Kav Senasinghe October 2016

Pulmonary Embolism

Management Options

Why follow the guidelines?• Yield of CT Pulmonary Angiography in the Emergency Department When Providers

Override Evidence-based Clinical Decision Support.

• Compared CTPA yield for PE in clinicians who overrode CDS (Clinical Decision Support) vs. those adherent to CDS

• Wells Score </= 4 and normal D-dimer or no D-dimer (override group) vs Adherent group

• 2993 CTPAs in 2655 patients.

• 563 had Wells </= 4 and did not undergo D-Dimer testing

• 26 had Wells </= 4 and a normal D-Dimer

• i.e. most overrides due to lack of D-Dimer testing

• Positive for PE 4.2% in override group vs. 11.2%

• After adjustment, the odds of an acute PE finding were 51.3% lower in the override group

Definitions

Massive PE

Acute PE with sustained hypotension (SBP<90mmHg for at least 15 mins or requiring inotropic support, not due to a cause other than PE), pulselessness, or persistent profound bradycardia (HR<40bpm with signs or symptoms of shock)

Definitions

Submassive PEAcute PE without systemic hypotension (SBP >90mmHg) but with either RV dysfunction or myocardial necrosis

RV Dysfunction:• RV dysfunction or dilatation on echo• RV dilatation on CT• elevated BNP• ECG changes

Myocardial Necrosis: • elevated Troponin T• elevated Troponin I

PE Relevance• It is estimated that there are approximately 17 000 new cases of

venous thromboembolism (VTE) in Australia per year. Pulmonary embolism (PE) accounts for about 40% of these events

• 151,923 North-East Metropolitan Perth residents from 01/10/2003 - 31/10/2004

• 87 DVT, 53 PE

• 0.31 per 1000 residents per year

• WHO age-adjusted incidence of 0.21 per 1000

PE relevance• ~20% of all PE are submassive PE

(numbers vary as we get better at detecting PE)

• a meta-analysis by Cho et al, 2014 found increased short-term mortality for haemodynamically stable patients with RV dysfunction (OR 2.29; 13.7% vs 6.5% without RV dysfunction)

• there may be selection bias, as those patients that get an echo are more likely to be sick

• Leads to long term morbidity - pulmonary hypertension and reduced functional outcome

Treatments• Anticoagulation

• NOACs

• Warfarin

• Heparin/LMWH

• Thrombolysis

• Intra-arterial Thrombolysis

• Interventional Clot Disruption

• Surgical Embolectomy

• ECMO?

Anticoagulation• Parenteral anticoagulants (Heparin/LMWH) overlapping the start of Warfarin Therapy

• RivaroXaban (Factor Xa inhibitor)

• PBS: Initial and continuing treatment of confirmed, acute symptomatic pulmonary embolism

• Rivaroxaban is no worse than enoxaparin plus warfarin for preventing VTE recurrence in initial treatment of acute DVT or PE

• Contraindicated in severe renal impairment

• Currently no antidote

• Associated with more GI bleeding compared to Warfarin - 3.61/100 patient years vs 2.60, but no significant difference in Severe or Fatal GI bleeding (ROCKET AF Trial)

• ApiXaban

• Also on the PBS for PE

• Similar in efficacy to Rivaroxaban

• Appears to be associated with a lower bleeding risk - indirect comparisons. More studies required

• DabigaTran - not on PBS for treatment of acute PE. Does have antidote.

Thrombolysis

• Pros:

• Less long-term pulmonary hypertension (MOPETT trial)

• Clots resolve faster

• Patients appear to improve faster clinically

• Decreased death or haemodynamic instability (PEITHO trial)

• Cons:

• Risk of ICH (2% in >75yo in PEITHO)

• Risk of other haemorrhage (~6% in PEITHO)

• similar improvement at 7 days overall (~65% reduction in size of total defect regardless of whether thrombolysed or anti coagulated)

PEITHO Trial (Pulmonary EmbolIsm THrOmbolysis)

• Tenecteplase vs. Placebo for intermediate risk PE

• 1005 patients

• Death or haemodynamic compromise in 2.6% vs 5.6% in placebo

• Major extra cranial bleeding in 6.3% vs 1.2 % in placebo

• <75yo 4.1% vs 1.5% - not significant

• >75yo 11.1% vs 0.6%

• Intracranial Bleeding in 2% vs 0.2% in placebo

MOPETT Trial (Moderate Pulmonary Embolism treated with Thrombolysis)

• “In patients with submassive PE does low-dose tPA reduce the incidence of pulmonary hypertension recurrent PE when compared to anticoagulation alone?”

• 121 patients. single center. unblinded.

