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Original Nomination

Draft Key Questions:
These questions were available for public comment from Mar. 6–26, 2014

Comparative Effectiveness of Calcineurin Inhibitor Monitoring and Treatment for Renal Transplantation

Draft Key Questions

Question 1
Monitoring assays for calcineurin inhibitors (CNIs)
  1. Mass Spectrometry versus Immunoassay: In renal transplants, for therapeutic monitoring of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus, how does mass spectrometric analysis compare with immunoassay analysis for health outcomes?
  2. Sensitivity of monitoring for low dose CNIs: Are analytical capabilities sufficient to measure CNIs in the lower ranges that multidrug protocols are targeting?
Question 2
Cyclosporine monitoring timepoints: C2 versus CT: In renal transplants, how does 2-hour post administration cyclosporine monitoring (C2) compare with trough monitoring (CT) for health outcomes?
Question 3
CNI minimization versus CNI conventional regimens: In renal transplants, is CNI minimization effective compared with conventional CNI regimens:
  1. Does the type of induction agent (including when no induction is used) impact outcomes?
  2. Do the outcomes vary with different protocols (i.e., timing)?
  3. What are the outcomes when minimization is used due to complications compared to when it is planned?
Question 4
CNI minimization strategies compared with each other: In renal transplants, what is the effectiveness of specific CNI minimization strategies compared with any other CNI minimization strategies:
  1. Does the type of induction agent (including when no induction is used) impact outcomes?
  2. Do the outcomes vary with different protocols (i.e., timing)?
  3. What are the outcomes when minimization is used due to complications compared to when it is planned?
Question 5
General Comments

Draft Analytic Framework

The analytic framework defines the population of interest (adult patients receiving renal transplantation) and the impact of monitoring (Key Questions 1 and 2) on health outcomes (both harms and benefits); mortality, organ survival, acute rejection, chronic allograft injury, nephrotoxicity, resource utilization, re-hospitalization, and quality of life). Additionally, the analytic framework illustrates how decisions about use of conventional therapy (Key Question 3), maintenance decisions regarding minimization therapy (Key Question 4) impact these same health outcomes.

Background

There are over 15,000 kidney transplants each year in the United States, mostly occurring in people between the ages of 35 and 65,1 at a cost of approximately $263,000 each.2 Approximately 164,200 adults were surviving with a functioning kidney allograft in the United States in 2011,2 with estimated yearly immunosuppression costs around $8,000 each.3 The cost of kidney graft failure was estimated as $138,000 per patient during the first year in 2004.4

Calcineurin inhibitors (CNIs) are part of immunosuppressive therapy for transplant patients. Cyclosporine and tacrolimus are considered CNIs and have a similar mechanism of action. Cyclosporine was first studied as an immunosuppressive agent in solid organ transplant recipients in 1980 and its efficacy led to U.S. Food and Drug Administration approval in 1983. Tacrolimus was first approved for use by the FDA in 1994 for liver transplant recipients and subsequently in 1997 for kidney transplant recipients. While very effective, CNIs have a narrow therapeutic window between efficacy and toxicity, thereby requiring monitoring of drug levels. Clinically important dose dependent toxicities with CNIs include hypertension and renal dysfunction. Early outcomes after kidney transplantation (up to a year post-transplant) have improved dramatically in the last two decades but late outcomes (beyond 1 year) remain stagnant and relatively poor. Poor long term outcomes are a result of chronic allograft injury and its various phenotypes, including nephrotoxicity from immunosuppressive agents. Ironically, CNIs are responsible for the improvement in early outcomes following kidney transplantation, but also are nephrotoxic and therefore responsible for long-term kidney graft loss. There are currently two broad approaches to reducing exposure to toxic levels of CNIs, while preserving their efficacy for immunosuppression: (i) more precise monitoring techniques and (ii) minimization strategies.

(i) CNI therapeutic monitoring

There are several commercial assays available to monitor CNI drug levels, including mass spectrometry and immunoassay, but it is not clear if either offer enough of an improvement in control of drug levels to translate into an improvement in patient outcomes (KQ1). In addition to type of assay used, the time point of drug monitoring may also affect control of drug levels. Tacrolimus is the predominant calcineurin inhibitor in the United States, and it has become standard to perform trough monitoring of its drug levels. Trough cyclosporine levels (CT) became the standard for adjusting dosing of the medication, and many transplant centers continue to use trough levels to adjust dosing in recipients. However, further study has demonstrated cyclosporine exposure during the first 4 hours after dosing (4-hour area under the curve) to be more predictive of efficacy and to allow for a lower quantity of medication to be used, resulting in less toxicity. A more convenient single 2 hour peak post dose cyclosporine level (C2) has been shown to be a good predictor of the 4-hour area under the curve. It is not clear whether this two hour or the current standard of trough monitoring results in better health outcomes (KQ2). Objective endpoints for examining monitoring effectiveness include graft and patient survival, renal function, side effect profile, adherence to regimen, and cost. In addition, calcineurin inhibitor dose minimization strategies (discussed below) have raised the question of whether standard immunoassays and mass spectrometry/high-performance liquid chromatography are sensitive enough to detect and quantitate the lower doses of these agents now being used (KQ1b).

