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Extending Medicare Coverage for Preventive and Other Services APPENDIX D, PART 1 Immunosuppressive Therapy: The Scientific Basis and Clinical Practice of Immunosuppressive Therapy in the Management of Transplant Recipients Robert S.Gaston, M.D.* INTRODUCTION The development and evolution of solid organ transplantation in the second half of the twentieth century is a unique achievement of modern medical technology. In 1964, Dr. Thomas E.Starzl noted that, to be considered a standard treatment, transplantation must “…first, be performed with an acceptably low mortality; second, the patient be restored to a reasonable state of health for a significant period of time; and finally,…the financial burden of care should be within the reach of the patient, the hospital, and the community.”1 Reflecting remarkable scientific and clinical progress, Starz’s original criteria have now been fulfilled, as thousands of patients with previously fatal cardiac, hepatic, and renal diseases now routinely undergo transplantation, which affords complete or near-complete restoration of organ function. For the majority of allograft recipients, life is not only longer, but better. Current successes are the result of tireless efforts of transplant professionals to overcome the original hurdles of technical feasibility and immunological rejection. Now, the focus of transplantation is changing. As recently as 20 years ago, Rennie editorialized that “…even though it offers a much better quality of life while it works, a transplant in most cases (of kidney failure) can be considered only a temporary respite from the basic form of treatment, which is dialysis.”2 No longer is it practical to look at transplantation as a temporary intervention. For the kidney recipient, long-term graft survival is the best route to highly functional living; for the heart or liver recipient, survival of the allograft means life itself. Ensuring long-term success * Associate Professor, Department of Medicine, Associate Professor, Department of Surgery, University of Alabama at Birmingham.
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Extending Medicare Coverage for Preventive and Other Services for as many transplant recipients as possible is the new challenge for the next century. The interest of the federal government in solid organ transplantation dates back to 1972, when passage of the Social Security Amendments authorized Medicare entitlements for patients with end stage renal disease (ESRD) and included funding for kidney transplantation. At the time, for most patients, dialysis was considered optimal therapy.3 Subsequent clinical developments led to a marked shift in the scientific underpinnings of the Medicare ESRD program, as data ever more convincingly confirmed the benefits of transplantation relative to dialysis. Medicare policies evolved to keep pace with these technological changes. However, recent clinical advances have again tilted the balance away from scientific and economic symmetry, particularly regarding issues related to long-term graft survival. In addition, funding considerations have previously focused only on kidney disease through the ESRD entitlements but in recent years, advances in transplantation of other solid organs have meant that recipients of other types of transplants are also affected by coverage policies. This changing environment challenges the rationale underlying current Medicare funding of transplantation. In this document, we will explore the scientific and clinical bases for current approaches to transplantation, and their relationship to other therapies (notably dialysis, for patients with ESRD). Successful transplantation has become inseparably linked to pharmacological immunosuppression that must be maintained for the life of the graft. By limiting payment for immunosuppressive drugs, current policies not only place a heavy burden on Medicare beneficiaries who have received transplants but continue to reflect the early impression that transplantation and pharmacological immunosuppression are temporary interventions. THE SCIENTIFIC BASIS OF LONG-TERM ALLOGRAFT SURVIVAL Expected Outcomes—Beyond Three Years In 1963, future Nobel laureate Joseph Murray noted: “At present there is good evidence that chemical suppressive agents may be temporarily effective, [but] many questions remain unsolved. The eventual status of these homografted kidneys, the length of time for which the drug must be continued, whether or not the possibility for rejection diminishes with the passage of time and whether the original kidney disease will develop in the homograft are all unsolved problems. The total immunological potential of the host is not known when one is considering the course of his future lifetime. However, this report permits a note of cautious optimism in a problem that 10 years ago was considered almost insoluble.”4 Transplantation has evolved in a very short time from a spectacular, experimental procedure to a commonplace event. Patients who previously faced near-
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Extending Medicare Coverage for Preventive and Other Services certain death with cirrhosis, cardiomyopathy, or pulmonary hypertension now can return to functional, high-quality life with hepatic, cardiac, or pulmonary transplantation. Although challenges persist (particularly in lung transplantation), the overwhelming majority of transplant recipients can expect to be alive 1 year after transplantation, most with functioning grafts.5,6 For patients with ESRD, transplantation from virtually any donor is now preferred over dialysis. In renal transplantation, graft losses for primary cadaver-donor renal transplants during the first year after transplantation declined from 26 percent in 1985 to 12 percent in 1995.5 More recent data from single centers are reporting even fewer early losses.7 Length of initial hospitalization has declined at many centers from several weeks to less than a week for live-donor transplantation and only incrementally longer for recipients of cadaver kidneys.8 In the early days of transplantation, at least one episode of acute rejection was the norm for every patient, leading to prolonged initial hospitalization and frequent readmissions, with substantial infectious and other consequences of treating these episodes. Now, rejection rates of less than 50 percent are commonplace, and more than half of recipients are not readmitted to the hospital during the first posttransplant year.7,9 In summary, these numbers reflect the ability to provide organs of ever-greater quality for recipients who have received better pretransplant care, coupled with the ability to reduce the impact of immunological rejection with less toxic and more specific immunosuppressive therapies. Murray’s note of cautious optimism has evolved into a symphony of successful transplants. Given these changes, the attention of the transplant community has also shifted and is now clearly focused on pursuing knowledge and interventions that facilitate long-term graft survival. Some investigators, citing a relatively stable attrition rate of functioning grafts over time, contend that improvement in short-term graft survival has not translated into a similar benefit in long-term graft survival.10,11 Most data, however, document a steady, if not spectacular, increase in the “half-life” (the time at which 50 percent of grafts functioning at 1 year are lost) of both cadaveric-donor (from 5.4 to 8.5 years) and living-donor (from 10 to 14.7 years) transplants between 1986 and 1993.5 If one excludes those graft losses due to death in a patient with a functioning allograft (death-censored survival), the half-life for cadaver-donor transplants rose from 11.1 to 16 years during the same period.12 Data from the United Network for Organ Sharing (UNOS) Scientific Renal Transplant Registry indicate that 86 percent of kidney transplants performed between 1992 and 1994 were functional 1 year later, and 91 percent of those functioning at 1 year are still working at 3 years (actual 3-year graft survival of 78 percent).6 More recent data, for transplants performed in 1995, indicate one-year graft survivals of 88 percent for recipients of first cadaveric kidneys and 93 percent for recipients of kidneys from living-related donors.5 Since 1995, a watershed year for new transplant therapeutics (see below), it has not been unusual for single centers to report overall one-year graft survival in excess of 90 percent.13 Thus, a reasonable projection for the next decade might be
