APFN 2002
Tacrolimus – the ANZDATA
perspective
(and a bit on rejection too)
Stephen McDonald
ANZDATA Registry
Adelaide Australia
APFN 2002: ANZDATA & Tacrolimus
Availability
Australia - Section 100
No set criteria about availability vs CsA
TGA 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
2
APFN 2002: ANZDATA & Tacrolimus
Trends in tacrolimus - Australia
100%
3
6
53
80%
134
104
60%
375
495
40%
388
Tac
No tac
372
268
2000
2001 (9
months)
20%
0%
1997
1998
1999
Use of tacrolimus at initial treatment for all grafts performed in Australia, 19972001. 2001 data to end September only. Multiple grafts excluded.
3
APFN 2002: ANZDATA & Tacrolimus
Trends in tacrolimus – New Zealand
100%
0
0
1
1
0
89
104
109
102
66
1997
1998
1999
2000
2001
80%
60%
40%
Tac
No Tac
20%
0%
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.4
APFN 2002: ANZDATA & Tacrolimus
Regional variation – tacrolimus
Number of grafts
300
Tac
250
200
No Tac
76
57
100
1
30
150
166
177
22
148
50
96
53
168
44
0
NSW
Vic
Qld
SA
WA
NZ
Transplant location
Immunosuppressive drugs at initial treatment all grafts, 2000-9/2001. Multiple
organ grafts excluded.
5
APFN 2002: ANZDATA & Tacrolimus
Tacrolimus use by age & gender
P=0.1
0.4
0.35
0.3
Proportion
No variation with
gender
Some variation with
age, but no clear
trend
0.45
0.25
0.2
0.15
0.1
0.05
0
5-
15-
25-
35-
45-
55-
65-
Age (years)
Immunosuppressive drugs at initial treatment, all grafts, Australia 2000-9/2001.
6
Multiple organ grafts excluded.
APFN 2002: ANZDATA & Tacrolimus
Tacrolimus by graft type
P=0.08
P=0.4
P=0.03
P=0.001
100%
119
23
80%
80
16
60%
40%
Tac
No Tac
371
39
218
12
20%
0%
CD1
CD2+
LD1
LD2+
Graft type
Immunosuppressive drugs at initial treatment all grafts, 2000-9/2001, Australia
only, multiple grafts excluded
7
APFN 2002: ANZDATA & Tacrolimus
Multiple grafts
Organ
No tacrol
Tacrolimus
Total
Kidney only
Heart-kidney
Pancreas-kidney
Total
640
2
16
658
238
0
25
263
878
2 p<0.001
41 p<0.001
921
Immunosuppressive drugs at initial treatment multiple grafts, 2000-9/2001,
Australia only
8
APFN 2002: ANZDATA & Tacrolimus
Patterns of tacrolimus at baseline
No tac (n=640)
Male
403 (63%)
Subsequent grafts 51 (8%)
Live donor
230 (36%)
Max PRA > 50%
87 (14%)
Current PRA >50% 41 (6%)
Diabetes type 1
20 (3%)
Diabetes type 2
49 (7%)
Cor. artery Dis
71 (11%)
tac (n=238)
140 (59%)
39 (16%)
p<0.01
96 (40%)
43 (18%)
p=0.13
14 (6%)
10 (4%)
6 (3%),
p=0.006
15 (6%)
p=0.03
Immunosuppressive drugs at initial treatment, all grafts, Australia 2000-9/2001
9
APFN 2002: ANZDATA & Tacrolimus
Tacrolimus usage at baseline
Tacrolimus usage from time of transplantation
62 people (24%) over 2000/2001 received tacrolimus &
sirolimus at baseline – presumed RAPATAC
Diabetes 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=0.4
Among subsequent grafts, tended to be more common in LD
(57%) than CD (37%), p=0.08
10
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
11
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%
12
APFN 2002: ANZDATA & Tacrolimus
Graft rejection in ANZDATA
1185 (83%) rejection episodes biopsy
proven, increasing over time
100%
80%
60%
Biopsy
No biopsy
40%
20%
0%
1997
1998
1999
2000
2001
Proportion of rejection episodes proven by biopsy, first rejection episodes only,
1997-2001
13
APFN 2002: ANZDATA & Tacrolimus
Classification of rejection
N = 1181
Glomerular
(17 %)
22
2%
72
25
6%
2%
78
7%
716
201
64
61 %
17 %
5%
Vascular
Cellular
(90 %)
(31 %)
3
(0 %)
Venn diagram, biopsy proven rejection by type, 1997-2001
14
APFN 2002: ANZDATA & Tacrolimus
When does rejection occur?
Kaplan-Meier survival estimates, by graft type
1
CD1 vs LD1, p=0.006
CD2 vs LD2, p=0.5
.8
CD1
LD1
CD2+
.6
LD2+
0
50
100
150
200
Days post transplant
Rejection-free survival, grafts performed 14/9/7-30/9/01 (multiple grafts excluded)
15
APFN 2002: ANZDATA & Tacrolimus
Unadjusted Probabilities and 95% CI
Demography of rejection
.5
.4
.3
.2
5-
15-
25-
35Age (years)
45-
55-
65-
Proportion of primary grafts performed 14/9/7-30/9/01 with at least one episode of
16
rejection, by age category. Australia + NZ.
