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Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients

  1. Luit Penninga1,*,
  2. Elisabeth I Penninga2,
  3. Christian H Møller3,
  4. Martin Iversen4,
  5. Daniel A Steinbrüchel3,
  6. Christian Gluud5

Editorial Group: Cochrane Kidney and Transplant Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 10 APR 2013

DOI: 10.1002/14651858.CD008817.pub2


How to Cite

Penninga L, Penninga EI, Møller CH, Iversen M, Steinbrüchel DA, Gluud C. Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD008817. DOI: 10.1002/14651858.CD008817.pub2.

Author Information

  1. 1

    Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Copenhagen, Denmark

  2. 2

    Bispebjerg Hospital, Department of Clinical Pharmacology, Copenhagen, Denmark

  3. 3

    Rigshospitalet, Copenhagen University Hospital, Department of Cardiothoracic Surgery, RT 2152, Copenhagen, Denmark

  4. 4

    Rigshospitalet, Copenhagen University Hospital, Medical Department B-2142, Division of Lung Transplantation, Copenhagen, Denmark

  5. 5

    Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, The Cochrane Hepato-Biliary Group, Copenhagen, Denmark

*Luit Penninga, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. LP@ctu.dk. luitpenninga@hotmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 31 MAY 2013

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Characteristics of included studies [ordered by study ID]
Hachem 2007

Methods
  • Study design: open-label RCT
  • Language: English
  • Type of publication: journal articles and abstracts
  • Year of study: September 2002 to July 2006
  • Judgement of the quality: high risk of bias


Participants
  • Setting: Barnes-Jewish Hospital, St Louis (USA)
  • Number of participants: 90 patients; TAC (44), CSA (46)
  • Sex ratio
    • TAC: 20 (45% males); 24 (55% females)
    • CSA: 25 (54% males); 21 (46% females)
  • Mean age: TAC (50.7 years); CSA (49.7 years)
  • Indication (No.)
    • COPD: TAC (19 (43%)); CSA (21 (46%))
    • Alpha-1 antitrypsin deficiency: TAC (3 (7%)); CSA (5 (11%))
    • Pulmonary fibrosis: TAC (11 (25%)); CSA (3 (7%))
    • Cystic fibrosis: TAC (10 (23%)); CSA (12 (26%))
    • Pulmonary hypertension: TAC (1 (2%)); CSA (2 (4%))
    • Other: TAC (0 (0%)); CSA (3 (6%5))


  • Transplant procedure (No.)
    • Single lung transplantation: TAC (3 (7%)); CSA (3 (7%))
    • Bilateral lung transplantation: TAC (41 (93%)); CSA (43 (93%))


InterventionsTreatment group A

  • TAC target trough level 5 to 15 mg/mL


Treatment group B

  • CSA target trough level 175 to 325 ng/mL
  • Type of CSA: microemulsion (Neoral) or oral solution (Gengraf)


Follow-up: 2.17 ± 0.82 years

Concomitant immunosuppressive treatment

  • Induction: basiliximab 20 mg on day 0 and day 4
  • Maintenance: methylprednisolone (500 mg) and azathioprine (2 mg/kg) intravenously before perfusion of the allograft. All recipients were treated postoperatively with azathioprine at 2 mg/kg daily and methylprednisolone at 0.5 mg/kg twice daily for a total of 6 doses. Thereafter, prednisone was started at 0.5 mg/kg daily and tapered to 15 mg daily by 6 months and 7.5 mg daily by 12 months


OutcomesPrimary outcomes

  • The primary endpoint was defined as a composite of a cumulative acute rejection A score of 3 or higher, a cumulative lymphocytic bronchitis B score of 4 or higher, or the development of bronchiolitis obliterans syndrome stage 0-p. The cumulative acute rejection A score was defined as the sum of all A scores for each subject. Likewise, the cumulative lymphocytic bronchitis B score was defined as the sum of all B scores for each subject, excluding B scores in the setting of a confirmed bacterial or viral respiratory tract infection. Bronchiolitis obliterans syndrome stage 0-p was diagnosed according to the ISHLT definition using only the forced expiratory volume in 1 second (FEV1) criterion (10% decline from baseline).


