PowerPoint Presentation

Evidence Based Approach toPulmonary ThromboembolismKristopher R. Maday, MS, PA-C, CNSCUniversity of Alabama at Birmingham PA ProgramPegasus Emergency Group

@PA_Maday#MadayAAPAFollow Along at

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Evidence Based ______?

Positive Predictive ValueRelative Risk ReductionNumber Needed to TreatLikelihood RatioConfidence IntervalsOdds RatioPre-test ProbabilitySensitivity/SpecificityMedicineMasturbation

ObjectivesDiscuss landmark and most recent publications that have led to current recommendations in PTE managementEvaluate pre-test probability decision toolsCompare diagnostic modalitiesAppraise current literature regarding treatment Develop comprehensive decision algorithm

Why Do We Care?300,000-600,000 cases per year1 to 2 cases per 1000 of the population1/3rd will have recurrence within 10 years

30-50% will have chronic post-thrombotic syndromes

Beckman MG. Am J Prev Med. 2010;38(4S):S495-S501

Incidence rates vary greatly between age, gender, and race (worse in old, blacks/whites, men overal but women during childbearing years)Highest risk is within the 1st year why we treat for so longEquates to $2-10 billion in total annual health care costs6

Why Are We Scared?10-20% have no identified risk factor10-30% die in 1st 30 days20-25% as sudden deathUp to 50% miss rate by clinicians32% of patients with DVT have Silent PTEFear of litigation is #1 reason clinicians work-up low-risk patientsBeckman MG. Am J Prev Med. 2010;38(4S):S495-S501Calder KK. Ann Emerg Med. 2005;45(3):302-310Stein PD. Am J Med. 2010;123:426-431

1. 50% miss rate highly debated but published non-textbook/variable presentations, occur with other easily explainable but less deadly diseases7

Why Cant We Test Everybody?Newman DH. Ann Emerg Med. 2011;57:622-627

Spyropoulous A. J Manag Care Pharm. 2007;13(6):475-486

$7,500-16,000 per patient in total health care cost6x more deaths with testing ATN8

Signs and SymptomsPIOPED StudyEMPEROR Registry

We need to talk about common S&S in order to put the clinical decision instruments into context9

Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED II)Dyspnea (73%)Chest pain (64%)Leg pain/swelling (44%)Cough (43%)Wheezing (21%)Hemoptysis (13%)

SymptomsTachypnea (57%)DVT Findings (47%)Abnormal Lung Exam (37%)Tachycardia (26%)Abnormal Heart Exam (22%)

Physical Exam FindingsStein PD. Am J Med. 2007;120:871-879

Started in 1990 and in 3rd installment looking at radiographic modalities in diagnosis of PTE 824 patientsPIOPED II (2007) is most cited in regards to S&S of PTEDyspnea is both exertion or at restChest Pain includes pleuritic and non-pleuriticTachypnea = > 20/min and Tachycardia = >100/minDVT findings = Calf or thigh swelling, erythema, edema, tenderness, palpable cordsAbnormal lung exam = rales, crackles, wheezes, rhonchi, decreased BS, pleural friction rubAbnormal cardiac exam = increased S2, right ventricular lift, JVDCombination S&S dyspnea or tachypnea (86%) and dyspnea,tachypne, or CP (92%)10

Emergency Medicine Pulmonary Embolism in the Real World Registry (EMPEROR)Dyspnea (77%)Chest Pain (55%)Cough (31%)Dizziness (12%)Hemoptysis (8%)Extremity pain (6%)

SymptomsMean HR 95.7 beats/minMean RR 20.5 breaths/minMean O2 95% on room air

DVT Findings (24%)Respiratory Distress (16%)Physical Exam FindingsPollack CV. JACC. 2011;57(6):700-706

National, multicenter, observational registry Designed to establish more definitively the presentation S&S of PTE presenting to the ED22 community and academic EDs 1880 patientsDyspnea with exertion or at restChest pain pleuritic or substernal

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Pre-Test ProbabilityWells CriteriaSimplified Geneva ScorePulmonary Embolism Rule-out Criteria (PERC)Clinical Gestalt

Wells Criteria for PTEDeveloped in 1998 2000 2001Clinical decision instrument using a point system to grade pre-test probabilityApplied AFTER history and physical examRisk-assessment gradesWells PS. Ann Intern Med. 2001;135:98-107Wells PS. Ann Intern Med. 1998;129:997-1005Wells PS. Thromb Haemost. 2000;83:416-420

