Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Abstract

BACKGROUND Tacrolimus is an established component of immunosuppressive regimens for kidney transplant recipients (KTRs); however, data comparing long-term outcomes between formulations are lacking. We conducted a systematic literature review and network meta-analysis assessing tacrolimus (primarily Advagraf [once-daily] and Prograf [twice-daily])-based maintenance regimens. MATERIAL AND METHODS Embase, MEDLINE, and Cochrane databases and congress proceedings were searched to identify studies of adult de novo KTRs who received tacrolimus-based therapy in phase II/III randomized controlled trials. Outcomes were acute rejection, graft/patient survival, and incidence of new-onset diabetes mellitus after transplantation (NODAT) and cytomegalovirus (CMV) infection. Bayesian network meta-analysis was used to analyze treatment effects on graft/patient survival. RESULTS Sixty-eight publications (61 primary) were included. Of 21 publications reporting graft rejection following Advagraf or Prograf treatment in ≥1 study arm, 12-month biopsy-proven acute rejection (BPAR) ranged from 3.3% with Prograf to 55.0% with mycophenolic acid (MPA)+corticosteroids (CS); >24 month BPAR ranged from 0% to 58.7% (the latter with bleselumab-based therapy). Fourteen publications reported graft loss following Advagraf (0-9.6%) or Prograf (0-7.5%). Patient mortality ≤24 months after transplantation (14 publications) ranged from 0% to 8.1% with Advagraf or Prograf. Advagraf+MPA+CS and reference treatment, Prograf+MPA+CS, were associated with a similar risk of graft loss (odds ratio 1.19; 95% credible-interval 0.51, 3.06) and mortality (odds ratio 1.21; 95% credible-interval 0.1557, 9.03). Incidence of NODAT and CMV varied by treatment arm. CONCLUSIONS Graft loss and patient mortality rates were generally comparable between Advagraf- and Prograf-based regimens. Further prospective studies are needed to evaluate longer-term outcomes.

Figure 1. PRISMA flow diagram

Figure created using PowerPoint for Microsoft 365, Microsoft. EBM – evidence-based medicine; PRISMA – Preferred Reporting Items for Systematic Reviews and Meta-analyses; TAC – tacrolimus.

Figure 2. Risk of bias among the 61 primary studies as a percentage of the total included studies

Risk of bias was assessed based on the recommendations of the Cochrane guide for systematic reviews. Figure created using R 3.6.0, The R Foundation.

Figure 3. Network plot for graft loss at 6 to 12 months

The plot is based on 23 studies (8 studies in which 1 or more of the treatment arms used Advagraf or Prograf, and 15 studies in which the tacrolimus formulation was unknown). Figure created using R 3.6.0, The R Foundation. BID – twice daily; CS – corticosteroids; CsA – cyclosporin; EVR – everolimus; FK778 – manitimus; MPA – mycophenolic acid; QD – once daily; SRL – sirolimus; STN – sotrastaurin; TAC – tacrolimus.

Figure 4. Network plot for mortality rate at 6 to 12 months

The plot is based on 25 studies (7 studies in which 1 or more of the treatment arms used Advagraf or Prograf, and 18 studies in which the tacrolimus formulation was unknown). Figure created using R 3.6.0, The R Foundation. AZA – azathioprine; BEL – belimumab; BID – twice daily; CS – corticosteroids; CsA – cyclosporin; EVR – everolimus; FK778 – manitimus; MPA – mycophenolic acid; QD – once daily; SRL – sirolimus; STN – sotrastaurin; TAC – tacrolimus.

Figure 5. Forest plot for the random-effects model for graft loss (6–12 months) relative to reference treatment with Prograf plus mycophenolic acid plus a corticosteroid

The plot is based on 23 studies (8 studies in which 1 or more of the treatment arms used Advagraf or Prograf, and 15 studies in which the tacrolimus formulation was unknown). Figure created using R 3.6.0, The R Foundation. BID – twice daily; CrI – credible interval; CS – corticosteroids; CsA – cyclosporin; EVR – everolimus; FK778 – manitimus; MPA – mycophenolic acid; QD – once daily; SRL – sirolimus; STN – sotrastaurin; TAC – tacrolimus.

Figure 6. Forest plot for the random-effects model for mortality (6–12 months) relative to reference treatment with Prograf plus mycophenolic acid plus a corticosteroid

The plot is based on 25 studies (7 studies in which 1 or more of the treatment arms used Advagraf or Prograf, and 18 studies in which the tacrolimus formulation was unknown). Figure created using R 3.6.0, The R Foundation. AZA – azathioprine; BEL – belimumab; BID – twice daily; CrI – credible interval; CS – corticosteroids; CsA – cyclosporin; EVR – everolimus; FK778 – manitimus; MPA – mycophenolic acid; QD – once daily; SRL – sirolimus; STN – sotrastaurin; TAC – tacrolimus.