Coenie Koegelenberg
Division of Pulmonology, Department of Medicine
 Incidence according to two UK studies:
 1 in 1000 per year
 Incidence doubles for
each 10-year  age
 Post mortem studies:
 Microemboli are found in 60 % of autopsies
 30 % of all inpatient deaths (western world)
 Immediate Mortality of untreated PE: 30%
 With treatment: 2-8%
 International Co-operative PE Registry1:
Three-Month Mortality = 17.5 %
1. Kniffin WD Jr, et al. The
epidemiology of diagnosed
pulmonary embolism and
deep venous thrombosis
in the elderly. Arch Intern
Med 1994;154:861-866.
 Rudolf Karl Ludwig Virchow (1856)
"Thrombose und Embolie"
 Stasis
 Hypercoagulability
 Vascular injury
 Arterial obstruction
 Release of vasogenic peptides
 Neurogenic broncho- & vasoconstriction
 Increase in pulm vasc resistance
 Increased alveolar dead space
 Shunt / V/Q mismatch due to
atelectasis & alveolar oedema
 Increased Raw
 Decreased lung compliance
Hypoxaemia
 Increase in pulm vasc resistance
 Increased alveolar dead space
 Shunt / V/Q mismatch due to
atelectasis & alveolar oedema
 Increased Raw
 Decreased lung compliance
RV
Afterload
 Increased RV afterload
 Increased wall tension RV
 Dilatation RV  Tricuspid prolapse
 RCA compressed  Ischaemia
 Dysrythmias
 RV Failure / Dysfunction
 RV Dysfunction
Important prognostic
Implications
 Septal shift to left
 Underfilling of LV
 Fall is CO   Blood pressure
 LV myocardial ischaemia
 Circulatory collapse
 DEATH
 Analysis of the four major PE registries:
 RH hypokinesis
Mortality
 Normal Systemic BP
 Doubling of mortality at 14 days
& 3 times higher at one year !
 Three large trails (incl. MAPPET1):
Similar relationship RV dysf and mortality
 RV dysfunction = adverse outcome
1. Konstantinides S, et al. Comparison of alteplase versus heparin for resolution of
major pulmonary embolism. Am J Cardiol. 1998;82:966-970
 Acute PE - Spectrum that ranges from:
 Clinically unimportant / incidental
 Minor emboli ± infarction
 Large pulmonary emboli
 Massive emboli
 Acute PE - Spectrum that ranges from:
 Clinically unimportant / incidental
 Minor emboli ± infarction
Haemoptysis
Pleuritic pain
Pulmonary signs
 Large pulmonary emboli
Dyspnoea
 Massive emboli
Ischaemic pain
Collapse
Cardiac signs
 Diagnostic difficulties!
 Signs / symptoms non-specific
 Only 25% of suspected cases
actually have pulmonary emboli1,2
1. Lee AY, Hirsh J. Diagnosis and treatment of venous thromboembolism.
Annu Rev Med. 2002;53:15-33.
2. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute
pulmonary embolism: results of the Prospective Investigation of Pulmonary
Embolism Diagnosis (PIOPED).JAMA. 1990;263:2753-2759.
 Modified Wells score1 (“dichotomised”)
≤ 4 PE
“unlikely”
Score
> 4 PE
“likely”
1. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to
categorize patients’ probability of pulmonary embolism: increasing the model’s
utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83:416-420.
 D-Dimer
 Patho-physiological background
 D-Dimer
SA Labs < 0.25 mg/l
 Quantitative D-Dimer (ELISA) > 500 ng/ml
 Present in > 95 % of patients with PE
 High sensitivity (>96 %)
 Low specificity (AMI, pneumonia, etc)
 High negative predictive value (99.0%)
 Useful in excluding PE in outpatients
 Not to be used to “diagnose” PE
 D-Dimer
 Quantitative D-Dimer (ELISA) > 500 ng/ml
 Not useful in inpatients1:
 AUC of ROC Curves
0.8 for outpatients
0.5 for inpatients
1. Schreceqost JE, et al. Comparison of diagnostic accuracies in
outpatients and hospitalized patients of D-dimer testing for the
evaluation of suspected pulmonary embolism.
