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Updates in Diagnosis & Management of Venous Thromboembolic Disease

Tracy Minichiello, MDProfessor of Medicine

University of California, San FranciscoChief, SFVA Anticoagulation & Thrombosis Service

TOPICS

• Risk stratification for PE• Thrombolysis for submassive PE• Duration of anticoagulation for VTE• DOACS for treatment of VTE• Management of isolated subsegmental PE

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CASE #1

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 #1

You would consider PE ruled out in this gentleman if d-dimer is less than:1) 500 mcg/L 2) 650 mcg/L3) Hold please. I need to look this one up.

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Righini et al ADJUST-PE study JAMA. 2014

Assessing Pretest Probability of PE

Ann Intern Med 2015.

Evaluation of Patients with Suspected PE : ACP recommendations

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Selective Testing for Low Prob PE

FOCUS ON REDUCING OVERUSEOF IMAGING NOT A SCREENING TOOL FOR ALL PATIENTSPERC to be applied to very low risk patientsTo determine if d-dimertesting indicated97% sensitivityOnly 0.3% risk of missed PE

Kline et al Ann Emerg Med 2004

Date of download: 10/9/2014

Righini et al ADJUST PE study JAMA. 2014

• 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

Age > 50 (yrs)x 10 mcg/L

Age-Adjusted D-dimer

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Copyright © American College of Physicians. All rights reserved.

TO REDUCE OVER TESTING

• Use validated clinical prediction rule to estimate pretest probability

• DO NOT get d-dimer OR imaging if low pretest probability and meet PERC criteria

• Get high sensitivity d-dimer as initial test if intermediate probability or low and do not meet PERC criteria

• Use age adjusted d-dimer threshold if > 50 up• DO NOT get imaging study if below age adjusted cut

off• Get CT scan to r/o high prob PE unless

contraindicated.

Case #1

You would consider PE ruled out in this gentleman if highly sensitive d-dimer is less than:1) 500 mcg/L 2) 650 mcg/L3) Hold please. I need to look this one up.

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CASE #1a

His d-dimer returns. It is 2000 mcg/L. A CTa shows multiple pulmonary emboli. Does this patient need to be admitted?A) Yes he needs to be admitted.B) No, send him home.C) I suppose you can send him home, but then I wont

sleep tonight.

Pulmonary Embolism Severity Index

Aujesky et al Eur Heart Journal 2006

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Simplified Pulmonary Embolism Severity Index

Jimenez, D. et al. Arch Intern Med 2010

Outpatient Treatment of Pulmonary Embolism (OPTE)

outcome p value InN=168

Difference in %

Recurrent VTE

1 0 0.6% 0.01

Major bleed* 3 0 1.8% 0.08

Mortality 1 1 0.6% 0.05

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

• Excluded: O2 sat < 90%, SBP<100, chest pain active or high riskbleeding, 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

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PE Risk Stratification Protocol

Ahmad N et al. Thorax 2011

CASE #1a

His d-dimer returns. It is 2000 mcg/L. A CTa shows multiple pulmonary emboli. Does this patient need to be admitted or can he be treated as an outpatient?A) Yes.B) No.C) I suppose so but then I wont sleep tonight.

65 yo male with PMHx, normal VS except HR 95PESI IISimplified PESI 030 day mortality < 1%

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Case #2

60 year old man with COPD admitted with sudden onset SOB and chest pain. CT with bilateral PE. HR 100 BP 125/80. O2 sat on presentation 89% on RA. He is started on anticoagulation and admitted. On hospital day #1 his O2 sat is 92% on RA and he is taking rivaroxaban. How long does he need to stay in the hospital?