Some may use a newer 2 grade approach13

Wells Criteria for PTEHistory and Physical Exam FindingsPointsClinical Signs and Symptoms of DVT+3Heart Rate > 100 beats/min+1.5Immobilization 3 days or Surgery in Previous 4 weeks+1.5Previously Diagnosed DVT or PTE+1.5Hemoptysis+1Malignancy (Active, Treated in last 6 months, or Palliative)+1PTE is #1 Diagnosis, or at east as likely+3

Pre-Test ProbabilityPointsLow-Risk (1.3%)< 2Moderate Risk (16.2%)3-6High Risk (40.6%)> 6

Wells PS. Ann Intern Med. 2001;135:98-107Pre-Test ProbabilityPointsPTE Unlikely (3%) 4PTE Likely (28%)> 4

van Belle A. JAMA. 2006;295(2):172-179

Geneva Score2001

2006

2008Klok FA. Ann Intern Med. 2008;168(19):2131-2136Wicki J. Arch Intern Med. 2001;161:997-92-97Le Gal G. Ann Intern Med. 2006;144:165-171Original ScoreRevised ScoreSimplified Score

Original Score used CXR and ABG needed studies to useSimplified Score made all criteria 1 point to decrease liklihood or error15

Simplified Geneva ScoreHistory and Physical Exam FindingsPointsAge 65 years or greater+1Previous History of DVT/PTE+1Surgery or Fracture within 1 Month+1Active Malignant Condition+1Unilateral Lower Limb Pain+1Hemoptysis+1Heart Rate 75-94 beats/min+1Heart Rate > 94 beats/min+2Unilateral Lower Leg Edema and Pain on Deep Palpation+1

Pre-Test ProbabilityPointsLow-Risk (7.7%)< 2Moderate Risk (29.4%)2-4High Risk (64.3%)> 4

Klok FA. Ann Intern Med. 2008;168(19):2131-2136

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Pulmonary Embolism Rule-out CriteriaDeveloped in 2008Rules-out PTE if all criteria (-) AND pre-test probability is low

Kline JA. J Thromb Haemost. 2008;6:772-780

1% false negative rate..98% sensitivity17

PERC CriteriaHormone UseAge (50)DVT or PE HistoryCoughing Up BloodLeg SwellingO2 Sats < 95%Tachycardia (>100)Surgery or TraumaThoma B. Tiny Tips: PERC Rule. Boring EM Blog. 2013 July. Available at http://boringem.org/2013/07/02/tiny-tips-perc-rule/

Kline JA. J Thromb Haemost. 2008;6:772-780

What About Clinical Gestalt?

Penaloza A. Ann Emerg Med. 2013;62(2):117-124

http://stemlynsblog.org/gestalt-st-emlyns/19

The Work-UpEKGD-DimerComputed TomographyVentilation / Perfusion Scan

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D-DimerHigh sensitivity, Low specificityFalse NegativesSmall clot, impaired fibrinolytic activityFalse PositivesAge, smoking, functional impairment

***Should only be used AFTER pre-test probability***

D-dimers are specific cross-linked fibrin derivatives that are the product of plasmin-mediated fibrinolytic degradation. They are an excellent marker of fibrinolytic activity.

The fact that a normal D-dimer has a lower LR(-) [~0.07-0.12] than CTPA [0.10-0.20] still seems to surprise a lot of clinicians.

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ADJUST-PE StudyMulticenter, multinational, prospective study3346 patientsUsed traditional D-Dimer (> 500 ng/mL) and age-adjusted ( > age x 10 ng/mL)Patients who fell between and had a low pre-test probability were followed for 3 months0.3% failure rate (1/331)Decrease imaging in patients > 75yo by 29%Righini M. NEJM. 2014;311(11):1117-1124

Radiographic ImagingGold StandardHigher radiation exposuresLarge contrast bolusComputed TomographyLower radiation exposure2/3rd are non-diagnosticSafer in renal patientsVentilation/Perfusion ScanStein PD. Am J Med. 2007;120:871-879Anderson DR. Curr Opin Pulm Med. 2009;15:425429

PIOPED II subgroup analysis showed increased rate of false abnormality when compared to CTPA24

Risk AssessmentEchocardiographyBiomarkersPulmonary Embolism Severity Index (PESI)

EchocardiographyIncreasingly utilized at bedside by cliniciansHelps with determining severity of clot burdenRV StrainRV:LV 1RV hypokinesisParadoxical septal movementTricuspid regurgitationRudoni RR. J Emerg Med. 1998;16(1):5-8Taylor RA. J Emerg Med. 2013;45(3):392-399

Kline JE. YouTube. Posted on 07/29/2014. https://www.youtube.com/watch?v=pGNpmZhkS7A&feature=youtu.beRV Dilation andHypokinesisLV CollapseParadoxicalSeptalMovement

