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DVT & PE

James Huffman & Dr. Trevor Langhan

11.12.2009

• DVT– Diagnostic Algorithm– Determining Pre-test Probability– Useful Diagnostics– Treatment– Disposition– Special Circumstances

• PE– Similar topics, PLUS:– Controversies

Virchow’s TriadWhite, RH: The epidemiology of venous thromboembolism. Circulation 107(23 Suppl 1):I4, 2003.

1. Injury to the vascular endothelium

2. Alterations in blood flow3. Hypercoagulability

Anything else associated with imbalanced clot formation?

Age

Case 1

• 55♀: Referred to ED for pain, redness and swelling of the right calf– WIC today: Sent to ED with note:

Diagnostic Approach: Pre-test ProbabilityScarvelis, D., and P. Wells. 2006. Diagnosis and Treatment of DVT. CMAJ: 175(9); 1087

DVT: History & PE are Risk Assessment

• Goals of H&P?– Determine pre-test

probability– Look for other causes

Case 1: History & Physical Exam

History & Physical are Risk AssessmentAnand, SS, Wells, PS, et al. 1998. Does this Patient have deep vein thrombosis? JAMA:279(14)

DVT: H&P Bottom Line

• Neither is sensitive or specific– i.e. you can’t rule-in or rule-out a DVT

• Use them to decide pre-test probability

Pretest Probability

Pretest Probability

• This algorithm re-presented in JAMA rational clinical examination series

Anand SS, Wells PS, Hunt D, Brill-Edwards P, Cook D, Ginsberg JS. Does this patient have deep vein thrombosis? JAMA. 1998 Dec 2;280(21):1828-9.

• What’s missing?

The Dimer!

D-Dimer TestingKline, et al. Ann Emerg Med (2003); 42(2): 266-275.

Degradation product of fibrin

Non-specific

– PPV bad

– +ve: surgery, trauma, hemorrhage, CA, pregnancy, sepsis, >80 yrs old

Sensitivity variable

Need Pre-test probability to r/o DVT

Assay

Sensitivity Specificity

Whole blood agglutination (SimpliRED)

80-85% 70-90%

Latex agglutination

90-95% 40-90%

Rapid ELISA 95-100% 30-60%

CLS uses

Clinical Variable Score

“Active” Cancer (treatment ongoing, within 6 months or palliative) 1

Paralysis, Paresis or recent casting of lower extremities 1

Recently bedridden 3 days or more, or Surgery A in past 3 months 1

Localized tenderness along distribution of deep venous system 1

Entire leg swollen 1

Calf swelling at least 3cm larger than asymptomatic leg 1

Pitting edema confined to the symptomatic leg 1

Collateral superficial veins (Non-varicose) 1

Previously documented DVT 1

Alternative Diagnosis at least as likely as DVT -2

D-Dimer TestingWells, P., et al. 2003. NEJM: 349(13); pp1227-35

RCT (N=1096)

D-Dimer vs no D-Dimer

DVT unlikely (Wells < 2)

# of U/S per pt decreased in D-dimer group (0.78 vs 1.34)

D-Dimer TestingWells, P., et al. 2003. NEJM: 349(13); pp1227-35

• “Modified” Wells Criteria

• Used SimpliRED and IL-Test assays (less sens than ours)

• Conclusion:

– Wells <2 and negative D-Dimer can safely r/o DVT

Level 1 – Pretest Probability

Case 1 continued

• Pretest probability?

– Active cancer (1)

– Localized tenderness (1)

– Calf swelling (1)

– Edema (1)

– Other Diagnosis? Compression by pelvic nodes? (Doesn’t matter – score would still be “not low risk”)

So she gets either 4 or 2 points = DVT likely

What next Einstein?

Level 2 – D-dimer

• Her d-dimer was positive at 1.23

Level 3 – Ultrasound (or not)

UltrasoundAmerican Journal of Respiratory Critical Care Medicine. 1999: 160; 1043-66

Bottom line: U/S is the test of choice for DVT

Anatomy

• Depth:– Deep– Superficial*

• Proximity:– Popliteal v. or

higher– Distal

*Superficial femoral vein is a member of the deep group

Emerg Med Clin N Am. 26 (2008)

Ultrasound Fields, JM, & Goyal, M. Venothromboembolism. Emerg Med Clin of N Am. 2008; 26: 649-83

Bedside U/S?