PESI 48Moores L et al Eur Respir J 2013

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Case # 2

60 year old man with COPD admitted with sudden onset SOB and chest pain. CT with bilateral PE. HR 100 BP 125/80. O2 sat on presentation 89% on RA. He is started on anticoagulation and admitted. How long does he need to stay in the hospital?Consider risk stratifying again after 48 hours to identify potential candidates for abbreviated hospital stay

Case #3

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. Youa) Treat with IV heparinb) 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 bleed11% 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

IDENTIFICATION OF HIGH RISK NORMOTENSIVE PATIENTS WITH PE

Jiménez D et al. Thorax 2011;66:75-81

Mortality1%

15-20%

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Case # 3

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. Youa)Treat with heparinb)Consider thrombolytics and heparin

Additional studies to consider to identify high intermediate risk PETrop/BNPU/SConsider half dose exp if < 65 kg

Case # 4

58 yo male presents to ED with chest pain and shortness of breath. CT reveals bilateral PE. Vital are stable. He has no other past medical history. Which of the following do you recommend for initial PE treatment?a. Enoxaparin->warfarinb. Enoxaparin-> dabigatranc. Rivaroxaban 15 mg BID x21 days then 20 mg daily

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DOAC: Mechanism of Action

Adapted from Weitz JI, Bates SM. J Thromb Haemost 2005; 3: 1843‐53.

Comparison of Oral Anticoagulants

Cove CL, Hylek EM. J Am Heart Assoc. 2013; 2:e000136

Agent Warfarin Dabigatran

Rivaroxaban

Apixaban Edoxaban

Target IIa,VIIa,IXa,Xa

IIa Xa Xa Xa

Prodrug No Yes No No No

Peak effect 4-5 days 1.5-3 h 2-4 h 1-3 h 1-2 h

Half-life 40 h 12-17 h 5-9 h 9-14 h 9-11 h

Renal elim. None 80% 33% 25% 35-50%

Dialyzable No Yes No No No

Interactions

Many P-gp CYP 3A4, P-gp

CYP 3A4, P-gp

CYP 3A4, P-gp

Monitoring Yes No No No No

Antidote Vitamin K No No No No

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Dabigatran 150 mg BID

VKA

LMWH *

Day 1

Edoxaban 60 mg QD LMWH*

At least 3 months

SwitchingSwitchingDay 6 -11

BridgingBridging

Onset of Anticoagulant Effect: Clinical Implications in VTE

At least 3 months

Rivaroxaban 15 mg BID X 3 weeks, then 20 mg QD

Day 1 Single drug approachSingle drug approach

DabigatranEdoxaban

*Or UFH or fondaparinux

Apixaban 10 mg BID X 1 week, then 5 mg BID

Current VTE treatment

RivaroxabanApixaban

KEY DIFFERENCES between DOACSBID vs QDNeed for parenteral therapyDegree of renal clearance

DOACs: Potential for Drug InteractionsCYP3A4

Inducers Inhibitors

Carbamazepine Amiodarone Itraconazole

Efavirenz Aprepitant Ketoconazole

Glucocorticoids Cimetidine Nefazodone

Nevirapine Clarithromycin Protease inhibitors

Phenobarbital Cyclosporine Verapamil

Phenytoin Diltiazem Voriconazole

Primidone Erythromycin

Rifampin Fluconazole

Rifapentine Fluoxetine

St. John’s wort Fluvoxamine

P-Glycoprotein

Inducers Inhibitors

Midazolam Amiodarone Dronaderone

Nifedipine

Nifedipine Ceftriaxone Propranolol

Phenobarbital Clarithromycin Quinidine

Phenytoin Cyclosporine Tacrolimus

Rifampin Diltiazem Verapamil

St. John’s wort Dipyridamole

Erythromycin

Hydrocortisone

Itraconazole

Ketoconazole

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DOACs: Formulation Issues, Food Effects

Dabigatran Rivaroxaban Apixaban Edoxaban

Formulationissues

-Don’t crush/chew/ open capsules

- Store in original container

-Expires 4 months after bottle opened

May be crushed

May be placed in G-tube, but not in J-tube

May be crushed

May be placed in G-tube

No information

Foodeffects

With or without 15 and 20 mg: with largest meal of day

10-mg tablet: may be taken with/without food

With or without With or without

GI adverse effects

Dyspepsia (~10%) Rare Rare Rare

Optimal Candidates for New Drugs

� Have difficulty getting INR testing or, despite adherence to recommendations, have low ‘time-in-range’

