Treatment of VTE Guidelines 2016 Update of ACCP Treatment of VTE Guidelines ACP 30th Congress, Anaheim 5 November 2016 Clive Kearon, McMaster University, Canada

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

Overview Topics updated Grading of recommendations Recommendations (for selected topics)

Update Topics: Which & Why

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

Update Topics: Which & Why Old (in AT9) New evidence Controversial New Demand 12 topics 26 statements 49 recommends 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 topics) Thromboendarterectomy for CTEPH Upper DVT lytic therapy Recurrent VTE treatment

Topics new new new 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 topics) Thromboendarterectomy for CTEPH Upper DVT lytic therapy Recurrent VTE treatment new new new

Topics 7 I will review new new new 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 new new new

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

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

Choice of anticoagulant

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

Choice of anticoagulant No Cancer DOAC over VKA Grade 2B VKA over LMWH Grade 2C similar efficacy ~2/3 major bleeding, ~1/2 ICB easier for patients

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

Choice of anticoagulant Not Grade 1 for LMWH because: VKA/DOAC often reasonable (eg, no chemo, remission, non-metastatic, later) No Cancer DOAC over VKA Grade 2B VKA over LMWH Grade 2C Cancer LMWH over VKA Grade 2B over DOAC Grade 2B

for extended treatment VTE? Aspirin for extended treatment VTE?

Studies: 2 Participants: 1,224 ASA vs. Placebo for Extended Treatment Unprovoked VTE Studies: 2 Participants: 1,224 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 VTE Mod 0.65 (0.49, 0.86) -60 (-24, -89) Mj Bleeding 1.31 (0.48, 3.5) +4 (-6, +29) Mortality Low 0.82 (0.45, 1.5) -1 (-3, +3) Simes Circ 2014

Studies: 2 Participants: 1,224 ASA vs. Placebo for Extended Treatment Unprovoked VTE Studies: 2 Participants: 1,224 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 VTE Mod 0.65 (0.49, 0.86) -60 (-24, -89) Mj Bleeding 1.31 (0.48, 3.5) +4 (-6, +29) Mortality Low 0.82 (0.45, 1.5) -1 (-3, +3) Simes Circ 2014

Studies: 2 Participants: 1,224 ASA vs. Placebo for Extended Treatment Unprovoked VTE Studies: 2 Participants: 1,224 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 VTE Mod 0.65 (0.49, 0.86) -60 (-24, -89) Mj Bleeding 1.31 (0.48, 3.5) +4 (-6, +29) Mortality Low 0.82 (0.45, 1.5) -1 (-3, +3) Simes Circ 2014

Studies: 2 Participants: 1,224 ASA vs. Placebo for Extended Treatment Unprovoked VTE Studies: 2 Participants: 1,224 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 VTE Mod 0.65 (0.49, 0.86) -60 (-24, -89) Mj Bleeding 1.31 (0.48, 3.5) +4 (-6, +29) Mortality Low 0.82 (0.45, 1.5) -1 (-3, +3) Simes Circ 2014

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

Limitations Unprovoked proximal DVT or PE 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

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 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PE-sympt* Mod 2.0 (0.51, 7.9) +15 (-7, +104) Mj Bleeding 0.80 (0.32, 2.0) -10 (-34, +49) Mortality 1.25 (0.60, 2.6) (-24, +96) * Fatal PE: 6/6 vs 2/3 Mismetti, PREPIC 2, JAMA 2015

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 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PE-sympt* Mod 2.0 (0.51, 7.9) +15 (-7, +104) Mj Bleeding 0.80 (0.32, 2.0) -10 (-34, +49) Mortality 1.25 (0.60, 2.6) (-24, +96) * Fatal PE: 6/6 vs 2/3 Mismetti, PREPIC 2, JAMA 2015

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 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PE-sympt* Mod 2.0 (0.51, 7.9) +15 (-7, +104) Mj Bleeding 0.80 (0.32, 2.0) -10 (-34, +49) Mortality 1.25 (0.60, 2.6) (-24, +96) * Fatal PE: 6/6 vs 2/3 Mismetti, PREPIC 2, JAMA 2015