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Extending Medicare Coverage for Preventive and Other Services three-year renal allograft survival of 85 percent or better. Long-term graft survival is fast becoming the norm. Transplant Immunology and Pharmacology It is increasingly evident that the field of solid organ transplantation is entering a new era in which short-term success mandates greater attention to issues of long-term care. As noted elsewhere, this sea change is the result of the interplay of many scientific and clinical advances. When one views the improved outcomes against the backdrop of wider availability of the procedure with less selectivity of patients, the picture is even more dramatic. Although pretransplant medical care of potential candidates has improved significantly, transplantation is now offered to a greater percentage of older, high-risk ESRD patients.5,14 Since many comorbid conditions worsen more rapidly in a patient on dialysis, lengthier waiting times may also negate the beneficial effect of better pretransplant care.6 While techniques of organ procurement and preservation continue to improve, utilization of more and more organs from “extended-criteria donors” compromises quality, and an ever-greater percentage of organs is allocated to transplant centers beyond their area of procurement, resulting in longer preservation times*,15,16 Organ allocation policies have resulted in a greater percentage of kidneys transplanted into extremely well-matched recipients.15 However, fully 80 percent of cadaveric kidneys are transplanted despite significant HLA (human lymphocyte antigen) mismatches, and multicenter data document a progressively diminishing benefit of matching on outcome.17 Better management of posttransplant medical and surgical complications (e.g., modern antibiotics and antivirals to treat the infectious complications of immunosuppression, effective prophylaxis of gastrointestinal hemorrhage) is not new. For each of these beneficial changes, there is a countervening variable with a potentially negative impact on graft survival—save one. The major factor contributing to dramatically improved outcomes is the ability to safely prevent and treat immunological rejection using newer and better immunosuppressant drugs.18–20 Human immune responses are complex, involving the interaction of cells, antibodies, and soluble proteins. These immune responses protect the body from injury and disease caused by bacteria, viruses, and malignant cell transformation. When non-self tissue (an allograft) is transplanted, the normal response of the immune system is to recognize the tissue as foreign and destroy it, a process known as rejection.21 At this time, successful organ transplantation in humans is possible only by administration of pharmacological immunosuppressants that * In an attempt to attenuate the imbalance between transplant candidates and available organs, many transplant centers now utilize organs from cadavers previously considered outside acceptable limits of age (6–55 years) and with limited comorbidity (well-controlled diabetes mellitus or hypertension). These are termed “extended-criteria donors.”
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Extending Medicare Coverage for Preventive and Other Services prevent rejection. Preservation of long-term graft function requires ongoing treatment with these agents for the overwhelming majority of recipients.22 Immunosuppressive agents can be divided into four classes based on pharmacological characteristics and mode of action. The standard approach to long-term immunosuppressive therapy in this country is a multidrug protocol combining single agents from each class in order to maximize efficacy and minimize toxicity.20,22,23 Antibodies: Protein-Based Therapy Antibodies are naturally occurring proteins whose function is to circulate in an animal, bind to specific tissues, and induce some immunological response as a consequence of the binding. These properties can be captured and manipulated for therapeutic benefit in transplantation (and other medical fields). In transplantation, antibodies are administered for short periods of time (usually 1–2 weeks) to achieve a specific goal. They may be utilized in the immediate posttransplant period to provide effective early immunosuppression, allowing time for institution and adjustment of maintenance therapy. They are also quite useful in treating episodes of acute rejection.24 At most transplant centers, these agents are initially administered in an inpatient setting for a limited time. The newer monoclonal antibodies (daclizumab and basiliximab, approved by the Food and Drug Administration [FDA] in 1997 and 1998, respectively) have been genetically manipulated to confer low immunogenicity and long half-lives.25,26 While it is conceivable that these (or other similar agents in development) may ultimately be used as a component of maintenance therapy for some outpatients, this is not current practice. Thus, although antibodies are quite expensive, reimbursement for their use in outpatients is rarely an issue. Antiproliferative Agents (Azathioprine and Mycophenolate Mofetil) The development of an effective oral immunosuppressant, azathioprine (Imuran®), resulted in the first long-term survivors of transplants between genetically nonidentical individuals (allografts) in the late 1950s and early 1960s.4 Azathioprine is a thiopurine, the nitroimidazole derivative of 6-mercaptopurine.27 As a purine analog, it blocks nucleic acid synthesis in rapidly dividing cells, preventing cellular differentiation and proliferation. The azathioprine dose is usually adjusted for body weight and reduced in the face of toxicity. Adverse effects of azathioprine are fairly predictable, reflecting the impact of an antimetabolite on rapidly dividing cells. These include marrow suppression (primarily neutrophils and platelets), hair loss, and stomatitis. Azathioprine may also cause hepatic dysfunction. All of these effects are typically dose related. Azathioprine is metabolized by xanthine oxidase; thus, allopurinol (a xanthine oxidase inhibitor indi-
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Extending Medicare Coverage for Preventive and Other Services cated for the treatment of gout) inhibits degradation of azathioprine, and the combination is relatively contraindicated (an unfortunate circumstance given the prevalence of gout among transplant recipients). Over the long-term, the imidazole moiety of azathioprine may be an important factor contributing to the excess incidence of cutaneous malignancies in allograft recipients. Azathioprine, administered in combination with low-dose corticosteroids, was the cornerstone of long-term immunosuppressive therapy from 1962 to 1984. Almost all patients experienced at least one episode of acute rejection, and 1-year graft survival for recipients of cadaver kidneys was around 50 percent.28 Infectious complications, related mostly to steroid administration, caused substantial morbidity, and one-year mortality was as high as 25 percent. Nonetheless, the effectiveness of such a regimen in some recipients of kidney transplants fueled ongoing work in cardiac and hepatic transplantation. Although such pioneering efforts allowed perfection of surgical techniques, they were rarely successful in inducing long-term survival among extrarenal recipients. Mycophenolate mofetil (MMF) has been used clinically in the United States since its approval by the FDA in 1995. Its availability is a major reason that 1995 now appears to have been a watershed year in the advancement of transplant therapeutics. At most centers, MMF has supplanted azathioprine as the antiproliferative agent of choice, at least during the early posttransplant period (1–3 years).13,18 While MMF inhibits purine synthesis, similar to azathioprine (albeit via a different mechanism), its effect is largely limited to lymphocytes (the key cells involved in rejection), imparting greater efficacy and less toxicity.29,30 MMF appears to be most effective in combination with a cytokine inhibitor (cyclosporine or tacrolimus, see below) and has shown efficacy in both preventing and reversing acute rejection episodes. Common adverse effects associated with MMF are primarily gastrointestinal in nature, consisting of dose-dependent nausea, vomiting, and diarrhea, with occasional mild marrow suppression. Despite a slight increase in viral infections (especially cytomegalovirus, or CMV) in MMF-treated patients, the drug is generally well tolerated.31 Drug-drug interactions are uncommon. Unlike azathioprine, mycophenolate metabolism is unaffected by allopurinol, facilitating management of gout. In three randomized, blinded multicenter trials (approximately 500 patients each in the United States, Europe, Canada, and Australia), maintenance immunosuppression with MMF, cyclosporine, and prednisone reduced the risk of acute rejection (in comparison to three different cyclosporine-based protocols) by 50 percent, with 1-year survival of primary cadaveric transplants in excess of 90 percent.32–34 Pooling data from all 1,500 patients demonstrated a benefit in overall graft survival as well.18 The effect on graft survival of including MMF as part of long-term therapy is uncertain.35,36 Likewise, the impact of discontinuing MMF after a defined period of time is unknown.