(ii) Calcineurin inhibitor dose minimization

CNI-minimization protocols seek to reduce the amount of drug to which the patient is exposed. Since metabolism of CNI varies by patient, reduction refers not only to lower doses of the drug, but also to lower monitored serum concentration, either at trough or at peak level. The risk with reduced exposure to CNI is an increased risk of acute rejection, given that CNI treatment is one of the mainstays of immunosuppression. Two proposed approaches to compensate for the lower CNI dose are (1) to use a strong induction agent, such as anti-thymocyte globulin (ATG), daclizumab, basiliximab, or alemtuzumab, and/or (2) to replace the CNI with an agent of a different mechanism (such as sirolimus). Therefore throughout treatment, clinicians and patients have to decide whether to use a conventional CNI regimen or a CNI minimization strategy (KQ3) and, if opting for a minimization strategy, which combination of drugs and timing will provide the best outcome for that patient (KQ4).

Any comparison of treatments also needs to take into account other factors. During the pre and/or peri-operative period, the physician will make a decision about whether to use an induction agent, and if so, which type to use. This decision will impact subsequent levels of CNI and outcomes and is thus included as subgroup analysis within the key questions to be addressed in this review (i.e., KQ3a, KQ4a). Decisions about maintenance therapy are made immediately post-operatively and up to 3 months post-surgery, when the patient is typically managed by a surgeon, and 3 to 12 months post-surgery when the management typically shifts to a nephrologist. After 3 months, type of maintenance therapy (conventional versus minimization) and goal drug levels may be adjusted; however, the timing and level of this change varies across transplant center practices (KQ3b, KQ4b). Patients may also switch to CNI minimization regimens during this period due to complications from conventional regimens rather than according to a planned protocol, which may also affect outcomes (KQ3c, KQ4c).Other factors that are considered in the decisions, and impact outcomes, are patient-level factors such as age and immunosuppressive responsivity, and donor characteristics such as live versus deceased. These factors will be important to consider and are listed in the PICOTS elements of the questions.

Need for Evidence Review

The search for Key Question 1 identified 55 articles. There are no reviews that address Key Question 1, we identified 14 observational studies from this search that address immunoassay versus mass spectrometry. Of these, it appears that only one study reports on clinical outcomes.

Of the four applicable systematic reviews and meta-analyses potentially relevant to for KQ2, two focus on the intervention and outcomes of graft loss and optimized immunosuppression. These reviews were published in 2007 and 2002 respectively. Upon preliminary scan we were not able to identify any RCTs that applied to this Key Question but found six observational studies that addressed clinical outcomes of interest. Based on these results we believe that a systematic review will be most beneficial in identifying gaps in the literature.

Key Questions 3 and 4 have been addressed by one meta-analysis each; however, some of these meta-analyses focus on limited sets of outcomes. Due to these differences and the complexity of this proposed review, we are not proposing updating any of the existing reviews that apply to Key Questions 3 or 4. Results of preliminary screening estimate at least 50 applicable RCTs and not more than 39 observational studies addressing these two key questions.

Relevance to Policy and Decision-Making

This topic is relevant for decision makers and is of importance given the societal burden of renal transplantation and immunosuppressive medications, and the medical cost of such treatments to individuals and society.

This review will be of value to those making health care decisions including health care providers taking care of patients who anticipate or have undergone renal transplantation, including internists, nurse practitioners, nephrologists, transplant specialists, immunologists, and pharmacists. Patients and patient advocates will find this review of value when making decisions about treatment options.

Preliminary PICOTS (Patients, Interventions, Comparators, Outcomes, Timing, Setting)

PICOTS for CNI monitoring: Key Questions 1 and 2

Populations
  • Adult patients undergoing renal transplantation
  • Subgroups of interest include patients with demographic and clinical factors
    • Age, race/ethnicity, diabetes mellitus, cause of end stage renal disease, live or deceased donor
Intervention(s)
  • Immunoassay (KQ1)
  • CNI monitoring timepoints: C2 (KQ2)
Comparator(s)
  • Mass spectrometry (KQ1)
  • CNI monitoring timepoints: CT (peak or trough) (KQ2)
Outcomes
  • Mortality (Patient survival)
  • Organ survival (Graft survival)
  • Acute rejection
    • Cellular rejection
    • Antibody mediated rejection
  • Chronic allograft injury
    • Chronic allograft nephropathy
    • Chronic transplant glomerulopathy
    • Interstitial fibrosis and tubular atrophy (IFTA)
  • Nephrotoxicity
    • Creatinine
    • Estimated glomerular filtration rate (GFR)
    • Slope or change in GFR
  • Resource utilization
  • Re-hospitalization
  • Quality of life
Timing of Outcome Assessment
  • Early defined as1 year after transplant
  • Later defined as beyond one year
    • 3 years
    • 5 years
    • 10 years and greater than 10 years
Setting

