This document discusses the diagnostic and treatment approaches to venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). It provides details on evaluating patients using Wells criteria and D-dimer testing to determine pre-test probability and decide between imaging with CT pulmonary angiogram or VQ scan. For confirmed VTE, treatment options include warfarin, novel oral anticoagulants (NOACs), inferior vena cava filters or thrombolytics. The document reviews best practices for treating isolated distal DVT, catheter-related thrombosis, and selecting appropriate long-term anticoagulation therapy.

1. Diagnostic and Therapeutic
Approach to Venous
Thromboembolism
Dr. Mark Choi, MD
General Internal Medicine
Abbotsford Regional Hospital and Cancer
Centre

2. Disclosure
 Bayer Inc.

3. Pulmonary Embolism
 VTE incidence in total population is
~100/100 000 patients/year
 1/3 of VTE cases are PE
 Acute PE has an estimated 30-day
mortality ranging from 5 to 30%1
 Causes ~300,000 deaths in the
United States and over 500,000
deaths in Europe per year2,3
 In the EU, more than twice as
many people die from VTE than
from AIDS, breast cancer, prostate
cancer and transportation
accidents combined3
296,370
543,454
• Régie de l'assurance maladie du Québec
(RAMQ) retrospective health database
review study suggests that the overall
incidence of first definite or probable PE
event is 4.5/10,000 person-years4
• 15,700 annual incident cases of PE
across Canada4

4. DVT: Distal or Proximal
 DVT can be:
 Distal
 Below the knee in the deep
veins of the calf
 Proximal
 Above the knee, primarily
in the popliteal and
femoral veins
 DVT usually begins distally
 A thrombus may grow and
extend to the proximal veins
and embolize1
 Risk of recurrence or extension is
greater for proximal DVT’s 2
External iliac
Deep femoral
Great saphenous
Popliteal
Anterior tibial
Posterior tibial
Dorsal venous arch
Distal Proximal

5. Venous Thromboembolism
 Deep Vein Thrombosis
 Diagnostic Algorithm / Wells Criteria for DVT
 Are isolated distal DVTs treated the same way as above
knee DVTs?
 Are superficial vein thromboses ever treated with OAC?
 Iatrogenic venous thrombosis
 Treatment and its duration
 Congenital workup
 Pulmonary Embolism
 Diagnostic Algorithm / Wells Criteria for PE
 Is CT chest always superior to VQ scan?
 What is the VQ criteria?
 Treatment Options
 Warfarin vs. NOACs (dabigatran and rivaroxaban)
 Pros and Cons of NOACs

6. Deep Vein Thrombosis

7. Diagnostic Approach
Scarvelis D , and Wells P S CMAJ 2006;175:1087-1092

8. Well’s Criteria for DVT
 1 point each for below:
 Paralysis, paresis or recent orthopedic casting of lower
extremity
 Recently bedridden (> 3 days) or major Sx within 4
weeks
 Localized tenderness in deep vein system
 Swelling of entire leg
 Calf swelling 3cm greater than other leg (measured 10cm
below the tibial tuberosity)
 Pitting edema greater in the symptomatic leg
 Collateral non-varicosesuperficial veins
 Active cancer or cancer treated within 6 months
 -2 points for alternative more likely diagnosis (baker’s cyst,
cellulitis, muscle damage, SVT, post-thrombotic syndrome,
inguinal lymphadenopathy, external venous compression)

9. Isolated Distal DVT
 Conflicting studies. Extension to proximal veins noted
in 4 to 16% of patients without treatment; 7 to 10% of
PE’s found to have isolated distal DVTs
 Issues:
 Fewer late sequelae than proximal DVT
 Operator dependent
 Less sensitive than proximal vein examination
 Major risk factor for extension was active cancer
 Isolated distal DVT had lower rate of recurrence
whereas bilateral distal DVT had same recurrence as
proximal DVT
 Current guideline: treat for 3 months

10. Superficial Vein Thrombosis
 Treatment
 Elevation of affected limb
 Warm and cold compresses
 Topical or oral NSAID’s
 Encourage ambulation
 Treat pts with OAC (3 months) in higher
risk for extension
 High risk features:
 Affected vein segment > 5cm,
saphenofemoral/saphenopopliteal junction, <
5cm to deep venous system, medical risk factors
 Chest. 2008;133(6 Suppl):454S

