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Venous Thromboembolism
Core Rounds
April 10, 2003
A.F. Chad, MD, CCFP
DVT Objectives
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Epidemiology
Natural History
Risk Factors
Hx & PHx & Pre-test Probability
Wells & Perrier
Tests (D-dimer, Doppler, IPG, Venography)
Upper Extremity DVT (Dx, RF, Rx, risk PE)
Rx
DVT:
Submission move by
Jake “The Snake” Roberts
OR Badness in the Veins?
Epidemiology
• Lifetime incidence VTE 2-5%
– PE: 0.5/1,000/year
– DVT: 1/1,100/year
• Prospective studies of DVT:
– 10-13% medical pts on bed rest 1 week
– 29-33% pts in ICU
– 20-26% pts pulmonary diseases given bed rest
>3d
– 27-33% CCU pts
History
• 1550 BC: Ebers papyrus documented
peripheral venous disease
• 1644 Schenk observed venous thrombosis
with occlusion in the IVC
• 1846 Virchow -> association b/n venous
thrombosis in legs & PE
• 1937: Heparin comes into practice
Natural History
• 19th C Virchow’s triad: venous stasis, injury
to intima, hypercoagulability
• Thrombosis: platelet nidus near venous
valves->platelets and fibrin -> thrombus ->
occlusion, embolism
• Endogenous thrombolytic system -> partial
dissolution-> organized into venous wall
Natural History
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Most go away w/o Rx
20% propagate proximally
Organize into vein by day 5-10
Biggest risk of propagation, embolization is
before this
Natural History
• Debate whether isolated calf thrombi are
important
• Some said to have low risk PE
• Others said just as bad
Risk Factors: General
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Age
Immobilization longer than 3 days
Pregnancy and the postpartum period
Major surgery in previous 4 weeks
Long plane or car trips (>4-6 h) in previous
4 weeks
• Wrestling Jake “The Snake” Roberts
Risk Factors: Specific
• Medical
• Clotting D/O
– Cancer,Previous DVT,
stroke, MI, CHF, sepsis,
nephrotic, UC
– Antithrombin III , Protein
C, Protein S, Factor V
Leiden,
Dysfibrinogenemias and
disorders of plasminogen
activation
• Trauma
– Multiple trauma, CHI, SCI,
Burn, LE #
• Vasculitis
– SLE / LAC, Bechet,
Homocystinuria
• Hematologic
– PRV, Thrombocytosis
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Drugs/medications
IV drug abuse
Oral contraceptives
Estrogens
HIT
Risk Factors
• 50% without risk factors
• OCP/HRT: 3x baseline risk
– 0.3/10,000/yr; 15/10,000/yr
– higher in 3rd gen progesterones
• pregnancy: 5x baseline risk
– 75% DVT antepartum, 66% PE postpartum
Pathophysiology:
Source of VTE
– most start in calf, extend proximally
– 70% PE have DVT evidence at autopsy
– 70-90% known source: IVC, ileofemoral or pelvic
veins, 10-20% SVC
– incidence of PE from DVT
• calf: 46%
• thigh: 67%
• pelvic: 77%
– other: UE, jugular, mesenteric, cerebral
History
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Many No Sx
Edema (unilateral) specific
Leg pain in 50% -> nonspecific
Tenderness in 75%, but also in 50% w/o DVT
10% Sx PE
Amount pain / tenderness do not correlate to
severity
• Warmth, erythema
Physical
• No ONE reliable history / physical finding
• Sensitivity 60-96%, Specificity 20-72%
• Need to look @ combination of factors
– Anand SS, Wells PS, Hunt D, Brill-Edwards P, Cook D,
Ginsberg JS. Does this patient have deep vein
thrombosis? JAMA. 1998 Dec 2;280(21):1828-9.
Physical
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Edema (unilateral) (> 3cm)
Homan’s (50% sens)
Superficial thrombophlebitis (up to 40% can have)
Fever (>39.5, something else)
Phlegmasia cerulea dolens
– Swollen purple leg re venous engorgement
– Cyanosis re massive venous obstruction
• Phlegmasia alba dolens
– Whitish inflammation associated with arterial spasm
2nd to massive venous obstruction
– Worry about arterial occlusion
Clinical Presentation:
DVT
• Calf-popliteal
– 80-90%, many asymptomatic
– pain & swelling
– 10-20% spreads proximally
• Ileofemoral
– pain in buttock, groin
– thigh swelling
– 10-20% cases
• Do not adhere to vessel walls until 5-10d post
formation -> high risk to propagate / embolize
Clinical Prediction Model for DVT
Wells et al. Ann Int Med, 1997
Active cancer
Paralysis,plaster
immobilization
Immobilzation
Leg tenderness of deep
veins
Entire leg swollen
Calf swelling >3cm
Pitting edema
Dilated superficial veins
Alternative diagnosis
for DVT
Score
1
1
1
1
1
1
1
1
-2
Clinical Model for DVT
Pre-test probability
Score
High
3
Moderate
1 or 2
Low
0
Incidence of DVT by Clinical
Probability
100
90
80
70
60
50
40
30
20
10
0
Wells, 1997
Perrier, 1999
Low
Mod
High
Overall
Algorithm for Suspected first DVT:
Perrier. Lancet, 1999
suspected DVT
D-dimer
DVT excluded
+
U/S
+
treat for DVT
consider clinical probability
Low
DVT excluded
Mod/High
serial U/S
DVT excluded
+
treat for DVT
Tests
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D-dimer
Doppler U/S
IPG
Venography
D-Dimer
• Not “Clot specific”
• recent surgery, trauma, MI, pregnancy, CA
can all give false +
D-dimer Assays
Van der Graaf. Thromb Haemost, 2000.