Clin Chem. 2003;49(9):1483-90
 Combing Clinical Probability & D-Dimer
 Christopher Study1 (n = 3,306)
 Dichotomized Wells score ≤ 4
 D-Dimer ≤ 500 ng/ml
 Negative predictive value > 99.5%
 Useful in excluding PE in outpatients
 Safe to withhold treatment
1. Van Belle A, et al. Effectiveness of Managing Suspected Pulmonary Embolism
Using an Algorithm Combining Clinical Probability, D-Dimer Testing, and
Computed Tomography. JAMA 2006;295(2):172-179
 ABG
 Hypoxaemia
 Hypocapnia
 Not specific or sensitive1
 Biochemistry
 Troponin T/I
 Brain natriuretic peptide (BNP)
 Surrogate markers for RV dysfunction
1. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute
pulmonary embolism: results of the Prospective Investigation of Pulmonary
Embolism Diagnosis (PIOPED).JAMA. 1990;263:2753-2759.
 ECG
 Sinus tachycardia
 New onset / Paroxysmal AF/Afl/SVT
 Right heart strain:
 Right atrial enlargement
 Partial/complete RBBB
 RVH
 T-wave inversion ant chest leads (V1-V4)
 Classic: SI, QIII, TIII (rare)
 Differential Diagnosis
 CXR
 Often normal
 Linear atelectasis
 Small effusions
 Focal oligaemia
 Peripheral wedge-shape densities
 Palla’s sign: enlarged right descending
pulmonary artery
 CXR
 Often normal
 Linear atelectasis
 Small effusions
 Focal oligaemia
 Peripheral wedge-shape densities
 Palla’s sign: enlarged right descending
pulmonary artery
 CXR
 Often normal
 Linear atelectasis
 Small effusions
 Focal oligaemia
 Peripheral wedge-shape densities
 Palla’s sign: enlarged right descending
pulmonary artery
 CXR
 Often normal
 Linear atelectasis
 Small effusions
 Focal oligaemia
 Peripheral wedge-shape densities
 Palla’s sign: enlarged right descending
pulmonary artery
 Echocardiography
 Rapidly gaining importance (risk stratify)
 40 % have abnormalities:
 RV pressure overload
 McConnel sign:
Regional RV dysfunction
Apical wall motion remains normal
Hypokinesis of free wall
 Dif Diagnosis:
AMI, Aortic dissection,
Pericardial tamponade
 Echocardiography
 V/Q – Scan
 Perfusion: Tc-99M
 Ventilation: Xenon
 Underperfusion ~ V/Q mismatch
 V/Q – Scan
 Greatest limiting factors:
 Structural lung disease
 Availability
 Often non-diagnostic (60%!)1
 Still useful: peripheral small/multiple PEs
1. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute
pulmonary embolism: results of the Prospective Investigation of Pulmonary
Embolism Diagnosis (PIOPED).JAMA. 1990;263:2753-2759.
 V/Q – Scan
 Diagnostic in the minority (41% in PIOPED)
High Probability
PE Diagnosed
Intermediate Probability
Low Probability
Normal Scan
P
T
P
Non-diagnostic
PE Excluded
 Helical CT Pulmonary Angiography (CTPA)
 First line / principal imaging!!!
