New Guidance in AT10 Clive Kearon, MD, PhD,

New Guidance in AT10 Clive Kearon, MD, PhD, Professor, Department of Medicine, McMaster University; Program Director, McMaster Clinical Investigator Program, McMaster University Head, Clinical Thromboembolism Service, Juravinkl Hospital; Hamilton, Ontario Objectives: Define the role of aspirin as a means of secondary prevention of venous thromboembolism. Describe a decision-making process to determine whether to offer anticoagulant therapy to patients with isolated sub-segmental pulmonary embolism. Indicate the pharmacologic management options for patients who sustain a new event of venous thromboembolism while receiving therapeutic anticoagulation.

New Guidance in AT10 (Update ACCP/CHEST VTE Treatment) Thrombosis Guidelines 2016 22 April 2016 Murray, Utah Clive Kearon, McMaster University, Canada

Relevant Disclosures Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Canadian Institutes Health Research D-dimer Optimal Duration Study (DODS) No relevant Boehringer Ingelheim Steering Committees & Bayer Inc. No relevant No relevant No relevant No relevant

ACPE Learning Objectives At the conclusion of this activity, participants should be able to successfully: Outline the role of aspirin as a means of secondary prevention of venous thromboembolism. Describe a decision-making process to determine whether to offer anticoagulant therapy to patients with isolated subsegmental pulmonary embolism. Indicate the pharmacologic management options for patients who sustain a new event of venous thromboembolism while receiving therapeutic anticoagulation.

Overview Topics updated Methods & Grading Recommendations (for selected topics)

Update Topics: Which & Why

Update Topics: Which & Why Old (in AT9) New evidence Controversial New New evidence Controversial Demand

Update Topics: Which & Why Old (in AT9) New evidence Controversial 12 topics 26 statements 49 recommends New New evidence Controversial Demand 3 topics 4 statements 5 recommends

Topics Choice of anticoagulant Duration of anticoagulant Aspirin for extended treatment Isolated distal DVT & anticoagulation Catheter Directed Thrombolysis for DVT IVC filters additional to anticoagulation Stockings to prevent PTS Subsegmental PE & anticoagulation Out of hospital PE treatment PE: Lytics, Route & Catheter-based (3) Thromboendarterectomy for CTEPH Upper DVT lytic therapy Recurrent VTE treatment

Topics Choice of anticoagulant Duration of anticoagulant Aspirin for extended treatment Isolated distal DVT & anticoagulation Catheter directed thrombolysis for DVT IVC filters additional to anticoagulation Stockings to prevent PTS Subsegmental PE & anticoagulation Out of hospital PE treatment PE: Lytics, Route & Catheter-based (3) Thromboendarterectomy for CTEPH Upper DVT lytic therapy Recurrent VTE treatment Covered by others

6 Topics I will review Choice of anticoagulant Duration of anticoagulant Aspirin for extended treatment Isolated distal DVT & anticoagulation Catheter directed thrombolysis for DVT IVC filters additional to anticoagulation Stockings to prevent PTS Subsegmental PE & anticoagulation Out of hospital PE treatment PE: Lytics, Route & Catheter-based (3) Thromboendarterectomy for CTEPH Upper DVT lytic therapy Recurrent VTE treatment

Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report Clive Kearon; Elie Akl; Joseph Ornelas; Allen Blaivas; David Jimenez; Henri Bounameaux; Menno Huisman; Christopher King; Timothy Morris; Namita Sood; Scott Stevens; Janine Vintch; Philip Wells; Scott Woller; Lisa Moores. CHEST 2016; 149:315-352

Methods Systematic Review / Meta-Analysis Predefined outcomes (VTE, Bleeding, Mortality) Balance of benefits, harms/burden, costs Quality of evidence Recommendations

Grading of Recommendations

Grading of Recommendations Strength (For or Against) Grade 1: STRONG (stated as: We recommend ) clear benefit applies to most just do it Grade 2: WEAK (stated as: We suggest ) not large benefit or uncertain benefit Decision strongly influenced by: clinical differences patient preference Quality of Evidence A Randomized Trials Precise (narrow CIs) and Bias very unlikely and Consistent B Randomized Trials Less precise (wider CIs) or Bias likely but not major or Inconsistent C Randomized Trials Major limitations Observational Studies (only) not very strong or exceptional

Aspirin for extended treatment VTE?

