Venous
Thromboembolic
Disease
Chris Hall, MD, FRCPC
Emergency Medicine Resident Rounds
January 12, 2012
One Night in the ED…
 36 yo Female
 Sudden onset right-sided pleuritic CP
 Feels SOB
 Physical examination ‘normal’
 PMHx: Nil
 Meds: None
 ECG, CXR normal
WHY I HATE PE…
 Potentially fatal (“can’t
miss”)
 Challenging to diagnose
 Evidence base is HUGE…
and growing
 Rapid advances in
technology: evidence is
obsolete (?!)
Objectives
 To simplify YOUR life when it comes to PE in the ED
 To provide an update on the latest state of the evidence
regarding PE:
 Diagnosis
 Management
 Risk Stratification
Epidemiology
 PE Incidence
 115 cases per 100,000 population / yr
 Mortality Rate
 12 per 100,000 / yr
 Case Fatality
 8% overall (30% if untreated!)
Pathophysiology
 Virchow’s Triad
 Stasis
 Injury
 Hypercoagulability
 > 90% Deep venous source
 Iliofemoral > Pelvic > Renal > IVC
 Calf veins (< 10%)
Pathophysiology
 Multiple mechanisms of hypoxia
 V/Q mismatch
 Inflammatory cascade  surfactant dysfxn
 Functional intrapulmonary shunting
 75% obstruction of PA bed = reduced CO
Risk Factors
 Malignancy
 Immobilization / Paresis
 Surgery / Trauma
 Prior hx of VTE
 Thrombophilia
 Family history
 Pregnancy
 Estrogen use
PE: Our Worst Nightmare…?
 Presentation often non-specific
 Many clinical mimics
 Up to 40% of fatal PE < 35 yo
missed on first MD contact
…or an iatrogenic epidemic?
 1998 – 2006:
 PE Indicence  86%
 Case Fatality  36%
 CTPA use > 10-fold 
 Pop’n Mortality: NO CHANGE
 More testing / treatment to get the
same result?
A Balance of Risks
 PE mortality: 8%
 (?? 25-30% if untreated)
 LAR for cancer from one
CTPA
 25yF: 1 / 400
 55yF: 1 / 950
 25yM: 1/ 2000
 Contrast nephropathy
 Overanticoagulation
More investigation
Less Investigation
Fewer missed PE
More missed PE
??
??
What Risk is ‘Acceptable’?
 At what pre-test probability would you discharge your
patient without further testing?
 10%
 5%
 2%
 1%
 0.5%
 0.1%
What Risk is ‘Acceptable’?
 Lessler et al, Ann Emerg Med 2010
 Theoretical decision analysis
 Risk of missed PE vs. risk of investigation / overtreatment
 At 1.4% probability, risks are equal
 If probability of PE < 1.4%, do not test
 Can clinical exam achieve PTP < 1.4%?
PE: Clinical Presentation
 What symptoms / signs make you think of PE?
 What is the most common symptom / sign?
Clinical Presentation
Symptom
Dyspnea
At rest
Exertional only
Chest Pain
Pleuritic
Non-pleuritic
% of PE
61%
16%
47%
17%
Cough
No blood
Hemoptysis
32%
11%
Orthopnea
Syncope
36%
12%
Clinical Presentation
Sign
% of PE
Tachypnea
57%
Signs of DVT
47%
Tachycardia
29%
Abn. Lung Sounds
26%
Fever
2%
One Night in the ED…
 36 yo Female
 Sudden onset right-sided pleuritic CP
 Feels SOB
 Physical examination ‘normal’
 PMHx: Nil
 Meds: None
 ECG, CXR normal
Would You…
 Send a d-dimer?
 Proceed directly to imaging?
 Do nothing?
 Is this patient’s pre-test probability of PE below the “no-
test” threshold?
Wells Rule
Geneva Rule
 55,268 patients
 10 CDRs + MD gestalt reviewed
CDR
SN
SP
NLR
PLR
Wells
84 %
58 %
0.3
2.0
Geneva
84 %
50 %
0.3
1.7
Revised Geneva
91 %
37 %
0.2
1.4
MD Gestalt
85%
51 %
0.3
1.7
PERC
 Pulmonary Embolism Rule-out Criteria
 Derived 2004
 Validated 2008 (multi-center)
 Provides CLINICAL basis to rule out PE
 GOAL: < 1.5% probability
PERC
PERC Validation
 8138 patients
 Results:
 SN 97.4% (if MD gestalt ‘low-risk’)
 Post-test prob: 1.0%
 PE prevalence 7% (3% in low-risk pts)
 Only useful in ‘low-risk’ population (MD gestalt)
(BUT - who qualifies?? < 5% PTP?? )
Caveat Emptor…
 Hugli et al. J Thromb Haemost., Feb 2011
 1675 consecutive patients
 21.3% prevalence of PE
 Low-risk revised Geneva: 6.4% PE
 Low-risk Geveva + PERC (-): 5.8% PE
 PERC NLR = 0.63 in LOW RISK pop’n
PERC Bottom Line
 Achieves ‘no-test’ threshold in ‘low-risk’ patients
 Endorsed in ACEP Clinical Policy (2011)
 Select patients carefully
Back to our case
 How many will now send a d-dimer?
The test you love to hate…
 D-dimer = FDP
 SN 75 – 97%
 SP 43 – 99%
 Depends on assay type
 Depends on clinical context (CDRs)
 Higher PTP = Lower SN
(-)
Low
Apply CDR
Not Low
D-dimer
(+)
Further
testing
STOP
Further
Testing
‘Wells Rule’
Quantitative D-dimer + CDR
CDR
Failure Rate
Efficiency
Simplified Wells (≤4)
0.5 %
39 %
Geneva
0.0 %
21 %
MD Gestalt **
0.7 %
52 %
D-dimer: Bottom Line
 In low-intermed. probability patients, d-dimer rules out PE
ACEP Clinical Policy 2011
 Efficiency of PERC + CDR / d-dimer strategy unknown
PTP Above no-test
threshold?
Yes
No
Pretest risk
stratification (CDR)
No further testing
Not High
High
Imaging
D-dimer
Positive
Imaging
Negative
No further
testing
Back to our case…
 D-dimer result = 0.89
 Patient remains stable
 Do you now:
 Order a V/Q scan?
 Order a CTPA?
 Order U/S dopplers of the legs?
PE: Imaging
 What is the ideal strategy for imaging in suspected
pulmonary embolism?
V/Q Scan
 Advantages
 Lower radiation dose (7 – 10 x less than CTPA)
 No iodinated contrast
 Disadvantages
 Harder to obtain ‘after hours’
 Higher rate of non-diagnostic scans
 Cannot diagnose other causes for symptoms
 CT diagnosed more PE
 19.2% vs 14.2%
 LARGE non-diagnostic V/Q scan rate (> 50%)
 V/Q noninferior to CT
 VTE @ 3 mos 1.0% vs 0.4%
V/Q Scan: Don’t Bury it Yet!
 Good option if:
 Normal CXR
 Younger patients
 Lower PTP
 Contraindications to CT
CT Pulmonary Angiogram
 Advantages
 Speed
 Available after hours (in Calgary)
 Confirms alternative diagnoses
 Disadvantages
 Contrast load
 Radiation dose
 Our ‘de facto’ gold standard
 3306 consecutive patients
 Utilized dichotomous Wells (≤ 4 = “low”)
 D-dimer if Wells low; MDCT if d-dimer (+) or Wells high
 No Rx if d-dimer (-) or MDCT (-)
 VTE rate @ 3 months:
 0.5% for Wells / d-dimer (-)
 1.3% for CT (-)
 PIOPED II
 CTPA SN: 85%
 VTE @ 6 mos: 14% for Int. / High PTP if CTPA (-)
CTPA Bottom Line:
 For Wells ≤ 4, CTPA (-) rules out PE
 If PTP ‘intermediate’, consider additional testing** if still
‘concerned’ about PE
 If PTP ‘high’, obtain additional testing**
ACEP Clinical Policy, 2011
**(D-dimer acceptable)
What if I add CTV?
 ~ 2 – 4% pick-up of isolated DVT
 Universal CTV use still controversial
 Intermediate – High PTP would benefit if CTPA (-)
 More studies using newer technology are needed
U/S: 1st-Line Imaging?
 Righini et al., Lancet 2008
 1819 patients with suspected PE
 U/S eliminated need for CTPA in 10%
 “NNI” = 10
 In both trial arms 3-month VTE risk = 0.3%
 CT-only arm 24% less expensive
Venous Imaging: Bottom Line
 Routine venous imaging not usually recommended
 Consider U/S first if:
 Leg symptoms present
 CT contraindicated or unavailable
Our Case…
 CT refused RE: pregnancy test (+)
Diagnostic Controversy:
PE in Pregnancy
 Pregnancy = PE Risk factor
 Overall risk still low: 10.6 / 100,000
 Risk greatest in post-partum period
 3-6% of suspected cases are PE (+)
 PE symptoms overlap with changes of pregnancy
 Strong desire to avoid ionizing radiation in workup
PE in Pregnancy: D-dimer
 True prognostic value unkown
 EVIDENCE IS WEAK on either side
 ESC Guidelines: USE D-DIMER TO R/O PE!
 ATS Guidelines: DO NOT USE D-DIMER TO R/O PE!
