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

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Ra

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%)

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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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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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