Secondary outcomes

  • Graft survival, freedom from bronchiolitis obliterans syndrome stage 1, the incidence of bacterial, viral, and fungal infections, hypertension, new-onset diabetes mellitus, and chronic kidney disease


Notes
  • Single centre study
  • Cross-over between treatment groups: no
  • Sample size calculation: yes
  • When subjects met the composite primary end point, sirolimus was substituted for azathioprine, the sirolimus dose was adjusted to target a trough blood level of 5 to 15 ng/mL, the TAC target trough blood level was changed to 4 to 10 ng/mL, and the CSA target trough blood level was changed to 100 to 175 ng/mL.
  • Primary author contacted by e-mail: no reply received
  • Sources of funding: supported by a grant from Astellas Pharma Inc


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated method

Allocation concealment (selection bias)Unclear riskNot clearly reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskPartially blinding as only the pathologists who examined the transbronchial lung biopsy specimens were blinded to the study drug assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe number and reasons for dropouts and withdrawals in all intervention groups were described

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasHigh riskThe study was industry sponsored by Astellas Pharma Inc

Treede 2012

Methods
  • Study design: prospective investigator-driven RCT
  • Language: English
  • Type of publication: journal article and abstracts
  • Judgement of the quality: high risk of bias


Participants
  • Setting: European-Australian transplant centres
  • Number of participants: 249 patients; TAC (124), CSA (125)
  • Sex ratio
    • TAC: 69 (56%) males; 55 (44%) females
    • CSA: 73 (58%) males; 52 (42%) females
  • Mean age ± SD: TAC (46 ± 13 years); CSA (44 ± 13 years)


Indication (No.)

  • Idiopathic pulmonary fibrosis: TAC (22 (18%)); CSA (33 (26%))
  • Emphysema: TAC (39 (31%)); CSA (28 (22%))
  • Cystic fibrosis: TAC (32 (26%)); CSA (30 (24%))
  • Idiopathic pulmonary hypertension: TAC (6 (5%)); CSA (9 (7%))
  • Alpha-1-anti-trypsin deficiency: TAC (7 (6%)); CSA (5 (4%))
  • Other: TAC (18 (15%)); CSA (20 (16%))


Transplant procedure (No.)

  • Single lung transplantation: TAC (32 (26%)); CSA (21 (17%))
  • Bilateral lung transplantation: TAC (86 (69%)); CSA (99 (79%))
  • Heart-lung transplantation: TAC (6 (5%)); CSA (5 (4%))


InterventionsTreatment group A

  • TAC therapy was started immediately after transplantation with a continuous intravenous infusion of 0.01 to 0.03 mg/kg/d
  • After extubation the mode of delivery was switched to oral administration twice daily (0.05 to 0.3 mg/kg/d). Doses were adjusted to trough levels. Target C0 (trough) levels were 10 to 15 ng/mL for the first 3 months after transplantation and 8 to 12 ng/mL thereafter, with dose adjustments according to patient outcome.


Treatment group B

  • CSA therapy was started immediately after transplantation with a continuous intravenous infusion of 1 to 3 mg/kg/d
  • After extubation, delivery was switched to oral administration (2 or 3 times daily at 4 to 18 mg/kg/d). CSA doses were adjusted to C0 or C2 levels according to local practice (C0: trough level before drug intake; C2: trough level 2 hours after drug intake). C0 target trough levels were 200 to 300 ng/mL for the first 3 months after transplantation and 150 to 200 ng/mL thereafter.
  • Type of CSA: microemulsion


Follow-up: 3 years

Concomitant immunosuppressive treatment

  • No induction therapy
  • MMF therapy was also started immediately after surgery with fixed doses of 1 g MMF intravenously or via nasogastric tube twice per day for 2 or 3 days. After extubation, the mode of delivery was switched to oral administration (2 or 3 times daily at 2 to 3 g). Trough level measurements for mycophenolic acid were not mandated by the protocol, but when performed, the doses were adjusted according to mycophenolic acid trough levels targeting a level of 2 to 3 g/mL (EMIT assay; Behring). Centres obtaining mycophenolic acid levels were equally distributed between the two groups. The upper dose limit was 4 g/d. MMF dose adjustment required 3 consecutive out-of-range values or a clinical indication.
  • A 500 mg to 1 g intravenous dose of methylprednisolone was given during the transplant surgical procedure before the start of reperfusion, followed by 3 doses of 125 mg every 8 hours in the intensive care unit. Prednisolone was started on day 1 postoperatively at 0.5 to 1 mg/kg/d (twice daily), then tapered to 0.1 to 0.2 mg/kg/d within the first 3 months. Other steroids were given in prednisolone equivalent doses.