Assay
Ease of Sensitivity Specificity
use
Whole blood
agglutination
(SimpliRED)
++++
80-85%
70-90%
Latex
agglutination
+++
90-95%
40-90%
Rapid ELISA
++++
95-100%
30-60%
Diagnostic Imaging for DVT
• Duplex / compression U/S
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non-invasive, portable
direct visualization of veins and flow
loss of compression = DVT
97% sensitive & specific for symptomatic
proximal/popliteal DVT
– 62% sensitive for asymptomatic DVT
– +ve in 30-50% PE; 5% non-dx V/Q scans
Serial Venous U/S
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2 protocols: Wells & Hull
may avoid angiography in ?PE
2% +ve in 2 weeks (?PE)
if U/S -ve 2 weeks apart, <2% have VTE in
next 6 mos
Diagnostic Imaging for DVT
• IPG
– detects changes in flow before and after cuff
inflated
– sensitivity 60%
IPG vs. Doppler
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N=985
PPV U/S=94% (CI 87-98%)
PPV IPG =83% (CI 75-90%)
P=0.02
– Harriet Heijboer, Harry R. Buller, Anthonie Lensing,
Alexander Turpie, Louisa P. Colly, and Jan Wouter ten
Cate. A Comparison of Real-Time Compression
Ultrasonography with Impedance Plethysmography
for the Diagnosis of Deep-Vein Thrombosis in
Symptomatic Outpatients NEJM Volume 329:13651369November 4, 1993Number 19.
Venography
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“?Gold Standard?”
Invasive
Contrast
Need experienced readers
Non-diagnostic up to 25%
Upper Extremity DVT
• 8% of all DVT
• 75% are related to hypercoag, CVC
• 25% Paget-von Schroetter syndrome
– Exertional DVT
– Caused by underlying MSK deformities
(Thoracic outlet, extra rib)
Upper Extremity DVT
• Prandoni P, Polistena P, Bernardi E, Cogo
A, Casara D, Verlato F, Angelini F, Simioni
P, Signorini GP, Benedetti L, Girolami A.
Upper-extremity deep vein thrombosis.
Risk factors, diagnosis, and
complications. Arch Intern Med. 1998 Sep
28;158(17):1950-2.
Upper Extremity DVT
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N=58 Sx UEDVT
IPG, Doppler, venography
27 (47%) + UEDVT
Test Sens & Spec:
– compression ultrasonography (96% and 93.5%)
– color flow Doppler imaging (100% and 93%)
Upper Extremity DVT
• PE “Objectively” found in 36%
• 2 yr F/U: 2 recurrent VTE
• RF:
– CVC
– Thrombophilia
– Previous VTE
U/S Upper Extremity DVT
• The sensitivity of duplex ultrasonography ranged
from 56% to 100%, and the specificity ranged
from 94% to 100%
• Unsure if Helpful
– Bisher O. Mustafa, MD; Suman W. Rathbun, MD;
Thomas L. Whitsett, MD; Gary E. Raskob, PhD
Sensitivity and Specificity of Ultrasonography in the
Diagnosis of Upper Extremity Deep Vein Thrombosis:
A Systematic Review Arch Int Med Vol. 162 No. 4,
February 25, 2002.
