Transcript Acute PE Risk Stratification_THEPVD.ORG

Pulmonary Embolism
Review and An Update
Pulmonary Embolism: A Major Cause
of Hospital Death
Accounts for
10% of all in
hospital deaths
Major contributing
factor in a
further 10%
Overall mortality
rate of
approximately
14%
Linblad B. Br Med J 1991;302:709-711
Wessler S. NIH 1986 Consensus Development Conference on Prevention of PE
Pathophysiology of Cardiac
Compensatory Mechanisms In APE
Important Variables
• Pt’s baseline characteristics/comorbidities
• Embolus size: anatomic vs. physiologic
• Adequacy of cardiopulmonary compensatory
mechanisms
• Time to presentation, diagnosis,and initiation of
proper therapy
Magnitude of the Problem: PE
CHF
Via Venous Stasis
Existing pts w CHF
Mechanisms of Heart Failure
Post-PE
• Pressure Effects
• Volume Effects
Increased incidence
of PE
• Neurohormonal changes
• Remodeling
• Coronary Ischemia
Via Recurrent PE
PE pts developing CHF
Pathophysiology of Right Ventricular Dysfunction After
Acute Pulmonary Embolism
Pulmonary Embolism
PA Pressure
RV Afterload
RV Ischemia/
Infarction
RV Dilatation/
Dysfunction
RV Wall Tension
RV O2 Demand
RV O2 Supply
RV Cardiac
Output
IV Septal Shift
Toward the LV
Coronary
Perfusion
LV Preload
LV Output
IDENTIFY PTS BEFORE THEY
CROSS THIS BRIDGE
Lualdi and Goldhaber. Am Heart J. 1995;130:1276-1282.
Hypotension
Venous Thromboembolic Disease
Magnitude of the Problem
DVT
2-6 Million
Post-thrombotic
Syndrome
800,000
Recurrence
Silent PE
1 Million
Clinical
PE
+ 600,000
Internal Medicine Consensus Reports, July, 2002.
Pulmonary
Hypertension
30,000
Incidence of Symptomatic CTPH after a
First, Symptomatic, Properly Treated PE
VTE is a CHRONIC disease
Pengo, V. et al. N Engl J Med 2004;350:2257-2264
Incidence of Symptomatic CTPH after a
First, Symptomatic, Properly Treated PE
• Only those who
developed
“unexplained
persistent dyspnea”
had echo
• S PA pressure > 40
mmHg and mean PA
pressure > 25 mmHg
• We know: 5 yr
survival when S PA
pressure > 40 is 30%,
10% w S PA pressure
> 50 mmHg
Pengo, V. et al. N Engl J Med 2004;350:2257-2264
Risk Stratification of APE
APE = Acute Cardiopulmonary
Syndrome
Important Aspects in Risk
Stratification in APE
• Time is survival: The golden hours/days
• Minor APE, vs. Major APE, vs. Massive APE
• Do not forget the surgical option
• Aggressive? (vs. PROACTIVE)
Risk Stratification of PE
• The Traditional: Clinical Criteria
• The Sophisticated But Old: Radiographic
Criteria, Echocardiographic Criteria
• The New and Evolving: The Physiologic
Criteria, I.e., Cardiospecific Biomarkers
CLINICAL CRITERIA
The Bounameaux PE Point Score
(The Geneva Risk Score)
Variable
Point Score
Cancer
+2
Heart Failure
+1
SBP < 90mmHg
Prior DVT
Hypoxaemia
DVT on US
Vicki J et.al Thromb Haemost 2000; 84: 548-552
+1
+1
+1
Score of > 2 predicts death
recurrent VTE, or major
bleed at 3 months
+1
Risk Factors for Mortality after PE in
the ICOPER: a Multivariate Analysis of 815 patients
Variable
Hazard Ratio (95% CI)
Age > 70 yrs
1.6 (1.1-2.3)
Cancer
2.3 (1.5-3.5)
Clinical CHF
2.4 (1.5-3.7)
SBP < 90mmHg
2.9 (1.7-5)
COPD
1.8 (1.2-2.7)
RR > 20 breath/min
2.0 (1.2-3.2)
RV Hypokinesis
2.0 (1.3-2.9)
Goldhaber SZ et.al Lancet 1999;353: 1386-1389
History of congestive heart failure is
associated with a worse long - term survival
following acute PE
29 months follow up
