1. Outpatient Treatment of Acute Pulmonary Embolism: Review of Published Studies Amjad AlMahameed, MD, MPH

2. OP Rx of PE with Dalteparin (Kovacs MJ, J thromb and Haemoat. 2000;83: 209-11) Prospective cohort study All pts with PE (2/1996- 11/1998) unless excluded 158 patients identified, 108 managed as OP PE Dx: High prob. V/Q, PA gram, spiral CT, DVT (by US or venogram) with symptoms of PE and nonhigh prob V/Q 3 teaching hospitals, Canada Dalteparin 200 U/kg s/c daily for a minimum of 5 days until INR > 1.9 (1 st dose given as soon as possible after PE is diagnosed, usually w/I 2 hrs) Warfarin given on day of Dx and continued for 3 months 3 months f/u for “clinically apparent” recurrence of VTE and bleeding Included pts w CA or hypercoag. (LA)

3. 158 APE patients 108 managed as OP 50 managed as inpatient 27 discharged after 2.5 days In house Continue LMWH To Coumadin as OP 81 managed exclusively As OP (Dalteparin to Warfarin) 3 months F/U for recurrent VTE/bleed 11 received 2.1 Days of UFH 16 2.8 days Of LMWH

4. Folow Up Post Discharge INR Days 1, 3, and 5 Follow Up Visits I wk, 1 mo, 3 mos Patients phoned at Least QOD Recurrent DVT: US (or venogram) Recurrent PE: V/Q scan (or US legs +/- PA gram) Bleeding:  Hgb or clinical bleed Further eval. per MD Mortality: PE-related Non PE-related Pts asked to report signs/Sxs of DVT/PE

5. OutpatientEarly DischargeTotal N8127108 Mean Age56.159.456.9 Concomitant Symptomatic DVT 23 (28%)8 (30%)31 (29%) Cancer20 (25)4 (15)25 (23) Idiopathic39 (48)16 (59)45 (42) V/Q scan70 (86)20 (74)90 (83) Spiral Ct5 (6)5 (19)10 (9.2) PA gram3 (4)2 (7)5 (4.6) DVT with compatible Sxs3 (4)0 (0)3 (2.8) Hereditary hypercoaguable State 10 (12)2 (7)12 (11) Lupus Anticoagulant Baseline Characteristics of OP PE patients

6. Outpatient (n 81) Early Discharge (n 27) Total Recurrent DVT/PE 5 (6.2)1 (3.7)6 (5.6) Minor Bleed 3 (3.7)2 (7.4)5 (4.6) Major Bleed 1 (1.2)1 (3.7)2 (1.9) Deaths 4 (4.9)0 (0)4 (3.7) Outcome Results for OP Rx of PE

7. Low risk (as per Wicki et al) symptomatic PE patients OP Rx of PE is Feasible and Safe in a Substantial Proportion of Patients (Beer JH et al. J thromb and Haemoat. 2003;1:186-202) No CANo CHFNo hypotension No hypoxemiaNo prior DVTNo concomitant DVT Contraindications to AC Rx with warfarin X 24 hrs Weight > 110 kg CRI (Cr. Cl < 30 ml/min) Thrombocytopenia (< 120k) Drug addiction Noncompliance Psychiatric condition Age < 18 EXCLUSION

8. Variable Point Score Heart Failure +1 Prior DVT +1 Hypoxaemia +1 DVT on US +1 The Bounameaux PE Point Score (The Geneva Risk Score) Vicki J et.al Thromb Haemost 2000; 84: 548-552 SBP < 90mmHg+1 Cancer+2 Score of > 2 predicts death recurrent VTE, or major bleed at 3 months

9. Regimen Nadroparin calcium (LMWH) 171 IU anti-factor Xa Kg for minimum 5-10 days Phenoprocoumon until INR 2-3 for 2 consecutive days for 6-12 months 3 months follow up: recorrent VTE, bleed (major vs. minor), and mortality

