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.*
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
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-
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
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
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-
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.
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
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.
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.
TABLE D-1 Currently Available Immunosuppressants
Cost Per Year ($)*
*Retail pharmacy costs in Birmingham, Alabama (May 1999) for average doses in a 70-kg patient.
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
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
$1.2 billion annually, or $3,900 per patient per year.66 It has achieved very high penetration in the dialysis community due to its relatively benign side-effect profile, its efficacy, and hopes of reduced morbidity among dialysis patients. Despite the absence of direct evidence that it improves survival in addition to quality of life, its benefits are deemed to exceed associated costs.67,68 As these trends continue, with further improvement in transplant outcomes and increases in dialysis costs, the time necessary to recover the initial costs of transplantation will continue to decrease.
The cost of maintenance immunosuppressive therapy after the first posttransplant year can vary from $5,900 (generic cyclosporine, azathioprine, prednisone) to $13,000 (Neoral®, MMF, prednisone) annually. Based on currently available data, the most cost-effective approach to reduce rejection early after transplantation might be tacrolimus-azathioprine-prednisone ($7,000); however, in attempts to further reduce rejection rates, some prefer tacrolimus-MMF-prednisone, despite its higher cost.51,69,70 Between 1994 and 1996, overall Medicare spending for immunosuppressive drugs doubled due to an increase in both the number of patients covered and the per-patient costs of therapy.5 This increase coincides with the introduction of tacrolimus, Neoral®, and MMF into the U.S. market. As a potential offset to this expense are significant reductions in hospital readmissions and graft loss, which may ultimately reduce overall per-patient costs.69,71 Indeed, a single-center report from the University of Alabama indicates that hospital readmissions in the first year after transplant have declined by 57 percent since 1995.7 However, reliable long-term multicenter data concerning the impact of newer immunosuppressive therapies on overall costs do not yet exist.
At least three factors seem likely to keep long-term immunosuppressive costs at or below current levels for both renal and extrarenal transplant recipients. First, sirolimus, or other new agents, will not be added to regimens (as was the case with MMF in 1995) but will likely supplant an equally expensive agent (cyclosporine, tacrolimus, or MMF) from an immunosuppressive protocol. Second, given that some accommodation between patient and allograft underlies long-term graft survival, the practice of reducing immunosuppression over time is likely to continue. This means that, for each patient, overall immunosuppressive costs decrease over time, and the difference in cost between expensive and inexpensive regimens is minimized.* Finally, the introduction of quality generic
equivalents for cyclosporine (of which SangCyA®, cyclosporine microemulsion, is the first), tacrolimus, and MMF will accelerate, with the potential to lower costs dramatically as the marketplace becomes more competitive.
ESSENTIALS OF LONG-TERM ALLOGRAFT SURVIVAL
Causes of Late Allograft Loss in Renal Transplantation
Under current therapies, early graft loss after solid organ transplantation is increasingly rare.5–7,72,73 The majority of renal graft losses during the first year are due to either acute rejection of the transplanted organ or death of the patient from other causes while the graft is still functional. As improvements in the ability to manage the immune response have reduced the impact of rejection, the proportion of organs lost due to patient death has increased.17 Beyond the first year, cadaveric grafts are lost at the relatively constant rate of 5–6 percent per year.5,28 Death with function and chronic rejection account for roughly 70 percent of late losses, with recurrent kidney diseases (primarily glomerulonephritis) causing about 10 percent, and acute rejection even fewer.74 Any strategy to improve long-term graft survival must address each of these causes.
