how to manage pulmonary embolism - esim2014 pulmonary embolism diagnosis... · how to manage...

How to manage pulmonary embolism

Giancarlo Agnelli

Internal and Cardiovascular Medicine– Stroke Unit

University of Perugia, Italy

Risk stratification

Diagnosis Treatment

Management of acute pulmonary embolism

Improvement of clinical outcome

Clinical suspicion

1. Why patients with pulmonary embolism should undergo risk stratification?

2. How risk stratification should be done (and in whom)?

3. Implications of risk stratification (diagnosis & treatment)

My talk today

Risk stratification in patients with acute PE

PE-related shock Mild clinical symptoms

The spectrum of clinical presentation of PE

Mortality <1%>30%

Thrombolysis/Embolectomy LMWH (NOAs)

(Home-treatment/early discharge)

The spectrum of clinical outcome of PE

The spectrum of clinical management of PE




My talk today


Clinical presentation

Shock or sustained hypotension:

- systolic BP<90mmHg

- pressure drop of ≥40 mmHg >15 minutes

Hemodynamically unstable

High-risk patients

Hemodynamically stable

Intermediate- or low-risk patients

Proceed to thrombolysis

or surgery- or catheter-

embolectomy

Stratify for adverse outcome

Risk stratification in acute pulmonary embolism

Agnelli & Becattini, N Engl J Med 2010


Shock or

sustained hypotension:



High-risk patients

Proceed to thrombolysis

or surgery or catheter

embolectomy

Stratify for adverse outcome

Clinical evaluation Markers of RV

Dysfunction Injury

Echocardiography Troponin

MDCT

BNP levels

R L

Risk stratification in acute pulmonary embolism


Intermediate- or low-risk patients


Right ventricle assessments

Markers of dysfunction

Marker of injury

Entity of obstruction (burden of emboli)

Tools for stratification in acute pulmonary embolism


Geneva

PESI

sPESI

Spanish score

LR-PED

Home criteria

HESTIA

Common finding: high NPV (>95%)

Implications: Should all patients undergo risk stratification?

Risk stratification in acute PE: clinical scores

Vedovati et al., Int Emerg Med 2010

0

5

10

15

20

Ov

era

ll m

ort

ality

(%

)

no RVD 0 5,7 8,1 0 3,1 0 1,1 0

RVD 14,3 19,0 16,1 17,9 6,2 11,4 3,3 4,4

Ribeiro Kasper ICOPERJerjes-

SanchezGrif oni Pieralli Frémont Goldhaber * stable and

unstable

° stable

In-h

os

pit

al

*

*

*

*

°

°

°°

Risk stratification in acute PE: RVD at echo

RV

LV

PE-MAP Study

CT-RVD and clinical course in HD stable patients

Death due to PE

262 patients

RV/LV ≥0.9 at MDCT

149 patients

RV/LV <0.9 at MDCT

411 HD stable patients

Clinical deterioration

Death

15 (5%) 3 (2%)

14 (5%) 3 (2%)

9 (3%) 0

Death or

clinical deterioration24 (9.1%) 4 (2.7%)

Becattini et al., Eur Heart J, 2011

CT-RVD and short-term mortality in PE

Becattini et al., 2014 Eur Resp J

Meta-analysis of 20 studies

Markers of dysfunction: BNP

Klock et al., AJRCCM, 2008

Troponin and Short-term Outcome

Becattini et al. Circulation, 2007

OR CI

5.24 (3.28-8.38)

9.44 (4.14-21.49)

7.03 (2.42-20.43)

5.90 (2.68-12.95)

Death in overall population

PE related death

Adverse outcome

Death in stable patients

RVD more common in patients with elevated troponin (p < 0.05)

HR 8.3, 95% CI 1.0-67 for central emboli

HR 7.57, 95% CI 0.95-60.16 for lobar

emboli

Vedovati et al., Chest 2012

Localization of emboli & clinical outcome

+-

-+

LOW

INTERMEDIATE

consider

early

discharge or

ambulatory

---

Hospital

treatment

++

-NON

HIGH

Thrombolysis

or

embolectomy+HIGH

(Clinically Massive PE)

Treatment

implications

Myocardial

Injury

Myocardial

dysfunction

CLINICALMARKERS

RISK

Definitions related to

severity of pulmonary embolism and risk stratification

869 hemodynamically stable patients

Becattini et al., Chest 2013

Clinical outcome, n (%) RVD &

Elevated troponin

(n=363)

RVD or

elevated

troponin

(n=317)

No RVD and

normal

troponin

(n=189)

