VTE. The 3 rd vascular diagnosis after Heart Attack and Stroke. Affects 300, ,000 Americans each year.

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1 VTE DVT & PE

2 VTE The 3 rd vascular diagnosis after Heart Attack and Stroke Affects 300, ,000 Americans each year. PE is the most common preventable cause of death among hospitalized patients.

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5 Signs & Symptoms Classical symptoms: Calf pain, swelling, tenderness, warmth Wells criteria:

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7 Proximal DVT Distal DVT Phlegmasia cerulea dolens

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10 DVT Inherited Acquired Combination

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12 VIRCHOW'S TRIAD Alterations in blood flow (ie, stasis) Vascular endothelial injury Alterations in the constituents of the blood (ie, inherited or acquired hypercoagulable state)

13 56% had 3 or more of following Factors More than 48 hours of immobility in the preceding month 45 percent Hospital admission in the past three months 39 percent Surgery in the past three months 34 percent Malignancy in the past three months 34 percent Infection in the past three months 34 percent Current hospitalization 26 percent Thromb Haemost. 2001;86(1):92. (up To date)

14 Low Probability High Sensitivity D-Dimer Normal D-Dimer: No further testing Positive D- Dimer: Compression Ultrasound imaging Positive Ultrasound for DVT: Treat

15 Moderate Probability High Sensitivity D-Dimer Normal D-Dimer: no further testing Positive D-Dimer : Compression Ultrasonography Proximal DVT : Treat Distal DVT meeting criteria for treatment Treat If proximal DVT negative by CU repeat CU in one week to evaluate for possible extension of DVT.

16 High Probability D-Dimer can not be used. Not reliable in HP Compression ultrasonography of whole leg. If Positive: Treat If Negative : No further testing Doppler Ultrasound of the iliac veins Repeat study in 24 hours CT venography

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18 Treatment for DVT Heparin Enoxaparin Warfarin DOACs CDT Thrombolytic IVC filter

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22 Pulmonary embolism Obstruction of the pulmonary artery on its branches by material originating from other part of the body Air, blood clots, tumor or fat. Acute: as soon as the event happens Subacute: within days or weeks Chronic: Years, CTEPH

23 Hemodynamic Unstable (massive ) PE Hypotension BP less than 90mmHg or greater than 40mmHg BP drop from baseline for over 15min Requirement of vasopressors Unexplained by other causes. Hemodynamically stable (sub massive) PE Does not meet the above, respond rapidly to fluids May have right ventricular strain and dysfunction Low risk : normal RV function with no strain

24 Anatomic Location Saddle Lobar Segmental Sub segmental Unilateral Bilateral Symptomatic asymptomatic

25 Clinical Presentation abrupt onset of pleuritic chest pain, shortness of breath, hypoxia.

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27 Clinical signs Tachypnea (respiratory rate >16/min): 96% Rales: 58% Accentuated second heart sound: 53% Tachycardia (heart rate >100/min): 44% Fever (temperature >37.8 C): 43% Diaphoresis: 36% S 3 or S 4 gallop: 34% Clinical signs and symptoms suggesting thrombophlebitis: 32% Lower extremity edema: 24% Cardiac murmur: 23% Cyanosis: 19%

28 Atypical Symptoms Seizures Syncope Abdominal pain Fever Productive cough Wheezing Decreasing level of consciousness New onset of atrial fibrillation Hemoptysis Flank pain Delirium (in elderly patients)

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30 Diagnositc test ABG Hypoxemia (74 percent) Widened alveolar-arterial gradient for oxygen (62 to 86 percent) Respiratory alkalosis and hypocapnia (41 percent) CBC, CMP, LDH D-Dimer EKG

31 Chest X-Ray

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36 February 2016, Vol 149, No. 2 Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report

37 Stroke Prevention in Atrial Fibrillation INR Control in the ACTIVE-W Study The ACTIVE-W Study INR Range Percent patient months in range < > Lancet 2006; 367:

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42 Indications Reduction of stroke and systemic embolism in non valvular Afib Treatment of DVT Treatment of PE DVT prophylaxis Knee or hip replacement.

43 Rivoraxaban Selective Inhibitor of Factor Xa and the prothombinase activity. In-Vitro selectively inhibits both free and clot bound Fxa and prothombinase activity.