Death with a functioning allograft, the ultimate in finite end points, is the most common cause of renal transplant failure after successful engraftment. The ultimate goal of renal transplantation is that every patient die with a functioning graft, just not prematurely. Currently, the death rate for transplanted patients is lower than for dialysis patients awaiting transplantation but higher than would expected for unaffected persons with a similar demographic background.*,5,75 Although death with function is obviously the same finite end point, it reflects the impact of substantially different factors than before. In the early years of transplantation, death was most often a complication of the transplant procedure, commonly occurring during the first year after a transplant and many times the result of sepsis.76,77 Of late, the demographics of those transplanted have changed dramatically. Diabetic patients account for a greater proportion of kidney recipients, increasing from 20 percent in 1986 to 25 percent in 1996. Fewer recipients are less than 45 years of age (69 percent in 1986 versus 53 percent in
Mortality from any cause is significantly more common among dialysis patients than after renal transplantation. The death rate per 100 patient-years at risk in 1995 was 24.6 for dialysis patients versus 7.8 for cadaveric transplant recipients and 3.7 for recipients of live-donor transplants. However, older, sicker patients are not candidates for transplantation and remain clustered in the dialyis pool. The most meaningful group for comparison is dialysis patients who are wait-listed for transplantation and therefore thought to be physiologically similar. Beyond a year after transplant, relative risk of death is less than half for cadaveric transplant recipients compared to wait-listed dialysis patients.5,75
1996), and more are over age 64 (1 percent versus 5 percent).5 Death is now most often caused by complications that are expected to be more common among these older individuals and diabetics (e.g., cardiovascular disease).78 While long-term immunosuppressive therapy undoubtedly contributes to late mortality and better management of extrarenal comorbidity is highly desirable, it is difficult to envision significant declines in death rate without more restrictive transplant recipient selection.
Chronic rejection is undoubtedly a misnomer, implying a specific immunological event. In truth, chronic rejection is an amalgam of immunological and nonimmunological processes, resulting in gradual loss of allograft function over time. More accurate terminology would label the syndrome as chronic allograft nephropathy (CAN), defined as a state of impaired renal allograft function at least 3 months after transplantation, independent of acute rejection, overt drug toxicity, and recurrent or de novo specific disease entities, with supporting histological features on biopsy.79,80 CAN is the main reason for returning to dialysis after transplantation and a major cause of ESRD in the Western world.80,81 Its pathogenesis clearly has a strong underlying immunological basis, with previous episodes of acute rejection and degree of HLA incompatibility as strong predictive factors.17,82,83 Late episodes of acute rejection and noncompliance with complicated medical regimens also are clearly associated with CAN.83–85 However, the syndrome also reflects the impact of such nonimmunological factors as quality of implanted organ, size mismatch, hypertension, drug toxicity, and hyperlipidemia.86–91 Nonetheless, the transplant community continues to focus on the underlying immunological basis of CAN and the provision of adequate immunosuppression to prevent graft loss.80
The first successful human renal transplants in the mid-1950s were isografts, performed between immunologically identical twins.92 Rejection was not a problem, but over time, some of these transplants lost function due to recurrence of the recipient’s original renal disease.1,92 As effective immunosuppression became available, azathioprine and/or prednisone were administered even to identical-twin recipients in hopes of preventing recurrent disease. In the 1990s, with effective control of acute rejection in all transplants, recurrent diseases (including focal glomerulosclerosis, lupus, immunoglobulin [IgA] nephropathy, membranous nephropathy, and necrotizing vasculitis) account for approximately 10 percent of late allograft losses.74 Evidence indicates that provision of adequate long-term immunosuppressive therapy may be critical in minimizing graft losses due to these diseases.93,94 Finally, it seems likely that recurrence of some microangiopathic diseases, notably hemolyticuremic syndrome, may be potentiated by the vascular toxicities of cyclosporine and tacrolimus, emphasizing the need for ongoing surveillance of recipients by physicians experienced in the use of these drugs.95
Causes of Late Allograft Loss in Transplantation of Organs Other than Kidneys
Transplantation of each of the nonrenal organs is associated with a distinct constellation of long-term complications. Obviously, graft failure, in the absence of retransplantation, equates with death in recipients of heart, liver, and lung transplants. Although early rejection episodes are common in those receiving liver transplants, late rejection (episodes occurring beyond 6 months) is distinctly uncommon. Accordingly, chronic rejection is also uncommon, and most hepatic recipients require significantly less long-term immunosuppression than other transplanted patients. Late graft failure is a relatively rare event, resulting most commonly from recurrent disease (hepatitis B and C, autoimmune hepatitis).72,96 In cardiac and pulmonary transplantation, late graft loss occurs more frequently. Chronic rejection (transplant coronary artery disease and bronchiolitis obliterans, respectively) is a significant long-term complication that requires substantial care and immunosuppressive monitoring.97,98 Given the more potent immunosuppression required by those receiving thoracic transplants, infection and malignancy pose greater threats to long-term survival than in kidney and liver recipients.