Upper Extremity DVT
• 10-30% incidence PE associated
• Therapy:
– Usual Rx
– Local thrombolytics appears to be Rx of choice
with literature mainly case studies
Treatment of VTE:
Goals
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reduce mortality
prevent extension/recurrence
restore pulmonary vascular resistance
prevent pulmonary hypertension
Treatment of VTE:
Anticoagulation
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Out-patient LMWH
LMWH superior to UFH? (Gould 1999)
out-pt Rx safe in PE (Kovacs, 2000)
DVT: start Rx, definitive test in 24hr
baseline B/W
Anticoagulation
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Enoxaparin 1mg/kg bid or 1.5 od
Tinzaparin 175 anti-Xa u/kg od
start warfarin 5mg on day 1
d/c LMWH when INR >2.0 x 2 days
Rx 3 mos if 1st and reversible cause
6 mos if non-reversible
indefinite if recurrent, CA, genetic
Anticoagulation Clinic
LMWH vs. UFH
• N=432
• No difference in new VTE
• Less died, complications in LMWH (SS)
– RD Hull, GE Raskob, GF Pineo, D Green, AA
Trowbridge, CG Elliott, RG Lerner, J Hall, T Sparling,
HR Brettell, and et al Subcutaneous low-molecularweight heparin compared with continuous
intravenous heparin in the treatment of proximalvein thrombosis NEJM Volume 326:975-982April 9,
1992Number 15
Pregnancy
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V/Q safe, no breastfeed x 15hr post
D-dimer  in pregnancy, wide Aa
angiography safer than empiric Rx
LMWH in DVT, not studied in PE
PE: UFH IV x 4-5 days, then s/c
treat x 3 months or 6 weeks postpartum
switch to oral postpartum
PE:
Early Rappers OR
Badness in the Veins?
PE Objectives
• Epidemiology & Natural History
– Mortality & Pathophysiology
• Hx & PHx
– Pre-test Probability
• Dx
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Angio, Echo, CT, algorithms
Which tests / combo rules in / out
What to do if non-Dx results
Confounding Clinical Situations
• Rx
– Heparin, Thrombolysis (massive, submassive),
Epidemiology
• USA: 60-80% patients with DVT, >50% Sx
free
• 3rd in hospital mortality, 650,000 cases/yr
• Autopsy studies: 60% pts who die in
hospital had PE, diagnosis missed ~ 70%
Natural History
• Most pulmonary emboli are multiple, and the
lower lobes are involved
– From deep veins of lower extremities
– Also pelvic, renal, upper extremity, right heart
chambers
• Large thrombi lodge @ bifurcation of main PA or
lobar branches -> hemodynamic compromise
• Smaller thrombi occlude smaller vessels in
periphery
– More likely to cause pleuritic chest pain (inflammatory
response adjacent to parietal pleura)
Mortality
• Approximately 10% of patients who
develop PE die within the first hour,
• 30% die from recurrent embolism.
Anticoagulant Rx decreases mortality < 5%
Pathophysiology Review
• Normal RV has a narrow range over which it can
compensate for acute increases in afterload. The
pericardium has a limited ability to distend.
• Increased RV afterload
elevation in RV wall pressures
dilation and hypokinesis of the RV wall
shift of intraventricular septum towards left ventricle
(tricuspid regurgitation) and decreased LV output.
Respiratory Consequences
• Early
– Increased alveolar dead space, Pneumoconstriction, hypoxemia,
hyperventilation
• Late:
– regional loss surfactant, pulmonary infarction
• Arterial hypoxemia frequent, not universal
– V/Q mismatch, shunts, reduced CO, intracardiac shunt via PFO
• Infarction uncommon re bronchial arterial collateral
circulation
Hemodynamic Consequences
• Reduces X-sectional area of pulmonary
vascular bed -> incr pulmonary vascular
resistance -> RV afterload -> RV failure
• Reflex PA constriction
• Prior poor cardiopulmonary status important
factor re hemodynamic collapse
Resolution
• Anticoagulant therapy -> resolution of
emboli rapidly 2 weeks Rx
• Significant long-term nonresolution of
emboli causing pulmonary HTN or
cardiopulmonary symptoms uncommon
History: Size Matters
• DVT Risk factors, DVT
• Massive:
– Shock, arrest (“Do you have any cousins with Factor V
Leiden?”)
• Acute pulmonary Infarction:
– pleuritic CP, SOB, hemoptysis
• Acute Emboli:
– SOB, non-specific CP
• Multiple Small Emboli:
– Progressive SOB, SOBOE, exertional CP, Cor
Pulmonale
PIOPED Sx
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dyspnea (73%)
pleuritic chest pain (66%)
cough (37%)
hemoptysis (13%)
Physical: Size Matters
• Massive pulmonary embolism
– Shock , hypotension, poor perfusion,
tachycardia, and tachypnea.
– Signs of pulmonary hypertension
• palpable impulse over 2nd LICS, loud
P2, RV S3 gallop, and a systolic
murmur louder on inspiration at left
sternal border (TR)
Physical: Size Matters
• Acute pulmonary infarction
– Decreased excursion of involved hemithorax,
palpable or audible pleural friction rub,
localized tenderness
– Signs of pleural effusion
Physical: Size Matters
• Acute pulmonary Embolus (no infarct)
– Non-specific
– Tachypnea, tachycardia, pleuritic pain, crackles
and local wheeze @ embolus site
Physical: Size Matters
• Multiple pulmonary emboli or thrombi
– Non-specific
– Pulmonary HTN and cor pulmonale
– High JVD, RV heave, palpable impulse 2nd
LICS, RV S3 gallop, systolic murmur over the
left sternal border that is louder during
inspiration, hepatomegaly, ascites, dependent
pitting edema.
