Pulmonary EmbolismReview and An Update

Pulmonary Embolism: A Major Cause of Hospital Death

Linblad B. Br Med J 1991;302:709-711

Wessler S. NIH 1986 Consensus Development Conference on Prevention of PE

Accounts for

10% of all in

hospital deaths Major contributing

factor in a

further 10%

Overall mortality

rate of

approximately

14%

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 Recurrent PE

Via Venous Stasis

Increased incidence of PE

Mechanisms of Heart Failure Post-PE

• Pressure Effects

• Volume Effects

• Neurohormonal changes

• Remodeling

• Coronary Ischemia

Existing pts w CHF

PE pts developing CHF

Pathophysiology of Right Ventricular Dysfunction After Acute Pulmonary Embolism

Lualdi and Goldhaber. Am Heart J. 1995;130:1276-1282.

Pulmonary Embolism

PA Pressure RV Afterload

RV Dilatation/Dysfunction

RV Cardiac Output

LV Preload

LV Output

RV Wall Tension

RV O2 Demand

RV Ischemia/Infarction

IV Septal ShiftToward the LV

RV O2 Supply

Coronary Perfusion

HypotensionIDENTIFY PTS BEFORE THEY

CROSS THIS BRIDGE

Venous Thromboembolic DiseaseMagnitude of the Problem

Internal Medicine Consensus Reports, July, 2002.

DVTDVT2-6 Million2-6 Million

Clinical Clinical PEPE

+ 600,000+ 600,000

Post-thrombotic Post-thrombotic SyndromeSyndrome800,000800,000

Silent PESilent PE1 Million1 Million

Pulmonary Pulmonary HypertensionHypertension

30,00030,000

Recurrence

Pengo, V. et al. N Engl J Med 2004;350:2257-2264Pengo, V. et al. N Engl J Med 2004;350:2257-2264

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;350:2257-2264Pengo, 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

APE = Acute Cardiopulmonary Syndrome

Risk Stratification of APE

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

Variable Point Score

Heart Failure +1

Prior DVT +1

Hypoxaemia +1

DVT on US +1

The Bounameaux PE Point Score(The Geneva Risk Score)

Vicki J et.al Thromb Haemost 2000; 84: 548-552

SBP < 90mmHg +1

Cancer +2

Score of > 2 predicts death recurrent VTE, or major

bleed at 3 months

Risk Factors for Mortality after PE in the ICOPER: a Multivariate Analysis of 815 patients

Goldhaber SZ et.al Lancet 1999;353: 1386-1389

Variable Hazard Ratio (95% CI)

Age > 70 yrs 1.6 (1.1-2.3)

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)

Clinical CHF 2.4 (1.5-3.7)

SBP < 90mmHg 2.9 (1.7-5)

Cancer 2.3 (1.5-3.5)

History of congestive heart failure is associated with a worse long - term survival

following acute PE

0

10

20

30

40

50

60

70

80

90

No CHF CHF

• Less reserve allows small emboli to have significant effects

• Pre-existing RV dysfunction decreases cardiac output

• Unpredictable clinical response to emboli

• Increased risk for recurrent emboli

% M

orta

lity

Paraskos et al. NEJM 1973;289:55-8

Factors affecting outcome29 months follow up

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

Physical signs• Systemic hypotension• Right-sided S3

• Increased jugular venous pressure

• Cyanosis• Tricuspid regurgitation• Parasternal lift• Palpable impulse at

LUSB

Symptoms

• Dyspnea

• Lightheadedness

• Syncope

RV dysfunction in APE

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

Echo findings in acute PE

• RV dilatation

• RV hypokinesis

• IV septal flattening

• Dec. inspiratory collapse of IVC

• Right PA dilatation

• Tricuspid regurgitation

McConnell’s Sign in the Diagnosis of PE

Potential Mechanisms

• Acute afterload RV more spherical shape to distribute pressure

• Localized ischemia of the RV free wall

• Tethering of RV apex to hyperdynamic LV

Regional Pattern

• Akinesia of the mid-RV free wall

• Normal RV apex and base

Sensitivity=77%Specificity=94%PPV=71%NPV=96%

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) PEA (n = 25)

RV enlargement w/oLV enlargement (n = 14)