• low-dose tPA vs control

• All patients received anticoagulation with LMWH or UFH and warfarin

• Thrombolysis associated with reduction in Pulm. HTN 16% vs 57% in control - mean follow-up 2.3 years

• No significant difference in rates of recurrent PE

• tPA did not confer a survival benefit

Thrombolysis: how to give it• Tenecteplase - weight-based calculation

• Alteplase

• >65kg given 100mg total

• 10mg bolus, 90mg over next 2 hours

• <65kg adjust total dose not to exceed 1.5mg/kg

• Start heparin infusion

• LMWH efficacy is unknown

Thrombolysis: Contraindications• Absolute contraindications include

• any prior intracranial haemorrhage• known structural intracranial cerebrovascular disease (eg, arteriovenous malformation)• known malignant intracranial neoplasm• ischaemic stroke within 3 months• suspected aortic dissection• active bleeding or bleeding diathesis• recent surgery encroaching on the spinal canal or brain, and• recent significant closed-head or facial trauma with radiographic evidence of bony fracture or brain injury

• Relative contraindications include• age >75 years• current use of anticoagulation• pregnancy• non-compressible vascular punctures• traumatic or prolonged cardiopulmonary resuscitation (>10 minutes)• recent internal bleeding (within 2 to 4 weeks)• history of chronic, severe, and poorly controlled hypertension• severe uncontrolled hypertension on presentation (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg)• dementia• remote (>3 months) ischaemic stroke; and• major surgery within 3 weeks

Intra-Arterial Thrombolysis• Potential for same benefits as systemic

thrombolysis with lower bleeding risk

• Wire passed through embolus followed by an infusion catheter with multiple openings - thrombolytic is then infused to the clot

• Evidence is lacking - SEATTLE-II trial 2015

Endovascular Procedures

• An option when thrombolysis is contraindicated or the condition is refractory to thrombolysis

• Patient preference, institute and operator preference and availability

• case-by-case basis

• https://www.youtube.com/watch?v=cWh1ovlJg24

Surgical Embolectomy• An option when thrombolysis is

contraindicated or the condition is refractory to thrombolysis

• Pt on CPB

• Usually limited to directly visualised clot

• Patient preference, institute and operator preference and availability

• case-by-case basis

• https://www.youtube.com/watch?v=SzsQWIMYbN8

SirCharlesGairdnerHospitalPulmonaryEmbolismAdvancedCarePathway

Nonmassive&Lowrisksubmassive PE

• Notclinicallycompromised

Aseniorclinician should beinvolvedintheassessmentofpatientswith pulmonaryembolism, anddiscussion betweenEmergencymedicine, respiratory medicine, cardiothoracic surgeryandinterventional radiologyisencouraged.

Theseareonlyguidelines,patientsareunique,thereisabroadandcomplexspectrumofpresentation,anddefinitiveevidence islimited.

Highbleedingrisk

Lowbleedingrisk

AccessiblePE(≥lobar PAinvolved)• Surgical

embolectomy

PeripheralPE• FulldosetPA

Options include:• Standardanticoagulation• Catheterdirectedlysis• Surgicalembolectomy• ½dosesystemicthrombolysisDiscuss with appropriate specialty: • Central clot - Respiratory Medicine plus Cardiothoracic surgery if clinical compromise• Peripheral clot – Respiratory Medicineplus Interventional radiology if clinicalcompromise• Plus make ICU aware

•Decision basedon:• Clotburdenandlocation• Highversuslowbleedingrisk• Clinicalstateandcomorbidities• Resourceavailability• Patientpreference

AccessiblePE(≥lobar PAinvolved)• Surgical

embolectomy

PeripheralPE• Catheter

directedlysis

Lowmolecularweightheparin/anticoagulation

ICUorHDU/Resp HDUHDU/Resp HDU

Considerdischargeifnoconcerningfeatures(seelistunder highrisksubmassive PE)

Ensureappropriatefollowup– anticoag nurse/resp /+/- haematology

Otherwisegenerallyadmitrespiratorymedicine

MassivePulmonaryEmbolism

•Ongoinghypotensionwithsignificantclinicalcompromise

(<90mmHgor>40mmHgdropinsystolicBP)

High risksubmassive PEFeaturesfromatleast2ofthebelowcategories:1. Clinical: looksunwellorcompromised,

deteriorating, severehypoxia, syncopehx2. Imaging:largeclotburden,concerning echo3. Laboratory: Elevatedlactate, BNP, troponin

Designedincollaborationandwithagreement fromEmergency Medicine,RespiratoryMedicine,InterventionalRadiologyandCardiothoracicSurgery ForReview 2017Reference: ModifiedfromtheEMCrit.orgwebsiteMay2015.http://i2.wp.com/emcrit.org/wp-content/uploads/2014/07/Orens-PE-Algo.jpg JamesRippey

SirCharlesGairdnerHospitalPulmonaryEmbolismAdvancedCarePathway– additionalinformation

Absolute• Knownallergy /hypersensitivity/adverse reactiontothrombolytics orallergyto

