1. Controversies in the management of Pulmonary Embolism
Joel Frankel, MD, FACP, FCCP
Plantation General Hospital
February 27, 2014

2. Clinical Case
62 y.o. male presents to ED with 48 hours of worsening dyspnea after returning from a 3 day business trip to China
Vitals: BP 110/60, P 102, O2 sat 86% on RA
PE: Distended neck veins, RR w/o murmur, lungs clear, normal LE exam
D Dimer = 2496
CT chest multiple thrombi in PA and dilated right ventricle
Management?

3. Questions Which form of Heparin? Disposition Lovenox (1 mg/kg SC)
Unfractionated Heparin
(80 U/kg bolus; 18 U/kg drip)
Disposition
ICU
Medicine
Home

4. Very Simple Goals Remember atypical cases Know why PE is missed
Make your chart bullet proof

5. Why is the diagnosis delayed or missed?
Not considering the diagnosis
Presentation too atypical
PE looks like many diseases
The obvious miss
Misinterpretation of studies
Reliance on normal VS

6. Elevated troponin Not just in MI !!! Myocarditis, tachycardia
CHF, pericarditis, stroke, sepsis
Pulmonary embolism

7. Who do we miss the diagnosis in?
Obese females on OCP
Patients with medical comorbidities

8. The Pulmonary Embolism Rule-Out Criteria (PERC) rule
Less than 2% chance of PE if clinician pre-test probability < 15% and all of the following:
Age < 50
HR < 100
SpO2 > 96%
No unilateral leg swelling
No hemoptysis
No recent trauma
No h/o VTE/PE
No OCP/exogenous estrogen use

9. PE myths All patients with PE are tachycardic
About 50%
Hypoxia is usually present
Most patients have risk factors
20-25 % with risk factors
Classic presentation common

10. Protective documentation
Thought process
Leg exam, Homan’s sign
Risk factor analysis
Clinical gestalt
Clinical decision rule

11. The chart Any patient with cardiopulmonary symptoms VTE risk factors
Attention to the VS
Leg exam
Evidence that you thought about VTE

12. Epidemiology PE is common PE has high morbidity and mortality
600, ,000 patients annually in US
PE has high morbidity and mortality
Mortality rate 10 – 17.5% overall
Likely responsible for over 50,000 deaths annually
Optimal management can improve these outcomes

13. Questions for Discussion
Which is the optimal form of heparin to be used in the treatment of PE?
Do all patients with a new diagnosis of PE need to be admitted?
When are thrombolytics indicated in the management of PE?

14. Which is the optimal form of heparin to be used in the treatment of PE?
Options for bridging anticoagulation in acute PE
Unfractionated heparin (UFH)
Low-molecular weight heparin (LMWH)
LMWH has multiple potential advantages over UFH
Use of LMWH for most patients is standard of care and recommended by multiple professional societies

15. Evidence Supporting Use
Multiple RCTs have established efficacy and safety between LMWH and UFH for the treatment of PE
3 month recurrence of VTE: 3.0% vs. 4.4 % (NS)
Major bleeding: 1.3% vs. 2.1 % (NS)

16. Other Considerations
LMWH is renally cleared – use with caution with poor renal function
UFH preferred in hemodynamically unstable patients, especially if considering thrombolysis
No clear difference in efficacy or safetey when comparing once a day (1.5 mg/kg) vs. twice a day (1 mg/kg) dosing regimens

17. Do all patients with a new diagnosis of PE need to be admitted?
Current standard of care is outpatient management for DVT
30-40% of patients with DVTs have been found to have asymptomatic PEs
Although DVT and PE have different outcomes, they exist on the same spectrum of disease (VTE)
Likely there is some group of low-risk patients with PE that can be managed similarly to DVT

18. Aujesky et al 2011
Open-label, multi-center, international, non-inferiority, RCT
339 adult patients with confirmed acute PE randomized to inpatient vs. outpatient management
Outpatients treated with 1 mg/kg LMWH BID until INR > 2.0 for > 2 days
Primary end-point was recurrent VTE
Secondary end-points included
Major bleeding
All cause mortality