 Has superseded VQ scans
 Widely available, performed rapidly
 Also provides alternative diagnoses
 Attention to protocol…
•Collimation, pitch, volume, field
•Tube amperage
•Contrast injection and timing
 Helical CT Pulmonary Angiography (CTPA)
 Multidetector Row Helical CT Systems
•Additional detectors
•Rapid scanning vascular bed
(4 slice 3 x faster than SDCT)
•Narrow collimation (1.25 mm)
•Increased spatial resolution
 May combine with Helical CT Venography
(see later)
 Helical CT Pulmonary Angiography (CTPA)
 Findings of Acute PE
 Intraluminal filling defect surrounded by
contrast
 Ancillary findings that are suggestive:
•Expanded unopicified vessels
•Eccentric filling defects
•Peripheral wedge-shaped consolidation
•Oligaemia
•Pleural effusion
 Helical CT Pulmonary Angiography (CTPA)
 Helical CT Pulmonary Angiography (CTPA)
 Helical CT Pulmonary Angiography (CTPA)
 Helical CT Pulmonary Angiography (CTPA)
 Helical CT Pulmonary Angiography (CTPA)
 Helical CT Pulmonary Angiography (CTPA)
 Helical CT Pulmonary Angiography (CTPA)
Saddle Embolism: pre- & post- thrombolysis
 Helical CT Pulmonary Angiography (CTPA)
 Helical CT Pulmonary Angiography (CTPA)
 Pitfalls
•
•
•
•
•
Lymph nodes
Impacted bronchi
Pulmonary artery catheters
Pulmonary sarcomas
Technical: Respiratory motion
Improper contrast
Incorrect reconstruction algorithms
 Helical CT Pulmonary Angiography (CTPA)
 Diagnostic accuracy
• Large central emboli
• Segmental (up to 5th)
• Small subsegmental
Sensitivity = 100%
Specificity = 100%
Sensitivity = 95-98%
Specificity = 97%
Sensitivity ?
Specificity ?
Relevance of small emboli?
Diagnostic accuracy equal to angiography!
Gold standard?
 Helical CT Pulmonary Angiography (CTPA)
 Best evidence – PIOPED II Study1
• n = 1 090 (Outpatients)
• Investigated the diagnostic accuracy of
multidetector CTA alone and
combined CTA–CTV (CT Venography)
1. Stein PD, et al. Multidetector Computer Tomography for Acute
Pulmonary Embolism. N Engl J Med 2006;354(22):2317-2327
 Helical CT Pulmonary Angiography (CTPA)
 Best evidence – PIOPED II Study1
• Redefined the “reference standard”
Abnormal VQ scan
Abnormal venous ultrasonography
Abnormal digital subtraction angiography
Subsequent events (F/U 3 and 6 months)
1. Stein PD, et al. Multidetector Computer Tomography for Acute
Pulmonary Embolism. N Engl J Med 2006;354(22):2317-2327
 Helical CT Pulmonary Angiography (CTPA)
 Best evidence – PIOPED II Study1
• CTA
Sensitivity = 83%
Specificity = 96%
PPV = 96%
• CTA-CTV
Sensitivity = 90%
Specificity = 95%
NPV = 97%
1. Stein PD, et al. Multidetector Computer Tomography for Acute
Pulmonary Embolism. N Engl J Med 2006;354(22):2317-2327
 Helical CT Pulmonary Angiography (CTPA)
 Best evidence – PIOPED II Study1
• Both have a high PPV with concordant clinical
assessment, but
• Additional testing is necessary when clinical
probability is inconsistent
1. Stein PD, et al. Multidetector Computer Tomography for Acute
Pulmonary Embolism. N Engl J Med 2006;354(22):2317-2327
 Pulmonary Angiography
 Gold Standard? Challenged in PIOPED II
 Can detect emboli as small as 1 – 2 mm
 Diagnostic: filling defects
 Secondary signs:
 ‘Cut-off’ of vessels
 Segmental oligaemia
 Prolonged arterial phase, slow filling
 Tapering of vessels
 Alt: Digital subtraction angiography
 Pulmonary Angiography
 Pulmonary Angiography
 Main Indications
 Diagnostic dilemmas
 Prior to catheter embolectomy
 Mortality: 0.5%1
1. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute
pulmonary embolism: results of the Prospective Investigation of Pulmonary
Embolism Diagnosis (PIOPED).JAMA. 1990;263:2753-2759.
