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12/15/2016
1
Pulmonary Embolisman update on therapy
Thomas J Piskorowski, DO
11/17/2016
Pulmonary embolism
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Incidence
• 75‐269/100,000patients
• Up to 700/100,000 age > 70
• 100,000 to 180,000 PE related deaths in US annually (US Surgeon General)
• Most preventable cause of death among hospitalized patients
• Up to 15% of hospital deaths
• 20‐30% of deaths associated with pregnancy & delivery in US & Europe
diagnosis
• Non‐specific symptoms
• CTPA current preferred diagnostic modality
• PE confirmed in 10‐20% of CTPA
• validated clinical algorithm
– Clinical decision rule
– D‐dimer
Wells rule
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Geneva score
D‐dimer
• Sensitivity: 95‐100%
• Specificity:43‐93%
• <500ug/L: 3 month incidence of PE with anticoagulation held: 0.04‐0.95%
• Age adjusted D‐dimer: (Age X 10ug/L) 3 month incidence of PE 0.3%
• PE can be ruled out in 25‐46% without CTPA
CTPA
• Inconclusive in 0.9‐4.6%
• CTPA negative: 1.2% PE in 3 month with high clinical tool & D‐dimer
• 1.1% 3 month risk if lower limb US added
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Normal V/Q 0.9% risk of PE in 3 months
High probabilityinconclusive in 28‐48% with 15‐50% risk of PE
CTPA
• Hemodynamic status, not degree of obstruction is most important short term prognostic factor
• RV dysfunction (RV /LV diameter >0.9, reflux of contrast into IVC / hepatic vein) >8% vs 5% short term PE related mortality
• Troponin elevation 18% vs 2.3 % PE mortality
• BNP 17% vs 1.7% short term PE related mortality
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Non Massive, Low risk PDNormal BP, normal RV, normal biomarkers
early mortality risk: 1‐2 %70% 0f all PE
Possible out‐patient treatment
Other variables to consider
• High bleed risk• GI bleed last 14 days• Recent stroke: 4 weeks• Platelets < 75,000• Uncontrolled HTN• Creatinine clearance < 30 ml/min• Documented HITS• Need for IV analgesia• Severe liver disease• Pregnant
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Massive, High Risk PEincidence 5%Mortality >50%
therapy
• IV thrombolysis– 9.2% risk of major bleeding complications
• Surgical embolectomy– Contraindications to thrombolysis
– Failed fibrinolysis
– Concomitant cardiac or paradoxical emboli
– Mortality:• <1985: 32%
• 1985‐2006: 20%
• Current: 8% (if before CPR)
Submassive, intermediate risk Pulmonary embolism
25 % of all (50‐66%)
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Submassive, Intermediate Risk PE
• Risk of death: 7‐15% (dependent on underlying conditions)
• Preserved SBP• Elevated cardiac biomarkers
– Troponin– BNP
• Signs of RV dysfunction– CT signs include:
• RV/LV ration > 0.9• Septal bulge to left• Reflux of contrast to IVC& hepatic vein• Dilated, contrast filled azygos vein
Reflux of contrast to IVC & hepatic vein
Management Strategies & Prognosis of Pulmonary Embolism‐3MAPPET‐3
S Kontanrinides. NEJM 2002, (347).1143‐1150
• 256 enrolled
• Heparin + alteplase 100 mg vs. heparin + placebo
• Pulmonary HTN or RV dysfunction
• 25% in placebo group had escalation of therapy to alteplase (shock, respiratory distress, persistent or worsening pulm HTN
• Mortality: alteplase 3.4%; placebo 2.2% (only 1 fatal bleed – in placebo group)
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Thrombolysis for PE & ALL cause Mortality, Major Bleeding & Intracranial Hemorrhage: a Meta‐analysis
JAMA 2014 (311), 2414‐21
• Decrease in all cause mortality: 2.17% vs. 3.89%
• Lower risk for recurrent PE (1.17% vs. 3.04%)
• Higher risk for Major bleed (9.24% vs. 3.42%)
• Higher risk for age > 65
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Chinese VTE Study groupWang. Chest 2010 (137) 254‐62
• TPA 100 mg over 2 hr vs. 50 mg over 2 hr
• RV function improved in both
• Major bleed 10% full dose vs. 3% 50 mg TPA group
• Bleed risk especially high with wt. < 65kg
Moderate Pulmonary Embolism Treated with Thrombolytics“MOPETT”
Sharifi, AJCard 2013 (111): 273‐77
• > 2 lobar pulmonary arteries or left or right PA
• 50 mg TPA over 2 hr (1 mg/kg of < 50 kg) with heparin vs heparin alone
• Lower incidence of Pulm HTN on TPA group
• No difference in recurrent PE
• No major bleeding with low dose thrombolytics
Fibrinolysis for patients with Intermediate Risk Pulmonary EmbolismPEITHO; NEJM 2014 (370) 1402‐11
• Intermediate risk PE with RV dysfunction on CTPA or TTE& elevated troponin (1005 pt.)
• Wt. based tenecteplase 30‐50 mg IVP over 5‐10 seconds
• Death: 1.2% (tenecteplase) vs. 1.8% (placebo)
• Hemodynamic decompensation: 1.6% vs. 5%
• CPR: 1 pt. vs. 5
• Major bleed: 11.5% vs. 1.2 (IC Bleed 2% vs 0.2%) (risk greatest in age > 75)
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Greenfield Suction embolectomy catheter
Cut down required
Pig tail catheter
Thrombus fragmentation
Also Fogarty balloon embolectomy
Catheter Assisted ThrombolysisEKOS catheter
5.2 French multi side‐hole infusion catheter
Microsonic core with ultrasound elements
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First 2 slides show thrombus3rd slide with 2 catheters in place for infusion: 12 cm treatment zone
EKOS Catheter
• High frequency low power ultrasound
• Loosen fibrin strands
• Enhance thrombus penetration of the fibrinolytic agent
• 2 ports
– Fibrinolytic
– Coolant solution (NaCl @ 35 ml/hr
• Peeling layers off an onion?
ULTIMAKucher N, Circulation 2014, (129):479‐86
• First randomized, controlled trial of US assisted catheter based reperfusion therapy for intermediate risk PE (main or lower lobe PA with RV/LV >1)
• TPA 10‐20 mg over 15 hr with low dose UFH (30 pt.) vs UFH alone (29 pt.)
• Decrease in RV size
• Minor bleed 10% (TPA) vs 3%, no major bleed
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SEATTLE IIUS based Submassive & Massive PE treatment with US Accelerated Thrombolysis
Piazza G, Circulation, JACC Cardiovascular interv., 2015 (8);1382‐1392
• 150 patients (21% with massive PE)
• TPA 1 mg/hr for 24 hr (or 12 hr if bilateral disease) (UHF for PTT 40‐60sec?)
• RV/LV diameter ration decreased 25% by 48hr
• Mean PA pressure decreased 30%
• Major bleed 10%, no IC bleed
• FDA approved EKOSONIC Endovascular System May 21, 2014
Best thing since sliced bread?
EKOS
• Expensive
• Learning curve
• Complications:
– Pulmonary artery injury, dissection
– Distal embolization (intracardiac or IVC?)
– Hemoptysis
– Site Bleeding
– Pericardial tamponade
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Is US assistance needed?
• Engelberger RP, Circ Interventions 2015
• 48 pts. With acute iliofemoral DVT (not PE)
• 20 mg alteplase catheter directed over 15 hr
• No change in thrombus load reduction (55% vs. 54%)
Prevalence of PE among Patients Hospitalized for PEPrandoni P, NEJM 2016 (375): 1524‐31
PESITPulmonary Embolism in Syncope Italian Trial
• 560 patients
• 59% PE ruled out by D‐dimer & low pretest clinical probability score
• PE found in 97 (42%) of remaining
• Main pulmonary artery or perfusion defects > 25% of lungs in 61 pts.
• 17.3% of PE in entire cohort
• 18% of 355 patients that had an alternative explanation for syncope.
Also :
Prolonged (>10 min) or traumatic CPR
?pregnancy
Any stroke within 3 months
?age > 75
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Algorithms:
Algorhithm 2
Algorithm 3
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IVC Filter
• Absolute contra‐indication to anticoagulation
• Recurrent PE despite adequate anticoagilation
• Prevention of Recurrent PE by IVC Interruption (PREPIC2) JAMA 2015 (313) 1627‐1635
– IVC filter & anticoagulation: 3% risk of recurrent PE
– Anticoagulation alone: 1.5% risk of recurrent PE
– Does not support use of IVC filter vs. anticoagulation
Possible conclusions
• Use of Wells clinical tool & D dimer
• CTPA
• High Risk PE: thrombolysis (benefit > risk)
• Low risk: anticoagulation (home vs hospital –PESI)
• Intermediate risk: risk vs benefit uncertain:– RV dysfunction; biomarkers; PESI
– ? Low IV thrombolysis ( MOPPETT)
– ? EKOS US facilitated catheter directed thrombolysis (ULTIMA / SEATTLE)
– ? Anticoagulation alone
Pulmonary Embolism Response Team
• PERT trademarked
• Adequate studies scarce, inconclussive or lacking
• Not addressed in current guidelines
• Composition:– Interventional Cardiology
– Radiology
– Thoracic Surgery
– PCCM
– Vascular Surgery
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Initial anticoagulation
• LMWH ?drug of choice– At least 6 months for cancer patients
• Fondaparinux: alternative for heparin induced thrombocytopenia
• UFH:– Pts. With high risk for bleed, including post thrombolysis
– Creatinine Clearance < 20‐30ml/min
– Extremes of age / weight
Oral anticoagulation 1
• VKA therapy : INR 2.0 to 3.0• Risk of recurrent VTE at 3 month 3‐4 %• Major hemorrhage at 3 Month: 1‐2%• NOACs• Direct factor Xa inhibitor
– Rivaroxaban (Xarelto)– Apixaban (Eliquis)– Edoxaban ( Savaysa)
• Direct thrombin inhibitor– Dabigatran (Pradaxa)
• Short half life• Reversal
– Idarucizumab (Praxbind) humanized monoclonal antibody for dabigatran REVERSAL– Andexanet (AndexXa) “decoy” factor Xa molecule (may also reverse enoxaparin)– 4 factor prothrombin complex (PCC) contains factors II, VII, IX, X and proteins C & S along with
heparin & albumin
Oral anticoagulation 2
• Risk for major hemorrhage after 3 mo. estimated at 2.74/100 patient years.
• Variable risk– Previous GI bleed– Previous stroke– Chronic renal or liver disease– Alcohol abuse– Concomitant antiplatelet therapy– Presence of serious comorbities– Poor control of anticoagulant therapy
• Case fatality rate of anticoagulant‐associated major hemorrhage: 13.4 %
• Case fatality for recurrent VTE: 3.6%
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Oral Anticoagulation 3
• Duration of anticoagulant therapy only postpones a potential VTE without diminishing the risk once stopped.
• 2.5% recurrence per year if related to transient provoking factor– Recent surgery, immobilization, pregnancy or oral contraceptive use
• 20.7% recurrence per year with active malignancy• Antiphospholipid syndrome or recurrent VTE with in 4 years after 6 month of therapy 20% VTE
Oral anticoagulation 4
• Unprovoked PE not associated with malignancy or antiphospholipid syndrome recurrence: 4.5 –11%/ year; no definite recommendations for duration of therapy
• ASA secondary prevention of VTE:– WARFASA ‐ NEJM 2012 (366): 1954‐67
• ASA 100 mg/day• Risk 6.6% for ASA vs placebo 11.2%• No increase in major hemorrhage
– ASPIRE – NEJM 2012 (367): 1979‐87• 4.8%/year vs placebo 6.6%• Decreased risk of VTE, MI, stroke 34% (5.2% vs 8%)
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General references
• Van der Hulle T et al. Recent Developments in the Diagnosis & Treatment of Pulmonary Embolism, Journal of Internal Medicine, 2016,(279):16‐29
• Wadhera R, Piazza G. Treatment Options in Massive & Submassive Pulmonary Embolism, Cardiology in Review, 2016 (24): 19‐25
• Sanchez O et al. Management of Massive & Submassive Pulmonary Embolism: focus on recent randomized trials, Curr Opin Pulm Med, 2014 (20): 393‐99
• Marshall P et al. Controversies in the management of life Threatening Pulmonary Embolism, Semin Respir Crit Care Med 2015 (36) 835‐41