Venous Thromboembolism

1
Venous Thromboembolism

• Core Rounds
• April 10, 2003
• A.F. Chad, MD, CCFP

2
DVT Objectives

• 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

3
DVT Submission move by Jake The Snake
Roberts OR Badness in the Veins?
4
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 gt3d
• 27-33 CCU pts
• 48 pts post CABG

5
History

• 1550 BC Ebers papyrus documented peripheral
  venous disease
• 1644 Schenk observed venous thrombosis with
  occlusion in the IVC
• 1846 Virchow -gt association b/n venous thrombosis
  in legs PE
• 1937 Heparin comes into practice

6
Natural History

• 19th C Virchows triad venous stasis, injury to
  intima, hypercoagulability
• Thrombosis platelet nidus near venous
  valves-gtplatelets and fibrin -gt thrombus -gt
  occlusion, embolism
• Endogenous thrombolytic system -gt partial
  dissolution-gt organized into venous wall

7
Natural History

• Most go away w/o Rx
• 20 propagate proximally
• Organize into vein by day 5-10
• Biggest risk of propagation, embolization is
  before this

8
Natural History

• Debate whether isolated calf thrombi are
  important
• Some said to have low risk PE
• Others said just as bad

9
Risk Factors General

• Age
• Immobilization longer than 3 days
• Pregnancy and the postpartum period
• Major surgery in previous 4 weeks
• Long plane or car trips (gt4-6 h) in previous 4
  weeks
• Wrestling Jake The Snake Roberts

10
Risk Factors Specific

• Medical
• Cancer,Previous DVT, stroke, MI, CHF, sepsis,
  nephrotic, UC
• Trauma
• Multiple trauma, CHI, SCI, Burn, LE
• Vasculitis
• SLE / LAC, Bechet, Homocystinuria
• Hematologic
• PRV, Thrombocytosis

• Clotting D/O
• Antithrombin III , Protein C, Protein S, Factor V
  Leiden, Dysfibrinogenemias and disorders of
  plasminogen activation
• Drugs/medications
• IV drug abuse
• Oral contraceptives
• Estrogens
• HIT

11
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

12
PathophysiologySource 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

13
History

• Many No Sx
• Edema (unilateral) specific
• Leg pain in 50 -gt nonspecific
• Tenderness in 75, but also in 50 w/o DVT
• 10 Sx PE
• Amount pain / tenderness do not correlate to
  severity
• Warmth, erythema

14
Physical

• No ONE reliable history / physical finding
• Sensitivity 60-96, Specificity 20-72
• Need to look _at_ 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 2280(21)1828-9.

15
Physical

• Edema (unilateral) (gt 3cm)
• Homans (50 sens)
• Superficial thrombophlebitis (up to 40 can have)
• Fever (gt39.5, 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

16
Clinical PresentationDVT

• 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 -gt high risk to propagate / embolize

17
Clinical Prediction Model for DVTWells et al.
Ann Int Med, 1997
18
Clinical Model for DVT
19
Incidence of DVT by Clinical Probability
20
Algorithm for Suspected first DVTPerrier.
Lancet, 1999
21
Tests

• D-dimer
• Doppler U/S
• IPG
• Venography

22
D-Dimer

• Not Clot specific
• recent surgery, trauma, MI, pregnancy, CA can all
  give false

23
D-dimer AssaysVan der Graaf. Thromb Haemost,
2000.
24
Diagnostic Imaging for DVT

• Duplex / compression U/S
• 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

25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
Serial Venous U/S

• 2 protocols Wells Hull
• may avoid angiography in ?PE
• 2 ve in 2 weeks (?PE)
• if U/S -ve 2 weeks apart, lt2 have VTE in next 6
  mos

29
Diagnostic Imaging for DVT

• IPG
• detects changes in flow before and after cuff
  inflated
• sensitivity 60

30
IPG vs. Doppler

• N985
• PPV U/S94 (CI 87-98)
• PPV IPG 83 (CI 75-90)
• P0.02
• 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
  3291365-1369November 4, 1993Number 19.

31
Venography

• ?Gold Standard?
• Invasive
• Contrast
• Need experienced readers
• Non-diagnostic up to 25

32
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)

33
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 28158(17)1950-2.