Barriers to Long-Term Survival
Looking forward, advances in scientific understanding and clinical intervention for comorbid conditions, chronic allograft nephropathy, and recurrent disease are essential in prolonging allograft survival. However, evidence exists that substantial improvement may be possible with better use of currently available tools.
Providing Adequate Immunosuppression
Long-term allograft survival is impossible without adequate immunosuppression, but controversy exists regarding the precise definition of “adequate.” Too little immunosuppression results in rejection and graft loss; too much in untoward complications. Transplant physicians and surgeons have always been trapped between these competing goals. Unfortunately, an accurate technique to assess how much immunosuppression is necessary for each individual patient does not exist. In the absence of an adequate measurement, those involved in monitoring immunosuppression have learned to negotiate narrow therapeutic limits with surprisingly little guidance from objective findings in clinical trials.
In the early days of transplantation, reduction and/or withdrawal of immunosuppression was almost always accompanied by rejection and graft loss.4,99,100 Virtually all subsequent attempts to withdraw even a single drug from therapies have repeated this experience, at least to some degree in some patients. Because of their inherent toxicities, withdrawal of corticosteroids has been the goal of
multiple trials. Most studies of complete steroid withdrawal document 10–40 percent risk of acute rejection depending on the patient population studied and the timing of withdrawal.38,101–104 While this finding is relatively uniform, controversy exists regarding the ultimate impact of these rejection episodes on graft and patient survival. Some have found these rejections, despite requiring reinstitution of steroid therapy, to have little or no impact on graft survival.105 Others have noted increased risk of CAN and graft loss among the steroid withdrawal group.106,107 A recent randomized trial of steroid withdrawal (supported by the National Institutes of Health) using the most modern immunosuppressants available was terminated early due to increased incidence of acute rejection (19 percent versus 5 percent) in the withdrawal group, despite the absence of any differential effect on graft survival.37
Because of its toxicity and cost, CyA withdrawal has been attempted in multiple studies, again with very consistent results. The incidence of acute rejection rises after even gradual dose reduction and withdrawal, but with controversial implications.108,111 A meta-analysis of 10 randomized and 7 nonrandomized trials of cyclosporine withdrawal found a 26 percent greater incidence of acute rejection in the withdrawal group, but without adverse impact on short-term graft loss or mortality.110 In a nonrandomized trial of gradual CyA withdrawal for financial reasons in otherwise stable patients, there was substantial risk of late rejection and graft loss, particularly among African-American recipients.111 When a similar group of socioeconomically disadvantaged recipients was provided cyclosporine indefinitely, outcomes were substantially improved.112 Others have shown maintenance of therapeutic cyclosporine levels to be a critical factor in reducing the risk of chronic rejection and improving long-term graft survival.113,114
Since it has been difficult to document a beneficial effect of azathioprine in combination with CyA and prednisone, it should not be too surprising that azathioprine withdrawal, though poorly studied, appears to have little adverse impact. Studies of tacrolimus and MMF withdrawal are underway, but results as yet are unavailable. Thus, the preponderance of data concerning withdrawal of a single agent indicates that, while this feasible in some patients, adverse consequences may develop in others. As previously noted, to truly define the adequacy of immunosuppression, some reliable measurement of donor-specific immunological responsiveness is necessary.115 Without such a measurement, it is obvious that across-the-board drug withdrawal is a hazardous approach for many patients. Thus, in the clinical arena, adequacy of immunosuppression will continue to be determined by laboratory and physical assessment of the recipient, performed at recurring intervals by providers familiar with the issues involved.
