Download - Tacrolimus – the ANZDATA perspective
APFN 2002
Tacrolimus – the ANZDATA perspective
(and a bit on rejection too)
Stephen McDonaldANZDATA RegistryAdelaide Australia
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APFN 2002: ANZDATA & Tacrolimus
Availability
Australia - Section 100 No set criteria about availability vs CsATGA 1 Sep 1998 (1 Aug 1997 for liver tx)PBS 1 Jan 2000 (1 Nov 1997 for liver tx)
NZ licensed as “rescue therapy” only
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APFN 2002: ANZDATA & Tacrolimus
Trends in tacrolimus - Australia
375 495388
372 268
3 653
134 104
0%
20%
40%
60%
80%
100%
1997 1998 1999 2000 2001 (9months)
TacNo tac
Use of tacrolimus at initial treatment for all grafts performed in Australia, 1997-2001. 2001 data to end September only. Multiple grafts excluded.
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APFN 2002: ANZDATA & Tacrolimus
Trends in tacrolimus – New Zealand
89 104 109 102 66
0 0 1 1 0
0%
20%
40%
60%
80%
100%
1997 1998 1999 2000 2001
TacNo Tac
Use of tacrolimus at initial treatment for all grafts performed in New Zealand, 1997-2001. 2001 data to end September only.Multiple organ grafts excluded.
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APFN 2002: ANZDATA & Tacrolimus
Regional variation – tacrolimus
Immunosuppressive drugs at initial treatment all grafts, 2000-9/2001. Multiple organ grafts excluded.
166 177 14896
44
168
76 57
30
22
53
1
0
50
100
150
200
250
300
NSW Vic Qld SA WA NZ
Transplant location
Num
ber o
f gra
fts
Tac
No Tac
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APFN 2002: ANZDATA & Tacrolimus
Tacrolimus use by age & gender
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
5- 15- 25- 35- 45- 55- 65-
Age (years)
Pro
po
rtio
n
P=0.1
Immunosuppressive drugs at initial treatment, all grafts, Australia 2000-9/2001. Multiple organ grafts excluded.
No variation with genderSome variation with age, but no clear trend
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APFN 2002: ANZDATA & Tacrolimus
Tacrolimus by graft type
37139
218
12
11923
80
16
0%
20%
40%
60%
80%
100%
CD1 CD2+ LD1 LD2+
Graft type
Tac
No Tac
Immunosuppressive drugs at initial treatment all grafts, 2000-9/2001, Australia only, multiple grafts excluded
P=0.03 P=0.001
P=0.4 P=0.08
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APFN 2002: ANZDATA & Tacrolimus
Multiple grafts
Organ No tacrol Tacrolimus Total
Kidney only 640 238 878 Heart-kidney 2 0 2
p<0.001
Pancreas-kidney 16 25 41 p<0.001
Total 658 263 921
Immunosuppressive drugs at initial treatment multiple grafts, 2000-9/2001, Australia only
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APFN 2002: ANZDATA & Tacrolimus
Patterns of tacrolimus at baselineNo tac (n=640) tac (n=238)
Male 403 (63%) 140 (59%)Subsequent grafts 51 (8%) 39 (16%) p<0.01
Live donor 230 (36%) 96 (40%)Max PRA > 50% 87 (14%) 43 (18%) p=0.13
Current PRA >50% 41 (6%) 14 (6%)Diabetes type 1 20 (3%) 10 (4%)Diabetes type 2 49 (7%) 6 (3%), p=0.006
Cor. artery Dis 71 (11%) 15 (6%) p=0.03
Immunosuppressive drugs at initial treatment, all grafts, Australia 2000-9/2001
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APFN 2002: ANZDATA & Tacrolimus
Tacrolimus usage at baselineTacrolimus usage from time of transplantation
62 people (24%) over 2000/2001 received tacrolimus & sirolimus at baseline – presumed RAPATACDiabetes type 2 association was independent of age, gender and graft type
• adjusted OR 0.33 [0.14-0.78], p=0.01
Among first grafts, did not differ between CD (24%) and LD (27%), p=0.4Among subsequent grafts, tended to be more common in LD (57%) than CD (37%), p=0.08
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APFN 2002: ANZDATA & Tacrolimus
Tacrolimus over time
Analysis complicated by rapidly changing patterns at baseline
For Australian grafts, 2000-6/2001 (with at least 3 months follow-up, multiple grafts excluded, n=712)• 199 (28%) taking tac at 0 months• 266 (37%) taking tac at 3 months
– Includes 180 who were taking at baseline and 86 conversions (17% of non-tac at baseline)
– 19 (10%) ceased tac between 0 and 3 months
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APFN 2002: ANZDATA & Tacrolimus
Graft rejection in ANZDATA
Since 1/4/97, episodes of rejection in first 6 months post graft collected
To date (30/9/01), 1429 episodes in 970 grafts• 2770 grafts performed over this time• Crude rejection rate 35%
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APFN 2002: ANZDATA & Tacrolimus
Graft rejection in ANZDATA
1185 (83%) rejection episodes biopsy proven, increasing over time
0%
20%
40%
60%
80%
100%
1997 1998 1999 2000 2001
Biopsy
No biopsy
Proportion of rejection episodes proven by biopsy, first rejection episodes only, 1997-2001
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APFN 2002: ANZDATA & Tacrolimus
Classification of rejection
N = 1181
Cellular Vascular
Glomerular
3
201 64 716
78
22
72 25
(90 %) (31 %)
(17 %)
(0 %)
17 % 5 % 61 %
7 %
2 %
6 % 2 %
Venn diagram, biopsy proven rejection by type, 1997-2001
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APFN 2002: ANZDATA & Tacrolimus
When does rejection occur?
