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Meta-Analysis
. 2013 May 31;2013(5):CD008817.
doi: 10.1002/14651858.CD008817.pub2.

Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients

Luit Penninga  1 , Elisabeth I Penninga, Christian H Møller, Martin Iversen, Daniel A Steinbrüchel, Christian Gluud
Affiliations
Meta-Analysis

Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients

Luit Penninga et al. Cochrane Database Syst Rev. .

Abstract

Background: Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects.

Objectives: To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients.

Search methods: We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013.

Selection criteria: We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study.

Data collection and analysis: Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance).

Main results: We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures.

Authors' conclusions: Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Trial sequential analysis of the effect of tacrolimus versus cyclosporin on mortality based on three studies (n = 413). The required information size of 2436 patients was calculated based on an observed mortality of 23% in the cyclosporin group in the meta‐analysis (Pc); a relative risk reduction (RRR) of 20 % in the tacrolimus group; a type I error (α) of 5%; a type II error (β) of 20%, and the observed heterogeneity in the meta‐analysis (I² = 0%)
4
4
Trial sequential analysis of the effect of tacrolimus versus cyclosporin on bronchiolitis obliterans syndrome based on three studies (n = 413). The required information size of 2436 patients was calculated based on an observed bronchiolitis obliterans syndrome incidence of 23% in the cyclosporin group in the meta‐analysis (Pc); a relative risk reduction (RRR) of 20 % in the tacrolimus group; a type I error (α) of 5%; a type II error (β) of 20%, and the observed heterogeneity in the meta‐analysis (I² = 0%)
5
5
Trial sequential analysis of the effect of tacrolimus versus cyclosporin on acute rejection based on two studies (n = 323). The required information size of 332 patients was calculated based on an observed acute rejection incidence of 73% in the cyclosporin group in the meta‐analysis (Pc); a relative risk reduction (RRR) of 20 % in the tacrolimus group; a type I error (α) of 5%; a type II error (β) of 20%, and the observed heterogeneity in the meta‐analysis (I² = 0%)
6
6
Trial sequential analysis of the effect of tacrolimus versus cyclosporin on acute rejection based on two studies (n = 323). The required information size of 332 patients was calculated based on an observed acute rejection incidence of 73% in the cyclosporin group in the meta‐analysis (Pc); a relative risk reduction (RRR) of 15% in the tacrolimus group; a type I error (α) of 5%; a type II error (β) of 20%, and the observed heterogeneity in the meta‐analysis (I² = 0%)
1.1
1.1. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 2 Acute rejection.
1.3
1.3. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 3 Acute rejection (episodes/100 patient‐days).
1.4
1.4. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 4 Bronchiolitis obliterans syndrome.
1.5
1.5. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 5 Infection or sepsis (episodes/100 patient‐days).
1.6
1.6. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 6 Adverse events.
1.7
1.7. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 7 Treatment withdrawal.
1.8
1.8. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 8 Lymphocytic bronchitis score.
1.9
1.9. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 9 Cancer.
1.10
1.10. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 10 Kidney failure.
1.11
1.11. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 11 Kidney dysfunction.
1.12
1.12. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 12 Creatinine.
1.13
1.13. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 13 Arterial hypertension.
1.14
1.14. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 14 New‐onset diabetes mellitus.
1.15
1.15. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 15 Hyperlipidaemia.
1.16
1.16. Analysis
Comparison 1 Tacrolimus versus cyclosporin, Outcome 16 Neurotoxicity.
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Update of

References

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