Avoiding Excessive Immunosuppression
Given that long-term graft survival requires ongoing immunosuppression, maximizing outcomes means minimizing complications of immunosuppressive therapies. Early after transplantation, when immunosuppression is most intense, risk of infectious complications is greatest.116 In 1999, these infections are primarily viral, with bacterial and fungal infections posing life-threatening risk in only a limited number of patients. For long-term survivors, risk of infection diminishes with time, at least partially due to reduction in immunosuppressant drug dosages. However, risk of malignancy, itself often viral related, increases and remains substantially greater in transplant recipients than in the general population.117 In addition, there are specific adverse effects of each immunosuppressive agent that require surveillance, such as cyclosporine nephrotoxicity and hypertension, steroid-induced bone disease, or hyperlipidemia.118–120
SUMMARY AND CONCLUSION
A common aphorism is that successful transplantation is not a cure, but rather substitutes the manageable disease of immunosuppression for the incurable and fatal disease of organ failure. Current clinical practice, with substantial scientific underpinnings, requires continual provision of adequate immunosuppression to ensure optimal outcomes for recipients. While future developments may change this paradigm, long-term survival of both graft and patient mandates ongoing access not only to a full complement of immunosuppressive agents, but also to requisite clinical expertise.
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APPENDIX D, PART 2
Transplantation and Immunosuppressive Medications: Evolution of Medicare Policy Involving Transplantation and Immunosuppressive Medications—Past Developments and Future Directions
Robert S.Gaston, M.D.*
Medicare’s policies for covering immunosuppressive drugs for recipients of renal and other solid organ transplants are unusual and often misinterpreted. They are unusual because they constitute one of the very few exceptions to Medicare’s basic policy of excluding coverage of prescription drugs. This appendix reviews the history of Medicare coverage of both organ transplants and immunosuppressive drugs for transplant recipients. This review emphasizes the evolving relationship between technological advances and Medicare financing of transplantation. It also includes a section documenting the impact of Medicare policy on current beneficiaries, and, looking ahead, summarizes some possible future modifications.†
EVENTS IN THE EVOLUTION OF MEDICARE POLICY REGARDING TRANSPLANTATION
Medicare Policy and the Science of Transplantation: 1972
The 92nd Congress passed H.R. 1 as section 299I of the Social Security Amendments of 1972 (PL 92–603).1 This legislation created a new entitlement
for those (regardless of age) suffering from irreversible chronic kidney failure. Virtually all Americans, after a brief waiting period, would be eligible for Medicare benefits that included the costs of dialysis and/or renal transplantation. Senator Vance Hartke of Indiana, responding to the plight of those afflicted with the previously fatal disease of kidney failure, said, “How do we explain that the difference between life and death in this country is a matter of dollars?”2 The legislation passed after 30 minutes discussion, part of a frenzy of legislative activity immediately preceding the 1972 election, and was signed by President Nixon on October 30. Proponents of the program were optimistic regarding costs, projected to be approximately $500 million annually to treat about 40,000 beneficiaries. This ultimately monumental miscalculation was but the first of many. Hartke also stated that, “Sixty percent of those on dialysis can return to work but require retraining and most of the remaining 40 percent need no retraining whatsoever.”2
Subsection (f) of the bill authorized indefinite benefits for those remaining on dialysis, but terminated coverage for transplant recipients at 1 year following successful engraftment. At the time, it was generally accepted that for most end stage renal disease (ESRD) patients, chronic hemodialysis was the treatment of choice.2,3 Only those patients fortunate enough to have a well-matched living donor might expect to derive greater benefit from transplantation than dialysis, a total of fewer than 500 patients nationally in 1972.4 Receiving a cadaver kidney was associated with substantially greater mortality than remaining on dialysis, and only 40% of those transplanted maintained function 1 year later.3,5
In the early days of transplantation, a common assumption was that successfully engrafted patients were “cured,” no longer subject to the unaffordable costs of maintenance dialysis therapy that had precipitated passage of the Social Security amendments in the first place. Some hoped that long-term allograft survival might be achieved without long-term immunosuppression.6–8 However, seminal work in animals and early observations in humans during the 1960s established the necessity of ongoing immunosuppression to maintain stable allograft function.9–13 Without chronic pharmacological immunosuppression, most grafts were lost to acute rejection, chronic rejection, or recurrent kidney disease.14 The most commonly used immunosuppressants at the time were azathioprine and corticosteroids. Because these drugs were inexpensive, the cost of maintaining long-term allograft function was not an issue.2,3,5,15 In 1974, transplantation accounted for 18% ($51 million) of total Medicare ESRD expenditures ($283 million).1
