4/25/2016

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John R. Bartholomew, MD, FACC, MSVM

Professor of Medicine – Cleveland Clinic Lerner College of Medicine

Section Head – Vascular Medicine

Department of Cardiovascular Medicine

Pulmonary Embolism

A Team Approach to Diagnosis and Management

Disclosure Slide

Consultant - Portola Pharmaceuticals Consultant - Boehringer Ingelheim

Consultant - Daiichi Sankyo Research - Siemens

Burden of Venous Thromboembolism

Am Journal of Therapeutics 2009;16: 300-303

Death

Pulmonary hypertension

Pulmonary embolism

Post-thrombotic syndrome

Symptomatic DVT

Asymptomatic DVT

Circulation 2015;131:e29-e322 © 2015 by the American College of Cardiology Foundation and the American Heart Association, Inc. . Published by American Heart Association.

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PE is the 3rd Leading Cause of CV Death

AHA - 2015 Statistics

PE

Stroke

MI

Venous Thromboembolism The Incidence is Increasing

• MI: # 1 - rate is trending downward

• Stroke: #2 - rate has plateaued

• PE/DVT: #3 - rate is increasing in men and women

Am J Med 2014;127:829-839

Management of Acute Pulmonary Embolism

Risk Stratification

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Classification of Acute PE Risk Stratification

Massive PE (~5%) • Hypotension (< 90 mmHg), syncope, cardiac arrest

• Respiratory failure

• Often fatal if more aggressive treatment not initiated

Submassive PE (~25%) • Normotensive

• RV dysfunction

• Increased risk of adverse outcomes

Low Risk PE (~70%) • Normotensive

• Normal RV function

• Excellent prognosis with anticoagulation alone

Lancet 1999;353:138 Circulation 2011; 123: 1788-1830 Circulation 2013; 127: 2458-2464

Most Patients with PE do well, but some do not!

Chest 2002;122:1801-1817

Thromb Haemost 2008;100(5):747-751 Imaging Insights 2011;2:705-715

Predictors of Mortality from PE and their Influence on Clinical Management

Treatment Options for Acute Pulmonary Embolism • Monotherapy: Heparin, LMWH, Fondaparinux,

Rivaroxaban, Apixaban • Transition Therapy: Dabigatran, Edoxaban, Warfarin • Thrombolytic Therapy (including catheter directed) • IVC filter • Surgery/interventional approaches

CHEST 2016;149(2):313-352

Am J Med 2012; 125: 465-470

• Data from 1999 to 2008

• 2,110,320 patients discharged from short stay hospital in US with a diagnosis of PE

• 72,230 (3.4%) were unstable (in shock or ventilator dependent)

Data from Nationwide Inpatient Sample

Thrombolytic therapy in unstable patients with acute PE saves lives

All-cause case fatality rate in unstable patients with thrombolytic

therapy was 15% vs. 47% without thrombolytic therapy. (p <.0001)

Am J Med 2012; 125: 465-470

Thrombolytic

therapy

No thrombolytic

therapy

In-h

os

pit

al a

ll-c

au

se

ca

se

fata

lity

ra

te in

un

sta

ble

pa

tie

nts

(%

)

15% n=21,390

n=50,840

47%

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MOPETT: Half-Dose Fibrinolysis for Anatomically Large PE

0

10

20

30

40

50

60

PulmonaryHypertension (%)

Mean length ofstay (d)

In-HospitalBleeding (%)

Half-Dose t-PA

Standard Anticoagulation

n = 121

16%

57%

2.2 4.9

P < 0.001

P < 0.001

Am J Cardiol 2013;111:273-277

0 0

Variable Low dose Alteplase (n=61)% Control (n=60)%`

P value

Recurrent PE 0 3(5) 0.08

Total mortality 1(1.6) 3(5) 0.30

NEJM 2014;370:1402-1411

PEITHO

Fibrinolysis for PE Meta-Analysis: Mortality Reduction

Fibrinolysis

Anticoagulation0

2

4

6

8

10

All-causemortality

RecurrentPE

Majorbleed

ICH

JAMA 2014;311:2414 -2421

%

2.2

3.9

9.2

3.4

1.2 0.2 1.5

3.0

p = 0.01

p < 0.001

p = 0.002

p = 0.003

Among patients with PE (including those who were hemodynamically stable with RV dysfunction), thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and ICH.

