Tac vs Cyc Non DM Pt Post RTx

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

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

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

QUESTION OF TREATMENT SYSTEMATIC REVIEW

# 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

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

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

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?

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

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

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

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

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 Thorough search strategy + Inclusion of foreign & unpublished studies Publication bias is minimized

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

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

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

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?

GRAFT LOSS

Graft Loss @ 3/12 FAVOURS FAVOURS TACROLIMUS CYCLOSPORIN

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 = 0.0079)

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)

GRAFT REJECTION

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)

Graft Rejection @ 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 < 0.00001)

Graft Rejection @ 12/12 Heterogeneity: Chi2 = 17.85, df = 13, p = 0.16; I2 =27% Overall effect: Z = 5.53 (P < 0.00001)

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 < 0.00001 T1568 C1186 0.69 0.60 ~ 0.79 27%

What does it mean? Graft loss @ 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 rejection @ 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

What does it mean? Graft loss @ 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 rejection @ 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

DM @ 12/12 requiring insulin

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?

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

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

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

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

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

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

TAKE HOME MESSAGE

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