1. Outpatient treatment of pulmonary embolism
Sam Schulman, MD, PhD
Dept. of Medicine
McMaster University

2. Faculty/Presenter Disclosure
Faculty: Dr. Sam Schulman
Program: 51st Annual Scientific Assembly
Relationships with commercial interests:
Grants/Research Support: N/A
Speakers Bureau/Honoraria: Boehringer Ingelheim and Bayer Healthcare for work in study-related committees
Consulting Fees: N/A
Other: N/A

3. Disclosure of Commercial Support
This program has received financial support from Boehringer Ingelheim and Bayer Healthcare in the form of Honorarium.
This program has received in-kind support from N/A
Potential for conflict(s) of interest:
Dr. Sam Schulman has received Honorarium from Bayer Healthcare whose product is being discussed in this program.
Bayer Healthcare sells a product that will be discussed in this program: rivaroxaban.

4. Mitigating Potential Bias
All treatment alternatives are discussed

5. Contents Case discussion Epidemiological data
Who is at the highest risk
Extended prophylaxis – when?
Diagnosis – mainly risk stratification
Treatment – a lot easier now
How long after VTE – a dilemma

6. PE-case 37-year old female
Cough and some SOB since 4 weeks, went to ER 3 weeks ago, got antibiotics.
Slowly getting worse, more since 2 days
Started oral contraceptives 3 months ago but has been on it for 10 years in the past.
Returns now to ER, HR 95, BP 95/60, RR 20, SaO2 88% on room air, legs normal

8. Patient wants to go home
Has small children to take care of.
After some efforts convinced to stay. HR increases to 110/min.
Gets t-PA (alteplase) 100 mg over 2 h, rapid improvement of symptoms

10. Epidemiology

11. Data on incidence of VTE
Worcester, MA – all medical records 1999 with VTE diagnosis: 104 per 100,0001
Olmsted County, MN – medical records of all residents with VTE , incl PE on autopsy: 117 per 100,0002
Sweden – Men born 1913, followed from age 50: 387 per 100,0003
Bretagne, France – Diagnosis data: 184/100,0004
Spencer FA. J Gen Intern Med 2006
Silverstein MD. Arch Intern Med 1998
Hansson PO. Arch Intern Med 1997
Oger E and EPI-GETBO. Thromb Haemost 2000

12. Effect of age White, R. H. Circulation 2003;107:I-4-I-8
Annual incidence of VTE among residents of Worcester MA 1986, by age and sex
White, R. H. Circulation 2003;107:I-4-I-8
Copyright ©2003 American Heart Association 12 12

13. And then mainly more PE
PE – pulmonary embolism; DVT – deep vein thrombosis

14. Who is at the highest risk?
3 points each
Cancer
Prior VTE
Hypercoagulability
2 points
Major surgery
1 point each
Age >70
Obesity (BMI >29)
Bed rest
HRT or COC
Increased risk >4 points at any time point after admission
Kucher, N. et al. N Engl J Med 2005;352:

15. Major hemorrhage (30 d) 1.5% in both groups
Kaplan-Meier Estimates of the Absence of Deep-Vein Thrombosis or Pulmonary Embolism in the Intervention Group and the Control Group
8.2%  4.9%
P<0.001
Figure 1. Kaplan-Meier Estimates of the Absence of Deep-Vein Thrombosis or Pulmonary Embolism in the Intervention Group and the Control Group. P
Major hemorrhage (30 d) 1.5% in both groups
Kucher, N. et al. N Engl J Med 2005;352: 15

16. Extended prophylaxis – for whom?

17. Extended prophylaxis after THR Symptomatic VTE
Venographic DVT: 9.6 vs 19.6%; OR 0.48
Eikelboom JW, et al. Lancet 2001;358:9–15

18. Extended prophylaxis in THR
% VTE %
P=0.001
Hull et al. Ann Intern Med 2001;135:858
Prandoni et al. Arch Intern Med 2002;162:1966
Samama CM et al Arch Intern Med 2002;162:2191

19. Extension with rivaroxaban THR
Eriksson et al., N Engl J Med 2008; 358:2765–75

20. RECORD1 (THR): summary RRR 70% Rivaroxaban 10 mg od4
3.7%
Enoxaparin 40 mg od
Rivaroxaban 10 mg od 3
RRR 88%
2.0%
Incidence (%) 2
1.1% 1
0.5%
0.3%
0.3%
0.2%
0.1%
Total VTE
Major VTE
Symptomatic VTE
Major bleeding
p<0.001
p<0.001
p=0.22
p=0.18
Eriksson et al., N Engl J Med 2008;358:2765–2775

21. Extension with dabigatran THR RE-NOVATE II
Dabigatran 150/220 qd
Enoxaparin 40 mg qd
Total VTE
7.7%
8.8%
Major VTE or fatal PE
2.2%
4.2%
Major bleeding
1.4%
0.9%
Clin rel non-major bleed
2.3%
2.0%
P=0.03
Eriksson B et al. Thromb Haemost 2011;105:721-9

