Refinements in solid organ transplantation techniques have resulted in improvements in patient and graft survival, and transplants are a cost-effective option for appropriate patients. Lack of improvement in graft survival, despite a reduction in acute rejection episodes, has sparked interest in both newer medications/treatment regimens and strategies to improve outcomes. Even as transplant professionals seek to optimize the therapeutic regimen for each patient, there are steps that managed care can take to further reduce costs and improve patient and graft survival. This review addresses factors that impact graft survival and focuses on the role of managed care clinicians in adherence assessment and improvement as a means to enhance patient and graft outcomes. Improvements in graft and patient survival are expected to preserve and maximize the usefulness of the limited supply of organ and financial-related resources in the United States.
Am J Manag Care. 2015;21:S24-S30Background
The current status of solid organ transplantation in the United States is the result of some of the most substantial advances in medicine in recent decades. In a relatively short time, this field has transformed from an experimental endeavor to a lifesaving and cost-effective management strategy for end organ failure. The introduction of the calcineurin inhibitor, cyclosporine, into clinical practice in the early 1980s solidified the role of medication to prevent organ rejection, due to dramatic increases in graft and patient survival.1 Once immunosuppressive regimens became more widely used and studied, it became possible to evaluate the outcomes of renal transplantation compared with dialysis. (The kidney is the most commonly studied solid organ because it is the most common transplant procedure performed.2
A study compared patients on dialysis, those on dialysis awaiting transplantation, and recipients of a first cadaveric renal transplant, and found that patients awaiting transplantation had a 38% to 58% lower annual death rate (6.3 per 100 patient-years) than patients on dialysis who were not listed (16.1 per 100 patient-years).3 Recipients of a first cadaveric transplant had the lowest mortality rate (3.8 per 100 patient-years). By day 106, the risk of death posttransplantation was lower than the risk of death associated with dialysis. Organ transplantation has long been considered cost-effective due to the documented favorable costs per life-year gained, with estimates ranging from $3600 to $100,000 (1993 US$) for heart transplantation and $17,000 to $46,000 for renal transplantation.4
Living donation renal transplants are slightly more costeffective than cadaveric transplants due to better patient and graft survival. A study that specifically examined the costeffectiveness of renal transplantation found that the cost of pre-transplant care in the year leading up to the procedure was $66,782 (1994 Canadian dollars), $66,290 in the first year after the transplant, and $27,875 in the second year—demonstrating that over 2 years, transplantation was more effective and less costly than dialysis.5 Although these data4,5 are somewhat dated, transplantation does reduce long-term costs compared with dialysis.
As patient outcomes have improved in transplantation, funding and access have increased through research and government programs. Research efforts have been undertaken to expand these life- and cost-saving opportunities to more patients in an effort to improve patient survival and save money in the US healthcare system. Consequently, transplant programs have begun to manage more complex patients, such as those who are broadly sensitized (ie, high panel reactive antibodies and/or preformed antibodies to the donor organ) and would not otherwise be candidates for transplantation.6 A costeffectiveness analysis demonstrated that the 3-year cost in broadly sensitized patients requiring a desensitization protocol (intravenous immune globulin and rituximab) prior to transplantation was $219,914 per patient (2011 US dollars) compared with $238,667 in patients receiving dialysis. Patient survival was 96.6% in the desensitization group compared with 79% for the age-, end-stage renal disease etiology—, and panel reactive antibody–matched group of patients receiving dialysis, indicating that this protocol saved money and improved patient outcomes.6
Efforts have also been undertaken to improve outcomes for post transplant patients by extending financial support. The cost-effectiveness of extending Medicare coverage for those receiving a kidney transplant and its impact on outcomes were studied. Extension of immunosuppressive coverage improved graft survival from 38.6% to 47.6% and patient survival from 55.4% to 61.8%, with an annualized savings to society of $136 million if the transplant rates in the study continued into the future.7 The authors also noted that an estimated 25% of renal transplant recipients are gainfully employed and eligible for employer-sponsored insurance.7 Taken together, transplantation, or at least kidney transplantation as a marker for solid organ transplantation, is cost-saving and improves patient survival compared with alternative strategies.
