pulmonary embolism treatment in cancer - is it different 34th brazilian thoracic conference 6th alat...

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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

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Pulmonary Embolism Treatment in Cancer - Is It Different

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

DisclosuresDisclosures

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

Epidemiology of VTE in the Community

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

VTE and CancerVTE 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 CardiologyEuropean Heart J 2008;29:2276-2315

Natural Course of Hemodynamically Stable PE

(prospective study of 673 consecutive patients with PE)

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)

Incidence VTE in Patients Hospitalized With Cancer

(National Hospital Discharge Survey 1979-1999)

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

VTE Affects CancerVTE 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

VTE Affects CancerVTE 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

VTE & Cancer - AnticoagulantsVTE & 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

Anticoagulation For The Initial Treatment

of VTE in Patients With Cancer 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

Anticoagulation For The Initial Treatment

of VTE in Patients With Cancer - Results 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

Anticoagulation For The Initial Treatment

of VTE in Patients With Cancer 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

Anticoagulation For The Initial Treatment

of VTE in Patients With Cancer 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

Recurrent VTE & Bleeding Complications in Patients with Cancer & Venous Thrombosis

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

VTE & Cancer Long-termTherapy

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

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

VTE & Cancer Long-termTherapy

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

VTE and Cancer - Treatment Recommendations

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

The EndThe End

VTE and Cancer - Treatment Recommendations

VTE and Cancer - Treatment Recommendations

Kearon c et al. Chest 2008;133:454S-545S

The EndThe End