1. When Should I Utilize Aggressive Therapy for PE?
Ido Weinberg, MD MSc
Assistant Professor of Medicine
Harvard Medical School
Vascular Medicine
Massachusetts General Hospital

2. Disclosures
I have no relevant disclosures for this talk

3. Zsa Zsa Gabor Suffered a ‘Massive’ Clot that ‘Could Move to Her Heart’
February, 2013

4. Jerome Kersey of the Portland Trailblazers Recently Died of a Post-Op PE
February, 2015

5. A 49 Year Old Woman with Chest Pain
PMHx: None
HR – BP – 110/60, 110 bpm, RR – 18
Troponin T – 0.4 (Positive)
BNP – 1511 (Positive)
Echocardiogram – RV dilatation and dysfunction

6. A 49 Year Old Woman with Chest Pain

7. What Now? Anticoagulation Alone or Add a Lytic Agent?

8. Pulmonary Embolism is not a Homogeneous Disease
MASSIVE
Shock / Hypotension
SUBMASSIVE
Normotensive + RV Strain
LOW RISK
None of the above

9. PE Therapeutic Options: All Over the Map
Anticoagulation
IV Thrombolysis
IVC Filter
Catheter Directed
Thrombolysis
Surgical
Embolectomy
Pharmaco-Mechanical
Catheter Treatment
ECMO

10. Most Patients with PE do Well
The classification relies on outcome
However, outcome also relies heavily on patient characteristics
Mortality for patients with PE and shock exceeds 30% despite treatment
Becattini C, Agnelli G. Predictors of mortality from pulmonary embolism and their influence on clinical management. Thromb Haemost. 2008; 100(5): 747–751
Abrahams van-Doorn P. and Hartmann IJC. Imaging Insights. 2011; 2:
Dalen JE. Chest. 2002; 122:

11. Identifying Patients who don’t do Well is Limited
Clot burden is not a prognostic marker
Members ATF et. al. Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2008; 29(18) :2276–2315

12. Thrombolysis in PE: Multiple Positive Physiological Effects
Improved early clot resolution
Reduced pulmonary arterial pressure
Improved lung perfusion
Improved early angiographic flow
PIOPED Investigators. Chest. 1990; 97:
Levine M. et al. Chest. 1990; 98(6):
Dalla-Volta S. et al. JACC (3): 520-6
Goldhaber SZ. et al. Lancet. 1993; 341(8844):
Jaff MR. et al. Circulation. 2011; 123:
Daniels LB. AJC. 1997; 80: 184-8

13. There is One Obvious Downside…

14. The Higher the PE-Related Risk, the Easier to Administer Lytics

15. Thrombolysis Performed Better Than Anticoagulation for Massive PE
The only randomized study for massive PE
This is an old study that randomized only 8 patients to STK or Heparin
4 patients died – all in the heparin group. P=0.02
Follow-up at 2 years revealed the 4 thrombolysis patients to be alive and without PHTN
Jerjez-Sanchez C. et al. J Thromb Thrombolysis. 1995; 2(3): 227-8

16. Thrombolysis for Unstable Patients Results in Improved Outcome
Data from the Nationwide Inpatient Sample between which represent 20% of all hospitalizations in the US
30% of patients received thrombolysis
Case fatality rate attributable to pulmonary embolism in unstable patients was 820 of 9810 (8.4%) with thrombolytic therapy versus 1080
of 2600 (42%) with no thrombolytic therapy (P<0.0001)
Stein PD. and Matta F. AJM. 2012; 125:

17. Thrombolysis for Unstable Patients Results in Improved PE-related Outcomes
Only 16% of unstable patients with PE died during the first day, allowing time for thrombolysis administration
Stein PD. and Matta F. AJM. 2012; 125:

18. Submassive PE Patients Represent Lower PE-Related Risk

19. Right Ventricular Dysfunction is Common after Sub-Massive PE
This diagram represents RV pressure at the time of diagnosis and after 6 months in patients who were treated with heparin.
The RV size and function was normal in most of these patients
Kline JA. et al. Chest :

