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Ed Kersh, MD, FACCChief of Cardiology, St Luke’s, SF

Clinical Professor of Medicine,UCSF and Dartmouth School of Medicine

History Epidemiology Anatomy Risk Factors Diagnosis Consequences Acute treatment Long term treatment Prevention

1821 – 1902 Father of modern

pathology (Virchow’s node)

Described PE as a consequence of DVT in 1856

Died of pulmonary embolism after leg fracture

Virchow’s Triad

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The Vascular, Rheologic, Biochemical, and Molecular Environment of Deep-Vein Thrombosis.

proponent for democracy social welfare programs medical care for the impoverished prohibition of child labor protection for pregnant women decrease of the work day in hazardous jobs separation of church and state The Sausage Duel

Annual incidence 2-3/1000 Incidence increases with age 100,000 deaths/year 550,000 hospitalizations 50% no obvious factor (unprovoked) Recurrence rate 10%/year unprovoked Recurrence rate 1%/year transient provoked

Deep Veins Superficial Veins Proximal Veins Distal Veins

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Most DVTstarts here

Most pulmonary emboli start here

Rarely thrombusextends fromthe GSV intothe femoralvein

Surgery Trauma Immobility Thrombophillia Cancer Hormones

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Risk Factors for Venous Thromboembolism. Recurrent VTE among Women on OC’s vs. Women Not Taking OC’s at the Time of a First Thrombotic Event

Kyrle, P. et al. N Engl J Med 2004;350:2558-2563

CLINICAL SITUATION DURATION OF TREATMENT

Provoked with transient risk factor

Provoked with ongoing risk factor

Unprovoked

Recurrent

Distal (provoked or unprovoked)

3 months

Indefinite or until resolution

6 months + investigate

Indefinite

3 months

Duration of Anticoagulant Therapy for Patients with Acute Deep-Vein Thrombosis

About 20% of patients with unprovoked venous thrombosis and no defined risk factors have a recurrence within the first 2 years after stopping anticoagulation.

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Low Wells Score + negative D-dimer 99% negative predictive value

THROMBUS

Rarely PerformedCostDye

InvasivePainful

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Limb Swelling Unilateral—acute (9) Unilateral—chronic, persistent (7) Bilateral—acute (8) Bilateral—chronic, persistent No alternative diagnosis identified(6)Limb Pain (Without Swelling) Nonarticular (7) Knee pain (4) Tender, palpable cord in the lower extremity (8) Shortness of Breath Suspected pulmonary embolus (8) Diagnosed pulmonary embolus (7) Fever of unknown origin (no indwelling lower extremity venous catheter) (5) Fever with indwelling lower extremity venous catheter (5)Surveillance of calf vein thrombosis for proximal propagation in patient with contraindication to anticoagulation (7) New lower extremity pain or swelling while on anticoagulation (7) Before anticipated discontinuation of anticoagulation treatment (5) Shortness of breath in a patient with known lower extremity DVT (5) Surveillance after diagnosis of lower extremity superficial phlebitis not on anticoagulation, phlebitis location ≤5 cm

from deep vein junction (7)Surveillance after diagnosis of lower extremity superficial phlebitis not on anticoagulation, phlebitis location ≥5 cm

from deep vein junction (5) Screening Examination for Lower Extremity DVT after orthopedic surgery (3) Prolonged ICU stay (e.g., >4 days) (3) In those with high risk: acquired, inherited, or hypercoagulable state (3) Positive D-dimer test in a hospital inpatient (2) Post-Endovenous Saphenous Ablation + Lower extremity swelling or pain (8) Patent foramen ovale with suspected paradoxical embolism for patient without lower extremity pain or swelling

obstruction (7)

CBC with platelets PT/INR, PTT Homocysteine Protein C Protein S Factor V Leiden Lupus anticoagulant Anticardiolipin Ab

Who to test:UnprovokedFamily hxRecurrentUnusual locationsWarfarin skin necrosis

Embolism (50%) Phlegmasia Venous incompetance CTEPH

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Phlegmasia Cerulea Dolens

Can producelower limb ischemia with compartmentsyndrome and venous gangrene

Contrasting Effects of Steady, Laminar Shear Stress (Panel A) and Turbulent or Reversing Shear Stress (Panel B) on Vessel Walls

Bergan J et al. N Engl J Med 2006;355:488-498

Action of the Musculovenous Pump in Lowering Venous Pressure in the Leg

Bergan J et al. N Engl J Med 2006;355:488-498

Clinical Manifestations of Chronic Venous Disease

Bergan J et al. N Engl J Med 2006;355:488-498

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Thrombolytics Unstable PE Massive iliofemoral thrombosis

Filters Cannot use anticoagulants Proximal thrombosis and/or PE Acute recurrence

Heparin + Coumadin NOAC’s

Contraindications to Anticoagulant Therapy.