11. Catheter-related venous
thrombosis
 Risk of thrombosis present with central
(CVCs) and peripheral catheters (PICCs)
 Most patients are asymptomatic
 Higher risks of thrombosis with PICCs (both
peripheral and central venous thrombsis)
 RFs for CRVT = mal-positioned catheter,
larger diameter catheters, active cancer,
prior hx of DVT, hormonal therapy and
congenital VTE predisposition

12. Catheter-related venous
thrombosis
 Superficial phlebitis
 Remove catheter
 Elevate affected limb
 Warm or cold compresses
 Topical or oral NSAIDs
 Repeat U/S in 1 week in patients with RF’s
 Upper extremity DVT
 OAC as long as the catheter is in situ and
consider longer depending on RFs
 If OAC is discontinued, repeat U/S to look for
extension in patients with RFs

13. Treatment of proximal/distal DVT
 Provoked DVT = treat for 3 months
 Unprovoked DVT = treat for 3 months and
consider longer
 Rebound DVT = Risk roughly 20% in 2 years
after discontinuation of OAC.
 Follow-up Baseline DVT and d-dimer necessary
at the end of treatment with OAC in order to
differentiate between recurrent DVT and post-thrombotic
syndrome if his/her symptoms
return
 Congenital workup = reserved for unprovoked
VTE’s in younger patients or strong family
history of VTE

14. Pulmonary Embolism

15. Pulmonary Embolism
 Diagnostic approach that we are used to:
RYU JH, SWENSEN SJ, OLSON EJ, PELLIKKA PA. DIAGNOSIS OF PULMONARY EMBOLISM WITH
USE OF COMPUTED TOMOGRAPHIC ANGIOGRAPHY. MAYO CLIN PROC 2001;76:63.

16. Wells Criteria for PE
 Alternative diagnosis less likely than PE 3.0
 Signs or symptoms of DVT 3.0
 History of PE or DVT 1.5
 Immobilization for at least 3 days or surgery 1.5
in the previous month
 Heart rate >100 beats/min 1.5
 Hemoptysis 1.0
 Active cancer (treatment ongoing, within 1.0
previous 6 months or palliative)
 For high sensitivity D-dimer:
Low probability: <2 points
Intermediate probability: 2–6 points
High probability: ≥6 points

17. Is CT chest superior to VQ scan?
 Initial VQ study showed good
sensitivity and specificity to the gold
standard (pulmonary angiogram)
 CTPA compared to VQ study and
deemed non-inferior to VQ for
diagnosis of PE

18. Pros and Cons of CT Chest
 CT chest with IV contrast
 Pros
 Non-inferior to VQ scan in diagnosis of PE
 May catch other pulmonary findings (pneumonia, mass,
emphysema, ILD etc)
 Cons
 Radiation exposure (ei. Pregnancy)
 Risk of contrast-induced nephropathy in kidney dz
 May give indeterminate findings
 Patient may move during the study
 IV contrast timed incorrectly
 Incidental findings of isolated subsegmental PE may
lead to over-treatment
 Potential risk of allergy to IV contrast dye

19. Pros and Cons of VQ Scan
 VQ Scan
 Pros
 Good sensitivity and specificity in comparison to gold
standard (pulmonary angiogram)
 May catch other pulmonary findings (focal
consolidation)
 Safe in kidney disease
 Relatively small radiation exposure (equiv ~ 5 CXRs)
 Cons
 May give indeterminate findings
 If performed in patients with chronic cardiac or
pulmonary disease
 Availability: nuclear medicine open daytime Mon to Fri
in most tertiary centres

20. Radiation Exposure
 64-slice CTPA delivers 50-60mSv to
the breast
 V/Q Scan delivers only 0.28-0.9mSv
 In comparison, a 2-view
mammogram is associated with 3mSv
 Radiation exposure to female breast
is 70 to 100-fold greater in CTPA vs.
V/Q scan
Einstein AJ. Estimating risk of cancer associated with radiation exposure from 64-slice CT angiography. JAMA. 2007; 298: 317-323
Parker MS. Female breast radiation exposure during CT pulmonary angiography. Am J Radiol. 2005. 185: 1229-1233
Cook JV. Radiation from CT and perfusion scanning in prengnancy
Task Group on Control of Radiation Dose in CT: a report of the International Commission on Radiological Protection. AnnICRP 2000;30:7-45

21. Radiation Exposure
 There is non-negligible increase in
lifetime attributable risk of cancer,
particularly to the breasts of young
women
 1 in 143 for a 20-year-old woman
 1 in 284 for a 40-year-old woman
 There is also increased odds of lung
cancer in both gender
Einstein AJ. Estimating risk of cancer associated with radiation exposure from 64-slice CT angiography. JAMA. 2007; 298: 317-323