 “Kline” protocol:
 PERC + TM-specific cut-offs
 PERC alone may be good enough (~5% PTP)
PE Imaging in Pregnancy
 U/S
 1st-line if DVT symptoms; if no leg symptoms – skip it
 V/Q
 If CXR normal, > 90% of scans are “definitive”
 Fetal radiation similar / maternal lower than CT ***
 Preferred 1st-line test
 CT
 30% of scans ‘non-diagnostic’
 1st-line if CXR abnormal
NCRPM Cut-off
1/10,000 risk
of CA by age 25
Background
radiation over
9 mos
50 mSv
V/Q scan
0.32-0.74
mSv
CTPA
0.03-0.66
mSv
CXR
0.002 mSv
10 mSv
5 mSv
You Call THAT Simplified??!!
 MY approach
 ‘PERC’ them
 D-dimer w/ ‘standard’ cut-offs
 CXR
 V/Q
 (U/S first if leg symptoms)
Case
 CTPA result:
 Several right-side PE
 Moderate clot burden
 RV normal
 Treatment?
 Disposition?
PE: Treatment
 LMWH is preferred
 Warfarin is OAC of choice
 Dabigatran: ? Non-inferior to warfarin
 IVC Filters:
 Absolute CI to anticoag
 Failure of warfarin
Treatment Duration
Condition
Duration of Therapy
Reversible cause 3 months
Idiopathic (1st)
3 months minimum; indefinite if low bleed
risk
Idiopathic (2nd +) Indefinite
Cancer
LWMH x 3-6 mos, then warfarin until CA
“cured”
Source: ESC PE Guidelines, 2008
Management:
Sub / Massive PE
 Massive PE:
 SBP < 90 mmHg (w/o other cause)
 Pulselessness
 HR < 40 with shock
 Submassive PE:
 Not hypotensive
 RV dysfunction (+)
 Myocardial necrosis (+)
Supportive Care
 IV Fluids
 Use caution: 250-500cc then consider echo
 Pressors
 Levophed or dopamine OK; phenylephrine less OK
 Intubation
 Keep PEEP low (< 6)
 Use low TV (6cc/kg)
Thrombolysis
 Indicated in massive PE
 AHA & ACEP endorsed
 NNT = 10
 Subset of submassive PE may benefit
 Progressive deterioration (AHA)
 Insufficient evidence (ACEP)
Thrombolysis
 Secure Dx before Rx
 CT vs echo
 Alteplase 100mg IV preferred
 Bolus vs infusion / 2hr
 UFH infusion after
 Avoid in undifferentiated VSA
Adjuncts
 Catheter fragmentation
 Surgical Embolectomy
 Pulmonary vasodilators
 NOx
 Sildenafil
 Inhaled prostacyclin
 IVC Filters
Risk Stratification
 Many (most?) jurisdictions practice universal admission
 Calgary (Canadian?) practice heavily outpatient-based
 Who is safe to d/c home?
Risk Stratification
 Potential Tools
 Biomarkers
 Imaging
 Clinical risk scores
Troponin
 Conventional Tn useful if positive:
 OR = 5.3 (short term death)
 SN = 70.5, NLR = 0.42
Becattini et al, Circulation 2008
 hs TnT better for rule-out use:
 OR = 5.0
 SN = 87.0, NLR = 0.31
Lankeit et al, Circulation 2011
Imaging
 RV Dysfunction
 CT: debated
 Echo: gold standard
 ECG
 Useful if positive, less so if negative
 CT ‘clot burden’ not predictive
Pulmonary Embolism Severity
Index
 Prospectively validated
 Purely clinical variables
 For STABLE patients
 SN ~ 95%; NLR ~ 0.1 for 30-day mortality
 < 1% in low-risk
 8-9% in non-low-risk
 30-40% of patients are low-risk
Simplified PESI
PESI in Practice
 Lancet, 2011
 RCT of inpatient vs outpatient for PESI class I / II
 30-day mortality very low (< 1% overall)
 No difference between groups
Risk Stratification Pearls
 Outpatient Rx:
 Low-risk PESI / sPESI
 No RV dysfunction on echo / CT / ECG
 Negative TnT / hsTnT
Case Conclusion…
 Patient does not have a GP
 What follow-up is needed?
Anticoagulation Clinic
 Single visit; subsequent follow up on phone
 Rely on GP for additional work-up
 Director (MD) available for help if needed
Malignancy Screening
 10% risk of malignancy in ‘idiopathic’ VTE
 Highly age-dependent
 Aggressive screening identifies more CA sooner
 Guidelines suggest symptom-based screening
 DO A THOUROUGH Hx & P/E
 Consider aggressive screen if > 60yo
Summary
 PERC is useful if low-risk population
 D-dimer + CDR highly sensitive and moderately efficient
 Don’t bury the V/Q yet!
 Routine venous imaging generally low-yield
 V/Q is preferred 1st-line image in pregnancy
 PESI can identify low-risk patients for outpatient Rx
 Consider a malignancy screen in older idiopathic VTE
Questions?