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Extending Medicare Coverage for Preventive and Other Services Corticosteroids For over 40 years, corticosteroids have been a mainstay of pharmacological immunosuppression, despite early recognition of their association with significant adverse events. Early on, their use was restricted to a short course of high-dose therapy to reverse established acute rejection. Soon, it came to be recognized that ongoing administration of low doses of these agents (prednisone, methylprednisolone, etc.) might prevent rejection, making prednisone an essential part of maintenance therapy.1,4 Currently, short courses of high-dose corticosteroids (2–7 mg/kg/d) are administered to treat or prevent acute rejection during the early posttransplant period, with rapid tapering of maintenance doses to 0.1–0.15 mg/kg/d. The paradox of using corticosteroids in transplantation is that while they are effective and inexpensive, their use is limited by toxicity. Complications of steroid therapy are well documented and include weight gain, altered body habitus, moon facies, metabolic disturbances (hyperglycemia, hyperlipidemia), fluid retention, hypertension, bone disease, growth retardation, and depression. Sentiment within the transplant community has always favored steroid avoidance or withdrawal; with each advance in immunosuppression, the persistent preference of patients and physicians alike has been to do away with long-term steroid therapy.1,37,38 However, given the immunological risks that accompany steroid withdrawal, current practice at most centers is to continue low-dose corticosteroid therapy for the duration of allograft function. Calcineurin Phosphatase Inhibitors (Cyclosporine, Tacrolimus) The introduction of cyclosporine (CyA) in 1984 revolutionized solid organ transplantation, enhancing outcomes for recipients of kidney transplants and providing immunosuppression potent enough to support engraftment of hearts and livers. Although clinical practices have undergone substantial evolution over the last 15 years, CyA remains the cornerstone around which most immunosuppressive protocols are constructed. Early clinical trials in humans showed CyA to be effective in preventing rejection, but highly nephrotoxic. In combination with prednisone, CyA was further associated with an increased risk of infection and lymphoma.39–42 Combination therapy evolved to capture the immunosuppressive benefits of cyclosporine, while minimizing the complications.43–45 The attractiveness of combination therapy versus cyclosporine-prednisone dual therapy remains controversial, even as the agents used in combination continue to evolve.*,22,46 * Many European centers and a few in the United States remain committed to dual CyA-prednisone therapy, attributing early difficulties with this regimen to inappropriate dosing of the drugs. Alternatively, most centers in this country add azathioprine or MMF,
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Extending Medicare Coverage for Preventive and Other Services Cyclosporine is a difficult drug to use. Its lipophilic nature makes absorption difficult, relatively unpredictable, and subject to widespread variability.46 Neoral® is a new cyclosporine formulation, introduced in 1995, designed to improve absorption and reduce both inter- and intrapatient variability.47,48 The therapeutic window for CyA is quite narrow, and blood levels demonstrate only rough correlation with clinical effect, making monitoring difficult.49 CyA is metabolized by the P450 cytochrome system in the liver, and drug-drug interactions are common.50 Adverse effects (including hypertension, nephrotoxicity, gingival hyperplasia, neurotoxicity, hirsutism, hyperuricemia, cholestasis, and hyperlipidemia) are ubiquitous. Thus, long-term management of cyclosporine-treated patients requires substantial familiarity with the drug. Tacrolimus was approved by the FDA for use in transplantation of livers in 1994 and kidneys in 1997. Its immunosuppressive properties (inhibition of cytokine synthesis) are similar to CyA, although, on a milligram-for-milligram basis, it is 100-fold more potent.19 The basic side-effect profile of tacrolimus is also similar to CyA (nephrotoxicity, hypertension, tremor, seizures, etc.), as are drug-drug interactions. However, tacrolimus appears to have a slight advantage in not causing gingival problems or hirsutism, and it may be less detrimental to lipid metabolism.51 The chief disadvantage of tacrolimus is a greater tendency to elicit posttransplant glucose intolerance.51,52 Some studies have reported enhanced efficacy of tacrolimus relative to CyA, while others find use of the two calcineurin inhibitors to result in similar outcomes.51,52 Tacrolimus has also been used as rescue therapy for refractory rejection, with promising results in both single- and multicenter studies.53,54 A remarkable clinical trend has emerged since tacrolimus was introduced: administered doses and desirable therapeutic levels of the agent have declined substantially, reducing both toxicity and cost without any apparent adverse impact on efficacy.55 Currently, tacrolimus is the calcineurin inhibitor of choice in most liver transplant centers and is administered as well to 30–40 percent of de novo kidney transplant recipients. Additional Agents In the past 5 years, the FDA has approved seven new products for use in transplantation, including the Neoral® preparation of CyA, MMF, tacrolimus, daclizumab, basiliximab, and Thymoglobulin® (see Table D-1), and, most recently, sirolimus, which was approved in September 1999. At the time of this along with a short-term course of prophylactic antibody administration, to the CyA-prednisone combination in order to enhance efficacy and reduce specific toxic effects of the two-drug combination. Experimental data exist to support both approaches.
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Extending Medicare Coverage for Preventive and Other Services TABLE D-1 Currently Available Immunosuppressants Class Drug Product Dosage Duration Cost Per Year ($)* Cytokine Inhibitors Cyclosporine (Neoral®) 4–10 mg/kg/d Long term 6,400 Cyclosporine (SangCyA®) 4–10 mg/kg/d Long term 4,800 Tacrolimus (Prograf®) 0.1–0.3 mg/kg/d Long-term 6,050 Antiproliferative Agents Azathioprine (Imuran®) 1–2 mg/kg/d Long term 900 Mycophenolate (CellCept®) 1.5–3 g/d Long term 4,800–9,700 Corticosteroids Prednisone 0.1–0.15 mg/kg/d Long term 200 Antilymphocyte agents Atgam® 15 mg/kg/d 7–14 days 7,000 Thymoglobulin® 1.5 mg/kg/d 7–14 days 6,300 OKT3 (Orthoclone®) 5 mg/d 7–14 days 7,000 Simulect® (basiliximab) 20 mg/dose 2 doses 2,500 Zenapax® (daclizumab) 1 mg/kg/dose 5 doses 5,500 *Retail pharmacy costs in Birmingham, Alabama (May 1999) for average doses in a 70-kg patient.