Major bleeding was not significantly increased in patients 65 years or younger.

• 16 RCT comparing thrombolysis to standard anticoagulation (n=2115)

• 71% (1449) had intermediate risk PE (RV dysfunction)

Risk Factors for Bleeding with, and Contraindications

to Use of, Thrombolytic Therapy (systemic and CDT)

CHEST 2016;149(2):313-352

Potential Advantages of US-Facilitated Catheter-Directed Low-Dose Fibrinolysis

Avoids the high risk of major bleeding associated with systemic fibrinolysis

• Including intracranial hemorrhage

• Dose-related: 25 mg vs. 100 mg

More complete thrombus resolution

• Catheter-directed fibrinolysis targets the area of highest thrombotic burden

More effective for subacute thrombus

• Pharmacomechanical therapy enhances fibrinolytic surface area by conditioning the thrombus

Slide courtesy of Greg Piazza

EKOS + Heparin

Heparin

0

0.1

0.2

0.3

0.4

0.5

0.6

Baseline to 24hours Baseline to 90 days

ULTIMA: Primary Outcomes

Red

ucti

on

in

RV

/LV

Rati

o

p < 0.001 p = 0.07

0.3

0.03

0.35

0.24

Circulation 2014;129:479-486

USAT regimen (10-20 mg t-PA) was superior to heparin alone in reversing RV dilatation at 24 hours without an increase in bleeding complications

59 patients Echo RV/LV ratio >1.0

UFH vs. USAT 1 death (UFH)

No major bleeding

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SEATTLE II: RV/LV Ratio (Reduction)

0

0.5

1

1.5

2

Pre-Procedure

48 Hours

1.55

1.13

RV

/LV

Ra

tio

p < 0.0001

JACC Cardiovasc Interv 2015;8(10):1382-1392

Catheter-directed Ultrasound Thrombolysis

150 patients with massive (31) or submassive (119) PE received low dose (24 mg) of tPA with unilateral (24 hours)

or bilateral (12 hours) catheters. NO ICH or fatal bleeds

Catheter Intervention Techniques and Devices

Circulation 2011;124:2139-2144

Hydrolyzer

Amplatz Oasis

Aspirex

Pigtail

Catheter Intervention Techniques and Devices Catheter Interventions without Thrombolysis

Other Therapies

• VORTEX AngioVac® -

thrombus vacuum

• Inari - large bore percutaneous thrombus extraction

• Penumbra - thrombus aspiration

• Argon Cleaner - clot macerator

• ECMO – hemodynamic support as bridge to definitive treatment Argon Cleaner

ECMO

Vortex

Penumbra

Surgical Embolectomy or Catheter-Based Interventions

• Patients with absolute

contraindications to

thrombolysis or (thrombolysis

has failed) surgical

embolectomy is preferred

therapy (Grade 2C)

• If not immediately available,

catheter embolectomy or

thrombus fragmentation may

be considered (Grade 2C)

Chest 2007;132:657-663

Eur Heart Journal 2008; 29: 2276-2315

Circulation 2011; 123: 1788-1830

Grade 2C: weak recommendation,

low or very low quality evidence

Am J Med 2012; 125:478-484

Case fatality rate was lower in each group that received an IVC filter

PREPIC2: Anticoagulation ± IVC Filter for High-Risk PE

JAMA 2015;313:1627-1635

• Among hospitalized patients with severe PE, the use of a ALN retrievable filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent PE at 3 months.