Rejection-free survival, grafts performed 14/9/7-30/9/01 (multiple grafts excluded)
CD1 vs LD1, p=0.006CD2 vs LD2, p=0.5
Kaplan-Meier survival estimates, by graft type
Days post transplant
0 50 100 150 200
1
.8
.6CD2+
LD2+
CD1
LD1
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APFN 2002: ANZDATA & Tacrolimus
Demography of rejection
Proportion of primary grafts performed 14/9/7-30/9/01 with at least one episode of rejection, by age category. Australia + NZ.
Un
ad
just
ed
Pro
ba
bili
ties
an
d 9
5%
CI
Age (years)5- 15- 25- 35- 45- 55- 65-
.2
.3
.4
.5
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APFN 2002: ANZDATA & Tacrolimus
Rejection and genderO
R [9
5% C
I]
Graft typeCD1 CD2+ LD1 LD2+
.25
.5
1
2
4
Odds ratio of rejection in first 6 months and male gender, by type of grafts. All grafts 1/4/1997-9/2001, Australia + NZ. M-H heterogeneity p=0.09
Overall OR for male gender1.3 [1.1-1.6], p=0.006
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APFN 2002: ANZDATA & Tacrolimus
HLA mismatches
Rejection free survival among CD1, by number of HLA mismatches, Australian & NZ grafts 1/4/97-30/9/01
CD1 only, by HLA mismatch
Days post transplant0 50 100 150 200
1
.8
.6
01
2
3
4
5
6
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APFN 2002: ANZDATA & Tacrolimus
PRA and rejection
Rejection in primary grafts, by number maximum PRA, Australian & NZ grafts 1/4/97-30/9/01. Observed points and locally weighted line.
Running mean smoother, bandwidth = .8
Rej
ectio
n in
firs
t 6 m
onth
s
Maximum PRA0 25 50 75 100
0
.25
.5
.75
1
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APFN 2002: ANZDATA & Tacrolimus
Rejection and tacrolimus
Any rejection in first 6 months
Graft Tacrolimus No Tacrolimus
CD1 41/150 (27%) 330/1073 (31%)LD1 40/102 (39%) 218/610 (36%)CD2+ 12/29 (41%) 65/170 (38%)LD2+ 8/19 (42%) 20/45
(44%) Proportion of grafts with at least one rejection episode in first 6 months, Australia, 1/4/97-30/9/01. All differences are statistically insignificant
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APFN 2002: ANZDATA & Tacrolimus
Rejection free survivalKaplan-Meier survival estimates, by tac0m
Days0 50 100 150 200
0.00
0.25
0.50
0.75
1.00
No tacrolimus at bas
Tacrolimus from base
Rejection-free survival,Australia, 14/9/7-30/9/01. All differences are statistically insignificant
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APFN 2002: ANZDATA & Tacrolimus
Vascular rejection307 people had an episode of vascular rejection
12% of all grafts 1997-2001
Is there a relationship of vascular rejection with tacrolimus use?