44 Rivoroxaban Elimination half life: 5-9 hours in healthy year old hours in the elderly 15 & 20 mg dose should be taken food 10 mg dose can be taken with or without food.

45 WARNINGs Black box warning: 1. Premature discontinuation 2. Spinal/ Epidural Hematoma

46 Study Overview In this clinical trial, rivaroxaban, an oral factor Xa inhibitor, was effective in the initial and continued treatment of symptomatic venous thromboembolism; it may become part of the treatment armamentarium for this common clinical problem.

47 Rivaroxaban Einstein- DVT Einstein PE Einstein Extended (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT and NCT )

48 Original Article Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism The EINSTEIN PE Investigators N Engl J Med Volume 366(14): April 5, 2012

49 EINSTEIN - PE

50 Einstein- PE

51 Cumulative Rates of the Primary Efficacy and Safety Outcomes and Rates of Major Bleeding. The EINSTEIN PE Investigators. N Engl J Med 2012;366:

52 Einstein - DVT

53 Kaplan Meier Cumulative Event Rates for the Primary Efficacy Outcome in the Two Studies. The EINSTEIN Investigators. N Engl J Med 2010;363:

54 Einstein DVT

55 EINSTEIN-EXTENTION

56 EINSTEIN-EXTENTION

57 ELIQUIS (Apixaban)

58 Original Article Oral Apixaban for the Treatment of Acute Venous Thromboembolism Giancarlo Agnelli, M.D., Harry R. Buller, M.D., Ph.D., Alexander Cohen, M.D., Madelyn Curto, D.V.M., Alexander S. Gallus, M.D., Margot Johnson, M.D., Urszula Masiukiewicz, M.D., Raphael Pak, Ph.D., John Thompson, Ph.D., Gary E. Raskob, Ph.D., Jeffrey I. Weitz, M.D., for the AMPLIFY Investigators N Engl J Med Volume 369(9): August 29, 2013

59 Study Overview In this multicenter trial, the oral factor Xa inhibitor apixaban was compared with enoxaparin and warfarin for the treatment of acute venous thromboembolism. Apixaban was noninferior to enoxaparin and warfarin with respect to efficacy and superior with respect to safety.

60 Kaplan Meier Cumulative Event Rates. Agnelli G et al. N Engl J Med 2013;369:

61 Conclusions A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding.

62 ENDOXABAN

63 Original Article Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism The Hokusai-VTE Investigators N Engl J Med Volume 369(15): October 10, 2013

64 Study Overview The anticoagulant edoxaban, an oral inhibitor of activated factor X, does not require monitoring. As initial treatment for acute venous thromboembolism, heparin edoxaban was noninferior to heparin warfarin and caused less bleeding.

65 Randomization and Follow-up. The Hokusai-VTE Investigators. N Engl J Med 2013;369:

66 K Kaplan MeieKaplan Meier Cumulative Event Rates for the Primary Efficacy Outcomer Cumulative Event Rates for the Primary Efficacy Outcome aplan Meier Cumulative Event Rates for the Primary Efficacy Outcome. The Hokusai-VTE Investigators. N Engl J Med 2013;369:

67 Kaplan Meier Cumulative Event Rates for the Principal Safety Outcome. The Hokusai-VTE Investigators. N Engl J Med 2013;369:

68 Conclusions Edoxaban administered once daily after initial treatment with heparin was noninferior to highquality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism.

69 DABIGATRAN

70 Original Article Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism Sam Schulman, M.D., Clive Kearon, M.D., Ajay K. Kakkar, M.D., Patrick Mismetti, M.D., Sebastian Schellong, M.D., Henry Eriksson, M.D., David Baanstra, M.Sc., Janet Schnee, M.D., Samuel Z. Goldhaber, M.D., for the RE-COVER Study Group N Engl J Med Volume 361(24): December 10, 2009

71 Study Overview In this comparative-effectiveness trial, the oral direct thrombin inhibitor dabigatran was shown to be as effective as warfarin in the prevention of recurrent venous thromboembolism Bleeding complications were similar Dabigatran therapy offers the advantage that monitoring of anticoagulation is not necessary

72 Cumulative Risks of a First Event of Major Bleeding and of Any Bleeding among Patients Randomly Assigned to Dabigatran or Warfarin Schulman S et al. N Engl J Med 2009;361:

73 Cumulative Risk of Recurrent Venous Thromboembolism or Related Death during 6 Months of Treatment among Patients Randomly Assigned to Dabigatran or Warfarin Schulman S et al. N Engl J Med 2009;361:

74 Adverse Events during the Double-Dummy Phase and during the Total Period of Treatment Schulman S et al. N Engl J Med 2009;361:

75 Specific Patient Characteristics Which DOAC? High Risk of Bleeding (eg, HAS-BLED 3) Previous GI bleeding or high risk High risk of ischemia stroke, low bleeding risk Consider agent/dose with lowest incident of bleeding Consider agent with lowest reported incident of GI bleed Consider agent/dose with best reduction of ischemia stroke Apixaban Edoxaban Apixaban Dabigatran Previous stroke (secondary prevention) Consider best investigated agent Rivarox aban CAD, previous MI or high risk for ACS/MI Consider agent with a positive effect in ACS Rivarox aban Renal impairment Consider agent least dependent on renal function/best data Apixaban Edoxaban GI/upset disorders Consider agent/dose with no reported GI/effects Apixaban Edoxaban Rivaroxaba n Patient preference Consider once-daily formulation Edoxaban Rivaroxab an

76 Discuss important treatment consideration with patient. Do not discontinue therapy without consulting healthcare provider Be alert for signs and symptoms of bleeding Inform clinician before undergoing any invasive procedure, including dental work, Neuraxial procedures

77 Management of Interruption of DOAC Therapy Drug Patient Procedure Drug half-life Renal function Bleeding risk Route of clearance Concomitant drugs (eg, Aspirin) Thrombotic risk Epidural or spinal hematoma, which may result in long term or permanent paralysis, have occurred in patients treated with Dabigatran or Rivaroxaban who are receiving neuroaxial anesthesia or undergoing spinal puncture

78 Cessation of NOAC Before Planned Surgery Dabigatran Apixaban Edoxaban Rivaroxaban CrCl, ml/min No important bleeding risking/or adequate local hemostasis possible: perform at trough level (ie, 12h or 24h after last intake) Low Risk High Risk Low Risk High Risk Low Risk High Risk Low Risk High Risk 80 24h 48h 24h 48h 24h 48h 24h 48h h 72h 24h 48h 24h 48h 24h 48h h 96h 24h 48h 24h 48h 24h 48h Not indicated Not indicated 36h 48h 36h 48h 36h 48h <15 No official indication for use

79 Cessation of NOAC Before Planned Surgery Dabigatran Apixaban Edoxaban Rivaroxaban CrCl, ml/min No important bleeding risking/or adequate local hemostasis possible: perform at trough level (ie, 12h or 24h after last intake) Low Risk High Risk Low Risk High Risk Low Risk High Risk Low Risk High Risk 80 24h 48h 24h 48h 24h 48h 24h 48h h 72h 24h 48h 24h 48h 24h 48h h 96h 24h 48h 24h 48h 24h 48h Not indicated Not indicated 36h 48h 36h 48h 36h 48h <15 No official indication for use

80 Post-operative Resumption of DOACs: A Sug Management Approach Drug Dabigatran Surgery With Low Bleeding Risk Resume one day after surgery (24 h post-operative) 150 mg BID Surgery With High Bleeding Risk Resume 2-3 days after surgery (48-72 h postoperative) 150 mg BID Rivaroxaban Apixaban Resume one day after surgery (24 h post-operative) 20 mg QD Resume one day after surgery (24 h post-operative) 5 mg BID Resume 2-3 days after surgery (48-72 h postoperative) 20 mg QD Resume 2-3 days after surgery (48-72 h postoperative) 5 mg BID Caution is advised with re-administration of a DOAC following neuro-axial anesthesia or procedures. Caution is also advised with removal of epidural catheters following re-dosage of a DOACs. For patients at high risk for thromboembolism, consider administrating Dabigatran at 50% of the total dose for thromboprophylaxis on the evening after surgery and on the following day (1st post-op day) Consider a reduced dose (Rivaroxaban 10 mg QD or Apixaban 2.5 mg BID) starting the morning after surgery for the 1st 2-3 days followed by increasing the treatment dose regimen