 MRI
 Limited use
 Gadolinium-enhanced MR angiography
 Anatomical features
 RV motion
 Evaluation for DVTs
 Duplex Doppler
 Compression Ultrasound
 Venogram (diagnostic dilemmas)
 MRI
 Evaluation for DVTs
 Helical CT Venography (CTV)
 Simultaneous with CT Chest (3 min)
 Single contrast dose
 Can detect proximal (IVC) thrombi
 Direct sign: intraluminal filling defect
 Indirect signs: non-opacified segments,
acute venous distention,
and prolonged arterial filling
 Evaluation for DVTs
 Helical CT Venography (CTV)
Poplitial DVT
 Evaluation for DVTs
 Helical CT Venography (CTV)
Pelvic DVT
 Evaluation for DVTs
 Helical CT Venography (CTV)
 Sensitivity: 93-100%
 > 95% studies are adequate
 Limitations: PVD, orthopaedic hardware
venous catheters
 Evidence: PIOPED II1
1. Stein PD, et al. Multidetector Computer Tomography for Acute
Pulmonary Embolism. N Engl J Med 2006;354(22):2317-2327
 Christopher Study1
 n = 3306
 Diagnostic strategy:
Clinical info (Wells)
D-Dimer
CT
1. Van Belle A, et al. Effectiveness of Managing Suspected Pulmonary Embolism Using an
Algorithm Combining Clinical Probability, D-Dimer Testing, and Computed Tomography.
JAMA 2006;295(2):172-179
 Christopher Study1
 NPV = 99.5%
 Algorithm completed and allowed decision
making in 97.9%
 “Effective”
 “…low risk for subsequent fatal and nonfatal
VTE”
1. Van Belle A, et al. Effectiveness of Managing Suspected Pulmonary Embolism Using an
Algorithm Combining Clinical Probability, D-Dimer Testing, and Computed Tomography.
JAMA 2006;295(2):172-179
PE?
Clinical Probability: Wells Score
≤4
>4
Imaging, e.g. CTPA
PE?
Clinical Probability: Wells Score
≤4
>4
D-Dimer
≤ 0.5
> 0.5
Pulmonary Embolism excluded
Imaging, e.g. CTPA
PE?
Imaging
CT
VQ
Principle investigation
Contrast allergy
Structural lung disease
Renal Impairment
Availability
Normal lungs
Speed
Multiple PEs
PE?
N
Imaging
Treat
PE
Non Diagn
1
1 Am J Respir Crit Care
Med1999;160:1043-1066
PE?
N
Imaging
PE
Non Diagn
Stable
Unstable
Treat
PE?
Imaging
PE
Non Diagn
Stable
Unstable
Treat
PE
Pulm Angio
N
N
PE?
Imaging
Treat
PE
Non Diagn
Stable
PE
Unstable
Pulm Angio
DVT
Bilat lower extrem eval
N
N
N
Risk
Risk Stratification
Stratification
High Risk
Hypotension
RV Strain
Hypoxia
Lower Risk
Hypotension
RV Strain
Hypoxia
Risk
Risk Stratification
Stratification
Lower Risk
High Risk
Secondary Therapy
Primary Therapy
Thrombolysis
Embolectomy
Heparin
Adjuvant Therapy
Oxygen
Inotropes
Warferin
IVC Filter
Hypotension
RV Strain
Hypoxia
Risk
Risk Stratification
Stratification
Lower Risk
High Risk
Secondary Therapy
Heparin
Adjuvant Therapy
Oxygen
Inotropes
Warferin
IVC Filter
 Adjuvant Therapy
 Manage respiratory failure
 Oxygen
 Mechanical ventilation
 Improve right ventricular function
 Inotropes (Dobutamine)
 Heparin
 Still cornerstone of acute management
 Unfractionated Heparin IV ?
 Low-molecular-weight Heparin SC ?
 Heparin
 2007 ACP Guidelines1
 Pooled data from 11 reviews
 Outcome and safety at six months
1. Snow V, et al. Management of Venous Thromboembolism. Ann Intern
Med 2007;146:204-210
 Heparin
 2007 ACP Guidelines1
 LMWH >> UH for DVT
 LMWH = UH for PE
 Outpatient treatment is safe
1. Snow V, et al. Management of Venous Thromboembolism. Ann Intern
Med 2007;146:204-210
 Heparin
 2007 ACP Guidelines1
 LMWH well established role in:
 Recurrent DVTs (therapeutic INR)
 Problematic INR
 Malignancies
1. Snow V, et al. Management of Venous Thromboembolism. Ann Intern
Med 2007;146:204-210
 Heparin
 CLOT Study1
 Large prospective study
 LMWH vs. Warfarin
 High risk (recurrent, cancer, etc.)
