1. 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

2. 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

3. Venous Thromboembolism
Overview
Estimated 300, ,000 affected yearly in USA
60, ,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:

4. 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:

5. 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:

6. Chest 2002; 121: 878

7. Chest 2002; 121: 878

8. Mortality Associated with Pulmonary Emboli

9. 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

10. 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:

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

12. Thrombolysis is Not Without Risk
Lancet 1999; 353:
(ICOPER)

13. Thrombolysis is Not Without Risk
Lancet 1999; 353:
(ICOPER)

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

15. Chest 2002; 121: 878

16. 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

17. 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:

18. 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:

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

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

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

22. 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

23. PESI INDEX AJRCCM 2005;172:

24. 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: /**Thromb Res. 2010;125:e82-86

25. 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)

26. 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)

27. 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)

28. 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%

29. 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

30. 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”

31. 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”

32. “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:

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

34. 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:

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

36. EKOS® DRUG DELIVERY CATHETER
ULTRASOUND
TRANSDUCERS

38. 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.

39. 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

40. 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…….

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

42. 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

43. Trial Summary

44. 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

45. 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

46. Timing of Recurrent PE

47. Risk of PE with Proximal DVTs

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

49. Impact of IVC Filter on Mortality
AJM. 2012; 125:

50. IVC Filter on PE Mortality

51. Caution: Long Term IVC Filters Increase DVT
Circ. 2005;112:

52. 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:

53. 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:

54. 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

55. 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

56. 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: