giancarlo agnelli università di perugia anticoagulant treatment for pe: optimal duration
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Giancarlo Agnelli
Università di Perugia
Anticoagulant treatment for PE: optimal duration
≥ 5 days 3-123-12 months months > 3-12 months> 3-12 months
vitamin K antagonists vitamin K antagonists INR 2.0-3.0INR 2.0-3.0
Heparin Heparin LMWH LMWH TrombolysisTrombolysis
Treatment of pulmonary embolism
Initial treatment
Long term-treatment
Extended treatment
Long-term anticoagulation for PE
• Long-term outcome of DVT or PE patientsLong-term outcome of DVT or PE patients
• Available evidence from clinical trialsAvailable evidence from clinical trials
• Patient categories (& recommendations)Patient categories (& recommendations)
• Risk factors for recurrencesRisk factors for recurrences
Long-term anticoagulation for PE
• Long-term outcome of DVT or PE patientsLong-term outcome of DVT or PE patients
• Available evidence from clinical trialsAvailable evidence from clinical trials
• Patient categories (& recommendations)Patient categories (& recommendations)
• Risk factors for recurrencesRisk factors for recurrences
Long-term outcome of DVT and PE
1. Same recurrence rate
2. Higher risk for recurrent PE after a first PE
Douketis et al., Arch Intern Med 2000 Agnelli et al., Ann Intern Med 2001 Prandoni et al., JTH 2006 Long-term anticoagulation study group,
2006
PE and DVT: recurrent VTE
Schulman et al., N Eng J Med 1995Pinede et al., Circulation 2001Long-term anticoagulation study group, 2006
Long-term anticoagulation for PE
• Long-term outcome of DVT or PE patientsLong-term outcome of DVT or PE patients
• Available evidence from clinical trialsAvailable evidence from clinical trials
• Patient categories (& recommendations)Patient categories (& recommendations)
• Risk factors for recurrencesRisk factors for recurrences
Schulman et al., N Engl J Med 1995
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MonthsMonths
0.20.2
0.10.1
0.00.000 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424
Six-week groupSix-week group
Six-month groupSix-month group
DURAC I
Kearon et., N Engl J Med 1999
Ev
ent
Ra
te (
%)
Ev
ent
Ra
te (
%)
Months After RandomizationMonths After Randomization
5050
4040
3030
2020
1010
00
00 66 1212 1818 2424
PlaceboPlacebo
WarfarinWarfarin
PP<.001<.001
Patients at RiskPatients at RiskPlaceboPlacebo 8383 4444 2525 1414 44WarfarinWarfarin 7979 5757 3636 2121 1111
LAFIT
Agnelli et al., N Engl J Med 2001
MonthsMonths
0.300.30
0.200.20
0.100.10
0.000.0000 66 1212 1818 2424 3030 3636
3 months3 months
1 year1 year
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Ha
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0.050.05
0.250.25
0.150.15
33 99 1515 2121 2727 3333
WODIT WODIT DVTDVT
Agnelli et al., Ann Intern Med. 2003
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3 months3 months
>3 months>3 months
0.30.3
0.20.2
0.10.1
0.00.000 66 1212 1818 2424 3030 3636
MonthsMonths
WODIT WODIT PEPE
*Composite study endpoint of recurrent venous thromboembolism, major hemorrhage, or death *Composite study endpoint of recurrent venous thromboembolism, major hemorrhage, or death from any cause (right).from any cause (right).