• Findings do not support the use of ALN filter in patients who can be treated with anticoagulation

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Case Report

• 69 year old female

• PMH - HTN, diabetes mellitus, asthma

• Previous PE after surgery in 2010

• Left total knee replacement on 6/24/14

• LMWH for DVT prophylaxis

Case Report

• Developed shortness of breath, chest pain and syncope (7/2/14)

• 911 called, BP < 90 mmHg (responded to IV fluids)

• Required O2

• ER - CTPA positive for an acute saddle PE

• Started on IV heparin

• Thrombocytopenia noted (heparin stopped)

• Argatroban initiated

Case Report

• Hemoglobin 12, platelets 18,000

• BUN 18, creatinine 1.21

• INR 1.1

• aPTT 57 seconds (target 46-84)

• PF4 strongly positive

CTPA

Case Report

• Transferred – Cleveland Clinic Medical ICU

(BP 105/63, HR 108, RR 22)

– Pulse oximetry - 94% on 4 liters of oxygen

• Mild distress

• Echo: moderate RV dilation and moderate to severe RV dysfunction

• Duplex US: acute left femoral-popliteal DVT

Case Report - PERT Call

• Develops atrial fibrillation with RVR 148

– oxygen requirements increasing

– More short of breath

– Hypotensive again (BP < 90 mmHg)

• Troponin positive

• Platelet count 24,000, hemoglobin stable

• PERT TEAM CALLED

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What to do Next?

What do the Guidelines Tell Us?

CHEST 2016;149(2):315-352

Grade 2C: weak recommendation, low or very low quality evidence

Grade 2B: weak recommendation, moderate-quality evidence

Benefits closely balanced with risk and burden

Circulation 2011;123:1788-1830

Class IIa; Level of Evidence B = Benefit >> than risk. Reasonable to perform treatment being useful/effective.

PE with Shock or Hypotension (High-Risk) Recommendations Class Level

Thrombolytic therapy is recommended I B

Surgical pulmonary embolectomy is recommended for patients in whom thrombolysis is contraindicated or has failed

I C

Percutaneous catheter-directed treatment should be considered as an alternative to surgical pulmonary embolectomy for patients in whom full-dose systemic thrombolysis is contraindicated or has failed

IIa C

Class I: evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective Class IIb: usefulness/efficacy is less well established by evidence/opinion

Level B: data derived from a single randomized clinical trial or larger non-randomized studies Level C: consensus of opinion of the experts and/or small studies, retrospective studies, registries

European Heart J 2014;35:3033-3080

Circulation 2004;110(6):744-749 Chest 2006;129(4):1043-1050

Interpreting 3 Sets of Guidelines: Who Should Get Advanced Therapy?

• AHA (“reasonable”)

• ACCP (“suggested”)

• ESC (“recommended”)

Massive PE

Factors Associated with Clinical Deterioration Shortly after PE (in our patient)

• Hypotension • Hypoxia • Coronary artery disease • Residual deep vein thrombosis • Right heart strain on echocardiogram • Elevated biomarkers • RV enlargement on CT

Circulation 2004;109(20):2401-2404 Thorax 2104;68:835-842

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What did we Do?

Case Report - PERT CALL

• 50 mg tissue plasminogen activator infused over 2 hours

• At the end of the infusion – HR low 70’s (NSR) – Blood pressure normalized – Oxygen requirements decreased – Clinically significantly improved – Discharged home 10 days later on warfarin

Case Report

• 24 year old female develops acute onset SOB, chest pain and a swollen left leg.

• PMH unremarkable • Recently started on OCP’s • ER - hemodynamically stable • Left common femoral/femoral

vein DVT • CT - submassive PE • Elevated biomarkers and echo

reveals moderate RV dysfunction • What are your treatment

options?

Interpreting 3 Sets of Guidelines: Who Should Get Advanced Therapy?

