1. Pulmonary Embolism Treatment in Cancer - Is It Different 34th Brazilian Thoracic Conference 6th ALAT Congress 5th Brazil-Portugal Congress Brazilia/DF November 22, 2008 Alvin V. Thomas, Jr., M.D., FACP, FCCP Immediate Past President ACCP Howard University 34th Brazilian Thoracic Conference 6th ALAT Congress 5th Brazil-Portugal Congress Brazilia/DF November 22, 2008 Alvin V. Thomas, Jr., M.D., FACP, FCCP Immediate Past President ACCP Howard University

2. Disclosures I have no conflicts of interest Alvin V. Thomas, Jr., M.D., FCCP I have no conflicts of interest Alvin V. Thomas, Jr., M.D., FCCP

3. Epidemiology of VTE in the Community Active cancer accounts for almost 20% of incident VTE in the community Risk for VTE higher for patients with –Pancreatic cancer, lymphoma, malignant brain tumors, liver cancer, leukemia, colorectal and other digestive cancers Active cancer accounts for almost 20% of incident VTE in the community Risk for VTE higher for patients with –Pancreatic cancer, lymphoma, malignant brain tumors, liver cancer, leukemia, colorectal and other digestive cancers Heit JA. Arterioscler Thromb Vasc Biol 2008;28:370-372

4. VTE and Cancer Patients with idiopathic or unprovoked PE subsequently develop a cancer in 10% of cases over 5 years of follow-up Risk of thrombosis in cancer patients is 4 times higher than the general population –Risk increases 6.7 fold in patients on chemotherapy Cancer patients with VTE are more likely to develop –Recurrent VTE –Major bleeding during anticoagulant Rx –Risk correlates with the extent of CA Patients with idiopathic or unprovoked PE subsequently develop a cancer in 10% of cases over 5 years of follow-up Risk of thrombosis in cancer patients is 4 times higher than the general population –Risk increases 6.7 fold in patients on chemotherapy Cancer patients with VTE are more likely to develop –Recurrent VTE –Major bleeding during anticoagulant Rx –Risk correlates with the extent of CA Guidelines on Dx & Rx of Acute PE. Task Force European Society of Cardiology European Heart J 2008;29:2276-2315

5. Natural Course of Hemodynamically Stable PE (prospective study of 673 consecutive patients with PE) Nijkeuter M et al. Chest 2007;131:517-523 Risk factors for clinically relevant and major bleeding in patients with PE (multivariate analysis) –Hospitalization, p = 0.05, OR 2.63 (1.02-6.77) –Surgery, p = 0.23, OR 1.92 (0.66-5.59) –COPD, p = 0.02, OR 3.89 (1.22-12.4) –Malignancy, p = 0.02, OR 3.04 (1.16-7.97) Risk factors for clinically relevant and major bleeding in patients with PE (multivariate analysis) –Hospitalization, p = 0.05, OR 2.63 (1.02-6.77) –Surgery, p = 0.23, OR 1.92 (0.66-5.59) –COPD, p = 0.02, OR 3.89 (1.22-12.4) –Malignancy, p = 0.02, OR 3.04 (1.16-7.97)

6. Incidence VTE in Patients Hospitalized With Cancer (National Hospital Discharge Survey 1979-1999) 19 malignancies studied –Incidence in patients with Ca - 2% –Incidence in patients w/o Ca - 1% Highest incidence - pancreatic Ca - 4.3% Lowest incidences - Ca of bladder, lip, oral cavity or pharynx Overall incidence of VTE twice the rates in non cancer patients Incidences not age dependent Incidence VTE in patients with Ca began increase in late 1980’s 19 malignancies studied –Incidence in patients with Ca - 2% –Incidence in patients w/o Ca - 1% Highest incidence - pancreatic Ca - 4.3% Lowest incidences - Ca of bladder, lip, oral cavity or pharynx Overall incidence of VTE twice the rates in non cancer patients Incidences not age dependent Incidence VTE in patients with Ca began increase in late 1980’s Stein PD et al. Am J Med 2006;119:60-68

