Diagnosis and Management of VTE

Diagnosis and Management of VTE Tracy Minichiello, M.D. Professor of Medicine University of California, San Francisco Chief, SF VA Anticoagulation & Thrombosis Service Disclosures I have nothing to disclose 1

TOPICS Diagnostic algorithm for DVT/PE Risk stratification for PE Thrombolysis for submassive PE Thrombophilia work up Duration of anticoagulation for VTE CASE #1 A 55 yo morbidly obese man presents with pain and swelling in his calf. Right calf is 4 cm greater than left. A proximal leg ultrasound is negative for DVT. You: 1) Send him home. DVT ruled out. 2) Get a d-dimer 1 st and if negative send him home. DVT ruled out. 3) Send him home without d-dimer but have him return for repeat ultrasound in 1 week 2

it Or if u/s non diagnostic For patients with moderate pre test probability: If u/s of proximal veins only will need repeat u/s in one week UNLESS d-dimer negative For high pretest Prob start with u/s. cannot use d-dimer alone Repeat u/s in 1 week ACCP Guideline Imaging Whole leg ultrasound preferred if low probability of returning for serial studies or severe symptoms c/w calf vein thrombosis Follow up imaging Isolated calf vein thrombosis and no tx Mod/high pretest prob, + d-dimer, prox u/s: get repeat u/s in 1 week Extensive swelling and positive d-dimer or no d-dimer and u/s negative-look for iliac vein thrombus 3

Recurrent DVT diagnosis Use highly sensitive d-dimer over moderately sensitive d-dimer If initial u/s is negative and d-dimer is negative DVT ruled out. If initial u/s is negative and d-dimer is positive or not done then get repeat u/s on day 7 If initial u/s is abnormal but not clearly positive get repeat u/s on day 2 and day 7 CASE #1 A 55 yo morbidly obese man presents with pain and swelling in his calf. Right calf is 4 cm greater than left. A proximal leg ultrasound is negative for DVT. You: 1) Send him home. DVT ruled out. 2) Get a d-dimer 1 st and if negative send him home. DVT ruled out. 3) Send him home without d-dimer but have him return for repeat ultrasound in 1 week 4

CASE #2 A 65 year-old man presents with pleuritic chest pain. His BP is 120/70, HR 95, RR is 18, and his O2 sat is 98%. His physical exam is unremarkable. You determine he is low probability for PE. Case #2 You would consider PE ruled out in this gentleman if d-dimer is less than: 1) 500 mcg/l 2) 650 mcg/l 3) Hold please. I need to look this one up. 5

Determining Pretest Probability of PE WELLS: modified-includes clinician judgment ;has been evaluated in small studies on inpatients 80-99% NPV if score 4 Geneva: simplified revisedoutpatients only Miniati/Charlotte Clinician s gestalt Posadas-Martinex. Thromb Reseach 2014.Bahi J Hosp Med 2011: Ceriani et al J Thromb Haemost. 2010 Penazola et al Ann Emerg Med 2013 6

Age Adjusted D-dimer in Low/Int Prob PE Age (yrs)x 10 mcg/l Figure Legend: Righini et al ADJUST-PE study JAMA. 2014 6 highly sensitive d-dimer assays used Date of download: 10/9/2014 Copyright 2014 American Medical Association. All rights reserved. Age Adjusted D- Dimer to Rule Out PE 3 month failure rate of d-dimer between 500 and age adjusted cut off was 0.3% pts> 75 yo - % of pts in whom PE could be excluded from 6% to 30% 1 in 3.4 would have PE ruled out with age adjusted vs 1 in 16 if not adjusted Righini et al ADJUST PE study JAMA. 2014 Date of download: 10/9/2014 7

Case #2 You would consider PE ruled out in this gentleman if highly sensitive d-dimer is less than: 1) 500 mcg/l 2) 650 mcg/l 3) I can never remember the cut off. CASE #2a His d-dimer returns. It is 2000 mcg/l. A CTa shows multiple pulmonary emboli. What is this patient's risk of early mortality related to PE? A) 1% B) 15% C) 30% 8

