2. What’s New in the Treatment of Pulmonary Embolism December 2009 David Garcia, MD Associate Professor University of New Mexico

3. Outline Can we identify PE patients at low risk of adverse outcomes? How long should patients with PE be treated with warfarin? When is thrombolysis appropriate?

4. Risk-stratifying PE patients Mortality among patients with PE is high – 17% in one study Many clinicians believe that a subset of patients with PE could be safely treated out of hospital How to identify patients at high or low risk of adverse outcomes

5. PE Severity Index (PESI) Aujesky, et al. Archives Internal Medicine. 2006;166:169-175

6. INDEPENDENT PREDICTORS OF 30-DAY MORTALITY IN THE DERIVATION SAMPLE AND POINTS ASSIGNED TO THE RISK SCORE Predictors B-Coefficients (95% C1)Points Assigned Demographic characteristics Age, per yr0.03 (0.02-0.03)Age, in yr Male sex0.17 (0.02-0.32)+10 Co-morbid illnesses Cancer0.87 (0.71-1.03)+30 Heart failure0.31 (0.14-0.49)+10 Chronic lung disease0.30 (0.12-0.47)+10 Clinical findings Pulse > 110/min0.60 (0.44-0.76)+20 Systolic blood pressure < 100mm Hg0.86 (0.67-1.04)+30 Respiratory rate > 30/min0.41 (0.23-0.58)+20 Temperature < 36 C0.42 (0.25-0.59)+20 Altered mental status *1.50 (1.30-1.69)+60 Arterial oxygen saturation < 90%0.58 (0.37-0.79)+20 Point total and risk class: 125 class V.

7. Validation Cohort 30-Day Mortality and Adverse Events Within Risk Strata Derived From the PESI Prediction Rule ** PESIn = 10,354n = 953n = 599n = 43 I 19.4 (18.7–20.2)1.1 (0.7–1.7)12.3 (9.7–15.0)0 II 21.5 (20.7–22.3)3.1 (2.5–4.0)23.7 (20.3–27.1)1.4 (0.5–3.3) III 21.7 (20.9–22.5)6.5 (5.5–7.6)28.9 (25.2–32.5)6.9 (3.9–13.0) IV 16.4 (15.7–17.1)10.4 (9.0–11.9)21.5 (18.2–24.8)10.1 (4.9–15.3) V 21 (20.3–21.8)24.5 (22.7–26.9)13.5 (10.8–16.3)19.7 (11.1–28.4) Jimenez et al Chest 2007 vol. 132(1):P 7-8. % in risk class*% dead* % in risk class* % dead* * Parentheses are 95% CI

8. Although not yet the U.S. standard of care, medium-quality evidence supports out-of- hospital PE treatment in selected patients 1.Wells PS. A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2005;165:733-738 2.Kovacs MJ. Outpatient treatment of pulmonary embolism with dalteparin. Thrombosis & Haemostasis. 2000;83:209-211 3.Kearon C. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. Jama. 2006;296:935-942 4.Buller HR. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349:1695-1702

9. Outpatient VTE Protocol Clinical Exclusionary Criteria* Absolute Active bleeding or positive stool guiac Thrombocytopenia <100K Major surgery/trauma or CVA <2 weeks Phlegmasia Symptomatic PE Severe renal dysfunction Recent GI bleeding Hypertensive emergency History of heparin sensitivity or HIT Active or major comorbid illness Relative History of familial bleeding disorder Morbid obesity Iliofemoral DVT Pregnancy Underlying liver disorder Age > 75yrs Acquired or congenital hypercoagulable state Based on compedium of RCT’s and observational studies

10. Psychosocial and/or Socioeconomic Exclusionary Factors from Outpatient VTE Treatment History of non-compliance with medicines History of substance abuse Language barrier Inability to pay for LMWH Inaccessibility to clinic or telephone Unstable home environment Incompetence to assume responsibility for self- care or inability for family/friend/nurse to administer care Above are relative exclusionary risk factors

11. Product Dosing heparin aPTT or anti-Xa 1.5-2.5 x control (use nomogram) OR (unfract.) give weight-based SC dosing (see Kearon et al. JAMA 2006) enoxaparin 1.0 mg/kg sc. every 12 hrs OR 1.5 mg/kg sc. once a day tinzaparin 175 anti Xa IU/kg once daily dalteparin 200 anti Xa IU/kg once daily OR 100 anti Xa IU/kg every 12 hrs fondaparinux 7.5 mg SC q.d. Acute Treatment of DVT

12. ACCP Consensus Conference on Antithrombotic Therapy In patients with acute DVT and “submassive” PE, initial treatment with LMWH or fondaparinux recommended over unfractionated heparin… Kearon et al. Chest 2008.