22. When do physicians choose VQ
Scan?
 In the setting of decreased eGFR
 Known IV contrast allergy
 When CTPA result is indeterminate
 Pregnancy and Post-Partum
 Because it causes less radiation

23. So when is V/Q scan more appropriate to
order over a CT scan?
 younger population
 female population
 no other intrathoracic disease is
suspected
 decreased eGFR
 Pregnancy/Post Partum
 Consider in those meeting the “VQ
criteria”

24. The VQ Criteria
 There are 2 VQ Criteria
 A normal CXR
 No history of chronic lung disease or
congestive heart failure
 If above 2 criteria are met, it is very
unlikely that the VQ scan will give an
indeterminate finding

25. V/Q vs. CTPE Study
 Data on all CT and V/Q scans performed to
assess for PE in St. Michael's Hospital
(SMH) inpatients over 2-year period
collected
 Exclusion
 CT scans ordered at hours when V/Q scan is
unavailable (weeknights, weekends and
holidays) were excluded
 CT scans looking for PE and other diagnoses
were excluded
 CT scans ordered on intensive care patients
were excluded.

26. V/Q vs. CTPE Study
 29.2% of CTPE studies met the V/Q
criteria

27. Reasons for choosing V/Q Scan

28. V/Q Scan as primary imaging
modality
 Only half (14 of 28) of these studies
met the VQ Criteria

29. V/Q vs. CTPE study conclusion
 V/Q scan under-utilized in patients
meeting V/Q criteria
 Not using the V/Q criteria leads to
many indeterminate findings

30. Preferred Algorithm
Pre-test Probability using Dichotomized Well’s Score
Low (4 or less) High (5 or higher)
D-dimer Normal CXR and no hx of
cardiopulmonary disease
Low (< 500) High (>500) Yes No
PE ruled out
VQ Scan
Renal Dysfunction or
IV contrast allergy
Yes No
CT Scan
If either test indeterminate

31. Case Scenarios

32. Case 1
 29 year-old female with acute left-sided
pleuritic chest pain with dyspnea and
palpitations. No leg symptoms
 PMH: none; FmHx: none
 HR 120bpm. Afebrile. SpO2 86% on RA
 Investigation:
 ECG = sinus tachy
 CXR PA+lateral = nil acute
 D-dimer 1200
 Imaging Modality?

33. Case 2
 75 year old with acute right-sided pleuritic
chest pain, wheezing and SOB. No leg
symptoms
 PMH: COPD, HTN.
 HR = 105bpm, temp 39.1C SpO2 82% on
RA, Resp: bilateral wheezing
 Investigation
 CXR = new right middle lobe consolidation
 D-dimer = 790
 Cr = 180
 Imaging Modality?

34. Case 3
 45 year-old woman with acute right-sided
pleuritic chest pain with SOB. No leg symptoms
 PMH: CHF (35%), HTN , chol, DM
 HR: 109 bpm, temp = 36.5C, Sp02 = 88% RA
 Investigation:
 CXR = cardiomegaly, trace bilateral effusion
 ECG = rapid AF
 D-dimer = >4000
 Cr = 80
 Imaging Modality?

35. Case 4
 45 year-old woman with acute right-sided
pleuritic chest pain with SOB. No leg
symptoms
 PMH: CHF (35%), HTN , chol, DM
 HR: 109 bpm, temp = 36.5C
 Investigation:
 CXR = cardiomegaly, trace bilateral effusion
 ECG = rapid AF
 D-dimer = >4000
 Cr = 220
 Imaging Modality?

36. Treatment Options

37. Treatment Options
 Warfarin
 vitamin K antagonist
 IV heparin
 binds AT and inactivates fXa and prevents conversion of
fibrinogen to fibrin
 LMWH
 binds AT and inactivates fXa
 fondaparinux
 enhances the anti-Xa activity of AT by 300-fold
 NOAC’s
 Dabigatran (direct thrombin inhibitor)
 Rivaroxaban (direct factor Xa inhibitor)
 Apixaban (not approved in Canada for treatment of PE or DVT
yet)
 IVC filter
 Intravenous thrombolytics

38. Warfarin is Highly Effective for the
Prevention of Stroke in AF or Recurrent VTE
Stroke Prevention in Atrial
Fibrillation
Treatment of Venous
Thromboembolism (VTE)
Standard Care: Warfarin (INR 2.0-3.0) Standard Care: Warfarin (INR 2.0-3.0),
initial parenteral anticoagulation until INR >2
Chance of recurrent VTE in
first 3 months
47%
If proximal DVT inadequately treated3
1
1
2
<2%
If adequate anticoagulant
response is achieved4
1. Hart et al Ann Intern Med. 2007;146:857-867; 2. Connolly et al. Lancet. 2006;367:1903-12; 3. Line B. Semin Nucl Med. 2001;31:90–101 4. Kearon C. Circulation 2003;107:I22–I30.