A critical shortage of available organs exists, and demand far exceeds supply.2 Organ demand is generally increasing over time, while transplant procedure rates are relatively flat. Therefore, the success of organ transplantation is dependent on supplying needed organs and maximizing organ functionality over time after the surgery. The consequences of kidney transplant failure are alarming: death within 2 years occurs in 22.7% of patients returning to dialysis.7 Failure of other organs, such as the heart and lungs, may result in a more immediate demise.2 Consequently, the survival of the transplanted organs must be optimized to maximize the value of this limited resource. In the past 20 years, cyclosporine and tacrolimus have failed to improve long-term graft survival, despite control of acute rejection.8,9 Furthermore, the more recently introduced immunosuppressive agents have generally failed to improve cost-effectiveness estimates within an acceptable range or to dramatically extend long-term graft survival.10
Improving Long-Term Graft Survival
The main strategies to improve long-term graft survival include using more effective therapies and providing better quality of care.8,9,11 In recent years, registries and public reporting of transplant program outcomes may have disincentivized transplant programs from trying novel regimens or taking on risky patients or procedures. The low acute rejection rates achieved by many transplant centers are seen as a quality indicator, when in reality, long-term graft survival is a better marker. However, inadequate adjustment of reported data for the risk status of the candidates and recipients and a focus on surrogate outcomes, such as acute rejection rates, have led to controversy over what these data mean and how they affect payers, contracting, and patient referrals. Improper adjustment may lead to too many futile transplants and a decrease in organ supply if overadjusted, or decreased recipient access and donor utilization if underadjusted.12
Recent trends show that immunosuppressive therapy involving calcineurin inhibitors has significantly reduced acute rejection rates, but only modestly improved longterm graft and patient survival.13 To improve long-term graft survival, strategies include reducing calcineurin inhibitor exposure to minimize the negative impact on renal function.14-16 Nankivell and colleagues demonstrated (over time, through biopsies in kidney-pancreas transplant recipients) that by 10 years, nephrotoxicity from the calcineurin inhibitor was present in nearly 100% of patients, severe chronic allograft nephropathy was present in 58.4%, and irreversible glomerular sclerosis was present in 37.3%.14 In 69,321 nonrenal solid organ transplants performed between 1990 and 2000, Ojo et al demonstrated a 16.5% rate of chronic renal failure over 36 months of follow-up and a subsequent increased risk of death (relative risk [RR], 4.55; P <.001).15 The 5-year risk of chronic renal failure was attributed to calcineurin inhibitor therapy and varied by transplant type: 6.9% of heart-lung transplants, 10.9% of heart transplants, 15.8% of lung transplants, 18.1% of liver transplants, and 21.3% of intestine transplants. These results support the investigation of regimens that spare the calcineurin inhibitors, but many calcineurin inhibitor—free regimens have high acute rejection rates or intolerable adverse effects, such as those involving sirolimus.16,17 Still, data show that at least 90% of adult patients who underwent a kidney, pancreas, liver, intestine, heart, or lung transplant in 2012 were started on calcineurin inhibitors.2
Transplant centers have a tendency to be loyal to local treatment protocols and may be slow to adopt research from other centers due to lack of generalizability to their treatment protocols or patient populations.18 This means that until the transplant centers have the long-term data to convincingly adopt a new treatment protocol with clearly superior long-term outcomes, caregivers and payers will have to optimize care of the already transplanted organ. A major strategy to optimize care is to focus on minimizing the common complications of solid organ transplantation. Besides managing immunosuppression to prevent organ rejection, long-term management involves treating common complications, including the recurrence of disease, comorbidities, cardiovascular disease, infection, renal dysfunction, diabetes and other metabolic complications, and malignancy.2,19-25 Premature cardiovascular disease is the leading cause of death after solid organ transplantation; it involves acceleration of risk factors such as diabetes mellitus, hypertension, renal dysfunction, and dyslipidemia. Cardiovascular disease risk factors are directly impacted by immunosuppressive agents. For example, corticosteroids increase the risk of diabetes, fluid retention, dyslipidemia, and weight gain.17,19,24,25 Nontransplant clinicians have the opportunity to improve care of transplant patients by focusing on prevention and treatment of these conditions and encouraging medication adherence.
