Transcript thrombophilia

LONG TERM TREATMENT
AFTER VENOUS THROMBOEMBOLISM
ERIC WATTS
BASILDON + THURROCK UNIVERSITY HOSPITAL
TO TREAT OR NOT TO TREAT?
TO STOP OR CONTINUE?
TO DECIDE ON CLINICAL GROUNDS OR ON
THE BASIS OF INFORMATION WHICH CAN
PREDICT RECURRENCE?
CAN WE DETERMINE THE RISK OF STOPPING
OR CONTINUING IN ORDER TO MAKE AN
INFORMED DECISION?
Subsequent management following 1st spontaneous
thrombosis
Risk of recurrence 20% at 2yrs 1% fatal if no AC
Annual mortality approx. 0.2%
On warfarin risk of serious Hge 1%
25% fatal
Annual mortality approx. 0.25%
How can we quantify the risk of recurrence?
Provoked vs unprovoked
Past history
Family history
? Thrombo screen
GS
Aged 14 admitted with abdo pain
Found to have ileo femoral DVT
Mother – a long term anticoagulant patient with
recurrent DVT
Thrombo testing:
Mother - S deficiency
Son – S deficiency & FVL
Thrombophilic families
• Recognised for decades
• Some associated with other genetic markers
eg blood group A&B
• In these families the age of onset of 1st
thrombosis would often be less than 30 yrs
• Antithrombin III deficiency reported in such
kindreds in 1965 – a single gene defect
THROMBOPHILIA CONFERENCE 1988
ATIII, S, C, + LAC - defective fibrinolysis
‘Abnormalities are present in situations with
thrombotic risk – detailed studies are
required to establish the nature of the
relationships.’
Thrombosis is Multifactorial
• Most patients are elderly bedridden
hospitalised post op or other illnesses IV
cannulae etc
• How relevant are findings from such
patients to fit young mobile relatives?
Virchow’s Triad
abnormalities in
•
•
•
•
Vessel wall
Composition of the blood
Stasis
The evidence is emerging through a fog
The Assays
• Functional
• Antithrombin reliable test with tight normal
range & good QC
• Prot C results vary with technique & lab
overlap between normal & heterozygotes
• Prot S more variable than Prot C
• APCR differing methods - a screening test
Genetic Tests
• Factor V Leiden- reliable test –takes time
• Prothrombin G20210A genetic test only –
no screening test
• Homocysteine- thermolabile
tetrahydrofolate reductase variant can be
identified but does not correlate with
thrombosis
Risk Factor %gp %VTE Ratio
• Antithrombin
0.02
• Prot C
0.2-0.4
• Prot S varies
0.1-0.4
-?co factors
• Factor V Leiden
5
1
3
1-2
x50
x10
x5-10
20
x4
Risk Factor %gp %VTE Ratio
• Prothrombin G20210A 2
• FVIII >150%
12
• Hyperhomocystein 5
6
24
10
x3
x2
x2
• >18.5umol/l
• Hyperhomocysteinaemia can be secondary to a wide
range of chronic inflammatory & Malignant disease
& renal failure poor diet etc
Population based perspective
• Worcester DVT Study Anderson FA
Arch Intern Med 1991 151(5):933-8
• Population of 380,000 served by 16
hospitals 78-578 beds –all cases of DVT &
PE documented for 18/12 & followed up for
4 years
Worcester study
• Overall inc of DVT 48/100,000
• Overall inc of PE 23/100,000
• Average age 67 but exponential increase
with age
600
Male Patients
Female Patients
Incidence rate per 100,000
500
400
300
200
100
0
0-9
1 0-19 20-29 3 0-39 40-49 5 0-59 60-69 7 0-79 >80
Age years
Worcester Study long term case
fatality post discharge
• 1yr
• 2yrs
• 3yrs
19%
25%
30%
•
•
•
•
•
•
Co morbid conditions
Cancer
29%
CCF
23%
COPD
26%
Fractures
12%
MI
6%
FH of thrombosis
• The potential value value of testing families is in
the possibility of preventing a first thrombosis the EFECTIVENESS & RISKS of this approach
have not been formally assessed
• If there is a very strong FH prophylaxis may be
justified should all tests be normal
• Large families with several affected members
where the abnormality corresponds with
thrombosis may informative
Basildon Experience
• 8yrs – 500+ young patients
• All advised that they have an increased risk of
thrombosis but that the absolute risk is small
• The risk of a second thrombosis overall is 20% in 2 yrs
• Patients are advised to report early if they have any
relevant symptoms- pain & swelling
