Submassive Pulmonary Emboli: New Therapeutic Strategies Thomas Jefferson University Hospital Critical Care Grand Rounds Ryan D. Reber, D.O. Lankenau Medical Center Pulmonary and Critical Care Medicine Fellow March 29, 2013

Submassive Pulmonary Emboli Goals and Objectives: Overview of venous thromboembolism Massive pulmonary embolism and thrombolytics Normotensive pulmonary embolism and the need to identify the subset of submassive pulmonary emboli at risk of mortality/morbidity Therapeutic approaches to submassive pulmonary emboli Thrombolysis Half Dose Thrombolysis Ultrasound Accelerated Thrombolysis IVC Filter

Venous Thromboembolism Overview Estimated 300,000-600,000 affected yearly in USA 60,000-100,000 Americans will die 30% mortality rate if left untreated Primarily as a result of recurrent embolism Majority dying with in first 30 days Mortality reduced to 2-10% with accurate diagnosis and effective therapy Centers For Disease Control and Prevention; Data and Statistics: 2012 JVIR 2008; 19:372-376

Stratifying Pulmonary Emboli Massive PE (5-10%): Sustained hypotension (SBP < 90 mmHg for 15 minutes or requiring inotropes) Pulselessness Persistent and profound bradycardia Submassive PE (20-25%): RV dysfunction or myocardial necrosis without hypotension Low Risk PE (70%): Normotensive and no markers of adverse prognosis Circulation 2011; 123: 1788-1830

Stratifying Pulmonary Emboli Massive PE (5-10%): Sustained hypotension (SBP < 90 mmHg for 15 minutes or requiring inotropes) Pulselessness Persistent and profound bradycardia Submassive PE (20-25%): RV dysfunction or myocardial necrosis without hypotension Low Risk PE (70%): Normotensive and no markers of adverse prognosis Circulation 2011; 123: 1788-1830

Chest 2002; 121: 878

Chest 2002; 121: 878

Mortality Associated with Pulmonary Emboli

Massive Pulmonary Embolism ACCP 2012 Guidelines “Acute PE associated with hypotension who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy…(Grade 2C)” Chest. 2012; 141(Suppl 2): 24S

Reduction in clot burden: Heparin vs Heparin and Thrombolytics By day 7, similar 65-70% reduction in total defect Compared to heparin alone, thrombolysis and heparin result in 30-35% reduction in perfusion defect at 24 hours Arch Int Med 1997; 157: 2550-2556

Impact of Systemic Thrombolytics in Unstable PE* on Mortality AJM 2012; 125:465-470 *Defined as Shock or VDRF

Thrombolysis is Not Without Risk Lancet 1999; 353: 1386-1389 (ICOPER)

Thrombolysis is Not Without Risk Lancet 1999; 353: 1386-1389 (ICOPER)

Normotensive Pulmonary Emboli: Submassive and Low Risk Thought to have more favorable outcomes because of hemodynamic stability JVIR 2008; 19:372-376

Chest 2002; 121: 878

Normotensive PE with RV dysfunction (ie Submassive) up to 30% mortality!!! thus Relying soley on BP may fail to identify key prognostic features and delay more appropriate therapy Chest 2002; 121: 878

Stratifying Pulmonary Emboli Massive PE (5-10%): Sustained hypotension (SBP < 90 mmHg for 15 minutes or requiring inotropes Pulselessness Persistent and profound bradycardia Submassive PE (20-25%): RV dysfunction or myocardial necrosis without hypotension Low Risk PE (70%): Normotensive and no markers of adverse prognosis Circulation 2011; 123: 1788-1830

Submassive Pulmonary Emboli ANY ONE OF THE FOLLOWING: RV Dysfunction RV dilation on echo (RV d/LV d > 0.9) RV systolic dysfunction on echo RV dilation on CT Elevated BNP EKG New RBBB, anteroseptal STE/D/TWI Myocardial Necrosis Elevation in Troponin Circulation 2011; 123: 1788-1830

CAUTION: Submassive Pulmonary Emboli: All are not with same mortality

RV DYSFUNCTION/ TN ELEVATION COMBO in PE: PROGNOSIS (n=1,273) Stein et al. Am J Cardiol 2010; 106: 558-563

Submassive PE: Combining Prognosticators   30 Day Mortality ECHO+ DVT+ 19.6% Trop+ DVT+ 17.1% Trop+ ECHO+ 15.2% Thorax. 2011; 66:75-81

Submassive Pulmonary Emboli: All are not with the same mortality AHA defines submassive pulmonary emboli solely on hemodynamic, electrocardiogram, biomarkers and echo/CT parameters and fails to identify clinical risk factors associated with increased morbidity/mortality…thus with POOR CARDIOPULMONARY RESERVE Role of clinical risk scores may help further stratify the submassive group

PESI INDEX AJRCCM 2005;172:1041-1046

Submassive PE and Benefit of Systemic Thrombolytics? Given increased mortality associated with submassive PE, is there mortality benefit from thrombolytics like in massive PE? To date: Reduction in clinical deterioration requiring escalation of care* Reduction in RV dysfunction at 24 hours based on ECHO** No difference in mortality*/** *NEJM. 2002;347:1143-1150/**Thromb Res. 2010;125:e82-86

Systemic Thrombolysis and Submassive PE Limitations of studies Not all submassive PEs are equivalent (PE with slight trop/-ECHO VS. PE with hi trop/+ECHO)

Pulmonary Embolism Thrombolysis Study PEITHO (ACC 2013 Meeting-3/11/13) Normotensive acute PE with abnormal RV on echo/CT and a positive troponin More “high risk” submassive PEs Tenecteplase/heparin (506 pts) vs placebo/heparin (499 pts)

Pulmonary Embolism Thrombolysis Study PEITHO Combined mortality and hemodynamic collapse within 7 days of randomization Tenecteplase/UFH 2.6% Placebo/UFH 5.6% (no difference in mortality alone but difference in collapse…also no 30 day mortality difference)

Pulmonary Embolism Thrombolysis Study PEITHO Non-intracranial bleeds Tenecteplase/UFH 6.3% Placebo/UFH 1.5% Strokes (predom. Hemorrhagic) Tenecteplase/UFH 2.4% Placebo/UFH 0.2%

Pulmonary Embolism Thrombolysis Study PEITHO Conclusions: Lysis/UFH reduces combined endpoint of death and hemodynamic collapse at 7 days, but no improvement in mortality alone at end of day 7 and 30 Benefits came at risk of both major and intracranial bleeds

Submassive PE and Systemic Lytics No mortality improvement Reduction in RV dysfunction Significant risk of major hemorrhagic complications What about “low dose systemic lysis” or even “catheter based lytics”

Submassive PE and Systemic Lytics No mortality improvement Reduction in RV dysfunction Significant risk of major hemorrhagic complications What about “low dose systemic lysis” or even “catheter based lytics”

“Safe Dose” tPA in Submassive PE Moderate Pulmonary Embolism Treated with Thrombolysis-”MOPETT” Trial “Moderate” acute PE based on clot burden/perfusion defects and signs and symptoms, not RV dysfunction or cardiac biomarker elevation tPA/heparin (61 pt) vs heparin alone (60 pt) “MOPETT” AJC. 2013; 111: 273-277

Moderate Pulmonary Embolism Treated with Thrombolysis-”MOPETT” Trial Reduced PASP on ECHO “MOPETT” AJC. 2013; 111: 273-277

Moderate Pulmonary Embolism Treated with Thrombolysis-”MOPETT” Trial While there was no bleeding events there was No change in mortality at end of 22 month “MOPETT” AJC. 2013; 111: 273-277

Catheter Techniques: “Pharmacomechanical” Therapy Mechanical Fragmentation Hydrodynamic (AngioJet®) Ultrasound-Accelerated Fibrinolysis (EKOS®) Suction Embolectomy (AngioVac®)

EKOS® DRUG DELIVERY CATHETER ULTRASOUND TRANSDUCERS

Ultrasound Accelerated Thrombolysis Fibrin without Ultrasound Fibrin With Ultrasound The premise: Low-power ultrasound energy loosens fibrin strands, increases thrombus surface area, enhances lytic penetration, speeding thrombolysis, and facilitates reduction in fibrinolytic drug dose.

Ultrasound Accelerated Thrombolysis of Pulmonary Embolism (ULTIMA) Preliminary data from the ACC 2013 Meeting, March 9, 2013 59-patients, European study Ultrasound accelerated thrombolysis (EKOS) and UFH versus UFH alone <20 mg of rt-PA used

Ultrasound Accelerated Thrombolysis of Pulmonary Embolism (ULTIMA) EKOS reduced right heart enlargement by 23% vs only 3% in UFH at 24 hours No serious bleeding events in either group Minimal to no systemic lytic effect??? EKOS greater reduction in right heart dysfunction at 90 days AWAITING SECONDARY ENDPOINT OF MORTALITY…….

Complications of Catheter based Ultrasound Accelerated Thrombolysis Bleeding at catheter site, non fatal hemoptysis (10 mass) JVIR. 2008; 19:372-376 Bleeding at catheter site (24 mass and sub) Thrombosis Res. 2011; 128: 149-154 No bleeding complications vs 21.4%(CDT 18 vs UAT 15 mass) Vascular. 2009; 17: (Supp 3): S137-S147 41

Additional Considerations Pulmonary hemorrhage/ pericardial tamponade RV failure from distal embolization Reperfusion edema Systemic bleeding from anticoagulation Contrast-induced anaphylaxis Contrast-induced nephropathy Vascular access complications

Trial Summary

Submassive Pulmonary Embolism ACCP 2012 Guidelines “In most patients with acute PE not associated with hypotension, recommend against systemically administered thrombolytic therapy…(Grade 1C)” “In selected patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation, or clinical course after starting AC therapy, suggests a high risk of developing hypotension, suggest administration of thrombolytic therapy…(Grade 2C)” Chest. 2012; 141(Suppl 2): 24S

Submassive Pulmonary Embolism ACCP 2012 Guidelines “In patients with acute PE assoc. with hypotension and who have contraind. to thrombolysis, failed lysis, or has shock likely to cause death before systemic lysis can take effect (within hours), if appropriate resources available, suggest catheter assisted thrombus removal over no such intervention…(Grade 2C)” Chest. 2012; 141(Suppl 2): 24S

Timing of Recurrent PE

Risk of PE with Proximal DVTs

IVC Filters Reduce Recurrent PE Decousus H et al. N Engl J Med 1998;338:409-416

Impact of IVC Filter on Mortality AJM. 2012; 125:478-484

IVC Filter on PE Mortality

Caution: Long Term IVC Filters Increase DVT Circ. 2005;112: 416-422

IVC Filter Summary IVC Filters: Reduce recurrent PE’s Most of which occur within first 30 days Reduce mortality in massive PE’s Certain submassive PE’s have higher 30 day mortality High Troponin with RV dysfunction on ECHO/CT and lower extremity DVT Pts with submassive PE and poor cardiopulmonary reserve may not be able to tolerate an additional PE insult and thus may benefit from reduced incidence of recurrent PE gained from temporary filter placement Long term IVC filter placement increases incidence of DVT and attempts should be had to remove* *Circ. 2005;112: 416-422

AHA 2011 Recommendations IVC Filter Placement: “Placement of an IVC filter may be considered for patients with acute PE and very poor cardiopulmonary reserve, including those with massive PE...(Class IIB Level C)” “An IVC filter should not be used routinely as an adjuvant to anticoagulation and systemic fibrinolysis in the treatment of acute PE…Class III Level C)” Circulation 2011; 123: 1788-1830

Conclusions Submassive PE’s have varying degrees of mortality RV dysfunction on echo/CT and the presence of a DVT are a “high risk” groups within the submassive category Severity Indices Scores help predict the patient with poor cardiopulmonary reserve that may benefit from additional therapy beyond anticoagulation

Conclusions To date, thrombolysis of any kind has yet to prove mortality benefit in submassive PE Half dose tPA and ultrasound accelerated thrombolysis appear to have less bleeding risks with improvement in hemodynamic parameters Ultrasound accelerated thrombolysis/EKOS uses less lytic, may reduce mortality, and thus may have a role in the “high risk” submassive PE’s

Conclusions While we focused strictly on a early mortality benefit; data show that an RASP on echo >50 mmHg on presentation and after 12 weeks of anticoagulation is a predictor for CTEPH*. Improvements in hemodynamic parameters may alter the prevalence of CTEPH *Circ. 1999;99:1325-1330