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Dilemmas in Venous Thromboembolic Disease 2013
Margaret M. Johnson, MD Associate Professor of Medicine
Chair, Division of Pulmonary Medicine Mayo Clinic Florida
16 November 2013
Santiago, Chile
Outline
• Role of new anticoagulant therapy in thromboembolic disease
– Prophylaxis & treatment
• Clinical decisions
– Duration of anticoagulation after an unprovoked VTE
– Is aspirin indicated for secondary prevention ?
– When should inferior vena cava filters be placed
– Management upper extremity deep vein thrombosis
Prophylaxis and Treatment:2000
Prophylaxis
• Heparin
• Low molecular weight heparin
Treatment
• Heparin
• IV
• Subcutaneous
• Low molecular weight heparin
• Warfarin /Vit K antagonist
• Alteplase
Prophylaxis and Treatment:2013
Prophylaxis
• Heparin
• Subcutaneous
• Low molecular weight heparin
• Fondaparinux
• Rivaroxaban
• Apixaban
• Dabigatran
Treatment
• Heparin
• IV
• Subcutaneous
• Low molecular weight heparin
• Warfarin /Vit K antagonist
• Fondaparinux
• Rivoraxaban
• Alteplase
New Anticoagulants For Venous Thromboembolsim
• Factor Xa inhibitor
– Subcutaneous
• Fondaparinux (Arixtra)
– Oral
• Rivaroxaban (Xarelto)
• Apixiban (Eliquis)
• Edoxaban
• Direct thrombin inhibitor
– Oral
• Dabigatran (Pradaxa)
Fondaparinux Dosing Prophylaxis: Fixed dose Treatment: Weight Based
Prophylaxis
• 2.5 mg/daily
• Subcutaneously Treatment of DVT or
PE
• 5.0 mg/daily
• Wt < 50 kg
• 7.5 mg/daily
• Wt 50-100 kg
• 10 mg/daily
• Wt> 100 kg
Summary of Fondaparinux
• Approved for prophylaxis in patients undergoing hip, knee and abdominal surgery
• Fewer DVT following hip and knee surgery compared with enoxaparin
• Similar bleeding
• Treatment of DVT and PE
• PE therapy must begin in hospital
• Noninferior – Compared with LMWH in DVT treatment
– Compared with UFH in PE treatment
» No comparison between fondaparinux & LMWH in PE treatment
Rivaroxaban (Xarelto) • Oral, once daily, Factor Xa inhibitor
• Limited food/drug interactions
• Approved (July 2011) for VTE prophylaxis in orthopedic surgery after comparison with enoxparin
– Significant reduction in
• All VTE
• Major VTE
• VTE + all cause mortality (RECORD 4)
– Equivalent bleeding
Oral Rivaroxaban for Symptomatic DVT & PE • Acute DVT treatment: Rivaroxaban
NONINFERIOR1 to enoxaparin + warfarin
• 36 events (2.1%) Rivaroxaban v. 51 events (3.0%) enoxaparin + warfarin – HR 0.68 (CI 0.44 – 1.04), p < 0.001-noninferiority
• Acute PE treatment (4,000 patients)2
– Rivoroxaban v. enoxaparin + warfarin
• Similar number of recurrences
• Less major bleeding with rivoroxaban
1The EINSTEIN Investigators. N. Eng J Med 2010;363:2499 2The EINSTEIN Investigators. N. Eng J Med 2012;366(14) 1287
Apixaban (Eliquis)
• Oral direct factor Xa inhibitor
• In 5395 patients with acute DVT or PE, Apixiban was NONINFERIOR compared with enoxaparin
– Lower rate of major bleeding (RR 0.31, CI 0.17-0.55)
» Giancarlo A NEJM 2013;369:799-808
• Not currently FDA approved for VTE in US
– Orthopedics prophylaxis in Europe
Dabigatran (Pradaxa) • Oral direct thrombin inhibitor
• Approved for DVT prophylaxis in orthopedic surgery in Europe and Canada
• RECOVER Study
– 2500 patients with acute PE
• Dabigatran v. warfarin
– Similar recurrence and major bleed
• Total bleed lower with dabigatran » NEJM 2009
• No approval in US for VTE prophylaxis or treatment
Take Home Points: New Anticoagulants • Factor Xa inhibitors
• Fondaparinux: (Arixtra)
– Subcutaneous
– Prophylaxis in orthopedic & abdominal surgery
– Treatment of deep vein thrombosis and pulmonary embolism
» Pulmonary embolism treatment must begin in hospital