 One year follow up
 Safe and effective
 Similar to 9 smaller studies
1. Lee AY, et al. Low-molecular-weight heparin versus a coumarin for
the prevention of recurrent venous thromboembolism in patients with
cancer. N Engl J Med. 2003;349:146-53.
 Warfarin
 Still the oral anticoagulant of choice
 Commence after initiating Heparin
 Takes at least five days to deplete FII
 Aim for INR of 2.0 – 3.0
 Lower INR (1.5)
 Better than controls
 Worse than INR > 2
 Warfarin
 Duration
Clear precipitant
3 Months
No apparent cause
6 Months
Thrombophylia
Lifelong
1st Episode
?
2nd Episode
> 1 Year
 Newer anticoagulants
 Many new drugs (PO/SC/IV) in pipeline
 NO evidence as yet that they are
equivalent to LMW Heparin or Warfarin
 Concerns:
 Efficacy
 Safety
 Cost
Target
IIa
VIIa/TF
Drug
Hirudin
Route
IV
Stautus
Indication
Approved
Heparin-induced thrombocytopenia
Not
approved
Unstable angina and non-ST elevation MI
Bivalirudin
IV
Approved
Alternative to heparin in patients undergoing percutaneous coronary interventions
Argatroban
IV
Approved
Heparin-induced thrombocytopenia
H376/95
PO
Phase III
Thromboprophylaxis in patients undergoing elective hip or knee arthroplasty;
treatment of venous thrombosis
Phase II
Alternative to warfarin in patients with atrial fibrillation
TFPI
IV
Phase III
Sepsis
NAPc2
SC
Phase II
Thromboprophylaxis in patients undergoing elective knee arthroplasty
Va/VIIIa
APC
IV
Phase III
Sepsis
Xa
Pentasaccharide
SC
Phase III
Thromboprophylaxis in patients undergoing fractured hip, elective hip, or knee
surgery
Treatment of venous thrombosis
DX-9065a
IV
Phase II
Unstable angina
SNAC/heparin
PO
Phase III
Thromboprophylaxis in patients undergoing elective hip or knee arthroplasty
Xa/IIa
 Idraparinux
 Pentasaccharide (MW = 1,853 Daltons)
 Long t½ (200 hours)
 Selective factor Xa inhibitor
 Given once weekly (2.5 mg SC)
 Idraparinux
 Matisse Trial1
 Open label
 Daily acc weight
 Vs. UFH
1. Buller HR, et al. Subcutaneous fondaparinux
versus intravenous unfractionated heparin
in the initial treatment of pulmonary embolism.
N Engl J Med 2003;349:1695-1702
 Idraparinux
 Van Gogh PE1
 Open label - weekly (3-6 months)
 Vs. LMWH & Warfarin
 Could not show non-inferiority
 Mortality:
6.4% - Idraparinux
4.4% - LMW Heparin & Warfarin
1 Unpublished…
 Idraparinux
 Van Gogh PE
 IVC Filters
 Randomised trial by Razavi1
 Filters vs. Filters + Warfarin
 2 Year follow up
 20.8% vs. 11.6% recurrence (p = 0.02)
 Safe…
1 Razavi MK, et al. Initial clinical results of tenecteplase (TNK) in catheterdirected thrombolytic therapy. J Endovasc Ther. 2002;9:593-598
 IVC Filters
 Randomised trial by Decousus1
 Filters vs. LMW Heparin
 2 Year follow up
 OR = 1.87 (also no mortality benefit)
 No advantage proximal free-floating
thrombi
 Safe…
1 Decousus H, et al. A clinical trial of vena caval filters in the prevention of
pulmonary embolism in patients with proximal deep-vein thrombosis.
