provider for independent dialysis providers, has changed the company name to Ascend Clinical. Privately held Ascend Clinical is a U.S. provider of ESRD laboratory testing and electronic reporting for independent and hospitalbased dialysis facilities, headquartered in Redwood City, Calif.

Genzyme Corporation has announced results of a pivotal study of Renvela (sevelamer carbonate) in Chinese patients with chronic kidney disease (CKD) on hemodialysis.This is the first study that Genzyme has ever completed exclusively in China. The studymet its primary endpoint, showing that serum phosphorus lowering with Renvela was statistically significantly greater than with placebo. Reductions in serum phosphorus were statistically and clinically significant, and similar to the results of other Renvela studies.

At the end of the study, the serum phosphorus levels of patients treated with Renvela were lower than their pre-study levels, when patients were taking calcium-based phosphate binders. Renvela also reduced total and LDL-cholesterol levels in a statistically significant and clinically meaningful manner. The results of this study showed that Renvela is an effective phosphate binder and generally well tolerated in Chinese CKD patients. Overall, the nature of the adverse events was consistent with the currently approved labelworldwide.

This randomized, double-blind, placebo-controlled, dose-titration study was designed to test the efficacy and safety of Renvela for hyperphosphatemic CKD patients on hemodialysis.More than 200 patients were enrolled at 18 hospitals in China. Patients were randomized 2:1 to receive one 800 mg tablet of sevelamer carbonate or placebo three times a day (for a total daily dose of 2.4 g) withmeals. The dose was titrated by one 800 mg tablet every two weeks for eight weeks to reach a serum phosphorus target of ≤ 5.5 mg/dL (1.78 mmol/L).

Genzyme anticipates filing for approval of Renvela's use in treating hyperphosphatemic dialysis patients in China during the first half of 2011.

Satellite Healthcare has developed a website directed at educating patients about many aspects of kidney disease. The site, www.kidneysdothat.org, provides information for patients through short informative videos; guides offering kidney health tips; information about diabetes, high blood pressure and high cholesterol; and kidney-friendly nutritional guidelines and recipes.

The site benefits anyone who has been diagnosed with kidney disease, cares for someone who has, or wants to learn more about kidney disease. It also provides connections to resources, such as how and where to get tested for the disease.

For more information, visit www.kidneysdothat.org.