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 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 .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.
| Mortality at maximal follow-up (follow-up period 6 to 144 months | ||||||||
|---|---|---|---|---|---|---|---|---|
| Intervention | Assumed risk - Control- Tacrolimus | Corresponding risk - Intervention (95% CI) | Relative effect (95% CI) | No. of participants (trials) Quality of evidence | ||||
| Direct comparison | Indirect comparison | Network meta-analysis (95% CrI) | ||||||
| Cyclosporine A | 154 per 1000 | 170 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 azathioprine | 154 per 1000 | 202 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 glucocorticosteroids | 154 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 glucocorticosteroids | 154 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 glucocorticosteroids | 154 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 |
| Everolimus | 154 per 1000 | 250 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 azathioprine | 154 per 1000 | 70 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 glucocorticosteroids | 154 per 1000 | 89 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 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.