Options for the Initial Treatment of Deep-Vein Thrombosis with Anticoagulant Agents.

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Rivaroxaban vs Enoxaparin/Warfarin in Acute DVT:Noninferior with equal bleeding

The EINSTEIN Investigators. N Engl J Med 2010;363:2499-2510

Schulman S et al. N Engl J Med 2009;361:2342-2352 RE-COVER

Dabigatran was shown to be as effective as warfarin in Acute VTE

Less bleeding among Patients Randomly Assigned to Dabigatran vs. Warfarin

Schulman S et al. N Engl J Med 2009;361:2342-2352 RE-COVER

Apixaban in Acute DVT: Non-inferior with less bleeding

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Complications:EmbolizationMigrationFracture

Urban>RuralUse drivenBy the Rule ofThe Hammer

<10% ofRemovable filtersAre removed

50% have noclear indication

IVC filters: in use for 30 years, but efficacy never proven Long Term Treatment

40%

Likelihood of Recurrent Venous Thromboembolism According to Sex

Kyrle, P. et al. N Engl J Med 2004;350:2558-2563

Thrombophilic Abnormalities Associated with Recurrent VTE after the Cessation of Anticoagulants

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Einstein Extended: Rivaroxaban vs Placebo Superior Long Term

The EINSTEIN Investigators. N Engl J Med 2010;363:2499-2510

Einstein Extended: Rivaroxaban vs PlaceboDecreased VTE but more bleeding

The EINSTEIN Investigators. N Engl J Med 2010;363:2499-2510

Agnelli G et al. N Engl J Med 2013;368:699-708

apixaban reduced the risk of recurrence without increasing the rate of bleeding n=2400

Amplify Extended: APIXABAN VS PLACEBO Apixaban vs Warfarin Extended Treatment of VTEafter 6 to 12 months of anticoagulation therapy for VTE, apixaban vs warfarin reduced the risk of

recurrence with less serious bleeding n=5400)

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Schulman S et al. N Engl J Med 2013;368:709-718

Dabigatran carried a lower risk of bleeding than warfarin but a higher risk than placebo

Major Outcomes of Four Trials Comparing Extended Treatments for Venous Thromboembolism.

What about Aspirin?

Brighton TA et al. N Engl J Med 2012;367:1979-1987

ASPIRIN: Risks of First Recurrent VTE and Major Vascular Events

Brighton TA et al. N Engl J Med 2012;367:1979-1987

aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of VTE but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit.

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Aspirin or PlaceboRisk of Recurrent VTE in Patients with

Unprovoked VTE following 6-18 months of Warfarin.

Becattini C et al. N Engl J Med 2012;366:1959-1967

Travelling Post THR/TKR Medically ill Recurrence

Dress in loose-fitting clothes and shoes. No banded constriction.

Stay well hydrated. Exercise legs and feet Fitted compression stockings of 20 mm. Hg Anticoagulants : ASA, enoxaparin, NOAC’s??

THR Efficacy Outcomes: Apixaban vs Enoxaparinn= 5765

Apixaban was superior to enoxaparin for the prevention of thromboembolism after hip replacement,without an increase in the risk of bleeding

Lassen MR et al. N Engl J Med 2010;363:2487-2498

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Eriksson BI et al. N Engl J Med 2008;358:2765-2775

THR: rivaroxaban vs enoxaparin was more effective in preventing VTEwithout a significant increase in major bleeding

TKR Efficacy Outcomes: Apixaban vs EnoxaparinN= 3195

Lassen MR et al. N Engl J Med 2009;361:594-604

Statistically, the noninferiority of apixaban was not demonstrated, but its use was associated with lower rates of clinically relevant bleeding

The Medically Ill Patient:Risk Factors for Venous Thromboembolism in Hospitalized Patients

Francis C. N Engl J Med 2007;356:1438-1444

Prophylaxis for VTE in High-Risk Hospitalized Patients

Francis C. N Engl J Med 2007;356:1438-1444

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Kakkar AK et al. N Engl J Med 2011;365:2463-2472

enoxaparin plus elastic stockings vs elastic stockings alone

Cohen AT et al. N Engl J Med 2013;368:513-523

Medical Patients: 10 days of rivaroxaban was noninferior to 10 days of enoxaparin for thromboprophylaxis.

Extended-duration rivaroxaban treatment (35 days) reduced the risk of venous thromboembolism.

Rivaroxaban was associated with an increased risk of bleeding

History – Virchow’s Triad Epidemiology Anatomy Risk Factors Diagnosis Consequences Acute treatment – NOAC’s will replace warfarin Long term treatment – provoked vs unprovoked Prevention