No isolated RV enlargement (n = 11)

No PE (n = 5) PE (n = 9)

PE seen on TEE(n = 8)

PE seen at autopsy(n = 1)

Contusion (n = 1)RV infarct (n = 1)

Cor Pulmonale (n = 1)Ventricular Hypertrophy (n = 2)

2 survived hospitaliz.Comess KA, et al. Am J Med 2000;109:351-356

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

Total mortality

Hemodynamically unstable (103; 4.2%)

Hemodynamically stable (2182; 88.9%)

No RV dysfunction(n = 263)

RV dysfunction (n = 428)

Hospital

Goldhaber et al. Lancet. 1999;353:1386—1389.

2 weeks 3 months

N/A

N/A

N/A

10%

19%

11.4%

N/A

N/A

11%

21%

17.4%

58.3%

15.1%

15.0%

23.0%

Mortality Rates in 2454 patients (52 hospitals, 7 countries)

X 4

X 1.5

M/S RVD and Other Benefits of Echo in APE

• 15%, mortality independent of BP

• Predicts complicated in-hospital course

• Predicts recurrence (mortality 50%)

• Predicts persistent pulmonary HTN (initial RVSP > 50 mmHg, persistance >38 days)

• 15%, mortality independent of BP

• Predicts complicated in-hospital 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 (Hemo- dynamically 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

• Diagnostic tool (Hemo- dynamically 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

80

0

20

40

60

100

Pat

ien

t (

%)

+ Tn

- Tn

CPKEchoECG BP

Cardiac Troponins (I & T) and Other Findings at Presentation

P<0.05

P<0.001

Mortality Complications Recurrence

40

0

10

20

30

50

60

Pat

ien

t (

%)

Normal Tn

Moderately Tn

High Tn

In-Hospital Course Based on cTn at Presentation

40

0

10

20

30

36

4.8

0

Relation Between cTnI Concentrations on Admission and Mortality (%).

La Vecchia: Heart, Volume 90(6).June 2004.633-637

< 0.07

0.07 – 0.6

> 0.6

%

Mortality

Event Hospital Mortality Complicated Hospital Course

OR (95% CI) 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) P=0.095 P=0.079

>1.5 16.9 (1.6-177.6) 15.4 (3.8-62.6)

P=0.019 P= <0.0001

cTn –T (ng/ml)

<0.04 ------- ------

0.04-1 2.3 (0.2-27.4) 4.4 (0.1-19.1) P=0.504 P=0.046

>1.5 6.5 (1.1-38.1) 8.71 (2.5-29.5)

P=0.038 P= <0.0005

Cardiac Troponins as Determinants of Outcome in APE

Prediction of In-Hospital Mortality

P value (univar.)

P Value (multivar.)

OR 95% CI

Heart Rate

PAP

O2 Sat

+ cTnI on admit

cTnI concentration on admit

0.027

0.022

<0.0001

0.002

<0.0001

0.10

NS

NS

0.046

0.007

1.24

1.17

0.44

17.9

9.27

0.96-1.61

0.66-2.07

0.07-2.7

1.06-303.8

1.82-47.1

La Vecchia: Heart, Volume 90(6).June 2004.633-637

cTnTRelease

AMI (moderate/large)

ACS (microinfarction)

APE

Peak

Shape

Timing

MC

Repetitive up/down sloping

Possible Possible Not seen

Duration of elevation

10-14 days >120 hours 40 hours p admission

MC

Time

MC

Time

MC

Time

Proposed cTnT Curve Release Characteristics

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

• 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

BNP in APE

Tulevski et al November 2001 Kucher et al, April 2003

ten Wolde et alApril 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 alMay 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 (1.0-1560.0)

• 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

• 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 Outcome

SK+Heparin 0 of 4 died

Heparin 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

Konstantinides, S. et al. N Engl J Med 2002;347:1143-1150

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

256 normotensive pts w PE and pulm. HTN or RV dysfunctionRCDB Trial: 100 mg Alteplase over 2 hrs (118 pts) vs.UFH and placeboEnd points: in hospital mortality or escalation of Rx (pressors,secondary lysis, intubation, CPR, thrombectomy)

P = 0.006

The MAPPET Registry

The Management and Prognosis of Pulmonary Embolism Registry (MAPPET)Konstantinides et al. Circulation. 1997;96:882–888.

