Journal Club February 24th 2008

Christos Argyropoulos

Opelz et al. Long term prospective study of steroid withdrawal in

Kidney and Heart Transplantation. American Journal of

Transplantation 5:720-728, 2006

Background for the study

• Steroids are associated with significant morbidity at the doses/regimens

• Prospective randomized trials of steroid minimization have yielded conflicting results and are plagued by small, very diverse populations

• In meta-analyses of these trials it appears that the incidence of Acute Rejection (AR) is increased and long-term outcomes may not be favourable in terms of graft survival

• CTS initiated a prospective evaluation (case/control design) in 1994 to explore the long term safety of steroid withdrawal.

General Study Design

• Enrolled patients from 30 kidney and 13 heart centers that participate in the CTS (400 centers in 45 countries, very few in the US)

• Enrollment period: 1994-2002 (majority of patients between 1994-1997)

• Participating centers were required to follow local IRB regulations

• No mention of whether patients provided informed consent or not

Enrollment Criteria for Patients

• Inclusion Criteria:1. Serum Creatinine <3 mg/dl (Kidney) or 2.26 mg/dl

(Heart)

2. “Good” graft function for >6 mos post and >3 months preceding enrollment

• Exclusion Criteria:– PRA > 80%– Previous vascular (?AMR) or steroid resistant

rejection– “Rapid” (?) rejection of a previous graft

Control Group• Each patient was matched to 3 controls by:

1. Donor/Recipient Age2. Race3. Year of Transplant4. First/retransplant status5. Cause of ESRD6. Cold Ischemia Time7. Continent8. # of HLA mismatches9. % of PRA10. Duration since current transplantation date

Controls were NOT matched for level of renal function (were required to have SCr < 1.5 mg/dl!)

Controls were NOT matched for the occurrence of treated AR prior to enrollment.

Controls for heart were required to have had a clinical outcome evaluation of “excellent – on minimal immunosuppression” defined by individual centers

Intervention Protocol I

• Left to the individual Centers: only requirement to be steroid free within 6 months after patient was enrolled

• Usually stepwise – could he halted if allograft function deteriorated

• In case of AR, each center was allowed to follow their own protocol, but steroid withdrawal was only allowed after 3 mos of stable allograft function post treatment

Intervention Protocol II

• Monitoring of renal function: – Every 15 days during weaning (recommended, not

mandated)– Monthly thereafter

• Whole blood CSA level : 150-250 ng/ml during conversion and three months afterwards

• Patient and Graft Survival: Assessed 6 months after enrollment and yearly thereafter

• Only patients with full data in the CTS database were analyzed.

Primary Outcome Measures

1. Patient Survival (PO1)

2. Graft Survival (PO2)

3. Death Censored Graft Survival (“functional graft survival”) (PO3)

4. Rates of impaired renal function & AR episodes (defined by need for treatment, not by protocol biopsies)

Secondary Outcome Measures

• Incidence of steroid related complications: osteoporosis, osteonecrosis, cataracts

• HTN defined as SBP > 150 mmHg or initiation of new antihypertensive medications

• Hypercholesterolemia (TC > 300mg/dl)• Assessment of SOs was not specified in

the protocol but was left to the discretion of the clinical center

Statistical Methods

• Kaplan – Meier curves• KM curves were compared by the log-rank test

(emphasizes late differences in survival curves) with p=0.05 significant

• Outcomes Analyzed by KM curves: – Patient Survival– Graft survival – Discrete Creatinine Outcome: > 1.5 mg/dl– First AR episode– Re-instatement of steroids

Results I

• 1110 Kidney allograft recipients (61 retransplants)

• 450 Cardiac Allograft recipients• 16% of patients had SCr> 1.5 mg/dl vs 0%

controls (exclusion criterion)• Median time from transplantation to initiation of

weaning: 1.1 yrs in K, 1.4 yrs in hearts• Mean f/u: 5 yrs (K), 6.3 (H)• 94% of patients were on CsA regimens

Results II

Results III• 81.3 ± 1.7% (K), 76.9 ±

2.3% (H)• 87.0 ± 2.5% (CsA) 86.2

± 1.8% (CsA/Aza) 89.8 ± 3.1% (CsA/MMF)

• Stratified Analyses of Survival for time between transplantation and withdrawal (<1 vs >1), pre-withdrawal rejection episodes : NS

Results IV

Pts 81.9±1.8% 88.8±1.5% 91.8±1.3%

Cntrls 75.3±1.2% 84.3±1.0% 87.9±1.0%

p 0.0001 0.0016 0.0091

“Although only patients with matching controls were included in this analysis, graft survival was virtually identical to that obtained with the series as a whole”