N Engl J Med. 1998;338:409-415
 IVC Filters
 The evidence – summery:
 Safe
 No benefit vs. LMWH
 Relatively useless without Warfarin
 IVC Filters
 Limited indications:
 Active haemorrhage
 Absolute C/I anticoagulation
 VTE despite therapeutic INR
(better to use LMW Heparin)
 Thrombolytic Therapy ~ Background
Faster clot lysis
Dissolves obstruction
May reverse RV failure
Dissolves much of source
Decrease risk of recurrence
Well tolerated PE
~ excellent prognosis
Risks:
~ major haemorrhage:
1.8 – 6.3%
~ ICH: 1.2%
 Thrombolytic Therapy ~ Evidence
 PE with circulatory collapse
 Single study1
 n = 8, BP < 90 mmHg
 4 thrombolysed (all survived)
 All 4 NOT thrombolysed died
 BTS Guidelines & FDA approval
based on this single study!
1. Jerjes-Sanchez C, et al. Streptokinase and heparin versus heparin in massive
pulmonary embolism: a randomised controlled trial. J Tromb Thrombolysis
1995;2:227-229
 Thrombolytic Therapy ~ Evidence
 PE with circulatory collapse
 Compare to AMI thrombolysis
 > 20 000 patients (multiple trails)
 Easier to diagnose
 Subgroup definition
(<12 hr, ST Elev)
 Symptoms to thrombolysis in PEs:
 3.7 +/- 0.2 days (vs 12 hr)
 Pharmaceutical industry ‘not interested’
 Thrombolytic Therapy ~ Evidence
 PE without circulatory collapse
 Submassive pulmonary emboli
 Much less evidence
 Only 9 randomised studies, N < 500
 Not adequately powered to show
statistical benefit in mortality
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-1 1
 Retrospective analysis showed
trends towards survival benefit
 Limitations of this study:
Non-randomized & Retrospective
1. Konstantinides S, et al. Comparison of alteplase versus heparin for resolution of
major pulmonary embolism. Am J Cardiol. 1998;82:966-970
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Largest ever, n = 247
 Specifically looked at patients with
confirmed PE and RV dysfunction
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Patients with haemodynamic
instability were excluded
 Heparin +/- rTPA (random, <96hr)
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Primary end points:
 In-hospital deaths
 Escalation of therapy
Inotropes
Intubation
CPR
Embolectomy
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Secondary end points:
 Recurrent PEs
 Major bleeding
 Ischaemic stroke
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Prematurely discontinued (IA)
 Major advantage with TPA
 Primary endpoints much higher in
placebo group (p = 0.006)
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Probability of 30-day event-free
survival much higher in rTPA
group (p = 0.005)
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Difference were due to higher
incidence of escalation of therapy
in placebo group:
24.6 % vs 10.2 % (p = 0.004)
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Mortality was low in both groups,
thus no mortality benefit…
 No increase in fatal haemorrhage
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with RV dysfunction &
No haemodynamic compromise
 MAPPET-3 1
 Authors concluded:
“…alteplase can improve the clinical course of
stable patients with submassive pulmonary
embolism…”
1. Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in
patients with submassive pulmonary embolism. N Eng J Med 2002;347:1143-1150
 Thrombolytic Therapy ~ Evidence
 PE with Hypoxaemia
 PE severity vs. PaO2 or P(A-a)O21
 Linear relationship:
% pulm vasc obstructed and PO2
 PaO2 < 6.7 ~ > 50% of vasc obstr
 PaO2 < 8.0 ~ worse prognosis2
1. McIntyre KM, et al. The haemodynamic response to pulmonary embolism in
patients without prior cardio-pulmonary disease. Am J Cardiol 1971;28:288-294
2. Wicki J, et al. Predicting adverse outcome in patients with acute pulmonary
embolism: a risk scor. Thromb Haemost 2000;84:548-552
 Thrombolytic Therapy ~ Evidence
 PE with Hypoxaemia
 Thrombolysis – small open study1
n=4
 Average PaO2 = 7.81 (on max FiO2)