Physical: PIOPED
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Tachypnea (70%)
Rales (51%)
Tachycardia (30%)
Fourth heart sound (24%)
Accentuated P2 (23%)
Fever < 39°C ( 14%) of patients (> 39.5°C not
from PE)
• Palpable Chest wall tenderness w/o Hx trauma
Diagnostic Imaging for PE:
Pulmonary Angiography
• Gold standard (imperfect)
– sens 98%, spec 95-98%
• ED physicians reluctant to use:
– invasive, risks, requires expertise, not readily
available, time consuming, $
• relative contraindications
• indicated if non-invasive tests inconclusive
Diagnostic Imaging in PE:
Echocardiography
• useful for patients in shock/arrest
– r/o DDx: tamponade, Ao dissection, AMI
• indirect evidence of PE:
– RV overload, septal shift to L, TR,  PA pressure, RV
wall motion abn
– sens 93%, spec 81%
• ‘sub-massive’ PE: independent predictor of
mortality (?significance)
Grifoni et al. Short-Term Clinical
Outcome of Patient With Acute
Pulmonary Embolism, Normal Blood
Pressure and Echocardiographic Right
Ventricular Dysfunction. Circulation,
101. 2000,
• Prospective clinical outcome study
– 209 consecutive patients with documented PE
– all patients had an TTE within 1 hr of
admission
– patients stratified into one of four groups
– results only for in-hospital period
Grifoni et al, Circulation, 2000.
• 4 groups
– Shock (N=28,13.4%)
• SBP<100 with signs of organ hypoperfusion
– Hypotensive without signs of shock (N=19,
9.1%)
– Normotensive with RV strain (N=65, 31.1%)
– Normotensive without RV strain (N=97,
46.4%)
Grifoni et al, Circulation, 2000.
• Patients with hypotension/shock (22%, N=47)
– Mortality 19%
• Normotensive without evidence of RV strain
(46.5%, n=97)
– 0 PE-related deaths
• Normotensive with RV strain (31.1%, N=65)
– 10% (n=6) clinically deteriorated due to PE
recurrence
– 5% (n=3) PE-related deaths
Grifoni et al, Circulation, 2000.
• Positive predictive value of echocardiography was
low
• NPV was 100%
• good tool for screening low risk patients
• The detection of RV dysfunction defines a subset of
patients with short-term risk of PE-related
mortality.
Ribeiro et al. Echocardiography
Doppler in Pulmonary Embolism:
Right Ventricular Dysfunction as a
Predictor of Mortality Rate.
American Heart Journal, 134.
1997.
• RV dysfunction at diagnosis of PE is a predictor of
mortality
– 126 ‘consecutive’ PE patients assessed by TTE on day of diagnosis
– stratified into 2 groups based on severity of RV systolic
dysfunction on TTE
– (A) normal to mildly hypokinetic and
– (B) moderate to severely hypokinetic
– Follow-up TTE within 1 year
Ribeiro et al. American Heart
Journal, 1997.
• 56 patients in group A and 70 in group B
– baseline characteristics similar (except over twice as
many with symptoms >14days (sig.), malignancy and
CHF (NS)in B)
• In-hospital PE mortality all in group B (n=9), p=0.002
• 1 year overall mortality rate 15.1% (n=19)
– group A, 7.1% (n=4) mortality, all non-PE.
– group B, 27.7 % (n=15) mortality, 9 due to PE
(p=0.04)
• Group B
– RR for in-hospital death 6.0 (95% CI 1.1 to 111.5)
– RR for death within 1 year 2.4(95% CI 1.2 to 4.5)
Ribeiro et al. American Heart
Journal, 1997.
• Subgroup analysis of patients without cancer
(n=101)
– In-hospital mortality
• Group A 0%
• Group B 7.7% (N=4/52)
– 1 year cumulative mortality
• Group A 2%, (N=1)
• Group B 9.8%, (N=5)
Moore, et al. Determination of Left
Ventricular Function by Emergency
Physician Echocardiography of
Hypotensive Patients. Academic
Emergency Medicine, vol. 9, no. 3,
2002.
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Prospective, observational study, convenience sample of 51.
