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
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
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
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
Clinical presentation
Shock or
sustained hypotension:
- systolic BP<90mmHg
- pressure drop of ≥40 mmHg >15 minutes
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
Agnelli & Becattini, N Engl J Med 2010
Intermediate- or low-risk patients
Clinical presentation
Right ventricle assessments
Markers of dysfunction
Marker of injury
Entity of obstruction (burden of emboli)
Tools for stratification in acute pulmonary embolism
Agnelli & Becattini, N Engl J Med 2010
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
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
Suspected PEnew or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
Risk stratification-driven diagnostic flow
Clinical probability assessment
Suspected PEnew or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
Risk stratification-driven diagnostic flow
Clinical probability assessment
Suspected PEnew or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
Risk stratification-driven diagnostic flow
Clinical probability assessment
Suspected PEnew or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
hemodynamically stable
Risk stratification-driven diagnostic flow
hemodynamically unstable
Clinical probability assessment
Suspected PEnew or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
hemodynamically stable
Risk stratification-driven diagnostic flow
hemodynamically unstable
Shock or sustained hypotension:
- systolic BP<90mmHg
- pressure drop of ≥40 mmHg >15 minutes
Clinical probability assessment
Suspected PE
new or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
hemodynamically stable hemodynamically unstable
Not Critically ill Critically ill and high
clinical probability
Risk stratification-driven diagnostic flow
Clinical probability assessment*
Suspected PE
new or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
hemodynamically stable hemodynamically unstable
RVD
Not Critically ill Critically ill and high
clinical probability
No RVD
Search for alternative
diagnosis
TT or TE
echocardiography
Risk stratification-driven diagnostic flow
PE
confirmed
Clinical probability assessment*
Suspected PE
new or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
hemodynamically stable hemodynamically unstable
Multidetector CT
available
Multidetector CT
not available
RVD
Not Critically ill Critically ill and high
clinical probability
No RVD
Search for alternative
diagnosis
TT or TE
echocardiography
Risk stratification-driven diagnostic flow
PE
confirmed
PE
confirmed
Clinical probability assessment
Suspected PE
new or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
hemodynamically stable hemodynamically unstable°
Multidetector CT
available
Multidetector CT
not available
RVD°°
Not Critically ill Critically ill and high
clinical probability
No RVD
Search for alternative
diagnosis
TT or TE
echocardiography
Risk stratification-driven diagnostic flow
Risk stratification-driven diagnostic flow
Clinical probability assessment
Suspected PE
new or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
Low or intermediate High
D-dimer
normal elevated Multidetector CT
PE excluded PE confirmedPE excluded
hemodynamically stable
Risk stratification-driven diagnostic flow
Clinical probability assessment
Suspected PE
new or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
Low or intermediate High
D-dimer
normal elevated Multidetector CT
PE excluded PE confirmedPE excluded
hemodynamically stable
3-mo VTE 0.14%
(95% CI 0.05-0.41)
3-mo VTE 1.5%
95% CI 0.8-3.0
Risk stratification-driven diagnostic flow
Clinical probability assessment
Suspected PE
new or worsening dyspnea, chest pain or sustained hypotension
without another obvious cause
Low or intermediate High
D-dimer
normal elevated Multidetector CT
negative PE confirmed PE excluded
hemodynamically stable
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
NOA in patients with pulmonary embolism
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
Test for overall effect: Z = 0.44 (P = 0.66)
Total (95% CI)
Total events
Heterogeneity: Chi² = 2.51, df = 3 (P = 0.47); I² = 0%
Test for overall effect: Z = 0.98 (P = 0.32)
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
NOA in patients with pulmonary embolism
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
Heterogeneity: Chi² = 0.00, df = 1 (P = 0.95); I² = 0%
Test for overall effect: Z = 1.60 (P = 0.11)
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]
DOA conv. treat. Odds Ratio Odds Ratio
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%
Test for overall effect: Z = 2.04 (P = 0.04)
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]
DOA conv. treat. Odds Ratio Odds Ratio
M-H, Random, 95% CI
0.01 0.1 1 10 100
Favours DOA Favours conv. treat.
NOA in patients with pulmonary embolism
+-
-+
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
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