39. Properties of an Ideal Anticoagulant vs.
Currently Available Agents
IDEAL LMWH UFH VKA NOAC
Oral
No significant food/drug
interactions
Predictable response
No requirement for
coagulation monitoring
Fixed dosing
No HIT
Cost
Reversible
HIT: Heparin induced thrombocytopenia
?

40. Canadian Approvals of New Oral
Anticoagulants
Rivaroxaban
VTE prophylaxis
following THR/TKR
2008 2009 2010 2011
2012 2013
Dabigatran
VTE prophylaxis
following THR/TKR
Health Canada NOC database: http://webprod5.hc-sc.gc.ca/noc-ac/index-eng.jsp
Apixaban
VTE prophylaxis
following THR/TKR
Dabigatran
Stroke prevention
in AF
Rivaroxaban
Stroke prevention
in AF
Rivaroxaban
Treatment and secondary prevention
of DVT (2012) and PE (2013)
New oral anticoagulants
Dabigatran
Treatment and
secondary
prevention of DVT
Apixaban and PE
Stroke prevention
in AF
2014

41. Novel Oral Anticoagulants –
Pharmacological Properties
Characteristic Rivaroxaban1 Dabigatran2 Apixaban3
Target Factor Xa Factor IIa Factor Xa
Dosing OD BID BID
Bioavailability, % 80-100%* 6.5% 50%
Half-life 5-13h 12-14 h 8-15 h
Renal clearance
(unchanged
~33% 85% 27%†
bioavailable drug)
Cmax 2-4 h 1-2 h 3-4 h
Bridging with
No Yes No
LMWH
* When the 15mg and 20mg dose is taken with food
† Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine
1. Xarelto® PM, June 2013; 2. Pradaxa ® PM November, 2012; 3. Eliquis® PM November, 2012;
4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review

42. New Oral Anticoagulants: Total Drug Exposure
(AUC) with Declining Renal Function
Rivaroxaban
(33% cleared renally*)1
Dabigatran
(85% cleared renally)2
Apixaban
(27% cleared renally†)3
* active drug
† Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine
1. Xarelto® PM, June 2013; 2. Pradaxa ® PM November, 2012; 3. Eliquis® PM November, 2012;
4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review

43. Landmark DVT/PE Trials
Phase II Phase III
Rivaroxaban
Oral, direct Factor Xa
inhibitor
EINSTEIN DVT2
Rivaroxaban vs LMWH/UFH
followed by VKA
ODIXa-DVT3
Rivaroxaban vs enoxaparin
followed by VKA
EINSTEIN DVT/PE5,6
Rivaroxaban for 3, 6 or 12 months vs enoxaparin for ≥5 days
followed by VKA for 3, 6, or 12 months
EINSTEIN EXT5
Pre-treatment with rivaroxaban or VKA for 6 or
12 months followed by rivaroxaban or placebo for 6 or 12 months
Dabigatran
Oral, direct thrombin
inhibitor
RE-COVER7 & RE-COVER II8
5–10 days pre-treatment with LMWH bridging to dabigatran or VKA
for 6 months
RE-MEDY9
3–6 months’ treatment with approved anticoagulant; switch to
dabigatran or VKA
RE-SONATE10
6–18 months’ VKA treatment followed by 6 months dabigatran or
placebo
Apixaban
Oral, direct Factor Xa
inhibitor
Botticelli-DVT4
Apixaban vs LMWH or
fondaparinux followed
by VKA
AMPLIFY1
Apixaban 10 mg bid followed by 5 mg bid for 6 months vs.
enoxaparin followed by VKA
AMPLIFY-EXT11
Apixaban 2.5 mg bid or 5 mg bid for extended 12 months period vs
placebo
Bridging with LMWH and duration of treatment are the main differences between the trials
The following slides summarize trial results with NOACs in VTE treatment
Not intended as cross-trial comparison
1. http://clinicaltrials.gov; 2. Buller HR et al. Blood 2008; 3. Agnelli GA, et al. Circulation 2007; 4. Büller HR, et al. J Thromb Haemost 2008; 5. The EINSTEIN Investigators. N Engl
J Med 2010; 6. The EINSTEIN–PE Investigators. N Engl J Med 2012; 7. Schulman S, et al. N Engl J Med 2009; 8. Schulman S, et al. ASH Annual Meeting Abstracts. Blood 2011;
9. Schulmann S et al. ISTH 2011; 10. Schulman S, et al. ISTH 2011; 11. Agnelli G et al. N Engl J Med 2012; 12. Raskob G et al. J Thromb Haemost. 2013.