Confusing picture across different graft types
Graft OR (Vasc rejection / tac0m)CD1 0.48 [0.21-0.95], p=0.04LD1 1.5 [0.75-2.7], p=0.2CD2+ 1.1 [0.35-3.2], p=0.8LD2+ 0.22 [0.005-1.9], p=0.14
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APFN 2002: ANZDATA & Tacrolimus
Demography of rejectionThe occurrence of at least one episode of rejection in first 6 months in this data set
is associated with• Graft type• Male gender• Age• HLA mismatches
is not associated with• Cold ischaemic time in CD, CMV or EBV status of recipient• PRA once stratified by graft type• Use of tacrolimus at baseline
– Except less vascular rejection in CD1
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APFN 2002: ANZDATA & Tacrolimus
Multivariate predictors of rejection free survival
Multivariate analysis, tacrolimus and rejection
Adjustment using Cox model for age category, gender, PRA, live donor, subsequent graft, cold ischaemic timeAdjusted HR 1.0 [0.85-1.3], p=0.7
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APFN 2002: ANZDATA & Tacrolimus
Treatment of rejection
1050 (73%) treated initially with steroids
189 (13% treated with steroids and antibody
Introduction or increase in dose of tacrolimus in 191 (13%) cases
Resolution to baseline in 62%
11735
10
1712
Return to pre-rejection
Resolution, but creatinine not to baseline
Resolution, no improvement, creat<250
Resolution, no improvement, creat>250
No resolution - graft loss in < 1 month
Outcome of rejection episodes 1997-2001 where tacrolimus used as part of Rx
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APFN 2002: ANZDATA & Tacrolimus
Calculated GFR (mean [95% CI]) at 6months for kidney transplants in Australia, 1/4/97-30/9/01 by type of graft
Calculated GFR at 6 months
Graft type
P=0.5 P<0.0001
Una
djus
ted
Mea
ns a
nd 9
5% C
ILe
vey
4 po
int G
FR
, ml/m
in/1
.73m
2
CD2+ LD2+ CD1 LD1
45
50
55
60
65
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APFN 2002: ANZDATA & Tacrolimus
Calculated GFR at 6 months
Calculated GFR (mean [95% CI]) at 6months for primary kidney transplants in Australia, 1/4/97-30/9/01 by type of graft and use of tacrolimus. Similar differences apply when serum creatinine alone used.
P=0.8 P=0.03
Una
djus
ted
Mea
ns a
nd 9
5% C
I
Leve
y 4
poin
t GF
R, m
l/min
/1.7
3m2
CD, no tac CD+Tac LD, no tac LD + tac
40
50
60
70
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APFN 2002: ANZDATA & Tacrolimus
Graft survival-first grafts
No tacrolimus at baseline (n=1683)
Tacrolimus from baseline (n=252)
Graft survival of primary kidney transplants in Australia, 1/4/97-30/9/01 by use of tacrolimus at baseline
P=0.3
Graft survival by tacrolimus at baseline, adjusted for LD / CD
0 10 20 30 40
1
.9
.8
Months
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APFN 2002: ANZDATA & Tacrolimus
Graft survival-subsequent Graft survival by tacrolimus t0, subsequent graftsadjusted for livedonor
Months0 10 20 30 40
1
.9
.8
.7
No tacrolimus at baseline, n = 215
Tacrolimus from baseline, n = 48
Graft survival of subsequent kidney transplants in Australia, 1/4/97-30/9/01 by use of tacrolimus at baseline, adjusted for CD/LD
P=0.8
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APFN 2002: ANZDATA & Tacrolimus
Tacrolimus and graft survival
Multivariate analysisAdjustment using Cox model for age category, gender, PRA, live donor, subsequent graft, cold ischaemic time, year of transplantationAdjusted HR 0.79 [0.47-1.31], p=0.36
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APFN 2002: ANZDATA & Tacrolimus
Summary
Immunosuppressive drug usage is rapidly changing, especially for tacrolimusRapidly increasing use of tacrolimus driven by several factors
AvailabilityTrial useThese factors are difficult to include in models, and may well have affected observations
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APFN 2002: ANZDATA & Tacrolimus
Summary
OutcomesRejection
• Overall rejection rate & associations comparable with expectations
No clear evidence of difference associated with use of tacrolimus at baseline
– Possibly less vascular rejection in CD1– Unknown why people were Rx tacrolimus instead of
CsA– Trials– Local factors (variation between states)
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APFN 2002: ANZDATA & Tacrolimus
Outcomes-renal function
Renal function Calculated GFR at 6 months used, to maximise data inclusion• Grafts 1/4/97 to 30/3/01 available
Renal function at 6 monthsNo convincing trends associated with use of tacrolimus from time of transplantation
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APFN 2002: ANZDATA & Tacrolimus
Outcomes- graft survival
Graft lossTrend towards lower rates of graft loss in tacrolimus treated groupStatistically insignificant• especially once multivariate analysis
performedGraft survival
Analysis of graft failure and patient deaths limited because of short follow-up time available -> poor power
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APFN 2002: ANZDATA & Tacrolimus
ANZDATA Registry
These slides, and other presentations, are posted on the ANZDATA web site www.anzdata.org.au
General or specific data enquiries about this or other matters are welcomed
WWW-based data entry coming soon…
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APFN 2002: ANZDATA & Tacrolimus
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APFN 2002: ANZDATA & Tacrolimus
Spare slides
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APFN 2002: ANZDATA & Tacrolimus
Structure
Epidemiology of tacrolimus useWho, where, when
Associations of tacrolimus use with outcome
tacrolimus use from baseline• Rejection rates• Renal function
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APFN 2002: ANZDATA & Tacrolimus
Trends in sirolimus - Australia
344404
402 492315
3497
39 1457
0%
20%
40%
60%
80%
100%
1997 1998 1999 2000 2001
SiroimusNo sirolimus
Use of sirolimus at initial treatment for all grafts performed in Australia, 1997-2001. 2001 data to end September only. Multiple grafts excluded.
