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Pulmonary Thromboembolic Disease Risk Stratification & Approach For Management Majdy M Idrees Division of Pulmonary Medicine Riyadh Armed Forces Hospital.

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Presentation on theme: "Pulmonary Thromboembolic Disease Risk Stratification & Approach For Management Majdy M Idrees Division of Pulmonary Medicine Riyadh Armed Forces Hospital."— Presentation transcript:

1 Pulmonary Thromboembolic Disease Risk Stratification & Approach For Management Majdy M Idrees Division of Pulmonary Medicine Riyadh Armed Forces Hospital 10 th Advanced Medicine Symposium November 2006 RMH, Riyadh

2 An Expert: A man who has stopped thinking: He Knows!!

3 Pulmonary Embolism Risk Stratification & Approach of Management “Venous thrombosis is always a severe disease and is often fatal, because fragments of the thrombi may detach and occlude branches of the pulmonary artery... the occlusion of the main branches of the pulmonary artery causes a striking rise of the blood pressure in these vessels. This rise, which the right heart might fight in order to ensure circulation, may sometimes lead to cardiac arrest.” Picot 1884 Lecons de Clinique Médicale

4 It is a clinical syndrome of high mortality characterized by acute pulmonary arterial occlusion with resultant sudden elevation in pulmonary artery pressure and right ventricular failure Definition Pulmonary Embolism Risk Stratification & Approach of Management

5 Simple Complicated SubmassiveMassive Pulmonary Embolism Risk Stratification Pulmonary Embolism Risk Stratification

6 Complicated Pulmonary Embolism Massive Pulmonary Embolism 1.Perfusion defect >50% 2.Filling defect / obstruction in 2 lobar arteries 3.Obstruction of main (R/L) PA 2. Hemodynamic instability 1. Severe refractory hypoxic 3. Acute RV failure 4. Tissue hypoperfusion (low urine output) Visual ScoringFunctional Scoring

7 Predicting PE Perfusion Defects Resp rate/min172228 Heart rate/min9599100 (A-a)O 2 kPa3.64.46.3 D-dimer ug/L273160907950  4000ug/L33%67%94% < 4000ug/L67%33%6% US proximal DVT(+) 33%(+) 76%(+) 66% (-) 67%(-) 24%(-) 34% Galle Thromb Haemost 2001; 86:1156-60 < 30%30% - 50%>50%

8 PE Severity: Echo Assessment Echo Cor Pulmonale (+) (22)56% Echo Cor Pulmonale (-) (14)28% Pulmonary Artery Pressures 26 mmHg (4)< 30% 36 mmHg (6)30% - 49% 48 mmHg (6)50% - 74% 44 mmHg (20)> 75% % Obstruction Mastora Eur Radiol 2003; 13:29-35

9 CT Severity Assessment Vascular obstruction index 54%24% Minimum LV diameter 33 mm40 mm RV/LV Ratio1.631.09 Central PA diameter 32 mm28 mm Severe PE Non-severe PE (Lysis/Embolectomy) (Heparin tx) Collomb Eur Radiol 2003; 13:1508-14

10 RV Pressure Load RV Decompensation Increase RV Volume Septal Shift Pericardial Restriction Decrease LV Distensiblity Decreased LV Preload Decrease RV Output Ischemia ObstructionNeuro-hormonal  COP / MAP Decreased RV CPP  VO 2  Wall stress Pathophysiology

11 Vascular Obstruction and Acute Pulmonary Hypertension McIntyre Am J Card 1971; 28:288-294 Pulmonary Arterial Mean Pressure (mmHg) Pulmonary Vascular Obstruction Angiogram (%) 10 20 30 40 10 30 50 70

12 Vascular Resistance vs Obstruction 0 30 20 30 10 20 Miller index TPVR (mmhg.1.min.m) ° ° ° ° ° ° ° ° Petitpretz Circ 1984; 70:861-866.