Pulmonary Embolism Severity Index Risk Factor points Age age Male 10 Cancer 30 Heart failure 10 Chronic lung 10 disease HR > 110 20 SBP < 100 mmhg 20 RR >30 20 Temp < 36 20 Δ mental status 60 O2 sat <90% 20 Aujesky et al Eur Heart Journal 2006 class Points 30 day mortality I 0-65 <1.7% II 66-85 <3.5% III 86-105 <7.1% IV 106-125 4-11% V >125 10-25% Simplified Pulmonary Embolism Severity Index Risk Factor points Age 1 if > 80 Cancer 1 Heart failure lung 1 disease SBP < 100 mmhg 1 O2 sat <90% 1 Severity class Points 30 day mortality LOW 0 1% HIGH 1 or more 10% Jimenez, D. et al. Arch Intern Med 2010 9

Hestia Criteria Hestia criteria Zondag et al Journal of Thrombosis and Haemostasis, 11 APR 2013 10

IDENTIFICATION OF HIGH RISK NORMOTENSIVE PATIENTS WITH PE Mortality 1% 15-20% Jiménez D et al. Thorax 2011;66:75-81 Pulmonary embolism protocol Ahmad N et al. Thorax 2011 11

CASE #2 What is this patient's risk of early mortality related to PE? A) 1% B) 15% C) 30% 65 yo male with PMHx, normal VS except HR 95 PESI II Simplified PESI 0 Hestia negative Case #3 You decide to a) Admit the patient for anticoagulation and monitoring b) Discharge patient to home with LMWH/warfarin or rivaroxaban and arrange close follow up as outpatient 12

Outpatient Treatment of Pulmonary Embolism (OPTE) outcome Out N=171 In N=168 Difference in %age p value Recurrent 1 0 0.6% 0.01 VTE Major 3 0 1.8% 0.08 bleed* Mortality 1 1 0.6% 0.05 Excluded: O2 sat < 90%, SBP<100, chest pain active or high risk bleeding, recent CVA GIB in past 2 weeks, plt<75k, crcl < 30, wt > 150 kg, anticoagulation failure, poor follow up If discharged called every day for one week major bleeds-2 IM hematomas day 3/13; 1 DUB day 50 No difference in #hospital readmissions, ED visits, in 90 days LOS 0.5 days vs 3.9 days Aujesky D. et al. Lancet. 2011 Jul 2;378 How Long is Long Enough? Aujesky Arch Intern Med. 2008 13

PESI 48 Case #4a A 55 year old man presents with sudden onset chest pain and shortness of breath. A CT shows saddle PE. BP is 120/85 HR 115 O2 sat 92% on RA. ECG with right heart strain. Echo confirms right heart strain with RV dilation and loss of inspiratory collapse. You a) Treat with heparin b) Treat with thrombolytics and heparin 14

Thrombolysis for Submassive PE Thrombolysis for Submassive PE 15

PEITHO Trial Major bleed 11% v 2.4% > 75 highest risk Meyer NEJM 2014 Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage: A Meta-analysis Mortality with lysis 2.17% vs 3.89% without; NNT 59 : Risk of recurrent PE 1.17% vs 3.04% Major bleed 9.24% vs 3.42% NNH 18 (not ed if 65 yo) ICH 1.46% vs 0.19% NNH 78 Chaterjee JAMA 2014 Date of download: 8/12/2014 16

MOPPET Trial Case #4a A 55 year old man presents with sudden onset chest pain and shortness of breath. A CT shows saddle PE. BP is 120/85 HR 115 O2 sat 92% on RA. ECG with right heart strain. Echo confirms right heart strain with RV dilation and loss of inspiratory collapse. You a)treat with heparin b)consider thrombolytics and heparin Get troponin,? U/S LE Consider half dose esp if <65 kg 17

Case #4b Should you send a thrombophilia work up on this gentleman? a) Yes b) No Impact of Thrombophilia on Recurrence Risk Patient group Recurrence of VTE per Year total 2.6% 1 thrombophilia defect 2.5% Iniitial VTE provoked 1.8% Initial VTE unprovoked 3.3% Unprovoked with thrombophilia 3.4% Unprovoked without thrombophilia 3.2% Christiansen JAMA 2005 Shulman Amer j Med 1998 18

