Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients

Review question

We assessed whether avoiding or withdrawing glucocorticosteroids was better or worse than continuing to use glucocorticosteroids for immunosuppression after liver transplantation.

Background

Glucocorticosteroids are used to prevent rejection of the liver after transplantation by suppressing the immune system. Some centres use glucocorticosteroids indefinitely after liver transplantation whilst others slowly reduce them, and others do not use glucocorticosteroids at all. Glucocorticosteroids have a number of important adverse effects, which may lead to illness and sometimes death in liver transplantation. These adverse effects include diabetes mellitus, high blood pressure, and infection.

With recent developments in immunosuppression, glucocorticosteroids no longer feature as the main immunosuppressant used following transplantation. The use of new immunosuppressant medication may mean that glucocorticosteroids may no longer be necessary after transplantation. Rather than helping to prevent rejection of the liver graft they might cause adverse effects. The benefits of avoiding glucocorticosteroids or withdrawing them after a short while remain unclear.

Study characteristics
We searched for trials comparing glucocorticosteroid avoidance or withdrawal to continuing glucocorticosteroids and we found 16 randomised clinical trials including 1347 participants. All of the studies assessed adults who had received a liver transplant. We found one more trial that was not completed when our review was completed, so it could not be assessed in our review. Of the 16 randomised clinical trials, 10 trials assessed avoidance of glucocorticosteroids compared with slowly reducing glucocorticosteroids (782 participants) and six trials assessed withdrawal of glucocorticosteroids following a slow reduction compared with a longer reduction or long-term use of glucocorticosteroids (565 participants). The evidence is current to September 2014.

Key results
Rejection, severe rejection, and kidney failure may be increased by avoiding or withdrawing glucocorticosteroids compared with continuing glucocorticosteroids. Diabetes mellitus and high blood pressure may be reduced by avoiding or withdrawing glucocorticosteroids compared with continuing glucocorticosteroids. We did not find any difference in survival of the patients, survival of the liver, other adverse effects, or health-related quality of life.

Quality of the evidence

We assessed all of the trials we included as being at high risk of bias, which means that they may overestimate the benefits and underestimate the harms of avoiding or withdrawing glucocorticosteroids. The evidence for glucocorticosteroid avoidance or withdrawal increasing acute rejection was of moderate quality. The evidence for the remainder of the effects was either low quality or very low quality.

Conclusion
There is still some uncertainty about the benefits and harms of avoiding or withdrawing glucocorticosteroids after transplantation. Avoiding or withdrawing glucocorticosteroids appears to increase rejection, severe rejection, and kidney failure but seems to reduce diabetes mellitus and high blood pressure. We found no other obvious benefits or harms of avoiding or withdrawing glucocorticosteroids. More randomised clinical trials are needed to assess avoidance and withdrawal of glucocorticosteroids for liver transplanted patients.

Authors' conclusions: 

Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error.

Read the full abstract...
Background: 

Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects.

Objectives: 

To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation.

Search strategy: 

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded and Social Sciences Citation Index, The Transplant Library, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) until September 2014.

Selection criteria: 

Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver-transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding the perioperative period and excluding the occurrence of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids.

Data collection and analysis: 

We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed. We assessed the risk of systematic errors using risk of bias domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a 'Summary of findings' table.

Main results: 

We included 16 completed randomised clinical trials with a total of 1347 participants. We found 10 trials that assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use and treatment of rejection) versus short-term glucocorticosteroids (782 participants) and six trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). We found one ongoing trial assessing complete postoperative glucocorticosteroid avoidance versus short-term glucocorticosteroids, which is expected to enrol 300 participants. All trials were at high risk of bias. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.16, 95% CI 0.91 to 1.48; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; moderate-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses.

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