Pulmonary Embolism

Todd A. May, M.D.Todd A. May, M.D.Director, Family Practice Inpatient ServiceDirector, Family Practice Inpatient Service

San Francisco General HospitalSan Francisco General Hospital

Associate Clinical ProfessorAssociate Clinical Professor

University of California, San FranciscoUniversity of California, San Francisco

PE: A Clinical Challenge

Common: 250,000 cases/yearCommon: 250,000 cases/year Mimics many other illnessesMimics many other illnesses Potentially fatal (15%)Potentially fatal (15%) Treatment potentially dangerousTreatment potentially dangerous No single reliable diagnostic testNo single reliable diagnostic test Under- and over-diagnosedUnder- and over-diagnosed

Diagnostic Testing

NoNo single noninvasive test is single noninvasive test is sufficiently sensitive or specific to sufficiently sensitive or specific to diagnose or exclude PE in all diagnose or exclude PE in all patientspatients

No single test can reliably rule out No single test can reliably rule out PEPE

Yep, that includes CT Angio (right?)Yep, that includes CT Angio (right?)

Clinical Approach

Consider PE in DDxConsider PE in DDx Stratify risk for PE (H&P, initial lab)Stratify risk for PE (H&P, initial lab) Select appropriate diagnostic Select appropriate diagnostic

test(s)test(s) Interpret results in clinical contextInterpret results in clinical context Select therapy based on clinical Select therapy based on clinical

statusstatus

Risk Factors

GeneralGeneral HypercoagulabilityHypercoagulability StasisStasis Vascular injuryVascular injury

Clinical Presentation

97% with PE have at least one of 97% with PE have at least one of the following:the following: DyspneaDyspnea TachypneaTachypnea Pleuritic painPleuritic pain

Presence should trigger initial Presence should trigger initial suspicionsuspicion

Clinical Presentation

SymptomsSymptoms Dyspnea, pleuritic chest painDyspnea, pleuritic chest pain Cough, hemoptysis, syncopeCough, hemoptysis, syncope

SignsSigns Tachypnea, tachycardiaTachypnea, tachycardia JVD, loud PJVD, loud P22, TR murmur, rales, TR murmur, rales Signs of DVTSigns of DVT

Chest Radiograph

Electrocardiogram

Oxygenation

Pulse Oximetry (SpOPulse Oximetry (SpO22)) Normal SpONormal SpO22 does not exclude PE does not exclude PE Interpret with RRInterpret with RR

ABGABG

pOpO2 2 pCO pCO22

Increased A-a gradientIncreased A-a gradient

Risk Stratification

Determine probability of PEDetermine probability of PE LowLow ModerateModerate HighHigh

Overall clinical impressionOverall clinical impression Models/scoring systemsModels/scoring systems

PE Probability Prediction Rule

DVT signs/symptomsDVT signs/symptoms 3.03.0

HR > 100 HR > 100 1.5 1.5

Immobilization/Surgery < 4 wk Immobilization/Surgery < 4 wk 1.5 1.5

Previous DVT or PE Previous DVT or PE 1.5 1.5

Hemoptysis Hemoptysis 1.0 1.0

Malignancy (current) Malignancy (current) 1.0 1.0

Alternative Dx less likelyAlternative Dx less likely 3.0 3.0

Probability: Low<2, Moderate 2-6, High>6Probability: Low<2, Moderate 2-6, High>6

D-Dimers

Valuable screening testValuable screening test High sensitivity; low specificityHigh sensitivity; low specificity

Helpful only if Helpful only if NegativeNegativeStrong Negative Predictive Strong Negative Predictive Value-- Rules out PE when low Value-- Rules out PE when low probabilityprobability

Safe, noninvasiveSafe, noninvasive Rapid, inexpensiveRapid, inexpensive

D-Dimers

Available assaysAvailable assays Standard ELISAStandard ELISA Latex agglutinationLatex agglutination Erythrocyte agglutination (SimpliRED)Erythrocyte agglutination (SimpliRED) Turbidimetric assay (Liatest)Turbidimetric assay (Liatest) Rapid ELISA (VIDAS)Rapid ELISA (VIDAS) Immunofiltration (NycoCard)Immunofiltration (NycoCard)