Results V

Cumulative Incidence of Discrete Creatinine Outcome:

37.3 ± 1.9 % (patients) vs 35.1 ± 1.0% (controls), p –value 0.45 (all patients)

33.6 ± 2.6% (patients) vs 50.4 ± 3.0% (controls), p-value < 0.0001 (patients who never required steroids after weaning)

Results VI

Cumulative Incidence of Acure Rejection Outcome :

8.6 ± 1.1 % (patients) vs 10.2 ± 0.7% (controls), p –value 0.21 (Kidney)

35.3 ± 2.8% (patients) vs 30.6 ± 2.3% (controls), p-value 0.15 (Heart)

Results VIICumulative Incidence of Steroid Use at 5 years: 41.4 ± 1.5 % (K) and 55.7 ± 2.5% (H)

Statin Use at 5 years: 51.3 (patients) and 59.6 (controls)

Results VIII

Cumulative Incidence of Osteoporosis : • 13.6 ± 2.4 % (patients) vs 24.3 ± 1.9% (controls), p –value 0.002Cumulative Incidence of Cataracts :• 7.2 ± 1.8% (patients) vs 13.6 ± 1.5% (controls), p-value 0.009Cumulative Incidence of Osteonecrosis : No difference

Summary & Conclusions

• Steroid withdrawal after the first 6 months leads to superior patient and graft outcomes at 7 years

• The cumulative incidence of specific steroid – related complications may be reduced

• No impact on AR rates

Strengths & Limitations

• Caucasians• Immunologically low risk patients• Selection of the control group• Handling of missingness (? What is the true

denominator)• Definitions of outcomes (especially the

creatinine) and enrollment criteria• No standardized steroid withdrawal protocol• “ITT” analysis without “AT” limits the ability to

draw conclusions about the safety and the effectiveness of the protocol

Vincenti et al. A Randomized, Multicenter Study of Steroid

Avoidance, Early Steroid Withdrawal or Standard Steroid Therapy in Kidney Transplant Recipients.

American Journal of Transplantation 8:307-316, 2008

Background for the study

• Steroids are associated with significant morbidity at the doses/regimens

• Introduction of MMF based combination regimens and antibody induction protocols implies that earlier trials of steroid “minimization” (Aza regimens/no Ab induction) are not as relevant today.

• Open label RCT of steroid avoidance/freedom (SF) v.s. steroid withdrawal (SW) v.s. conventional steroids (CS)

General Study Design

• 12 month, open label multi-center RCT enrolled patients in 40 transplant centers in 9 countries (including the US)

• Randomization 1:1:1 to the three arms

• Participating centers were required to follow local IRB regulations

• Patients provided informed consent

Enrollment Criteria for Patients

• Inclusion Criteria: Patients between 18-75 y/o who received a

de novo non HLA identical, kidney allograft

• Exclusion Criteria: Marginal donor (>60 y/o, NHBD) Previous transplant of any kind PRA > 20% Cold Ischemia Time > 24hr

Intervention Protocol I

• Three treatment arms:– SF: no IV or oral steroids– SW: Solumedrol tapered down as 500mg

(D1), 250mg (D2), 125mg (D3) switched to prednisolone as 60mg (D4) ->20 mg (D7)

– CS: Solumedrol tapered down as 500mg (D1), 250mg (D2), 125mg (D3) switched to prednisolone as 60mg (D4) ->20 mg (D7). Then prednisolone was given as: 10-30mg (M1) -> 10-20 mg (M2) -> 5-10 mg thereafter

Intervention Protocol II

• Additional Immuno-suppression :– Neoral 10mg/kgr/day within 24hrs post TxP,

adjusted to achieve the C2 target by day 3.– C2 targets for Neoral:

• 1700 (1500 – 2000 ng/ml) during M1• 1500 (1300 – 1700 ng/ml) during M2• 1300 (1100 – 1500 ng/ml) during M3• 1100 ( 900 – 1300 ng/ml) during M4-6• 900 ( 800 – 1000 ng/ml) after M6

Intervention Protocol III• Additional Immuno-suppression :

– Myfortic 720-1440 pre transplant, followed by 720 mg po bid indefinitely

– Basiliximab (Simulect) 20 mg IV D1 and D4

• Acute Rejection Regimen:– SM 500-1000mg/d x 1-3 d– Conversion to CS was recommended for

patients who rejected on SF/SW arms

• OI prophylaxis:– PCP left to centers– CMV > 3 mos (except (-) to (-) )