20. rtPA in Patients with Sub-Massive PE Resulted in Reduced RVSP
As total mortality in low-risk PE is less than the complication rate with rtPA, there is no logic in this treatment in this population
Why would you use thrombolysis on a submassive PE? Improving mortality is difficult. But preventing RV strain and PHT and CTEPH is a concern.
Altogether, there is little information to support this.
These are the RVSP results of 21 patients with sub-massive PE who received rtPA. However, the rtPA was given to those patients who developed hypotension or respiratory failure. At 6 months the RSVP decreased
There was no difference between groups (rtPA/heparin) in the 6 minute walk distance.
46% of the patients of the heparin treatment who also had an increase in RVSP had dyspnea at rest or exercise intolerance (i.e. about 25% of all patients treated with heparin), compared to 28% in the rtPA group.
No patient in either group had a serious bleed
Kline JA. et al. Chest :
Konstantinides S. NEJM. 2008; 359(26):

21. Less treatment escalation with lysis
Prospective, randomized, double-blind, placebo-controlled trial of tPA+heparin (n=118) vs. placebo+heparin (n=138) for sub-massive PE
The definition for sub-massive PE in this study was somewhat broad and included also ECG markers and not only very objective echo or CT markers
No biomarker data
Unstable patients and patients with increased bleeding risk were excluded
Outcomes were measured at discharge or at 30 days of treatment, whichever came first
The mortality rate was low in both treatment groups
There was no mortality benefit. There was a benefit in the “less escalation of treatment” measure
Recurrent PE was low in both groups. Bleeding was also not different between groups.
Konstantinides S. et al . NEJM. 2002; 347:

22. PEITHO: Reduced combined endpoint with thrombolysis for some
N Engl J Med 2014;370:

23. PEITHO: Advantage driven by reduced hemodynamic collapse
No mortality advantage
Less treatment escalation
N Engl J Med 2014;370:

24. More bleeding with thrombolysis
N Engl J Med 2014;370:

25. PEITHO: Older Patient = No Benefit for Lysis
N Engl J Med 2014;370:

26. TOPCOAT: Systemic Lysis for Sub-massive PE
Underpowered
Terminated at 86 patients
J Thromb Haemost. 2014 Apr;12(4):459-68

27. TOPCOAT: Shorter ICU Stay with Lytics
Courtesy of Jeffrey A. Kline, MD

28. TOPCOAT: Quicker Discharge with Lytics
Courtesy of Jeffrey A. Kline, MD

29. TOPCOAT: More Bleeding with Lytics
Courtesy of Jeffrey A. Kline, MD

30. TOPCOAT: Benefit for Lytics with Combined Outcomes
Courtesy of Jeffrey A. Kline, MD

31. Contraindications to Lysis are Common
MAPPET registry - In a registry of 1001 patients with massive or sub-massive PE in 204 participating centers
Kasper W. et al. JACC. 1997; 30(5):

32. Local thrombolysis for sub-massive PE

33. Would you invest in something that promises 10% profit within 30 days?

34. ULTIMA Randomized, Controlled Trial
Ultrasound-Assisted Catheter-Directed Thrombolysis
Acute Intermediate-Risk PE

35. ULTIMA: Design Randomized, Controlled
Ultrasound-Assisted Catheter-Directed Thrombolysis
Acute Intermediate-Risk PE
Circulation. 2014 Jan 28;129(4):479-86

36. ULTIMA: Patients had Intermediate-Risk PE
No BNP data
Circulation. 2014 Jan 28;129(4):479-86

37. ULTIMA: Outcome Definitions
The primary end point of ULTIMA was the difference in the RV/LV ratio from baseline to 24 hours
Safety outcomes included death, hemodynamic decompensation as defined in the exclusion criteria, major and minor bleeding, recurrent venous thromboembolism (VTE), and serious adverse events up to 90 days after randomization
Circulation. 2014 Jan 28;129(4):479-86

38. ULTIMA: Outcomes – Cont’d
Major bleeding - Overt bleeding associated with a fall in the hemoglobin level of at least 2.0 g/dL or with transfusion of ≥2 U of red blood cells or involvement of a critical site (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome)
Minor bleeding - Clinically overt bleeding not fulfilling the criteria of major bleeding
Circulation. 2014 Jan 28;129(4):479-86

39. Quicker Resolution of RV Dysfunction: Indirect Evidence of Efficacy
Circulation Jan 28;129(4):479-86

40. ULTIMA: Complications
No major bleeding
4 minor bleeding:
3 patients in the USAT group (10%): Transient hemoptysis, access site groin hematoma
1 patient in the heparin group (3%): Muscular hematoma
Circulation. 2014 Jan 28;129(4):479-86

