Tacrolimus – the ANZDATA perspective

APFN 2002

Tacrolimus – the ANZDATA perspective

(and a bit on rejection too)

Stephen McDonaldANZDATA RegistryAdelaide Australia

2

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

3


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.

4


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.

5


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

6


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

7


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

8


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

9


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

10


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

11


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

12


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%

13


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

14


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

15


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

16


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

17


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

18


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

19


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

20


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

21


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

22


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

23


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

24


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

25


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

26


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

27


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

28


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

29


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

30


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

31


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

32


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)

33


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

34


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

35


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…

36


37


Spare slides

38


Structure

Epidemiology of tacrolimus useWho, where, when

Associations of tacrolimus use with outcome

tacrolimus use from baseline• Rejection rates• Renal function

39


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


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.

41


Regional variation – tacrolimus

Australia270135

27

No TacTac

Immunosuppressive drugs at initial treatment all grafts, 2000-9/2001

NZ

42


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

43


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

44


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

45


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

46


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

47


Graft outcomes

48


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

49


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

50


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

51


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

Documents

Tacrolimus – the ANZDATA perspective