Expanding the treatment options of Superficial vein thrombosis with Rivaroxaban

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1 Expanding the treatment options of Superficial vein thrombosis with Rivaroxaban Athanasios D. Giannoukas MD, MSc(Lond.), PhD(Lond.), FEBVS Professor of Vascular Surgery Faculty of Medicine, School of Health Sciences, University of Thessalia, Greece Chairman, Dept. of Vascular Surgery, University Hospital of Larissa Larissa, Greece

2 DISCLOSURES Participation in CALISTO Trial sponsored by GLAXO Honoraria from BAYER and Leo

3 Annual rate per 1000 SVT is a frequent disease STEPH 1 and EPI-GETBO 2 : Two French prospective epidemiological studies with comparable methodology [ ] 1.24 [ ] 0.60 [ ] SVT STEPH DVT EPI-GETBO PE EPI-GETBO 1. Frappé P. et al. J Thromb Haemost 2014; 12: Oger E. Thromb Haemost 2000; 83: DVT = deep vein thrombosis; PE = pulmonary embolism; SVT = superficial vein thrombosis.

4 Concomitant DVT or PE is frequent in patients with SVT at first presentation Setting Study POST [1.4] OPTIMEV [2,4] STEPH [3,4] Secondary/tertia ry Secondary/tertiary Primary No. of SVT patients Concomitant DVT or PE, % Concomitant DVT*, % Concomitant symptomatic PE, % *40 to 50% are proximal DVT, 40 to 45% are non-contiguous to SVT Systematic research of PE symptoms and ultrasonography 1. Decousus H. et al. Ann Intern Med 2010; 152: Galanaud JP. et al. Thromb Hemost 2011; 105: Frappé P. et al. J Thromb Hemost 2014; 12: Decousus H. et al. J Thromb Haemost 2015; 13 Suppl 1:S DVT = deep vein thrombosis; PE = pulmonary embolism; SVT = superficial vein thrombosis.

5 Patients with isolated SVT* are at significant risk of subsequent symptomatic DVT or PE at 3 6 months Study/setting Treatment received DVT, % PE, % STENOX 3 months, N = 427 VESALIO 3 months, N = 164 LMWH for 12 days in 50% LMWH for 30 days in all POST 3 months, N = 600 One or more anticoagulants in 90.5% (LMWH for a median of 11 days) OPTIMEV 3 months, N = 499 CALISTO* 77 days, N = 1,500 STEFLUX 3 months, N = 648 Van Weert 6 months, N = 185 Danish Registry 3 months, N = 10,973 Anticoagulants in 76.4% (for > 45 days in 24.6%) Placebo (patients at high risk excluded) * SVT without concomitant DVT or PE at first presentation. Decousus H. et al. J Thromb Haemost 2015; 13 Suppl 1:S LMWH for days in all No treatment in 83% No routine anticoagulant treatment DVT = deep vein thrombosis LMWH = low-molecular-weight heparin PE = pulmonary embolism SVT = superficial vein thrombosis

6 SVT close to SFJ

7 Guidelines (ACCP - International Consensus) Fondaparinux 2.5 mg daily for at least 4 weeks is an effective treatment (Grade 1b) LMWH in intermediate doses for at least one month is recommended (Grade 2a )

8 2010;363:

9 Fondaparinux for the treatment of superficial-vein thrombosis in the legs (Calisto) Décousus, H, Prandoni P, Mismetti P, Bauersachs R, Boda Z, Brenner N, Laporte S, Matyas L, Middeldord S, Sokurenko G, Leizorovicz A; N Engl J Med 2010; 363: 13: Inclusion Hospitalized or non-hospitalized patients 18 yrs With acute symptomatic SVT of the lower limbs at least 5 cm long and with thrombus head > 3 cm from the saphenofemoral or sapheno-popliteal junctions Confirmed by standard compression ultrasonography (CUS) Without concomitant DVT or PE at inclusion Able and willing to provide written informed consent Exclusion Symptomatic or asymptomatic DVT on qualifying CUS and/or PE SVT with thrombus head within 3 cm from the sapheno-femoral or sapheno-popliteal junctions SVT with an history of documented DVT/PE within the last 6 months SVT in patients with active cancer i.e. cancer within the last 6 months SVT in severe renal impairment (<30 ml/min) Treatment with anticoagulant therapy > 48 hours prior to inclusion Requirement for ligation of the sapheno-femoral junction or thrombectomy SVT following sclerotherapy or resulting as a complication of an IV line