• Rivoroxaban (Xarelto)
– Prophylaxis (orthopedic surgery)
– Treatment in DVT and PE
• Apixaban (Eliquis)
– Supportive data for orthopedic prophylaxis and treatment; not FDA approved
• Direct thrombin inhibitors
• Dabigatran (Pradxa)
– No indication in US for VTE prophylaxis or treatment despite similar efficacy in pulmonary embolism treatment
Duration of Anticoagulation
• Unprovoked proximal deep vein thrombosis or pulmonary embolism and low to moderate risk of bleeding, extended anticoagulation therapy is recommended
• For those with high risk of bleeding, three months of anticoagulation is recommended
ACCP 2012;141(2)
Duration of Anticoagulation
• Unprovoked venous thromboembolism associated with high rate of recurrence
• Extended anticoagulation with warfarin
– Risk of bleeding, costly, bothersome, drug interactions
Clot Predicts Clot… Risk of Recurrence
• 474 patients followed for recurrence
– 13% recurrence after 5 yrs
– Unprovoked clot greater risk for recurrence than thrombophilia
» Christiansen, SC. JAMA 293; 19: 2352. 2005
• 1626 patients after anticoagulation stopped
– Unprovoked clot associated with 40 % recurrence rate at 10 years
– Odds ratio higher than with thrombophilia » Prandoni P. Haematologica 2007;92(2)199
Recurrence Risk • Patients presenting with pulmonary embolism
are more likely to have a subsequent pulmonary embolism rather than deep vein thrombosis
• Males are at greater risk of recurrence after unprovoked episode
• Risk of recurrence is higher if initial anticoagulation < 3 months
– Recurrence is the same with 3 or 6 months of therapy
Oral Rivaroxaban for VTE: Prolongation Trial
• Rivaroxaban v. placebo • Superiority trial comparing additional 6-12 months
anticoagulation after 6-12 months anticoagulation
• Prolonged therapy associated with lower recurrence
– Recurrent VTE
• 8 events (1.3%) v. 42 events (7.1%) – HR 0.18 (CI 0.09 – 0.39), p < 0.001)
– Bleeding not significantly different
• 4 nonfatal bleeds with rivaroxaban (0.7%) v. none
The EINSTEIN Investigators. N. Eng J Med 2010;363:2499
Oral Apixiban for VTE: Prolongation Trial
• 2,482 patients who had completed 6-12 months of anticoagulation
• Randomized to apixiban 2.5 mg, 5.0 mg or placebo
• Risk of recurrence 8.8% in placebo v. 1.7% in apixiban group
– Recurrence rate not different between two doses
• No significant excess bleeding with apixiban
– All cause mortality higher in placebo group
Giancarlo A. NEJM 2013:368:699-708
Can Aspirin Effective in Secondary Prevention ? (ASPIRE Trial)
• 822 patients with first unprovoked clot who had completed anticoagulation
• Randomized to aspirin (100 mg) or placebo
• Recurrence of VTE less but not significantly so (6.5% v. 4.8%, p=0.09)
– Underpowered-Had planned for N= 3,000
• Lower incidence of both composite outcome of myocardial infarction, stroke or recurrent clot (8.0% v. 5.2%)
Brighton TA. NEJM 367:21, 1979. 2013
WARFASA Trial
• Similar design as ASPIRE trial
• 402 patients who had completed anticoagulation randomized to aspirin or placebo
• Aspirin significantly reduced recurrence of venous thromboembolism
– 6.6% v. 11.8%, HR 0.58, (CI 0.36-0.93)
• No difference in major or minor bleeding or mortality
Becattini C NEJM 2012;366:1959
Take Home Points • Risk of recurrent venous thromboembolism is
substantial
• Extended duration of anticoagulation reduces recurrences
• Continuation of warfarin associated with bleeding risk, monitoring, and drug interactions
• Data supports reduced recurrence risk with rivoroxaban and apixiban compared with placebo
• Aspirin appears to reduce risk of recurrence