Factors affecting outcome
90
• Less reserve allows
small emboli to have
significant effects
80
70
% Mortality
60
• Pre-existing RV
dysfunction decreases
cardiac output
50
40
30
20
• Unpredictable clinical
response to emboli
10
0
No CHF
CHF
Paraskos et al. NEJM 1973;289:55-8
• Increased risk for
recurrent emboli
ECHOCARDIOGRAPHY IN APE
Echocardiography in the
diagnosis of PE
• Cannot use as a single diagnostic tool
• RV hypokinesis present in only 40% of patients with
APE with normal systemic pressure
• Useful tool to risk stratify in patients diagnosed with PE
• Larger perfusion defect on V/Q scan are associated with
RV dysfunction
• Transesophageal echo useful in assessing thrombus in
pulmonary artery
Clinical Manifestations of RV
Dysfunction
Symptoms
• Dyspnea
• Lightheadedness
• Syncope
Physical signs
• Systemic hypotension
• Right-sided S3
• Increased jugular
venous pressure
• Cyanosis
• Tricuspid regurgitation
• Parasternal lift
• Palpable impulse at
LUSB
RV dysfunction in APE
Echo findings in acute PE
• RV dilatation
• RV hypokinesis
• IV septal flattening
• Dec. inspiratory
collapse of IVC
• Right PA dilatation
• Tricuspid regurgitation
Outcomes with RV
Dysfunction
• 2-fold increased 14-day
mortality rate
• 3-fold increase in 1-year
mortality rate
• Increased risk of
recurrent PE
• ?Increased risk of in situ
thrombosis in RV and
RA
McConnell’s Sign in the Diagnosis
of PE
Regional Pattern
Potential Mechanisms
• Akinesia of the midRV free wall
• Normal RV apex and
base
• Acute  afterload  RV
more spherical shape to
distribute pressure
Sensitivity=77%
Specificity=94%
PPV=71%
NPV=96%
• Tethering of RV apex to
hyperdynamic LV
• Localized ischemia of
the RV free wall
McConnell et al. Am J Card 1996;78:469-73
The Incidence of PE in unexplained sudden cardiac arrest with
PEA
Emergency TEE for Sudden Cardiac Arrest (n = 36)
V Fib, VT, Asystole (n = 11)
No isolated RV
enlargement (n = 11)
No PE (n = 5)
Contusion (n = 1)
RV infarct (n = 1)
Cor Pulmonale (n = 1)
Ventricular Hypertrophy (n = 2)
Comess KA, et al. Am J Med 2000;109:351-356
PEA (n = 25)
RV enlargement w/o
LV enlargement (n = 14)
PE (n = 9)
PE seen at autopsy
(n = 1)
PE seen on TEE
(n = 8)
2 survived hospitaliz.
Problems with Echocardiography
• Findings are operator-dependent
• Only able to visualize thrombus in PA (0 -19%)
• Left PA distal to left main bronchus not examined
• Specificity of isolated RV dilatation is low (COPD,
RV infarct, Cardiomyopathy, Valvular heart
disease, cardiac sarcoidosis, technical error)
• Low utility for TTE in critically-ill patients
Gossage JR. Chest 1997;112:1158-1159
ICOPER
Mortality Rates in 2454 patients
(52 hospitals, 7 countries)
Hospital
2 weeks
3 months
Total mortality
N/A
11.4%
17.4%
Hemodynamically unstable
(103; 4.2%)
N/A
N/A
58.3%
Hemodynamically stable
(2182; 88.9%)
X4
N/A
N/A
15.1%
No RV dysfunction
(n = 263)
10%
11%
15.0%
RV dysfunction (n = 428)
19%
X 1.5
Goldhaber et al. Lancet. 1999;353:1386—1389.
21%
23.0%
M/S RVD and Other Benefits of Echo in APE
• 15%, mortality
independent of BP
• Predicts complicated inhospital course
• Predicts recurrence
(mortality 50%)
• Predicts persistent
pulmonary HTN (initial
RVSP > 50 mmHg,
persistance >38 days)
Goldhaber, Lancet, 1993 & 1999.
Grifoni, Circ 2000. Kasper, Heart 1997.
Ribeiro Am Heart J 1997 & J Intern Med 1999.