• Very few good FHs
• More married couples than parents and children
A decision analysis based on epidemiological data
Risk of recurrent VTE (0-20% first 2-3 years then declines)
Risk higher in spontaneous VTE
Incidence of major bleeding higher with age
Continue R
9%
Non Fatal VTE
Fatal MB
91%
15%
Non Fatal MB
85%
Fatal VTE
9%
Non Fatal VTE
91%
First MB
No event
Cor S defie
Fatal VTE
3/12 after 1st VTE
Stop R
No event
Oral anticoagulation 90% successful in preventing recurrences
Baseline estimates and ranges
Recurrent VTE (% per 3 months)
Time since initial VTE (months) Spontaneous
4-6
7-12
13-24
25-36
>36
Case fatality 9%
5.60
2.70
2.30
1.50
1.00
Secondary
2.78
1.35
1.15
0.77
0.48
Major bleeding (% per 3 months)
Age (years)
<40
0.16
40-49
0.25
50-59
0.37
60-69
0.57
>70
0.87
Case fatality 15%
Relative risk reduction achieved with treatment with vitamin K antagonists: 90%
Time since initial VTA (months)
4-6
Age
(years)
Change in
MB incidence
<40
+0.16
7-12
13-24
25-36
>36
Change in recurrent VTE incidence
-2.50
-1.21
-1.03
-0.70
-0.43
-0.20
498
-0.08
1178
-0.07
1453
-0.04
2596
-0.01
6710
-0.07
1398
-0.06
1801
-0.03
3966
-0.002
62833
40-49
+0.25
-0.19
553
50-59
+0.37
-0.17
590
-0.05
1868
-0.04
2666
-0.01
13861
+0.02
-
60-69
+0.57
-0.14
717
-0.02
4247
-0.01
13311
-0.02
-
+0.05
-
+0.87
-0.09
1059
+0.02
-
+0.04
-
+0.07
-
+0.09
-
>70
ISTH JULY 2003
Risk factors for recurrent VTE
De Stefano 2003
205 patients medium age 36
36% had thrombophilia markers
Relative risk of recurrence
Tphil/Normal = 1.1 CI =00.9-1.4
Risk factors for recurrent VTE
Leiden Thrombophilia Study (LETS)
S Christiansen 2003
474 consecutive patients with a first episode
of VTE
Age 18-70 without known malignancy
94% followed up for 7 years
87 recurrences (16%)
Factor V Leiden
Confidence interval
Hazard ratio
(95%)
1.2
07.-1.9
PT 20210A
0.8
0.3-2.0
F.VIII elevation
1.1
0.7-1.8
F.IX elevation
1.0
0.5-1.8
F.XI elevation
0.6
0.3-1.1
PC/PS/AT-def
1.7
0.8-3.5
Influence of Thrombophilia
Efficacy of warfarin for prevention of recurrent VTE
a randomised trial Kearon 2003
Objective ‘to determine if the risk of recurrence
during anticoagulation is increased by thrombophilia
markers’
661 patients with spontaneous VTE
1600 patient years follow up
Overall risk of recurrence 3%
Marker
RR
C1
FVL
0.7
0.2-2.1
FVIII
1.1
0.2-4.6
FXI
0.5
0.1-3.5
H Hcy
0.5
0.1-3.5
LAC
1.9
0.6-6.5
Why?
The new genetics and genome scanning ‘Novel familybased approaches to genetic risk in Thrombosis’
J Blangero JT Williams L Almasy Journal of
Thrombosis and Haemostasis 2003 1,7 1391-1397
Few diseases are the result of a single gene defect. The
field of common complex disease genetics has progressed
through a major paradigmatic change focussing on
measurable quantitative traits that correlate with disease as
against dichotomous disease traits.
They identify quantitative trait loci (QTL) – works best on
extended families
The bigger the pedigree, the more information.
Biggest is from Jirel, 2000 relatives gerome
scanned and being assessed for haemostasis related
traits.
The story so far
Trait
Score
Location
Gene
FXII/Thrombosis
11.7
5q35
F12
FII/Thrombosis
4.7
11p11
F2
APCR/FVIIIc/
Thrombosis
4.5
18p11
?
Recommendations
Indefinite anticoagulation at a target of 2.0-3.0 is recommended
only in these high risk patients
Bauer KA The Thrombophilias – well defined risk factors with
uncertain therapeutic implications Am.Int.Med. 2001 135 367-73
2 or more spontaneous thromboses
One spontaneous thrombosis and LAC
One spontaneous life threatening thrombosis
One spontaneous thrombosis at an unusual site eg. mesenteric or
cerebral
One spontaneous thrombosis with multiple thrombophilic
abnormalities
CONCLUSION
In spite of many years of thrombophilia testing, the
usefulness of this approach is unproven.
There are still differing approaches in clinical practice.
The main purpose of thrombophilia testing is to
generate data for epidemiological research.