Inferior Vena Cava Filters
• Consensus
– Use in acute venous thromboembolism when anticoagulation is CONTRAINDICATED
• Also, complication or failure of anticoagulation
– Do not use routinely in DVT or PE when anticoagulation is not contraindicated
• Uncertain
– Use as adjunctive therapy to anticoagulation or thrombolytic therapy in massive PE
– Prophylactic use in trauma
Adjunctive Therapy in Massive PE • 108 patients with massive PE in International
Cooperative Pulmonary Embolism Registry (ICOPER)1
– 11 patients received an IVC filter
• No recurrent clot in these – 12% recurrence without filter
• 10/11 survived 90 days
• Retrospective review2
– 33/248 (13%) got IVC filter + anticoagulation
– No in hospital deaths in those with filter
– NOT significant difference
1Kucher N Vasc Med 2005; 2Jha VM Cardiovas Intervent Rad 2010;33(4)739
Prophylactic Use of Inferior Vena Cava Filters in Trauma
• Highest incidence of venous thromboembolism among all hospital patients
– Up to 10% DESPITE pharmacological prophylaxis
• Filter placement may be associated with increased risk of deep vein thrombosis in spinal cord injury
– Incidence of DVT 11/54 (20%) with filter v. 3/58 (5%)
– Only 1/112 had pulmonary emobolism-also had filter
» Gorman PH. J Trauma 2009 66: (3)707
Recommendations for Prophylaxis in Trauma
• Prophylaxis
– Heparin or low molecular weight heparin
– Use with sequential compression devices if extremely high risk
– ACCP recommends AGAINST prophylactic use in trauma
» ACCP 2012;141(2)
• All Grade 2C recommendations
– Weak recommendation
– Low or very low quality of data
Inferior Vena Cava Filters Associated with Increased DVT at 2 Years
• Are removable filters the answer?
• Maybe, but…
• Removable filters often aren’t removed
– 71/679 (10%) were removed or attempted to be removed
» Sarosiek S. JAMA Int Med 2013; 173(7) 513
– 17/72 (23%)were removed or attempted to be removed
» Gaspard SF. Am Surg 2009 75(5):426
PREPIC 1998 NEJM
Caveats: Inferior Vena Cava Filters
• The presence of an IVC filter is not an indication for anticoagulation
– Ungraded recommendation ACCP
• The chance of successful removal decreases with increasing duration of a removable filter
• Filters should be imaged prior to removal
– If substantial clot is present weeks of anticoagulation should be utilized before removal
» Kaufman JA. J Vasc Interv Radiol 2006;17:449
Upper Extremity Clot
• Upper extremity clot involving the axillary or more proximal veins
– Anticoagulate
– 3 months duration
– Fondaparinux or low molecular weight heparin recommended over unfractionated heparin
ACCP 2012;141(2)
Catheter Associated Upper Extremity Clot
• Don’t remove the catheter IF
– It is still required
– Is functional
• Anticoagulate * 3 months
– Even if catheter is removed
– Continue anticoagulation if catheter remains
ACCP 2012;141(2)
Take Home Points • Acute clot with contraindication to or
complication or failure of anticoagulation is the only consensus indication for IVC filter
– Data limited on use as adjunctive therapy in massive clot
– Not indicated for routine prophylaxis
– Conflicting data on use in trauma patients » VERY limited data
• Removable filters are not commonly removed
• IVC filter alone is NOT an indication for anticoagulation
Take Home Points
• Anticoagulation for 3 months recommended for upper extremity clot
• For catheter associated upper extremity clot
– Make decision regarding removal of line based on need for line NOT presence of clot
– Anticoagulation is recommended for 3 months even if catheter is removed
– Continue anticoagulation longer than 3 months if catheter remains in place