• Diagnostic tool (Hemodynamically unstable pts
w unexplained dyspnea,
syncope, or RVD)
• PFO: 35% prevalence in
pts w APE and RVD,
mortality 33% (vs 14%
w/o PFO)
• RAT: Double mortality at
14 days (21% vs 11%)
compared to those w/o
RAT
Circulation. 1998 May 19;97(19):1946-51.
J Am Coll Cardiol. 2003 Jun 18;41(12):2245-51
Cardiospecific Troponins in APE
Cardiac Troponins (I & T) and Other
Findings at Presentation
100
80
Patient (%)
+ Tn
P<0.05
- Tn
60
P<0.001
40
20
0
 BP
ECG
Echo
CPK
In-Hospital Course Based on cTn
at Presentation
Patient (%)
Normal Tn
60
Moderately  Tn
50
High Tn
40
30
20
10
0
Mortality
Complications
Recurrence
Relation Between cTnI Concentrations on
Admission and Mortality (%).
40
36
< 0.07
30
0.07 – 0.6
> 0.6
%
20
10
4.8
0
0
Mortality
La Vecchia: Heart, Volume 90(6).June 2004.633-637
Cardiac Troponins as Determinants of Outcome in APE
Event
Hospital Mortality
OR (95% CI)
Complicated Hospital Course
OR (95% CI)
cTn -I (ng/ml)
<0.07
0.07-1.5
------7.1 (0.7-7.0)
-----3.16 (0.8-1.4)
>1.5
P=0.095
16.9 (1.6-177.6)
P=0.019
P=0.079
15.4 (3.8-62.6)
P= <0.0001
<0.04
0.04-1
------2.3 (0.2-27.4)
-----4.4 (0.1-19.1)
>1.5
P=0.504
6.5 (1.1-38.1)
P=0.038
P=0.046
8.71 (2.5-29.5)
P= <0.0005
cTn –T
(ng/ml)
Prediction of In-Hospital Mortality
Heart Rate
PAP
O2 Sat
+ cTnI on admit
cTnI concentration on admit
P value
(univar.)
P Value
OR
(multivar.)
95% CI
0.027
0.022
<0.0001
0.002
<0.0001
0.10
NS
NS
0.046
0.007
0.96-1.61
0.66-2.07
0.07-2.7
1.06303.8
1.82-47.1
La Vecchia: Heart, Volume 90(6).June 2004.633-637
1.24
1.17
0.44
17.9
9.27
Proposed cTnT Curve Release Characteristics
cTnT
Release
Peak
Shape
Timing
MC
AMI
ACS
APE
(moderate/large) (microinfarction)
MC
MC
Time
MC
Time
Time
Repetitive
up/down
sloping
Possible
Possible
Not seen
Duration of
elevation
10-14 days
>120 hours
40 hours p
admission
Elevated Cardiac Tn in the Absence
of Acute MI
• Acute PE
• Acute pericarditis
• Acute or severe heart failure
• Myocarditis
• Sepsis and/or shock
• Renal failure
• False positive troponin
BNP in APE
• low median BNP levels predict benign clinical
outcome in APE
• No correlation between RV systolic pressure and
BNP
• NPV for proBNP < 500 pg/mL to predict adverse
outcome was 97%
• proBNP independent predictor of adverse clinical
outcome: OR 14.6 (1.5-139), P 0.02, even after
adjustment for: Submassive or massive
Tulevski et al November 2001 Kucher et al, April 2003
ten Wolde et al
April 2003
• Higher median BNP levels were associated
with:
- death within 3 months, P <0.001
- all cause death (adjusted for age and cancer)
OR 9.4 (1.8-49.2)
- death related to PE: OR 14.1 (1.5-131.1)
• NPV for uneventful outcome of a BNP value <21.7
pmol/L is 99% (93%-100%)
Kucher et al
May 2003
• Median BNP higher in patients with adverse
events than in patents with benign course:
- 194.2 pg/mL (3.7-1201.1) vs 39.1 (1.01560.0)
• A cut-off of < 50 pg/mL (lower than that used
as the cut-off value for CHF, <90 pg/mL)
identified 95% of patients with a benign
clinical course
Reasons to Consider Thrombolysis in
Pulmonary Embolism
• Treat acute hemodynamic instability
– Reverse abnormal hemodynamics
– Lower mortality
• Reverse acute and subacute RV dysfunction
• Prevent chronic thromboembolic-induced pulmonary
hypertension
1,500,000 U/1 Hour streptokinase with
heparin is more effective than heparin
alone in PE with heart failure
• Randomized trial
intending to enroll 40
patients
• Massive PE,
hypotension, and
heart failure
• Stopped after 8
patients
Results
Group
SK+Heparin
Heparin
Outcome
0 of 4 died
4 of 4 died
Autopsy in 3 of 4 revealed
evidence of RV infarct and no
significant CAD
Jerjes-Sanchez et al. J Thromb Thrombolysis 1995;2:227-9
Kaplan-Meier Estimates of the Probability of Event-free Survival among Patients with Acute
Submassive Pulmonary Embolism, According to Treatment with Heparin plus Alteplase or
Heparin plus Placebo
P = 0.006
256 normotensive pts w PE and pulm. HTN or RV dysfunction
RCDB Trial: 100 mg Alteplase over 2 hrs (118 pts) vs.