OutcomesPrimary outcomes

  • Incidence of bronchiolitis obliterans syndrome


Secondary outcomes

  • Incidence of acute rejection and infection, survival and adverse events


Notes
  • Multicentre study
  • Switch to other immunosuppressive treatment groups: yes
    • CSA ⇨ Other: 41 patients
    • TAC ⇨ Other: 3 patients
  • Sample size calculation: yes
  • Primary author contacted by email: no reply received
  • Sources of funding: Astellas (TAC) and Roche (MMF)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentralised telephone-based computer randomisation tool

Allocation concealment (selection bias)Unclear riskCentralised telephone-based computer randomisation tool

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskMissing data were addressed, 41 patients randomised to CSA switched to TAC, and 3 patients randomised to TAC switched to CSA

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasHigh riskFunded by Astellas (TAC) and Roche (MMF)

Zuckermann 2003

Methods
  • Study design: prospective, open, two-centre RCT
  • Language: English
  • Type of publication: journal articles and abstracts
  • Year of study/inclusion period: September 1997 to April 1999
  • Judgement of the quality: high risk of bias


Participants
  • Setting: Vienna (Austria), Munich (Germany)
  • Number of participants: 74 patients; TAC (37), CSA (37)
  • Sex ratio
    • TAC: 22 (59%) males; 15 (41%) females
    • CSA: 15 (41%) males; 22 (59%) females
  • Mean age ± SD: TAC (50 ± 10 years); CSA (46 ± 13 years)
  • Indication (No.)
    • Emphysema: TAC (22 (59%)); CSA (15 (41%))
    • Pulmonary fibrosis: TAC (9 (24%)); CSA (12 (32%))
    • Sarcoidosis: TAC (1 (3%)); CSA (0 (0%))
    • Lymphangioleiomyomatosis: TAC (0 (0%)); CSA (1 (3%))
    • Bronchiolitis obliterans syndrome: TAC (0 (0%)); CSA (1 (3%))
    • Pulmonary hypertension: TAC (2 (6%)); CSA (5 (13%))
    • Cystic fibrosis: TAC (3 (8%)); CSA (3 (8%))


Transplant procedure (No.)

  • Single lung transplantation: TAC (16 (43%)); CSA (12 (32%))
  • Bilateral lung transplantation: TAC (21 (57%)); CSA (25 (68%))


InterventionsTreatment group A

  • TAC: started intravenously at a dose of 0.05 mg/kg/d immediately after surgery, and were then switched to oral TAC at a dose of 0.1 to 0.3 mg/kg/d after extubation. Target whole-blood trough levels were 12 to 15 ng/mL (immunofluorescence absorption method)


Intervention B: CSA

  • CSA: started intravenously at a dose of 2 mg/kg/d immediately after surgery, and were then switched to oral CSA at a dose of 3 to 5 mg/kg/d after extubation with target whole blood trough levels of 250 to 300 ng/mL (monospecific, Syva method, Behring assay)
  • Type of CSA: microemulsion


Follow-up: 3 years

Concomitant immunosuppression

  • Induction therapy: rat antithymocyte globulin for the first 3 post-operative days. Prednisolone was started in both groups at a postoperative dose of 0.3 mg/kg/d and tapered to 0.15 mg/kg/d within the first 6 weeks after transplantation. MMF was initiated via a nasogastric tube at a dose of 2 g/d and was switched to oral administration after extubation. Dose adjustments were done in the presence of clinical side effects (e.g. leucopenia or thrombopenia, gastrointestinal symptoms, etc.)


OutcomesPrimary outcomes

  • Freedom from rejection, incidence of rejection episodes/100 patient-days


Secondary outcomes

  • Survival, incidence of infection episodes, adverse events


Notes
  • Two-centre study
  • Cross-over between treatment groups: yes
    • CSA ⇨ TAC: 4 patients
    • TAC ⇨ CSA: 0 patients
  • Sample size calculation: NS
  • Primary author contacted by email: no reply received
  • Sources of funding: NS


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskUnclear, the authors write: randomisation was performed in a 1:1 fashion with regard to a similar distribution of cytomegalovirus mismatches (D+/R-) in both groups

Allocation concealment (selection bias)Unclear riskNS

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen label

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe number and reasons for dropouts and withdrawals in all intervention groups were described

Selective reporting (reporting bias)Low riskAll expected outcomes were reported

Other biasLow riskStudy appears to be free of other bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bhorade 2002Retrospective comparison of three immunosuppressive regimens

Fung 1994Not randomised

Keenan 1995Alternate randomisation; quasi-RCT; study excluded for assessment of benefits. Study was carefully assessed for the incidence and nature of harms.