EPs with prior US training underwent focused echo training
inclusion: symptomatic hypotension
exclusion: trauma, CPR, ECG of AMI
EPs estimation of EF
– compared with cardiologist; correlation coefficient of 0.86
– between cardiologists 0.84
• EP categorization of EF,
– agreement 84% (kappa 0.61)
Diagnostic Imaging for PE:
V/Q scan
• PIOPED: ventilation component adds little info
• PISAPED criteria:
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normal, non-diagnostic, high probability
25%, 50%, 25% respectively
high prob: 85-90% PPV
non-diagnostic: 25% PE
• interpret in context of PTP
Relationship between degree of RV
dysfunction and degree of perfusion scan
deficits
• Wolfe, 1994. N=90
– degree of perfusion deficit greater in patients with RVD
(54% vs 30%, p<0.001)
• all patients with recurrent PE in group with initial
RVD, p<0.01
• Ribiero, 1998
– correlation between RVD and perfusion scan deficit but
wide CI.
• Miller, 1998. N=64
– failed to demonstrate a correlation between RVD and
perfusion deficit
Diagnostic Imaging for PE:
Spiral CT
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IV contrast, direct visualization
subsegmental PE not well seen
more specific, underlying lung dx
sens depends on CT, experience
wide variation in studies
– Rathbun. Ann Intern Med, 2000 (review)
• sens 53-100%, spec 81-100%
• poor methodology of studies
Spiral CT
• Perrier. Ann Intern Med, 2001
– sens 70%, spec 91% , 4% inconclusive
– good interobserver agreement
• CT venography:
– benefit over U/S not determined
• role?
– no evidence to withhold Rx if CT negative
– may replace angiography
Clive Kearon. Diagnosis of
pulmonary embolism. CMAJ:
January 21, 2003; 168 (2)
Non -Invasive Testing
• NEED TO Dx PE as HIGH MORTALITY
IN THOSE NOT Dx or MISDIAGNOSED!
• Angiography carries risk
• Mortality 0.5%, invasive, labour intensive
• Can make Dx without P. angio
Standardized Clinical Assessment
• Well Criteria: 2% low, 19% intermediate,
50% high
• Pisa-PED: Sx, ECG, CXR -> 2%, 50%,
100%
• Perrier:8 clinical, blood gas or CXR ->
10%, 38%, 81%
Clinical Prediction Model for PE
Wells. Ann Int Med, 1998
Score
1.0
1.0
1.5
1.5
1.5
3.0
3.0
Active cancer
Hemoptysis
Recent surgery
Previous VTE
HR > 100
Clinical signs DVT
No alternate diagnosis
Pre-test probability
High
6
Moderate
2.5-5.5
Low
2
Incidence of PE by Clinical
Probability
80
70
60
50
PIOPED, 1990
Wells, 1998
Perrier, 1999
40
30
20
10
0
Low
Mod
High
Overall
Algorithm for suspected PE:
Wells. Ann Int Med, 2001
PTP
Low
D-dimer
PE excluded
Mod/High
D-dimer
+
V/Q
normal
PE excluded
non-diagnostic
leg U/S
- DVT
consider PTP
Low
high probability
treat for PE
+ DVT
Mod
D-dimer
High
D-dimer
-
+
-
+
PE excluded
serial U/S
serial U/S
angiography
Wells’ Algorithm:
Criticism
• Uses SimpliRED assay: lower sens.
• sCT not included
– could replace angiography?
• Low prevalence of PE (9%)
• not validated by other RCTs
Treatment of PE:
Criteria for admission
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Hemodynamic instability
O2 requirement
surgery < 48hr
risk of active bleeding
history of HIT
IV pain control
Thrombolytics & Heparin
• Randomised trials comparing thrombolytics to heparin
– UPET 1970 -- prospective, Randomised.
– USET
– PIOPED 1990
– Levine et al. 1990
– PAIMS 2. 1992
– Goldhaber et al. 1993
• Non-randomized
– Dalla-Volta, 1993
– Konstantanindes, 1997
– Hamel, 2001
Thrombolytics
• 2 week window of opportunity!
– effect  with time
• no advantage of t-PA bolus
• protocols:
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t-PA: 100mg over 2 hr
UK: 4400U/kg over 10min; rpt x 12-24hr
SK: 250,000U over 30min; 100,000 x 24h
arrest: t-PA 10mg/kg bolus x 2 q 30 min
Treatment of massive PE
• judicious fluids (500cc max)
• NE, dopamine, dobutamine prn
• O2, intubate if shock
– positive pressure worsens RV fn
• anticoagulation
– if no contraindications
– UFH if hypotensive
– PTT 1.5-2.5 x normal
Treatment of massive PE:
Thrombolytics
• no evidence of mortality benefit
– including in cardiac arrest (case series)
• no benefit in hemodynamically stable
• improves pul. perfusion (15% vs. 2%), RV
function (34% vs.. 17%) cf. heparin
• t-PA faster hemodynamic effect
• IV same as intrapulmonary
• 5-10% major bleed, 1-2% ICH
Treatment of massive PE:
Thrombolytics
• Abu-Laban, R et al. Tissue Plasminogen
Activator in Cardiac Arrest With Pulseless
Electrical Activity. NEJM, vol 346, No 20, May
16, 2002.