V/Q Scan

V/Q Lung Scan

Normal V/Q Sensitivity 99%Normal V/Q Sensitivity 99% Rules Rules outout PE PE

High Prob V/Q Specificity 96%High Prob V/Q Specificity 96% Rules Rules inin PE PE

But, >60% nondiagnosticBut, >60% nondiagnostic Takes >2 hr to performTakes >2 hr to perform Not available at all timesNot available at all times

V/Q Lung Scan

V/Q ResultV/Q Result True PE True PE (+Angio)(+Angio)

PPV if prob PPV if prob concordant concordant

High probabilityHigh probability 87%87% 96%96%

IntermediateIntermediate 30%30% 33%33%

LowLow 14%14% 4%4%

NormalNormal <2%<2% <2%<2%

PIOPED. PIOPED. JAMAJAMA. 1990; 263:2753-59. 1990; 263:2753-59

Ultrasound for DVT

Positive testPositive test Inability to compress femoral or Inability to compress femoral or

popliteal veinpopliteal vein Positive Predictive Value 97%Positive Predictive Value 97%

Negative testNegative test Full compressibilityFull compressibility Negative Predictive Value 98%Negative Predictive Value 98%

Kearon et al. Kearon et al. Ann Intern MedAnn Intern Med. 1998; 129:1044-49. 1998; 129:1044-49

Ultrasound and PE

US +DVT in 30-50% with PEUS +DVT in 30-50% with PE Positive US—confirms PEPositive US—confirms PE Negative ultrasoundNegative ultrasound

PE less likely, but not excludedPE less likely, but not excluded Sequential ultrasoundSequential ultrasound

Persistently negativePersistently negative ultrasound at ultrasound at 1-2 wks 1-2 wks <2% DVT/PE at 6mos <2% DVT/PE at 6mos

Hull et al. Hull et al. J. ThrombJ. Thromb 1996; 3:5-8. 1996; 3:5-8.

CT Angiogram

CT Angiogram

BenefitsBenefits AvailableAvailable Direct imageDirect image Alternative DxAlternative Dx Pelvic/leg veinsPelvic/leg veins

LimitationsLimitations IV contrastIV contrast ExpensiveExpensive Patient Patient

cooperationcooperation Uncertain Uncertain

sens/specsens/spec

CT Angiogram

““Helical CT is a reliable Helical CT is a reliable imaging tool for imaging tool for excluding clinically excluding clinically important PE”important PE”

Goodman LR et al. Radiology 2000;215:535-42.

CT Angiogram

1015 patients evaluated for PE1015 patients evaluated for PE Nonrandomized, not controlled Nonrandomized, not controlled

Two diagnostic arms “recommended”Two diagnostic arms “recommended” Substantial differences between groupsSubstantial differences between groups

285 patients with negative CT Angio285 patients with negative CT Angio 22% were treated anyway22% were treated anyway

< 2% risk of subsequent PE in 3 months< 2% risk of subsequent PE in 3 months Only 70% completed 3mo f/u!Only 70% completed 3mo f/u!

CT Angiogram

Prospective study of consecutive, Prospective study of consecutive, nonselected patients in a Geneva nonselected patients in a Geneva ER included 299 with suspected PEER included 299 with suspected PE

39% had confirmed PE39% had confirmed PE High prob V/Q, +US, or +AngioHigh prob V/Q, +US, or +Angio

CT Sensitivity 70%CT Sensitivity 70% CT Specificity 91%CT Specificity 91%

Perrier et al. Perrier et al. Ann Intern MedAnn Intern Med. 2001; 135:88-97. 2001; 135:88-97

CT Angiogram 35 35 false negativefalse negative on CT on CT

1919 High prob V/QHigh prob V/Q 1212 +DVT on US+DVT on US 33 +Angio+Angio 11 Dx at f/uDx at f/u

““CT should not be used alone for CT should not be used alone for suspected PE, but combining tests suspected PE, but combining tests improves accuracy and reduces need improves accuracy and reduces need for angiography”for angiography”

CT Angiogram

TESTSTESTS AccuracyAccuracy False False NegativeNegative

Helical CT Helical CT alonealone

70%70% 30%30%

CT plus CT plus Negative USNegative US

87%87% 21%21%

CT plus Neg CT plus Neg US plus V/QUS plus V/Q

94%94% 5%5%

CT Angiogram

New Systematic ReviewNew Systematic Review 15 studies met criteria15 studies met criteria VTE after negative CT Angio:VTE after negative CT Angio:

NLR 0.07NLR 0.07 NPV 99.1%NPV 99.1%

““The clinical validity of using CT to r/o The clinical validity of using CT to r/o PE is similar to that reported for PE is similar to that reported for pulmonary angiographypulmonary angiography””

Quiroz R et al. JAMA 2005;293:2012-17.