Patient management is determined largely by clinical
factors
Ximelagatran Overview
• Oral ximelagatran rapidly absorbed
•
•
•
•
•
and biotransformed to the active form,
melagatran
Renal excretion
Clinical studies demonstrate efficacy
with bid dosing
No coagulation monitoring required
Low potential for drug/food/alcohol interaction
Fixed dosing and predictable response
Extended secondary
prevention with the oral direct
THRombin Inhibitor ximelagatran
in patients with VEnous
thromboembolism
THRIVE III
Study design
Initial VTE
event
ximelagatran 24 mg bid
n=612
R
INR <1.5
ITT
placebo
n=611
Standard AC
6±1 months
18 months
Baseline: Ultrasonography
Perfusion lung scan
2-week follow-up
VTE events - DVT and/or PE
Estimated cumulative
risk (%)
14
12.6%
p<0.0001
HR=0.16 (95% CI 0.09;0.30)
RRR=78%
12
10
9.8%
8
placebo
6
ximelagatran
4
2.8%
2
0
0
3
6
9
Months
12
15
18
Major and/or minor bleeding
Estimated cumulative events
risk (%)
30
p=0.1703
HR=1.19 (95% CI 0.93;1.53)
25
23.9%
21.0%
20
15
placebo
ximelagatran
10
5
0
0
3
6
9
Months
12
15
18
Efficacy and safety of the oral direct
thrombin inhibitor ximelagatran
for acute symptomatic deep vein
thrombosis with or without
pulmonary embolism
THRIVE Treatment Study
DVT  PE
(onset of
symptoms)
Study design
ximelagatran 36 mg bid
R
enoxaparin 1 mg/kg sc bid* 
warfarin INR 2-3
E
14
days
6 months
24
hours
Objective
confirmation
of DVT
E = study entry;
14 days
follow up
End of
treatment
R = randomisation
Double-blind, double-dummy design
* enoxaparin 5 - 20 days until INR  2.0 on warfarin
Total VTE
Estimated treatment differences at 182
days
enoxaparin/
Difference
warfarin
ximelagatran
x-e/w
with 95% confidence
intervals
(n=1249)
(n=1240)
(95% CI)
Total
VTE, ITT
2.0%
(n=24)
2.1%
(n=26)
+0.2%
(-1.0; 1.3%)
Total
VTE, OT
1.5%
(n=17)
2.0%
(n=23)
+0.5%
(-0.6; 1.6%)
Non-inferiority
-4
-2
0
2
4
ximelagatran
enoxaparin/
better
warfarin better
Total VTE
Cumulative
risk versus time after randomisation
Cumulative
risk (%)
5
ximelagatran (23 events)
ximelagatran (26 events)
enoxaparin/warfarin (17 events)
enoxaparin/warfarin (24 events)
4
3
2.1%
2.0%
2
2.0%
1.5%
1
95% CI: –0.6%; 1.6%
95% CI: –1.0%; 1.3%
0
0
30
60
90
120
Days after randomisation
150
180
Major bleeding
Cumulative
risk versus time after randomisation
Cumulative
risk (%)
5
ximelagatran (14 events)
enoxaparin/warfarin (25 events)
4
3
2.2%
2
NS
1
1.3%
0
0
30
60
90
120
Days after randomisation
150
180
Stroke Prevention Using the
ORal Direct Thrombin Inhibitor
Ximelagatran in Patients With
Nonvalvular Atrial Fibrillation
SPORTIF III
Primary events: stroke and SEE
Intention-to-treat analysis
Cumulative
event rate (%)
4
warfarin
56 events (2.3%/year)
ximelagatran
3
2
40 events (1.6%/year)
1
0
0
3
6
9
12
15
Duration (months)
18
21
Primary events: stroke and SEE
Intention-to-treat analysis
ximelagatran
better
warfarin
better
Superiority
warfarin
2.3%/year
(56 events)
Non-inferiority
-3
-2
-1
0
1
Event rate difference (%)
ximelagatran
1.6%/year
(40 events)
2
Difference per year = –0.7% (95% CI: –1.5, 0.1; p=0.10)
3
Adverse events
Event rate
(% per year)
Haemorrhage
30
p=0.007
29.8%
warfarin
25.8%
ximelagatran
25
20
15
10
5
0.4% 0.2%
1.8% 1.3%
0
Intracranial
haemorrhage
Major
bleeding
Major + minor
bleeding
•
•
•
•
Warfarin
Decades of
experience
Vast quantities of data
Patients and
professionals familiar
with the INR
Cheap
•
•
•
•
Ximelagatran
Appears safe and
effective
No drug interactions
No tests
? cost
Risk of treatment
•
•
•
•
•
Serious haemorrhage from warfarin
1% pa
¼ are fatal
70% in range is good control
Many bleeds occur in control range
Time since initial VTA (months)
4-6
Age
(years)
Change in
MB incidence
<40
+0.16
7-12
13-24
25-36
>36
Change in recurrent VTE incidence
-5.00
-2.42
-2.07
-1.39
-0.87
-0.43
235
-0.19
516
-0.16
618
-0.10
988
-0.05
1852
-0.18
554
-0.15
673
-0.09
1137
-0.04
2458
40-49
+0.25
-0.41
242
50-59
+0.37
-0.39
254
-0.16
615
-0.13
766
-0.07
1430
-0.02
4409
60-69
+0.57
-0.36
274
-0.13
754
-0.10
995
-0.04
2504
+0.01
-
+0.87
-0.32
313
-0.09
1142
-0.06
1801
+0.01
-
+0.05
-
>70