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 >3d –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 -> association b/n venous thrombosis in legs & PE 1937: Heparin comes into practice

6. 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

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 (>4-6 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. 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

13. History 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

14. 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.

15. Physical 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

16. 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

17. Clinical Prediction Model for DVT Wells et al. Ann Int Med, 1997

18. Clinical Model for DVT

19. Incidence of DVT by Clinical Probability

20. Algorithm for Suspected first DVT: Perrier. 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 Assays Van 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

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, <2% 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 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 329:1365- 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 28;158(17):1950-2.

34. Upper Extremity DVT 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%)

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 VTE: Goals reduce mortality prevent extension/recurrence restore pulmonary vascular resistance prevent pulmonary hypertension

39. Treatment of VTE: Anticoagulation 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 >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

41. 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-molecular- weight heparin compared with continuous intravenous heparin in the treatment of proximal- vein thrombosis NEJM Volume 326:975-982April 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, >50% 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 @ 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)

47. Mortality Approximately 10% of patients who develop PE die within the first hour, 30% die from recurrent embolism. Anticoagulant Rx decreases mortality < 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 -> incr pulmonary vascular resistance -> RV afterload -> RV failure Reflex PA constriction Prior poor cardiopulmonary status important factor re hemodynamic collapse

51. Resolution Anticoagulant therapy -> 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

57. Physical: Size Matters Acute pulmonary Embolus (no infarct) –Non-specific –Tachypnea, tachycardia, pleuritic pain, crackles and local wheeze @ embolus site

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 39.5°C not from PE) Palpable Chest wall tenderness w/o Hx trauma

61. 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

63. 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)

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 (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%)

66. 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

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 >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) *(malignancy RR 3.0).

70. 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)

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 PE: V/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. 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

77. Diagnostic Imaging for PE: Spiral 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

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 -> 2%, 50%, 100% Perrier:8 clinical, blood gas or CXR -> 10%, 38%, 81%

88. Clinical Prediction Model for PE Wells. Ann Int Med, 1998

89. Incidence of PE by Clinical Probability

90. Algorithm for suspected PE: Wells. Ann Int Med, 2001

91. Wells’ Algorithm: Criticism Uses SimpliRED assay: lower sens. sCT not included –could replace angiography? Low prevalence of PE (9%) not validated by other RCTs

95. Treatment of PE: Criteria for admission Hemodynamic instability O2 requirement surgery < 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 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

100. 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. –Reviewed @ J-club –N=233 –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, 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

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, 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)

104. 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. –Reviewed @ J-club –N=256 –10mg bolus ->90mg 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 (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).

109. 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

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 (SBP<90) without signs of shock and those on low dose (<5mcg/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% (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.

114. 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

115. 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)

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. 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

119. 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

120. 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

121. 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)

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. 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 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 >50% improvement in perfusion defect over baseline and major bleeding events; –intracranial, retroperitoneal, requires transfusion >2U or fall in Hgb >20g/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 >50% in the placebo group (p=0.017). Mean absolute improvement of 9.7% in rt- PA (5.2% in placebo, p=0.07)

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, 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.

128. 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.

129. 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).

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”