Medication adherence after solid organ transplantation is a critical, but often overlooked, facet of improving transplant outcomes.26 A systematic review of the frequency and impact of nonadherence (typically defined as missing 3% to 20% or more of scheduled doses) in renal transplant recipients found a median nonadherence rate of 22.3% in 14 cross-sectional studies and 15% in 11 cohort studies.27 In fact, the cohort studies showed that a median 36.4% of graft losses were associated with prior nonadherence. Nonadherence increased the odds of graft loss by 4.8%, and a series of reported cases showed that 14.4% of graft failures were associated with nonadherence. The final random effects model demonstrated a 7.1-fold increased risk (95% CI, 4.4-11.7; P <.001) for graft failure in patients who were nonadherent compared with those who were adherent to therapy.27
A more recent study examined the United States Renal Data System and Medicare coverage data to quantify the relationship between adherence and risk of graft failure in renal transplant recipients.28 Adherence was measured by calculating the medication possession ratio (MPR), defined as the number of prescription fills per 30-, 60-, or 90-day cycle adjusted for the cycle duration and number of cycles in the study. The MPRs were compared with the outcomes in quartiles of adherence. A total of 31,913 patients between 1999 and 2005 met criteria for analysis. MPR was shown to influence graft survival, with higher quartiles (higher MPRs) associated with higher graft survival (P <.0001),28 and greater adherence was associated with older age, female sex, white race, deceased donors, and tacrolimus immunosuppression (P <.001). Cox proportional hazards modeling indicated that adherence, white race, and having a living donor were significantly associated with longer graft survival (P <.05). The authors concluded that adherence rates of at least 80% were associated with reduced risk of graft loss in patients who underwent renal transplantation.28 These data support the importance of immunosuppressant medication adherence in long-term graft survival.26-28
Role of Managed CareCosts
The goal of managed care has traditionally been to control costs; this is a goal shared with Affordable Care Act legislation.29 Moving forward, delivering quality at a reduced cost is of major importance for healthcare and a healthy economy. According to the 2013 Drug Trend Report published by Express Scripts, the specialty medication market drove the drug trend in 2013 with a 2.5% growth in utilization from the previous year, while traditional prescription medications grew 0.5%. The corresponding spend increase was 14.1% for specialty medications and 2.4% for traditional medications.30 Transplant medications are ranked number 9 among specialty therapy classes by market share.30 The per member per year spend for transplant medications across the entire insured population (all members, not just those with transplants) was $5.07, and this value increased 1.8% from 2012 to 2013. The average cost per transplant prescription filled was $292.64, the lowest among the specialty classes; this is largely due to the availability and use of generic mycophenolate, tacrolimus, and cyclosporine. Moreover, generic mycophenolate, tacrolimus, and cyclosporine made up about two-thirds of the specialty market share for this class.30
The finding of high utilization of generic medication in transplantation is interesting because of the controversy that has existed over generic narrow therapeutic index drugs, particularly immunosuppressants.31,32 One study of administrative claims from 8 private US health plans evaluated 227 renal transplant recipients from 1996 to 2004.32 Data were adjusted for demographics, clinical characteristics, and transplant center, and a log-transformed multiple-linear regression model was constructed to compare first-year costs in patients who underwent a transplant and received branded cyclosporine (n = 183) or generic cyclosporine (n = 44). The mean total healthcare costs in the first year trended lower in the branded cyclosporine arm, while there was an average $4300 increase in the generic group (P = .07) due to mean higher immunosuppressant costs of about $3700 (P = .02), suggesting that the savings was overcompensated for by higher costs of other agents. Inpatient days and 1-year dialysis rates were similar.32 The relevance of these findings is unclear because most centers use tacrolimus now.2
Studies have been performed to compare the pharmacokinetics of generic and reference formulations of calcineurin inhibitors and ease concerns about variability in exposure. One such study compared branded tacrolimus and generic tacrolimus in patients who underwent a renal transplant and found no difference in area-underthe- curve from 0 to 12 hours or concentration at 12 hours (C12); and 90% CIs were between 80% and 125% for all subpopulations (ie, diabetic or nondiabetic, male or female, African American or non—African American, and steroids or no steroids).33 In contrast, a more “realworld” study, performed in stable patients who underwent liver or kidney transplants, identified differences in the concentration-to-dose (C/D) ratio when patients were switched from branded to generic tacrolimus. In liver and kidney transplant recipients, the C/D ratio decreased (P <.05 for both populations) and the average trough level (C12) declined 1.98 ng/mL and 0.87 ng/mL, respectively, suggesting some pharmacokinetic variability. However, no changes in liver or kidney function occurred, and there were no episodes of acute rejection.34 These data suggest that although the products have demonstrated bioequivalence, there may be some variability in drug concentrations when patients are switched between agents. Moreover, position statements from transplantation societies both support the use of generic medications that are considered therapeutically equivalent, and recommended notifying the transplant physicians of such changes so that enhanced monitoring can be employed.35,36