19. Inclusion/Exclusion Patients excluded if any of the following
Pulmonary Embolus Severity Score of I or II (<86 points)
Patients excluded if any of the following
O2 sat < 90%
SBP < 100 mmHg
Chest pain requiring IV opiates
Active bleeding
Stroke within 10 days
GI bleed within 14 days
< 75,000 platelets
Cr Clearance < 30
Extreme obesity (>150 kg)
History of HIT
Already being treated with oral anticoagulant
Any barriers to follow up
Points Assigned
Age
+1/year
Male
+10
Cancer
+30
Heart Failure
Chronic Lung Disease
Pulse > 100 bpm
+20
SPB < 100 mm Hg
RR > 30 bpm
T < 36 degrees C
Altered Mental Status
+60
Oxygen Sat < 90%

20. Outcomes *P-value represents one-sided p-value for non-inferiority
Outpatient Group (n=171)
Inpatient Group (n=168)
P-Value*
90-day outcomes
Recurrent VTE
1 (0.6%)
0 (0%)
0.011
Major Bleeding
3 (1.8%)
0.086
Mortality
0.005
14-day outcomes
0.003
2 (1.2%)
0.031
*P-value represents one-sided p-value for non-inferiority

21. Erkens et al 2010
Retrospective cohort study of consecutive patients with confirmed acute PE
Decision for outpatient treatment by treating physician based on hospital protocol
SPB > 100 mmHG
O2 sat > 92%
No contraindication to LMWH
Does not need admission for other reasons
Outpatients treated with LMWH
Patient followed-up at 14 days and 90 days

22. Outcomes Outpatient Group (n=260) Inpatient Group (n=213) P-Value*
90-day outcomes
Recurrent VTE
10 (3.8%)
10 (4.7%)
0.654
Major Bleeding
4 (1.5%)
17 (8.0%)
0.001
Readmission Rate
6 (2.3%)
11 (5.2%)
0.135
Mortality*
5 (5%)
57 (26.7%)
<0.001
14-day outcomes
1 (0.4%)
4 (1.9%)
0.180
0 (0%)
13 (6.1%)
1.0
27 (12.7%)

23. Are there other factors that can help risk stratify patients?
Troponin is a predictor of complicated clinical course or death
NPV for death 96-97%
NPV for complicated clinical course 92-94%
Pro-BNP is a predictor of mortality or adverse outcomes
NPV for death 99%
NPV for adverse outcome 95%
RV dysfunction on CT
NPV for PE related death 100%

24. Take Home Message
Outpatient management of PE is not common practice currently, but feasible and safe in selected low-risk patients with acute PE
Standard of care is likely to shift in the near future given pressures to lower resource utilization
It is reasonable to offer outpatient management in the patient with low PE severity index, normal BP, normal O2 sats, normal EKG, normal troponin, normal pro-BNP, and no evidence of RV dysfunction
An informed discussion with the patient and careful documentation are necessary to attempt this approach

25. When are thrombolytics indicated in the management of PE?
Risk of Bleeding with Thrombolysis in PE
Fatal Hemorrhage: 0.5 %
Intracranial Hemorrhage : %
Major Hemorrhage: %
Potential Benefits of Decreasing
Mortality
PE recurrence
Pulmonary Hypertension
In-Hospital Complications

26. Differences in Outcomes
The mortality of patients with PE vary depending on the clinical circumstances
Cardiac Arrest: 66-95%
Massive PE: 22-53%
Submassive PE: 8-13%
Uncomplicated PE: 1-4%
The clinical circumstances should drive decision making with the use of thrombolytics

27. Contraindications to Fibrinolytics
Trauma within 15 days
Uncontrolled HTN (SBP > 180; DBP > 100)
Hemorrhagic disorder or thrombocytopenia (<100,000)
Impaired hepatic or renal function
GI bleeding within 10 days
Pregnancy
Active internal bleeding
Recent intracranial bleeding
Intracranial tumor or seizure history
Ischemic stroke within 2 months
Neurosurgery within the past 1 month
Surgery within the past 10 days
Puncture of non-compressible vessel within past 10 days

28. Cardiac Arrest 10-20% of all PE cases
Dismal outcomes with 66-95% mortality
No RCTs address this clinical scenario
3 major studies show significant increase in ROSC rate and trend toward increased survival in cardiac arrest
Overall bleeding complication rare is low when used in cardiac arrest
Multiple professional societies have supported use of thrombolytics in this clinical situation

29. Bottiger et al 2001
90 patients with out-of-hospital cardiac arrest undergoing CPR without ROSC within 15 minutes
40 patients received 50 mg tPA and 5000 U of heparin as bolus vs. 50 patients with standard ACLS
ROSC: 68% vs. 58% (p=0.026)
Survival to ICU admission: 58% vs. 44% (p=0.009)
24 hr Survival: 35% vs. 22% (p=0.171)
Hospital Discharge: 15% vs. 8% (NS)
No CPR related bleeding complications