� Can afford (or arrange to get) them� Refuse parenteral therapy� Are not taking medications known to interact

with the new anticoagulants� Have normal renal function or only moderate

stable renal insufficiency

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NOT GOOD CANDIDATES FOR DOACS

• Have significant renal insufficiency or likely spurious decline in renal function

• Are likely to skip doses• Have reservations about the lack of antidote• Have significant thrombophilia or clots in

unusual places • Have cancer • Weigh > 150kg < 50kg • Have recurrent thrombosis despite therapeutic

warfarin

Transition in Care

• Transition in care of fully anticoagulated patient is VERY HIGH RISK and should be meticulously arranged and documented EVEN though no INR monitoring required!

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Case # 4

58 yo male presents to ED with chest pain and shortness of breath. CT reveals bilateral PE. Vital are stable. He has no other past medical history. Which of the following do you recommend for initial PE treatment?a. Enoxaparin-> warfarinb. Enoxaparin-> dabigatranc. Rivaroxaban 15 mg BID x21 days then 20 mg daily

Case #5a

55 yo man with unprovoked PE-how long should he remain on anticoagulation?

a) 3 monthsb) 6 monthsc) 12 monthsd) Indefinitely

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Case #5b

68 yo woman with provoked PE s/p THA- how long should she remain on anticoagulation ?

a) 3 monthsb) 6 monthsc) 12 monthsd) Indefinitely

•

Risk of VTE Recurrence After Cessation of AnticoagulationRisk 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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Recurrent VTE according to provoking Risk Factor

Surgery(N = 86)

Non-SurgicalTriggers(N = 279)

Unprovoked(N = 192)

Cu

mu

lati

ve p

ropo

rtio

n

0 4 8 12 16 20 24

0.15

0.10

0.05

0.20

MonthBaglin Lancet 2000

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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Duration of Anticoagulation Unprovoked PE: 6 vs 18 months

Coutrand et al PADIS-PE RCT JAMA 2015

ACCP 2012 Guidelines for Duration of Anticoagulation for VTE

INDICATION DURATION

First episode of VTE secondary to a transient risk factor(provoked)

3 months (Grade 1B).

First episode of unprovoked VTE At least 3 months, Consider long-term treatment if low bleed risk(Grade 2B).

Recurrent unprovokedVTE

Long term(Grade 1B).

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Short (3 months) duration best for:

• Distal (calf vein)• Estrogen-related, surgery-related• Patients at high risk of bleeding• Majorly provoked (major trauma, surgery)

Risk Factors For Anticoagulation-Related Bleedingmay favor defined course of therapy

• Age > 75• Previous GI bleed with no

reversible cause• Previous bleed on warfarin• Renal/hepatic failure• Antiplatelet therapy

Carrier Ann Intern Med 2010

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D-dimer and Recurrent VTE

D-dmer + D-dimer -

Prolong(18 months)

D-dimer @ 1 month after AC stopped

15% 6.2%

Annals 2008(one year)

Systematic review 8.9 3.5%

Prolong II(one year)

d-dimer q 2 months after 1st

negative d-dimer

27% 2.9%

Cosmi et al(18 months)

d-dimer & RVO 9-12% 0-5%

Verhovsek et al Ann Intern Med 2008;Cosmi et al Blood 2010;Palareti NEJM 2006;Cosmi Thromb Haemost 2011

Clinical Scores to Predict Recurrence

Kyrle et al Thromb Haemost. Dec 2012

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Options for Secondary Prevention in Unprovoked VTE

Therapy Recurrence risk Bleeding riskMajor/crnm/yr

No therapy 30% in 5 years 0.4% major bleed/yr

Full dose anticoagulation

95% risk reduction

1-3%/5%/yr

Prophylactic dose apixaban

95% risk reduction

0.2%/3%/yr

Low dose aspirin

25-30% risk reduction

1.5%/3%/yr

Duration of Anticoagulation for Unprovoked VTE

After 3 months of txAssess bleeding risk

Consider indefinite tx(esp PE, male, thrombophilia)

patient preference

Female DVT:Clinical prediction

rule:<1 and wants to stop

anticoagulation-ok

Male DVT:Stop AC and

Measure serial D-dimer, if elevated consider restart

High bleed riskBleed on AC

Strong preference to come off

STOP AC-start ASA

If initial event is PE, subsequent event will likely be PE.(60-80%)PADIS-PE-8% recurrent PE fatal

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Case #5a/b:How long will you recommend these patients stay on anticoagulation?