• AHA (severe right ventricular dysfunction and/or major biomarker elevation)

• ACCP (clinical gestalt)

• ESC (right ventricular dysfunction and biomarker elevation (intermediate-high risk)

Submassive PE

(Normotensive, Right Ventricular

Dysfunction, Elevated

Biomarkers)

CHEST 2016;149(2):315-352

Grade 1B: strong recommendation, moderated quality evidence

PE without shock or hypotension Intermediate or Low Risk

European Heart J 2014;35:3033-3080

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Circulation 2011;123:1788-1830

Class IIb; Level of Evidence C = Benefit > risk. Limited population studied. Procedure/treatment may be considered. Recommendations/usefulness, efficacy less well established.

Case Report - PERT Call

• 100 mg tissue plasminogen activator infused over two hours

• Patient converted to Rivaroxaban at discharge

PE Therapeutic Options: All Over the Map

Anticoagulation IV Thrombolysis

Catheter Directed Thrombolysis

Pharmaco-Mechanical Catheter Treatment

ECMO

IVC Filter

Surgical Embolectomy

Slide courtesy of PERT Consortium

Which Therapy to Use?

• Best treatment unknown – No standard approach

– No “appropriate use criteria” for intervention

– Practice varies by medical service, location, size

– No standard algorithm or consistency in decision-making

– No single team

– No centralized locations for care or “centers of excellence”

– No systematic evaluation of results

How do we decide whether to “intervene” and by what modality? Who decides? What is the endpoint?

Treatment Gap in Pulmonary Embolism

• <5% of patients with PE receive “advanced therapy”, including those with clear indications (hypotension, RV dysfunction, biomarkers, etc.)

• Many more are eligible than receive

• Reasons: – Failure to recognize potential benefit and integrate

data in “real time”

– Fear of complications

– Inability to respond rapidly (systems issues)

– “Paralysis in decision-making”

Slide courtesy of PERT Consortium

Multidisciplinary Pulmonary Embolism Response Teams:

Making Order out of Chaos

Slide courtesy of PERT Consortium

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The Perks of PERTs

• PERTs provide rapid bedside evaluation and risk stratification of patients with acute PE.

• PERTs help interpret recommendations from 3 sets of guidelines in the context of the individual patient.

• PERTs facilitate access to advanced therapies such as systemic fibrinolysis, catheter-directed therapy, surgical pulmonary embolectomy, and IVC filter insertion.

• PERTs guide the utilization of advanced techniques such as ECMO for critically-ill PE patients.

Slide courtesy of PERT Consortium

PERT Program Flow Map

Handoff to

therapeutic site

ED

Hospital

OSH

PERT fellow:

History

Physical

Labs

EKG

Echo

CT-PE Ultrasound leg

Massive

Surgery

Vortex

ECMO

Lytic

Submassive CDT

Low Risk

Expeditious input and clinical judgment from

multiple specialties to optimize therapy

A/C

ACTIVATE PERT

Electronic Meeting

Vascular Medicine

Cardiac Surgery ICU/Pulmonary

Cardiology

Interventional Radiology

Hematology

Slide courtesy of PERT Consortium

Cleveland Clinic – PERT Team A Multidisciplinary Team

Internal Medicine and Hematology

Outcomes - 82 patients (July 2014 – Present)

• Average age - -57 years (22 to 89)

• 4 surgical embolectomy

• 20 IVC filters placed

• 13 catheter directed tPA

• 11 half dose tPA (50 mg)

• 2 full dose tPA (100 mg)

• 20 bleeding complications

• 6 deaths (2 CDT and 4 standard heparin)

Summary

• The best methods for risk stratification (ACCP, AHA, ESC) remains to be determined.

• The optimal strategy for selection of advanced therapies for moderate and high-risk PE patients is unclear.

• The role of advanced circulatory support for PE has yet to be defined.

• Multidisciplinary PE Response Teams provide real-time individualized bedside evaluation and recommendations until definitive management algorithms are established.

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PE and DVT: A National Crisis The Incidence is Increasing!

• Severely under-recognized and undertreated

• Significant immediate and long-term sequelae

• High recurrence rate

• Treatments available that reduce mortality, morbidity and sequelae

Chest 2008:133:454S-545S

Am J Med 2104;127:829-839