UFH and placebo
End points: in hospital mortality or escalation of Rx (pressors,
secondary lysis, intubation, CPR, thrombectomy)
Konstantinides, S. et al. N Engl J Med 2002;347:1143-1150
The MAPPET Registry
1001 patints from 204 prticipating German venters 9/1993-12/1994.
PE with RV dysfunction and/or Pulmonary HTN
In-Hospital
Event
Thrombolysis
(n = 169)
Heparin
(n = 550)
P Value
Death
4.7%
11.0%
.016
Death from PE
4.1%
10.0%
Recurrent PE
7.7%
19.0%
<.001
22.0%
7.8%
<.001
1.2%
0.4%
Major bleeding
Intracranial bleed
The Management and Prognosis of Pulmonary Embolism Registry (MAPPET)
Konstantinides et al. Circulation. 1997;96:882–888.
DDx of A PE
Must Rule Out Other Potentially Life-Threatening Disorders
• A MI
• Pericardial
Tamponade
• H&P
• Aortic Dissection
• ECG
• Fulminant
Pneumonia
• Echocardiogram
• CXR
Long-Term Hemodynamic Benefit of lytic Rx in
Patients With PE
Thrombolysis (n = 12)
Rest
Pulmonary artery
pressure
Pulmonary vascular
resistance
Exercise
Heparin (n = 11)
Rest
Exercise
17
19
22*
32
171
179
351**
437
*P <. 05
**P < .02
Sharma et al. Vasc Med. 2000;5:91–95.
Contraindications to Fibrinolytic Therapy
• Recent major trauma or surgery (within 10 days)
• Recent CVA, intracranial, intraspinal trauma or surgery
(within 2 months)
• Bleeding diathesis
• Active internal bleeding
• Uncontrolled hypertension (SBP >200 or DBP >110 mmHg)
• Cardiopulmonary resuscitation (prolonged)
• Pregnancy
• Infective endocarditis
• Diabetic proliferative retinopathy
Analysis of 312 patients who received lytic Rx in
5 clinical trials (t-PA and UK)
Thrombolytic Regiments:
•
T-PA 50-90 mg
47 pts
•
T-PA 100 mg
138 pts
•
T-PA 0.6 mg/kg bolus
59 pts
•
UK 2000u/lb/hr x 24 hrs 23 pts
•
UK 3 million U/2 hrs
45 pts
Risk Factors for Bleeding
•
Age >70 y led to x 4 bleeding risk
compared to those < 50 y/o
•
Increased BMI > 30 leads to x 2
increased bleeding risk compared
to <25
•
Catheterization leads to x 5
bleeding risk compared to no
catheterization
Mikkola KM, et al. Am Heart J1997;134:69-72
Treatment of Acute PE: Old Algorithm
Massive PE (>50% perfusion defect)
Moderate to large PE (>30% perfusion
defect)
Hemodynamic
instability
RV dysfunction
on echocardiogram
Small PE
Hemodynamically
stable; normal RV
Hemodynamically
stable; normal RV
Young, lowrisk patient
Thrombolysis
(unless contraindicated)
Heparin
Long-term
anticoagulation
Modified from Olin in: Stoller JK et al. Cleveland Clinic Intensive Rev Internal Med. 2nd ed;2000: 413–427.