34
Upper Extremity DVT

• N58 Sx UEDVT
• IPG, Doppler, venography
• 27 (47) UEDVT
• Test Sens Spec
• compression ultrasonography (96 and 93.5)
• color flow Doppler imaging (100 and 93)

35
Upper Extremity DVT

• PE Objectively found in 36
• 2 yr F/U 2 recurrent VTE
• RF
• CVC
• Thrombophilia
• Previous VTE

36
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.
•  

37
Upper Extremity DVT

• 10-30 incidence PE associated
• Therapy
• Usual Rx
• Local thrombolytics appears to be Rx of choice
  with literature mainly case studies

38
Treatment of VTEGoals

• reduce mortality
• prevent extension/recurrence
• restore pulmonary vascular resistance
• prevent pulmonary hypertension

39
Treatment of VTEAnticoagulation

• 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

40
Anticoagulation

• 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 gt2.0 x 2 days
• Rx 3 mos if 1st and reversible cause
• 6 mos if non-reversible
• indefinite if recurrent, CA, genetic
• Anticoagulation Clinic

41
LMWH vs. UFH

• N432
• 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-molecular-weight heparin compared with
  continuous intravenous heparin in the treatment
  of proximal-vein thrombosis NEJM Volume
  326975-982April 9, 1992Number 15

42
Pregnancy

• 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

43
PE Early Rappers OR Badness in the Veins?
44
PE Objectives

• Epidemiology Natural History
• Mortality Pathophysiology
• Hx PHx
• Pre-test Probability
• Dx
• 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),
  embolectomy, IVC filter

45
Epidemiology

• USA 60-80 patients with DVT, gt50 Sx free
• 3rd in hospital mortality, 650,000 cases/yr
• Autopsy studies 60 pts who die in hospital had
  PE, diagnosis missed 70

46
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 _at_ bifurcation of main PA or
  lobar branches -gt hemodynamic compromise
• Smaller thrombi occlude smaller vessels in
  periphery
• More likely to cause pleuritic chest pain
  (inflammatory response adjacent to parietal
  pleura)

47
Mortality

• Approximately 10 of patients who develop PE die
  within the first hour,
• 30 die from recurrent embolism. Anticoagulant Rx
  decreases mortality lt 5

48
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.

49
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

50
Hemodynamic Consequences

• Reduces X-sectional area of pulmonary vascular
  bed -gt incr pulmonary vascular resistance -gt RV
  afterload -gt RV failure
• Reflex PA constriction
• Prior poor cardiopulmonary status important
  factor re hemodynamic collapse

51
Resolution

• Anticoagulant therapy -gt resolution of emboli
  rapidly 2 weeks Rx
• Significant long-term nonresolution of emboli
  causing pulmonary HTN or cardiopulmonary symptoms
  uncommon

52
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

53
PIOPED Sx

• dyspnea (73)
• pleuritic chest pain (66)
• cough (37)
• hemoptysis (13)

54
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)

55
Physical Size Matters

• Acute pulmonary infarction
• Decreased excursion of involved hemithorax,
  palpable or audible pleural friction rub,
  localized tenderness
• Signs of pleural effusion

56
(No Transcript)
57
Physical Size Matters

• Acute pulmonary Embolus (no infarct)
• Non-specific
• Tachypnea, tachycardia, pleuritic pain, crackles
  and local wheeze _at_ embolus site

58
(No Transcript)
59
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.

60
Physical PIOPED

• Tachypnea (70)
• Rales (51)
• Tachycardia (30)
• Fourth heart sound (24)
• Accentuated P2 (23)
• Fever lt 39C ( 14) of patients (gt 39.5C not
  from PE)
• Palpable Chest wall tenderness w/o Hx trauma

61
Diagnostic Imaging for PEPulmonary 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

62
(No Transcript)
63
Diagnostic Imaging in PEEchocardiography

• 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)

64
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

65
Grifoni et al, Circulation, 2000.

• 4 groups
• Shock (N28,13.4)
• SBPlt100 with signs of organ hypoperfusion
• Hypotensive without signs of shock (N19, 9.1)
• Normotensive with RV strain (N65, 31.1)
• Normotensive without RV strain (N97, 46.4)

66
Grifoni et al, Circulation, 2000.

• Patients with hypotension/shock (22, N47)
• Mortality 19
• Normotensive without evidence of RV strain
  (46.5, n97)
• 0 PE-related deaths
• Normotensive with RV strain (31.1, N65)
• 10 (n6) clinically deteriorated due to PE
  recurrence
• 5 (n3) PE-related deaths

67
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.