30. Lederer et al 2001
324 patients with out-of-hospital cardiac arrest undergoing CPR
108 received 50 mg tPA as bolus vs. 216 with standard ACLS (retrospective)
ROSC: 70.4% vs. 51.0% (p=0.001)
24 hr Survival: 48.1% vs. 32.9% (p=0.003)
Hospital Discharge: 25% vs. 15.3% (p=0.048)
Bleeding complications low
ICH 0.9% vs. 0.9% (NS)
Major Hemorrhage 4.6% vs. 2.3% (NS)

31. Bozeman et al 2006
163 patients in cardiac arrest undergoing CPR not responding to standard ACLS (prospective)
50 received mg tPA bolus vs. 113 controls with standard ACLS
ROSC: 26% vs. 12.4% (p=0.04)
Survival to ICU admission: 12% vs. 0% (p=0.0007)
24 hr Survival: 4% vs. 0% (NS)
Hospital Discharge: 4%vs. 0% (NS)
1 patient with ICH in tPA group (2%)

32. Take Home Message
Although not definitely studied in patients with PE, likely benefit > risk to giving tPA in cardiac arrest with PE is suspected cause
Consider historical factors or bedside ultrasonography to guide decision making
When given, administer 50 mg tPA and 5000 U UFH as IV bolus
May repeat if no ROSC after 15 minutes
If ROSC occurs, start continuous infusion of UFH at 18 U/kg/hr

33. Massive PE 5% of all PE cases Mortality 22-53%
5 RCTs that included hemodynamically unstable patients suggest benefit
Meta-analysis of RCTs showed significant benefit
2 retrospective studies show trend to benefit
Bleeding complications low in selected patients
Multiple professional societies recommend use of thrombolytics in this scenario

34. Wan et al 2004
Meta analysis of 11 RCTs comparing thrombolysis + heparin vs. heparin alone
Subgroup analysis of 5 RCTs that included hemodynamically unstable patients
128 patients received thrombolysis, 126 received heparin alone
Efficacy Outcomes
Mortality: 6.2% vs. 12.7% (NS)
Recurrent PE: 3.9% vs. 7.1% (NS)
Recurrent PE or Death: 9.4% vs. 19% (p<0.05)
Bleeding outcomes: 21.9% vs. 11.9% (p=0.05)

35. Take Home Message
Data regarding benefit not definitive, but benefit:risk ratio likely to support use in hemodynamically unstable patients
Consider use in select patients with CONFIRMED PE and hemodynamic instability keeping in mind patient risk for bleeding complications
When given, infuse 10 mg tPA as bolus followed by 90 mg infusion over 2 hours
Should be followed by 80 U/kg bolus of heparin followed by 18 U/kg/hr infusion

36. Submassive PE 23-40% of all PE cases
Increased mortality when compared to hemodynamically stable patients without RV dysfunction (9.3% vs. 0.4%)
Multiple studies have definitely shown improvement in hemodynamic or radiographic parameters, though improvement in clinical outcomes remains mixed

37. Take Home Message
Treatment of patients with submassive PE with thrombolytics is highly controversial
Current evidence is conflicting and filled with multiple flaws
Use of thrombolytics in this situation does not carry overall support from professional societies and is not standard of care
Use of thrombolytics may be considered in select patients with support from sub-specialists

38. Future Directions
The Pulmonary EmbolIsm THrOmbolysis (PEITHO) trial is a multi-center international RCT (double-blinded, placebo controlled) currently underway
Includes patients with
Confirmed acute PE
RV dysfunction on Echo or CT chest
Elevated Troponin
Treatment Protocol
Thrombolysis Group: tPA + UFH
Control Group: UFH only
Outcomes
Primary: Composite of Death or Hemodynamic Collapse < 7 days
Secondary: Death, Hemodynamic Collapse, Recurrent PE, ICH, Major Bleeding

39. Follow-up on Initial Questions
Which is the optimal form of heparin to be used in the treatment of PE?
LMWH in most cases
Do all patients with a new diagnosis of PE need to be admitted?
There may be a group of very low risk patients that can be managed primarily as outpatients
When are thrombolytics indicated in the management of PE?
Clearly indicated in cardiac arrest from PE and massive PE without contraindication to fibrinolytics
Utility in submassive PE unclear
Not indicated in uncomplicated PE