1. DVT & PE James Huffman & Dr. Trevor Langhan 11.12.2009

2. DVT –Diagnostic Algorithm –Determining Pre-test Probability –Useful Diagnostics –Treatment –Disposition –Special Circumstances PE –Similar topics, PLUS: –Controversies

5. Virchow’s Triad White, RH: The epidemiology of venous thromboembolism. Circulation 107(23 Suppl 1):I4, 2003.  Injury to the vascular endothelium  Alterations in blood flow  Hypercoagulability Anything else associated with imbalanced clot formation? Age

6. Case 1 55♀: Referred to ED for pain, redness and swelling of the right calf –WIC today: Sent to ED with note:

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

8. DVT: History & PE are Risk Assessment Goals of H&P? –Determine pre-test probability –Look for other causes

9. Case 1: History & Physical Exam

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

11. 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

13. Pretest Probability

14. 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!

15. D-Dimer Testing Kline, 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% RapidELISA 95-100% 30-60% CLS uses

16. Clinical VariableScore “Active” Cancer (treatment ongoing, within 6 months or palliative)1 Paralysis, Paresis or recent casting of lower extremities1 Recently bedridden 3 days or more, or Surgery A in past 3 months1 Localized tenderness along distribution of deep venous system1 Entire leg swollen1 Calf swelling at least 3cm larger than asymptomatic leg1 Pitting edema confined to the symptomatic leg1 Collateral superficial veins (Non-varicose)1 Previously documented DVT1 Alternative Diagnosis at least as likely as DVT-2

17. D-Dimer Testing Wells, 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)

18. D-Dimer Testing Wells, 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

19. Level 1 – Pretest Probability

20. 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

21. What next Einstein?

22. Level 2 – D-dimer Her d-dimer was positive at 1.23

23. Level 3 – Ultrasound (or not)

24. Ultrasound American Journal of Respiratory Critical Care Medicine. 1999: 160; 1043-66 Bottom line: U/S is the test of choice for DVT

25. 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)

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

27. 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.

28. 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

29. 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

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

31. DVT: Bottom Line Thus Far?  Hx/PE help decide pretest probability (Wells)  Add a sensitive test (D-Dimer)  Almost all cases, do a sensitive confirmatory test (U/S)

32. Case 1 Continued Okay back to it… U/S shows popliteal vein DVT Management Doctor?

33. Level 4 - Treatment

34. Medical Management Rosen’s Emergency Medicine 7 th Edition Scarvelis, D., and P. Wells. 2006. Diagnosis and Treatment of DVT. CMAJ: 175(9); 1087

35. Treatment: Bottom Line IV UFH, LMWH, Fondaparinux are all acceptable

36. 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

37. Special Circumstances

38. Superficial Thrombophlebitis Rosen’s Emergency Medicine 7 th Edition Uncommonly evolves into a thromboemboic event BUT, ~8% of patients have synchronous DVT

39. Isolated Calf or Saphenous V. Thrombosis Canadian 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

40. Phlegmasia Cerulea Dolens (Painful Blue Leg)

41. Pulmonary Embolism

42. Case 2 61♀ presents to ED complaining of mild pleuritic chest pain –Total knee arthroplasty 5/12 ago. Healthy otherwise

43. Risk Assessment Emergency 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

44. 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

45. Bottom Line: Use history & physical exam risk stratify patients Wells ≤ 4  PE Unlikely Wells > 4  PE Likely

46. H&P are Risk Assessment Wells, PS. J Thromb Haemost. 2007; 5(Suppl 1):41-50 Wells ≤ 4  Unlikely Wells > 4  Likely

47. Risk Assessment Emergency 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

48. Case 3 Continued HR: 104 Nil else She gets 1.5 points Now what? Do you even start to work her up for PE?

49. 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.

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

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

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

53. 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

54. Case 2 Continued Age > 50 HR >100 Does not meet PERC criteria. Wells 1.5 –  Send the D-dimer –Result: 0.59 mg/L (↑)

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

58. 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%

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

60. 8-bit vs 64-bit resolution

61. 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 CT Moores, L., et al. Ann Intern Med. 2004; 141:866-874

62. Bottom Line Multi-detector row CTPA should be considered the “gold standard”

63. Magnetic Resonance Angiography Fields, 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

64. 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

65. Case 3 Continued Recall… Low probability (Wells 1.5) D-Dimer: Positive Therefore... –CTPE  Positive

66. 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 2. Next decide prevention against future emboli –Anticoagulation –IVC filters

67. Spectrum of PE Kearon 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 ….

68. 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)

69. Fibrinolysis in sub-massive PE Ramakrishnan, 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.]

70. Fibrinolytics – Bottom Line Consider in PE with hypotension or systemic hypoperfusion or in the rapidly deteriorating patient

71. Out-Patient Treatment of PE Merli, 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)

72. V. Low Risk = 1.1% 30d Mortality 

73. 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

74. Out-Patient Treatment of PE Merli, 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

75. 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.

76. 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

77. PE in Pregnancy Winer-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.

78. PE in Pregnancy Cook 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

79. PE in Pregnancy - Treatment Same as other populations except Warfarin –Known Teratogen  don’t use.

80. 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

82. 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]

83. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism Van 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

84. Fondaparinux Matisse 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

85. 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