APFN 2002: ANZDATA & Tacrolimus
Rejection and gender
4
OR [95% CI]
2
1
.5
Overall OR for male gender
1.3 [1.1-1.6], p=0.006
.25
CD1
CD2+
Graft type
LD1
LD2+
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
17
APFN 2002: ANZDATA & Tacrolimus
HLA mismatches
CD1 only, by HLA mismatch
1
1
.8
0
2
3
5
4
.6
6
0
50
100
150
Days post transplant
200
Rejection free survival among CD1, by number of HLA mismatches, Australian &
18
NZ grafts 1/4/97-30/9/01
APFN 2002: ANZDATA & Tacrolimus
PRA and rejection
Running mean smoother, bandwidth = .8
Rejection in first 6 months
1
.75
.5
.25
0
0
25
50
Maximum PRA
75
100
Rejection in primary grafts, by number maximum PRA, Australian & NZ grafts
1/4/97-30/9/01. Observed points and locally weighted line.
19
APFN 2002: ANZDATA & Tacrolimus
Rejection and tacrolimus
Any rejection in first 6 months
Graft
Tacrolimus
No Tacrolimus
CD1
LD1
CD2+
LD2+
41/150 (27%)
40/102 (39%)
12/29 (41%)
8/19 (42%)
330/1073
218/610
65/170
20/45
(31%)
(36%)
(38%)
(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
20
APFN 2002: ANZDATA & Tacrolimus
Rejection free survival
Kaplan-Meier survival estimates, by tac0m
1.00
0.75
No tacrolimus at bas
Tacrolimus from base
0.50
0.25
0.00
0
50
100
Days
150
200
Rejection-free survival,Australia, 14/9/7-30/9/01. All differences are statistically
insignificant
21
APFN 2002: ANZDATA & Tacrolimus
Vascular rejection
307 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
LD1
CD2+
LD2+
0.48 [0.21-0.95],
1.5 [0.75-2.7],
1.1 [0.35-3.2],
0.22 [0.005-1.9],
p=0.04
p=0.2
p=0.8
p=0.14
22
APFN 2002: ANZDATA & Tacrolimus
Demography of rejection
The 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
23
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 time
Adjusted HR 1.0 [0.85-1.3], p=0.7
24
APFN 2002: ANZDATA & Tacrolimus
Treatment of rejection
12
1050 (73%) treated
initially with steroids
17
10
189 (13% treated with
steroids and antibody
Introduction or increase
in dose of tacrolimus in
191 (13%) cases
Resolution to baseline in
62%
35
117
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 25
APFN 2002: ANZDATA & Tacrolimus
Calculated GFR at 6 months
Unadjusted Means and 95% CI
Levey 4 point GFR, ml/min/1.73m2
P=0.5
P<0.0001
65
60
55
50
45
CD2+
LD2+
CD1
LD1
Graft type
Calculated GFR (mean [95% CI]) at 6months for kidney transplants in Australia,
26
1/4/97-30/9/01 by type of graft
APFN 2002: ANZDATA & Tacrolimus
Calculated GFR at 6 months
P=0.8
P=0.03
Unadjusted Means and 95% CI
Levey 4 point GFR, ml/min/1.73m2
70
60
50
40
CD, no tac
CD+Tac
LD, no tac
LD + tac
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.
27
APFN 2002: ANZDATA & Tacrolimus
Graft survival-first grafts
Graft survival by tacrolimus at baseline, adjusted for LD / CD
1
Tacrolimus from
baseline (n=252)
P=0.3
.9
No tacrolimus at
baseline (n=1683)
.8
0
10
20
30
40
Months
Graft survival of primary kidney transplants in Australia, 1/4/97-30/9/01 by use of
28
tacrolimus at baseline
APFN 2002: ANZDATA & Tacrolimus
Graft survival-subsequent
Graft survival by tacrolimus t0, subsequent grafts
adjusted for livedonor
1
.9
No tacrolimus at
baseline, n = 215
P=0.8
.8
Tacrolimus from baseline, n = 48
.7
0
10
20
Months
30
40
Graft survival of subsequent kidney transplants in Australia, 1/4/97-30/9/01 by
use of tacrolimus at baseline, adjusted for CD/LD
29
APFN 2002: ANZDATA & Tacrolimus
Tacrolimus and graft survival
Multivariate analysis
Adjustment using Cox model for age
category, gender, PRA, live donor,
subsequent graft, cold ischaemic time, year
of transplantation
Adjusted HR 0.79 [0.47-1.31], p=0.36
30
APFN 2002: ANZDATA & Tacrolimus
Summary
Immunosuppressive drug usage is rapidly
changing, especially for tacrolimus
Rapidly increasing use of tacrolimus driven by
several factors
Availability
Trial use
These factors are difficult to include in models,
and may well have affected observations
31
APFN 2002: ANZDATA & Tacrolimus
Summary
Outcomes
Rejection
• 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)
32
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 months
No convincing trends associated with use
of tacrolimus from time of transplantation
33
APFN 2002: ANZDATA & Tacrolimus
Outcomes- graft survival
Graft loss
Trend towards lower rates of graft loss in
tacrolimus treated group
Statistically insignificant
• especially once multivariate analysis
performedGraft survival
Analysis of graft failure and patient
deaths limited because of short followup time available -> poor power
34
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…
35
APFN 2002: ANZDATA & Tacrolimus
36
APFN 2002: ANZDATA & Tacrolimus
Spare slides
37
APFN 2002: ANZDATA & Tacrolimus
Structure
Epidemiology of tacrolimus use
Who, where, when
Associations of tacrolimus use with
outcome
tacrolimus use from baseline
• Rejection rates
• Renal function
38
APFN 2002: ANZDATA & Tacrolimus
Trends in sirolimus - Australia
100%
34
97
39
14
402
492
1999
2000
57
80%
60%
40%
344
404
315
Siroimus
No sirolimus
20%
0%
1997
1998
2001
Use of sirolimus at initial treatment for all grafts performed in Australia, 19972001. 2001 data to end September only. Multiple grafts excluded.