41. SEATTLE II A prospective, single-arm, multicenter trial to:
Evaluate the efficacy of ultrasound-facilitated, catheter-directed low- dose fibrinolysis to reverse RV dysfunction as measured by CT- determined RV/LV diameter ratio in patients with acute massive and submassive PE
Assess the safety of ultrasound-facilitated, catheter-directed low-dose fibrinolysis in patients with acute massive and submassive PE

42. Total Trial Population = 150
Study Overview
CT-confirmed PE
Symptoms ≤ 14 days
Massive or submassive
Meets all inclusion and no exclusion criteria
RV enlargement as documented by initial CT
RV:LV ratio ≥ 0.9
Ultrasound-facilitated fibrinolysis
t-PA 1 mg/hr for 24 hours (1 device)
t-PA 1 mg/hr for 12 hours (2 devices)
TOTAL t-PA Dose = 24 mg
Follow-up at 48 ±6 hours after start of the procedure
CT measurement of RV:LV ratio
Echocardiogram to estimate PA systolic pressure
Study Sites = 21
Total Trial Population = 150

43. Outcomes: RV/LV Ratio Improvement
1.55
RV/LV Ratio
1.13
Used Core/In-Window
3/5/14- clean

44. Outcomes: PA Systolic Pressure Improvement
51.4
Mean PA Systolic Pressure (mmHg)
37.5
36.9
3/5/14- clean

45. Clinical Outcomes Clinical outcomes* N = 150
Mean length of stay ± SD, days
8.8 ± 5
In-hospital death, n (%)
3 (2)
30-day mortality**, n (%)
4 (2.7)
Serious adverse events due to device, n (%)
2 (1.3)
Serious adverse events due to t-PA, n (%)
IVC filter placed, n (%)
24 (16)
Major bleeding within 30 days**, n (%)
GUSTO moderate**
GUSTO severe**
17 (11.4)
16 (10.7)
1 (0.7)
Intracranial hemorrhage, n (%)
0 (0)
3/5/14- clean
1 recurrent PE
*All death, serious adverse, and bleeding events were adjudicated by an independent safety monitor.
**N = 149 (1 patient lost to follow-up)

46. What is GUSTO bleed? Severe or life-threatening Moderate Mild
Intracerebral hemorrhage
Resulting in substantial hemodynamic compromise requiring treatment
Moderate
Requiring blood transfusion but not resulting in hemodynamic compromise
Mild
Bleeding that does not meet above criteria
Circulation. 2005 Apr 26;111(16):2042-9

47. So, What do you think of those 10% now?

48. There is Likely Less ICH with CDT than IV Lytics
Study
Intracranial Hemorrhage (Fibrinolysis Group)
ICOPER
(Goldhaber SZ, et al. 1999)
9/304 (3%)
PEITHO
(Meyer G, et al. 2014)
10/506 (2%)
SEATTLE II
(Piazza G, et al. 2014)
0/150 (0%)
Study limitations include lack of control arm, lack of clinical outcomes, unclear use of CT size (instead of echo derived and the 1.55 RV/LV ratio seems very high), mixture of echo and CT outcomes

49. Meta-analysis of lysis for PE
JAMA. 2014 Jun 18;311(23):

50. Mortality Benefit for Lytics in Sub-Massive PE
JAMA. 2014 Jun 18;311(23):

51. Absolute risk / benefit analysis: Know the #’s
JAMA. 2014 Jun 18;311(23):

52. PE Treatment Guidelines1 2 3
Jaff MR. et al. Circulation. 2011; 123:

53. ED / ICU / Floor Team Pulmonary Vascular Medicine/Cardiology
Usual PE Care vs. PERT
ED / ICU / Floor Team Pulmonary
Vascular Medicine/Cardiology
Cardiac Surgery

54. PERT Members – Collaborative Approach
Vascular Medicine and Intervention
Pulmonary/ Critical Care
Cardiac Surgery
Cardiac and Thoracic Imaging
Nursing
Quality & Safety
Research
Echocardiography
Cardiology
Hematology/ Oncology
Emergency Medicine

55. Conclusions
Thrombolysis should be administered emergently to patients with massive PE
Patient choice is crucial when considering IV tPA for sub-massive PE
Many patients with PE cannot receive thrombolytic therapy