Medicare Policy and the Science of Transplantation: 1978
By 1978, 5 years after implementation of the Medicare ESRD program, the landscape had changed. The overall costs of the program had proved much greater than anticipated, having risen to an annual expenditure of $1 billion dollars to treat 47,000 ESRD patients (increased from 19,000 in 1974).1 Projections
that outlays might increase to $2.5 billion by 1985 and $4.5 billion by 1995 reflected fears that the program was “out of control.”2,16 The increased costs reflected substantial broadening of eligibility criteria for ESRD therapy.2,17 It had become generally accepted that the Medicare ESRD program was essentially a dialysis entitlement, with transplant expenditures accounting for only nine percent of outlays.1,18 Emerging experience indicated that the original hopes of rehabilitation were unlikely to be realized for chronic dialysis patients; over half of beneficiaries remained disabled.2,15
In response to these trends, the 95th Congress in 1978 modified the original ESRD legislation by passing PL 95–292, an act intended to control program costs, in part by allowing a more favorable reimbursement policy for the less expensive modalities of home dialysis and transplantation.5 This legislation, among other provisions, extended time limits on Medicare benefits after kidney transplantation from 1 to 3 years but did not address the need for outpatient drugs.1,19 Implicit in these modifications was the changing clinical perception that transplant recipients did indeed require ongoing care to ensure allograft function; transplant as “cure” was a fading notion.
Between 1974 and 1978, there had been only minor changes in the clinical practice of transplantation. The number of transplants performed annually grew slowly, from 3,000 to about 4,000, with the majority (80%) originating in cadaver donors and imparting 1- and 3-year graft survival of 54% and 42%, respectively.20,21 However, the most notable change was an increase in patient survival for recipients of cadaver kidneys. Graft failure no longer equated with death.4 Nonetheless, absent a living-related donor, an ESRD patient remained statistically better off on chronic dialysis.2,15–17
Medicare Policy and the Science of Transplantation: 1984–1986
By the mid 1980s, the Medicare ESRD program was again changing dramatically, particularly as regards transplantation. Medicare ESRD expenditures had increased to $2.1 billion (less than had been predicted 6 years earlier, and in constant 1974 dollars to $1 billion). There was a 300% increase in outlay for a 600% increase in patients covered, as per patient costs of therapy actually declined, even in the face of an ever older population of ESRD beneficiaries.17,19 Transplant expenditures remained relatively small, accounting for only 6% of total Medicare ESRD outlays.
In previous years, there had been slow but steady improvement in graft survival for transplant recipients, but changes in immunosuppressive therapy in the mid-1980s revolutionized the field. Cyclosporine, first tested in humans in 1976, was approved for general use by the United States Food and Drug Administration in late 1983.22,23 Graft survival improved: 75 percent of recipients of cadaver kidneys could now expect to have functioning allografts after 1 year.20 In
addition, cyclosporine use was accompanied by a dramatic decline in the morbidity associated with transplantation. This fact, in conjunction with improved clinical management of coexisting conditions, resulted in a corresponding increase in patient survival at 1 year, which rose significantly above the 90% level.24–26
These advances led to at least two dramatic changes regarding perceptions of transplantation. First, both cadaver- and live-donor transplantation could now be performed with sufficient hopes of success that, in terms of both patient outcome and cost, renal transplantation was now the optimal therapy for end stage renal disease.21 The interests of both patient and government would be best served by promoting transplantation as much as possible vis-a-vis dialysis. For the first time, it became obvious that the availability of cadaver organs would become the key factor limiting access to transplantation.19 Second, the relationship between adequate maintenance immunosuppression and a successful transplant was now well-enough established, and the cost of cyclosporine sufficiently high, to make access to immunosuppressants an issue.19,27 Both were addressed by legislation passed in the mid-1980s. The National Organ Transplant Act of 1984 (PL 98–507) authorized:
creation of a National Task Force on Organ Transplantation,
assistance to organ procurement organizations,
establishment of the Organ Procurement and Transplantation Network (OPTN), and
creation of a scientific registry for organ transplantation.