Outpatients

PICOTS for CNI Management Strategies: Key Questions 3 and 4

Populations
  • Adult patients undergoing renal transplantation
  • Subgroups of interest include patients with demographic and clinical factors
    • Age, race/ethnicity, diabetes mellitus, cause of end stage renal disease, live or deceased donor
Intervention(s)
  • Conventional CNI dosing regimen (KQ3)
  • Minimization strategies: low dose, withdrawal, avoidance, replacement (i.e. sirolimus), or conversion from conventional (KQ4)
Comparator(s)
  • Minimization strategy (KQ3)
    • Comparison by type of induction agent (no induction agent, antithymocyte globulin, alemtuzumab, basiliximab, daclizumab)
    • Comparison at time of maintenance
    • Comparison by planned vs response to complications
  • Any other minimization strategy: low dose, withdrawal, avoidance, replacement, or conversion from conventional (KQ4)
    • Comparison by type of induction agent (no induction agent, antithymocyte globulin, alemtuzumab, basiliximab, daclizumab)
    • Comparison at time of maintenance
    • Comparison by planned vs response to complications
    • Comparison of early (ie. induction) versus late (ie. maintenance) minimization of CNI
Outcomes
  • Mortality (Patient survival)
  • Organ survival (Graft survival)
  • Acute rejection
    • Cellular rejection
    • Antibody mediated rejection
  • Chronic allograft injury
    • Chronic allograft nephropathy
    • Chronic transplant glomerulopathy
    • Interstitial fibrosis and tubular atrophy (IFTA)
  • Nephrotoxicity
    • Creatinine
    • Estimated glomerular filtration rate (GFR)
    • Slope or change in GFR
  • Resource utilization
  • Re-hospitalization
  • Quality of life
Timing of Outcome Assessment
  • Early defined as1 year after transplant
  • Later defined as beyond one year
    • 3 years
    • 5 years
    • 10 years and greater than 10 years
Setting

Outpatients

Definition of Terms

Acute rejection: Acute rejection is characterized by a decline in kidney function accompanied by diagnostic features on kidney allograft biopsy; when unaccompanied by symptoms these are subclinical. Acute rejections are either cellular rejections (T-cell–mediated) or antibody-mediated rejections (caused by a circulating, anti-HLA, donor-specificantibody.)5

Chronic allograft injury: Chronic allograft injury is characterized by the progressive reduction in graft function not due to recurrence of disease or other recognized causes. It is defined by interstitial fibrosis and tubular atrophy, and may also include subclinical rejection, transplant glomerulopathy, or transplant vasculopathy.7

Minimization therapy: Minimization of calcineurin inhibitors involves decreasing the drug to achieve a lower target drug level. This may be avoidance of the agent entirely (at the time of induction therapy), withdrawal of the agent (after a period of prior use), or achievement of a lower target level. A low-dose tacrolimus is defined as C0 of 5 (3–7) ng/m, and low dose CsA is defined as achieving C0 of 75 (50–100) ng/mL7

Conventional (standard) therapy: Standard-dose tacrolimus may be defined as the dose achieving 12-h trough levels (C0) of 10 (5–15) ng/mL. Standard-dose CsA may be defined as the dose achieving C0 of 200 (150–300) ng/mL or C2 1400–1800 ng/mL early and 800–1200 ng/mL later after transplantation.7

Resource utilization: long-term direct medical costs and health care utilization for patients

References

  1. Organ Procurement and Transplantation Network, OPTN. U.S. Department of Health and Human Services; Accessed 2/21/2013 [cited 2013 October 17]. Available at: http://optn.transplant.hrsa.gov/latestData/rptData.asp.
  2. Transplant Living. [cited 2013 October 17]. Available at: http://www.transplantliving.org/before-the-transplant/financing-a-transplant/the-costs/Exit Disclaimer
  3. Page TF, Woodward RS. Cost of lifetime immunosuppression coverage for kidney transplant recipients. Health Care Financ Rev. 2008;30(2):95-104.
  4. Yen EF, Hardinger K, Brennan DC, et al. Cost-effectiveness of extending Medicare coverage of immunosuppressive medications to the life of a kidney transplant. Am J Transplant. 2004;4(10):1703-8.
  5. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155.