CASE 2
 56 yo male
 3 weeks post-op for TKA
 Unilateral calf swelling, erythema, and tenderness x 2
days
 No trauma
 No chest pain / SOB
 No fever
Deep Vein Thrombosis
DVT: Objectives
 Diagnosis of DVT
 Diagnostic algorithms
 Novel ED-based imaging strategies
 Treatment of DVT
 Complications / special scenarios
Epidemiology
 Risk = 1.92 / 1000 person-years
 Higher risk in men
 50% will embolize eventually (PE)
 30% have silent embolism at diagnosis
Pathophysiology
 Virchow’s Triad
 50% will embolize eventually
 30% have silent emboli @ diagnosis
Classification
DVT
Proximal
Iliofemoral DVT
Distal (Calf DVT)
Risk Factors
 See PE…
 PLUS:
 IVC anomalies
 May-Thurner Syndrome
Clinical Presentation
 Pain / tenderness
 Erythema / warmth
 Swelling / edema
 Venous distension
 +/- ‘palpable cord’
 Homan’s Sign
 “Phlegmasia Cerulea Dolens” / “Phlegmasia Alba Dolens”
Differential Diagnosis
 Baker’s Cyst
 Cellulitis
 Venous Insufficiency
 Swelling due to paralysis
 Lymphangitis / lymphatic obstruction
 Non-specific swelling
Our Case
 Does this patient have a DVT?
 Can clinical features r/o DVT?
Wells’ DVT Criteria
Predicting DVT Clinically
Wells Score
PTP of DVT
Low
5%
Intermediate
17%
High
53%
D-dimer
 Wide range of sensitivities / specificities
 ELISA generally higher SN / lower SP than SimpliRED
 Primary utility is when combined with PTP
D-dimer
Wells Score
SN
SP
LR (+)
LR (-)
Low
95%
58%
2.4
0.10
Moderate
98%
41%
1.7
0.06
HIgh
97%
36%
1.5
0.07
D-dimers: Bottom Line
 In Low-Risk group, NLR is sufficient to R/O DVT
 In other groups, d-dimer insufficent to change decision to
image
DVT: Imaging
 Venography
 Impedance Plethysmography
 CT Venogram
 MRI Venogram
U/S for DVT
 Defacto ‘gold standard’
 No ionizing radiation
 No IV contrast
 Generally widely available
 Variable techniques
 Whole-leg Doppler
 2-point proximal vein compression
Whole-Leg U/S
 Detects calf vein DVTs
 Equivalent to strategy of serial proximal compression U/S
plus d-dimer
 May eliminate need for serial U/S
 Not performed routinely at AHS sites
ED Ultrasound
 Available “24 / 7”
 Easy to learn
 Variable SN: 70-100% depending on author
 Accuracy likely improved w/ clinical risk stratification
DVT Treatment
 LMWH
 UFH
 Fondaparinux
 Warfarin
 Dabigatran
LMWH
 Preferred 1st-line agent
 Better outcomes than IV UFH
 OD / BID dosing
 Predictable anticoagulation effect
 No monitoring needed
 Lower risk of HIT
 SAFE in pregnancy
SubQ UFH
 Equivalent to LMWH
 BID dosing (weight-adjusted, fixed-dose)
 Monitoring of APTT likely NOT needed
 Less concern in renal failure
 Risk of HIT
 Less expensive than LMWH
Fondaparinux
 Non-inferior to LMWH
 OD dosing (weight-based, fixed-dose)
 No monitoring needed
 Can be used (with limits) in renal failure (CR < 260)
Wafarin
 OAC of choice
 Initial 5-7 days need overlap with an anti-thrombin
 INR monitoring required
 UNSAFE in pregnancy
Dabigatran
 Oral anticoagulant;
 Non-inferior to warfarin
 No monitoring required
 Not yet approved for use in VTE
Other Therapies
 IVC Filter
 Failed anticoagulation
 Contraindications to A/C
 Catheter procedures (incl. thrombolysis)
 Circulatory compromise (PCD)
 IFDVT w/ rapid progression despite A/C
 “Selected” patients w/ IFDVT
 Stenting
 Advanced PTS / venous ulcers in setting of IFDVT
Condition
Duration of Therapy
Reversible cause 3 months
Idiopathic (1st)
3 mos minimum (6 mos IFDVT); indefinite if
low bleed risk
Idiopathic (2nd +) Indefinite
Cancer
LWMH x 3-6 mos, then warfarin until CA
“cured”
Calf DVT
6 wks – 3 mos
Summary
 Clinical exam insufficient when used alone
 D-dimer useful only in lowest-risk group
 Consider serial U/S if d-dimer (+) in non-low-risk patients
 LMWH / Warfarin are first-line agents
Questions?