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Extending Medicare Coverage for Preventive and Other Services writing, no other products appear close to approval, so the immunosuppressive armamentarium is likely to remain relatively unchanged for the next 5–10 years. Sirolimus (rapamycin, RAD) is structurally similar to tacrolimus, binds to the same receptor, but inhibits immune responses via a different mechanism (interrupting lymphocyte function by blocking growth factor-driven proliferation).30,56,57 The effects of sirolimus are not limited to T and B cells; it may also exert an inhibitory effect on proliferation of fibroblasts, endothelial cells, hepatocytes, and smooth muscle cells. Its immunosuppressive activity is synergistic with cyclosporine; proponents of sirolimus are hopeful that it will facilitate administration of significantly lower, less toxic doses of CyA.56 Sirolimus also may have promise in preventing chronic rejection. Adverse effects associated with sirolimus include hyperlipidemia, neutropenia, and thrombocytopenia. Sirolimus appears not to be nephrotoxic but may exacerbate the nephrotoxicity of CyA.56,58–60 Current Uses and Future Trends Currently, immunosuppressive therapy in the United States is in a state of flux. Before 1995, virtually all centers administered some combination of CyA, azathioprine, and steroids, with or without antibody “induction” in the early posttransplant period. Now, there is wide variability from center to center. Most still use “triple” therapy, with a calcineurin phosphatase inhibitor (CyA or tacrolimus), an antiproliferative agent (MMF or azathioprine), and steroids. The use of antibodies remains controversial, although the efficacy, side-effect profile, and relatively low cost of basiliximab and daclizumab have-gained them rapid acceptance. Sirolimus is likely to be used as an adjunct, perhaps supplanting the antiproliferative agents from the protocol, although it may also have the potential of replacing either CyA or tacrolimus.20,59 The risk of acute rejection, and immunological graft loss, is greatest during the first 3 to 6 months after transplantation, requiring intense immunosuppression during this period.61 Thereafter, most clinicians gradually reduce immunosuppressant doses or even discontinue a single agent (see below). This practice reflects “accommodation,” or partial tolerance, between graft and host, a process initially described over 30 years ago.4,62 In successful transplantation, there occurs over time a reduction in the intensity of anti-graft immunological responses that allows the transplant to function with lesser degrees of immunosuppression. Thus, patients are likely to be receiving substantially less pharmacological immunosuppression 3 or more years after their transplant than earlier in their course. Throughout the history of transplantation, investigators have pursued the “Holy Grail”: complete and specific tolerance of host to graft without any chronic immunosuppression. Although recent developments seem ever more intriguing, no clinically successful approach allowing drug-free graft maintenance has yet emerged.11,20,63
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Extending Medicare Coverage for Preventive and Other Services COSTS OF ESRD THERAPY: TRANSPLANTATION AND DIALYSIS Recent data from the United States Renal Data System (USRDS) indicate that, in 1996, 27 percent of Medicare ESRD patients in this country had functioning renal allografts and consumed approximately 11 percent of a $9.6 billion Medicare ESRD budget.5,64 The financial costs to Medicare of renal transplantation are well defined. During the year a transplant is performed, costs include the transplant hospitalization, organ acquisition, early readmissions (most commonly for acute rejection), outpatient labs and follow-up (which occur at more frequent intervals during the first year), and maintenance immunosuppressive therapy. In 1994, these initial costs amounted to $97,400 per patient.64 After the first year, costs are much lower ($13,800 per patient-year), consisting primarily of payment for immunosuppressant drugs, along with less frequent laboratory studies and outpatient visits.64 Relative to chronic dialysis (with 1994 per-patient costs of about $47,500 annually), transplant is significantly more expensive during the first year. However, after 3.1 years, the initial excess expenditure is recaptured. Thereafter, maintenance of a successful transplant is significantly less expensive than dialysis, with net savings of approximately $107,300 per patient over 10 years.64 Thus, the year-to-year financial costs of maintaining a successful allograft are substantially lower than those of maintenance dialysis, and the gap seems to be widening for at least two reasons. First, the improved outcomes of transplantation discussed above are enabling more recipients to become long-term survivors, able to recapture the initial investment and avoid the high costs of returning to dialysis or retransplantation. Currently, only 53 percent of successful transplant recipients have had their grafts for more than 3 years; based on recent advances in therapy, this percentage should grow rapidly.5,65 Second, costs of dialysis have increased dramatically, at least in part due to the addition of coverage for pharmacological therapies administered during dialysis treatments, Calcijex® and erythropoietin (rHuEPO). Neither drug necessarily reduces dialysis-related mortality, but they may improve overall well-being and decrease morbidity. Calcijex® is an intravenous version of 1,25-dihydroxycholecalciferol, a necessary supplement for patients with ESRD. An oral version of this agent (Rocaltrol®) has been available for some time, but it is expensive, it is not covered by Medicare, and its use is subject to the vagaries of patient compliance. Administration of Calcijex®, though even more expensive, is covered by Medicare (indefinitely) and has proved more effective in slowing the progression of dialysis-related bone disease. Severe anemia (hemoglobin, 6–10 mg/dl) due to erythropoietin deficiency was a major contributor to the morbidity of chronic dialysis, causing fatigue, weakness, cardiovascular compromise, and at times, frequent transfusions. rHuEPO, usually administered subcutaneously and available to ESRD dialysis beneficiaries as an unlimited benefit, now costs Medicare
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Extending Medicare Coverage for Preventive and Other Services tion, and hypertension. Thus, a large proportion of ESRD patients come to renal transplantation without any private insurance coverage. When patients begin ESRD therapy, regardless of age and including consideration of employment history, they become eligible for Medicare. For home dialysis or transplantation, coverage begins immediately, rewarding those choosing these less expensive therapies. For in-center dialysis, there is a 90-day waiting period before coverage is effective. If there is preexisting group health insurance, it remains primary for 30 months, with Medicare as secondary payer (paying for some expenses not paid by the group health plan). Medicare remains in force for the duration of dialysis therapy. Since dialysis confers almost certain eligibility for disability, most Medicare ESRD patients also receive Social Security disability benefits. If an ESRD Medicare beneficiary receives a transplant, coverage for medical care and immunosuppressive drugs continues for 3 years after transplantation, then ceases until the beneficiary establishes eligibility by reason of age or disability other than by ESRD status alone. In 1997, private insurance absorbed 29%, Medicaid 13%, and Medicare fully 58% of the overall costs of renal transplantation in the United States.51 As a transplant recipient progresses from short-term to long-term survivorship, the social worker, through whom comes knowledge and access to other resources, often becomes the key facilitator of Medicare, Medicaid, or other payment for services. Some centers have even hired “transplant financial coordinators” with the explicit task of helping patients navigate coverage complexities.47,52 For ESRD beneficiaries of Medicare, the first challenge after coverage expires is dealing with the cost of physician visits, laboratory tests, and hospitalizations when necessary. One recipient noted, We’re told, “Return to work to pay back your debt to society,” and “Productivity is important.”… You see, the doctors think we’re cured. But we’re not cured…we’re seen as unreliable employees, and health insurance companies redline transplant patients. If they hire you they may refuse to let you join the health plan.49 An approach frequently chosen is to maintain or establish disabled status by whatever means necessary, although the specific number doing so solely to maintain Medicare coverage is unknown. As of December 31, 1995, there were 72,785 persons with a functioning kidney transplant, 38 percent of whom were disabled and continued to receive Medicare entitlements on that basis.53 Many also receive Supplemental Security Income (SSI) and maintain Medicaid eligibility as well. In the current system, working enough to generate minimal income threatens all these benefits, a strong factor discouraging return to the workforce. The experience of many transplant social workers is that, due primarily to the high cost of health insurance, most small businesses and even many large corporations are reluctant to hire a transplant recipient, further discouraging return to work.
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Extending Medicare Coverage for Preventive and Other Services Eggers noted that, at the end of 1995, 26 percent of renal allograft recipients with functioning transplants had lost Medicare benefits due to time limitations on coverage.53 Although the exact number is uncertain, as many as half of these patients face the daunting costs of posttransplant care beyond 3 years with no Medicaid or private insurance resources. Having effectively negotiated some continued access to a medical provider, the next challenge for a recipient is ensuring an adequate supply of the immunosuppressive drugs essential to sustaining long-term allograft function. Average retail costs for these drugs for most patients are between $7,000 and $14,000 annually, an amount greater than an average homeowner spends on mortgage payments.48 In addition, many recipients are faced with the continued expenses for other drugs (which Medicare had not covered in the first place). Eighty percent require antihypertensive therapy, and many require care for hyperlipidemia and other comorbid conditions.54,55 Coping with these challenges requires efforts on the part of patients and providers to find alternatives to Medicare coverage. Even though Medicaid usually covers immunosuppressive drug expenses, income limits for eligibility vary widely from state to state, and some states impose prescription limits. Twenty-eight states have high-risk insurance pools, again with varying eligibility, premium, and coverage provisions. Twenty-eight also have financed State Kidney Programs, although only 19 of these programs assist with anti-rejection medication costs.47 For the recipient who does not have access to any of these programs (estimated by the Congressional Budget Office to represent 10% of all transplant recipients in 1996), payment options are limited.56 These include paying out-of-pocket or seeking free medications by filing applications for indigent care from each individual pharmaceutical company. Applying directly to pharmaceutical companies for assistance is an onerous task made more complicated by the varying requirements imposed by each firm. Patient support groups, assisted at times by medical professionals, often become forums for illegal bartering of medications as the only way to acquire necessary drugs.49 For those patients who are unable to successfully negotiate these burdensome options and are unable to obtain needed drugs, the consequence at some point will be rejection and graft loss due to noncompliance. A recent survey found that 35% of Medicare-HMO patients, when faced with loss of drug coverage, either reduced or discontinued their medications.57 Most studies of noncompliance among renal transplant recipients find rates approximating 20%, with graft loss in perhaps 30–40% of those.58–60 With recent dramatic reductions in acute rejection, and more transplanted organs surviving for longer periods of time, graft losses to noncompliance have become more visible. Given the increasing dependence of successful outcomes on advances in immunosuppressive therapy (see Appendix D Part 1), such losses have the potential to become more frequent as well.
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Extending Medicare Coverage for Preventive and Other Services Multicenter registries have not reliably collected data regarding noncompliance.61 In some single center reports, noncompliance may be the most common cause of graft loss beyond the first posttransplant year.60,62–64 Unfortunately, factors leading to noncompliance and the degree of noncompliance necessary to result in graft loss are highly variable, and the relative impact of financial limitations on outcome is uncertain.65,66 Nonetheless, limited evidence and experience indicate that at least some portion of noncompliant behavior is attributable to recipients’ inability to procure appropriate medication when Medicare coverage ends and no alternative resources are secured. Based on limited studies reviewed below and documented renal graft losses of 6% per year after the first year with somewhat higher loss rates for other organs, it is reasonable to estimate that perhaps a third to half of graft losses might reflect lack of financial access to immunosuppressive drugs.46,60,70 Thus, ongoing provision of immunosuppressive drugs might save 2–3% of all grafts at risk each year. Several investigators found low socioeconomic status to predict poorer long-term outcomes in renal transplantation.64,67–69 At least two groups of investigators have found significant benefit to ongoing provision of immunosuppressant drugs for such patients. In the previously noted studies of Sanders and colleagues, a cohort of recipients whose Medicare benefits expired a year after transplantation was at significant risk of late rejection and graft loss after stopping cyclosporine.69 When similar patients were furnished with maintenance cyclosporine via an indigent drug program, graft survival differences compared to a fully insured group of recipients disappeared.71 In a recently completed study, Woodward and coworkers compared renal allograft survival at 1 and 3 years after transplant in two time periods, stratified by median family income for each patient’s ZIP code.70 For those transplanted in 1992–1993, when Medicare covered immunosuppressants for 1 year after transplantation, the researchers found no difference in graft survival at 1 year among recipients in different quartiles of income. By 3 years, however, transplant recipients in lower income groups had significantly lower graft survival (77 vs. 72%, p<0.001). In contrast, since 1995, after 3 years of coverage had been completely phased in, differences in graft survival at 3 years by income grouping had disappeared (80% vs. 78%, p=n.s.), implying that ongoing access to medications made a significant impact on outcome for lower- and middle-income recipients. POTENTIAL MODIFICATIONS TO THE MEDICARE PROGRAM In 1972, Congress addressed the issue of ESRD care with the intention “to provide access to life-saving therapy for all who needed it where the costs of treatment were beyond the means of practically all individuals.”1 In the 1991 IOM report, it was noted that the Congress, via PL 95–292 in 1978, the National Organ Transplant Act of 1984, OBRA 1986, and the Transplant Amendments
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Extending Medicare Coverage for Preventive and Other Services Act of 1990, had consistently encouraged organ transplantation.19 In the face of increasingly successful outcomes, and given that Medicare had made the commitment to fund the transplant procedure itself (with its substantial outlays during the first year), the previous committee saw no scientific basis supporting termination of access to care and immunosuppressant drugs at an arbitrarily defined time. They recognized that renal transplant recipients were not “cured,” and that ongoing care was as essential to survival as the thrice-weekly dialysis treatments for non-transplanted ESRD patients. Now, almost a decade later, rapid advances in the science of transplantation have made current policy even less consistent with the original congressional intentions. As the issue of long-term care for Medicare-covered transplant recipients is revisited, what changes might restore equilibrium between policy and practice? Option A: Indefinite Benefits for ESRD Recipients with Coterminous Immunosuppressant Coverage for All Other Medicare Beneficiaries In 1991, the Institute of Medicine committee recommended: “that Congress eliminate the three-year limit on Medicare eligibility for ESRD patients who are successful transplant recipients and authorize an entitlement equal to that of ESRD patients who are treated by dialysis,” and “that coverage of immunosuppressive medications for kidney transplant patients be made coterminous with the period of a patient’s entitlement.”19 This option would place renal transplant recipients on the same footing as ESRD patients receiving dialysis. Such a policy (especially if it came with no Medicare secondary payer requirements) would facilitate those able to return to the workforce doing so and would relieve potential employers of the burden of providing health insurance for this high-cost group. In the 1991 report, potential costs for such an approach, to include those recipients who had already lost benefits, was estimated to be $415 million–$500 million annually for 55,000 renal transplant beneficiaries by 1995.19 Costs for indefinite immunosuppressant coverage alone were projected to have reached approximately $300 million annually by 1995. These cost estimates did not address any potential offsets, which might include the cost of graft failure and retransplantation due to noncompliance, reduced disability benefits, and reduction of Medicaid spending for those eligible for both Medicare and Medicaid. The IOM recommendation also did not address coverage for extrarenal allograft recipients. In 1989–1991, Medicare covered such a small percentage of extrarenal transplants that these costs were not an issue. Since then, the number of such beneficiaries has grown. The response of the Congress to the IOM report (as well as the concurrently prepared OTA report) was to extend coverage gradually for immunosuppres-
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Extending Medicare Coverage for Preventive and Other Services sants from 1 year to 3 years, making immunosuppressive drug coverage and other Medicare benefits coterminous for renal transplant recipients.19,33 Extrarenal transplant recipients saw their immunosuppressant coverage extended to 3 years as well. In 1999, due to scientific and clinical advances, more recipients and allografts are surviving beyond 3 years. Even though the great majority of Medicare beneficiaries with transplants are renal recipients, needs of those with extrarenal grafts must be addressed as well. Option B: Removing Limits on Immunosuppressant Coverage for Medicare Beneficiaries—H.R. 1115 H.R. 1115 was introduced in the 106th Congress on March 16, 1999, by Representatives Charles Canady and Karen Thurman of Florida, with 73 cosponsors. In essence, this bill would remove the 3-year limit on immunosuppressant coverage for all Medicare beneficiaries, without addressing the issue of loss of benefits at 3 years for ESRD recipients who do not qualify for Medicare by reason of age or disability. In 1996, the Congressional Budget Office projected Medicare costs for a similar proposal, which also did not address extension of other Medicare benefits for this group. The CBO projected savings of $166 million annually by reducing late graft loss; by 2002, these savings would mostly offset the additional $210 million to be spent on drugs, resulting in a projected net Medicare outlay of $44 million annually.56 Total Medicare ESRD expenditures were projected to rise by less than 1% annually as a result of such a change.46,56 Still, the quarter of renal allograft recipients who do not qualify for Medicare by reason of age or disability would continue to lose all benefits at 3 years and would have an even greater incentive to qualify for disability benefits and, thus, for Medicare. Given the original intent of the 1972 Social Security amendments to facilitate return of beneficiaries to productive life, the consequences of this legislation would appear to be counterproductive. Option C: Creating a New Class of Medicare Beneficiary—S. 631 This legislation (the Immunosuppressive Drug Coverage Act of 1999) was introduced in the Senate by Senator Mike DeWine of Ohio, also on March 16, with six cosponsors. Like its House counterpart, it would remove the 3-year cap on immunosuppressant coverage for Medicare beneficiaries, while extending Medicare secondary payer requirements to shift some costs of long-term benefits to private insurers. Under the provisions of this legislative effort, all recipients whose transplant was financed by Medicare would receive immunosuppressant drug coverage for the life of the allograft, even after other Medicare entitlements were terminated.
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Extending Medicare Coverage for Preventive and Other Services The expected benefits of this proposal would be indefinite drug coverage for Medicare-eligible transplant recipients, ensuring access to necessary immunosuppressive support for the life of the allograft and reducing graft losses to financially related noncompliance. Incentives to remain disabled would be less than with H.R. 1115, although the effect of this bill’s secondary payer requirements is uncertain. Costs, as estimated by the Lewin Group, would be significantly greater than the House version but still less than 2% of the Medicare ESRD budget, and less than 20% of the annual costs of erythropoietin for dialysis beneficiaries.72 A potential negative would be the vagaries of servicing a new class of beneficiaries not entitled to other Medicare benefits. These beneficiaries would thus not have Medicare coverage of visits to physicians/transplant centers for monitoring and other posttransplant care. Participating physicians would be placed in the unusual circumstance of supervising toxic immunosuppressive drugs without Medicare payment for blood monitoring or other care. Option D: Other Potential Solutions and Modifiers Several other initiatives and/or proposals might help transplant recipients pay for ongoing immunosuppressive therapy. Proposals to cover prescription drugs for all Medicare beneficiaries could help. However, circulating drafts of current proposals indicate an annual cap on benefits ($1,500–$2,000 per patient), which is far below the average cost of immunosuppressive drug regimens for transplant recipients (see Appendix D, Part 1). At least two other options might be considered, both of which would offer Medicare benefits to all extrarenal transplant recipients, even if the transplant was not covered by Medicare. A first option would make virtually all solid organ transplant recipients eligible (with a suitable work history, regardless of age or disability status) for full Medicare benefits to include uninterrupted immunosuppressant drug costs. The second option would extend coverage only for immunosuppressive drugs for transplant recipients whose transplant was not covered by Medicare, as described in the OTA Report of 1991.33 The potential drawback to either approach, apart from cost, is the absence of precedent for extending Medicare benefits to patients not otherwise eligible by reason of age, disability, or ESRD status. In order to attenuate the financial costs of adopting one (or more) of the above options, several modifying provisions might be considered. First, the new benefit might be phased in gradually for new transplant recipients only. Second, a Medicare immunosuppressive benefit might remain secondary to group health coverage available to a recipient. Third, a financial “cap” on immunosuppressive drug coverage beyond 3 years might limit costs while ensuring access to medications for transplanted beneficiaries. For example, a limit of $8,000 per year (plus a 20% copay) would easily cover a year of therapy with a combination of tacrolimus, mycophenolate mofetil, and steroids for an averaged-sized person.