Gentamicin(atrace residuefromthemanufacturingprocess)• Activeorrecentinternalbleedingwithin14days(excludesmenstruation)• Significantclosedhead,facialorothersevere traumawithinpast3months• Suspectedaorticdissectionorpericarditis• Priorintracranialhaemorrhage withinpast6months• Ischaemic strokewithin3monthsorprevioushaemorrhagic stroke• Knownstructuralcerebralvascularlesion(AVMoraneurysm)• Knownmalignantintracranialorintraspinal neoplasm• Knownseverebleedingdisorder• Recent(withinpast2months)intracranialorintraspinal surgery)

Relative• Agemore than75years• Currentanticoagulantuse(ifonwarfarin

onlythrombolyse ifINR<2.0)• Noncompressiblevascularpuncturewithin

past10days• Recentmajor surgery(within3weeks)• TraumaticorprolongedCPR(formorethan

10minutes)• Recentinternalbleeding (within2-4weeks)• Historyseverechronicpoorlycontrolled• Hypertension

• Uncontrolledhypertensiononpresentation(Systolic>180ordiastolic>110mmHg)

• Ischaemic strokeover3monthsago• Dementiaorknownintracranialpathology• Pregnancyorrecentdelivery• ReducedGCS• Haemorrhagic ophthalmicconditions• Activepepticulcerorotherulcerative

conditions(i.e.Crohn’s disease)• Advancedkidneyorliverdisease• PriorStreptokinase/Alteplase /Reteplase

Highbleedingriskandcontraindicationstothrombolysis

ConsiderationofimagingforsourceofPEandneedforIVCfilter• InpatientswithsuspectedmassiveorhighrisksubmassivePE,CTPAwithconcurrentCTVdowntopoplitealveinsisrecommended.• WhereCTVisnotprospectivelyperformedultrasoundofthelowerlimbsisanalternativeandstronglyrecommended ifconsidering majorRx(lysis,cath,embolectomy).• IVCfilter isplacedinpatientswhohaveundergonesurgicalpulmonaryembolectomyandinwhomthere remainssignificantlowerlimbthrombus.• IVCfilter isconsideredinpatientswithsubmassivePE,inwhomthereremainssignificantlowerlimbthrombus,particularlyifitappearsunstable.• AdviceontheuseofTEDstockingsisavailableontheSCGHEDDVTpathway

AdministrationofthrombolysisforpulmonaryembolismFulldosethrombolysis

Alteplase(tPA)>65kg 10mgIVbolus,followed by90mgIVinfusionover2hours<65kg adjustdosesoitdoesnotexceed1.5mg/kg;give10mgIVbolusthentheremainder ofthedoseover2hours

HalfdosethrombolysisAlteplase(tPA)>65kg 10mgIVbolus,followed by40mgIVinfusionover2hours<65kg adjustdosesoitdoesnotexceed0.75mg/kg;give10mgIVbolusthentheremainder ofthedoseover2hours

Follow theAlteplase2hour infusionwithanticoagulation withunfractionated heparinviaIVinfusionasperanticoagulation chartprotocol.Catheterdirected thrombolysis

Alteplase(tPA)asdirected byinterventional radiology

References1.Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic

Pulmonary Hypertension Circulation. AHA. 2011;123:1788-1830

2.Ho WK, Hankey GJ, Eikelboom JW. The incidence of venous thromboembolism: a prospective, community-based study in Perth, Western Australia. Med J Aust 2008;189:144–47

3.Yan Z et al. Yield of CT Pulmonary Angiography in the Emergency Department When Providers Override Evidence-based Clinical Decision Support. Radiology 2016 Sep30:151985

4.Cho JHet al. Right ventricular dysfunction as an echocardiographic prognostic factor in haemodynamically stable patients with acute pulmonary embolism: a meta-analysis. BMC Cardiovascular Disorders 2014, 14:64 dos: 10.1186/1471-2261-14-64

5.Pharmaceutical Benefits Scheme. http://www.pbs.gov.au/pbs/home

6.http://www.nps.org.au/medicines/heart-blood-and-blood-vessels/anti-clotting-medicines/for-individuals/anticoagulant-medicines/for-health-professionals/evidence-summary/venous-thromboembolism

7.Sherwood et al. Gastrointestinal Bleeding in Patients with Atrial Fibrillation Treated with Rivaroxaban or Warfarin. J Am Coll Cardiol. 2015 Dec 1;66(21):2271-81. doi: 10.1016/j.jacc.2015.09.024

8.Indirect comparison of dabigatran, rivaroxaban, apixaban and edoxaban for the treatment of acute venous thromboembolism. https://www.ncbi.nlm.nih.gov/pubmed/24989022

9.Sharif M et al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). J Cardio 2013; 111:273

10.Meyer et al, Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism N Engl J Med 2014;370:1402-11. DOI: 10.1056/NEJMoa1302097

11.Piazza G, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015 Aug 24;8(10):1382-92. doi: 10.1016/j.jcin.2015.04.020

12.Life in the Fast Lane www.lifeinthefastlane.com

13.Charlie’s ED www.scghed.com