Another way to reduce the risk of graft loss is to ensure patients adhere to their immunosuppressive medications.26-28 The 2013 Drug Trend Report identified that 33.2% of patients who underwent transplantation were nonadherent (parameters not defined in the report) with their immunosuppressive medications in 2013. Due to the negative consequences of nonadherence outlined previously, it is important that managed care professionals take an active role in improving medication adherence.26-28 A systematic review of adherence studies sought to compare educational/cognitive interventions, counseling/behavioral interventions, and psychologic/ affective interventions, as shown in the Table.26 Results were mixed, with 1 study demonstrating no change in adherence, another study documenting only reduced variability in tacrolimus blood levels (P = .04), and a third study demonstrating improved adherence (P <.02), which lasted to a 3-month post evaluation (P <.006). The authors noted that although there were many methodologic limitations of the studies used in this systematic review, the greatest limitation was that the same approach was taken for every patient in a given study when the intervention should have been individualized.26
Demonceau and colleagues published a systematic review and meta-analysis of adherence-enhancing interventions.37 They found an 8.8% (P <.01) increase in recent dosing history when patients received electronic monitoring feedback and a 5% increase when a cognitive-educational component was included (P = .02).37 Cognitive-educational components were defined as presentation of information individually or in a group setting to motivate, and education, given verbally, in writing, or audiovisually. Among high-quality studies (n = 48), electronic feedback improved adherence by 19.8% (95% CI, 10.7-28.9), and a cognitiveeducational component improved adherence by 16.1% (95% CI, 10.7-21.6). Of particular importance, the study identified that the effect of interventions diminished 1.1% each month, indicating that strategies to improve adherence need to be persistent and adaptive.37
Results from a number of studies on technology-based strategies to improve outcomes have been published recently. Regimen simplification with once-daily dosing, as in the case of the tacrolimus modified-release once-daily formulation, reduced nonadherence from 75% to 40.3% (P <.0001) over 8 months in patients who underwent a heart transplant.38 A study of an ingestible sensor system evaluated a gastric acid-activated microsensor placed on enteric-coated mycophenolate sodium and an adhesive personal monitor that documented intake and timing. The sensor detected 99.3% adherence over 9.2 weeks in 20 stable adult patients who underwent a kidney transplant. The accuracy was 100% over 34 direct observations, rash or erythema due to the monitor developed in 37%, and 10% required discontinuation.39 Although the results are impressive, the applicability in clinical practice and cost of this technology at this time is uncertain.
Multidisciplinary and Pharmacist Impact on Adherence
Other impressive results have been reported with behavioral-intervention strategies. Chisholm-Burns and colleagues reported on a behavioral adherence contract in adult patients who were more than 1 year post renal transplant and being served by a specialty pharmacy.40 All study activities were conducted by a clinical pharmacist who negotiated and administered the contract, and tried to address barriers to adherence and establish goals. Only the intervention group had meetings with the pharmacist to review the contract. The intervention group had higher adherence at 3 months (P = .044) and 12 months (P = .0076). At 1 year, the mean adherence was 89% in the intervention group compared with 79% in the control group (P <.01). Hospitalization rates were lower in the intervention group (23.9% vs 57.3%; P <.001), but other healthcare resource utilization rates were similar. Higher costs were observed in the control group and attributed to hospitalization.40
Another study also evaluated pharmaceutical care to improve medication adherence in patients during the first year after kidney transplantation.41 Interventions in the study were diverse, incorporating educational, behavioral, and technical strategies, and at least three 30-minute sessions were conducted in the hospital. Patients in the intensified care group received individualized interventions that were repeated after discharge by a clinical pharmacist. Patients in the control group received standard education and follow-up. Adherence was measured using pill count, an event monitoring system, drug holiday occurrence, and questionnaires. Daily adherence was significantly higher in the intensified care group (91% vs 75%; P = .014).41 These studies suggest that pharmacists can have a dramatic impact on adherence and patient outcomes.