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Extending Medicare Coverage for Preventive and Other Services Given current knowledge, the least expensive maintenance protocol acceptable to most transplant physicians would include generic cyclosporine, azathioprine, and steroids, at a cost to Medicare of less than $5,000 per annum. The absolute amount of such a cap might be reevaluated on a year-to-year basis. REFERENCES 1. Rettig RA, Marks EL: Implementing the end-stage renal disease program of Medicare (Rep. R-2505-HCFA/HEW). Santa Monica, California, the RAND Corporation, 1980. 2. Kolata BB: Dialysis after nearly a decade. Science 208:473–476, 1980. 3. Friedman EA, Kountz SL: Impact of HR-1 on the therapy of end-stage uremia: How and where should uremia be treated? N Engl J Med 288:1286–1288, 1973. 4. The 13th Report of the Human Renal Transplant Registry. Transplant Proc 9:9–26, 1977. 5. Stange PV, Sumner AT: Predicting treatment costs and life expectancy for end-stage renal disease. N Engl J Med 298:372–378, 1978. 6. Starzl TE: Experience in renal transplantation. Philadelphia, WB Saunders Co., 1964. 7. Hume DM: Kidney transplantation, in Human Transplantation, New York, Grune and Stratton, 1968, pp. 110–150. 8. Hume D, Merrill JP, Miller BF, Thorn GW: Experiences with renal homotransplantation in the human: Report of nine cases. J Clin Invest 34:327, 1955. 9. Alexandre GPJ, Murray JE, Dammin GJ, Nolan B: Immunosuppressive drug therapy in canine renal and skin homografts. Transplantation 1:432–461, 1963. 10. Calne RY, Alexandre GPJ, Murray JE: A study of the effects of drugs in prolonging survival of homologous renal transplants in dogs. Ann NY Acad Sci 99:1962. 11. Diethelm AG, Dubernard JM, Busch GJ, Murray JE: Critical re-evaluation of immunosuppressive therapy in canine renal allografts. Surg Gynecol Obstet 126:723–736 , 1968. 12. Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ: Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N Engl J Med 268:1315–1323, 1963. 13. Starzl TE, Marchioro TL, Waddell WR: The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 117:385, 1963. 14. Porter KA: Pathological changes in transplanted kidneys, in T.E.Starzl (ed), Experience in renal transplantation, Philadelphia, WB Saunders Co., 1964, pp. 299–359. 15. Friedman Ea, Delano BG, Butt KMH: Pragmatic realities in uremia therapy. N Engl J Med 298:368–371, 1978. 16. Rennie D: Home dialysis and the costs of uremia. N Engl J Med 298:399–400, 1978 17. Rosansky SJ, Eggers PW: Trends in the U.S. end-stage renal disease population: 1973–1983. Am J Kidney Dis 9:91–97, 1987. 18. Eggers PW: Health care policies/Economics of the geriatric renal population. Am J Kidney Dis 16:384–391, 1990.
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Extending Medicare Coverage for Preventive and Other Services 19. Institute of Medicine. Kidney failure and the federal government. Washington, D.C., National Academy Press, 1991. 20. Cook DJ: Long-term survival of kidney allografts, in P.I.Terasaki (ed), Clinical Transplants 1987, Los Angeles, UCLA Tissue Typing Laboratory, 1987, pp. 277–285. 21. Eggers PW: Effect of transplantation on the Medicare end-stage renal disease program. N Engl J Med 318:223–229, 1988. 22. Calne RY, Rolles K, White DJG, et al.: Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases and 2 livers. Lancet ii:1033–1036, 1979. 23. Powe NR, Eggers PW, Johnson CB: Early adoption of cyclosporine and recombinant human erythropoeitin: Clinical, economic, and policy issues with emergence of high-cost drugs. Am J Kidney Dis 24:33–41, 1994. 24. Cho YW, Terasaki PI, Graver B: Fifteen-year kidney graft survival, in P.I.Terasaki (ed), Clinical Transplants 1989, Los Angeles, UCLA Tissue Typing Laboratory, 1989, pp. 325–334. 25. Hill MN, Grossman RA, Feldman HI, Hurwitz S, Dafoe DC: Changes in causes of death after renal transplantation, 1966 to 1987. Am J Kidney Dis 17:512–518, 1991. 26. Mickey MR: Kidney transplant mortality relationships, in P.I.Terasaki (ed), Clinical Transplants 1988, Los Angeles, UCLA Tissue Typing Laboratory, 1988, pp. 263–276. 27. Cecka JM, Terasaki PI: The UNOS Scientific Renal Transplant Registry, in J.M. Cecka and P.I.Terasaki (ed), Clinical Transplants 1995, Los Angeles, UCLA Tissue Typing Laboratory, 1996, pp. 1–18. 28. HCFA: Web Site www.hcfa.gov. 1999. 29. Ojo A, Port FK: Influence of race and gender on related donor renal transplantation rates. Am J Kidney Dis 22:835–841, 1993. 30. Cecka JM: The UNOS Scientific Renal Transplant Registry, in J.M.Cecka and P.I. Terasaki (ed), Clinical Transplants 1996, Los Angeles, UCLA Tissue Typing Laboratory, 1997, pp. 1–14. 31. UNOS (United Network for Organ Sharing): 1996 Annual Report of the U.S. Scientific Registry for Transplant Recipients in the Organ Procurement and Transplantation Network: DHHS/HRSA, Richmond, Virginia, UNOS, 1996. 32. Eggers PW: Comparison of treatment costs between dialysis and transplantation. Semin Nephrol 12:284–289, 1992. 33. U.S. Congress, Office of Technology Assessment: Outpatient immunosuppressive drugs under Medicare, OTA-H-452, Washington, D.C., U.S. Government Printing Office, 1991. 34. Tobe SW, Senn JS: Foregoing renal dialysis: A case study and review of ethical issues. Am J Kidney Dis 28:147–153, 1996. 35. Holley JL, Nespor S: An analysis of factors affecting employment of chronic dialysis patients. Am J Kidney Dis 23(5):681–685, 1994. 36. Ifudu O, Paul H, Mayers JD, Cohen LS, Brezsnyak WF, Herman AI, Avram MM, Friedman EA: Pervasive failed rehabilitation in center-based maintenance hemodialysis patients. Am J Kidney Dis 23:394–400, 1994. 37. Manninen DL, Evans RW, Dugan MK: Work disability, functinal limitations, and the health status of kidney transplantation recipients posttransplant, in P.I.Terasaki