ASA vs. Placebo for Extended Treatment Unprovoked VTE Studies: 2 Participants: 1,224 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 VTE Mj Bleeding Mortality Simes Circ 2014

Limitations Anticoagulants reduce VTE >80% DOACS suggested if unprovoked & low risk bleeding Bleeding may be similar with ASA & DOACs Both trials stopped early, and imprecision

Limitations Anticoagulants reduce VTE >80% DOACS suggested if unprovoked & low risk bleeding Bleeding may be similar with ASA & DOACs Both trials stopped early, and imprecision Unprovoked proximal DVT or PE & stop anticoags & no contraindication Aspirin over No aspirin Grade 2B

Isolated Distal DVT (guidelines discourage routine calf vein examination)

Isolated Distal DVT (guidelines discourage routine calf vein examination) Symptoms Not Severe AND No RF for Extension* Surveillance US over anticoagulation (eg, repeat at 1 & 2 wks) Grade 2C Severe Symptoms OR Risk Factors for Extension* Anticoagulation over surveillance US Grade 2C (*Suggested: positive D-dimer; extensive thrombosis; close to proximal; no reversible RF; cancer; previous VTE; inpatients)

IVC Filters for DVT or PE

IVC Filters for DVT or PE (AT9) Anticoagulated No Filter* Grade 1B Not Anticoagulated Filter Grade 1B (* may not apply to PE with hypotension) Usual anticoagulation if becomes feasible # Grade 2B ( # permanent filter not a reason for indefinite anticoagulation) Kearon et al CHEST 2012

IVCF vs. No IVCF if anticoagulated PE + DVT + 1 severity factor (RVD in 2/3) Studies: 1 Participants: 399 F-U & Temp IVCF: 3 mo PE-sympt* Mj Bleeding Mortality Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 * Fatal PE: 6/6 vs 2/3 Mismetti, PREPIC 2, JAMA 2015

IVC Filters for DVT or PE Anticoagulated No Filter* Grade 1B Not Anticoagulated Filter Grade 1B (* may not apply to PE with hypotension)

Stockings to prevent PTS?

Stockings to prevent PTS? AT9 Acute DVT GCS* Grade 2B (*30-40 mmhg ankle, 2 yrs)

GCS vs. Placebo after DVT Studies: 1 Participants: 803 F-U: 2 years PTS VTE Pain & QoL Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 Kahn, SOX, Lancet 2014

Stockings to prevent PTS? Acute DVT No GCS Grade 2B

Subsegmental PE (SSPE)

Subsegmental PE (SSPE) (must exclude proximal DVT if not anticoagulating)

SSPE & Recurrence Risk Convincing for SSPE good quality CTPA surrounded by contrast multiple larger ( 1 image/projection) Symptomatic, high CPTP D-dimer elevated (marked, unexplained)

SSPE & Recurrence Risk Convincing for SSPE good quality CTPA surrounded by contrast multiple larger ( 1 image/projection) Symptomatic, high CPTP Higher risk for progression hospitalized/immobile active cancer no reversible RF D-dimer elevated (marked, unexplained)

Subsegmental PE (SSPE) (must exclude proximal DVT if not anticoagulating) Lower Risk Recurrence Clinical surveillance over anticoagulation (may repeat proximal US at 1 ± 2 wks) Grade 2C Higher Risk Recurrence Anticoagulation over clinical surveillance Grade 2C

Recurrent VTE on Anticoagulants

Recurrent VTE on Anticoagulants Management will depend on circumstances

Recurrent VTE on Anticoagulants Management will depend on circumstances Treatment-related questions: true recurrence? started treatment recently? adherent? subtherapeutic INR? drug-induced lowering of DOAC? LMWH therapy? stepped down dose?

Recurrent VTE on Anticoagulants Management will depend on circumstances Patient-related questions: known cancer? cancer needs to be excluded? antiphospholipid antibody? lupus anticoagulant increasing INR? prothrombotic therapy (avoidable)?

Choice of anticoagulant No Cancer DOAC over VKA VKA over LMWH Grade 2B Grade 2C Cancer LMWH over DOAC or VKA Grade 2B

Recurrent VTE on Anticoagulants On DOAC or VKA (and no correctable cause) Switch to LMWH ( 1 mo) Grade 2C Already on LMWH (and no correctable cause) Increase dose ~25% ( 1 mo) Grade 2C

Take Home Messages Unprovoked VTE & Aspirin YES: if stopping anticoagulants & no contra Isolated distal DVT or SubSeg PE YES: some; NO: others (look selectively for DDVT; r/o proximal DVT; US surveillance) Temporary IVCF & anticoagulated PE: NO GCS to prevent PTS: NO Recurrent VTE on anticoagulants Correct cause, LMWH, higher dose LMWH