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Evidence summaries

Maintenance Immunosuppression for Liver Transplanted Patients

Combination of different maintenance immunosuppressive regimens may be more effective than tacrolimus in liver transplanted patients. Tacrolimus may be superior to cyclosporin oreverolimus in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it may increase the risk of post-transplant diabetes. Level of evidence: "C"

Comment: The quality of evidence is downgraded by suspected publication bias (mostly commercially funded studies) and by imprecise results (wide confidence intervals).

A Cochrane review [Abstract] 2 included 23 studies with a total of 3693 subjects. The vast majority of the participants underwent primary liver transplantation. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis T1.There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. None of the trials reported number of serious adverse events, health-related quality of life, or costs.

Maintenance immunosuppressive interventins compared with tacrolimus for adults undergoing liver transplantation: a network meta-analysis

Mortality at maximal follow-up (follow-up period 6 to 144 months
InterventionAssumed risk - Control- TacrolimusCorresponding risk - Intervention (95% CI)Relative effect(95% CI)No. of participants(trials) Quality of evidence
Direct comparisonIndirect comparisonNetwork meta-analysis (95% CrI)
Cyclosporine A154 per 1000170 per 1000 (86 to 361)157 per 1000 (16 to 2125)173 per 1000 (112 to 278)HR 1.10(0.56 to 2.34)HR 1.02(0.11 to 13.80)HR 1.12 (0.73 to 1.81)1176(8 trials) Very low
Cyclosporine A plus azathioprine154 per 1000202 per 1000 (8 to 4917)172 per 1000 (105 to 290)206 per 1000 (85 to 459)HR 1.31(0.05 to 31.94)HR 1.11(0.68 to 1.89)HR 1.34(0.55 to 2.98)202(2 trials) Very low
Cyclosporine A plus azathioprine plus glucocorticosteroids154 per 1000--1673 per 1000 (53 to 183391)1447 per 1000 (44 to 365629)--HR 10.87 (0.34 to 1191.54)HR 9.40(0.28 to 2375.59)No direct comparison Very low
Cyclosporine A plus glucocorticosteroids154 per 1000--106 per 1000 (37 to 281)107 per 1000 (37 to 292)--HR 0.69 (0.24 to 1.82)HR 0.70(0.24 to 1.90)No direct comparison Very low
Cyclosporine A plus mycophenolate plus glucocorticosteroids154 per 1000--2256 per 1000 (37 to 306010)1695 per 1000 (24 to 496517)--HR 14.66(0.24 to 1988.23)HR 11.01(0.16 to 3226.01)No direct comparison Very low
Everolimus154 per 1000250 per 1000(113 to 615)306 per 1000 (61 to 1447)251 per 1000 (101 to 709)HR 1.62(0.73 to 3.99)HR 1.99(0.40 to 9.40)HR 1.63(0.66 to 4.60)474(1 trial) Very low
Tacrolimus plus azathioprine154 per 100070 per 1000(26 to 177)257 per 1000 (106 to 654)70 per 1000 (18 to 257)HR 0.46(0.17 to 1.15)HR 1.67(0.69 to 4.25)HR 0.46(0.12 to 1.67)97(1 trial) Very low
Tacrolimus plus mycophenolate plus glucocorticosteroids154 per 100089 per 1000(22 to 294)59 per 1000 (8 to 451)81 per 1000 (20 to 287)HR 0.58 (0.14 to 1.91)HR 0.38(0.05 to 2.93)HR 0.53(0.13 to 1.87)195(1 trial) Very low

A Cochrane review [Abstract] 1 included 16 studies with a total of 3813 subjects. At one year, mortality (RR 0.85, 95% CI 0.73 to 0.99) and graft loss (RR 0.73, 95% CI 0.61 to 0.86) were significantly reduced in tacrolimus-treated recipients. Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75 to 0.88), and steroid-resistant rejection (RR 0.54, 95% CI 0.47 to 0.74) in the first year. More new cases of insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid acute rejection and steroid-resistant rejection in nine and seven patients, respectively, and graft loss and death in five and two patients, respectively, but four additional patients would develop diabetes after liver transplantation.

    References

    • Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev 2006 Oct 18;(4):CD005161. [PubMed]
    • Rodríguez-Perálvarez M, Guerrero-Misas M, Thorburn D et al. Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis. Cochrane Database Syst Rev 2017;(3):CD011639.[PubMed]

Primary/Secondary Keywords