Outpatient Treatment of Acute Pulmonary Embolism Review of

Outpatient Treatment of Acute Pulmonary Embolism: Review of Published Studies Amjad Al. Mahameed, MD, MPH

OP Rx of PE with Dalteparin (Kovacs MJ, J thromb and Haemoat. 2000; 83: 209 -11) • Prospective cohort study • All pts with PE (2/199611/1998) 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)

158 APE patients 108 managed as OP 27 discharged after 2. 5 days In house 11 received 2. 1 Days of UFH 50 managed as inpatient 81 managed exclusively As OP (Dalteparin to Warfarin) 16 2. 8 days Of LMWH Continue LMWH To Coumadin as OP 3 months F/U for recurrent VTE/bleed

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

Baseline Characteristics of OP PE patients Outpatient N Early Discharge Total 81 27 108 56. 1 59. 4 56. 9 23 (28%) 8 (30%) 31 (29%) Cancer 20 (25) 4 (15) 25 (23) Idiopathic 39 (48) 16 (59) 45 (42) V/Q scan 70 (86) 20 (74) 90 (83) Spiral Ct 5 (6) 5 (19) 10 (9. 2) PA gram 3 (4) 2 (7) 5 (4. 6) DVT with compatible Sxs 3 (4) 0 (0) 3 (2. 8) 10 (12) 2 (7) 12 (11) Mean Age Concomitant Symptomatic DVT Hereditary hypercoaguable State Lupus Anticoagulant

Outcome Results for OP Rx of PE 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)

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) Low risk (as per Wicki et al) symptomatic PE patients No CA No CHF No hypotension No hypoxemia No prior DVT No concomitant DVT EXCLUSION • • • Contraindications to AC Rx with warfarin X 24 hrs Weight > 110 kg CRI (Cr. Cl < 30 ml/min) Thrombocytopenia (< 120 k) • • Drug addiction Noncompliance Psychiatric condition Age < 18

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

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

255 Patients with Symptomatic PE 105/255 Patients Included 43/105 Outpatient Rx (41%) 150/255 patients excluded 62/105 Hospitalized Patients (59%) 54/65 (83%) low risk score No major bleed 1 Recurrent PE 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)

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

Clinical Outcomes During the Study Period Fondaparinux UFH 14 (1. 3%) 42 (3. 8%) 19 (1. 7%) 56 (5%) 16 14 12 15 24 17 14 (1. 3%) 22 (2. 0%) 12 (1. 1%) 26 (2. 4%) 9 (0. 8%) 57 (5. 2%) 12 (1. 1%) 48 (4. 4%) Recurrent VTE Initial Rx Entire study Type of Recurrence Fatal PE Non-fatal PE DVT Major Bleed Initial Rx Entire study Death Initial Rx Entire study

Rates of Recurrent VTE and Major Bleeding According to Body Weight Study Group Recurrent VTE During the 3 mos Period Major Bleeding During the Initial Rx Period <50 kg Arixtra UFH 50 -100 kg >100 kg <50 kg 50 -100 kg >100 kg 5/22 (22. 7) 32/945 (3. 4) 5/132 (3. 8) 0/21 (0) 13/939 (1. 4) 1/130 (0. 8) 4/25 (16) 41/948 (4. 3) 11/136 (8. 1) 1/25 (4) 10/931 (1. 1) 1/134 (0. 7) NEJM 2003; 349: 1695 -702

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

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

Stable PE • Hemodynamically stable • FI O 2< 4 L/min • No ECG criteria for RV strain • Non-massive PE (radiographically) • No cardiopulmonary disease • Negative Tn. T and BNP • No moderate or severe RV dysfunction on echocardiography (done for selected patients)

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

Clinical Suspicion for PE Can keep patient hospitalized up to 48 hrs after PE diagnosis to complete eval for eligibility and Initiate initial Rx in-house/observe pt PE Confirmed (within the past 48 hrs) Patient Enrolled • • 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