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 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PE-sympt* Mod 2.0 (0.51, 7.9) +15 (-7, +104) Mj Bleeding 0.80 (0.32, 2.0) -10 (-34, +49) Mortality 1.25 (0.60, 2.6) (-24, +96) * 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 Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PTS Mod 1.01 (0.86, 1.18) +5 (-67, +86) VTE 0.84 (0.54, 1.3) -34 (-97, +65) Pain & QoL No difference Kahn, SOX, Lancet 2014

GCS vs. Placebo after DVT Studies: 1 Participants: 803 F-U: 2 years Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PTS Mod 1.01 (0.86, 1.18) +5 (-67, +86) VTE 0.84 (0.54, 1.3) -34 (-97, +65) Pain & QoL No difference Kahn, SOX, Lancet 2014

GCS vs. Placebo after DVT Studies: 1 Participants: 803 F-U: 2 years Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PTS Mod 1.01 (0.86, 1.18) +5 (-67, +86) VTE 0.84 (0.54, 1.3) -34 (-97, +65) Pain & QoL No difference Kahn, SOX, Lancet 2014

GCS vs. Placebo after DVT Studies: 1 Participants: 803 F-U: 2 years Qual Evid (GRADE) Hazard Ratio Difference Per 1,000 PTS Mod 1.01 (0.86, 1.18) +5 (-67, +86) VTE 0.84 (0.54, 1.3) -34 (-97, +65) Pain & QoL No difference 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)

Others that favor no anticoagulation 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) Others that favor no anticoagulation High bleeding risk; Good cardiopulmonary reserve Patient preference

Others that favor no anticoagulation 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) Others that favor no anticoagulation High bleeding risk; Good cardiopulmonary reserve Patient preference

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

PE and Systemic Thrombolysis AT9 No hypotension (BP >90 mmHg) No Lysis Grade 1C Hypotension & Not High Bleeding Risk Lysis Grade 2B

Fibrinolysis for Intermediate-Risk PE RVD (echo or CTPA) + Myocardial injury (troponin I or T) 1006 patients (tenecteplase ~0.5 mg or 100 U/kg) 7 days Tenect. Placebo Diff. Death 6 9 PE 1 7 -6 Bleeding 5 +5 Non-fatal Strokes +6 Major Bleeds 58 12 +46 Cardio Decomp. 8 25 -17 Meyer, PEITHO, NEJM 2014

Fibrinolysis for Intermediate-Risk PE RVD (echo or CTPA) + Myocardial injury (troponin I or T) 1006 patients (tenecteplase ~0.5 mg or 100 U/kg) 7 days Tenect. Placebo Diff. Death 6 9 PE 1 7 -6 Bleeding 5 +5 Non-fatal Strokes +6 Major Bleeds 58 12 +46 Cardio Decomp. 8 25 -17 Meyer, PEITHO, NEJM 2014

Fibrinolysis for Intermediate-Risk PE RVD (echo or CTPA) + Myocardial injury (troponin I or T) 1006 patients (tenecteplase ~0.5 mg or 100 U/kg) 7 days Tenect. Placebo Diff. Death 6 9 PE 1 7 -6 Bleeding 5 +5 Non-fatal Strokes +6 Major Bleeds 58 12 +46 Cardio Decomp. 8 25 -17 Meyer, PEITHO, NEJM 2014

PE and Systemic Thrombolysis AT10 No hypotension (BP >90 mmHg) No Lysis Grade 1B Hypotension & Not High Bleeding Risk Lysis Grade 2B

PE and Systemic Thrombolysis AT10 No hypotension (BP >90 mmHg) No Lysis Grade 1B Hypotension & Not High Bleeding Risk Lysis Grade 2B Selected patients who deteriorate but not yet hypotensive & low bleeding risk (with qualifying remark) No Lysis 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 Grade 2B VKA over LMWH Grade 2C Cancer LMWH over VKA Grade 2B over DOAC Grade 2B

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

Take Home Messages DOACS over VKA Aspirin after anticoags in unprovoked VTE if Isolated SubSeg PE:YES: some; NO: others Temporary IVCF & anticoagulated PE: NO GCS to prevent PTS: NO Lytics only if PE with hypotension Recurrent VTE on anticoagulants Correct cause, LMWH, higher dose LMWH