Dilemmas in Venous Thromboembolic Disease 2013

Margaret M. Johnson, MD Associate Professor of Medicine

Chair, Division of Pulmonary Medicine Mayo Clinic Florida

Johnson.margaret2@mayo.edu

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

Is Aspirin the Answer?

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