Δορυφορικό Συμπόσιο: Αντιμετωπίζοντας τη θρόμβωση με Rivaroxaban. Κλινικές μελέτες και πρακτική διαχείριση σε ασθενείς με Φλεβική Θρομβοεμβολική Νόσο

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1 Δορυφορικό Συμπόσιο: Αντιμετωπίζοντας τη θρόμβωση με Rivaroxaban Κλινικές μελέτες και πρακτική διαχείριση σε ασθενείς με Φλεβική Θρομβοεμβολική Νόσο Μ. Ματσάγκας, MD, PhD, FEBVS Αναπληρωτής Καθηγητής Αγγειοχειρουργικής Ιατρική Σχολή, Πανεπιστήμιο Ιωαννίνων

2 Conflict of Interest Disclosure Form I have no potential conflict of interest to report I have the following potential conflict(s) of interest to report: Type of affiliation / financial interest Receipt of grants/research supports: Name of commercial company Leo, Sanofi, Bayer Receipt of honoraria or consultation fees: Participation in a company sponsored speaker s bureau: Leo, Sanofi, Bayer Stock shareholder: - Spouse/partner: - Other support (please specify): - Bayer

3 Two types of thrombosis Arterial Venous Platelet-rich clot (platelets and coagulation) Fibrin-rich clot (coagulation)

4 VTE: DVT and PE Pulmonary embolism Migration Embolus As the venous clot grows, it extends along the vein Thrombus

5 Acute CFV thrombosis

6 Acute CFV thrombosis

7 Venous gangrene

8

9 Fatal PE

10 Post thrombotic syndrome

11 VTE: a leading cause of death worldwide VTE is estimated to cause >500,000 deaths in Europe every year 1 An estimated 300,000 VTE-related deaths occur in the US each year 2 VTE is estimated to cause at least 3 million deaths a year worldwide 1. Cohen AT et al. Thromb Haemost 2007;98: ; 2. Heit JA et al. Blood 2005;106:Abstract 910

12 VTE : a major problem of public health in EU Deaths / year % of total deaths / year in EU countries VTE Breast cancer transport accidents AIDS prostate cancer Cohen AT, et al (VITAE). Thromb Haemost 2007; 98:

13 VTE: an often undiagnosed disease Estimated number of VTE-related deaths from an epidemiological model in France, Germany, Italy, Spain, Sweden and the UK: Estimated number of VTE-related deaths Sudden fatal PE (34%) PE-related death after undiagnosed/untreated VTE (59%) 93% Diagnosed/treated VTE (7%) Cohen AT et al. Thromb Haemost 2007;98:

14 Venous thromboembolism an often silent disease Fatal PE Symptomatic PE Asymptomatic PE 100 Symptomatic DVT Asymptomatic DVT Iceberg model

15 VTE : poor doctors awareness Deaths due to VTE are 14 times more than these attributed to the disease by the treating physicians In EU countries many doctors do not have yet realize the extent of the VTE risk related to their patients

16 VTE : an in hospital disease 63% of VTE episodes occur during hospitalization 100% 80% 60% transport accidents prostate cancer Breast cancer 71% of in hospital deaths are attributed to VTE 40% 20% 0% deaths / annum AIDS VTE Cohen AT, et al (VITAE). Thromb Haemost 2007; 98:

17 The risk of recurrent VTE Most recurrent venous thromboembolic events can be avoided with adequate treatment 5 10% risk of recurrence in the year after anticoagulant discontinuation and ~30% after 8 years 1,2 Risk of recurrence on treatment cessation depends on cause of initial VTE 3 Recurrence tends to follow initial presentation 3 Cumulative incidence (%) Cumulative incidence of recurrent VTE after first episode of DVT 2 1. Hirsh J, Hoak J. Circulation 1996;93: ; 2. Prandoni P et al. Ann Intern Med 1996;125:1 7; 3. Kearon C. Circulation 2003;107:I22 I30

18 VTE We need prompt and accurate diagnosis We need adequate and reliable treatment

19 VTE Treatment Anticoagulants are the cornerstones of treatment for VTE

20 Commonly used anticoagulants in VTE Treatment Parenteral anticoagulants Unfractionated heparin Low molecular weight heparins Indirect Factor Xa inhibitor (fondaparinux) Oral anticoagulants Vitamin K antagonists

