Massive and Submassive Pulmonary Embolism: 2017 Update and Future Directions

Massive and Submassive Pulmonary Embolism: 2017 Update and Future Directions Kush R Desai, MD Assistant Professor of Radiology Northwestern University Feinberg School of Medicine Chicago, IL

Disclosures Speakers bureau/consulting, Cook Medical, Boston Scientific, AngioDynamics Consulting, Spectranetics

Estimated Prevalence (%) 5 10 20 Shock Highintermediate risk PE Low-intermediate risk PE Symptomatic PE affects 600,000 people annually - US 25 Low risk PE 40 Asymptomatic Becattini C, Agnelli G. Thromb Haemost. 2008; 100(5): 747 751 Abrahams van-doorn P. and Hartmann IJC. Imaging Insights. 2011; 2: 705-715 Dalen JE. Chest. 2002; 122: 1801-17

Life after acute PE Persistent thrombi 15-33% All PE patients CTEPH 0.1-4% Reduced functional status 50% Measurable limitation 10-30% Klok Blood Reviews 2014 Matthews Pulm Circulation 2016

Definitions

Pulmonary Embolism Definitions AHA Guidelines 2011 Massive: Acute PE with sustained hypotension SBP <90mmHg for at least 15 min or requiring inotropic support, not due to a cause other than PE (arrythmias, hypovolemia, sepsis, LV dysfunction, pulselessness, profound bradycardia with shock) Submassive: Acute PE without systemic hypotension (SBP >90mmHG) AND either.. RV dysfunction (RV/LV ratio >0.9, RV dysfunction on echo, RV dilation on CT scan, Elevated BNP (90) or NtproBNP (500), EKG evidence RV strain) Myocardial necrosis (elevated TNI >0.4ng/mL, TNT >0.1ng/mL) Non-massive Acute PE without clinical markers of adverse prognosis ESC Guidelines 2014 High Risk: Acute PE with shock or hypotension SBP <90mmHg, or SBP drop by > 40mmHg, for at least 15 min, not due to a cause other than PE Intermediate High Risk: Acute PE without hypotension and elevated PESI score with RV dysfunction AND serology Pos Intermediate Low Risk: Acute PE without hypotension and elevated PESI score with or without RV dysfunction OR serology Pos Low Risk: Acute PE with low PESI score * Jaff et al; Circulation. 2011; 123: 1788-1830 ** Konstantinides et al; EurHeartJ. 2014; t Kearon et al; CHEST. 2016; 149(2): 315-352 ACCP/CHEST Guidelines 2016 PE with Hypotension: Acute PE with sustained hypotension SBP <90mmHg for at least 15 min, not due to a cause other than PE High vs Low Bleeding Risk PE without Hypotension: Acute PE without systemic hypotension (SBP >90mmHG) and Using clinical judgement and testing (imaging, serology etc..) to determine level of monitoring and support needed

Risk Stratification in PE Mortality Related to Hemodynamic Stability Hypotensive (SBP < 90mmHG) Normotensive t International Cooperative Pulmonary Embolism Registry (ICOPER) * 52.4% [43.3, 62.1] 14.7% [13.3, 16.2] Management Strategy and Prognosis of Pulmonary Embolism Registry (MAPPET) ** 25% (65% if required CPR) 8.1% * Goldhaber et al; Lancet 1999 **Kasper et al; JACC 1997 t Wood et al; Chest, 2002

Treatment of Massive Pulmonary Embolism Supportive Anticoagulation Ventilatory/Pressor support ECMO Systemic/Interventional/Surgical IV tpa CDT Open embolectomy

Systemic thrombolysis 11 trials, 748 patients Reduction in death and recurrent PE in trials that included unstable PE patients (9.4 19%, OR 0.45, 95% CI 0.22-0.92. NNT=10) Circulation. 2004 Aug 10;110(6):744-9

Chest 2016

Systemic thrombolysis protocol Evaluate for contraindications Active bleeding Intracranial mass or metastasis (relative) Several other relative contraindications 100 mg tpa IV over 2 hours Benefit greatest if administered within first 48 hours

Role of catheter directed therapies Time is the enemy IV tpa is faster May have a role in patients who have not improved with IV tpa or have worsening shock before systemic lytic can take effect

Surgical embolectomy Depends on local expertise Current experience has shown lower morbidity and mortality relative to historic data Benefit larger volume of thrombus removal relative to CDT

Surgical embolectomy

Surgical embolectomy

Patient support in massive PE RV fatigue Impending shock Cardiac arrest VA ECMO

VA ECMO

Pulmonary Embolism Definitions AHA Guidelines 2011 Massive: Acute PE with sustained hypotension SBP <90mmHg for at least 15 min or requiring inotropic support, not due to a cause other than PE (arrythmias, hypovolemia, sepsis, LV dysfunction, pulselessness, profound bradycardia with shock) Submassive: Acute PE without systemic hypotension (SBP >90mmHG) AND either.. RV dysfunction (RV/LV ratio >0.9, RV dysfunction on echo, RV dilation on CT scan, Elevated BNP (90) or NtproBNP (500), EKG evidence RV strain) Myocardial necrosis (elevated TNI >0.4ng/mL, TNT >0.1ng/mL) Non-massive Acute PE without clinical markers of adverse prognosis ESC Guidelines 2014 High Risk: Acute PE with shock or hypotension SBP <90mmHg, or SBP drop by > 40mmHg, for at least 15 min, not due to a cause other than PE Intermediate High Risk: Acute PE without hypotension and elevated PESI score with RV dysfunction AND serology Pos Intermediate Low Risk: Acute PE without hypotension and elevated PESI score with or without RV dysfunction OR serology Pos Low Risk: Acute PE with low PESI score * Jaff et al; Circulation. 2011; 123: 1788-1830 ** Konstantinides et al; EurHeartJ. 2014; t Kearon et al; CHEST. 2016; 149(2): 315-352 ACCP/CHEST Guidelines 2016 PE with Hypotension: Acute PE with sustained hypotension SBP <90mmHg for at least 15 min, not due to a cause other than PE High vs Low Bleeding Risk PE without Hypotension: Acute PE without systemic hypotension (SBP >90mmHG) and Using clinical judgement and testing (imaging, serology etc..) to determine level of monitoring and support needed

ICOPER alerted us to RV dysfunction

Risk Stratification in PE Predictors of Early Mortality in Acute PE Test or Biomarker Echo CT scan Cut off RV dysfunction OR or HR 2.4 * [1.3, 4.3] RV/LV>1 1.5 * [0.7, 3.4] RV/LV >.9 2.8 ** [0.9, 8.2] BNP 75-100pg 6.5 t [2.0, 21] NT-proBNP 600pg/ml 6.3 [2.2-18.3] TNI Var 4.0 tt [2.2, 7.2] *Coutance et al Crit Care 2011; 15 103, t Klok et al, AJRCCM; 2008 ** Becattini Eur Heart J 2011; 32 1657-1663, tt becattini circ; 2007 Becattini et al Chest 2013; 144 (5): 1539-1545 869 patients normotensive PE with echo and troponin. More evidence of RV strain larger the risk of death or clinical decompensation

Evaluating the RV Biomarkers BNP, Troponin Imaging Echocardiography CT RV/LV ratio

PESI score Aujesky et al, Am J Resp Crit Care Med 2005

Role of systemic thrombolytics in PE PEITHO trial 2014 Placebo controlled, multicenter RCT Heparin + fibrinolytic vs heparin alone Patients had elevated troponin and RV dysfunction Treatment arm weight based tenecteplase dosing (30-50 mg)

Stroke risk 2.4% vs 0.2% N Engl J Med. 2014 Apr 10;370(15):1402-11

The rationale for catheter directed therapy

Catheter-Directed techniques Infusion of thrombolytics via drug dispersion catheters Mechanical thrombectomy Ultrasound-assisted thrombolytic infusion

Ultrasound-assisted thrombolysis FDA approved for treatment of acute PE

59 patients, intermediate risk (RV:LV ratio >1) US-assisted CDT (USAT) vs. heparin alone Reduction in RV/LV ratio at 24 hours Ratio reduction: USAT 0.3+/-0.2 vs heparin 0.03 +/-0.16 (p<0.001) No major bleeding, 4 minor bleeding episodes Circulation. 2014 Jan 28;129(4):479-86

150 patients, massive and submassive PE, single-arm Reduction of RV/LV ratio at 24 hours Low dose, total 1 mg tpa/h (split-dose for bilateral) Mean ratio reduction of 0.42, mean PA pressure reduction 14.5 mmhg (p<0.0001) 1 groin hematoma, no intracranial bleeding JACC Cardiovasc Interv. 2015 Aug 24;8(10):1382-92

101 patients, massive and submassive PE Operator discretion on method of CDT Clinical success defined as HD stabilization, pulm HTN and/or improvement in RV strain, survival at discharge Success in 85.7% massive PE pts, 97.3 submassive PE pts, 89.1% showed improvement in RV strain on echo (p<0.0001) No major complications Chest. 2015 Sep;148(3):667-73

What about endpoints? Studies thus far have examined endpoints such as reduction of RV/LV ratio, PA systolic pressure Clinically meaningful? Physiologic parameters?

Prospective cohort study, 100 patients, 2010-2013 Measurement of cardiopulmonary exercise testing at 1 and 12 months, QOL, 6 minute walk distance, residual clot burden, cardiac function, PFTs 46.5% (40/86) patients had VO 2 peak < 80% at 1 year Associated with decreased QOL, dyspnea, 6MWD Kahn et al, Chest 2017

Future directions: PE-TRACT Multicenter, blinded, randomized trial comparing CDT + anticoagulation vs anticoagulation alone Primary outcome to assess patient endurance post therapy at 1 yr 6 minute walk distance Secondary outcomes to include QOL measures, NYHA class, safety events, and recurrent VTE rates amongst others Planned submission to NIH/NHLBI

Tips for PE intervention How I do it Select the appropriate patient (AHA guidelines) Right IJ access x 2 (my preference) Long, 7Fr 45 cm curved sheaths, sheath in the PA Access PA with C2 and J-wire 90 cm (10-20 cm infusion length) catheters 0.45 mg/hr per catheter Q6 fibrinogen, 12-18 hr infusion Measure peak systolic pressure before and after through sheath

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