In addition to the pharmacist-patient interaction, a team approach was evaluated. The previously discussed systematic review of interventions to improve medication adherence after solid organ transplantation found that no single intervention was superior to another to improve adherence, but that a team approach for chronic disease management was more effective and an individualized approach was preferred.26
Multidisciplinary and multi-interventional care has also been studied in managed care and specialty pharmacy settings. Tschida and colleagues reported on a multidisciplinary specialty pharmacy program for oral renal transplant immunosuppressants.42 The 1-year study evaluated implementation of a specialty pharmacy program that included adherence and clinical management programs, patient education, and counseling services provided by transplant pharmacy experts. Via propensity scoring, patients using the specialty pharmacy program (n = 519) were matched to patients using a retail pharmacy (n = 519). Specialty pharmacy patients had lower total healthcare costs ($24,315 vs $27,891, respectively; P = .03), lower transplant-related costs ($5960 vs $8486; P = .04), and lower transplant-related office visit costs ($395 vs $555; P = .04). Weighted MPR, a marker for adherence, was also higher for patients using a specialty pharmacy compared with those using a retail pharmacy (0.87 vs 0.83; P <.0001).42 These results demonstrated the potential of specialty pharmacy to reduce healthcare costs and improve adherence. Managed care may consider these results when contracting for services. The study supported a multidisciplinary, multi-interventional approach to the care of transplant patients, which has been supported by other studies.43-45 These studies,43-45 and others not limited to transplant patients, also emphasized the importance of comprehensive care that focuses on drug therapy problems.46-48 Factors not related to transplantation, such as renal function and hepatitis C infection, can also increase costs dramatically and have benefitted from a multidisciplinary approach to care.46-49
Managed care professionals need to understand and address the reasons for nonadherence. Weng and colleagues, using the Immunosuppression Therapy Adherence Scale [ITAS] (scored 0-12) and barriers to adherence using the Immunosuppressive Therapy Barriers Scale [ITBS] (scored 13-65), examined self-reported adherence in 252 patients who underwent a kidney transplant. Adherence (an ITAS score of 10-12) occurred in 85.7% and nonadherence (an ITAS score ≤9) in 14.3%. After adjusting for sociodemographic data, higher scores on the ITBS were associated with lower scores on ITAS (ie, lower adherence). Significant barriers related to immunosuppressant therapy which increased the ITBS score included:
Additional factors such as reduced renal function and adverse effects increase pill burden in patients receiving numerous medications, and can lead to nonadherence.49 Understanding these factors and individualizing the approach to the patient have the potential to improve adherence.
Author affiliation: Monmouth Medical Center, Long Branch, NJ.
Funding source: This activity is supported by an educational grant from Astellas Scientific and Medical Affairs, Inc.
Author disclosures: Dr Mathis has no relevant commercial financial relationships or affiliations to disclose.
Authorship information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; administrative, technical, or logistic support; and supervision.
Address correspondence to: Smathis@barnabashealth.org.
Solid organ transplantation is associated with improved patient survival and reduced healthcare costs compared with other end-organ-failure treatment modalities. In recent years, however, graft survival has not improved appreciably, despite a reduction in acute rejection episodes. Transplant professionals continue to define the optimal regimen for each transplant and patient type. Managed care practitioners also continue to work toward further reducing costs and improving patient and graft survival. Addressing nonadherence to immunosuppressive agents appears to be a major step to improving long-term graft survival. Addressing generic substitution issues, acting on factors that may affect adherence, and taking an aggressive and multi-interventional approach to improving adherence are expected to produce gains in organ survival and to preserve and maximize the limited supply of organ- and financial-related resources.