44. VTE treatment Results comparison: pivotal
phase III clinical trials – Efficacy
Study drug
n (%)
LMWH/
VKA
n (%)
ARD
%
HR 95% CI P
EINSTEIN
Pooled
3, 6, 12 months
86 (2.1) 95
(2.3)
0.2 0.89 0.66-
1.19
N-inf
RE-COVER
Pooled
6 months
(2.7) (2.4) -0.3 1.09 0.77-
1.54
N-inf
AMPLIFY
6 months
59 (2.3) 71
(2.7)
0.4 0.84 0.60–
1.18
N-inf
Recurrent VTE or VTE-related death
Hazard ratio
and 95% CIs
Favours study
drug
Favours
LMWH/VKA
* Event during on-treatment period
Hazard ratio
and 95% CIs
Favours study drug Favours
LMWH/VKA

45. VTE treatment Results comparison: pivotal
phase III clinical trials – Safety
Major Bleeding
Study
drug
n (%)
LMWH/VK
A
n (%)
ARR
%
HR 95% CI P
EINSTEIN
Pooled
3, 6, 12
Months
40 (1.0) 72 (1.7) 0.7 0.54 0.37-0.79 Sup.
RE-COVER
Pooled
6 months
37 (1.4) 51 (2.0) 0.6 0.73 0.48-1.11 N-inf
AMPLIFY
6 months
15 (0.6) 49 (1.8) 1.2 0.31 0.17–0.55 Sup.
Hazard ratio
and 95% CIs
Favours study drug
Favours
LMWH/VKA

46. Summary
 Main Phase
 Few differences in trial designs
 Bridging with LMWH in RE-COVER vs. Single-drug
approach in EINSTEIN and AMPLIFY
 Duration of treatment – 6 months in RE-COVER
and AMPLIFY vs. 3, 6 or 12 months in EINSTEIN
 OD in EINSTEIN (after initial acute phase for
EINSTEIN) vs. BID in RE-COVER and AMPLIFY
 All agents were non-inferior vs. warfarin in
preventing VTE recurrence
 Rivaroxaban and apixaban were superior to warfarin
in reducing major bleeding whereas dabigatran was
non-inferior

47. Cost of NOAC’s
 May apply for Special Authority for the
treatment of DVT with rivaroxaban. Special
Authority not approved for dabigatran for
treatment of DVT or PE.
 If the patient has reached his/her
deductible on Pharmacare, rivaroxaban
does not cost the patient any money
 Otherwise, cost of rivaroxaban is ~$3/day
for 20mg po daily. Cost of dabigatran is
~$3.4/day.

48. Rivaroxaban vs. Dabigatran
 No bridging with LMWH required with
rivaroxaban
 OD vs. BID dosing
 Rivaroxaban is superior to warfarin in reducing
major bleeding events whereas dabigatran is
non-inferior
 Rivaroxaban is cheaper; rivaroxaban may be free
for patients who have reached their deductible
 Less renally cleared
 Both irreversible but rivaroxaban has shorter
half-life

49. Rivaroxaban vs. Apixaban
 No bridging needed for both drugs
 OD vs. BID dosing
 Both non-inferior to warfarin in
recurrent VTEs and VTE-related
deaths
 Both superior to warfarin in number
of major bleeding events
 Both are less renally cleared in
comparison to dabigatran

50. Take Away Points
 Not all SVT are treated conservatively
 Remember to utilize VQ scans in those who
meet the VQ criteria
 Direct Factor Xa inhibitors are superior to
warfarin in reducing major bleeding risk
 Bridging not required for rivaroxaban or
apixaban
 Your patient’s rivaroxaban cost may be
covered fully in the treatment of DVT.
Please use special authority.

51. Questions?
 Thank you!