40
APFN 2002: ANZDATA & Tacrolimus
Trends in mycophenolate - Australia
183179
11856
112
195322
323450
260
0%
20%
40%
60%
80%
100%
1997 1998 1999 2000 2001
MycophenolateNo mycophenolate
Use of mycophenolate at initial treatment for all grafts performed in Australia, 1997-2001. 2001 data to end September only. Multiple grafts excluded.
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APFN 2002: ANZDATA & Tacrolimus
Regional variation – tacrolimus
Australia270135
27
No TacTac
Immunosuppressive drugs at initial treatment all grafts, 2000-9/2001
NZ
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APFN 2002: ANZDATA & Tacrolimus
Tacrolimus use by age & gender
0
50
100
150
200
250
300
0- 5 to14
15-24
25-34
35-44
45-54
55-64
65+
Tac
No tac
No variation with genderTrend towards less common use in younger, very old recipients, p=0.2
Less significant when adjusted for diabetes type 2 (p=0.5)
Immunosuppressive drugs at initial treatment, all grafts, Australia 2000-9/2001
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APFN 2002: ANZDATA & Tacrolimus
Trends in immunosuppression
0%
20%
40%
60%
80%
100%
1993 1994 1995 1996 1997 1998 1999 2000
Sirolimus trial
Tacrolimus combo
Cya / MMF
Cya / Aza
Cya / MMF / Pred
Cya / Aza /Pred
Immunosuppressive drugs at initial treatment for primary cadaver grafts, 1993-2000
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APFN 2002: ANZDATA & Tacrolimus
Do some centres do more biopsies?
Proportion of first rejection episodes proven by biopsy, 1997-2001
Pro
por
tion
of f
irst
reje
ctio
n e
piso
des
prov
en b
y bi
opsy
Tx centres, ordered by size
0
.5
1
Overall ANZ average
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APFN 2002: ANZDATA & Tacrolimus
Use of biopsy to prove rejection
174 46 13 6 2
2
0
796 255 92 31 9
2
1
0%
20%
40%
60%
80%
100%
1 2 3 4 5 6 7
Rejection episode number
Biopsy
No biopsy
Proportion of rejection episodes proven by biopsy, 1997-2001
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APFN 2002: ANZDATA & Tacrolimus
Prevalence of rejection by state
Proportion of grafts performed 14/9/7-30/9/01 with at least one episode of rejection, by state of transplanting unit
Una
djus
ted
Pro
babi
litie
s an
d 95
% C
I
NSW Vic Qld SA WA NZ.2
.3
.4
.5
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APFN 2002: ANZDATA & Tacrolimus
Graft outcomes
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APFN 2002: ANZDATA & Tacrolimus
Is Rejection associated with poorer transplant outcome?
Survivor functions, by rej6adjusted for livedonor subsequent
Months0 20 40 60
1
.9
.8
.7
rej6 0
rej6 1
Graft survival of kidney transplants in Australia & NZ, 1/4/97-30/9/01 by occurrence of any rejection in first 6 months, adjusted to CD1
Adjusted for donor & graft number: HR 1.7 [1.4-2.1], p<0.001
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APFN 2002: ANZDATA & Tacrolimus
Calculated GFR at 6 months Kaplan-Meier survival estimates, by gfrcat
Months6 12 24 36 48 60
1
.9
.8
.7
0-
40-
50-
60-
Graft survival for kidney transplants in Australia 1997-2001 by calculated GFR at 6 months. Categories are quartiles (approximately) of GFR
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APFN 2002: ANZDATA & Tacrolimus
Creatinine at 6 monthsKaplan-Meier survival estimates, by creat category
Months0 6 12 24 36 48 60
1
.9
.8
.7
0-99
100-129
130-159
>160
Graft survival for kidney transplants in Australia 1997-2001 by creatinine at 6 months. Categories are quartiles (approximately) of creatinine
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APFN 2002: ANZDATA & Tacrolimus
Rejection rates over timeR
eje
ctio
n in
fir
st 6
mo
nth
s
year of Tx1997 1998 1999 2000 2001
.1
.2
.3
.4
.5
Proportion of rejection episodes proven by biopsy, first rejection episodes only, 1997-2001