Severe PE dilating the right ventricle (top) and compressing the left ventricle (bottom)27

Biomarkers***Hemodynamically stable patients***

Brain Natriuretic Peptide (BNP)> 90 pg/mL associated with increased mortalityTroponin I> 0.01 ng/mL suggests RV dysfunction

Kiely DG. Resp Med. 2005;99:1286-1291Keller K. Neth Heart J. 2015;23:55-61Jaff MR. Circulation. 2011;123:1788-1830

0.01 ng/mL had OR 3.954 (1.9498.024) 0.00014 and NPV of 73%CHEST 2015 negative high sensitive cTnI assay has excellent negative predictive value28

Pulmonary Embolism Severity IndexOriginally developed in 2005 to prognosticate 30-day mortality11 variables with 5 risk categoriesSimplified in 20105 variables with 2 risk categories96% sensitivity, 99% negative predictive value, and 0.12 negative likelihood ratioJimenez D. Arch Intern Med. 2010;170(15):1383-1389Aujesky D. Am J Respir Crit Care Med. 2005;172:1041-1046

96%/99%/0.12 shows that low risk patients may be managed outpatient29

Jimenez D. Arch Intern Med. 2010;170(15):1383-1389Simplified PESI ScoreVariableAge > 80History of CancerHistory of Chronic Cardiopulmonary DiseaseHeart Rate > 110 beats/minSystolic BP < 100 mmHgO2 Saturation < 90% on Room Air

Risk AssessmentScoreLow Risk (1.1% risk of death)0High Risk (8.9% risk of death) 1

DefinitionsLow-RiskIntermediate (Submassive)High Risk (Massive)

High Risk (Massive)SBP < 90mmHg for > 15minIntermediate (Submassive)SBP > 90mmHg withRV dysfunction or elevated biomarkersLow-Riskabsence of clinical markersJaff MR. Circulation. 2011;123:1788-1830

TreatmentAnticoagulationFibrinolytic TherapyCatheter-Directed TherapySurgical Embolectomy

AnticoagulationShould be started with:Confirmation of acute PTE orHigh pre-test probability during work-upOptionsLow-molecular weight heparin (LMWH)Unfractionated heparinDirect Thrombin Inhibitors (DTI)Factor Xa Inhibitors

Tapson VF. Crit Care Clin. 2011;27:825-839Jaff MR. Circulation. 2011;123:1788-1830

LMWH enoxaparin (1mg/kg BID or 1.5mg/kg daily) or fondaparinux (5mg if 100kg)Heparin 5000unit bolus followed by drip with PTT monitoringDTI lepirudin, bivalirudin, argatroban, dabigatranFactor Xa - rivaroxaban34

Fibrinolytic Therapy

Jaff MR. Circulation. 2011;123:1788-1830

This is with FULL DOSE therapy and this was not a randomized control trial35

MOderate Pulmonary Embolism Treated with ThrombolysisSharifi M. Am J Cardiol. 2013;111:273-277Reduction in pulmonary hypertension

No significant difference in recurrent PTE

Reduction in total mortality

Reduction in hospital stay

No difference in bleeding complications

Safe dose = < 50% of standard dosing

121 patients with submassive PTESafe Dose tPA vs PlaceboPrimary OutcomePulmonary hypertension and recurrent PTE at 28 monthsSecondary OutcomeTotal mortality, duration of hospital stay, bleeding, and recurrent PTE

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Zhang Z. Thrombosis Research. 2014;133:357-363

2014 Meta-Analysis5 studies 440 patients

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2013 Meta-Analysis

Zhang Z. Thrombosis Research. 2014;133:357-363

2014 Meta-Analysis5 studies 440 patients38

Peitho The Greek Goddess of Persuasion

Peitho on a pillar overseeing a scene of persuasion: Helen of Troy is below Peithosdangling feetwhileAphrodite speaks to her; Paris, at the far right, is also receiving a talking toby winged Eros39

Pulmonary EmbolIsm THrombOlysis Meyer GM. NEJM. 2014;370(15):1402-1411No significant overall mortality benefit

3-fold reduction of hemodynamic compromise

10-fold increase in intracranial hemorrhage

5-fold increase in major bleeding

1005 patientsRandomized to anticoagluation only vs tenecteplasePrimary outcomes death or hemodynamic decompensation within 7 daysSafety Outcomes extracranial major bleeding within 7 days, ischemic or hemorrhagic stroke within 7 daysResults1.2% (lytic) vs 1.8% (heparin) mortality reduction with p-value 0.421.6% vs 5.0% reduction in hemodynamic compromise6.3% vs 1.2% extracranial bleeding2.4% vs 0.2% stroke40

