Pulmonary Thromboembolic DiseaseRisk Stratification & Approach For Management Majdy M Idrees

Division of Pulmonary MedicineRiyadh Armed Forces Hospital10th Advanced Medicine SymposiumNovember 2006RMH, Riyadh

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

Pulmonary EmbolismRisk 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 1884Lecons de Clinique Mdicale

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 DefinitionPulmonary EmbolismRisk Stratification & Approach of Management

SimpleComplicatedSubmassiveMassive Pulmonary EmbolismRisk StratificationPulmonary EmbolismRisk Stratification

Complicated Pulmonary EmbolismMassive Pulmonary EmbolismPerfusion defect >50%Filling defect / obstruction in 2 lobar arteriesObstruction of main (R/L) PA 2. Hemodynamic instability 1. Severe refractory hypoxic3. Acute RV failure4. Tissue hypoperfusion (low urine output)Visual ScoringFunctional Scoring

Predicting PE Perfusion DefectsGalle Thromb Haemost 2001; 86:1156-60< 30%30% - 50%>50%

Resp rate/min172228Heart rate/min9599100(A-a)O2 kPa3.64.46.3D-dimer ug/L273160907950 4000ug/L33%67%94%< 4000ug/L67%33%6%US proximal DVT(+) 33%(+) 76%(+) 66%(-) 67%(-) 24%(-) 34%

PE Severity: Echo Assessment% Obstruction Mastora Eur Radiol 2003; 13:29-35

CT Severity AssessmentSevere PENon-severe PE(Lysis/Embolectomy)(Heparin tx) Collomb Eur Radiol 2003; 13:1508-14

RV Pressure LoadRV DecompensationIncrease RV Volume Septal Shift Pericardial RestrictionDecrease LV DistensiblityDecreased LV Preload Decrease RV OutputIschemiaObstructionNeuro-hormonal COP / MAPDecreased RV CPP VO2 Wall stressPathophysiology

Vascular Obstruction and Acute Pulmonary HypertensionMcIntyre Am J Card 1971; 28:288-294Pulmonary Arterial Mean Pressure (mmHg)Pulmonary Vascular Obstruction Angiogram (%)1020304010305070

Vascular Resistance vs ObstructionMiller indexTPVR(mmhg.1.min.m)Petitpretz Circ 1984; 70:861-866.

InterventionDiagnostic Therapeutic Approach

SeverityEmbolism size Cardiopulmonary Status100

70

30

100MortalitySudden DeathCardiac ArrestShockOutcome in Pulmonary EmbolismRisk StratificationHemodynamically Stable & RV NormalInfliction Point

SeverityEmbolism size Cardiopulmonary Status100

70

30

100MortalitySudden DeathCardiac ArrestShockOutcome in Pulmonary EmbolismRisk StratificationHemodynamically Stable & RV Normal

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

Cardiac Arrest

SeverityEmbolism size Cardiopulmonary Status100

70

30

100MortalitySudden DeathCardiac ArrestShockOutcome in Pulmonary EmbolismRisk StratificationHemodynamically Stable & RV Normal

Echo and Cardiac Arrest48 patients in/out hospital cardiac arrestDiagnosis obtained via TEEMyocardial infarction 21Cardiac tamponade 6Pulmonary embolism 6Aortic dissection/rupture 5Papillary muscle rupture 1Absence of cardiac structural abnormalities 7Other diagnosis 2Sensitivity 93% specificity 50%, positive predictive value 87%31% major therapeutic decisions based upon TEEJACC 30:780-783, 1997

Thrombolysis in CPRMajority of PE deaths within 1st hour of symptomsBolus thrombolysis in arrest- ReportedInitiated after failure of conventional CPRStabilization Minimal bleeding complicationsMicrocirculatory Reperfusion77% Stabilized67% SurvivedBottiger Fibrinolysis and Proteolysis, 1997