7. VTE Affects Cancer May delay planned chemotherapy Negative impact on patients quality of life Consumes considerable health care resources Accounts for nearly 10% of cancer deaths May delay planned chemotherapy Negative impact on patients quality of life Consumes considerable health care resources Accounts for nearly 10% of cancer deaths Khorana AA et al. J Thromb Haemost 2007;5(3): 632-634

8. VTE Affects Cancer Cancer patients with VTE have 2-fold or greater increase in mortality compared to patients without VTE (even when adjusting for stage) Therefore is poor prognosis for patients with cancer-associated thrombosis –Close association between activation of coagulation and aggressive tumor biology Therefore the natural history and malignant nature of VTE in cancer requires aggressive prevention and therapy Cancer patients with VTE have 2-fold or greater increase in mortality compared to patients without VTE (even when adjusting for stage) Therefore is poor prognosis for patients with cancer-associated thrombosis –Close association between activation of coagulation and aggressive tumor biology Therefore the natural history and malignant nature of VTE in cancer requires aggressive prevention and therapy Lee AYY. J Thromb Thrombolysis 2008; 25:33-36

9. VTE & Cancer - Anticoagulants Anticoagulants are usually efficacious for Rx VTE and have acceptable safety profile in most patients Compared to patients without cancer, cancer patients have –2-fold risk of recurrent VTE –3-fold risk of anticoagulant-related bleeding Anticoagulants are usually efficacious for Rx VTE and have acceptable safety profile in most patients Compared to patients without cancer, cancer patients have –2-fold risk of recurrent VTE –3-fold risk of anticoagulant-related bleeding Lee AYY, Levine MN. Circulation 2003;107(23Suppl1): 117-121

10. Anticoagulation For The Initial Treatment of VTE in Patients With Cancer Compared relative efficacy and safety of LMWH & UFH between patients with and without cancer Cochrane methodology for systematic reviews 8 randomized control trials were studied Compared relative efficacy and safety of LMWH & UFH between patients with and without cancer Cochrane methodology for systematic reviews 8 randomized control trials were studied Akl EA et al. Cancer 2008;113:1685-1694

11. Anticoagulation For The Initial Treatment of VTE in Patients With Cancer - Results LMWH reduced mortality significantly compared to UFH in patients with cancer –RR 0.71; 95%CI, 0.52-0.92 (moderate quality evidence) –No reduced mortality in patients with no Ca RR 0.97; 95%CI, 0.65-1.46 (low quality evidence) –Difference in RR for the 2 subgroups not significant (p = 0.113) LMWH reduced mortality significantly compared to UFH in patients with cancer –RR 0.71; 95%CI, 0.52-0.92 (moderate quality evidence) –No reduced mortality in patients with no Ca RR 0.97; 95%CI, 0.65-1.46 (low quality evidence) –Difference in RR for the 2 subgroups not significant (p = 0.113) Akl EA et al. Cancer 2008;113:1685-1694

12. Anticoagulation For The Initial Treatment of VTE in Patients With Cancer LMWH vs UFH effect on recurrent VTE –Difference not significant in Ca subgroup - RR 0.78; 95% CI 0.29-2.08 (low quality evidence) Subgroup without Ca - RR 0.94; 95%CI, 0.60-1.46 Or between the 2 subgroups (p = 0.367) No data on bleeding outcomes, thrombocytopenia or postphlebitic syndrome LMWH vs UFH effect on recurrent VTE –Difference not significant in Ca subgroup - RR 0.78; 95% CI 0.29-2.08 (low quality evidence) Subgroup without Ca - RR 0.94; 95%CI, 0.60-1.46 Or between the 2 subgroups (p = 0.367) No data on bleeding outcomes, thrombocytopenia or postphlebitic syndrome Akl EA et al. Cancer 2008;113:1685-1694

