1. Tac vs Cyc Non DM Pt Post RTx

2. MY PATIENT 56/F ESRD 2n HTN Day 14 post-RTx DCD Donor
ABOc 4/6 HLA mismatch
PMHx – otherwise unremarkable
PSHx – AV fistula
Meds – standard post-RTx concoction

3. Tacrolimus or cyclosporin Mycophenylate Prednisolone Valganciclovir
Post RTx Concoction
Tacrolimus or cyclosporin
Mycophenylate
Prednisolone
Valganciclovir
Bactrim
Nystatin
QUESTION – WHICH IMMUNOSUPPRESSANT?

4. P I C O Tacrolimus Cyclosporin Graft rejection + loss + others
Recipients post kidney transplant I
Tacrolimus C
Cyclosporin O
Graft rejection + loss + others

5. QUESTION OF TREATMENT
SYSTEMATIC REVIEW

6. # SEARCH TERM RESULT 1 2 3 4 5 6 tacrolimus.mp 54 cyclosporin.mp 81
ciclosporin.mp 19 4
kidney transplant.mp 49 5
2 or 3 90 6
1 and 4 and 5 12
Cochrane Library of SR – search conducted 11/04/10

7. Tacrolimus versus cyclosporin as primary immunosuppression
for kidney transplant recipients (Review)
Webster AC, Taylor RRS, Chapman JR, Craig JC

8. JAMA CRITERIA Are the results of the study valid?
What are the results?
Will the results help me in caring for my patients?

9. How to Appraise a SysRev?
Are the results of the study valid?
What are the results?
Will the results help me in caring for my patients?

10. Address a focused clinical Q?
The objective of this study was to systematically identify and summarise the evidence of transplant outcomes, toxicity and adverse effects when tacrolimus was compared directly with cyclosporin, in the treatment of kidney transplant recipients.
The objective of this study was to systematically identify and summarise the evidence of transplant outcomes, toxicity and adverse effects when tacrolimus was compared directly with cyclosporin, in the treatment of kidney transplant recipients.
P I C O

11. Selection criteria appropriate?
Inclusion criteria
Children and adults – recipients of a first or subsequent cadaveric or living donor renal transplant
Followed any duration
Exclusion criteria
Received another solid organ in addition to kidney transplant
Intervention
Tacrolimus vs cyclosporin (any form)
Any additional immunosuppressive therapies in intervention or control arms
Outcomes
Graft loss, graft rejection, mortality (subtypes), morbidity (infection, malignancy)
Other adverse reactions

12. Selection criteria appropriate?
Inclusion criteria
Children and adults – recipients of a first or subsequent cadaveric or living donor renal transplant
Followed any duration
Exclusion criteria
Received another solid organ in addition to kidney transplant
Intervention
Tacrolimus vs cyclosporin (any form)
Any additional immunosuppressive therapies in intervention or control arms
Outcomes
Graft loss, graft rejection, mortality (subtypes), morbidity (infection, malignancy)
Other adverse reactions

13. Relevant studies missed?
1. Cochrane Renal Group register of RCTs
2. Cochrane RCT CENTRAL
3. MEDLINE (1966 ~ 10/2003)
4. EMBASE (1980 ~ 10/2003)
5. Unpublished studies (Conferences, research groups, pharma)
1984 – tacrolimus/fujimycin/tsukubamycin
1972 – cyclosporin

14. Relevant studies missed?
Thorough search strategy +
Inclusion of foreign & unpublished studies
Publication bias is minimized

15. Validity of Included Studies
Validity assessed by two reviewers
Validity checklist:
Allocation concealment
Intention to treat
Follow up
Adequate blinding
Subjects and outcome assessment
Assessment method is reproducible
Discrepancies resolved by four reviewers

16. Summary of Included Articles
30 trials included
4102 patients
Criteria
# of studies
Randomisation 28
Allocation concealment 4
Intention to treat 12
Blinding

17. No allocation concealment No ITT No blinding Selection bias
Criteria
# of studies
Randomisation 28
Allocation concealment 4
Intention to treat 12
Blinding
No randomisation
No allocation concealment
No ITT
No blinding
Selection bias
Performance bias
Attrition bias
Detection bias

18. How to Appraise a SR? Are the results of the study valid?
What are the results?
Will the results help me in caring for my patients?