All-cause death 21 (5.8) 9 (2.8) 0

-

Death due to PE 7 (1.9) 5 (1.6) 0

-

Death or clinical deterioration 32 (8.8) 15 (4.7) 1 (0.5)

IPER registry*

* Supported by ANMCO

Combination of RVD and elevated troponin and risk stratification




My talk today


Suspected PEnew or worsening dyspnea, chest pain or sustained hypotension

without another obvious cause

Risk stratification-driven diagnostic flow

Clinical probability assessment







hemodynamically stable


hemodynamically unstable






hemodynamically unstable

Shock or sustained hypotension:




Suspected PE

new or worsening dyspnea, chest pain or sustained hypotension


hemodynamically stable hemodynamically unstable

Not Critically ill Critically ill and high

clinical probability


Clinical probability assessment*

Suspected PE




RVD



No RVD

Search for alternative

diagnosis

TT or TE

echocardiography


PE

confirmed

Clinical probability assessment*

Suspected PE




Multidetector CT

available

Multidetector CT

not available

RVD



No RVD


diagnosis

TT or TE

echocardiography


PE

confirmed

PE

confirmed


Suspected PE



hemodynamically stable hemodynamically unstable°

Multidetector CT

available

Multidetector CT

not available

RVD°°



No RVD


diagnosis

TT or TE

echocardiography




Suspected PE



Low or intermediate High

D-dimer

normal elevated Multidetector CT

PE excluded PE confirmedPE excluded




Suspected PE




D-dimer


PE excluded PE confirmedPE excluded


3-mo VTE 0.14%

(95% CI 0.05-0.41)

3-mo VTE 1.5%

95% CI 0.8-3.0



Suspected PE




D-dimer


negative PE confirmed PE excluded


Lower limb US

Peitho study Einstein

Amplify

Recover

Hokusai

The spectrum of treatment in low-medium risk PE

Risk stratification & PE treatment

Tenecteplase(n=506)

Placebo(n=499) P value

n (%) n (%)

All-cause mortality or

hemodynamic collapse within

7 days13 (2.6) 28 (5.6) 0.015

ITT population The PEITHO Investigators

Peitho: primary efficacy outcomes

Tenecteplase(n=506)

Placebo(n=499)

P value

n (%) n (%)

All-cause mortality

within 7 days

6 (1.2) 9 (1.8) 0.43

Hemodynamic collapse

within 7 days

8 (1.6) 25 (5.0) 0.002

Tenecteplase(n=506)

Placebo(n=499) P value

n (%) n (%)

Non-intracranial bleeding

Major 32 (6.3) 6 (1.5) <0.001

Minor 165 (32.6) 43 (8.6) <0.001

ITT population The PEITHO Investigators

Strokes by day 7 12 (2.4) 1 (0.2) 0.003

Hemorrhagic 10 1

Ischemic 2 0

Peitho: safety efficacy outcomes

3.0

2.5

2.0

1.5

1.0

0.0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve e

ven

t ra

te (

%)

Time to event (days)

Rivaroxaban

N=2419

Enoxaparin/VKA

N=2413

HR=1.12; p<0.0026 (non-inferiority)

Einstein PE: primary efficacy outcome

The EINSTEIN–PE Investigators. N Engl J Med 2012

37

For warfarin-treated subjects,

TTR was 60.9%

0 30 60 90 120 150 180 210 240 270 300

100

90

80

70

60

50

40

30

20

10

0

Perc

ent

of patients

0 30 60 90 120 150 180 210 240 270 300

3

2

1

0

Apixaban (events: 59/2691)

Enoxaparin/Warfarin (events: 71/2704)

Days to VTE/VTE-related death

Amplify: recurrent VTE & VTE-related death

Agnelli et al., N Engl J Med 2013

38

Apixaban (events: 15/2676)

0 30 60 90 120 150 180 210 240 270 300

100

90

80

70

60

50

40

30

20

10

0

Perc

ent

of patients

2

1

0

0 30 60 90 120 150 180 210 240 270 300

Enoxaparin/Warfarin (events: 49/2689)

Days to major bleeding

RR, 0.31; 95% CI, 0.17–0.55

Agnelli et al., N Engl J Med 2013

Amplify: Major bleeding

NOA in patients with pulmonary embolism

5 studies included in the meta-analysis: 11.539 patients

Drugs used: Heparin/Dabigatran in 2 studies

Heparin/Edoxaban in 1 study

Rivaroxaban in 1 study

Apixaban in 1 study

DOA LMWH - AVK

VTE recurrences 136/5764 153/5775

2.4% 2.6%

Clinically relevant bleeding* 415/4062 461/4064

10.2% 11.3%

Major bleeding° 30/3340 77/3307

0.9% 2.3%

* 2 studies included; ° 2 studies with the single-drug approach included


VTE recurrences: OR 0.89, 95% CI 0.70 - 1.12

Study or Subgroup

6.3.1 anti-Xa

AMPLIFY 2013

EINSTEIN-PE 2012

HOKUSAI 2013

Subtotal (95% CI)