13. DVT treatment: LMWH vs. IV UFH Major Bleeding (n=3674) Recurrent Thromboembolism (n=3566) OR, 0.57 (P=0.047) OR, 0.71 (P =0.25) OR, 0.85 (P=0.28) OR, 0.87 (P =0.40) 0.01 0.1 1 10 100 Favors LMWH Favors UFH Odds Ratio Favors LMWH Favors UFH Odds Ratio Primary Studies Duroux, 1991 (nadroparin) Hull, 1992 (tinzaparin) Prandoni, 1992 (nadroparin) Lopaciuk, 1992 (nadroparin) Simonneau, 1993 (enoxaparin) Lindmarker, 1994 (daltiparin) Levine, 1996 (enoxaparin) Koopman, 1995 (nadroparin) Fiessinger, 1996 (dalteparin) Luomanmaki, 1998 (dalteparin) Columbus, 1997 (riviparin) Gould ANN INT MED 1999

14. LMWH vs. UFH in treatment of PE – symptomatic VTE at end of treatment Quinlan Ann Int Med 2004

15. UFH in the “REAL WORLD” 311 patients being bridged with UFH to warfarin Once aPTT in range, next 2 measurements were therapeutic only 29% of the time Therapeutic range maintained for 4 consecutive days only 7% of the patients 54% had at least one prolonged interruption of their infusion Hylek et al. Arch Int Med 2003 163(5):621-7.

16. Are all “provoked” clots the same? Baglin et al. Lancet. 2003 Aug 16;362(9383):523-6. Unprovoked (n=192) Non-surgical RF: cast, immobilization, estrogen, travel (n=279) Surgery (n=86)

17. Risk factors for recurrence Factor Relative Risk DVT isolated to calf (vs. proximal)0.5 Low d-dimer 1 month after VKA stopped0.4 Asian ethnicity0.8 One or more prior VTE episodes1.5 Antiphospholipid antibody2.0 Protein C or Protein S deficiency1.5 Male gender (vs. female)1.6 Residual thrombosis in proximal veins1.5 Kearon et al Chest 2008 133: 454S-545S

18. Major Bleeding during Extended Treatment with Warfarin Study Events/patient-yrs (% / yr) (% / yr) DURAC 2 4/355 (1.1%) LAFIT (total) 4/268 (1.5%) ELATE 8/872 (0.9%) PROLONG 1/154 (0.6%) Total 24/1843 (1.3%)

19. Hylek, EM.

20. Hylek, EM

21. My Approach Treat Proximal DVT or PE (unprovoked) at least 3- 6 months Ensure the patient is up-to-date on age-appropriate cancer screening and perform careful physical exam and review of systems. Ensure the patient is up-to-date on age-appropriate cancer screening and perform careful physical exam and review of systems. Discuss risks/benefits of extended therapy with all patients. Discuss risks/benefits of extended therapy with all patients. Encourage extended therapy for patients who: Encourage extended therapy for patients who: are male have had previous VTE had PE (rather than DVT) as their index event have poor cardiopulmonary reserve have stable INR values Test young patients for antiphospholipid syndrome. Test young patients for antiphospholipid syndrome. Consider d-dimer testing and/or repeat ultrasound if other factors equivocal. Consider d-dimer testing and/or repeat ultrasound if other factors equivocal.

22. When are thrombolytic agents appropriate for patients with PE? Hypotension, shock –Consensus that risk > benefit RV dysfunction, elevated laboratory markers (e.g. troponin) –Evidence not definitive –Controversy persists

23. Odds of short-term death in patients with elevated (vs. normal) troponin levels Troponin I Troponin T Becattini C, et al. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007 Jul 24;116(4):427-33.