10. 255 Patients with Symptomatic PE 105/255 Patients Included 150/255 patients excluded 43/105 Outpatient Rx (41%) 62/105 Hospitalized Patients (59%) No major bleed 1 Recurrent PE 54/65 (83%) low risk score 11/65 (17%) high Risk score (> 2) No major bleed 2 Recurrent PE (Beer JH et al. J thromb and Haemoat. 2003;1:186-202)

11. Subcutaneous Fondaparinux versus IV UFH in the initial Rx of PE NEJM 2003;349:1695-702 Randomized open-label trial of 2213 pts with APE Noninferiority trial (efficacy) Minimum 5 days of parenteral AC Coumadin ASAP (w/I 72 hrs of AC) and continued for 3 months Efficacy end point: recurrent VTE Safety outcome: Major bleeding during the initial Rx period and death during the following 3 months

12. FondaparinuxUFH Recurrent VTE Initial Rx Entire study 14 (1.3%) 42 (3.8%) 19 (1.7%) 56 (5%) Type of Recurrence Fatal PE Non-fatal PE DVT 16 14 12 15 24 17 Major Bleed Initial Rx Entire study 14 (1.3%) 22 (2.0%) 12 (1.1%) 26 (2.4%) Death Initial Rx Entire study 9 (0.8%) 57 (5.2%) 12 (1.1%) 48 (4.4%) Clinical Outcomes During the Study Period

13. Study Group Recurrent VTE During the 3 mos Period Major Bleeding During the Initial Rx Period <50 kg50-100 kg>100kg<50 kg50-100 kg>100kg Arixtra 5/22 (22.7) 32/945 (3.4) 5/132 (3.8) 0/21 (0) 13/939 (1.4) 1/130 (0.8) UFH 4/25 (16) 41/948 (4.3) 11/136 (8.1) 1/25 (4) 10/931 (1.1) 1/134 (0.7) Rates of Recurrent VTE and Major Bleeding According to Body Weight NEJM 2003;349:1695-702

14. Fundaparinux Group N=1103 86% were 50-100 kg 2.4% Cr Cl < 30 Study Rx started 5.1 h Concomitant DVT 38% ICU 26% Active CA 10.2% 1 day(s) of initial Rx on an outpatient basis 158 (14.5%) Recurrent VTE: 5/158 (3.2%, 1.0-7.2) 0/158 (0%. 0.0-2.4) had major bleed Or died

15. Outpatient Management of Stable PE: Once Daily SC Fondaparinux vs. IV UFH Validate risk stratification criteria to predict suitability for outpatient Rx of PE Evaluate safety and efficacy of fundaparinux for outpatient management of PE Case series (100 consecutive patients) with PE Inclusion: > 18 y/o, objectively confirmed PE (CT, Hi Prob V/Q, or + US or venogram with inter. V/Q) Stable PE

16. Hemodynamically stable FI O2< 4 L/min No ECG criteria for RV strain Non-massive PE (radiographically) No cardiopulmonary disease Negative TnT and BNP No moderate or severe RV dysfunction on echocardiography (done for selected patients)

17. Exclusion Criteria Clinician/patient choice CI for AC Received LMWH, UFH, or Coumadin for > 48 hrs Thrombolysis within 24 hrs Platelets < 100k Cr Cl < 30 Epidural catheters Pregnancy Weight > 150 kg Life expectancy < 6 months Associated arterial thrombosis secondary to HIT

18. Clinical Suspicion for PE PE Confirmed (within the past 48 hrs) Patient Enrolled Can keep patient hospitalized up to 48 hrs after PE diagnosis to complete eval for eligibility and Initiate initial Rx in-house/observe pt Arixtra Rx Can keep in hospital up to 48 hrs Start coumadin ASAP Follow up for 3 mos but AC recommended for 6 mos Composite end point of death, recurrent symptomatic VTE, and major bleed INR: baseline, days 3, 5 and 10 Visits: 1 and 3 months