Total events

Heterogeneity: Chi² = 2.50, df = 2 (P = 0.29); I² = 20%

Test for overall effect: Z = 0.89 (P = 0.38)

6.3.2 anti-IIa

RECOVER I & II 2013

Subtotal (95% CI)

Total events

Heterogeneity: Not applicable


Total (95% CI)

Total events



Test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.93), I² = 0%

Events

21

50

47

118

18

18

136

Total

900

2419

1650

4969

795

795

5764

Events

23

44

65

132

21

21

153

Total

886

2413

1669

4968

807

807

5775

Weight

15.2%

29.0%

42.2%

86.3%

13.7%

13.7%

100.0%

M-H, Fixed, 95% CI

0.90 [0.49, 1.63]

1.14 [0.75, 1.71]

0.72 [0.49, 1.06]

0.89 [0.69, 1.15]

0.87 [0.46, 1.64]

0.87 [0.46, 1.64]

0.89 [0.70, 1.12]

DOA conv. treat. Odds Ratio Odds Ratio

M-H, Fixed, 95% CI

0.01 0.1 1 10 100

Favours DOA Favours conventional trea


CRBs: OR 0.89, 95% CI 0.77 - 1.03

Major bleeding: OR 0.30, 95% CI 0.10 – 0.95

Study or Subgroup

EINSTEIN-PE 2012

HOKUSAI 2013

Total (95% CI)

Total events



Events

249

166

415

Total

2412

1650

4062

Events

274

187

461

Total

2405

1669

4074

Weight

59.5%

40.5%

100.0%

M-H, Fixed, 95% CI

0.90 [0.75, 1.07]

0.89 [0.71, 1.11]

0.89 [0.77, 1.03]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100

Favours DOA Favours conv. treat.

Study or Subgroup

AMPLIFY 2013

EINSTEIN-PE 2012

Total (95% CI)

Total events

Heterogeneity: Tau² = 0.53; Chi² = 4.03, df = 1 (P = 0.04); I² = 75%


Events

4

26

30

Total

928

2412

3340

Events

25

52

77

Total

902

2405

3307

Weight

41.7%

58.3%

100.0%

M-H, Random, 95% CI

0.15 [0.05, 0.44]

0.49 [0.31, 0.79]

0.30 [0.10, 0.95]


M-H, Random, 95% CI

0.01 0.1 1 10 100

Favours DOA Favours conv. treat.


+-

-+

LOW

INTERMEDIATE

consider

early

discharge or

ambulatory

---

Hospital

treatment

++

-NON

HIGH

Thrombolysis

or

embolectomy+HIGH

(Clinically Massive PE)

Treatment

implications

Myocardial

Injury

Myocardial

dysfunction

CLINICALMARKERS

RISK

Definitions related to

severity of pulmonary embolism and risk stratification

869 hemodynamically stable patients

Becattini et al. Chest 2013

Clinical outcome, n (%) RVD &

Elevated troponin

(n=363)

RVD or

elevated

troponin

(n=317)

No RVD and

normal

troponin

(n=189)

All-cause death 21 (5.8) 9 (2.8) 0

-

Death due to PE 7 (1.9) 5 (1.6) 0

-

Death or clinical deterioration 32 (8.8) 15 (4.7) 1 (0.5)

IPER registry

NPP = 99% (95% CI 97-100)

PPV = 5.8% (95% CI 3.7%-8.8%)

Use clinical risk assessment to avoid further testing (CT scan)

Use d-dimer in low risk patients only (high NPP)

Avoid risk stratification in high-risk patients

Tailor antithrombotic treatment based on risk stratification

Risk stratification for adverse outcome:

practical indications

Take advantage of the high NPP of risk stratification to plan

home-treatment of early-discharge intervention study

To improve the PPV for adverse outcome by new strategies

or by combining the currently available approaches.

To test treatment upgrading in patients with well-defined risk

for adverse outcome

Risk stratification for adverse outcome:

future research

Thrombolysis

Extended treatment

ODTI or ODIXaInitial treatment

ODTI or ODIXa w/wo parenteral LMWH

P

High risk for adverse outcome

Low- medium risk of adverse outcome

Extended treatment

Treatment of pulmonary embolism 2014

Initial treatment*

* With home treatment or early discharge

how to manage pulmonary embolism - esim2014 pulmonary embolism diagnosis... · how to manage...

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