1000 - johnson venous thromb
TRANSCRIPT
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