68
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

69
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 gt14days (sig.),
  malignancy and CHF (NS)in B)
• In-hospital PE mortality all in group B (n9),
  p0.002
• 1 year overall mortality rate 15.1 (n19)
• group A, 7.1 (n4) mortality, all non-PE.
• group B, 27.7 (n15) mortality, 9 due to PE
  (p0.04)
• 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)
  
• (malignancy RR 3.0).

70
Ribeiro et al. American Heart Journal, 1997.

• Subgroup analysis of patients without cancer
  (n101)
• In-hospital mortality
• Group A 0
• Group B 7.7 (N4/52)
• 1 year cumulative mortality
• Group A 2, (N1)
• Group B 9.8, (N5)

71
Moore, et al. Determination of Left Ventricular
Function by Emergency Physician Echocardiography
of Hypotensive Patients. Academic Emergency
Medicine, vol. 9, no. 3, 2002.

• 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)

72
Diagnostic Imaging for PEV/Q scan

• PIOPED ventilation component adds little info
• PISAPED criteria
• normal, non-diagnostic, high probability
• 25, 50, 25 respectively
• high prob 85-90 PPV
• non-diagnostic 25 PE
• interpret in context of PTP

73
Relationship between degree of RV dysfunction and
degree of perfusion scan deficits

• Wolfe, 1994. N90
• degree of perfusion deficit greater in patients
  with RVD (54 vs 30, plt0.001)
• all patients with recurrent PE in group with
  initial RVD, plt0.01
• Ribiero, 1998
• correlation between RVD and perfusion scan
  deficit but wide CI.
• Miller, 1998. N64
• failed to demonstrate a correlation between RVD
  and perfusion deficit

74
(No Transcript)
75
(No Transcript)
76
(No Transcript)
77
Diagnostic Imaging for PESpiral CT

• 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

78
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

79
(No Transcript)
80
(No Transcript)
81
(No Transcript)
82
Clive Kearon. Diagnosis of pulmonary embolism.
CMAJ January 21, 2003 168 (2)
83
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

84
Standardized Clinical Assessment

• Well Criteria 2 low, 19 intermediate, 50 high
• Pisa-PED Sx, ECG, CXR -gt 2, 50, 100
• Perrier8 clinical, blood gas or CXR -gt 10, 38,
  81

85
(No Transcript)
86
(No Transcript)
87
(No Transcript)
88
Clinical Prediction Model for PEWells. Ann Int
Med, 1998
89
Incidence of PE by Clinical Probability
90
Algorithm for suspected PEWells. Ann Int Med,
2001
91
Wells AlgorithmCriticism

• Uses SimpliRED assay lower sens.
• sCT not included
• could replace angiography?
• Low prevalence of PE (9)
• not validated by other RCTs

92
(No Transcript)
93
(No Transcript)
94
(No Transcript)
95
Treatment of PECriteria for admission

• Hemodynamic instability
• O2 requirement
• surgery lt 48hr
• risk of active bleeding
• history of HIT
• IV pain control

96
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

97
Thrombolytics

• 2 week window of opportunity!
• effect ? with time
• no advantage of t-PA bolus
• protocols
• 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

98
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

99
Treatment of massive PEThrombolytics

• 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

100
Treatment of massive PEThrombolytics

• Abu-Laban, R et al. Tissue Plasminogen Activator
  in Cardiac Arrest With Pulseless Electrical
  Activity. NEJM, vol 346, No 20, May 16, 2002.
• Reviewed _at_ J-club
• N233
• No Benefit
• Only 1 of 42 autopsied showed PE
• Not great PE, Still ????

101
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

102
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, N8
• all had massive PE and in cardiogenic shock
• high prob. V/Q, with abnormal RH echo or
• gt9 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

103
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, N42 (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)

104
Treatment of Submassive PEThrombolytics

• 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.
• Reviewed _at_ J-club
• N256
• 10mg bolus -gt90mg over 1hr
• Three times less death / Rx escalation in
  Alteplase group

105
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.
106
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

107
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.