55 yo man with unprovoked PE?

a) 3 monthsb) 6 monthsc) 12 monthsd) Consider Indefinitely

68 yo woman with provoked PE ?

a) 3 monthsb) 6 monthsc) 12 monthsd) Indefinitely

Case #6

A 77 yo man had undergoes ORIF of the right hip. On POD#2 he becomes tachycardic to the 110s. Pain is well controlled and HGB is stable. O2 sat is normal. On POD#3 he is still tachycardic with normal ECG and normal troponin. No signs infection. The hospitalist orders a CTa to rule out PE. It shows an isolated subsegmental PE. Do you treat this?

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Isolated Subsegmental PE

Definition: PE shown on CT angiography that occurred in a subsegmental branch but no larger order of vessels. The subsegmental PE may involve one or more than one subsegmental branch

“Dots are not Clots”• One of the normal lung functions is to

remove small emboli• Many small PE may be part of “normal”

existence : DVT usually absent in ISSPE• FInding thrombus in subsegmental arteries

has ↑from 4.7% to 15% with multi-row detector CTPA

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Management of Subsegmental PE

Stein et al Clinical and Applied Thrombosis/Hemostasis 2012

• 105 untreated patients.DVT excluded in all with 3 months follow up. No fatal recurrences at 1-3 months.

• 121 treated patients.7% had major bleeding

Witholding Anticoagulation for Isolated Subsegmental PE

• No DVT� Autopsy studies show DVT LE 97% only 3% pelvic veins� Limitations of testing-sensitivity 92% if symptomatic 55% if

not� u/s should be done 3 or 4 times over a 10- to 14-day period

to detect a new proximal deep-vein thrombosis before it leads to important recurrent PE

• Adequate pulmonary reserve• A major risk factor for VTE that is no longer present

(surgery trauma) and no continuing risk factor• No central line/No AFIB• Reliable follow up

Stein et al Clinical and Applied Thromb/Hemostasis 2012/Raskob Blood 2013

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What to do?

• Treat isolated subsegmental PE if no absolute contraindication or not VERY high risk for bleeding

• Cochrane review-insufficient evidence to recommend for or against treating SSPE

• If absolute contraindication or high bleeding risk withholding anticoagulation is likely a safe alternative provided neg DVT/adequate reserve/ serial u/s possible/no ongoing risk factor and no AFIB/central line/reliable follow up

Take Home Points

• Use validated prediction tool to assign pre test probability of PE• Use PERC criteria in low risk patients to identify those who

need to go on to d-dimer testing• Use age adjusted d-dimer in low/int probability PE patients

over 50• Risk stratify all PE patients to determine disposition, triage and

treatment• Consider PESI48 to identify intermediate risk patients for

abbreviated hospital stay• Decision to use thrombolytics for submassive PE should be made

on a case by case basis• Know which patients are poor candidates for DOAC therapy• Arrange appropriate follow up for patients discharged on DOACs

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Take Home Points

• Duration of anticoagulation therapy for VTE guided by clinical scenario (provoked v unprovoked, ongoing risk factors, location of VTE, bleeding risk and patient preference)

• Reassess risk benefit of ongoing anticoagulation at least annually and after any bleeding event

• Consider isolated subsegemntal PE on case be case basis.

WORKSHOP

• When to restart anticoagulation after ICH/retroperitoneal bleed

• IVC filters• Isolated subsegmental PE• Thrombophilia work up• Transitioning between anticoagulants and other

pearls• Management of patient with recurrent VTE despite

therapeutic anticoagulation• Calf vein thrombosis, superficial vein thrombosis,

PICC line thrombosis and more

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QUESTIONS?