 tPA
 All 4 sats > 95 % next day
 No major complications
1. Loebinger MR, et al. Thrombolysis in pulmonary embolism: are we under-using it?
Q J Med 2004;97:361-364
 Thrombolytic Therapy ~ Evidence
 PE with patent foramen ovale
 Large PE & patent foramen ovale
 Severe hypoxia due to R – L shunt
(R atrial hypertension)
 Independent predictor of mortality1
1. Konstantinides S, et al. Patent foramen ovale is an important predictor of adverse
outcome in pateints with major pulmonary embolism. Circulation 1998;97:1946-1951
 Thrombolytic Therapy ~ Controversy
 For the ‘diehard’ EBM Clinician
 Circulatory collapse (BP < 90)  BTS
Sin. “Massive” PE  FDA
 Limited evidence, serious consideration1
 RV dysfunction (no haemodynamic
compromise)
 Respiratory failure (ventilatory support)
 Respiratory failure & PFO
1. Konstantinides S. Should thrombolytic therapy be used in patients with pulmonary
embolism? Am J Cardiovasc Drugs. 2004;4:69-74
 Thrombolytic Therapy ~ Controversy
 For the ‘diehard’ EBM Clinician
 Circulatory collapse (BP < 90)  BTS
Sin. “Massive” PE  FDA
 Limited evidence ? Cost-effectiveness1
 RV dysfunction (no haemodynamic
compromise)
 Respiratory failure (ventilatory support)
 Respiratory failure & PFO
1. Daniella J. Effectiveness and Cost-effectiveness of Thrombolysis in Submassive
pulmonary embolism. Arch Intern Med 2007;167:74-80
 Thrombolytic Therapy ~ The agents
 Streptokinase:
 250 000 IU over 30 – 60 min
 100 000 IU / hr for 24 hours
 rTPA
 10 mg stat (1-2 minutes)
 90 mg (over 2 hours)
 Maximum: 1.5 mg / kg (< 65 kg)
 Neoplasms
 Thrombophylias
 Neoplasms
 CXR
 Abdominal +/- pelvic ultrasound
 PSA
 According to clinical setting…
 Thrombophylia Screening:
 Inherited / acquired defects in haemostasis
 Predispose to venous / arterial thrombosis
 Consider in patients with:
 Recurrent DVTs
 Venous thrombosis < 40 yr
 Unusual DVTs (mesenteric)
 Neonatal thrombosis
 Recurrent miscarriages
 Arterial thromboses with no PVD
 Thrombophylia Screening:
 Polycythaemia & Thombocythaemia
 Activated Prot C resistance (Assay)
 Factor V Leiden (Molecular)
 Hyperhomocysteinaemia
 AFL Syndrome / Anti-Cardiolipin ABs
 ATIII Deficiency
 Protein C
 Protein S
 Thrombophylia Screening:
 Polycythaemia & Thombocythaemia
 Activated Prot C resistance Common!
 Factor V Leiden
Common!
 Hyperhomocysteinaemia
Treatable!
 AFL Syndrome
Intensive therapy!
 ATIII Deficiency
 Protein C
Rare!
 Protein S
 Thrombophylia Screening:
 Polycythaemia & Thombocythaemia
 Activated Prot C resistance Common!
 Factor V Leiden
Common!
 Hyperhomocysteinaemia
Treatable!
 AFL Syndrome
Intensive therapy!
 ATIII Deficiency
 Protein C
Rare!
 Protein S
 Keep in mind:
 ATIII, Prot C & S  during acute event
 Heparin  ATIII
 Warfarin  Prot C & S
 Pregnancy and OCP  Prot S
 ATIII, Prot C & S deficiencies are rare
 Use the Wells score and D-Dimer to exclude
 Spiral CT scanning is now well established
as the primary imaging modality
 LMW Heparin and Warfarin are still the
agents of choice
 IVC filters and newer drugs thus far
disappointing
 Thrombolysis remains controversial