Jolly BT, et al. Acad Emerg Med 1997;4(2):129–32.Frazee BW, et al. J Emerg Med 2001;20(2):107–12.

• Blaivas M, et al. Acad Emerg Med. 2000;7(2):120–6.– Median exam time of 3m 28s– 98% correlation with vascular lab-performed studies

• Theodoro D, et al. Am J Emerg Med. 2004;22(3):197–200.– 125m reduction in time to pt disposition with EP-performed US– Kappa = 0.9, 99% agreement (154/156 cases)

• Jang T, et al. Acad Emerg Med. 2004;11(3):319–22.– 8 emerg residents (4 PGY-1, 2 PGY-2, 2 PGY-3)– 1h focused training (didactic and practice on 2 healthy

volunteers)– SN = 100%, SP = 91.8%, avg scan time = 11.7min (self-

reported)– 4 false-positives (chronic DVT), 0 false-negatives

Ultrasound: Limitations

• Obese, ++edema, immobilsation devices (x-fix)

• Doesn’t see isolated thrombi in iliac or superficial femoral veins within abductor canal MRI better

• Pelvic masses may cause noncompressibility in absence of thrombus false +’ve

• Most importantly: U/S doesn’t return to normal after acute DVT

• Therefore use impedance plethysmography for recurrent DVT

– U/S - 60-70% of studies return to normal at one year

– IP – 90% return to normal within a year

CT-VenographyGoodman LR, Stein PD, Matta F, et al. AJR Am J Roentgenol 2007;189(5): 1071–6

DVT: Bottom Line Thus Far?

1. Hx/PE help decide pretest probability (Wells)

2. Add a sensitive test (D-Dimer)

3. Almost all cases, do a sensitive confirmatory test (U/S)

Case 1 Continued

• Okay back to it…• U/S shows popliteal vein DVT• Management Doctor?

Level 4 - Treatment

Medical ManagementRosen’s Emergency Medicine 7th EditionScarvelis, D., and P. Wells. 2006. Diagnosis and Treatment of DVT. CMAJ: 175(9); 1087

Treatment: Bottom Line

• IV UFH, LMWH, Fondaparinux are all acceptable

Case 1 Conclusion

• Pt started on Enoxaparin and Warfarin • Arranged to see her oncologist and a

hematologist as out-patient 2 days later

• In General, discharge home is safe. • Admission may be required if:

– Renal failure, high bleeding risk– Extensive DVT (painful blue leg)– Necessity for parenteral narcotics– Inability to have injections at home

Special Circumstances

Superficial ThrombophlebitisRosen’s Emergency Medicine 7th Edition

• Uncommonly evolves into a thromboemboic event

• BUT, ~8% of patients have synchronous DVT

Isolated Calf or Saphenous V. ThrombosisCanadian Medical Association Journal. 2003; 168(2)

• Rarely cause significant PE

• 25% of calf DVT extend to involve proximal veins

• Vast majority will extend within 7d

• DVT complications in 10-38% (untreated)

Clinically this means you can Rx ASA (325mg/d) and arrange for re-U/S in 7d or just start on full DVT

anticoagulation

Phlegmasia Cerulea Dolens (Painful Blue Leg)

Pulmonary Embolism

Case 2

• 61♀ presents to ED complaining of mild pleuritic chest pain

– Total knee arthroplasty 5/12 ago. Healthy otherwise

Risk AssessmentEmergency Medicine Reports. 2004;25(11)

• History and Physical do not confirm the diagnosis, they merely raise the suspicion of the diagnosis, triggering further investigation

• Hx:– Have to consider PE: dyspnea, tachypnea Pleuritic CP,

syncope, hypotension & hemoptysis– Non-specific

• PE:– Tachypnea and tachycardia are most common

Pretest Probability Emergency Medicine Reports. 2004;25(11)

