Venous Thromboembo

lic DiseaseChris Hall, MD, FRCPC

Emergency Medicine Resident RoundsJanuary 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Rapid advances in technology: evidence is obsolete (?!)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

Fewer missed PE

Less Investigation

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 PresentationSymptom % of PEDyspnea At rest Exertional only

61%16%

Chest Pain Pleuritic Non-pleuritic

47%17%

Cough No blood Hemoptysis

32%11%

Orthopnea 36%Syncope 12%

Clinical PresentationSign % 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 = FDPSN 75 – 97%SP 43 – 99%Depends on assay typeDepends on clinical context (CDRs)

Higher PTP = Lower SN

Low

Not Low

(-)

(+)

‘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

Not HighHigh

Yes No

Positive Negative

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

1/10,000 risk 10 mSv

of CA by age 25

NCRPM Cut-off 50 mSv

Background 5 mSv

radiation over 9 mos

V/Q scan0.32-0.74

mSvCTPA0.03-0.66

mSv

CXR0.002 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 TherapyReversible 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

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 TherapyReversible 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?