13. Anticoagulation For The Initial Treatment of VTE in Patients With Cancer Conclusion –Current results suggest that LMWH is most likely superior to UFH in reducing mortality in the initial Rx of VTE for patients with cancer –Need for more and better designed trials to confirm the findings Conclusion –Current results suggest that LMWH is most likely superior to UFH in reducing mortality in the initial Rx of VTE for patients with cancer –Need for more and better designed trials to confirm the findings Akl EA et al. Cancer 2008;113:1685-1694

14. Recurrent VTE & Bleeding Complications in Patients with Cancer & Venous Thrombosis Prospective cohort study of 12-month cumulative incidence of recurrent VTE & major bleeding from anticoagulants Incidence recurrent VTE –Cancer patients - 20.7% –Non cancer patients - 6.8% –HR 3.2, 95% CI 1.9-5.4 Major bleeding –Cancer patients - 12.4% –Non cancer patients - 4.9% –HR 2.2, 95% CI, 1.2-4.1 Prospective cohort study of 12-month cumulative incidence of recurrent VTE & major bleeding from anticoagulants Incidence recurrent VTE –Cancer patients - 20.7% –Non cancer patients - 6.8% –HR 3.2, 95% CI 1.9-5.4 Major bleeding –Cancer patients - 12.4% –Non cancer patients - 4.9% –HR 2.2, 95% CI, 1.2-4.1 Prandoni P et al. Blood 2002;100(10): 3484-3488

15. VTE & Cancer Long-termTherapy 676 cancer patients with acute DVT or PE were randomized to –6 month course of traditional dalteparin therapy, followed by warfarin –Or dalteparin alone (6 months) Dalteparin dose reduced by 20-25% after the first month of Rx (to reduce the risk of bleeding) 676 cancer patients with acute DVT or PE were randomized to –6 month course of traditional dalteparin therapy, followed by warfarin –Or dalteparin alone (6 months) Dalteparin dose reduced by 20-25% after the first month of Rx (to reduce the risk of bleeding) Lee AYY. J Thromb Thrombolysis 2008; 25:33-36

16. Kaplan-Meier Estimates of the Probability of Symptomatic Recurrent Venous Thromboembolism among Patients with Cancer, According to Whether They Received Secondary Prophylaxis with Dalteparin or Oral Anticoagulant Therapy for Acute Venous Thromboembolism Lee, A. et al. N Engl J Med 2003;349:146-153

17. VTE & Cancer Long-termTherapy Therefore after 6 months Rx the long-term dalteparin group experienced a 52% reduction in symptomatic recurrent VTE compared to the group on continuing warfarin Equivalent to preventing 1 episode of VTE for every 13 patients studied No significant difference in bleeding or in overall mortality Therefore after 6 months Rx the long-term dalteparin group experienced a 52% reduction in symptomatic recurrent VTE compared to the group on continuing warfarin Equivalent to preventing 1 episode of VTE for every 13 patients studied No significant difference in bleeding or in overall mortality Lee AYY. J Thromb Thrombolysis 2008; 25:33-36

18. VTE and Cancer - Treatment Recommendations For patients with PE (as well as DVT) and Cancer –LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade1A) –Subsequent anticoagulant therapy with VKA or LMWH indefinitely or until the cancer is resolved (Grade 1C) –The risk-benefit ratio of continuing such treatment should be reassessed in the individual patient at periodic intervals (Grade 1C) For patients with PE (as well as DVT) and Cancer –LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade1A) –Subsequent anticoagulant therapy with VKA or LMWH indefinitely or until the cancer is resolved (Grade 1C) –The risk-benefit ratio of continuing such treatment should be reassessed in the individual patient at periodic intervals (Grade 1C) Kearon c et al. Chest 2008;133:454S-545S

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20. VTE and Cancer - Treatment Recommendations Kearon c et al. Chest 2008;133:454S-545S

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