• All decision rules start w/ score

• Wells and Geneva validated• Wells NPV: 99.5%• Others more cumbersome

• Geneva (Wicki): adds ABG, CXR

• PISA-PED: Adds ECG

Bottom Line:

Use history & physical exam risk stratify patients

Wells ≤ 4 PE UnlikelyWells > 4 PE Likely

H&P are Risk AssessmentWells, PS. J Thromb Haemost. 2007; 5(Suppl 1):41-50

Wells ≤ 4 Unlikely

Wells > 4 Likely

Risk AssessmentEmergency Medicine Reports. 2004;25(11)

• CXR:

– Often AbN (Pleural effusion, atelectasis, elevated hemidiaphragm)

– N CXR with dyspnea & hypoxemia = PE

– Know Hampton’s and Westermark for exams

• EKG:

– Non-specific ST, Twave changes, Tachy • Signs of R heart strain (Anterior/Inferior T-wave inversions)

– Know SIQIIITIII for exams

– Simultaneous TWI in V1 and III are highly specific

• ABG:

– Hypoxemia common, but not always present

– AAD02 >20 suggests PE (PIOPED)

– 25-35% of pts with PE have normal blood gasses, pulse ox, and A-A gradient

Case 3 Continued

• HR: 104• Nil else

• She gets 1.5 points

• Now what?• Do you even start to work her up for PE?

PE Rule-Out Criteria (PERC Rule)Kline, JA. et al. J Thromb Haemost. 2004; 2:1247-55

• Based on the premise that overuse of D-dimer to screen for PE can have negative consequences

• Derivation phase:– 3148 patients evaluated for PE in 10 US EDs– Data collected on 21 variables– Logistic regression and inter-observer agreement used to

narrow to rule of 8.


• Age <50 • Pulse rate <100 beats/min • Oxygen saturation >94% • No hemoptysis • No unilateral leg swelling • No recent major surgery or trauma • No prior pulmonary embolism or deep

venous thrombosis • No hormone use


• Validation Phase:– 2 Groups:

1. Low risk (board certified EP believed D-dimer warranted but good enough to r/o PE) – n = 1427, 114 (8%) had VTE diagnosed within 90d

2. Very low risk (chief complain dyspnea – PE not suspected)– n = 382, 9 (2.4%) had VTE diagnosed within 90d


• Endpoint: VTE before 90 days. Good follow-up• Both Wells score and PERC rule functioned relatively

well– Wells <2 better with very low risk population and

included more patients in both groups– Both had very wide confidence intervals

PERC Rule – Bottom Line

• Compliments clinical judgment – DOESN’T REPLACE IT!

Pause before ordering a D-dimer in a patient

who does not have any of the eight criteria

Then order it if you still think it’s indicated

Case 2 Continued

• Age > 50• HR >100• Does not meet PERC criteria. Wells 1.5

– Send the D-dimer– Result: 0.59 mg/L (↑)

PIOPED I – V/Q ScanningPIOPED Investigators. JAMA. 1990;263:2753

PIOPED I – V/Q ScanningPIOPED Investigators. JAMA. 1990;263:2753

PIOPED II – CTA / CTV Stien, P. NEJM. 2006. 354; 22, pp 2317-2327

CTA inconclusive: 6%

CTA Sens: 83%, Spec: 96%

CTA-CTV 90% and 95%

PIOPED II – CTA / CTV Stien, P. NEJM. 2006. 354; 22, pp 2317-2327

8-bit vs 64-bit resolution

• Meta-analysis of 23 studies– Negative CT PE who didn’t receive AC– 4657 patients

• Results (3 month follow up)– VTE: 1.4% (1.1-1.8%)– Fatal PE: 0.51% (0.33-0.76%)

• Conclusions– CTPA has similar rates of recurrence as angiography– Appears safe to withhold anticoagulation based on negative

CTPA

Outcomes: Multi-detector Row CTMoores, L., et al. Ann Intern Med. 2004; 141:866-874

Bottom Line

Multi-detector row CTPA should be considered the “gold standard”

Magnetic Resonance AngiographyFields, JM, & Goyal, M. Venothromboembolism. Emerg Med Clin of N Am. 2008; 26: 649-83• Advantages:

– Eliminates radiation– Probably safer in pregnancy– Decreased nephrotoxicity

• Disadvantages:– Cost– Availability– Failure to demonstrate adequate SN in

preliminary studies

PIOPED III – MR-A

• Purpose

– Determine accuracy of Gd-MRA of pulmonary arteries with MRV of the thigh veins in pts with clinically suspected PE

– Rationale: In PIOPED II, 25% had contraindications to CTPA/Angio such patients could benefit from safer MR

– Expect 1250 pts (lots of exclusions incl Pregnant)

– Calgary is one of the Centres

Case 3 Continued

• Recall…• Low probability (Wells 1.5)• D-Dimer: Positive• Therefore...

– CTPE Positive

Treatment Emergency Medicine Reports. 2004;25(12)Houman et al. J Thromb Thrombolysis. 2009. 28:270-7

1. First decide primary therapy– Significant clot burden immediate removal

• Chemical - thrombolysis

• Mechanical – embolectomy

– Less Significant Anticoagulation• UFH, LMWH, (Fondaparinux) Coumadin

• Next decide prevention against future emboli– Anticoagulation– IVC filters

Spectrum of PEKearon et al. 2008 Chest.

• Massive (PE + shock)– Thrombolysis + ICU

• Submassive (PE + NBP + RV Dysfxn)– Admission, anticoagulation, +/- thrombolysis

• Symptomatic– probable admission, anticoagulated, +/- echo

• Asymptomatic– You probably don’t even know about it ….

Fibrinolysis Ramakrishnan, N. Thrombolsysis is not warranted in submassive pulmonary embolism: A systematic review and meta-analysis. Crit Care Resusc 2007; 9(4)

• Massive PE:– PE with systemic arterial hypotension, cardiogenic

shock, severe dyspnea or respiratory failure• Multiple case reports/series of improved outcomes and

ROSC• Kucher et al. 2006: no change in mortality or recurrence of

PE

• Submassive PE:– PE occurring in hemodynamically stable patients

with evidence of right ventricular heart strain, as seen on ECG or echocardiography

• NEJM 2002; 347(15) –100mg alteplase in addition to heparin improves clinical course (ARR = 13.6%, P=0.006)

Fibrinolysis in sub-massive PERamakrishnan, N. Thrombolsysis is not warranted in submassive pulmonary embolism: A systematic review and meta-analysis. Crit Care Resusc 2007; 9(4)

Results of randomized trials comparing the addition of thrombolytic therapy to standard heparin therapy for treatment of submassive pulmonary embolism fail to show any significant differences in clinically important outcomes. [Ann Emerg Med. 2007;50:78-84.]

Fibrinolytics – Bottom Line

Consider in PE with hypotension or systemic hypoperfusion or in the rapidly deteriorating patient

Out-Patient Treatment of PEMerli, GC. et al. Treating Acute Pulmonary Embolism: Outpatient or Inpatient or Somewhere in between? Thromb Res. 2008; doi:10.1016

1. Is it technically possible?– Newer treatments allow out-pt treatment of VTE

• LMWH• SC UFH

2. Is it safe?– Pts at high risk of “badness” shouldn’t go home

• Massive & Submassive PE – no brainers• Risk stratify the rest:

– Geneva Risk Score– Pulmonary Embolism Severity Index (PESI)

V. Low Risk = 1.1% 30d Mortality

GRS vs PESI

• GRS– Sn 34% (18-51)– Sp 85% (82-88)– PPV 11% (5-18)– NPV 96% (94-98)

• PESI– Sn 81% (68-95)– Sp 37% (33-41)– PPV 7% (4-9)– NPV 97% (95-99)

Jimenez. Chest 2007

Out-Patient Treatment of PEMerli, GC. et al. Treating Acute Pulmonary Embolism: Outpatient or Inpatient or Somewhere in between? Thromb Res. 2008; doi:10.1016

3. Is outpatient treatment appropriate in THIS patient?

– Medical and Social Issues:

• Bleeding risk, underlying malignancy, renal status, obesity, heart failure, thrombophilia, and concomitant medications that interact with anticoagulants (aspirin, clopidogrel, NSAID etc)

• Medication compliance, availability of home-care, living situation, logistics of bloodwork

Out-Pt Treatment of PE

• Bottom Line:

There is no consensus on who can safely be treated at home

If the patient is hemodynamically stable, with no signs of R heart strain and otherwise completely healthy,

consideration of out-pt treatment is reasonable.