Goldhaber, S. Z. N Engl J Med 2005;352:1812-1814

Two Cases of Pulmonary Embolism as Shown on Contrast-Enhanced 16-Slice Multidetector-Row Computed Tomography

Multidetector-Row CT

756 consecutive pts; 194 with PE756 consecutive pts; 194 with PE 82 High Prob: 78/82 +CT, 1 +US/-CT82 High Prob: 78/82 +CT, 1 +US/-CT 674 Lower Prob:674 Lower Prob:

232 neg D-dimer 232 neg D-dimer no TE no TE 109 +CT109 +CT 318 neg dimer and CT 318 neg dimer and CT 3 TE at 3mo 3 TE at 3mo

Neg CT plus Neg D-dimer: ~1% risk for Neg CT plus Neg D-dimer: ~1% risk for TE at 3 monthsTE at 3 months

Perrier A et al. NEJM 2005;352:1760-8.

CT Angiogram

My ConclusionsMy Conclusions CT Angio is good and getting CT Angio is good and getting

betterbetter It’s not perfect, so don’t over-rely It’s not perfect, so don’t over-rely

on iton it Do additional testing if clinical Do additional testing if clinical

suspicion is highsuspicion is high Neg D-dimer plus neg MDR CT may Neg D-dimer plus neg MDR CT may

be best to confidently r/o PEbe best to confidently r/o PE

MRI/MRA

No radiation or contrast exposureNo radiation or contrast exposure ExpensiveExpensive Not uniformly availableNot uniformly available Limited dataLimited data Role not establishedRole not established

Echocardiogram

Pulmonary Angiogram

Gold standardGold standard 98% Sensitive98% Sensitive 97% Specific97% Specific ComplicationsComplications

Death 0.5%Death 0.5% Major non-fatal 1%Major non-fatal 1% Minor 5%Minor 5%

Diagnostic Summary

Determine pre-test probability—Determine pre-test probability—be be selective when deciding to w/uselective when deciding to w/u

D-Dimers to r/o PE if low prob.D-Dimers to r/o PE if low prob. CT or V/Q (US CT or V/Q (US firstfirst if DVT likely) if DVT likely) Bilat. LE US if V/Q non-diagnostic and/or Bilat. LE US if V/Q non-diagnostic and/or

CT neg. and suspicion persistsCT neg. and suspicion persists Then, Then,

Serial US if moderate/high prob.Serial US if moderate/high prob. Angiogram if still high prob.Angiogram if still high prob.

Treatment

Unfractionated Heparin

Weight-based dosingWeight-based dosing (nomogram) (nomogram) IV bolus, then infusionIV bolus, then infusion Monitor PTT (1.5-2.0 x), CBCMonitor PTT (1.5-2.0 x), CBC Continue Continue 4-5d and therapeutic on 4-5d and therapeutic on

Warfarin for 2d (INR>2.0)Warfarin for 2d (INR>2.0)

Low Molecular Weight Heparin

Alternative regimenAlternative regimen Better bioavailability, longer half-Better bioavailability, longer half-

life, more predictable effectlife, more predictable effect No monitoring of PTT (follow CBC)No monitoring of PTT (follow CBC) Contraindications: renal failure Contraindications: renal failure

(CrCl<30), weight extremes(CrCl<30), weight extremes

Warfarin

Start when therapeutic on Start when therapeutic on HeparinHeparin

Monitor INR dailyMonitor INR daily Goal: INR 2.0-3.0 for Goal: INR 2.0-3.0 for

3-6 months3-6 months

Duration of anticoagulation

Identified precipitantIdentified precipitant 3 mos3 mos First idiopathic episodeFirst idiopathic episode 6 mos6 mos Prolonged/indefinite:Prolonged/indefinite:

2 thrombotic episodes2 thrombotic episodes 1 spont. life-threatening episode1 spont. life-threatening episode Anti-phospholipid antibody Anti-phospholipid antibody

syndrome, ATIII deficiencysyndrome, ATIII deficiency

Thrombolysis

Massive PEMassive PE Acute pulmonary hypertensionAcute pulmonary hypertension RV dysfunctionRV dysfunction Systemic hypotensionSystemic hypotension

All age groups benefitAll age groups benefit Addition to Heparin therapyAddition to Heparin therapy Various agents appear equivalentVarious agents appear equivalent

Thrombectomy

Surgical or transvenous (catheter)Surgical or transvenous (catheter) When thrombolysis unsuccessful or When thrombolysis unsuccessful or

contraindicated, orcontraindicated, or Massive PEMassive PE

Vena Cava Filters

Indications:Indications: Contraindication to anticoagulationContraindication to anticoagulation Recurrent PE on anticoagulationRecurrent PE on anticoagulation Complications from anticoagulationComplications from anticoagulation Massive PE with poor reserveMassive PE with poor reserve

Problems with filter thrombosisProblems with filter thrombosis

Prevention

Identify and minimize risk factorsIdentify and minimize risk factors Pneumatic compression devicesPneumatic compression devices S.Q. HeparinS.Q. Heparin

UnfractionatedUnfractionated Low molecular weightLow molecular weight

Thrombophilia evaluation

Hypercoagulable statesHypercoagulable states

Thrombophilia evaluation

Why test for hypercoagulability?Why test for hypercoagulability? May affect intensity/duration of May affect intensity/duration of

treatmenttreatment Family counseling about risksFamily counseling about risks Identify need for prophylaxis in Identify need for prophylaxis in

higher risk situationshigher risk situations

Risks of Venous Thrombosis

Risk factorRisk factor Relative riskRelative riskNormalNormal 11

HyperhomocysteinemiaHyperhomocysteinemia 2.52.5

Prothrombin gene mutationProthrombin gene mutation 2.82.8

Oral contraceptivesOral contraceptives 44

Factor V Leiden (heterozygous)Factor V Leiden (heterozygous) 77

Oral contraceptives plus heterozygous Oral contraceptives plus heterozygous Factor V LeidenFactor V Leiden

3535

Factor V Leiden (homozygous)Factor V Leiden (homozygous) 8080

Thrombophilia evaluation

Unprovoked thrombotic event andUnprovoked thrombotic event and Age < 45 yrsAge < 45 yrs Recurrent eventRecurrent event Family history of thrombosisFamily history of thrombosis Cerebral/visceral thrombosisCerebral/visceral thrombosis Fetal demiseFetal demise 3 or more SABs3 or more SABs

Thrombophilia evaluation

First unprovoked eventFirst unprovoked event Provoked by pregnancyProvoked by pregnancy Provoked by OCs or HRTProvoked by OCs or HRT

Thrombophilia evaluation

Testing caveatsTesting caveats C, S, ATIII C, S, ATIII in acute thrombosis in acute thrombosis Heparin interferes with ATIII, Heparin interferes with ATIII,

lupus anticoagulant, Factor VIII, lupus anticoagulant, Factor VIII, and some APC resistance testsand some APC resistance tests

Warfarin decreases C & SWarfarin decreases C & S

Thrombophilia evaluation

Tests performed acutelyTests performed acutely Leiden Factor V (APC resistance)Leiden Factor V (APC resistance) Prothrombin G20210A mutationProthrombin G20210A mutation Increased homocysteineIncreased homocysteine Anti-cardiolipin antibodiesAnti-cardiolipin antibodies

Thrombophilia evaluation

Consider testing laterConsider testing later Lupus anticoagulantLupus anticoagulant Decreased Proteins C & SDecreased Proteins C & S Decreased Anti-thrombin IIIDecreased Anti-thrombin III Increased Factor VIIIIncreased Factor VIII

Summary

Have index of suspicion for PEHave index of suspicion for PE Develop clinical probabilityDevelop clinical probability Interpret all tests in context of pre-Interpret all tests in context of pre-

test probabilitytest probability Selectively w/u for thrombophiliaSelectively w/u for thrombophilia Choose therapy based on clinical Choose therapy based on clinical

statusstatus