Death 4.7% 11.0% .016

Death from PE 4.1% 10.0%

Recurrent PE 7.7% 19.0% <.001

Major bleeding 22.0% 7.8% <.001

Intracranial bleed 1.2% 0.4%

In-HospitalEvent

Thrombolysis(n = 169)

Heparin(n = 550) P Value

PE with RV dysfunction and/or Pulmonary HTN

1001 patints from 204 prticipating German venters 9/1993-12/1994.

DDx of A PEMust Rule Out Other Potentially Life-Threatening Disorders

• A MI

• Pericardial Tamponade

• Aortic Dissection

• Fulminant Pneumonia

• H & P

• CXR

• ECG

• Echocardiogram

Long-Term Hemodynamic Benefit of lytic Rx in Patients With PE

*P <. 05**P < .02Sharma et al. Vasc Med. 2000;5:91–95.

Pulmonary artery pressure

Pulmonary vascular

resistance

17

171

19

179

22*

351**

32

437

ExerciseRest Rest Exercise

Thrombolysis (n = 12) Heparin (n = 11)

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

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.

Massive PE (>50% perfusion defect)Moderate to large PE (>30% perfusion defect)

Small PE

Hemodynamic instability

RV dysfunctionon echocardiogram

Thrombolysis(unless contraindicated)

Long-term anticoagulation

Hemodynamically stable; normal RV

Hemodynamically stable; normal RV

Impaired cardio-pulmonary reserve

Hemodynamicinstability and/orRV dysfunction

Thrombolysis

Heparin

Young, low-risk patient

Treatment of Acute PE: Old Algorithm

BNP TROPONIN

BNP ORTROPONIN

ECOCARDIOGRAPHY

NO RV DYSFUNCTION RV DYSFUNCTION

ANTICOAGULATION, ONGOING EVALUATION

THROMBOLYSIS OR EMBOLECTOMY

NO SHOCK SHOCK

PE

Treatment of Acute PE: Proposed Algorithm

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

1. Goldhaber et al. Lancet. 1988;1:293-298.

2. Goldhaber et al. J Am Coll Cardiol. 1992;20:24-30.

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

Surgical Results of Pulmonary Thromboendarterectomy (1997-2000)

PVR (dyn/sec/cm-5)

Study Location N Pre-op Post-op % Mortality

Nakajima et al, 1997 Japan 30 937±45 299±16 13

Mayer et al, 1997 Germany 32 967±238 301±151 9

Gilbert et al, 1998 Baltimore 17 700±200 170±80 24

Miller et al, 1998 Philadelphia 25 NA NA 24

Dartevelle et al, 1999 France 68 1174±416 519±250 13

Ando et al, 1999 Japan 24 1066±250 268±141 21

Jamieson & Kapelanski, 2000

San Diego, CA 457 877±452 267±192 7

Mares et al, 2000 Austria 33 148±107 975±93 9

Mares et al, 2000 Austria 14 1334±135 759±99 21

Rubens et al, 2000 Canada 21 765±372 208±92 5

D’Armini et al, 2000 Italy 33 1056±344 196±39 9

Fedullo PF et al. New Engl J Med. 2001.345:1465-72.

Goldhaber (1987)

Goldhaber (1988)

Verstraete (1988)

PIOPED (1990)

Levine (1990)

Goldhaber (1992)

Dalla-Volta (1992)

Meyer (1992)

Diehl (1992)

Goldhaber (1993)

Goldhaber (1994)

Sors (1994)

Gulba (1994)

Gisselbrecht (1996)

Total

Fatal ICH

50—90

100

50—100

40—80

~50

100

100

100

~67

100

50 or 100

50 or 100

120

50—100

0/47

0/22

0/34

0/9

0/33

2/44

1/20

0/34

2/54

1/46

3/87

0/53

1/22

2/54

12/559 (2.1%)

9/559 (1.6%)

Source (Year) Dose of rt-PA, mg Incidence of ICH

Incidence of Intracranial Hemorrhage Withrt-PA Treatment for Pulmonary Embolism

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)