Shock

SeverityEmbolism size Cardiopulmonary Status100

70

30

100MortalitySudden DeathCardiac ArrestShockOutcome in Pulmonary EmbolismRisk StratificationHemodynamically Stable & RV Normal

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

Pulmonary EmbolismShock vs. Non-Shock MortalityStudyTreatmentShock MortalityNon-Shock Mortality

Major Pulmonary EmbolismDiagnostic & Therapeutic Approach ShockECHOTEE/TTERV Pressure Overload?Alternative DX Resuscitate & Stabilize Establish DiagnosisNoYesStart HeparinCertain DiagnosesEmboli in PAAMI / Aortic Dissection / TamponadeSpiral CTV/QAngio-+Peruse other dx

Lysis Candidate

NoEmbolectomy YesLytic Rx

Measures to Improve HemodynamicsFlow (Cardiac Output)

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

Management Massive PE With Shock Heparin TherapyThe 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.

Thrombolytic Therapy

Thrombolists Perspective Works GreatHastens 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 hypertensionSasahara J Cardiovascular Medicine 1980

Traditionalists Perspective UnfulfillingDoes 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

Thrombolytic TherapyPutative Benefits

Accelerated Clot Lysis Recurrent EmbolismAngiogramsPerfusion scans Chronic Pul HTNPul capillary blood volume Quality of LifeHemodynamic ImprovementPulmonary pressuresSymptomsEchocardiogram Mortality

PROVENSPECULATIVE

Early Resolution Rate Lytic vs HeparinStudy/YrAgentTime PostResolutionMetric

Angiographic Severity UPETUPET JAMA 1970; 214:2163-2172321032104Heparin UrokinaseHeparin UrokinaseBaseline24 HoursSevereModerateNormalMinimalN = 57N = 57Complete (91-100%)Marked (61-90%)Moderate (31-60%)Slight Improvement ( 30%)No change

Rate and Extent Clinical-Hemodynamic Resolution Reported in UPETUPET JAMA 1970; 214:2163-2172HeparinUrokinaseBaseline24 hours 24 hours Baseline

Total Pulmonary Resistance EvolutionMeneveau European Heart Journal 1997; 18:1141-1148 0-40-20-60024681012Time (h)% change from baselinert-PAStreptokinaseHeparin

Right Ventricular Ejection Fraction EvolutionMeneveau European Heart Journal 1997; 18:1141-11488070602030405010024681012Time (h)% change from baselinert-PAStreptokinaseHeparin

Recurrent PE With Thrombolytic TherapyStudyAgentHeparinLyticDalen Venous Thromboembolism Lung Biology in Health and Disease 2003

UPET 1973Urokinase9.0% (7)6.1% (5)Levine 1990rt-PA0%0%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)

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

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

Infliction PointEmboli in TransitRV Dysfunction Submassive Pulmonary Embolism

SeverityEmbolism size Cardiopulmonary Status100

70

30

100MortalitySudden DeathCardiac ArrestShockOutcome in Pulmonary EmbolismRisk StratificationHemodynamically Stable & RV NormalInfliction Point RV Dysfunction Troponin T NDH

Isolated RV DysfunctionRV 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

Massive Pulmonary Embolism Prognostic Factors - ICOPERFactorHazard RatioGoldhaber Lancet 1997; 353: 1386-1389

Systolic arterial hypotension2.9 Congestive heart failure2.4 Cancer2.3 Tachypnea2.0 RV hypokinesis on echo2.0 COPD1.8Age > 70 1.6

Outcomes Hemodynamically Stable Confirmed PE with RV Dysfunction Tx HeparinStudyYearPE Deaths% Mortalityn

Goldhaber19932328.7%Grifoni20006135%Hamel20016400%Giannitsis20002627.7%Viellard-Baron20023213%Pruszczyk200364812.5%Pruszczyk2003511019.6%Kucher200319210.5%340288.2%