13 Intervention Diagnostic – Therapeutic Approach

14 Severity Embolism size Cardiopulmonary Status 100 70 30 10 0 Mortality Sudden Death Cardiac Arrest Shock Outcome in Pulmonary Embolism Risk Stratification Hemodynamically Stable & RV Normal Infliction Point

15 Severity Embolism size Cardiopulmonary Status 100 70 30 10 0 Mortality Sudden Death Cardiac Arrest Shock Outcome in Pulmonary Embolism Risk Stratification Hemodynamically Stable & RV Normal

16 Sudden Death in Massive PE Mortality is almost 100% No intervention measure has proven effective

17 Cardiac Arrest

18 Severity Embolism size Cardiopulmonary Status 100 70 30 10 0 Mortality Sudden Death Cardiac Arrest Shock Outcome in Pulmonary Embolism Risk Stratification Hemodynamically Stable & RV Normal

19 Echo and Cardiac Arrest 48 patients in/out hospital cardiac arrest Diagnosis obtained via TEE Myocardial infarction 21 Cardiac tamponade 6 Pulmonary embolism 6 Aortic dissection/rupture 5 Papillary muscle rupture 1 Absence of cardiac structural abnormalities 7 Other diagnosis 2 Sensitivity 93% specificity 50%, positive predictive value 87% 31% major therapeutic decisions based upon TEE JACC 30:780-783, 1997

20 Thrombolysis in CPR Majority of PE deaths within 1st hour of symptoms Bolus thrombolysis in arrest- “Reported” Initiated after failure of conventional CPR Stabilization Minimal bleeding complications Microcirculatory Reperfusion 77% Stabilized 67% Survived Bottiger Fibrinolysis and Proteolysis, 1997

21 Shock

22 Severity Embolism size Cardiopulmonary Status 100 70 30 10 0 Mortality Sudden Death Cardiac Arrest Shock Outcome in Pulmonary Embolism Risk Stratification Hemodynamically Stable & RV Normal

23 “In acute diseases,,, coldness of the extremities,, is a very bad sign.” The Aphorisms of Hippocrates

24 Pulmonary Embolism Shock vs. Non-Shock Mortality 2%40%ThrombolysisTilsner 1991 4%14%ThrombolysisVerstraete 1988 11%22%Heparin Thrombolysis Embolectomy Miller 1977 5%25%Heparin Venous Ligation Alpert 1976 6%36%Heparin Thrombolysis UPET 1970 StudyTreatment Shock Mortality Non-Shock Mortality

25 Major Pulmonary Embolism Diagnostic & Therapeutic Approach Shock ECHO TEE/TTE RV Pressure Overload? Alternative DX Resuscitate & Stabilize Establish Diagnosis No Yes Start Heparin Certain Diagnoses Emboli in PA AMI / Aortic Dissection / Tamponade Spiral CT V/Q Angio - + Peruse other dx Lysis Candidate No Embolectomy Yes Lytic Rx

26 Measures to Improve Hemodynamics  Flow (Cardiac Output)

27 “Patients with shock or major disability due to Pulmonary Embolism were excluded because random assignment to a placebo group was considered unethical.” Exclusion Criteria PIOPED PIOPED Investigators CHEST 1990; 97:528-33 Heparin Therapy

28 Management Massive PE With Shock Heparin Therapy The efficacy of heparin is attributed to an impairment of clot propagation and the prevention of recurrent PE Recurrent PE is reported to be the most common cause of death in hemodynamically stable patients Prog Cardiovasc Dis 17,257-270 An inability to establish an early therapeutic level for aPTT is associated with a higher rate of recurrence and impairs the efficacy of anticoagulation therapy with warfarin It is recommended that heparin therapy be given for 7 to 10 days and that the initiation of warfarin therapy be delayed until the aPTT is at a therapeutic level for 3 days.

