Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta‐analysis

Abstract Background & Aims Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term “pre‐withdrawal time”. To clarify the impact of pre‐withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta‐analysis. Methods We systematically interrogated the literature for LT recipient ISW studies reporting pre‐withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre‐withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time‐response curves were calculated using random‐effects meta‐analyses. Results We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study‐level risk of bias was heterogeneous. Mean pre‐withdrawal time was greater by 427 days [95% confidence interval (CI) 67–788] in OT compared to non‐OT patients. This increase was potentiated to 799 days (95% CI 369–1229) or 1074 days (95% CI 685–1463) when restricting analysis to adult or European study participants. In time‐response meta‐analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4–10%) per year after LT (GRADE low‐ and moderate‐certainty of evidence, respectively). Conclusions Our data support the impact of pre‐withdrawal time in ISW decision‐making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995.