1. Daniela Tormene MALATTIE TROMBOEMBOLICHE Anatomic theatre, Padua University

3. Brandjes DPM, Heijboer H, Büller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis (A.T.H.O.S.) N Engl J Med 1992

4. A.T.H.O.S. STUDY Results _______________________________________________ Sintrom Hep. + Sintrom (N=60) (N=60) _______________________________________________ Symptomatic VTE 20% 6.7% Asympt. DVT extens. 39.6% 8.2% Major bleeding 5.0% 3.0% _______________________________________________

5. Different heparin dosage regimens in venous thrombosis ___________________________________________________ Starting U/24 h Recurrent VTE (%) High Low High Low ___________________________________________________ Brandjes, 1992 30,000 0 6.7 20.0 Hull, 1986 30,000 iv 30,000 sc 5.2 19.8 Raschke, 1993 30,240 24,000 5.0 25.0 ___________________________________________________

6. Heparin nomogram (Cruikshank et al., 1991) Bolus: 5000 U followed by 1280 U/h. First APTT after 6h ___________________________________________________ APTTBolusHold Rate change Rep. APTT (sec) (U)(min) (U/h) < 505,0000+ 1206 h 50-5900+ 1206 h 60-85000 next morning 89-9500- 806 h 96-120030- 806 h > 120060- 1606 h

7. Current Treatments for Patients with Acute VTE Unfractionated or low-molecular-weight heparin followed by 3–6 months of oral anticoagulant therapy Thrombolytic treatment in selected patients with critical PE Intracaval filter in selected patients with contraindications to antithrombotic drugs Buller HR et al. Chest 2004

8. Efficacy and safety of LMWH in comparison to UFH

9. Thrombus reduction Recurrent VTE Major bleeding OR=0.69 (0.59-0.81) OR=0.68 (0.55–0.84) OR=0.57 (0.39–0.83) Favours LMWH RR Favours UFH 0.0 0.5 1.0 1.52.0 Effects of LMWH vs Unfractionated Heparin (UFH) in the Treatment of Acute VTE (22 studies, 8867 symptomatic patients) Total mortality OR=0.76 (0.62–0.92) Cochrane Review System 2004

10. New Therapeutic Opportunities Home treatment of DVT Treatment of PE HIT and Osteoporosis Treatment of DVT in cancer patients Treatment of SVT The potential of new drugs

11. Home treatment of suitable patients with DVT

12. Outpatient DVT treatment with LMWH TASMAN and North-American studies TASMAN North-American LMWHUFHLMWH UFH (n=202)(n=198)(n=247) (n=253) Recurrent VTE Recurrent VTE14 (6.9%)17 (8.6%)13 (5.3%)17 (6.7%) Major bleeding Major bleeding1 (0.5%)4 (2.0%)5 (2.0%)3 (1.2%) Mortality Mortality14 (6.9%)16 (8.1%)11 (4.4%)17 (6.7%)

13. Ambulatory treatment with LMWH AuthorLMWHSettingPts Grau ‘98NadroparinDVT39 Harrison ‘98Dalt/TinzapDVT89 Mattiasson ‘98DalteparinDVT240 Wells ‘98DalteparinDVT/PE184 Kovacs ‘00DalteparinPE108 Labas ‘01EnoxaparinDVT96 Lapidus ‘02TinzaparinDVT332 Beer ’03NadroparinPE104 Wells ’05Daltep/TinzapDVT/PE505

14. Wells PS, Kovacs MJ, Bormanis J, Forgie MA, Goudie D, Morrow B, Kovacs J Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low- molecular-weight heparin Arch Intern Med 1998

15. Study design  Prospective long-term evaluation of a wide series of patients with a broad spectrum of venous thromboembolic presentations treated at home with dalteparin (200 U/Kg every 24 hours) for a minimum of 5 days

16. Patients treated at home  Patients considered233 39  Patients excluded 39 - concomitant med. problems:20 - massive pulmonary embolism 6 - cost considerations 6 - active bleeding 4 - phlegmasia coerulea dolens 3  Patients treated on a home basis194

17. Features of home treated patients Characteristics Homecare Self-injection (N=95) (N=99) Mean age 63.5 + 16 63.1 + 17 Proximal DVT 77 77 Pulmonary embolism 16 18 Arm DVT 2 4 Idiopathic 28 32 Cancer 32 29 Previous DVT 14 15 DVT due to risk factors 21 23

18. Prospective 3-month evaluation of clinical outcomes Events Homecare Self-injection (N=95) (N=99) Recurrent VTE Recurrent VTE 3 (3.2%) 4 (4.0%) Major bleeding Major bleeding2 (2.1%) 2 (2.0%) Mortality Mortality * 6 (6.3%) 8 (8.0%) * due to cancer in 11 patients

19. ConclusionsConclusions  More than 80% of patients with acute venous thromboembolism can be treated at home with a low-molecular- weight heparin  Patients can safely and effectively perform self-injection of the anticoagulant drug

20. Treatment of Pulmonary Embolism

21. NEJM 1997: COLUMBUS and THESEE studies. Main results COLUMBUSTHESEE LMWH UFHLMWH UFH (n=510)(n=511)(n=304)(n=308) Recurrent VTE Recurrent VTE 27 (5.3%)25 (4.9%)5 (1.6%)6 (1.9%) Major bleeding Major bleeding16 (3.1%)12 (2.3%)6 (2.0%)8 (2.6%) Mortality Mortality36 (7.1%)39 (7.6%)12 (3.9%)14 (4.5%)

22. Ann Intern Med 2004; 140: 175-83 Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta- analysis of randomized, controlled trials Quinlan DJ, McQuillan A, Eikelboom JW

23. Recurrent VTE in patients with symptomatic PE

24. Short- and Long-term Outcome of Patients with PE Konstantinides S et al. Circulation 1997;96:882–8 Goldhaber SZ et al. Lancet 1999;353:1386–9 Ribeiro A et al. Circulation 1999;10:1325–30 Grifoni S et al. Circulation 2000;101:2817–22 Pengo V et al. N Engl J Med 2004; 350: 2257-64

25. Konstantinides S et al. N Engl J Med 2002;347:1143–50 Heparin Plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W

26. UFH plus alteplase (n = 118) UFH alone (n = 137) Event = in-hospital death or clinical deterioration requiring an escalation of treatment 70 80 90 100 5101520 25 30 Probability of event-free survival (%) Days Cumulative Probability of Event-free Survival Konstantidines S et al. N Engl J Med 2002;347:1143–50

27. HIT and Osteoporosis

28. Reduction of HIT and osteoporosis? Likely but not conclusively demonstrated Likely but not conclusively demonstrated At least in medical patients, the rate of LMWH- related HIT is not negligible (0.80%, Prandoni et al, Blood 2005) At least in medical patients, the rate of LMWH- related HIT is not negligible (0.80%, Prandoni et al, Blood 2005) In patients requiring the long-term administration of heparin, the use of UFH is associated with a higher rate of bone fractures than LMWH (Monreal et al, Thromb Haemost 1994) In patients requiring the long-term administration of heparin, the use of UFH is associated with a higher rate of bone fractures than LMWH (Monreal et al, Thromb Haemost 1994)

29. Potential benefit of LMWHs on survival in cancer patients Potential benefit of LMWHs on survival in cancer patients

30. LMWH UFH (n=85) (n=85) Generation of the hypothesis (Prandoni et al, Lancet 1992) 6-month mortality5 (5.9%)9 (10.6%) Cancer-related mortality1/15 (6.7%)8/18 (44.4%)

31. … although this is a post-hoc finding, it is interesting that 44% of the cancer patients in the standard heparin group died, compared with only 7% of cancer patients in the LMWH group. This difference is statistically unusual (p=0.021) if these treatments had no effect on the likelihood of succumbing to cancer … Prandoni et al, Lancet 1992

32. AuthorYearNo. of studies CancermortalityOR UFHLMWH Green1992 2 7/62 (11%) 21/67 (31%)0.28 Siragusa199513 10/74 (14%) 23/81 (28%)0.39 Hettiarachchi1999 947/306 (15%)71/323 (22%)0.61 Gould19991122/132 (17%)38/147 (26%)0.57 Meta-analyses of DVT treatment studies

33. Clinical trials addressing the value of LMWH on cancer survival FAMOUS (J Clin Oncol 2004) MALT (J Clin Oncol 2005) CLOT 2 (J Clin Oncol 2005) TURKISH STUDY (J Thromb Haemost 2004)

34. Persisting indications for UFH in the treatment of patients with VTE Renal insufficiency Relative contraindications to heparin Suspicion of PE in patients with critical presentation

35. The Potential of New Drugs

36. Factor Xa AT Arg Lys Pentasaccharide Factor Xa, the only target Pentasaccharides

37. A T I S S E M....... Fondaparinux in Comparison to (Low Molecular Weight) Heparin for the Initial Treatment of Patients with Symptomatic Deep Venous Thrombosis or Pulmonary Embolism The Matisse studies The Matisse Investigators. Blood 2002;100:A302

38. Fondaparinux (n=1098)LMWH (n=1107) Matisse DVT Fatal PE 5 (0.5%) 5 (0.5%) Non-fatal PE or DVT38 (3.5%)40 (3.6%) Total symptomatic recurrent VTE43 (3.9%)45 (4.1%) -0.15 %  = 3.5% 0 1.5% -1.8% Fondaparinux - LMWH (95% CI ) Fondaparinux (n=1103)UFH (n=1110) Fondaparinux - UFH (95% CI ) Matisse PE -1.2%  = 3.5% 0 0.5% -3.0% Fatal PE16 (1.5%)15 (1.4%) Non-fatal PE or DVT26 (2.4%)41 (3.6%) Total symptomatic recurrent VTE42 (3.8%)56 (5.0%) A T I S S E M....... Matisse: Primary Efficacy Outcome at 3 Months The Matisse Investigators. Blood 2002;100:A302

39. Matisse DVT 3.7% 4.2% Matisse PE 4.5% 6.3% A T I S S E M....... Major bleedClinically relevant non-major bleed Matisse: Principal Safety Outcome: Initial Treatment Fondaparinux LMWH Fondaparinux UFH The Matisse Investigators. Blood 2002;100:A302

40. Fondaparinux (Arixtra ® ) MOST LIKE NATURAL Once-a-day Org31550 MORE POTENT A new binding site discovered Idraparinux, SanOrg34006 SIMPLIFIEDOnce-a-weekPentasaccharides tailor made OCH 3

41. Asymptomatic + symptomatic VTE + unexplained death Overall dose trend P=0.062 2/128 3/119 2/124 PERSIST: Thrombotic Burden: Deterioration (ITT Population) 7.3 12.6 6.8 6.3 4.8 Persist Investigators. Blood 2002;100:A301 ITT = intent to treat

42. Major bleeding Any bleeding Idraparinux PERSIST: Bleeding Events Persist Investigators. Blood 2002;100:A301 0.0 3.0 1.5 6.9 0.8 2.3 11.9 13.8 15.3 8.3

43. VAN GOGH DVTVAN GOGH PE IDR VS ENOXAPARIN OR UFH FOLLOWED BY VKA IDRAPARINUX IN THE TREATMENT OF VTE Phase III studies

44. Conclusions Home treatment of DVT with LMWH is feasible, safe and cost-effective for selected patients Patients with acute PE and right-ventricular dysfunction might benefit from a combination of heparin and thrombolytic drugs to a greater extent than from heparin alone LMWH is more effective than oral anticoagulants for prevention of recurrent VTE in cancer patients Among the categories of emerging new compounds, for the time being only fondaparinux is an alternative to conventional anticoagulation, but can only be used for the initial VTE treatment

47. RE-COVER I 1 RE-COVER II 2 EINSTEIN-DVT 3 EINSTEIN-PE 4 AMPLIFY 5 Hokusai-VTE 6 Study drugDabigatranRivaroxabanApixabanEdoxaban Study design*Double-blindOpen-labelDouble-blind Pre- randomization heparin NR<48 hrs<36 hrs<48 hrs Heparin lead-inAt least 5 daysNone At least 5 days Dose150 mg BID 15 mg BID x 3 wk then 20 mg QD 10 mg BID x 7 d then 5 mg BID 60 mg QD 30 mg QD † Dose reductionNONE 18% Randomized population 2,564 1 2,568 2 3,449 3 4,833 4 5,4008,292 Treatment duration 6 monthsPre-specified 3, 6, 12 months 6 monthsFlexible 3 to 12 months 1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. Schulman et al. Blood 2011;118:Abstract 205 3. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 4. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297 5. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 6. The Hokusai-VTE Investigators. N Engl J Med 2013 VTE treatment: study designs *Comparator was warfarin in each case † Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding by predefined criteria NR=not reported