Wolfe et al. Curr Prob Cardiol. 1993;18:587–633.
Lualdi and Goldhaber. Am Heart J. 1995;130:1276–1282.
Impaired cardiopulmonary reserve
Hemodynamic
instability and/or
RV dysfunction
Thrombolysis
Treatment of Acute PE: Proposed Algorithm
PE
NO SHOCK
BNP 
TROPONIN 
SHOCK
BNP  OR
TROPONIN 
ECOCARDIOGRAPHY
NO RV DYSFUNCTION
RV DYSFUNCTION
THROMBOLYSIS OR
EMBOLECTOMY
ANTICOAGULATION,
ONGOING EVALUATION
Kucher and Goldhaber, Circ 11/2003
FDA-Approved Lytic
Regimens for PE
• Streptokinase
– 250,000 IU load over 30 minutes
– 100,000 IU/hr for 24 hours
• Urokinase
– 4400 IU/kg load over 10 minutes
– 4400 IU/kg/h for 12-24 hours
• rt-PA
– 100 mg IV over 2 hours
Thrombolytic Therapy in
Pulmonary Embolism
• rt-PA 100 mg over 2 hours was superior
to a low-dose regimen of UK (4400
/kg/h) at 2 hours, but there was no
difference at 24 hours1
• rt-PA 100 mg over 2 hours is equal in
efficacy to UK 3 million units over 2
hours2
1. Goldhaber et al. Lancet. 1988;1:293-298.
2. Goldhaber et al. J Am Coll Cardiol. 1992;20:24-30.
Surgical Results of Pulmonary
Thromboendarterectomy (1997-2000)
Study
Nakajima et al, 1997
Mayer et al, 1997
Gilbert et al, 1998
Miller et al, 1998
Dartevelle et al, 1999
Ando et al, 1999
Jamieson &
Kapelanski, 2000
Mares et al, 2000
Mares et al, 2000
Rubens et al, 2000
D’Armini et al, 2000
Location
Japan
Germany
Baltimore
Philadelphia
France
Japan
San Diego, CA
Austria
Austria
Canada
Italy
PVR (dyn/sec/cm-5)
N
Pre-op
Post-op
30
937±45 299±16
32
967±238 301±151
17
700±200 170±80
25
NA NA
68 1174±416 519±250
24 1066±250 268±141
457 877±452 267±192
33
14
21
33
148±107
1334±135
765±372
1056±344
Fedullo PF et al. New Engl J Med. 2001.345:1465-72.
975±93
759±99
208±92
196±39
% Mortality
13
9
24
24
13
21
7
9
21
5
9
Incidence of Intracranial Hemorrhage With
rt-PA Treatment for Pulmonary Embolism
Dose of rt-PA, mg
Incidence of ICH
Goldhaber (1987)
50—90
0/47
Goldhaber (1988)
100
0/22
Verstraete (1988)
50—100
0/34
40—80
0/9
Levine (1990)
~50
0/33
Goldhaber (1992)
100
2/44
Dalla-Volta (1992)
100
1/20
Meyer (1992)
100
0/34
Diehl (1992)
~67
2/54
Goldhaber (1993)
100
1/46
Goldhaber (1994)
50 or 100
3/87
Sors (1994)
50 or 100
0/53
120
1/22
50—100
2/54
Source (Year)
PIOPED (1990)
Gulba (1994)
Gisselbrecht (1996)
Total
Fatal ICH
12/559 (2.1%)
9/559 (1.6%)
Summary
• Mortality rate from PE is high and approaches 10% in
the first hour
• Thrombolysis should be considered in high-risk patients
who present with hemodynamic instability, acute PE,
right ventricular failure, or pulmonary hypertension
• Thrombolysis can reverse abnormal hemodynamics and
reduce mortality
• Expansion of thrombolysis usein APE should be
considered in light of “physiologic” risk stratification
• We may be able to identify a subgroup of APE patients
who may qualify for outpatient treatment
Oligemia
Oligemia
Massive PE: Saddle emboli
Oligemia
Massive PE: Saddle emboli
L lung: 12 hrs after of lytic Rx
R lung: 12 hrs after lytic Rx
R lung: 24 hrs after UK (via SG catheter)
R lung: 36 hrs after UK (via SG catheter)