Chatterjee S. JAMA. 2014;311(23):2414-2421

2014 Meta-Analysis JAMAALL PTEsFull dose lytics vs heparin aloneOverall mortality41

Chatterjee S. JAMA. 2014;311(23):2414-2421

Same 2014 meta-analysisSubmassive groupFull dose lytics vs heparinOverall mortality42

Same 2014 meta-analysisAbsolute risk metrics of outcomesALL PTEFull dose lytics43

Contraindications For FibrinolysisAny history of ICHStructural intracranial malformationKnown intracranial neoplasmIschemic CVA in last 3 monthsSuspected aortic dissectionActive bleedingHistory of bleeding dyscrasiasRecent CNS surgeryRecent history of facial/head traumaAbsoluteAge > 75 yearsCurrent anticoagulation usePregnancyNon-compressible punctureProlonged CPR > 10 minutesHistory of internal bleeding < 1 monthSBP > 180 or DBP > 110DementiaSurgery < 3 weeksIschemic CVA > 3 months

RelativeJaff MR. Circulation. 2011;123(16):1788-1830

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Curtis GM. Pharmacotherapy. 2014;34(8):818825

At least 1 RF increased risk of bleeding after tPA 5-foldPatients with one or more bleeding risk factors compared with patients without any bleeding risk factors had a significantly higher incidence of: major bleeding (68.0% vs 29.7%, p=0.003)ICU mortality (36.0% vs 2.8%, p=0.001)hospital mortality (36.0% vs 2.7%, p=0.001)45

Increased Risk of Bleeding?He Aint GotTime To Bleed

AngioJet-a catheter that breaks up the clot with a high speed jet of saline, heparin, or tPA that then sucks up clot using Bernoulli physics. Very little systemic drug is delivered. Orens center doesnt like the device; other centers use it. 48

http://www.angiodynamics.com/products/angiovac

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Catheter inserted in affected throbus and left in place for a period of time (15hr). US is then delivered to to promote dissociation of the fibrin matrix and increase penetration of locally delivered fibrinolytic50

Kennedy RJ. J Vasc Interv Radiol. 2013;24:841-848

Obstruction Index characterizes the anatomic distribution of emboli in the segmental PAOnly 60 patients, retrospectivePerfusion Index grades the degree of perfusion to each lungMiller Score Aggregate of the the two51

OutcomesReduction in PA pressures90-day SurvivalSubmassive Group = 98% (47/48)Massive Group = 75% (9/12)Adverse Events2 bleeding complications1 arrest with associated AKIKennedy RJ. J Vasc Interv Radiol. 2013;24:841-848

Two of the 3 massive patients had evidnce of MODS52

ULTIMA TrialProspective, Randomized Control TrialSUBMASSIVE PTE ONLY!!!59 patientsPrimary OutcomeDifference of RV/LV at 24oSafety OutcomeDeath, bleeding, and recurrent VTE at 90-days

Kucher N. Circulation. 2014;129:479-486

Ultrasound Accelerated Thrombolysis of Pulmonary EmbolismRandomized to US assistaed thrombolysis + heparin or heparin alonePlacement of US catheter into clot with local fibrinolytics for 15hrRV/LV ratio measured via ECHO53

ULTIMA TrialResultsPrimary End PointUSAT = RV/LV reduced by mean 0.29Heparin = RV/LV reduced by mean 0.03Safety End pointNo episodes of hemodynamic decompensation or recurrent VTE in either groupBleedingUSAT = 3 minor bleeding complicationsHeparin = 1 minor bleeding complicationKennedy RJ. J Vasc Interv Radiol. 2013;24:841-848

At 90-days though the RV/LV difference between groups was only 0.04USAT Bleeding 2 transient episodes of hemoptysis and 1 groin hematomaHeparin Bleeding 1 muscular hematoma and anal bleeding after endoscopic colonic polyp removal at 80-day54

Surgical Embolectomy

Old and Busted1960s (57%) 1990s (26%)

New Hotness2005 (6%)Cross FS. Circulation. 1967;35:186-191Stulz P. Eur J Cardio-thorac Surg. 1994;8:188-193Leacche M. J Thorac Cardiovasc Surg. 2005;129:1018-1023

Twitter - @FToranMD - 04/01/2015

Often thought of as last resortRetrospective review of 47 patients who underwent surgical embolectomyIndications Contraindications for thrombolysis, failed therapy (thrombolytics/catheter), RV dysfunction, large RV/RA thrombusImprovement due to advances in surgical technique, anesthesia, and more aggressive initial identificaiton and maagement

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Lets Put It All Together

Thank You!maday@uab.edu@PA_Maday

www.pamaday.net