Outcome Measures

1. eGFR at 12 months by the Nankivelli formula (PO1)

2. Composite outcome of death, graft loss OR Biopsy Proven AR (BPAR) at M3 and M12 (SO1)

3. Cumulative incidence of patient and graft survival at M12 (SO2)

4. Cumulative incidence of BPAR at M3 and M12 (SO3)

5. % of pts steroid free at M12 (SO4)

Safety Outcome Measures

• Incidence of steroid related complications: HTN, absolute lipid levels (LDL-C, HDL, TC), blood sugar levels

• Osteoporosis inferred from BMD measured at 2 anatomic sites and expressed as % change from baseline (M3-M8) relative to M12

• % Change in proximal femur BMD from baseline to M12

Evaluation

• Baseline, D1,3,5,8 W2, M1,3,6,9,12 : CBC, BMP, UA, HbA1c, VS, “adverse events”, “serious adverse events”

• GFR calculations : Used the Nankivelli except for dead patients or patients who have lost their grafts in whom the GFR was set to zero

• “Observed – case analyses” : excluded patients who have died or were back on RRT

• Staging of suspected rejection episodes used the Banf97 classification system

Statistical Methods• ITT population : all patients who were randomized, received a

kidney transplant and a single dose of Myfortic• Safety population: all patients who have received at least one dose

of Myfortic and had undergone one safety evaluation• Interim analysis: M3 to assess SO1-3• Study was powered at 80% level to detect non-inferiority in eGFR

(assuming a sd of 15 ml/min for the eGFR in the CS arm• Non-inferiority outcome: ΔeGFR ≤ 7ml/min/1.73 m2 BSA• Study was powered to detect a 3% ΔBMD on lumbar spine by a t-

test assuming a sd of 5.745%• Kaplan – Meier curves were used to assess discrete outcomes• KM curves were compared by the log-rank test (emphasizes late

differences in survival curves) with p=0.05 significant• Comparison of eGFR among groups used the Wilcoxon rank sum

test• Multiple comparisons adjustment for the interim analysis used the

Benjamini-Hochberg procedure

Results I

Delayed Graft Function: 26 (SF), 26 (SW), 23 (CS)

Results II

Results III

• At 12 months: 65 (89%) of the SF and 82 (71%) of the patients randomized to SW were steroid free. 13 pts (12%) in the CS were steroid free in violation of the protocol.

• Among the patients receiving steroids at M12 the mean dose were 11.5 ± 11.3 (SF), 12.6 ± 10.7 (SW) and 7.1 ± 4.2 (CS)

• There was no difference in mean Myfortic dose or need to reduce the dose

Results IV

Non – inferiority could not be demonstrated in the ITT analysis

In the observed case analysis, the primary non-inferiority point was met

for the SF and SW arms

Results V

Results VI• BPAR occurred significantly

earlier in the SF (p=0.003) and the SW group (p =0.03)

• CO1@M3 : SF group (n=31, 27.9% p=0.002) , SW (n=25, 21.7%, p=0.032) versus the CS (n =12, 11%)

• BPAR@M3: SF (n=28, 25.2%, p<0.001) , SW (n=21, 18.3%, p=0.017) versus the SF (n=8, 7.3%)

Results VII

•Significantly fewer biopsies were performed in the CS (n=130) versus the SF (n=189) and SW groups (n=209), p <0.001

•The median number of days to first BPAR was: 14 (SF), 53 (SW) and 104 (CS) p=0.003 and 0.022 respectively

•In the SF group (but not the others) BPAR rejections in the first months were associated with low C2 levels: 15/60 (C2 <1500ng/ml) vs 3/40 (C2>1500ng/ml)

Results VIII

Summary & Conclusions

• The authors conclusions: – Steroid withdrawal and steroid free ISP are non-

inferior to CS in terms of the primary outcome of the study (“observed-case analysis”)

– AR rates were increased relative to CS protocols but these rejections were mild and unlikely to impair long term outcomes

– Statistical significant reductions in steroid related metabolic effects were observed when steroid exposure was limited

Strengths & Limitations

• Extremely well designed study with a well specified immunosuppression management protocol

• Immunologically low risk patients• Crossovers between the SF/SW and CS arms• Open label study which introduced biases in the

rate of biopsies (?protocol biopsies as a remedy)• “ITT” analysis with “AT” allows one to draw

meaningful conclusions about the safety and the effectiveness of the protocol