29 Thrombolytic Therapy

30 Thrombolists Perspective – “Works Great” Hastens thromboembolic resolution Removes pulmonary thromboemboli more completely Hastens dissolution of thrombi in legs May decrease mortality from pulmonary embolism May diminish the incidence of chronic thromboembolic pulmonary hypertension Sasahara J Cardiovascular Medicine 1980

31 Traditionalists Perspective – “Unfulfilling” Does fibrinolytic therapy decrease mortality in acute PE? What is the impact of fibrinolytic therapy on short and long term recovery from acute PE? Does fibrinolytic therapy decrease the rate of recurrent PE? How do the complications and Cost of fibrinolytic therapy compare with those of heparin? “Available data does not support the FDA conclusion that fibrinolytic agents are indicated for massive PE… there is insufficient data to determine whether the second approved indication for fibrinolytic therapy – PE accompanied by failure to maintain BP without supportive measures – is appropriate.” Dalen J Cardiovascular Medicine 1980

32 Thrombolytic Therapy Putative Benefits Accelerated Clot Lysis  Recurrent Embolism Angiograms Perfusion scans Chronic Pul HTN Pul capillary blood volume Quality of Life Hemodynamic Improvement Pulmonary pressuresSymptoms Echocardiogram Mortality PROVENSPECULATIVE

33 Early Resolution Rate Lytic vs Heparin % scan1.5% 14.6%* 24rt-PAGoldhaber ‘93 Δ Angio severity-0.1-3.5*2rt-PAPAIMS 2 ‘92 % showing 50% improvement scan 12.0%34.4%24rt-PALevine ‘90 % Δ mismatch scan defect 0%10%24rt-PAPIOPED ‘90 Δ Angio severity-3.4-11.3*72SKLy ‘78 Δ Angio severity-2.8-13.3*72SKTibbutt ‘74 % Scan defect8.3% 24.1%* 24UKUPET ‘73 HeparinLytic Study/YrAgentTime PostResolutionMetric

34 Angiographic Severity UPET UPET JAMA 1970; 214:2163-2172 3 2 1 0 3 2 1 0 4 Heparin Urokinase Baseline 24 Hours Severe Moderate Normal Minimal N = 57 Complete (91-100%) Marked (61-90%) Moderate (31-60%) Slight Improvement ( 30%) No change

35 Rate and Extent Clinical-Hemodynamic Resolution Reported in UPET UPET JAMA 1970; 214:2163-2172 Heparin Urokinase Baseline 24 hours Δ Baseline mRAP mmHg5.860.336.58-1.61* RV Systolic mmHg44.4-3.244.5-10.1* RVEDP mmHg8.93-0.019.09-2.22* mPAP mmHg26-1.1826.3-5.59* PaO 2 62.7-0.1261.68.33* (A-V) O 2 4.920.084.90-0.23 CI L/minm 2 3.06-0.133.150.07 TPR5.850.005.84-0.33*

36 Total Pulmonary Resistance Evolution Meneveau European Heart Journal 1997; 18:1141-1148 0 -40 -20 -60 0 2 46 8 10 12 Time (h) % change from baseline rt-PA Streptokinase Heparin

37 Right Ventricular Ejection Fraction Evolution Meneveau European Heart Journal 1997; 18:1141-1148 80 70 60 20 30 40 50 10 0 2 46 8 12 Time (h) % change from baseline rt-PA Streptokinase Heparin

38 Recurrent PE With Thrombolytic Therapy UPET 1973Urokinase9.0% (7)6.1% (5) Levine 1990rt-PA0% PAIMS 2rt-PA0%5% (1) Goldhaber 1993rt-PA3.6% (2)0% Konstantinides 2003rt-PA2.9% (4)3.4% (4) Totalsrt-PA2.3% (5)2.6% (6) StudyAgent HeparinLytic Dalen Venous Thromboembolism Lung Biology in Health and Disease 2003

39 Thrombolytic Therapy Hemorrhagic Complications Major hemorrhage 8-12% Similar amongst agents Fatal hemorrhage 1-2% Intra-cranial hemorrhage 1.2-2.1% Fatal in 50% Arcasoy Chest 1999; 115:1695-1707

40 Allows rapid and complete removal of the clot Survival rate in retrospective review 40-60% Ann Thorac Surg 1991 Cardiac arrest is the most preoperative prognostic factor Indicated when Thrombolysis is contraindicated or failed “Unyeilding” hypotension despite max therapy for > 1 h Ongoing/intermittent cardiac arrest Management Massive PE With Shock Surgical Embolectomy