22. Extension with apixaban THR ADVANCE 3
Apixaban 2.5 mg bid
Enoxaparin 40 mg qd
Total VTE
1.4%
3.9%
Major VTE
0.5%
1.1%
Major bleeding
0.8%
0.7%
Clin rel non-major bleed
4.1%
4.5%
P<0.001
P=0.01
Lassen MR et al. N Engl J Med 2010; 363:

23. Extended therapy so much easier now
Oral medication
No monitoring
Once daily (rivaroxaban or dabigatran) or twice daily (apixaban)
LU-code to cover patients age 65 after orthopedic surgery

24. Other high-risk groups
Spinal cord injuries – 3 months
Abdominal/pelvic cancer surgery – 1 month
BUT
So far not in medically ill patients
3 large trials failed to demonstrate positive benefit/risk ratio

25. Diagnosis

26. Symptoms Most common symptoms Differential diagnosis
Pleuritic pain (65%)
Dyspnea (20%)
Syncope (10%)
(Hemoptysis is rare)
Differential diagnosis
Respiratory tract infection
Myocardial infarction
Pericarditis
Musculoskelettal conditions

27. Suspected PE Our case Wells’ clinical prediction score for PE
Previous PE or DVT +1.5
Heart rate > 100/min +1.5
Recent surgery or immobilization +1.5
Clinical signs of DVT +3
Alternative diagnosis less likely than PE +3
Hemoptysis +1
Cancer +1
Dichotomized rule
Unlikely < 4
Likely > 4
Wells PS et al. Thromb Haemost. 2000;83:416-20

28. D-dimer D-dimer: Not useful
In generally ill patients
Shortly after surgery
Differential vs cellulitis
Very elderly (>80)
Long duration of symptoms
A neg D-dimer in an outpatient with low pretest probability has a NPV of 99% for VTE in next 3 months

30. CT or VQ-scan? CT easier interpretation – but overdiagnosis?
Radiation >VQ – avoid in fertile women
Requires contrast injection – not in renal failure
VQ – less available
Actually 3 exams

31. Echocardiogram Transthoracic ECHO
In hemodynamically unstable patient for assessment of PA-pressure
RV-strain with dilatation and hypokinesia
Paradoxal septal movement
Occasionally clots are seen in RA, RV or right PA

32. Can my PE-patient in ER go home?
Pulmonary Embolism Severity Index (PESI)
Age 1 p / yr SBP < p
Male sex 10 p Pulse > p
Cancer 30 p RR>30 20 p
CHF 10 p Temp <36 20 p
Chron lung dis. 10 p SaO2 <90% 20 p
 mental status 60 p
Our case
Age 37
SBP 95
SaO2 88%
=87 p
85 p or less = low risk of fatal PE – NPV = 99%
Aujesky D et al. Am J Resp Crit Care Med 2005;172:1041–6 External validation in: J Intern Med 2007;261:

33. Simplified PESI Retrospective analysis of RIETE registry
Age >80 1 p
History of Cancer 1 p
Chron cardiopulmonary dis. 1 p
Pulse > p
CHF 1 p
SBP < p
SaO2 <90% 1 p
0 = low risk, 1 or more = high risk
Jiménez D et al. Arch Intern Med. 2010;170:1383-9

34. Simplified PESI result
Jiménez D et al. Arch Intern Med. 2010;170:1383-9

35. Other risk stratification - Hestia
Hemodynamically unstable (SBP <100, HR >100, ICU)
Thrombolysis/embolectomy required
High risk for bleeding (recent GI-bleed, CVA, Sx; Plt <75, SBP >180)
O2 to maintain SaO2 >90% >24h
Pulmonary embolism on anticoag Rx
IV pain medication >24 h
Medical or social reason for hospitalization >24 h
CrCl <30 mL/min (CG formula)
Severe liver impairment
Pregnancy
History of HIT
Any YES response = admit to hospital
Zondag W et al. Thromb Haemost 2013;109:47-52

36. Comparison sPESI vs Hestia
Both decision rules identified >50% of patients as ”low risk”
Negative predictive value for 30-day mortality
Hestia 99%
sPESI 100%

37. ESC criteria for outpatient Rx of PE
Low risk: Hemodynamically stable + no RV dysfunction (RV/LV 1.0)
Intermediate risk: Asymptomatic RV dysfunction
High risk: Cardiovascular shock/ SBP <100/assessed as hemodynamically unstable by physician
Comparison Hestia vs. ESC: NPV 100% vs 99%
Some Hestia-low risk had RV dysfunction
Zondag W et al. J Thromb Haemost 2013;11:686-92

38. Summary Diagnostic Rules
PESI/sPESI most validated – 7 items
HESTIA more complex – 11 items
ESC is minimalistic, although requires asessment of RV dysfunction, perhaps more dependent on how the physician assesses

39. Laboratory test in risk-strat?
N-terminal pro-Brain Natriuretic Peptide or NT-proBNP is associated with myocardial damage and prognosis after PE.
152 of 351 patients with PE were hemodynamically stable and NT-proBNP <500 pg/mL  outpatient management
No death, PE or major bleed in 3 months; 7 patients readmitted during 1st week but no new PE.
Agterof MJ et al. J Thromb Haemost 2010;8:

40. RCT on outpatient Rx of PE
Open label, non-inferiority trial
19 ER-sites in Switzerland, France, Belgium and US
PESI score 85 (= low risk; class I or II) were eligible.
Randomized (within mean 13 h) to outpatient or 5 days in hospital.
Enoxaparin  VKA for 90 days
Aujesky D et al. Lancet 2011;378:41-8

41. Results outpatient PE Rx RCT 90 days
Treatment
Outpatient
Inpatient
Randomized/ analyzed
172/ 171
172/ 168
Days on LMWH
11.5
8.9
VKA managed by GP
73%
75%
Recurrent VTE
1 (0.6%)
Major bleeding
3 (1.8%)
Death (no PE)
Another RCT stopped prematurely due to high mortality in both arms
Otero R, Uresandi F, Jimenez D, et al. Home treatment in pulmonary embolism. Thromb Res 2010; 126: e1–5.
Aujesky D et al. Lancet 2011;378:41-8

42. 2 Canadian management studies
Retrospective, single centre studies, treatment out of hospital, 3-month F-U.
A. 314 (49%) patients (London, ON)
B. 260 (55%) patients (Ottawa, ON)
Results
Cohort A
Cohort B
Thrombotic event
3 (0.95%)
10 (3.8%)
Major bleed
4 (1.5%)
Deaths*
9 (2.9%)
13 (5%)
*Almost all due to cancer
Kovacs MJ et al. J Thromb Haemost 2010; 8:
Erkens PMG et al. J Thromb Haemost 2010; 8:2412-7

43. Start treatment on suspicion
In patients with a high clinical suspicion
of acute PE, we suggest treatment with parenteral
anticoagulants compared with no treatment
while awaiting the results of diagnostic
tests (Grade 2C) .

44. No studies address this
Most patients have relatively low risk of bleeding – 1 dose of anticoagulants is unlikely to harm
The higher the suspicion, the more justified to give a dose.
For untreated PE a progression is potentially worse than for untreated DVT

45. Rivaroxaban – a new option Einstein PE
Major or clinically relevant bleeding in 10.3% (riva) vs % (standard Rx)
Büller HR et al. NEJM 2012

46. Rivaroxaban - Important to know
Starting dose 15 mg BID
Switch after 3 weeks to 20 mg daily
Must be taken with food
Tablets contain lactose (some get stomach pain)
Severe renal failure (CrCl <30 mL/min) or concomitant ketokonazole or other azoles, rifampicin and ritonavir are contraindications
Few of the study patients hade extensive DVT or large PE. These patients might benefit from intial parenteral Rx.

47. Acute treatment algorithm
Hemodynamic
Instability
(shock)
Large PE
But stable
Submassive PE
Rivaroxaban 15 mg bid  20 mg q.d.
t-PA
Heparin IV  LMWH
Vitamin K antagonist
LMWH therap dose 
cancer

48. Treat subsegmental PE?
SR with 22 articles on CTPA reporting subsegmental PE (ssPE).
Single detector Multi-detector CTPA
Incidence:
4.7% 9.4%
Suspected PE left untreated* - TE at 3 m
0.9% 1.1%
*based on diagnostic algorithm and neg CTPA
Carrier M et al. J Thromb Haemost 2010; 8: 1716–22

49. Duration of anticoagulation ???

50. A meta-analysis on individual data N=2474
PE as a risk factor
A meta-analysis on individual data N=2474
Pinede et al. ASH 2003

51. Recommended duration of Rx
6.2. In patients with PE provoked by a nonsurgical
transient risk factor, we recommend treatment
with anticoagulation for 3 months over
(i) treatment of a shorter period (Grade 1B) ,
(ii) treatment of a longer time-limited period
(eg, 6 or 12 months) (Grade 1B) , and (iii) extended
therapy if there is a high bleeding risk (Grade 1B) .
We suggest treatment with anticoagulation for
3 months over extended therapy if there is a
low or moderate bleeding risk (Grade 2B) .

52. Typical practice More respect for a PE than DVT.
Particularly if massive PE
Most will anticoagulate for 6 months
Some for 12 months

53. Management strategy – unprovoked VTE
D-dimer Dx
m m
+3 m
Neg Neg Pos 27%/yr
Neg Neg Neg 2.9%/yr
Pos
Neg Pos 8.9%/yr
Neg Neg 3.5%/yr
Verhovsek M. Ann Intern Med. 2008;149: Cosmi B, et al. Blood. 2010;115:

54. Why did I get the PE? (I was on COC for 10 years before)
Thrombosis
Threshold
With factor V Leiden or prothrombin mutation
+COC
+COC
Risk of VTE
Healthy person
Age

55. Conclusions PE occurs in about 1/3 of VTE patients
Proportionally more in elderly
High risk in cancer, prior PE, certain surgeries
Diagnosis – usually with CT
Fertile female or severe renal failure  VQ-scan
Treat on suspicion
Rivaroxaban p.o. A new option