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Disclosures
Grant/Research Support from:
–  LEO Pharma
–  Bristol-Myers Squibb
Symptomatic & Incidental Sub-Segmental PE
Marc Carrier MD MSc FRCPC
Objectives
•  Review the incidence of sub-segmental pulmonary
embolism (SSPE)
–  Are we overdiagnosing PE?
–  Are SSPE clinical important?
•  Propose a management strategy for patients with SSPE
•  Describe the incidence and management of incidental
SSPE in cancer patients
Ms. MT
•  55 yo woman on HRT, presents to ER with SOB and
pleuritic CP.
•  Likely PTP on Wells model + positive D-dimer
•  CTPA: single subsegmental filling defect in left upper lobe
•  Management options:
1. 
2. 
3. 
4. 
LMWH + warfarin/VKA
DOAC
No anticoagulation + no further investigations
US of lower limbs – No DVT then No anticoagulation
Background
•  Pulmonary embolism (PE) is a common disease and
associated with significant morbidity and mortality.
Statement of the clinical problem and
incidence of SSPE
•  For decades, clinicians have been taught that untreated
PE has a high mortality and high risk of recurrent venous
thromboembolism (VTE).
•  CTPA >>> VQ for diagnosis for PE
–  More available
–  Alternative diagnosis
–  Higher sensitivity for smaller vessels
•  Subsegmental pulmonary embolism (SSPE)
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Increasing use of CTPA leads to rising
rates of SSPE
CTPA for diagnosis of PE
•  ER physician survey
16 x 0.75
mm
10 sec
–  71% CTPA vs. 20% VQ
2-slice CT
•  Increase use of CTPA led to
increase rates of SSPE
diagnosis
1992
64 x 0.625
mm
4 sec
2 x 2.7 mm
25 sec
4-slice CT
–  5.4% (95%CI: 4.1 to 6.7)
1998
4 x 1 mm
25 sec
Weiss CR et al. Acad Radiol. 2006 Apr;13:434-46.
Auer RC, et al. J Am Coll Surg 2009;208(5):871-8.
16-slice CT
2002
64-slice
2004
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Increase incidence of SSPE with multiple
detector CT
Is SSPE a problem?
Carrier M et al, J Thromb Haemost. 2010;8:1716-22.
US Nationwide Inpatient Sample and Multiple Cause –of Death databases
Wiener RS et al. Arch Int Med 2011;171:831-837.
Are we now over-diagnosing PE?
(i.e. SSPE not clinically important)
Clinical importance of SSPE is unclear
•  US Nationwide Inpatient Sample and Multiple Cause –of
Death databases\
–  PE unchanged before CTPA but increased substantially after
CTPA
•  ↑81% - from 62.1 to 112.3 per 100,000 (P < .001)
–  PE mortality decreased
•  ↓3% - from 12.3 to 11.9 per 100,000 (P = .02)
–  Case fatality improved
•  ↓36% - from 12.1% to 7.8% (P < .001)
–  CTPA was associated with an increase in presumed
complications of anticoagulation for PE
•  ↑ 71% - from 3.1 to 5.3 per 100,000 (P < .001).
Wiener RS et al. Arch Int Med 2011;171:831-837.
Wiener RS et al. Arch Int Med 2011;171:831-837.
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Are we now over-diagnosing PE?
(i.e. SSPE not clinically important)
Wiener RS et al. Arch Int Med 2011;171:831-837.
Any other clues from the literature
suggesting overdiagnosis?
Anderson DR. JAMA. 2007;298:2743-53.
How reliable is the diagnosis of SSPE on
CTPA
•  11% of SSPE were deemed false positive when re-read
by an experienced thoracic radiologist
•  Positive predictive value of only 25%
What did we do to make a diagnosis of PE
before CT?
•  Low inter-observer variability
–  K: 0.38; (95%CI: 0.0-0.89)
•  EXPERIENCED thoracic radiologist should review all
SSPE diagnosis
Perrier A et al. Lancet 1999.353;190-5.
Ghanima W et al. Acta Radiol 2007;48:165-70.
PIOPED Study
We feel comfortable with int V/Q.
Why not CTPA?
17 % of patients with a low probability V/Q scan
in PIOPED had a isolated SSPE on
pulmonary angiography
PIOPED. JAMA. 1990;263:2753-59.
3-month risk
0.6% (0.2 to 1.4%)
Kearon C. CMAJ. 2003;168:183-194.
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Do we need to do treat SSPE?
Do we need to treat SSPE?
Carrier M et al, J Thromb Haemost. 2010;8:1716-22.
Any other clues from the literature?
Risk of recurrent VTE and bleeding
•  Cohort of 2213 patients who underwent CTPA
–  550 patients had PE (24.8%)
–  82 patients had SSPE
•  3.9% of total scans and 15.0% of PEs.
