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Appendix D: Immunosuppressive Therapy: The Scientific Basis and Clinical Practice of Immunosuppressive Therapy in the Management of Transplant Recipients
Appendix D: Immunosuppressive Therapy: The Scientific Basis and Clinical Practice of Immunosuppressive Therapy in the Management of Transplant Recipients
Pages 286-328
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From page 286... ...
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.
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From page 287... ...
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]
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From page 288... ...
, the overwhelming majority of transplant recipients can expect to be alive 1 year after transplantation, most with functioning grafts.56 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.
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From page 289... ...
is not new. For each of these beneficial changes, there is a countervening variable with a potentially negative impact on graft survival save one.
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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 fFDA]
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From page 291... ...
Azathioprine, administered in combination with low-dose corticosteroids, was the cornerstone of long-term immunosuppressive therapy from 1962 tol984. 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.
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From page 292... ...
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.
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From page 293... ...
However, tacrolimus appears to have a slight advantage in not causing gingival problems or hirsutism, and it may be less detrimental to lipid metabolism.5~ The chief disadvantage of tacrolimus is a greater tendency to elicit posttransplant glucose intolerance.5~ 52 Some studies have reported enhanced eff~cacy of tacrolimus relative to CyA, while others find use of the two calcineurin inhibitors to result in similar outcomes. 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 30~0 percent of de nova kidney transplant recipients.
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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.6i Thereafter, most clinicians gradually reduce immunosuppressant doses or even discontinue a single agent (see below)
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From page 296... ...
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)
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From page 297... ...
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.
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From page 298... ...
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.~7 Beyond the first year, cadaveric grafts are lost at the relatively constant rate of 5-6 percent per year.5 28 Death with Unction 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.
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From page 299... ...
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.~° 8~ Its pathogenesis clearly has a strong underlying immunological basis, with previous episodes of acute rejection and degree of HLA incompatibility as strong predictive factors.~78283 Late episodes of acute rejection and noncompliance with complicated medical regimens also are clearly associated with CAN.83-8s However, the syndrome also reflects the impact of such nonimmunological factors as quality of implanted organ, size mismatch, hypertension, drug toxicity, and hyperlipidemia.~9i Nonetheless, the transplant community continues to focus on the underlying immunological basis of CAN and the provision of adequate immunosuppression to prevent graft loss.~° The first successful human renal transplants in the mid-19SOs 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 diseased 92 As effective immunosuppression became available, azathioprine and/or prednisone were administered even to identical-twin recipients in hopes of preventing recurrent disease.
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From page 300... ...
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.
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From page 301... ...
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.~°~-~ 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 shortterm graft loss or mortality.~° 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.~ When a similar group of socioeconomically disadvantaged recipients was provided cyclosporine indefinitely, outcomes were substantially improved.~2 Others have shown maintenance of therapeutic cyclosporine levels to be a critical factor in reducing the risk of chronic rejection and improving longterm graft survival.~3 ~4 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.
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From page 302... ...
Gaston RS, Deierhoi MH, Hudson SL, Kew CE, Curtis JJ, Julian BA, Young CJ, Gallichio MJ, Diethelm AG: Sequential immunoprophylaxis in renal transplantation: Comparison of two doses of daclizumab to OKT3 induction (abstract)
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From page 303... ...
13. Gaston RS, Hudson SL, Curtis JJ, Julian BA, Kew CE, Young CJ, Gallichio MJ, Deierhoi MH, Diethelm AG: Treatment of acute rejection episodes in the 90s: Is there still an impact on outcome in renal transplantation (abstract)
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From page 304... ...
34. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation.
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Niese D: Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de nova renal transplantation. International SandimmunNeoral Study Group.
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Lang P et al: Sirolimusbased therapy in human renal transplantation: Similar efficacy and different toxicity compared with cyclosporine.
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Peddi VR, Savin VJ, Johnson CP, First MR, Roza AM, Adams MB: Recurrent and de novo renal diseases after renal transplantation: A report from the renal allograft disease registry. Am J Kidney Dis 31 :928-931, 1998.
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91. Naimark DMJ, Cole E: Determinants of long-term renal allograft survival.
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From page 309... ...
118. Gaston RS, Curtis JJ: Hypertension following renal transplantation, in S.G.
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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.
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From page 311... ...
patients, chronic hemodialysis was the treatment of choice.23 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.~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-~3 Without chronic pha~acological immunosuppression, most grafts were lost to acute rejection, chronic rejection, or recurrent kidney disease.~4 The most commonly used immunosuppressants at the time were azathioprine and corticosteroids.
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From page 312... ...
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 1983.2223 Graft survival improved: 75 percent of recipients of cadaver kidneys could now expect to have functioning allografts after 1 year.20 In
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From page 313... ...
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.
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From page 314... ...
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.~9 In its final report, published in 1991, the committee recommended that: .
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From page 315... ...
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.
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From page 317... ...
Under current policies, Medicare reimburses approximately 24% of expenditures for extrarenal transplantation. Medicaid reimburses approximately 18%, and 58% comes from other sources.si For patients with kidney failure, the system is more complex.
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From page 318... ...
In 1997, private insurance absorbed 29%, Medicaid 13%, and Medicare fully 58% of the overall costs of renal transplantation in the United States.5~ 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.
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From page 319... ...
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 30~0% of those.S8~° 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)
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From page 320... ...
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.7i 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.
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From page 321... ...
As the issue of longterm 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 successfi~1 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." 9 This option would place renal transplant recipients on the same footing as ESRD patients receiving dialysis.
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From page 322... ...
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.
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From page 323... ...
, 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.
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6. Starzl TE: Experience in renal transplantation.
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From page 325... ...
Dafoe DC: Changes in causes of death after renal transplantation, 1966 to 1987. Am J Kidney Dis 17:512-518, 1991.
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Ferguson B Wong C, Muirhead N: A study of the quality of life and cost-utility of renal transplantation.
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From page 327... ...
68. Kalil RSN, Heim-Duthoy KL, Kasiske BL: Patients with a low income have reduced renal allograft survival.
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Transplant patients ply an illicit market for vital medicines. Wall Street Journal, 6/21/99, p.
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