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–
–
–
–
Reviewed @ J-club
N=233
No Benefit
Only 1% of 42 autopsied showed PE
Not great PE, Still ????
Thrombolytics in Severe Shock
or During CPR in Fulminant
Pulmonary Embolism?
• Fulminant PE can produce CA in approx. 40% of
cases
• Mortality ranges from 65% to 95%
• Multiple purported mechanisms
– RV strain, AMI, arrhythmia.
– PEA or asystole
Jerjes-Sanchez C. et al. Streptokinase
and Heparin versus Heparin Alone in
Massive Pulmonary Embolism: A
Randomised Controlled Trial. Journal
of Thrombosis and Thrombolysis.
1995.
• Prospective and Randomised trial, N=8
– all had “massive” PE and in cardiogenic shock
• high prob. V/Q, with abnormal RH echo or
• >9 obstructed segments on V/Q
• autopsy in 3
– no significant baseline differences between the two groups, except
time elapsed from onset of symptoms to randomization (2.5 vs
34.75hrs)
– 100% survival in streptokinase plus heparin group
– 100% mortality in heparin group
– no bleeding complications
Thrombolytics in Severe Shock or
During CPR in Fulminant
Pulmonary Embolism?
Ruiz Bailen M. et al., Thrombolysis During Cardiopulmonary
Resuscitation in Fulminant Pulmonary Embolism: A Review.
Critical Care Medicine. 2001. Vol 29, No. 11.
– single cases and small series demonstrate promising outcomes
when PE suspected clinically.
• Kurkciyan et al. 2000
– retrospective, N=42 (thrombolysis 21, 21 no treatment)
» 9.5% survival in thrombolysis vs 4.5% in no
treatment
» ROSC in 81% vs 33.3%
• Survival from 9.5% to 100% (Sienblenlist, 1990; Sigmund,
1991; Hopf, 1991; Bittiger, 1991; Scheeren, 1994)
Treatment of Submassive PE:
Thrombolytics
• Konstantinides S et al. Heparin Plus Alteplase
Compared with Heparin Alone in Patients with
Submassive Pulmonary Embolism. NEJM, Vol
347, No 15, October 10, 2002.
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–
–
–
Reviewed @ J-club
N=256
10mg bolus ->90mg over 1hr
Three times less death / Rx escalation in Alteplase
group
Goldhaber, S. et al. Alteplase versus
Heparin in Acute Pulmonary
Embolism: Randomised Trial Assessing
Right-Ventricular Function and
Pulmonary Perfusion. The Lancet.
1993, no 8844. vol 341.
Goldhaber et al. The Lancet.
1993.
• Thrombolysis plus heparin is better than heparin alone
in reversing echo evidence of RV dysfunction
– Prospective and randomized, non-consecutive.
– 99 hemodynamically stable PE patients
– PE confirmed by high probability V/Q and/or
pulmonary angiogram
– excluded if at high risk of adverse hemorrhage.
– all had TTE assessments of right ventricular wall
motion at baseline, then repeated at 3 and 24 hours.
– Angiograms were obtained at baseline and at 24h
Goldhaber et al. The Lancet.
1993.
• 46 patients randomized to rt-PA followed by
heparin and 55 to heparin alone
• Endpoints; mortality, recurrent PE and major
bleeding (72h)
• Followed for 14 days for adverse outcomes (PE
recurrence or death), or longer if in hospital. 72
hrs for bleeding.
Goldhaber et al. The Lancet.
1993.
• Results
– follow-up echo (89 patients)
• rtPA group vs heparin
– 3 hrs -- greater improvement in RV wall motion (p=0.01)
– 24 hrs -- 39% improved, 2% worse vs 17% improved and
17% worse vs. 17% improvement and 17% worse in
heparin group (p=0.005)
– follow-up angiogram at 24hrs (95 patients)
• rtPA vs heparin -- mean absolute improvement in pulmonary
perfusion of 14.6% vs 1.5% in heparin (p<0.0001).
Goldhaber et al. The Lancet.
1993
• Subgroup analysis
– patients with right ventricular hypokinesis on echo (N=36)
• rtPA -- 89% improvement, 6% worsened
• heparin -- 44% improvement, 28% worsened (p=0.03)
• Deaths
– 2 in heparin group (1 refractory CA and 1 with CI to tPA)
• Recurrent PEs
– rtPA -- none
– heparin -- 5 (2 fatal)
• Significant hemorrhage
– heparin -- 1
– rtPA -- 3
Goldhaber et al. The Lancet.
1993.