108
Goldhaber et al. The Lancet. 1993.

• Results
• follow-up echo (89 patients)
• rtPA group vs heparin
• 3 hrs -- greater improvement in RV wall motion
  (p0.01)
• 24 hrs -- 39 improved, 2 worse vs 17 improved
  and 17 worse vs. 17 improvement and 17 worse
  in heparin group (p0.005)
• follow-up angiogram at 24hrs (95 patients)
• rtPA vs heparin -- mean absolute improvement in
  pulmonary perfusion of 14.6 vs 1.5 in heparin
  (plt0.0001).

109
Goldhaber et al. The Lancet. 1993

• Subgroup analysis
• patients with right ventricular hypokinesis on
  echo (N36)
• rtPA -- 89 improvement, 6 worsened
• heparin -- 44 improvement, 28 worsened (p0.03)
• 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

110
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

111
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
  (SBPlt90) without signs of shock and those on low
  dose (lt5mcg/kg/min) dopamine.

112
Konstantinides, et al. Circulation. 1997

• primary end-point -- overall 30-day mortality
• secondary endpoints -- PE recurrence, major
  bleeding

113
Konstantinides, et al. Circulation. 1997

• Treatment decisions made at discretion of
  physician
• 23.5 (n169) 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.

114
Konstantinides, et al. Circulation. 1997

• Findings
• overall 30d mortality higher in heparin group
  11.1 vs 4.7 (p0.016).
• 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,
  p0.001)
• higher rates of major bleeding events (21.9 vs
  7.8, p0.001)
• ICH and deaths due to bleeding were the same in
  the two groups

115
Konstantinides, et al. Circulation. 1997

• Subgroup analysis
• patients with a dilated right ventricle on echo
• 30 day mortality in (N380) 10 compared with
  4.1 in those without (p0.018), a 58 reduction
  in mortality.
• 58 reduction in mortality in patients treated
  with thrombolytics (4.7 vs 11.1 heparin,
  p0.16)

116
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

117
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.

118
Hamel et al. Thrombolysis or Heparin Therapy in
Massive Pulmonary Embolism With Right Ventricular
Dilation. Chest, 2001. Vol. 1201.

• 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

119
Hamel et al. Chest, 2001.

• Inclusion criteria
• included PIOPED criteria for high prob. V/Q
• Pulmonary vascular obstruction gt40 on V/Q or
  Miller index of 20/34
• RV to LV ratio of gt0.6 in absence of LV or Mv
  disease
• Exclusion criteria
• SBP lt90
• contraindications to thrombolysis
• inotropes
• syncope prior to presentation

120
Hamel et al. Chest, 2001.

• thrombolysis versus heparin
• higher mean relative improvement in lung scan at
  7-10 days (54 vs 42, p0.01)
• gt50 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

121
Hamel et al. Chest, 2001.

• PE recurrence
• rates were the same in both groups, 4.7 (N3).
• 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,
  N10 vs 0, p0.001)

122
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

123
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. 981473.

• 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 rt-PA (0.6mg/kg, given as a
  bolus over 2min) or placebo.
• 10 day study period

124
Levine et al. Chest. 1990

• End-points were gt50 improvement in perfusion
  defect over baseline and major bleeding events
• intracranial, retroperitoneal, requires
  transfusion gt2U or fall in Hgb gt20g/L

125
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
  gt50 in the placebo group (p0.017).
• Mean absolute improvement of 9.7 in rt-PA (5.2
  in placebo, p0.07)

126
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

127
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,
  N36.
• 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.

128
Dalla-Volta, S. et al. JACC. 1993

• Interim data analyzed for first 32 patients
  randomized
• study terminated due to gt3 SD (plt0.01) 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, plt0.01).
• CI increased from 2.1 to 2.4 L/min/m2, plt0.01
• patients treated with heparin
• no change in Miller Score or CI
• increase in PA pressure, plt0.001.

129
Dalla-Volta, S. et al. JACC. 1993

• Patient Subset with 7 and 30day follow-up
  perfusion scans
• No difference in Miller Scores (plt0.05)
• Bleeding complications
• 14/20 in tPA had, 3 were severe (Hb decreased by
  gt50g/L)
• 6/16 and 2 severe in heparin group (NS)
• Deaths
• 2 in tPA group (ICH, tamponade).

130
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.

131
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

132
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

133
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