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43 Infliction Point Emboli in Transit RV Dysfunction Submassive Pulmonary Embolism

44 Severity Embolism size Cardiopulmonary Status 100 70 30 10 0 Mortality Sudden Death Cardiac Arrest Shock Outcome in Pulmonary Embolism Risk Stratification Hemodynamically Stable & RV Normal Infliction Point RV Dysfunction Troponin T NDH

45 Isolated RV Dysfunction RV dysfunction has long been recognized as a marker for poor outcome in patients with PE, especially in those with hemodynamic instability RV dysfunction in hemodynamically stable patients has been identified as a predictor of worse outcome and appears to be related to the presence of recurrent PEs. 10% of hemodynamically stable patients with RV dysfunction will deteriorate into shock with a 50% mortality rate attributed to those with recurrent PEs

46 Massive Pulmonary Embolism Prognostic Factors - ICOPER Factor Hazard Ratio Systolic arterial hypotension2.9 Congestive heart failure2.4 Cancer2.3 Tachypnea2.0 RV hypokinesis on echo2.0 COPD1.8 Age > 701.6 Goldhaber Lancet 1997; 353: 1386-1389

47 Outcomes Hemodynamically Stable Confirmed PE with RV Dysfunction Tx Heparin StudyYearPE Deaths% Mortalityn Goldhaber19932328.7% Grifoni20006135% Hamel20016400% Giannitsis20002627.7% Viellard-Baron20023213% Pruszczyk200364812.5% Pruszczyk2003511019.6% Kucher200319210.5% 340288.2%

48 Alteplase vs Heparin Acute PE Assessing RV Function and Perfusion in Hemodynamically Stable Patients Improvement RV wall motion 24 hrs 39%17%  PVED Area 24 hours27.5  2425  25.3  Pulmonary perfusion14.6%1.5% Recurrent PE0%9% Mortality0%3.6% Rt-PAHeparin Goldhaber Lancet 1993; 341:507-11 2 fatal 3 non- fatal All RV Dysfxn

49 Major Pulmonary Embolism Thrombolytic Therapy - MAPPET Lysis (24%)Heparin (76%) Mortality 4.7% 11.1% Recurrent PE 7.7% 18.7% Major bleed 21.9% 7.8% Clinical factors  death: syncope,  BP, CHF, COPD Primary lysis independent predictor of survival Caution!! Heparin group old, CHF, COPD RV Dysfxn +  BP-No pressors (719) Konstantinides Circ 1997; 96:882-888

50 Non-shock Mortality Thrombolytic Therapy Patients Mortality Lytic % (N) Heparin % (N) Heparin Lytic Study UPET ’73 Urokinase73 2.7% (2)8.2% (6) Marini ’88 Urokinase20100% PIOPED ’90 rt-PA9411.1% (1)0% Levine ’90 rt-PA33253.0% (1)0% PAIMS 2 ’92 rt-PA201610% (2)6.3% (1) Goldhaber ’93 rt-PA46550%3.6% (2) Konstantinides ’02 rt-PA 1181383.4% (4)2.2% (3) Total3193213.1% (10)3.7% (12)

51 Submassive Complicated Pulmonary Embolism The role of Thrombolysis Early Lytic Treatment of Submassive Pulmonary Embolism: Clot Dissolving Therapy With Alteplase Plus Heparin Vs Heparin Alone Chest 2003

52 Randomized, DB, multicenter trial 256 pt PE confirmed by HP V/Q scan, spiral CT or angiogram Normal BP RV dysfunction (Echo, ECG or SG catheter) Submassive Complicated Pulmonary Embolism The role of Thrombolysis

53 Primary endpoint: In-hospital mortality Worsening circulation Need for additional therapy (surgical embolectomy or adding vasoactive drugs for shock) Secondary endpoint: 30-days mortality Recurrent PE Submassive Complicated Pulmonary Embolism The role of Thrombolysis

