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Meta-Analysis
. 2006 Oct 18;2006(4):CD005161.
doi: 10.1002/14651858.CD005161.pub2.

Cyclosporin versus tacrolimus for liver transplanted patients

E M Haddad  1 , V C McAlister, E Renouf, R Malthaner, M S Kjaer, L L Gluud
Affiliations
Meta-Analysis

Cyclosporin versus tacrolimus for liver transplanted patients

E M Haddad et al. Cochrane Database Syst Rev. .

Abstract

Background: Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection. Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities. The drugs have different pharmacokinetic profiles and potencies. Several randomised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients, but it remains unclear which is superior.

Objectives: To evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients.

Search strategy: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, and conference proceedings were searched (August 2005) to identify relevant randomised clinical trials. Our search included scanning of reference lists in relevant articles and correspondence with investigators and pharmaceutical companies.

Selection criteria: All randomised clinical trials where tacrolimus was compared with cyclosporin for the initial treatment of first-time liver transplant recipients. We included randomised trials irrespective of blinding, language, and publication status.

Data collection and analysis: The primary outcome measure was all-cause mortality. Data were synthesised (fixed-effect model) and results expressed as relative risk (RR), values less than 1.0 favouring tacrolimus, with 95% confidence intervals (CI). Two authors assessed trials for eligibility, quality, and extracted data independently.

Main results: We included 16 randomised trials. The number of deaths was 254 in the tacrolimus group (1899 patients) and 302 in the cyclosporin group (1914 patients). 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. Differences were not seen with respect to lymphoproliferative disorder or de-novo dialysis rates, but more de-novo insulin-requiring diabetes mellitus (RR 1.38, 95% CI 1.01 to 1.86) occurred in the tacrolimus group. More patients were withdrawn from cyclosporin therapy than from tacrolimus (RR 0.57, 95% CI 0.49 to 0.66).

Authors' conclusions: Tacrolimus is superior to cyclosporin in improving survival (patient and graft) and preventing acute rejection after liver transplantation, but it increases the risk of post-transplant diabetes. 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.

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Conflict of interest statement

V McAlister has taken part in clinical trials of tacrolimus and cyclosporin in liver and kidney transplantation. He has received grants‐in‐aid for laboratory research from Sandoz (Novartis) and Fujisawa (Astelis).

Figures

1.1
1.1. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 2 Graft loss.
1.3
1.3. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 3 Acute rejection.
1.4
1.4. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 4 Steroid‐resistent rejection.
1.5
1.5. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 5 Dialysis (de‐novo requirement post‐transplantation).
1.6
1.6. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 6 Creatinine (umol/L) before transplantation.
1.7
1.7. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 7 Creatinine (umol/L) 12 months after transplantation.
1.8
1.8. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 8 Diabetes mellitus: initially diagnosed after transplantation.
1.9
1.9. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 9 Post transplant lymphoproliferative disease.
1.10
1.10. Analysis
Comparison 1 Cyclosporin versus tacrolimus, Outcome 10 Patients withdrawn from tacrolimus or cyclosporin.
2.1
2.1. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 1 Mortality.
2.2
2.2. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 2 Graft loss.
2.3
2.3. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 3 Acute rejection.
2.4
2.4. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 4 Steroid‐resistent rejection.
2.5
2.5. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 5 Dialysis (de‐novo requirement post‐transplantation).
2.6
2.6. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 6 Diabetes mellitus: initially diagnosed after transplantation.
2.7
2.7. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 7 Post transplant lymphoproliferative disease.
2.8
2.8. Analysis
Comparison 2 Stratified analysis, by cyclosporin formulation, Outcome 8 Patients withdrawn from tacrolimus or cyclosporin.
3.1
3.1. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 1 Mortality.
3.2
3.2. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 2 Graft loss.
3.3
3.3. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 3 Acute rejection.
3.4
3.4. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 4 Steroid‐resistent rejection.
3.5
3.5. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 5 Dialysis (de‐novo requirement post‐transplantation).
3.6
3.6. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 6 Diabetes mellitus: initially diagnosed after transplantation.
3.7
3.7. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 7 Post transplant lymphoproliferative disease.
3.8
3.8. Analysis
Comparison 3 Stratified analysis, by inclusion of children, Outcome 8 Patients withdrawn from tacrolimus or cyclosporin.
4.1
4.1. Analysis
Comparison 4 Stratified analysis, by studies reporting 12 month data, Outcome 1 Mortality.
4.2
4.2. Analysis
Comparison 4 Stratified analysis, by studies reporting 12 month data, Outcome 2 Graft loss.
4.3
4.3. Analysis
Comparison 4 Stratified analysis, by studies reporting 12 month data, Outcome 3 Acute rejection.
4.4
4.4. Analysis
Comparison 4 Stratified analysis, by studies reporting 12 month data, Outcome 4 Steroid‐resistent rejection.
4.6
4.6. Analysis
Comparison 4 Stratified analysis, by studies reporting 12 month data, Outcome 6 Diabetes mellitus: initially diagnosed after transplantation.
4.8
4.8. Analysis
Comparison 4 Stratified analysis, by studies reporting 12 month data, Outcome 8 Patients withdrawn from tacrolimus or cyclosporin.
5.1
5.1. Analysis
Comparison 5 Stratified analysis, by studies confined to patients with hepatitis C virus, Outcome 1 Mortality.
5.2
5.2. Analysis
Comparison 5 Stratified analysis, by studies confined to patients with hepatitis C virus, Outcome 2 Graft loss.
5.3
5.3. Analysis
Comparison 5 Stratified analysis, by studies confined to patients with hepatitis C virus, Outcome 3 Acute rejection.
5.4
5.4. Analysis
Comparison 5 Stratified analysis, by studies confined to patients with hepatitis C virus, Outcome 4 Steroid‐resistent rejection.
5.5
5.5. Analysis
Comparison 5 Stratified analysis, by studies confined to patients with hepatitis C virus, Outcome 5 Post transplant lymphoproliferative disease.
5.6
5.6. Analysis
Comparison 5 Stratified analysis, by studies confined to patients with hepatitis C virus, Outcome 6 Patients withdrawn from tacrolimus or cyclosporin.
6.1
6.1. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 1 Mortality.
6.2
6.2. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 2 Graft loss.
6.3
6.3. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 3 Acute rejection.
6.4
6.4. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 4 Steroid‐resistent rejection.
6.5
6.5. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 5 Dialysis (de‐novo requirement post‐transplantation).
6.6
6.6. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 6 Diabetes mellitus: initially diagnosed after transplantation.
6.7
6.7. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 7 Post transplant lymphoproliferative disease.
6.8
6.8. Analysis
Comparison 6 Stratified analysis, by concomitant azathioprine or mycophenolate mofetil, Outcome 8 Patients withdrawn from tacrolimus or cyclosporin.
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Update of

References

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