Alteplase vs Heparin Acute PE Assessing RV Function and Perfusion in Hemodynamically Stable PatientsRt-PAHeparinGoldhaber Lancet 1993; 341:507-112 fatal 3 non-fatalAll RV Dysfxn

Major Pulmonary EmbolismThrombolytic Therapy - MAPPETLysis (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, COPDPrimary lysis independent predictor of survivalCaution!! Heparin group old, CHF, COPDRV Dysfxn + BP-No pressors (719)Konstantinides Circ 1997; 96:882-888

Non-shock Mortality Thrombolytic TherapyPatientsMortalityLytic % (N)Heparin % (N)HeparinLyticStudy

Submassive Complicated Pulmonary EmbolismThe role of ThrombolysisEarly Lytic Treatment of Submassive Pulmonary Embolism: Clot Dissolving Therapy With Alteplase Plus Heparin Vs Heparin AloneChest 2003

Submassive Complicated Pulmonary EmbolismThe role of ThrombolysisRandomized, DB, multicenter trial256 ptPE confirmed by HP V/Q scan, spiral CT or angiogramNormal BPRV dysfunction (Echo, ECG or SG catheter)

Submassive Complicated Pulmonary EmbolismThe role of ThrombolysisPrimary endpoint:In-hospital mortalityWorsening circulationNeed for additional therapy (surgical embolectomy or adding vasoactive drugs for shock) Secondary endpoint: 30-days mortality Recurrent PE

Submassive Complicated Pulmonary EmbolismThe role of ThrombolysisResults: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 EmbolismThe role of ThrombolysisConclusion: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.

BNP and TroponinComplementary Biomarkers for Risk Stratification Future Directions?Hemodynamically Stable PE And

Stretch Ischemia RVDysfxn RV damage BNP < 50 TnT > 0.01 detects detects low risk high riskBNPTroponin

Troponin T in Acute PEGiannitsis Cir 2000; 102:211-21756 PE PatientsTroponin (+) 32% (18)Troponin (-) 68% (38)Shock (17)Troponin (+)Troponin (-)76% (12)24% (5)

Troponin and PE Clinical OutcomeGiannitsis Cir 2000; 102:211-217OutcomeOdds Ratio

Troponin and PE OutcomeRV DysfunctionComplicated Course (OR)Mortality (OR)cTnI, ng/dlcTnT, ng/dlKonstantinides Circ 2002; 106:1263-68

Brain Natriuretic Peptide Kucher Circ 2003; 107:1576-78 SensitivitySpecificityNegativePositive 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

N-terminal proBNP and EchoNon-massiveSubmassiveMassivePruszczyk Eur Respir J 2003; 22:649-53 All deaths/SAE in NT-proBNP group Normal NT-proBNP 100% negative predictive value

NT-proBNP > 600

BP mmHg13212683RV:LV0.630.901.21Deaths0%20%44%SAE0%31%78%BNP pg/mL363 (56%)4650 (90%)9865 (100%)

Submassive Pulmonary EmbolismDiagnostic-Therapeutic ApproachNon ShockStart HeparinEstablish Diagnosis Spiral CT Scan V/Q Scan Angiogram -Pursue Alternative Diagnosis +BNP / TroponinNormalElevatedLow RiskHeparinHigh RiskFloor or Outpatient

Echo

RV NormalRV DysfxnHeparinHeparinVsLysis

Summary

SummaryMassive pulmonary embolism is rapidly fatal diseaseDiagnostic-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

SummaryTreatment approach should be directed towards:Maintaining oxygenationMaintaining MAPImproving Pulmonary hemodynamics (decreasing PAP by simultaneous RV COP and PVR)

SummaryThrombolytic therapy in massive PE:

Accelerated Clot Lysis Hemodynamic Improvement May Improve Recurrent Embolism Chronic Pul HTNQuality of Life Symptoms MortalityThrombolytic therapy in sub-massive PE:Controversial issueAdministrating early in the course of sub-massive pulmonary embolism prevents worsening of the disease