54 Results: The composite primary end point occurred in 11% in alteplase group Vs 24.6% in Heparin group (p=0.0058) In hospital mortality was the same in both group (2.4% Vs 2.2%), (p=NS) (intention to treat) Major bleeding was NS (1% Vs 3%), (p=NS) No significant differences in secondary endpoint Submassive Complicated Pulmonary Embolism The role of Thrombolysis

55 Conclusion: Administrating the clot-dissolving drug, alteplase, early in the course of massive pulmonary embolism prevents worsening of the disease, and is not associated by increase risk of side effect. Submassive Complicated Pulmonary Embolism The role of Thrombolysis

56 BNP and Troponin Complementary Biomarkers for Risk Stratification Future Directions? Hemodynamically Stable PE And  Stretch  Ischemia  RVDysfxn  RV damage  BNP 0.01 detects detects low risk high risk BNPTroponin

57 Troponin T in Acute PE Giannitsis Cir 2000; 102:211-217 56 PE Patients Troponin (+) 32% (18) Troponin (-) 68% (38) Dilated 100% (18) Normal 0% (0) Dilated 34% (13) Normal 66% (25) RV Shock (17) Troponin (+) Troponin (-) 76% (12) 24% (5)

58 Troponin and PE Clinical Outcome Hospital death (44% vs 3%)29.6 Need for resuscitation14.2 Inotropic support5.4 Mechanical ventilation11.5 Independent predictor 30 day mortality15.2 Giannitsis Cir 2000; 102:211-217 Outcome Odds Ratio

59 Troponin and PE Outcome < 0.07---- 9.6% 0.07 – 1.57.153.1643% > 1.516.91*15.47*50% < 0.04---- 18% 0.04 – 0.12.324.43*20% > 0.16.50*8.71*48% RV Dysfunction Complicated Course (OR) Mortality (OR) cTnI, ng/dl cTnT, ng/dl Konstantinides Circ 2002; 106:1263-68

60 Brain Natriuretic Peptide Kucher Circ 2003; 107:1576-78 BNP< 90 pg/ml85%75%93%57% BNP< 50 pg/ml95%60%97%48% Sensitivity Specificity Negative Positive BNP > 90 ng/ml independent predictor adverse (OR 8.0) “Congestive failure” cut off BNP < 90 ng/dl does NOT guarantee a benign course BNP < 50 ng/ml  highly sensitive, excellent negative predictive value

61 N-terminal proBNP and Echo Non-massiveSubmassiveMassive BP mmHg13212683 RV:LV0.630.901.21 Deaths0%20%44% SAE0%31%78% BNP pg/mL363 (56%)4650 (90%)9865 (100%) Pruszczyk Eur Respir J 2003; 22:649-53 All deaths/SAE in  NT-proBNP group Normal NT-proBNP 100% negative predictive value NT-proBNP > 600 96% sensitive 35% specific SAE 100% sensitive 33% specific death

62 Submassive Pulmonary Embolism Diagnostic-Therapeutic Approach Non Shock Start Heparin Establish Diagnosis Spiral CT Scan V/Q Scan Angiogram - Pursue Alternative Diagnosis + BNP / Troponin NormalElevated Low Risk Heparin High Risk Floor or Outpatient Echo RV Normal RV Dysfxn Heparin Vs Lysis

63 Summary

64 Massive pulmonary embolism is rapidly fatal disease Diagnostic-Therapeutic approach based on risk stratification is probably the most appropriate approach of the management Normal RV & Normal hemodynamics RV Dysfunction & Normal hemodynamics With or without Troponin T level / BNP Shock Cardiac arrest Sudden arrest

65 Summary Treatment approach should be directed towards: Maintaining oxygenation Maintaining MAP Improving Pulmonary hemodynamics (decreasing PAP by simultaneous  RV COP and  PVR)

66 Summary Thrombolytic therapy in massive PE: Accelerated Clot Lysis Hemodynamic Improvement May Improve  Recurrent Embolism  Chronic Pul HTN  Quality of Life  Symptoms  Mortality Thrombolytic therapy in sub-massive PE: Controversial issue Administrating early in the course of sub-massive pulmonary embolism prevents worsening of the disease

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