Impact of Acute Thrombosis & Anticoagulation on Thrombophilia Testing test Acute VTE Heparin Warfarin Anticardiolipin antibodies Lupus anticoagulant May be elevated May be prolonged no effect prolonged no effect prolonged Protein C, S decreased No effect decreased Antithrombin level decreased decreased increased Factor VIII level increased no effect no effect TSOAC and Thrombophilia Testing Mani et al White Paper Siemans 2013 19

Work up for Laboratory Thrombophilia Women of childbearing years Patients with suspicion for APLS Strong family history of VTE Patients with recurrent VTE Thrombosis in weird places Results will influence therapy If done prefer to do when out of acute phase (after 3 months/except when high suspicion for APLS) Case #5a:How long will you recommend this patient stay on anticoagulation? 55 yo man with unprovoked PE? a) 3 months b) 6 months c) 12 months d) Indefinitely 20

Case #5b:How long will you recommend this patient stay on anticoagulation? 68 yo woman with provoked PE? a) 3 months b) 6 months c) 12 months d) Indefinitely Risk of VTE Recurrence After Cessation of VTE Risk factor 1st yr Next 5 yrs Distal DVT 3% (6%) <10% Majortransient 3% 10% Minortransient 5-6% 15% Unprovoked At least 10% 30% Recurrent > 10% > 30% Kearon, Blood 2005 21

Guidelines for Duration of Anticoagulation for VTE Indication 8th ACCP guidelines 2012 AHA 2010 British Hematology 2011 First episode of VTE secondary to a transient risk factor First episode of idiopathic (unprovoked) VTE 3 months (Grade 1B). At least 3 months, prefer long-term treatment if risk/benefit ratio ok (Grade 2B). 3 months (Class I Level A) 3 months At least 6 months, consider indefinite (Class I Level A) At least months;consider long term if risk benefit favors (2B) Recurrent VTE Long term (Grade 1B). Indefinite Class I Level A). Clinical presentation predicts likelihood and type of recurrence Distal (calf vein thrombosis) Low risk of recurrence/pe Proximal- nearly 5 fold increased recurrence risk over distal PE vs. DVT Patients presenting with PE are 3x more likely to suffer recurrent PE than those presenting with DVT Baglin T et al J Thromb Haemost. 2010 22

Individual Bleeding Risk on Anticoagulation Bleeding Risk Factors Age > 75 Previous GI bleed with no reversible cause Previous bleed on warfarin Renal/hepatic failure Antiplatelet therapy Cancer Case fatality rate VTE Case fatality rate of recurrent VTE highest in 1 st 3-6 months-11% Case fatality rate of recurrent VTE decreases after 3-6 months to 3.6% Carrier Ann Intern Med 2010 Case #5a/b:How long will you recommend these patients stay on anticoagulation? 55 yo man with unprovoked PE? a) 3 months b) 6 months c) 12 months d) Consider Indefinitely 68 yo woman with provoked PE? a) 3 months b) 6 months c) 12 months d) Indefinitely 23

Take Home Points When assessing for DVT use clinical probability and d-dimer (especially if not doing whole leg ultrasound) Order follow up ultrasound in appropriate high risk patients Consider age adjusted d-dimer in low/int probability PE patients over 50 Risk stratify all PE patients to determine disposition, triage and treatment Take Home Points Consider PESI48 to identify intermediate risk patients for abbreviated hospital stay In general, avoid expense of comprehensive testing for laboratory thrombophilia given limited role in determining duration of anticoagulation in VTE (except where it will impact recommendations/management) 24

Take Home Points Decision to use thrombolytics for submassive PE should be made on a case by case basis Duration of therapy for VTE event dictated by presence or absence of transient removable risk factor, individual bleeding risk and patient preference. Minimum effective duration for all scenarios is 3 months WORKSHOP Catheter related thrombosis Calf vein thrombosis Duration of anticoagulation for VTE Management of recurrent VTE Management of subsegmental PE When to restart anticoagulation after warfarin associated GI bleed IVC filters 25