Kesten 1997Not randomised; the study investigated conversion to TAC from CSA

Kur 1999Not randomised; comparative study: The first 34 patients were treated with CSA, the remaining 28 patients with TAC

Schwaiblmair 2000Not randomised; comparative study

 
Comparison 1. Tacrolimus versus cyclosporin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality3413Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.75, 1.49]

 2 Acute rejection2323Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.77, 1.03]

 3 Acute rejection (episodes/100 patient-days)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Bronchiolitis obliterans syndrome3413Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.29, 0.74]

 5 Infection or sepsis (episodes/100 patient-days)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 7 Treatment withdrawal3413Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.16, 0.46]

 8 Lymphocytic bronchitis score1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 9 Cancer2164Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.04, 1.16]

 10 Kidney failure1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 11 Kidney dysfunction3413Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.93, 2.14]

 12 Creatinine1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 13 Arterial hypertension2164Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.50, 0.89]

 14 New-onset diabetes mellitus2164Risk Ratio (M-H, Random, 95% CI)4.43 [0.75, 26.05]

 15 Hyperlipidaemia1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 16 Neurotoxicity1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Summary of findings for the main comparison. Tacrolimus compared to cyclosporin for lung transplant recipients

Tacrolimus compared to cyclosporin for lung transplant recipients

Patient or population: Lung transplant recipients
Intervention: Tacrolimus
Comparison: Cyclosporin

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

CyclosporinTacrolimus

Mortality
Mortality at latest follow-up
Follow-up: 2.2 to 3 years
Study populationRR 1.06
(0.75 to 1.49)
413 (3)⊕⊕⊝⊝
low1

226 per 1000240 per 1000
(169 to 337)

Moderate

196 per 1000208 per 1000
(147 to 292)

Acute rejection
The number of patients who experienced at least one episode of rejection
Follow-up: mean 3 years
Study populationRR 0.89
(0.77 to 1.05)
323 (2)⊕⊕⊝⊝
low1

728 per 1000648 per 1000
(561 to 765)

Moderate

700 per 1000623 per 1000
(539 to 735)

Bronchiolitis obliterans syndrome
The number of patients diagnosed with the bronchiolitis obliterans syndrome
Follow-up: 2.2 to 3 years
Study populationRR 0.46
(0.29 to 0.74)
413 (3)⊕⊕⊕⊝
moderate1,2

231 per 1000106 per 1000
(67 to 171)

Moderate

208 per 100096 per 1000
(60 to 154)

Infection
The number of overall infections per 100 patient days
Follow-up: mean 1.4 years
The mean infection in the intervention groups was
0.15 lower
(0.3 lower to 0 higher)
74 (1)⊕⊕⊝⊝
low3

Treatment withdrawal
the number of patients stopping the assigned drug intervention
Follow-up: 2.2 to 3 years
260 per 100070 per 1000
(42 to 119)
RR 0.27
(0.16 to 0.46)
413 (3)⊕⊕⊝⊝
low1

Arterial hypertension
Follow-up: 2.2 to 3 years
Study populationRR 0.67
(0.5 to 0.89)
164 (2)⊕⊕⊝⊝
low1

614 per 1000412 per 1000
(307 to 547)

Moderate

599 per 1000401 per 1000
(300 to 533)

Diabetes mellitus
Follow-up: 2.2 to 3 years
Study populationRR 4.24
(1.58 to 11.4)
164 (2)⊕⊕⊝⊝
low1

48 per 1000204 per 1000
(76 to 549)

Moderate

44 per 1000187 per 1000
(70 to 502)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 ¹All included studies were at high risk of bias as assessed using the Cochrane risk of bias tool
²Large and consistent intervention effect in the included studies
³The only included study was assessed as high risk of bias using the Cochrane risk of bias tool