• Conclusions
– rtPA group
•
•
•
•
improved right heart function at 24 hours
improvement in pulmonary perfusion
decrease in recurrent PEs
lower rate of death
• Strong points
• randomization and similarities between groups
• echo and angiogram readers blinded to treatment and timing in relation to
therapy
• Limitations
• non-blinded to clinicians and open-labeled
• no long -term morbidity or mortality data
Konstantinides, et al. Association
Between Thrombolytic Treatment and
the prognosis of hemodynamically
Stable Patients with Major Pulmonary
Embolism: Results of a Multicenter
Registry. Circulation, 96. 1997
• Early thrombolysis favorably affects in-hospital clinical
outcome.
– Multicentred, registry study
– 719 consecutive patients analyzed; 73% PE confirmed by one or
more imaging study
– evidence of either increased right ventricular afterload or
pulmonary hypertension based on TTE or cath.
– all patients “hemodynamically stable”
• also included patients who were hypotensive (SBP<90) without signs
of shock and those on low dose (<5mcg/kg/min) dopamine.
Konstantinides, et al. Circulation.
1997
• primary end-point -- overall 30-day
mortality
• secondary endpoints -- PE recurrence,
major bleeding
Konstantinides, et al. Circulation.
1997
• Treatment decisions made at discretion of
physician
• 23.5% (n=169) received thrombolytic therapy
within 24h of diagnosis followed by heparin
• remaining patients treated with heparin alone
– unless the physician thought that they required
thrombolytics after the first 24h of heparin.
Konstantinides, et al. Circulation.
1997
Findings
• overall 30d mortality higher in heparin group 11.1% vs
4.7% (p=0.016).
• thrombolytic treatment was found by multivariate analysis
to be the only independent predictor of survival (OR 0.46
for in-hospital death)
• 95% CI 0.21 to 1.00
• thrombolytic group;
– lower rates of recurrent PE (7.7 vs. 18.7, p=0.001)
– higher rates of major bleeding events (21.9 vs 7.8, p=0.001)
• ICH and deaths due to bleeding were the same in the two groups
Konstantinides, et al. Circulation.
1997
• Subgroup analysis
– patients with a dilated right ventricle on echo
• 30 day mortality in (N=380) 10% compared
with 4.1% in those without (p=0.018), a 58%
reduction in mortality.
• 58% reduction in mortality in patients
treated with thrombolytics (4.7% vs 11.1%
heparin, p=0.16)
Konstantinides, et al. Circulation.
1997
• Limitations
– study design;
• non-randomised, heterogeneous thrombolytic regimens
• many patients had clinical signs of disease severity
• more with chronic lung disease in UF heparin group
• choice of treatment was at the discretion of the physician
– selection bias is likely
• distribution of many clinical variables were statistically
different between the two groups (esp. age, pre-existing CHF,
higher in heparin)
• major end point analyses required multivariate regression
model to account for the unequal distribution of clinical
variables
Konstantinides, et al. Circulation.
1997
• 40% of patients thrombolysed had
contraindications to lytics
• 25% in the heparin group ‘crossed over’ and
received thrombolytics. This data was not
reported.
Hamel et al. Thrombolysis or
Heparin Therapy in Massive
Pulmonary Embolism With Right
Ventricular Dilation. Chest, 2001.
Vol. 120:1.
• There is a benefit to thrombolysis over heparin in
stable PE patients with RVD
– Retrospective, cohort study of 153 consecutive patients
– PE confirmed by, V/Q or angiography
– RV function evaluated by TT E on admission
– 64 patients in each treatment group were matched on
the basis of RV/LV diameter ratio
– perfusion scans repeated on day 7 to 10 or earlier if
recurrent PE suspected
Hamel et al. Chest, 2001.
• Inclusion criteria
– included PIOPED criteria for high prob. V/Q
– Pulmonary vascular obstruction >40% on V/Q or Miller index of
20/34
– RV to LV ratio of >0.6* in absence of LV or Mv disease
• Exclusion criteria
–
–
–
–
SBP <90
contraindications to thrombolysis
inotropes
syncope prior to presentation
Hamel et al. Chest, 2001.
• thrombolysis versus heparin
– higher mean relative improvement in lung scan
at 7-10 days (54% vs 42%, p=0.01)
– >50% relative improvement in lung scan
perfusion defect seen in 57% (vs 37%)
– at day 7-10 follow-up scan, average defect
equal between two groups
Hamel et al. Chest, 2001.
• PE recurrence
– rates were the same in both groups, 4.7%
(N=3).
• Mortality
– 4 (6.3%) in thrombolytic and 0 in heparin (NS)
• Bleeding events
– 6 severe, 3 intracranial; significantly higher in
thrombolytic group. 4 died as a result. (15.6%,
N=10 vs 0, p=0.001)
Hamel et al. Chest, 2001.