Ridker et al., Ridker et al., N Engl J MedN Engl J Med 2003 2003
Recurrent VTE
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0.250.25
0.200.20
0.150.15
0.100.10
0.050.05
0.000.0000 11 22 33 44
PP<.001<.001PlaceboPlacebo
Low-intensityLow-intensitywarfarinwarfarin
Years of Follow-upYears of Follow-up
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Composite Endpoint*Composite Endpoint*
0.250.25
0.200.20
0.150.15
0.100.10
0.050.05
0.000.0000 11 22 33 44
PP=.01=.01 PlaceboPlacebo
Low-intensityLow-intensitywarfarinwarfarin
Years of Follow-upYears of Follow-up
Prevent
Kearon et al., N Engl J Med 2003
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Rec
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Rec
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Th
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smT
hro
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oem
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lism
0.100.10
0.090.09
0.080.08
0.070.07
0.060.06
0.050.05
0.040.04
0.030.03
0.020.02
0.010.01
0.000.000.00.0 1.01.0 2.02.0 3.03.0 4.04.0
Years Since RandomizationYears Since Randomization
PP=.03=.03
Low-intensityLow-intensitytherapy grouptherapy group
Conventional-intensityConventional-intensitytherapy grouptherapy group
Elate
• Anticoagulant therapy for six weeks is not long enough to prevent recurrences
• While on anticoagulant treatment, patients are protected from recurrent VTE
• About 15% of patients with a first idiopathic VTE have a recurrence in the 2 years after OAC discontinuation
• INR less than 2.0-3.0 provides no substantial benefit
Lessons from DURAC I, LAFIT and WODITs
A meta-analysis of randomized, controlled trials
Case-fatality rate Rate of intracranial of major bleeding bleeding
Entire period 9.4 1.15 % pts-yof anticoagulation (9.4-17.4) (1.14-1.16)
Initial 3 months 9.3 1.48% pts-yof therapy (3.1-20.3) (1.40-1.56%)
After initial 3 months 9.1 0.65 % pts-y (2.5-21.7) (0.63–0.68)
Linkins et al., Ann Intern Med 2003
Bleeding in patients receiving AVK for VTE
Long-term anticoagulation for PE
• Long-term outcome of DVT or PE patientsLong-term outcome of DVT or PE patients
• Available evidence from clinical trialsAvailable evidence from clinical trials
• Patient categories (& recommendations)Patient categories (& recommendations)
• Risk factors for recurrencesRisk factors for recurrences
Idiopathic Temporary RF RR % % 95% CI
WODIT PE 12.2 7.6 1.6
Agnelli et al., Ann Intern Med
2001
DOTAVK 9.1 5.2 1.7
Pinede et al., Circulation 2001
3-year recurrence rate according to nature of PE
Venous thromboembolism
Annual Rate Recommended of recurrence OAC duration
First episodeFirst episode
• Idiopathic/unprovokedIdiopathic/unprovoked ~ ~ 5%5% 6 months 6 months
• Associated with Associated with
transient risk factorstransient risk factors 2-3% 2-3% 3 months 3 months
cancercancer 10% 10% indefinite indefinite
major thrombophilia major thrombophilia ~ 5% ~ 5% 6 months 6 months
Recurrent episode 10% indefinite
Long-term anticoagulation for PE
• Long-term outcome of DVT or PE patientsLong-term outcome of DVT or PE patients
• Available evidence from clinical trialsAvailable evidence from clinical trials
• Patient categories (& recommendations)Patient categories (& recommendations)
• Risk factors for recurrences Risk factors for recurrences
1. Molecular thrombophilia (PE & DVT)
2. D-dimer one month after discontinuation of
anticoagulant treatment (DVT)
3. Residual venous occlusion (DVT) or RVD at
anticoagulant withdrawal (PE)
Risk factors for recurrence
155 (51%)155 (51%)
17 (11.0%)17 (11.0%) 3 (3.4%)3 (3.4%) 18 (30.5%)18 (30.5%)
Persistence of RVD & clinical outcome
No RVD RVD regression
Grifoni et al., 2006
301 patients with objectively confirmed PE
RVD persistence
87 (29%)87 (29%) 59 (20%)59 (20%)
Fatal and non fatal VTE recurrences
43210
.6
.5
.4
.3
.2
.1
RVD persistence
No RVD
RVD regression
Grifoni et al., 2006 (in press)
Recurrence HR = 2.7 (1.2 - 5.7)
Mortality HR 15.1 (3.1 – 75.9)
Persistence of RVD & clinical outcome
1. PE patients should receive at least 3-month anticoagulation
2. The recurrent rate and treatment duration is related to the
features of the index events (range 2-10% year)
3. The bleeding is not related to the features of the index
events (MB 1-2%year, ICH 0.6% year)
3. Treatment should be extended beyond 6-12 months in PE
patients with a risk of recurrence not < to 5%year
4. Cancer and RVD are the only risk factor for recurrence in PE
patients
Anticoagulant treatment for PE: how long?
Conclusions