Asymptomatic and symptomatic venous thromboembolic ep iso des Fatal P E Symptomatic Symptomatic PE Asymptomatic Asymptomatic PE

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1 La Malattia Tromboembolica Venosa La maggior parte degli emboli polmonari origina nelle vene profonde degli arti inferiori La diagnosi di trombosi venosa è inaccurata se emessa sulla base di sintomi i e segni clinici i i I trombi confinati nel polpaccio si associano ad un limitato rischio di embolia fatale. I trombi prossimali sintomatici si associano ad embolia oligo- o a-sintomatica nel 50%-80% dei casi (Rembrandt Study, Circulation 2000) Esistono fattori di rischio identificabili che predispongono allo sviluppo di tromboembolismo venoso Malattie Tromboemboliche - Pavia

2 Asymptomatic and symptomatic venous thromboembolic b episodes Fatal PE Symptomatic PE Asymptomatic PE Symptomatic DVT Asymptomatic DVT Iceberg model

3 PE Kills 3 Times More Medical Patients Than Surgical Patients 25% Medical patients Surgical patients 75% Sandler DA, et al. J R Soc Med. 1989;82:203-5.

4 Major PE diagnosed at autopsy Patient group Suspicion of PE prior to death No suspicion of PE prior to death Post-operative patients (n = 11) Medically ill patients (n = 50) 7 (64%) 4 (36%) 13 (26%) 37 (74%) Total (N = 61) 20 (33%) 41 (67%) 3,470 patients of the 5,209 patients initially evaluated in the Framingham Heart Study Autopsy results available for 392/998 patients t 61 (15.6%) patients died of PE Goldhaber SZ, et al. Am J Med. 1983;74:

5 Pulmonary embolism

6 Tromboembolismo Venoso

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8 Theauthors...havebeendoing... have an outstanding service in bringing the potential of these agents to the attention of the medical community in a convincing manner. It is likely that the first decade of the 21 st century will continue to be a time of great advances in the treatment of thrombotic disorders. Shapiro SS, NEJM; Editorial, October 30, 2003

9 Three Phases in the Evaluation of Antithrombotic Therapies in VTE and Evolution of Outcome Assessment First Phase 1938 late 1960 s Second Phase 1972 early 1990 s Third Phase

10 First Phase First use of heparin in 35 pts with VTE. Murray (1937) and Crafoord (1937) Heparin i.v. in 209 VTE pts with only 3 deaths. Bauer (1946) Heparin and Dicoumarol in 329 pts with one death. Allen et al (1947) Heparin i.v. and nicoumalone vs. no treatment randomized comparison in 35 PE pts. Barritt and Jordan (1960) Survival as major outcome

11 N fatal PE non fatal PE Untreated 19 5 (26%) 5 (26%) Treated Barrit & Jordan, Lancet; June 18, 1960

12 Antithrombotic treatment in venous thromboembolism Barrit & Jordan, Lancet; June 18, 1960

13 Antithrombotic treatment in venous thromboembolism Barrit & Jordan, Lancet; June 18, 1960

14 Antithrombotic treatment in venous thromboembolism Barrit & Jordan, Lancet; June 18, 1960 Malattie Tromboemboliche - Pavia

15 Second Phase Studies about the appropriate monitoring of APTT and INR, as well as the duration of initial therapy (1972 to early 1990 s) Symptomatic recurrent venous thromboembolism and major bleeding as major outcomes

16 Third Phase Studies with LMWH, pentasaccharides, thrombin inhibitors and factor Xa inhibitors. (1992 approx 2010) Out of hospital treatment, no laboratory monitoring, ease of use, non-inferiority for efficacy and clinically relevant/non major bleeding as major outcomes. No distinction between initial and long term treatment

17 The Tasman Study The Tasman Map, also known as the 'Bonaparte Map', made from information collated from voyages made by Abel Tasman between , 44, alongside information gathered by previous Dutch explorers in the region.

18 Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home Tasman Study N Engl J Med 1996;334:682-7 Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular molecular-weight l heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis Canadian Study N Engl J Med 1996;334: Malattie Tromboemboliche - Pavia

19 Home treatment of DVT with LMWHs is as effective and safe as in-hospital i UFH The TASMAN study 6.9% 8.6% 6.9% 8.1% Nadroparin UFH 0.5% 20% 2.0% % VTE recurrence Major bleeding Overall mortality Koopman MWM, Prandoni P, Piovella F., et al. N Engl J Med 1996;334:682 7.

20 Padova 78 Pavia 66 Amsterdam 61 Studio Tasman, NEJM 1996 Pazienti inclusi per Centro Auckland 56 Slatervaart 46 Groningen 37 Adelaide 27 Clamart 23 Sidney 6 Malattie Tromboemboliche - Pavia

21 The Columbus Study VÉÄâÅuâá _tçw Çz tà ZâtÇt{tÇ? DGLE

22 The Columbus Investigators t Low-molecular molecular-weight heparin in the treatment of patients with venous thromboembolism Columbus Study N Engl J Med 1997;337: Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular molecular-weight heparin with unfractionated heparin for acute pulmonary embolism Thésée Study N Engl J Med 1997;337:663-9 Malattie Tromboemboliche - Pavia

23 COLUMBUS and THÉSÉE studies. Main results COLUMBUS THÉSÉE LMWH UFH LMWH UFH (n=510) (n=511) (n=304) (n=308) Recurrent VTE 27 (5.3%) 25 (4.9%) 5 (1.6%) 6 (1.9%) Major bleeding 16 (3.1%) 12 (2.3%) 6 (2.0%) 8 (2.6%) Mortality 36 (7.1%) 39 (7.6%) 12 (3.9%) 14 (4.5%)

24 Studio Columbus, NEJM 1997 Pazienti inclusi per Centro Padova 96 Adelaide 33 Hamilton MMC 19 Pavia 81 Amsterdam (2) 33 Auckland 18 London 75 Quebec (2) 30 Montreal (2) 18 Amsterdam 71 Toronto 29 Nantes 17 Hamilton Hend. 53 Hamilton Gen. 29 Madrid 13 Munich 52 Ottawa 28 Sidney 13 Quebec 51 London (2) 26 Melbourne 10 Groningen 41 Barcelona 24 London (3) 9 Halifax 38 Clamart 20 Besancon 9 Montreal 35 Hamilton St. J. 19 Milano 5

25 The seventh ACCP conference on antithrombotic and thrombolytic therapy Chest 2004, 126: 401S-428S For patients with objectively confirmed DVT/non-massive PE, we recommend acute treatment with subcutaneous LMWH or intravenous UFH (both Grade 1A)

26 Recurrent symptomatic VTE, major bleeding and mortality at three months summary of two meta-analyses in deep vein thrombosis and pulmonary embolism Low Molecular Unfractionated Odds Ratio Weight Heparin Heparin (95% CI) Deep Vein Trombosis Recurrent VTE 86/1998 (4.3%) 113/2021 (5.6%) ( ) Major bleeding 30/2353 (1.3%) 51/2401 (2.1%) 0.60 ( ) 0 93) Mortality 135/2108 (6.4%) 172/2137 (8.0%) 0.78 ( ) Pulmonary Embolism Recurrent VTE 30/988 (3.0%) 39/895 (4.4%) 0.68 ( ) Major bleeding 14/1023 (1.4%) 21/928 (2.3%) 0.67 ( ) Mortality 46/988 (4.7%) 55/895 (6.1%) 0.77 ( ) A. van den Belt et al. 2002, The Cochrane Library D. Quinlan et al. 2004, Ann Intern Med

27 ABSENCE OF NON-SPECIFIC BINDING OF LMWHs LMWHs Malattie Tromboemboliche - Pavia

28 Available LMWHs for VTE Treatment DRUG DAILY DOSAGE Ardeparin 130 U/Kg/12 hr Bemiparin 100 U/Kg/12 hr Dalteparin 200 U/Kg/24 hr Enoxaparin 100 U/Kg/12 hr or 150U/Kg/24 hr Nadroparin 85 U/Kg/12 hr or 170 U/Kg/24 hr Parnaparin 6400 U/Kg/12 hr Reviparin 175 U/Kg/24 hr Tinzaparin 175 U/Kg/24 hr

29 New Anticoagulants Initiation Propagation X Thrombin activity Coagulation cascade TF/VIIa Xa II VIIIa IXa Va IX Drug Tissue factor Pathway inhibitor (TFPI) (Recombinant) Nematode Anticoagulant Peptide (NAPc2) Active Site Blocked FactorVIIa (FVIIai) Factor IXa Inhibitors Direct Factor Xa Inhibitors Apixaban Rivaroxaban YM-150 Razaxaban Indirect Factor Xa Inhibitors Fondaparinux Idraparinux Orally available heparins Inhibitors of Factor VIIIa and Va Protein C Activated Protein C Soluble Thrombomodulin Fibrinogen IIa Fibrin Hirudin Bivalirudin Argatroban Ximelagatran Dabigatran Orally available heparins

30 Fondaparinux* Targeted mechanism of action Intrinsic pathway Extrinsic pathway ATIII ATIII ATIII Xa Xa Org31540/ SR90107A II IIa Fibrinogen Fibrin clot *Arixtra Olson ST, et al. J Biol Chem. 1992;267:

31 The Matisse Studies

32 MATISSE Study Designs 5 days IV UFH (aptt ) + OAC (INR 2-3) Patients with PE ± DVT R Open-label 5 days 7.5-mg fondaparinux* SC + OAC (INR 2-3) Patients with DVT R Double-blind * 5 mg if body weight <50 kg 10 mg if body weight >100 kg 5 days SC enoxaparin (1 mg/kg bid) + OAC (INR 2-3) 90 ± 7 days Primary Efficacy Outcome (3 months) Fatal PE/unexplained death Recurrent symptomatic non fatal PE or DVT Principal Safety Outcome (initial treatment) Major bleed Clinically relevant non major bleed

33 MATISSE PE 1 Primary Efficacy Outcome Fondaparinux (n=1,103) UFH (n=1,110) Fatal PE 16 (1.5%) 15 (1.4%) Nonfatal PE or DVT 26 (2.4%) 41 (3.6%) Total symptomatic recurrent VTE 42 (3.8%) 56 (5.0%) -3.0% -1.2% 0 0.5% Δ=3.5% Fondaparinux - UFH (95% CI) MATISSE DVT 2 Fondaparinux (n=1,098) LMWH (n=1,107) Fatal PE 5 (0.5%) 5 (0.5%) Nonfatal PE or DVT 38 (3.5%) 40 (3.6%) Total symptomatic recurrent VTE 43 (3.9%) 45 (4.1%) -1.8% 0 1.5% -0.15% Fondaparinux - LMWH (95% CI) Δ=3.5% 1. The Matisse Investigators. N Engl J Med, The Matisse Investigators. Ann Intern Med, 2004

34 MATISSE PE 1 Fondaparinux Principal Safety Outcome: Initial Treatment 1.3% 3.2% 4.5 % 1.1% UFH 52% 5.2% 63% 6.3 0% 2% 4% 6% 8% Major bleed Clinically relevant nonmajor bleed MATISSE DVT 2 Fondaparinux 1.1% 2.6% 3.7% LMWH 12% 1.2% 30% 3.0% 42% 4.2% 0% 2% 4% 6% 8% 1. The Matisse Investigators. N Engl J Med, The Matisse Investigators. Ann Intern Med, 2004

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36 PENTASACCHARIDES Arixtra (fondaparinux) SanOrg34006 (idraparinux) in Arixtra HO OH OSO 3 Na COONa OSO 3 Na OSO 3 Na O O O O O OH OSO 3 Na COONa O OH OH O O O OMe NHSO 3 Na OH NHSO 3 Na OSO 3 Na NHSO 3 Na SanOrg T1 /2 suitable to treat o/week instea d of o/d More activity per mg administered 10 Na + MeO O SO 3 - O OMe OMe O COO- OMe O O O SO 3 - O OSO 3 - O O COO- OMe O O SO 3 - O OSO 3 - OMe OMe OSO 3 - OMe OSO 3-9 N a +

37 IDRAPARINUX IN THE TREATMENT OF VTE Phase III studies VAN GOGH DVT VAN GOGH PE IDR VS ENOXAPARIN IDR VS ENOXAPARIN/UFH

38 Idraparinux sodium (SanOrg34006) Phase III van Gogh-DVT Patients ts with symptomatic DVT ization Random LMWH + INR- adjusted VKA 2.5 mg idraparinux once weekly Treatment 3-6 months N=2,200; 1,100 patients per group Open-label EFFICACY: Symptomatic thromboembolic complications SAFETY: All bleeding

39 Idraparinux sodium (SanOrg34006) Phase III van Gogh-PE Patients ts with symptomatic PE ization Random LMWH + INR- adjusted VKA 2.5 mg idraparinux once weekly Treatment 3-6 months N=2,200; 1,100 patients per group Open-label EFFICACY: SAFETY: Symptomatic thromboembolic complications All bleeding

40 Long-term effects Post-thrombotic syndrome 1 Pulmonary hypertension 2 Recurrent VTE 34 Increased healthcare costs 1 Kahn S, Ginsberg J. Arch Intern Med. 2004;164: Pengo V, et al. N Engl J Med. 2004;350: Palareti G, Cosmi B. Curr Opin Hematol. 2004;11: Piovella F, Crippa L, Barone M, et al. Haematologica 2002; 87:515-22

41 Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH) In patients with a first episode of PE the cumulative incidence of symptomatic CTEPH is 38%attwoyears 3.8% two All CTPEH developed within two years of the acute episode Risk factors for CTPEH were large perfusion defects, increased age, previous PE, or idiopathic PE Prevention of recurrent PE has potential to decrease incidence of CTPEH Pengo et al. NEJM, 2004

42 Remarkable progress has been made in understanding the etiology, prevalence, natural history, and therapeutic approach to chronic c thromboembolic pulmonary hypertension (CTEPH) during the past two decades. This disease, first described as an autopsy curiosity (Ball 1956, Carrol 1950, Chait 1967, Hollister 1956), results from obstruction of the major (main, lobar, segmental) pulmonary arteries with incompletely resolved or organized pulmonary emboli which have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistance.

43 Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

44 Pavia CTPH Program Surgical Specimens from Different Patients t

45 In the final analysis, the therapeutic efficacy of any drug can only be demonstrated by clinical trials in man Annotation, British Journal of Haematology 1984

46 Franco Piovella Marisa Barone Luca Librè Chiara Piovella Artemisia Anna Natalizi Panou Silvia Serafini Chiara Beltrametti Sergio Siragusa Sandra Carbone Anna Samaden Servizio Malattie Tromboemboliche IRCCS Policlinico San Matteo Pavia