19. GRAFT LOSS

20. Graft 3/12
FAVOURS FAVOURS
TACROLIMUS CYCLOSPORIN

21. Graft Loss @ 6/12 Total events: 34 (Tacrolimus), 47 (Cyclosporin)
Heterogeneity: Chi2 = 2.79, df = 6, p = 0.84; I2 =0.0%
Overall effect: Z = 2.66 (P = )

22. Graft Loss @ 12/12 Total events: 99 (Tacrolimus), 99 (Cyclosporin)
Heterogeneity: Chi2 = 11.82; df = 12, p = 0.46; I2 =0.0%
Overall effect: Z = 1.82 (P = 0.068)

23. GRAFT REJECTION

24. Graft Rejection @ 3/12 Total events: 27 (Tacrolimus), 39 (Cyclosporin)
Heterogeneity: Chi2 = 7.99, df = 4, p = 0.09; I2 =50%
Overall effect: Z = 0.12 (P = 0.90)

25. Graft 6/12
Total events: 264 (Tacrolimus), 298 (Cyclosporin)
Heterogeneity: Chi2 = 6.07, df = 9, p = 0.73; I2 =0.0%
Overall effect: Z = 5.70 (P < )

26. Graft 12/12
Heterogeneity: Chi2 = 17.85, df = 13, p = 0.16; I2 =27%
Overall effect: Z = 5.53 (P < )

27. Results Summary Parameter # Studies Tacro Cyclo Risk Ratio 95% CI
P-value I2
G-Loss
@ 3/12 S1
T40 C40
0.14
0.01 ~ 2.68
0.19
N/A
@ 6/12 S7
T891 C661
0.56
0.36 ~ 0.86
0.0079
0.0%
@ 12/12
S14
T1481 C1123
0.77
0.58 ~ 1.02
0.068
G-Reject S5
T110 C138
0.95
0.44 ~ 2.08
0.90
50%
S10
T1028 C750
0.68
0.60 ~ 0.78
<
T1568 C1186
0.69
0.60 ~ 0.79
27%

28. What does it mean?
Graft 6/12 tacrolimus vs cyclosporin = 56% relative risk
At 6 months, patient on tacrolimus is 44% less likely to lose their kidney graft than if s/he were on cyclosporin
Graft 6/12 tacro vs cyclosporin = 68% relative risk
At 6 months, patient on tacrolimus is 32% less likely to suffer from graft rejection than if s/he were on cyclosporin

29. What does it mean?
Graft 6/12 tacrolimus vs cyclosporin = 56% relative risk
At 6 months, patient on tacrolimus is 44% less likely to lose their kidney graft than if s/he were on cyclosporin
Graft 6/12 tacro vs cyclosporin = 68% relative risk
At 6 months, patient on tacrolimus is 32% less likely to suffer from graft rejection than if s/he were on cyclosporin

30. DM @ 12/12 requiring insulin

31. How to Appraise a SR? Are the results of the study valid?
What are the results?
Will the results help me in caring for my patients?

32. Application to Patient
Yes
Directly answered my patient’s clinical question

33. Application to Patient
Yes
Directly answered my patient’s clinical question
Recommendation:
Tacrolimus is superior to cyclosporin as the main immunosuppressant post kidney transplantation

34. Strengths and Weaknesses
Addresses clinical question
Clear methodology
Thorough search strategy
Respectable size
Rigorous statistical analysis
Pooling of cyc data
Lacking long term f/u data

35. Strengths and Weaknesses
Addresses clinical question
Clear methodology
Thorough search strategy
Respectable size
Rigorous statistical analysis
Pooling of cyc data
Lacking long term f/u data

36. Systematic review of RCTs with homogeneity
Level of Evidence 1a
Systematic review of RCTs with homogeneity

37. Unaddressed Questions
Side effects of tacrolimus vs cyclosporin
Quality of Life
Patient preference
Long-term outcomes

38. TAKE HOME MESSAGE

39. Tacrolimus > Cyclosporin
Level 1a evidence
Tacrolimus > Cyclosporin
w.r.t. graft survival and graft rejection post RTx
contraindication of tacrolimus = DM