–  43 patients (52%) received anticoagulation for SSPE.
•  Major life-threatening bleeding complications occurred 2
patients receiving anticoagulation
–  No documented recurrent VTE in any patients with SSPE, with or
without anticoagulation.
Anderson DR. JAMA. 2007;298:2743-53.
Risk of recurrent VTE and bleeding
• 
• 
• 
• 
Post-hoc analysis from two cohort studies
3728 patients with suspected PE
116/748 (16%) SSPE
Risk of recurrent VTE
–  SSPE = Proximal PE
–  3.6% vs. 2.5% (p=0.42)
•  However:
–  Small number of recurrent event
–  No bil leg US
–  More patients with lower symptoms of DVT in baseline
characteristics
Goy J et al J Thromb Haemost. 2015Feb;13(2):214-8. .
What are the guidelines recommending?
•  ACCP
–  No specific recommendations
•  European Society of Cardiology
–  Individualized decision about anticoagulant therapy in patients
with isolated SSPE and negative leg ultrasonography.
–  Anticoagulation vs. serial ultrasonography
Den Exter PL et al Blood. 2013;122(7):1144-9. .
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Conclusion
•  SSPE are frequent and clinical relevant is unclear.
•  CTPA examinations with isolated SSPE diagnosis
should be reviewed by an experienced thoracic
radiologist.
Incidental SSPE in cancer patients
•  Patients with confirmed isolated SSPE and negative
leg CUS may not require anticoagulation.
•  Prospective cohort management studies are required
before withholding anticoagulant therapy becomes
common practice in patients with isolated SSPE.
Mr. MC
•  25yo male with HD.
•  Routine computed tomography (CT) of the chest for cancer staging.
•  Called by the radiologist because single SSPE incidentally found on
CT.
What will you do?
1.  Observation only (+/- repeating imaging)
2.  LMWH in combination with VKA for minimum of 6 months
3.  LMWH only (+/- dose reduction) for minimum of 6
months
•  Patients denies chest pain, shortness of breath or hemoptysis.
•  How will you manage Mr. MC?
Risk of incidental PE in cancer patients
4.  Rivaroxaban 15 mg BID X 3 weeks then 20 mg daily for
minimum of 6 months
Cumulative risk of recurrent VTE
Incidental Vs. Symptomatic PE (all receiving anticoagulation)
•  Approx 1 to 4% of routine CT Chest staging
–  In-patients > outpatients
Incidental PE: n=51
Symptomatic PE: n=144
•  Risk factors:
–  Metastatic disease
–  Recent chemotherapy
–  Types of cancer:
•  Pancreas
•  Melanoma/skin
•  Hepatobiliary
•  Kidney
•  etc
Browne AM et al. J Thorac Oncol. 2010;5:798-803.
Douma RA et al. Thromb Res 2010; 25:e306-e309.
Shinagore AB et al. Cancer. 2011; 117:3860-6.
Figure from: den Exter P L et al. JCO 2011;29:2405-2409
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Does size matter?
•  70 patients with incidental PE and 137 matched cancer
patients without incidental PE
Risk of recurrent VTE and bleeding
•  Patient-level meta-analysis of incidental PE In cancer
patients.
–  Risk of recurrent VTE
•  Incidental SSPE = more proximal PE
•  Risk of recurrent VTE was 56% in patients left untreated
•  But:
–  No bilateral leg US
–  Other cohort studies showed no difference
–  ? Risk of bleeding on oral anticoagulants
Model stratified for type and stage, age, gender and location of metastases.
Figure from: O’Connell C. et al. J Thromb Heamost 2011;9:305-311.
van der Hulle T et al. Blood. 2014; Abstract 590.
ISTH Cancer & Thrombosis SCC
recommendations
•  In patients with isolated SSPE, we recommend careful
review of the images by radiologists and suggest
performing compression ultrasonography of the lower
limbs to detect concomitant incidental DVT.
•  In patients with multiple SSPE, we recommend LMWH for
at least 6 months.
Di Nisio M et al. J Thromb Haemost. 2015 Feb 25. doi: 10.1111/jth.12883. [Epub ahead of print]
ISTH Cancer & Thrombosis SCC
recommendations
•  In patients with isolated SSPE with DVT, we recommend
LMWH for at least 6 months.
•  In patients with isolated with distal DVT or without DVT,
we suggest that the decision to provide anticoagulation is
made on a case-by-case basis, considering the risk of
bleeding, the presence of risk factors for recurrent
thrombosis, performance status of the patient, and patient
preference. If the decision is not to anticoagulate, we
suggest performing serial bilateral compression
ultrasonography after one week and clinical monitoring.
Di Nisio M et al. J Thromb Haemost. 2015 Feb 25. doi: 10.1111/jth.12883. [Epub ahead of print]
Thank You
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