Would make this decision in discussion with pulmonary or the patient’s FP.

Wait, is she just a little hefty or…?

• Common – VTE most frequent cause of death in pregnancy

– 0.5-3.0 / 1000 pregnancies

• Most trials exclude pregnant pts

• D-Dimer is less specific!

– More false positives more work-up

• US is great…if there’s a DVT

– + in 13-15% with suspected PE

• What about CTPE? V/Q?

• MRI/A not studied yet

PE in PregnancyWiner-Muram HT, et al. Pulmonary embolism in pregnant patients: fetal radiation dose with helical CT. Radiology 2002;224(2):487–92.

• Historically, V/Q recommended less radiation

• Newer scanners supposed to be better?• V/Q still gives indeterminate results

Average fetal radiation dose with helical CT is less than that with V/Q lung scanning during all trimesters. Pregnancy should not

preclude use of helical CT for the diagnosis of PE.

PE in PregnancyCook JV, Kyriou J. Radiation from CT and perfusion scanning in pregnancy. BMJ. 2005;331:350.

• Compared maternal and fetal-absorbed doses (16-slice)

• Maternal whole body effective dose:– CTPE: 2 mSv

– V/Q: 0.6 mSv

• Fetal absorbed doses:– CTPE: 0.01mGy (1/1 000 000 risk of Ca by age

15)

– V/Q: 0.12 mGy (1/280 000)

• Breast absorbed doses:– CTPE: 10 mGy

– V/Q: 0.28 mGy

CTPE: less risk to fetus, more to mom’s breasts

PE in Pregnancy - Treatment

• Same as other populations except Warfarin– Known Teratogen don’t use.

Bottom Lines

• History and Physical are insensitive and non-specific

– Use them to determine pretest probability

• D-dimer is a sensitive screening test

– But not benign – use your head

– Remember PERC “rule” – only a guideline

• CTPE is very powerful

– If neg – safe to withhold treatment

• Fibrinolysis if hypotensive, hypoperfused or circling

Pretest Probability Wells, P, et al. 1997. Lancet:350;1795.

593 pts w/ suspect DVT Stratified low, mod, high risk compression U/S /veno 3% of Low risk, 17% of moderate risk, 75% of high risk pts

had DVT Concluded that Clinical probability + U/S safe [0.6% missed]

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolismVan Dongen C. Cochrane Review 2005

• 22 studies (n = 8867)

• Thrombotic complications (18 trials)– LMWH = 151/4181 (3.6%)– UFH 211/3941 (5.4%)– OR 0.68; (0.55 to 0.84

• Thrombus size was reduced (12 trials)– LMWH= 53%– UFH 45%– OR 0.69 (0.59 to 0.81)

• Major hemorrhages (19 trials)– LMWH = 41/3500 (1.2%)– UFH 73/3624 (2.0%)– OR 0.57 (0.39 to 0.83)

• Mortality (18 trials)– LMWH 187/4193 (4.5%)– UFH 233/3861 (6.0%) – OR 0.76 (0.62 to 0.92)

• BID dosing ? Better– CI for OR crossed 0

Aric 2005

FondaparinuxMatisse Investigators. Ann Intern Med. 2004;140:867-73.

• Synthetic polysaccharide• Anti Factor Xa• DBRCT Fondaparinux vs Enoxaparin in symptomatic DVT

– 2205 pts with symptomatic DVT from 154 centres worldwide– Fondaparinux 7.5mg*sc od vs Enoxaparin 1mg/kg sc bid– Outcomes:

• Symptomatic recurrent VTE• Bleeding• Death

Fondaparinux Matisse Investigators. Ann Intern Med. 2004;140:867-73.

• At least as safe and effective as LMH• To date: no reported heparin-induced

thrombocytopenia

• However, not available in Canada at this time