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Tracy Minichiello, M.D. Professor of Medicine

University of California, San Francisco Chief, SF VA Anticoagulation & Thrombosis Service

Diagnosis and Management of VTE

Disclosures

I have nothing to disclose

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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 1st 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

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it

Repeat u/s in 1 week

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

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

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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 1st 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

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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.

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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 revised-outpatients 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

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Date of download: 10/9/2014! Copyright © 2014 American Medical Association. All rights reserved.!

Righini et al ADJUST-PE study JAMA. 2014!

Figure Legend:!

Age Adjusted D-dimer in Low/Int Prob PE

Age (yrs)x 10 mcg/L

6 highly sensitive d-dimer assays used

Date of download: 10/9/2014!

Righini et al ADJUST PE study JAMA. 2014

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

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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%

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Pulmonary Embolism Severity Index

Aujesky et al Eur Heart Journal 2006

Simplified Pulmonary Embolism Severity Index

Jimenez, D. et al. Arch Intern Med 2010

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Hestia Criteria

Hestia criteria

Zondag et al Journal of Thrombosis and Haemostasis, 11 APR 2013

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IDENTIFICATION OF HIGH RISK NORMOTENSIVE PATIENTS WITH PE

Jiménez D et al. Thorax 2011;66:75-81

Mortality 1%

15-20%

Pulmonary embolism protocol

Ahmad N et al. Thorax 2011

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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

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outcome Out N=171

In N=168

Difference in %age

p value

Recurrent VTE

1 0 0.6% 0.01

Major bleed*

3 0 1.8% 0.08

Mortality 1 1 0.6% 0.05

Outpatient Treatment of Pulmonary Embolism (OPTE)

Aujesky D. et al. Lancet. 2011 Jul 2;378

•  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

How Long is Long Enough?

Aujesky Arch Intern Med. 2008

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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

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Thrombolysis for Submassive PE

Thrombolysis for Submassive PE

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PEITHO Trial

Meyer NEJM 2014

Major bleed 11% v 2.4% > 75 highest risk

Date of download: 8/12/2014!

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

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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

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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

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Impact of Acute Thrombosis & Anticoagulation on Thrombophilia Testing

increased Factor VIII level

decreased Antithrombin level

decreased No effect decreased Protein C, S

prolonged prolonged Lupus anticoagulant

Anticardiolipin antibodies

Warfarin Heparin Acute VTE test

no effect no effect increased Factor VIII level

increased decreased decreased Antithrombin level

decreased No effect decreased Protein C, S

prolonged prolonged May be prolonged

Lupus anticoagulant

no effect no effect May be elevated

Anticardiolipin antibodies

Warfarin Heparin Acute VTE test

TSOAC and Thrombophilia Testing

Mani et al White Paper Siemans 2013

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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

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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%

Major- transient

3% 10%

Minor-transient

5-6% 15%

Unprovoked At least 10% 30%

Recurrent > 10% > 30%

Kearon, Blood 2005

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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

3 months (Grade 1B).

3 months (Class I Level A) 3 months

First episode of idiopathic (unprovoked) VTE

At least 3 months, prefer long-term treatment if risk/benefit ratio ok (Grade 2B).

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

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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 1st 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

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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)

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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