10 Primary Outcomes Primary efficacy outcome: Composite of symptomatic thromboembolic complications and all-cause death up to Day 47 in all randomized patients (ITT) Symptomatic non-fatal (confirmed by CT or V/Q scans) or fatal PE Symptomatic DVT (confirmed by CUS) Symptomatic extension of the initial SVT, at 3 cm from the saphenofemoral junction (confirmed by CUS) Symptomatic recurrent SVT (confirmed by CUS) All-cause death Primary safety outcome: Major bleeding and death up to Day 47 in all randomized patients having received 1 treatment dose

11 CALISTO study The primary efficacy outcome at day 47 (death from any cause or symptomatic PE, symptomatic DVT, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of DVT) occurred in 0.9% of patients in the fondaparinux group and 5.9% in the placebo group (P < 0.001). The rate of PE or DVT was 85% lower in the fondaparinux group at day 47. Similar risk reductions were observed at day 77. No difference was observed in major bleeding between the two groups. Decousus H et al. CALISTO Study Group. N Engl J Med 2010;363:

12 Placebo-controlled study (CALISTO) with clinical outcome in SVT patients patients with isolated SVT Placebo 45 days Primärer Wirksamkeits-Endpunkt HR, 0,14 (95% CI, 0,08 to 0,26; p<0,001) 2.5 mg Fondaparinux End of treatment Behandlungsende Death Tödlich Severe Schwer Clin Klin.relev. rel. Light Leicht all Gesamt Safety endpoint: bleeding (%) 0 0,5 1 Tage Décousus H, Prandoni, P, Mismetti, P, Bauersachs R, Boda, Z, et al. : N Engl J Med. 2010;363(13): Fondaparinux Plazebo

13 Goldman and Ginsberg. NEJM 2010;363:1278 Historical comparisons have shown extremely low mortality among untreated pts with SVT, which supports an initial no anticoagulation treatment approach unless conservative measures fail to resolve symptoms or DVT develops Treatment with Fondaparinux for 45 days may be reasonable in case of severe symptoms, thrombosis in the proximal saphenous vein, or in recurrent disease Cost-effectiveness issues Therapy with Fondaparinux 2.5 mg daily for 45 days costs $2,124 to $7,380

14 3-month incidence of symptomatic VTE (%) CALISTO in Real-world practice , , , , , p=0.06 DVT or PE DVT PE Patients that could have been included in CALISTO Patients that would not have been included in CALISTO Décousus H, Leizorovicz A, Bauersachs R, et al: N Engl J Med 2010; 363: Galanaud JP, J Thromb Haemost 2012; 10: Galanaud JP. The OPTIMEV study. Thromb Haemost 2011; 105: 31-9.

15 CALISTO: High-risk patients In the placebo group, subgroup analyses showed an increased incidence of symptomatic VTE complications at Day 47 (primary efficacy endpoint) in patients presenting one of the following characteristics at inclusion: Age > 75 yrs BMI 30 kg/m 2 CrCl < 50 ml/min History of DVT/PE (> 6 months previously) History of SVT (> 3 months previously) Absence of varicose veins at inclusion SVT abovethe knee SVT involving the great saphenous vein Distance between the thrombus head and the SFJ < 10 cm Decousus H. et al. for the CALISTO Study Group. N Engl J Med 2010; 363: BMI = body mass index; CrCl = creatinine clearance; DVT = deep vein thrombosis; PE = pulmonary embolism; SFJ = sapheno-femoral junction; SVT = superficial vein thrombosis; VTE = venous thromboembolism.

16 Superficial vein thrombosis treated for 45 days with rivaroxaban versus fondaparinux: rationale and design of the SURPRISE trial Werth S, Bauersachs R, Gerlach H, Rabe E, Schellong S, Beyer- Westendorf J J Thromb Thrombolysis (2016) 42: Open-label, masked endpoint, randomised, non-inferiority phase 3b trial Patients aged 18 years or older with symptomatic superficialvein thrombosis 27 sites (academic, community hospitals, and specialist practices) in Germany. Randomly assigned patients (1:1) to receive 10 mg oral rivaroxaban or 2 5 mg subcutaneous fondaparinux once a day for 45 days.