24. Right Ventricular Dysfunction (RVD): a risk factor for mortality (-) RVD(+) RVD Ribeiro ‘9756 (0)70 (4) Grifoni ‘0097 (0)65 (5) Viellard-Baron ‘0163 (3)32 (3) Total216 (0.9)167 (4) No. of patients (% mortality) Dalen, JE. Arch Int Med 2002, 162:2521-2523

25. Alteplase for PE Sexy, recombinant “clot-busting” technology Improves V/Q scans, reduces angiographic clot burden, lowers pulmonary artery & RV pressures More “active” than simple anticoagulation

26. Heparins for PE – Room to improve? For patients with PE treated with heparin (or LMWH) + warfarin, the overall in-hospital mortality due to PE is 2.2%. 1,2 1 Douketis, et al. “Risk of fatal PE in pts with treated venous thromboembolism” JAMA 1998, 279:458-462. 2 Carson, et al. “The clinical course of pulmonary embolism” NEJM 1992, 326:1240-1245..

27. Thrombolytic Therapy and Bleeding YearComment No. patients ICH (%) Fatal Bleed (%) Levine‘95 VTE review 223-2.2 Dalen‘97 PE review 5592.11.6 Kanter‘97 PE review 3121.9- Goldhaber‘99 PE registry 3043.0- Hamel‘01 PE – cohort 644.7- Konstantinides ‘03 PE - RCT 118

28. Other ideas that “made sense” Anti-arrhythmic drugs to suppress PVC’s post-MI Hormone replacement therapy to stroke and ACS in postmenopausal women

29. Thrombolysis for PE with RVD: a randomized, controlled trial. 256 patients Hemodynamically stable (+) RV dysfunction Heparin “5000/1000” + alteplase n=118 Heparin “5000/1000” + placebo n=138 RANDOMIZED, DOUBLE-BLIND* Primary end point: in-hospital death + “escalation of treatment”

30. “Escalation of Treatment” Endotracheal Intubation Catecholamine Infusion Cardiopulmonary Resuscitation “Secondary” Thrombolysis

31. Event-free Survival Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150. 50 60 70 80 90 100 0 0 51015202530 heparin + alteplase heparin + placebo P=0.005

32. In-Hospital Clinical Events (%) Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150. EventHeparin + alteplase (n=118) Heparin + placebo (n=138) P Primary endpoint11.024.60.006

33. In-Hospital Clinical Events (%) Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150. EventHeparin + alteplase (n=118) Heparin + placebo (n=138) P Primary endpoint11.024.60.006 Death3.42.20.71 Endotracheal Intubation2.52.20.85 Catecholamine Infusion2.55.80.33 CPR00.71.0

34. In-Hospital Clinical Events (%) Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150. EventHeparin + alteplase (n=118) Heparin + placebo (n=138) P Primary endpoint11.024.60.006 Death3.42.20.71 Endotracheal Intubation2.52.20.85 Catecholamine Infusion2.55.80.33 CPR00.71.0 Secondary Thrombolysis 7.6 (n=9) 23.2 (n=32) 0.001

35. MAPPET-3 Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150. Did the placebo patients really “deteriorate” more frequently than the alteplase patients?

36. Thrombolysis for PE with RVD: a randomized, controlled trial. 256 patients Hemodynamically stable (+) RV dysfunction heparin + alteplase n=118 heparin + placebo n=138 RANDOMIZED, DOUBLE-BLIND* *Investigators contemplating open-label alteplase were permitted to break the randomization code!

37. In-Hospital Clinical Events (%) Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150. EventHeparin + alteplase (n=118) Heparin + placebo (n=138) P Primary endpoint11.024.60.006 Death3.42.20.71 Endotracheal Intubation2.52.20.85 Catecholamine Infusion2.55.80.33 CPR00.71.0 Secondary Thrombolysis 7.6 (n=9) 23.2 (n=32) 0.001

38. Thrombolytic Therapy and Bleeding YearComment No. patients ICH (%) Fatal Bleed (%) Levine‘95 VTE review 223-2.2 Dalen‘97 PE review 5592.11.6 Kanter‘97 PE review 3121.9- Goldhaber‘99 PE registry 3043.0- Hamel‘01 PE – cohort 644.7- Konstantinides ‘03 PE - RCT 11800

39. MAPPET – 3: Conclusions Patients in the “heparin + placebo” arm received alteplase more often than patients in the “heparin + alteplase” arm. Patients with “RV dysfunction” given a suboptimal heparin regimen + placebo have an in-hospital mortality rate of only 2.2%!

40. Overall Conclusions Risk prediction models allow clinicians to identify PE patients at high (or low) risk of death. LMWH and fonda preferred over UFH. Further prospective studies are needed to confirm the hypothesis that selected “low risk” patients can be treated entirely out-of-hospital. Duration must be individualized but latest guidelines lean toward extended therapy Currently available evidence does not support the routine use of thrombolytic agents among patients with submassive PE.