39
APFN 2002: ANZDATA & Tacrolimus
Trends in mycophenolate Australia
100%
80%
195
322
60%
260
323
450
Mycophenolate
No mycophenolate
40%
20%
183
179
112
118
56
0%
1997
1998
1999
2000
2001
Use of mycophenolate 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
Regional variation – tacrolimus
NZ
Australia
270
135
27
No Tac
Tac
Immunosuppressive drugs at initial treatment all grafts, 2000-9/2001
41
APFN 2002: ANZDATA & Tacrolimus
Tacrolimus use by age & gender
No variation with
gender
Trend towards less
common use in
younger, very old
recipients, p=0.2
Less significant when
adjusted for diabetes
type 2 (p=0.5)
300
250
Tac
No tac
200
150
100
50
0
0-
5 to 15- 25- 35- 45- 55- 65+
14 24 34 44 54 64
Immunosuppressive drugs at initial treatment, all grafts, Australia 2000-9/2001
42
APFN 2002: ANZDATA & Tacrolimus
Trends in immunosuppression
100%
80%
Sirolimus trial
Tacrolimus combo
Cya / MMF
Cya / Aza
Cya / MMF / Pred
Cya / Aza /Pred
60%
40%
20%
0%
1993 1994 1995 1996 1997 1998 1999 2000
Immunosuppressive drugs at initial treatment for primary cadaver grafts, 19932000
43
APFN 2002: ANZDATA & Tacrolimus
Proportion of first rejection episodes
proven by biopsy
Do some centres do more biopsies?
1
Overall ANZ average
.5
0
Tx centres, ordered by size
Proportion of first rejection episodes proven by biopsy, 1997-2001
44
APFN 2002: ANZDATA & Tacrolimus
Use of biopsy to prove rejection
100%
Biopsy
No biopsy
80%
60%
796
255
92
2
31
9
1
40%
2
20%
174
0%
1
46
13
6
2
3
4
2
0
5
6
7
Rejection episode number
Proportion of rejection episodes proven by biopsy, 1997-2001
45
APFN 2002: ANZDATA & Tacrolimus
Prevalence of rejection by state
Unadjusted Probabilities and 95% CI
.5
.4
.3
.2
NSW
Vic
Qld
SA
WA
NZ
Proportion of grafts performed 14/9/7-30/9/01 with at least one episode of
rejection, by state of transplanting unit
46
APFN 2002: ANZDATA & Tacrolimus
Graft outcomes
47
APFN 2002: ANZDATA & Tacrolimus
Is Rejection associated with
poorer transplant outcome?
Survivor functions, by rej6
adjusted for livedonor subsequent
1
Adjusted for donor
& graft number:
HR 1.7 [1.4-2.1],
p<0.001
rej6 0
.9
.8
rej6 1
.7
0
20
Months
40
60
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
48
APFN 2002: ANZDATA & Tacrolimus
Calculated GFR at 6 months
Kaplan-Meier survival estimates, by gfrcat
1
504060-
.9
.8
0-
.7
6
12
24
Months
36
48
60
Graft survival for kidney transplants in Australia 1997-2001 by calculated GFR at
49
6 months. Categories are quartiles (approximately) of GFR
APFN 2002: ANZDATA & Tacrolimus
Creatinine at 6 months
Kaplan-Meier survival estimates, by creat category
1
100-129
130-159
.9
0-99
.8
>160
.7
0
6
12
24
Months
36
48
60
Graft survival for kidney transplants in Australia 1997-2001 by creatinine at 6
months. Categories are quartiles (approximately) of creatinine
50
APFN 2002: ANZDATA & Tacrolimus
Rejection rates over time
Rejection in first 6 months
.5
.4
.3
.2
.1
1997
1998
1999
year of Tx
2000
2001
Proportion of rejection episodes proven by biopsy, first rejection episodes only,
1997-2001
51