In addition, provisions in the Omnibus Budget Reconciliation Act of 1986 (PL 99–509) authorized payment for immunosuppressive medications for 1 year after a Medicare-covered renal transplant, at least partially in response to the high cost of cyclosporine.
The final important change of the mid-1980s regarding Medicare and transplantation resulted from the increasing success noted in extrarenal transplantation after the advent of cyclosporine-based immunosuppression. In a series of policy changes occurring between 1986 and 1991, Medicare authorized coverage of cardiac and hepatic transplantation in beneficiaries, with immunosuppressant coverage subject to the same 1-year limitations as in the ESRD program.28 However, unlike coverage for ESRD patients, these benefits were available only to patients who qualified for Medicare by reason of age or disability.
Medicare Policy and the Science of Transplantation: 1994
In the early 1990s, with broadening clinical experience and the introduction of new technologies, transplantation became even more successful. For recipients of cadaveric renal transplants, 80–85% graft survival at 1 year became the norm, and patient survival continued to rise well in excess of 95%, even as the procedure was offered to older and more complicated patients.27 Outcomes for recipients of live-donor kidneys were also incrementally better.29 These short-term improvements made long-term graft survival an increasingly important issue. Three-year cadaver graft survival for transplants performed in the early 1990s now approached 75% (in excess of what had been expected at 1 year only a decade earlier).27 Even cadaveric transplantation was now clearly associated with improved longevity relative to dialysis.30
During this time, the cost-effectiveness of transplantation relative to dialysis became better defined. Transplantation accounted for 12% of Medicare ESRD outlays between 1991 and 1993, but annual costs per patient were roughly 40% of those associated with maintenance dialysis.31 In an insightful analysis of transplants performed between 1987 and 1990, Paul Eggers of the Health Care Financing Administration (HCFA) noted that the high first-year costs of transplantation were recovered by Medicare within 4.9 years for recipients of cadaver kidneys, and even sooner (4 years) if the organ originated in a live donor.32
In the Omnibus Budget Reconciliation Act (OBRA) of 1987, Congress asked the Institute of Medicine (IOM) to evaluate the entire Medicare ESRD program. Subsequently, in a comprehensive analysis of ESRD in the United States, the IOM committee reaffirmed the benefits of renal transplantation, while acknowledging the financial burden even a successful transplant imposed on recipients in terms of need for lifelong medical supervision and pharmacologicaltherapy.19 In its final report, published in 1991, the committee recommended that:
…Congress eliminate the three-year Medicare eligibility limit for successful transplant patients and thereby authorize a lifetime entitlement comparable to that of dialysis patients….
…coverage for payment of immunosuppressive medications for kidney transplant patients be made coterminous with the period of entitlement.19
Contemporaneously, the Senate Finance Committee asked the Office of Technology Assessment to address Medicare coverage of immunosuppressants.33 The resulting document focused more closely on the issue of immunosuppressant coverage for all transplanted Medicare beneficiaries, without specifically endorsing any of several possible options for expansion. Despite strong support from the transplant community and patient advocacy groups for the IOM recommendations, the 102nd Congress in 1992 chose an intermediate approach.
They authorized a phased-in extension of the time limit for immunosuppressive drug coverage from 1 to 3 years posttransplant. They did not address extension of overall Medicare eligibility for kidney transplant recipients beyond the 3-year limit.
Thus, over a 27-year period, Medicare reimbursement policies and clinical transplantation evolved in tandem, with the government adjusting policy to address both the evolving clinical practice of transplantation and the changing needs of Medicare beneficiaries. Through these efforts, renal transplantation became available to virtually every American with ESRD via access to Medicare entitlements that continue for 3 years after the procedure. Renal transplants account for the majority of transplants and the majority of Medicare transplant spending. Extrarenal transplantation is also now covered, but only for those who were otherwise Medicare eligible. For all these beneficiaries, provision of immunosuppressive therapy is guaranteed for 3 years after transplant. As they were adopted, these policies represented a reasonable response to the realities of clinical transplantation. Even well into the 1990s, the focus was on the early posttransplant period, attempting to ensure successful engraftment of the transplanted organ.
