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

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

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

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

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

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

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

Kearon et., N Engl J Med 1999 Event Rate (%) Months After Randomization Placebo Warfarin P<.001 Patients at Risk Placebo Warfarin LAFIT

Agnelli et al., N Engl J Med 2001 Months months 1 year Cumulative Hazard WODIT DVT

Agnelli et al., Ann Intern Med Cumulative Hazard 3 months >3 months Months WODIT PE

*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 P<.001 Placebo Low-intensity warfarin Years of Follow-up Cumulative Rate of Events Composite Endpoint* P=.01 Placebo Low-intensity warfarin Years of Follow-up Prevent

Kearon et al., N Engl J Med 2003 Cumulative Probability of Recurrent Thromboembolism Years Since Randomization P=.03 Low-intensity therapy group Conventional-intensity therapy 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 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 % pts-y of anticoagulation ( ) ( ) Initial 3 months % pts-y of therapy ( ) ( %) After initial 3 months % pts-y ( ) (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 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

Idiopathic Temporary RF RR % % 95% CI WODIT PE Agnelli et al., Ann Intern Med 2001 DOTAVK Pinede et al., Circulation year recurrence rate according to nature of PE

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

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

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

RVD persistence No RVD RVD regression Grifoni et al., 2006 (in press) Recurrence HR = 2.7 ( ) Mortality HR 15.1 (3.1 – 75.9) Persistence of RVD & clinical outcome

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

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

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

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

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

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

Low-intensity anticoagulant therapy (INR ) 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 ) without causing excessive bleeding Lessons from ELATE

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

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

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

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