1. Giancarlo Agnelli Università di Perugia Anticoagulant treatment for PE: optimal duration

2. 3-12 months > 3-12 months 5 days 3-12 months > 3-12 months vitamin K antagonists INR 2.0-3.0 INR 2.0-3.0 Heparin LMWH Trombolysis Treatment of pulmonary embolism Initial treatment Long term-treatment Extended treatment

3. Long-term anticoagulation for PE Long-term outcome of DVT or PE patients Long-term outcome of DVT or PE patients Available evidence from clinical trials Available evidence from clinical trials Patient categories (& recommendations) Patient categories (& recommendations) Risk factors for recurrences Risk factors for recurrences

4. Long-term anticoagulation for PE Long-term outcome of DVT or PE patients Long-term outcome of DVT or PE patients Available evidence from clinical trials Available evidence from clinical trials Patient categories (& recommendations) Patient categories (& recommendations) Risk factors for recurrences Risk factors for recurrences

5. 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 1995 Pinede et al., Circulation 2001 Long-term anticoagulation study group, 2006

6. Long-term anticoagulation for PE Long-term outcome of DVT or PE patients Long-term outcome of DVT or PE patients Available evidence from clinical trials Available evidence from clinical trials Patient categories (& recommendations) Patient categories (& recommendations) Risk factors for recurrences Risk factors for recurrences

7. Schulman et al., N Engl J Med 1995 Cumulative Probability of Recurrence Months 0.2 0.1 0.0 024681012141618202224 Six-week group Six-month group DURAC I

8. Kearon et., N Engl J Med 1999 Event Rate (%) Months After Randomization 50 40 30 20 10 0 06121824 Placebo Warfarin P<.001 Patients at Risk Placebo83442514 4 Warfarin79573621 11 LAFIT

9. Agnelli et al., N Engl J Med 2001 Months 0.30 0.20 0.10 0.00 061218243036 3 months 1 year Cumulative Hazard 0.05 0.25 0.15 3915212733 WODIT DVT

10. Agnelli et al., Ann Intern Med. 2003 Cumulative Hazard 3 months >3 months 0.3 0.2 0.1 0.0 061218243036 Months WODIT PE

11. *Composite study endpoint of recurrent venous thromboembolism, major hemorrhage, or death from any cause (right). Ridker et al., N Engl J Med 2003 Ridker et al., N Engl J Med 2003 Recurrent VTE Cumulative Rate of Events 0.25 0.20 0.15 0.10 0.05 0.00 01234 P<.001 Placebo Low-intensity warfarin Years of Follow-up Cumulative Rate of Events Composite Endpoint* 0.25 0.20 0.15 0.10 0.05 0.00 01234 P=.01 Placebo Low-intensity warfarin Years of Follow-up Prevent

12. Kearon et al., N Engl J Med 2003 Cumulative Probability of Recurrent Thromboembolism 0.10 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00 0.01.02.03.04.0 Years Since Randomization P=.03 Low-intensity therapy group Conventional-intensity therapy group Elate

13. 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

14. A meta-analysis of randomized, controlled trials Case-fatality rate Rate of intracranial of major bleeding bleeding Entire period 9.4 1.15 % pts-y of anticoagulation (9.4-17.4) (1.14-1.16) Initial 3 months 9.3 1.48% pts-y of 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

15. Long-term anticoagulation for PE Long-term outcome of DVT or PE patients Long-term outcome of DVT or PE patients Available evidence from clinical trials Available evidence from clinical trials Patient categories (& recommendations) Patient categories (& recommendations) Risk factors for recurrences Risk factors for recurrences

16. 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

17. Venous thromboembolism Annual Rate Recommended of recurrence OAC duration First episode Idiopathic/unprovoked ~5% 6 months Idiopathic/unprovoked ~ 5% 6 months Associated with Associated with transient risk factors 2-3% 3 months transient risk factors 2-3% 3 months cancer 10% indefinite cancer 10% indefinite major thrombophilia ~ 5% 6 months major thrombophilia ~ 5% 6 months Recurrent episode 10% indefinite

18. Long-term anticoagulation for PE Long-term outcome of DVT or PE patients Long-term outcome of DVT or PE patients Available evidence from clinical trials Available evidence from clinical trials Patient categories (& recommendations) Patient categories (& recommendations) Risk factors for recurrences Risk factors for recurrences

19. 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

20. 155 (51%) 17 (11.0%) 3 (3.4%) 18 (30.5%) Persistence of RVD & clinical outcome No RVDRVD regression Grifoni et al., 2006 301 patients with objectively confirmed PE RVD persistence 87 (29%) 59 (20%) Fatal and non fatal VTE recurrences

21. 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

22. Becattini et al., Eur Heart J 2005 Idiopathic PE PE with transient RF Cardiovascular Events Cumulative Hazard 0.40 P=.005 0.30 0.20 0.10 0.00 0612182430364248 The long-term clinical course of PE

23. Warfasa study Aspirin 100 mg 24-month study period Idiopathic objectively confirmed VTE 6-12 month anticoagulation Placebo Recurrent VTE, AMI, stroke & sudden unexplained death

24. 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

25. agnellig@unipg.it

26. Treatment of pulmonary embolism: outcomes Initial treatment Long term-treatment After withdrawal < 1% per year 5 % per year Major bleeding 3% per year Long-term anticoagulation study group, 2006

27. Cumulative probability and hazard ratios (HR) of recurrent VTE in the 3 groups Palareti et al., in press

28. Low-intensity anticoagulant therapy (INR 1.5-1.9) is more effective than placebo after at least 3 months of standard-intensity anticoagulant therapy without causing excessive bleeding Lessons from PREVENT

29. Low-intensity anticoagulant therapy (INR 1.5-1.9) is more effective than placebo after at least 3 months of standard-intensity anticoagulant therapy without causing excessive bleeding Standard-intensity anticoagulant therapy (INR 2.0 to 3.0) is more effective than low-intensity anticoagulant therapy (INR 1.5-1.9) without causing excessive bleeding Lessons from ELATE

30. Venous thromboembolism First episode Idiopathic or unprovoked (in the absence of a Idiopathic or unprovoked (in the absence of a known identifiable risk factor) known identifiable risk factor) Associated with a transient risk factors Associated with a transient risk factors Associated with concurrent cancer Associated with concurrent cancer Associated with a prothrombotic genotype or Associated with a prothrombotic genotype or a marker of increased risk of recurrence a marker of increased risk of recurrence Recurrent episode

31. Months Cumulative Hazard of Recurrence Thrombophilia + Thrombophilia - HR=2.30 95% CI 1.13-4.72, p=0.022 Taliani et al., ISTH 2005 Patients treated for three months Thrombophilia & Recurrent VTE

32. Months Cumulative Hazard of Recurrence HR=1.10 95% CI 0.54-2.25, p=0.793 Thrombophilia + Thrombophilia - Taliani et al., ISTH 2005 Patients treated for 12 months Thrombophilia & Recurrent VTE

33. Optimal duration: a meta-analysis Ost et al., JAMA 2006