Recent clinical and scientific advances (as described in Appendix D, Part 1) have made the inpatient components of care amazingly routine and highly successful. In pursuing the new goal of long-term graft survival (see Box D-1), the ultimate fate of the allograft is increasingly dependent on what happens beyond the early posttransplant period.
IMPACT OF CURRENT POLICIES ON MEDICARE BENEFICIARIES
As the committee considers the expected effectiveness and cost of expanding Medicare coverage, it seems helpful to review current payment options and their impact on transplant recipients.‡ As previously noted (see Appendix D Part 1), maintaining an allograft requires ongoing access to medical care and pharmacological immunosuppression beyond the 3 years covered by Medicare. For some impoverished patients, Medicaid assistance may provide the necessary coverage for both services and drugs, although income eligibility requirements and payment restrictions vary by state.47 For other transplant recipients, financial coverage for posttransplant care is a responsibility shared among private insurers, specifically developed state and pharmaceutical company programs, and individual patients and their families. Because the ongoing expenses of transplantation far exceed what most individuals can afford (with maintenance drug
BOX D-1 Impact of Long-Term Transplant Survival
What does long-term graft survival mean to patients?
For recipients of hearts and livers, it means life itself.
For recipients of kidneys, it means:
“A year ago I would not let you see me without mascara. Today you can view me three times a week without my pride…. I am dry, and always, always thirsty…. I smell old and sick. And even Shalimar cannot cover the odor of dialysate…I am afraid…I am determined to escape this. I will not forget and I will not return.”41
What does long-term graft survival mean to payers?
For heart and liver transplants it means an ongoing commitment to ensure the heavy initial investment in the transplant procedure (often approaching $200,000) translates into the desired benefit.
For kidney transplants it means cost-savings relative to dialysis or retransplantation.
Most renal transplant candidates receive chronic dialysis, at a cost of $47,000 per patient/year. Although expenses in the transplant year average $92,000, lower costs associated with maintaining graft function result in net cost savings for individual recipients whose grafts function beyond 3 years.43
What does long-term graft survival mean to physicians?
It means better patient outcomes, with reduction in morbidity and mortality relative to all other therapies.44–46
What does long-term graft survival mean to society?
It means preserving and protecting the transplanted organ, a very valuable resource. Given the scarcity of available organs, the length of waiting lists, and the patients who die awaiting transplantation, the donated organ is priceless.
It means honoring the sacrifice of families who have donated the organs of a loved one, confident that these organs will receive optimal care.
charges in excess of federal poverty guidelines for a family of two persons), financing has evolved into a creative dance among interested parties.
Current Medicare policies impose a substantial burden on a group of beneficiaries already heavily afflicted. For many recipients, these circumstances lead to what Lesley Sharp has called the “survival paradox”: devoting the entirety of one’s energies to a desperate battle for medical survival against enormous financial obstacles.48,49
For patients with cardiac or hepatic failure, transplantation is financed on the framework of preexisting coverage. For a Medicare beneficiary, cost of the procedure and 80 percent of immunosuppressant costs are covered expenses, subject to the usual deductible and copay requirements. However, fewer than 5% of heart and liver recipients are over 65 years of age.50 Thus, many solid organ recipients establish Medicare coverage by qualifying for disability benefits during the illness preceding transplantation.47 At times, the transplant occurs before a patient has established Medicare eligibility; the care is often provided gratis by the transplant center or paid by state Medicaid funds, with Medicare eligibility established during the posttransplant phase (personal communication, L.Lockett, University of Alabama at Birmingham). Benefits continue as long as the patient retains eligibility, except that coverage for immunosuppressive drugs ends 3 years after hospital discharge following the transplant.
Under current policies, Medicare reimburses approximately 24% of expenditures for extrarenal transplantation. Medicaid reimburses approximately 18%, and 58% comes from other sources.51
For patients with kidney failure, the system is more complex. First, ESRD is a disease most common in patients of lower socioeconomic status, often evolving on a background of inadequate care for glomerular disease, chronic infec-
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.
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.
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
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-
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.
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.
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.
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