• Retrospective, case-controlled, consecutive
patients
• small numbers
• Two groups comparable at baseline for historic
factors, RV dysfunction, LS defect and all free of
signs of PE severity
– LS defect, RV/LV ratio and higher PAP higher
in thrombolysis group (not significant)
• heterogeneous treatment regimen in thrombolytic
group
Levine et al. A Randomised Trial of
a Single Bolus Dosage Regimen of
Recombinant Tissue Plasminogen
Activator in Patients with Acute
Pulmonary Embolism. Chest. 1990.
98:1473.
• rt-PA will benefit pulmonary perfusion in patients with
PE and demonstrated perfusion deficits
– Inclusion -- ‘symptomatic’ patients with either high probability
V/Q or angiographically proven PE and no contraindications to
thrombolytics.
– Excluded if hypotensive or hemodynamically unstable
– All patients received heparin bolus. Then randomized to either rtPA (0.6mg/kg, given as a bolus over 2min) or placebo.
– 10 day study period
Levine et al. Chest. 1990
• End-points were >50% improvement in perfusion
defect over baseline and major bleeding events;
– intracranial, retroperitoneal, requires
transfusion >2U or fall in Hgb >20g/L
Levine et al. Chest. 1990
• 58 patients randomized (33 to rt-PA) and groups
were comparable for baseline characteristics.
• Comparison lung scans (at 24h and 7days)
available for 57
– At 24 hours
• rt-PA group -- 34.4% demonstrated a
greater than 50% improvement in perfusion
scan (12% improved >50% in the placebo
group (p=0.017).
• Mean absolute improvement of 9.7% in rtPA (5.2% in placebo, p=0.07)
Levine et al. Chest. 1990
• At 7 days
– no statistically significant difference in lung
scan resolution
• No recurrent PEs in either group
• No major bleeding episodes
Dalla-Volta, S. et al. : Alteplase Combined
With Heparin Versus Heparin in the
Treatment of Acute Pulmonary Embolism.
Plasminogen Activator Italian Multicentre
Study 2 (PAIMS 2). Journal of the
American College or Cardiology 1992. 20;
520.
• tPA will result in more rapid improvement in
angiographic and hemodynamic variables.
–
–
–
–
–
Open, parallel, multicenter, randomized trial, N=36.
PE confirmed by angiogram with PA pressures recorded.
all patients hemodynamically stable
excluded if contraindications to thrombolytics
all patients received bolus UF heparin then Randomised to rt-PA or
heparin
– follow-up angiogram at end of randomized treatment (2hrs),
subset had lung scans at 7 and 30d.
Dalla-Volta, S. et al. JACC. 1993
• Interim data analyzed for first 32 patients randomized
• study terminated due to >3 SD (p<0.01) in the difference
between the angiographic index of the two groups
• patients treated with rt-PA
– decrease in Miller Score (mean 28.3 to 24.8) at 2 hours
– decrease in mean PA pressure (mean of 30.2mmHg to
21.4mmHg, p<0.01).
– CI increased from 2.1 to 2.4 L/min/m2, p<0.01
• patients treated with heparin
– no change in Miller Score or CI
– increase in PA pressure, p<0.001.
Dalla-Volta, S. et al. JACC. 1993
• Patient Subset with 7 and 30day follow-up perfusion
scans
– No difference in Miller Scores (p<0.05)
• Bleeding complications
– 14/20 in tPA had, 3 were severe (Hb decreased by
>50g/L)
– 6/16 and 2 severe in heparin group (NS)
• Deaths
– 2 in tPA group (ICH, tamponade).
Summary of Studies To-Date
•
•
•
•
•
•
•
•
Grifoni -- RVD = increased mortality, PE recurrence.
Ribeiro -- extent of RVD correlates with early & late death
Levine -- early improvement in scan ,no benefit at 7 days
Goldhaber -- improved short-term hemodynamics & lower
rate of short-term rec. PE and death. RCT, non-blinded.
Konstantinides - lower mortality in submassive Rx
thrombolysis
Konstantinides -- lower rate of mortality in subgroup of
pts with RVD & thrombolysis. *Non-randomized, groups
sig. different at baseline.
Dalla-Volta negative for mortality
Hammel no better survival (mortality higher in
thrombolysis group) and higher rate of serious bleeding.
Embolectomy
• Indicated in acute, massive PE if:
– contraindication to thrombolytics
– unresponsive to medical mgt
• moribund pt  poor results
• no evidence cf. with thrombolytics
• percutaneous vs.. surgical
– ?role
IVC Filters
• Indications:
– contraindication to anticoagulation
– recurrent VTE despite anticoagulation
– after surgical embolectomy
• no long term adv vs.. anticoagulation
• anticoagulate if no contraindications
– DVT and IVC occlusion
The END
• Special Thanks to:
– You
• For sitting through 133 slides
– Dr L. Mabon
• For clinical insight
– Dr A. Oster
• For “borrowed slides”
– Dr D. Watt
• For “borrowed slides”