Predicting and Preventing Recurrent Venous Thrombosis

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PredictingandPreventing Recurrent Venous
Thrombosis
Campbell Tait Royal Infirmary Glasgow
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TOPICS

• Why bother ?
• How to prevent recurrence
• Predicting Recurrence - What factors influence
  recurrence risk ?

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Why bother?

• immediate morbidity mortality
• 1-5 recurrences are fatal
• recurrent VTE is common
• approx. 30 at 8y
• delayed morbidity
• post thrombotic syndrome
• pulmonary hypertension

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Natural History of VTE
Cumulative Prevalence
after any VTE after DVT
recurrent VTE all PTS severe PTS 1y
12.8 18 2.7 2y 17.2 24.5 3.6 5y
24.3 29.6 8.1 8y 29.7 29.8
Association between recurrent ipsilateral DVT and
increased PTS (RR 2.4)
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How to prevent recurrent venous thrombosis
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Anticoagulation for PE in 1960

• 10,000u iv UFH - 6 doses 6 hourly
• Sinthrome for 14 days
• 10d bed rest
• n35 fatal PE non-fatal PE
• No therapy 26 26
• Therapy 0 0
• p 0.036

Barritt et al., Lancet 1960
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DURAC I Study6 weeks v 6 months oac after
1st VTE
Schulman et al, NEJM 1996
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Optimal duration of OACafter initial
heparinisation
DURATION
RECURRENCE _at_ 2y

• DURAC 1995 (897) 6w v 6m 18.1 9.5
• 1st DVT
• transient risk factor 8.6 4.8
• distal DVT only 11.4 5.8
• prox. DVT only 21.3 11.2
• pulmonary embolism 26.8 13.7

Schulman et al, NEJM 1996
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WODIT DVT Study3m v 12m warfarin after
idiopathic DVT
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3m v long term warfarinafter 1st idiopathic VTE
Kearon et al. NEJM 1999, 340901-7
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Bleeding complications with warfarin

• fatal haemorrhage 0.25 - 0.64 per year
• major haemorrhage 1.1 - 2.7 per year

Achieved INR major bleeds ( per year) minor
bleeds lt 2 1.5 11 2 - 3 2.5 12 3 -
4 2.5 15 4 - 5 4 20 5 - 6 5 34 ?
6 9 96
van der Meer et al., Arch Int Med 1993
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Duration of anticoagulation

• If recurrence risk is low
• 3-6 months
• If recurrence risk is moderate or high
• consider long term anticoagulation
• BALANCE
• Bleeding v Recurrent VTE
• (4 15y fatality rate 2)

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Recurrent VTE after idiopathic VTE dose
duration of warfarin
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WODIT 3m
Placebo PREVENT
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Low dose 1.5-2.0
Full dose ELATE
12m 24m
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Predicting risk of recurrent venous thrombosis
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Factors influencing risk of recurrent VTE

• site of initial VTE
• PE gt pDVT gt dDVT
• circumstances around initial VTE
• idiopathic gt transient risk factor
• initial anticoagulant treatment
• early therapeutic anticoagulation
• duration of anticoagulation
• at least 6 months
• presence of a continuing risk factor
• cancer, thrombophilia

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Thrombophilia and Risk of Recurrent VTE
Hazard Ratio
ve Lupus Anticoagulant 6.8 ve
anti-cardiolipin Ab 2.3 - 4.0 Elevated F
VIII 2.5 - 3.1 Elevated F IX
1.6 Antithrombin deficiency 2.2 Prothrombin
G20210A 1.7 - 2.2 F V Leiden NS
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Identifying the High Risk PatientPersisting
Hypercoagulability

• Can D-dimers help?

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P Bockenstedt, NEJM 2003 349 1203-4.
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Fibrin D-dimer

• A surrogate marker of fibrin formation

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Activation Markers in acute DVT
Elevated D-dimer -gt 94 sensitivity 95 NPV
B Boneu et al. (1991) Thrombosis Haemostasis
65 28-32
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Activation markers during treatment of acute DVT
A Elias et al. (1993) Thrombosis Haemostasis
69 302-5
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D-dimer gt500ng/mL after warfarin cessation
Idiopathic Persisting risk factor Transient risk
factor
0 30 90 Days after warfarin cessation
G Palareti et al. (2002) Thrombosis Haemostasis
87 7-12
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Mean D-dimer levels following cessation of
warfarin
G Palareti et al. (2002) Thrombosis Haemostasis
87 7-12
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D-dimers predict recurrent VTE

• 599 with 1st VTE (47 idiopathic, 42 transient
  RF)
• Vidas Dd measured 28d after stopping warfarin
• 21.7 cases had thrombophilia (FvL or G20210A)
• 9.7 cases with recVTE during 21m follow-up

RR p All subjects 2.61 (1.45
4.71) 0.001 Idiopathic VTE 2.75 (1.24
6.12) 0.013 Ca-associated 2.96 (0.8
10.88) 0.103 Transient RF 1.9 (0.5
7.28) 0.349 Thrombophilia 5.88 (1.46
23.72) 0.013
Palareti et al. (2003) Circulation 108313-8
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D-dimer predicts Recurrent VTE
D-dimer 1 month after oac cessation
G Papareti et al. (2003) Circulation 108313-8
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PROLONG Study

• Prospective study of 627 patients with idiopathic
  VTE treated with 6m warfarin.
• D-dimer measured 1m after stop warfarin 5
  patients already had recurrent VTE
• 25 with raised D-dimer -gt 15 recVTE
• 75 with normal D-dimer -gt 6 recVTE
• NNT with raised Dd
• to prevent 1 recVTE 8.4

G Papareti et al. (2006)
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CARROT Study Methods

• Prospective observational study (2001-2005)
• Inclusion criteria objectively confirmed VTE
  scheduled for 6 months anticoagulation
• Clinical Risk Factors recorded
• Blood samples
• Thrombophilia (AT,PC,PS,FvL,F2UT,ACA,L/A,
  FVIII,FIX,FXI)
• F12 / VIDAS D-dimer / TAT at entry, 6wk, oac
  cessatn, 24d 3m
• Follow-up 12-36 months
• Primary endpoint objectively confirmed recurrent
  VTE

CARROT 2006
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CARROT Study Cohort
Ineligible (51) long term warfarin -15
inconclusive scan -5 IVDU -17 short life
expectancy or dementia -9 other
-5 Declined consent (21) Excluded (1)
consent withdrawn inconclusive scan

• New acute VTE 1827
• (during 3y recruitment)
• 939
• Eligible 888 392
• Recruited 496
• 16
• Evaluable cohort 480

CARROT 2005
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CARROT Cohort Demographics (n480)

• Female 48.3
• Age 17-89 y (median 60y)
• PE 36 (19 with DVT)
• DVT 62 (83 proximal, 64 left
  leg)
• Prior VTE 6.5
• Family VTE 16.5
• Transient RF 53

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CARROT Study Results Summary

• Recurrent VTE rate around 7 per year.
• Major haemorrhage rate 2.7/y while on warfarin
• Idiopathic VTE associated with higher recurrence
  risk
• High levels of Factor VIII or IX associated with
  higher recurrence rate
• D-dimer (Vidas) measured at any time point
  associated with higher recurrent VTE rate

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D-dimer levels during follow-up
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Future Aims

• reduce the bleeding risk associated with long
  term anticoagulation
• better identify those patients at high and low
  risk of recurrence

More judicious use of warfarin