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Extending Medicare Coverage for Preventive and Other Services and J.M.Cecka (ed), Clinical Transplants 1991, Los Angeles, UCLA Tissue Typing Laboratory, 1992, pp. 193–203. 38. Markell MS, DiBenedetto A, Maursky V, Sumrani N, Hong JH, Distant DA, Miles A-MV, Sommer BG, Friedman EA: Unemployment in inner-city renal transplant recipients: Predictive and sociodemographic factors. Am J Kidney Dis 29:881–887, 1997. 39. Matas AJ, Lawson W, McHugh L, Gillingham K, Payne WD, Dunn DL, Gruessner RWG, Sutherland DER, Najarian JS: Employment patterns after successful kidney transplantation. Transplantation 6a:729–733, 1996. 40. Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N: A study of the quality of life and cost-utility of renal transplantation. Kidney Int 50:235–242, 1996. 41. Marden MC: Kidney chronicles. Am J Kidney Dis 25:967–970, 1995. 42. Ojo AO, Wolfe RA, Agodoa LY, Held PJ, Port FK, Leavey SF, Callard SE, Dickinson DM, Schmouder RL, Leichtman AB: Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation: Multivariate analyses from the United States Renal Data System. Transplantation 66:1651–1659, 1998. 43. Eggers P, Milam R: Cost comparison of dialysis and transplantation, in Immunosuppression Conference in Organ Transplantation: Patient Access to Long-Term Care, Philadelphia, 1998. 44. Belle SH, Beringer KC, Detre KM: Recent findings concerning liver transplantation in the United States, in J.M.Cecka and P.I.Terasaki (ed), Clinical Transplants 1996, Los Angeles, UCLA Tissue Typing Laboratory, 1997, pp. 15–29. 45. Keck BM, Bennett LE, Fiol BS, Daily OP, Novick RJ, Hosenpud JD: Worldwide thoracic organ transplantation: A report from the UNOS/ISHLT International Registry for Thoracic Organ Transplantation, in J.M.Cecka and P.I.Terasaki (ed), Clinical Transplants 1997, Los Angeles, UCLA Tissue Typing Laboratory, 1997, pp. 31–45. 46. United States Renal Data System: Excerpts from USRDS 1998 Annual Data Report. Am J Kidney Dis 32(Suppl 1):S1–S162, 1998. 47. Jacobs C: Current national coverage of immunosuppression medication, in (ed), Immunosuppression Conference in Organ Transplantation: Patient Access to Long-Term Care, Philadelphia, 1998. 48. Sharp LA: A medical anthropologist’s view on posttransplant compliance: The underground economy of medical survival. Transplant Proceedings 31(Suppl 4A):31S–33S, 1999. 49. Sharp LA: Organ transplantation as a transformative experience: Anthropological insights into the restructuring of the self. Medical Anthropology Quarterly 9:357–389, 1995. 50. UNOS (United Network for Organ Sharing): 1997 Annual Report of the U.S. Scientific Registry for Transplant Recipients in the Organ Procurement and Transplantation Network: DHHS/HRSA, Richmond, Virginia, UNOS, 1997. 51. Gorman K: The cost of immunosuppression and non-adherence, in Immunosuppression Conference in Organ Transplantation: Patient Access to Long-Term Care, Philadelphia, 1998. 52. Aguiar LJ: Role of the transplant financial coordinator and its effect on recipient compliance. Transplantation Proceedings 31(Suppl 4A):55S–56S, 1999.
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Extending Medicare Coverage for Preventive and Other Services 53. Eggers PW: Memo-Functioning graft patients in the Medicare ESRD population. 1997. 54. Gaston RS, Curtis JJ: Hypertension following renal transplantation, in S.G.Massry and R.J.Glassock (ed), Textbook of Nephrology, Baltimore, Williams and Wilkins, Co., 1995, pp. 1694–1700. 55. Kobashigawa JA, Kasiske BL: Hyperlipidemia in solid organ transplantation. Transplantation 63:331–338, 1997. 56. Congressional Budget Office: Cost estimate-elimination of time limitation on Medicare benefits for immunosuppressive drugs, Letter dated July 3, 1996, from June O’Neill to Charles T.Canady, 1996. 57. Jernigan CL, Cox ER, Coons SJ, Draugalis JR: Medicare beneficiaries management of capped prescription benefits (abstract), in Academy of Managed Care Pharmacists, 1999. 58. Kory L: Nonadherence to immunosuppressive medications: A pilot survey of members of TRIO. Transplantation Proceedings 31(Suppl 4A):14S–15S, 1999. 59. Nevins T, Thomas W, Skeans M, Matas A: Medication compliance following renal transplantation: The natural history (abstract). Transplantation 67:S115, 1999. 60. Gaston RS, Hudson SL, Ward M, Jones P, Macon R: Late renal allograft loss: Noncompliance masquerading as chronic rejection. Transplant Proc 31(Suppl 4A):21S–23S, 1999. 61. Isaacs RB, Conners A, Nock S, Spencer C, Lobo P: Noncompliance in living-related donor renal transplantation: The UNOS experience. Transplantation Proceedings 31(Suppl 4A):19S–20S, 1999. 62. Dunn J, Golden D, Van Buren CT, Lewis RM, Lawen J, Kahan BD: Causes of graft loss beyond two years in the cyclosporine era. Transplantation 49:349–353, 1990. 63. De Geest S, Borgermans L, Gemoets H, Abraham I, Vlaminck H, Evers G, Vanrenterghem Y: Incidence, determinants, and consequences of subclinical noncompliance with immunosuppressive therapy in renal transplant recipients. Transplantation 59:340–347, 1995. 64. Schweizer RT, Rovelli M, Palmeri D, Vossler E, Hull D, Bartus S: Noncompliance in organ transplant recipients. Transplantation 49:374–377, 1990. 65. Cramer JA: Relationship between medication compliance and medical outcomes. Am J Health-Syst Pharm 52(Suppl. 3):S27–S29, 1995. 66. Urquhart J: Patient noncompliance with drug regimens: Measurement, clinical correlates, economic impact. Eur Heart J 17(Suppl. A):8–15, 1995. 67. Butkus DE, Meydrech EF, Raju SS: Racial differences in the survival of cadaveric renal allografts: Overriding effects of HLA matching and socioeconomic factors. N Engl J Med 327:840–845, 1992. 68. Kalil RSN, Heim-Duthoy KL, Kasiske BL: Patients with a low income have reduced renal allograft survival. Am J Kidney Dis 20:63–69, 1992. 69. Sanders CE, Curtis JJ, Julian BA, Gaston RS, Jones PA, Laskow DA, Deierhoi MH, Barber WH, Diethelm AG: Tapering or discontinuing cyclosporine for financial reasons—A single center experience. Am J Kidney Dis 21:9–15, 1993. 70. Woodward RS, Schnitzler MA, Lowell JA, Singer GG, Cohen DS, Spitznagel EL, Brennan DC: Medicare’s extended immunosuppression coverage improved graft survival (abstract). J Am Soc Nephrol (in press) 1999.
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Extending Medicare Coverage for Preventive and Other Services 71. Sanders CE, Julian BA, Gaston RS, Deierhoi MH, Diethelm AG, Curtis JJ: Benefits of continued cyclosporine through an indigent drug program. Am J Kidney Dis 28:572–577, 1996. 72. Lagnado, L. Transplant patients ply an illicit market for vital medicines. Wall Street Journal, 6/21/99, p. 1.
Representative terms from entire chapter: