1. Massive and Submassive PE Is intravenous therapy sufficient or is intervention indicated?
Piotr Sobieszczyk M.D.
Cardiovascular Division
Vascular Medicine Section
Cardiac Catheterization Laboratory

2. No Financial Disclosures
This concept emphasizes the importance of intra-thrombus drug delivery

3. Choice of therapy depends on severity of PE, patient substrate
Pulmonary Embolism Wide spectrum of clinical manifestations and risk
Choice of therapy depends on severity of PE, patient substrate
and local expertise
Low Clinical Risk
Intermediate Clinical Risk
High Clinical Risk
Subsegmental,
hemodynamically
tolerated PE.
Favorable prognosis
with AC alone
4.5% of PE are “massive”:
RV failure
hemodynamic instability
SBP<90 mmHg,
↓ BP by 40 mmHg>15 min
Syncope, cardiac arrest.
90-day mortality of 50%%.
30-50% are sub-massive PE
RV strain w/o hemodynamic
compromise.
Increased mortality,
?10% progress
to massive PE
? Long term functional status

4. Massive and Submassive PE:
Treatment Strategies
Basic therapies
Intravenous anticoagulation
Supportive care, supplemental oxygen
Advanced Therapies
Intravenous thrombolysis: tPA, TNK
Invasive therapies
Surgical embolectomy
Catheter-based embolectomy and thrombolysis
Intravenous thrombolysis does nt preclude subsequent catheter based intervention or even surgery

5. Massive PE: Thrombolytic Therapy
Reversal of RV failure, restoration of hemodynamic stability and oxygenation
Despite paucity of data, systemic thrombolysis is the accepted standard of care
50% of these patients have contraindication to thrombolysis
Hemorrhagic complications
Delayed onset of action, prolonged infusion
Immediate triage is important

6. In vitro model of obstruction in the right main PA.
Intravenous Thrombolytic Delivery
In vitro model of obstruction in the right main PA.
High-speed photo of systemically injected glass beads demonstrates how a vortex forms proximal to the obstruction and alters systemic drug delivery away from target embolus.
This concept emphasizes the importance of intra-thrombus drug delivery

7. Massive PE: Surgical Embolectomy
Surgical embolectomy proposed by Trandelenburg 1908
First performed by Kirschner 1924 and soon abandoned
Revisited in 1960s and associated with 30% mortality
Technical advances lead to renewed interest, systemic reviews over last years still describe 20% mortality
Limited to centers with expertise and ability to rapidly mobilize the resources
Complete or near complete thrombus removal and reduction in RV afterload
This concept emphasizes the importance of intra-thrombus drug delivery

8. Less invasive, rapidly available
Endovascular Therapy
Less invasive, rapidly available
Lack of devices designed to deal with large volume of organized thrombus
Adaptation of techniques designed for acute thrombus in small vessels
Incomplete relief of obstruction – maybe enough to reverse RV failure in massive PE
This concept emphasizes the importance of intra-thrombus drug delivery

9. Catheter-based PE Therapies
This concept emphasizes the importance of intra-thrombus drug delivery

10. Endovascular Therapy:
Pooled clinical success rate: 86.5% (p=0.004)
Clinical success much higher with local lytic delivery during procedure and higher still with extended delivery
Minor complication rate was 8%
Major complication rate was 2.4%
This retrospective analysis of published reports established catheter based therapy as a reasonable options for patients with massive PE
Kuo WT, JVIR 2009;20:1431

11. Submassive PE: More of a dilemma….
Many of these patients do well with anticoagulation and supportive care
Some do not…..
Chronic PHT rare, RV remodels…..
Escalation of therapy may be harmful in many
Systemic thrombolysis not shown to be effective
But want is the long-term fate of the RV??
This concept emphasizes the importance of intra-thrombus drug delivery

12. Natural History of RV Dysfunction After PE:
Persistent RV dysfunction
Is there a clinical correlate of this?
Tricuspid Annular Motion
Systolic Velocity Gradient within RV
Chung T, J Am Soc Echocardiography 2007:20:885

13. RV Function and Functional Status 6 Months After Submassive PE
200 pts treated initially with UFH,
21 received IV tPA due to worsening cardiopulmonary status

14. RV Function and Functional Status 6 Months After Submassive PE
Higher proportion of patients in the heparin group suffered some degree of functional decrement

15. Long-term Effects of PE Thrombolysis
23 Patients Randomized to UFH vs. systemic thrombolysis: 7 year follow up.
Sharma GVRK, Vascular Medicine 2000;5:91

16. Long-term Effects of PE Thrombolysis
23 patients randomized to UFH vs. systemic thrombolysis: 7 year follow up
This concept emphasizes the importance of intra-thrombus drug delivery
Sharma GVRK, Vascular Medicine 2000;5:91

17. IV Thrombolytic Therapy for Submassive PE Meta-Analysis
Recurrent PE or death
Lysis 6.7% vs UFH 9.6%
p=NS

18. Systemic thrombolysis in submassive PE: ongoing randomized trials
PEITHO: Pulmonary Embolism Thrombolysis Study (tenectaplase):
1000 pts in Europe with RV dysfunction on echo and elevated troponin
Primary outcome: development of circulatory shock or respiratory failure
TOPCOAT: Tenectaplase or Placebo: Cardiopulmonary Outcomes at Three Months
200 patients in US with RV HK on echo, elevated troponin, elevated BNP or RA sat<95%
Primary outcome: RV dysfunction and NYHA association worse than II and 6 minute walk <330m
Peitho completed enrollment this August

19. Ultrasound-accelerated, Catheter-directed Thrombolysis
RV/LV ratio before and after the procedure
CTA 38±14 hrs after intervention
Mean RV/LV
1.33±0.24
1.00± 0.13
P<0.001
Less bleeding compared to traditional CDT
Engelhardt TC et al, Thrombosis Research 2011:128:149

20. Submassive PE BWH Experience
US-Accelerated Catheter-Directed Thrombolysis
Our experience includes obver 30 patients with submasive PE who were offered US accelerated CDT. The last 18 patients were analyzed so far.
BWH Experience

21. SEATTLE Trial
Hypothesis: Treatment of selected pulmonary embolism (PE) patients with intra-clot delivery of ultrasound-accelerated, low-dose thrombolysis will significantly improve their right heart function at 48 hours compared to anticoagulant-treated historical controls
Safety objectives: Major bleeding within 72 hours, periprocedural complications, death and recurrent PE at 30 d
Study population: 100 pts with acute, symptomatic PE and RV/LV end-diastolic ratio >0.9 on CT
Treatment: EKOS catheter delivered tPA 1mg/hr per lung for 12 hrs. if bilateral PE or 1mg/hr for 24 hrs if unilateral PE
Primary Efficacy Outcome: Change in RV/LV ratio from baseline to 48hrs.
Secondary Efficacy Outcome: Change in PA pressure from baseline to end of tPA infusion. PA pressure on echo 48 hrs. after start of procedure.

22. Rapid triage similar to acute coronary syndrome care
Massive PE: choice of therapy
Rapid triage similar to acute coronary syndrome care
Hemodynamic support
Inotropes
Percutaneous RVAD
ECMO
Rapid reduction of thrombotic burden: strategy based on local expertise
IV thrombolysis – transfer to “PE center”
Catheter-based intervention
Surgical embolectomy

23. Submassive PE: choice of therapy
Anticoagulation, supportive care
Systemic thrombolysis not beneficial at present
Surgical embolectomy: an “overkill”
Catheter-based thrombolysis in “PE center”
More rapid clinical improvement
Potential for shorter hospitalization
Possible long term functional benefit in selected patients.
More data is desperately needed