17 Inclusion criteria Acute symptomatic supragenicular SVT of the leg And at least one of the following risk factors Age over 65 years Male sex History of DVT/PE/SVT History of cancer or active cancer Autoimmune disease SVT of non-varicose veins Thrombus extension of at least 5 cm Proximal thrombus end with more than 3 cm distance to the saphenofemoral junction (SFJ) Age over 18 years Written informed consent

18 Efficacy outcome Primary Composite of death from any cause symptomatic PE (objectively confirmed by ventilationperfusion scanning, helical computed tomography, pulmonary angiography, or autopsy) symptomatic DVT (confirmed by ultrasonography or venography) symptomatic SVT extension towards the saphenofemoral junction symptomatic SVT recurrence (confirmed by ultrasonography) up to day 47 Secondary the composite primary efficacy outcome up to day 90 the separate items of the primary efficacy outcome up to day 47 and day 90 the rate of symptomatic pulmonary embolism, symptomatic proximal DVT, VTE-related death the rates of emergency surgery for SVT

19 Safety outcome Primary Clinically overt major bleeding according to the ISTH definition, defined as an overt bleeding that is either associated with a fall of haemoglobin of 2 g/l or more, leading to a transfusion of 2 or more units of packed red blood cells or whole blood occurring into a critical site such as intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal fatal bleeding. Secondary Clinically relevant non-major, minor and any bleeding and death from any cause. Clinically relevant, non-major bleeding (ISTH definition): any overt bleeding that is associated with a medical intervention by a healthcare professional, or an unscheduled physician s contact (presence or telephone contact), a temporary or complete cessation of study drug, any relevant discomfort to the patient (pain, impairment of activities of daily life).

20 Fondaparinux vs. Rivaroxaban in SVT patients with a higher VTE-risk : SURPRISE-Study SVT in the thigh and Age > 65 years or Male gender or Previous DVT/PE/SVT or History of or active cancer or Autoimmunologic disease or SVT in non-varicose veins or 472 risk-patients with isolated SVT Rivaroxaban 10 mg 2.5 mg 45 days Fondaparinux J. Beyer-Westendorf,SM Schellong, H. Gerlach, E. Rabe, J.I. Weitz, K. Jersemann, K. Sahin, R. Bauersachs THE LANCET HAEMATOLOGY-D S (17)

21 Patients and results

22 Fondaparinux vs. Rivaroxaban in SVT patients with a higher VTE-risk : SURPRISE-Study SVT in the thigh and Age > 65 years or Male gender or Previous DVT/PE/SVT or History of or active cancer or Autoimmunologic disease or SVT in non-varicose veins or 472 risk-patients with isolated SVT Rivaroxaban 10 mg 2.5 mg Fondaparinux 45 days HR, 1.1(0.5 to 2.2); p=0.047 for non-inferiority HR 6.1;( ) days days J. Beyer-Westendorf,SM Schellong, H. Gerlach, E. Rabe, J.I. Weitz, K. Jersemann, K. Sahin, R. Bauersachs THE LANCET HAEMATOLOGY-D S (17)

23 Conclusions 1 In patients on higher risk Rivaroxaban 10 mg od is not inferior to Fondaparinux 2.5 mg od in preventing overall VTE complications in SVT patients (3% vs. 2%) During treatment in both groups VTE was very rare but DVT occured slightly more frequent in the Rivaroxaban group (3/211 vs. 1/224) During follow up a rebound phenomenon was present in both groups resulting in primary efficacy outcome after 90 days in 15 patients (7%) in both groups Again DVT was more frequent in the Rivaroxaban group (6/211 vs. 2/224) No PE occured

24 Conclusions 2 Adverse events where rare in both groups No major bleeding occured The incidence of minor bleeding until day 45 was the same in both groups (6%) Clinically relevant non-major bleeding occured more often in the Rivaroxaban group (6/211 vs. 1/224)

25 Conclusions 3 Low dose (prophylactic dosage) of Rivaroxaban or Fondaparinux is effective in preventing VTE complications in SVT SVT patients on higher risk for VTE complications (SURPRISE) may benefit from anticoagulation longer than 45 days compared to low risk patients (CALISTO)

26 Summary SVT is part of VTE like DVT and PE VTE complications of SVT are frequent In patients with a low risk 45 days of a prophylactic dose of fondaparinux is enough High risk patients may need a prolonged treatment Pooled analyses of outcome studies are neededto better identify «risk-partients»

27 Thank you very much for the attention