21 Traditional anticoagulants: a lot of drawbacks UFH 1 Parenteral administration Monitoring and dose adjustment required Risk of HIT Oral VKAs 2 Narrow therapeutic window Interaction with food and drugs Frequent monitoring and dose adjustment required LMWH 1 Parenteral administration Weight adjusted dosing 1. Hirsh J et al. Chest 2008;133;141S 159S; 2. Ansell J et al. Chest 2008;133;160S 198S

22 Current Limitations Limitations Consequences UFH LMWH VKAs Parenteral Unpredictable due to unspecific binding Risk of HIT Parenteral Risk of HIT Unpredictable Slow onset of action Narrow therapeutic window Food and drug interactions Inconvenient for long term use Monitoring of aptt required Inconvenient and expensive for long term use Monitoring of platelets Regular monitoring and dose adjustments Risk of adverse events (bleeding) Fondaparinux Parenteral Inconvenient and expensive for long term use Lassen MR. Vasc Health Risk Manag. 2008

23 VTE: disease phases and conventional anticoagulation treatment strategies Phases of the disease Acute Intermediate Long term Types and intensity of conventional anticoagulation treatment UFH, LMWH, fondaparinux Initial, parenteral therapeutic dose At least 5 days VKA INR Early maintenance/secondary prevention At least 3 months VKA INR or Long-term maintenance anticoagulation/ secondary prevention >3 months/years/indefinite*

24 The evolution of anticoagulant drugs 1930s 1940s VKAs 1980s LMWHs 1990s Direct thrombin inhibitors 2002 Indirect Factor Xa inhibitor 2004 Oral direct thrombin inhibitors 2008 Oral direct Factor Xa inhibitors Heparin AT + Xa + IIa (1:1 ratio) II, VII, IX, X (Protein C, S) AT + Xa + IIa (Xa > IIa) IIa AT + Xa IIa Xa Perzborn E et al. Nat Rev Drug Discov 2011;10:61-75

25 Rivaroxaban: the first oral, direct Factor Xa inhibitor Direct, specific, competitive Factor Xa inhibitor Inhibits free and fibrin bound Factor Xa activity and prothrombinase activity Inhibits thrombin generation No direct effect on thrombin induced platelet aggregation Roehrig S et al. J Med Chem 2005;48: Perzborn E et al. J Thromb Haemost 2005;3: Perzborn E et al. Nat Rev Drug Discov 2011;10:61 75

26 Rivaroxaban suppresses thrombin generation in plasma Gerotziafas GT et al. J Thromb Haemost 2007;5:

27 Rivaroxaban has no significant effect on thrombin activity A single-dose study in healthy volunteers Thrombin activity (median change from baseline) mg rivaroxaban (n=8) 5 mg rivaroxaban (n=6) 10 mg rivaroxaban (n=8) 20 mg rivaroxaban (n=7) 40 mg rivaroxaban (n=6) 80 mg rivaroxaban (n=6) Placebo Time (hours) Kubitza D et al. Clin Pharmacol Ther 2005;78:

28 Rivaroxaban has no direct effect on platelet aggregation induced by several agonists Platelet aggregation (%) Rivaroxaban Control 0 ADP Collagen Adrenaline Arachidonic acid Fareed J et al. J Thromb Haemost 2005;3(Suppl. 1):P0518

29 Rivaroxaban is absorbed rapidly, with Cmax within 2 4 hours and a dose dependent exposure A single-dose study in healthy volunteers 300 Rivaroxaban plasma concentration (µg/l) mg rivaroxaban (n=8) 5 mg rivaroxaban (n=6) 10 mg rivaroxaban (n=8) 20 mg rivaroxaban (n=7) 40 mg rivaroxaban (n=8) 80 mg rivaroxaban (n=6) Time (hours) Kubitza D et al. Clin Pharmacol Ther 2005;78:

30 Rivaroxaban is absorbed rapidly without accumulation after multiple doses A multiple-dose study in healthy volunteers mg rivaroxaban (n=7) 10 mg rivaroxaban (n=7) 20 mg rivaroxaban (n=7) 30 mg rivaroxaban (n=8) Rivaroxaban plasma concentration (µg/l) Time (days) Kubitza D et al. Eur J Clin Pharmacol 2005;61:

31 Close correlation between rivaroxaban plasma concentrations and PT Phase I: healthy volunteers Observed values Model predictions PT (s) Rivaroxaban plasma concentration (µg/l) Kubitza D et al. Eur J Clin Pharmacol 2005;61:

32 Rivaroxaban Specific, direct Factor Xa inhibitor High oral bioavailability Rapid onset of action Half life: 7 11 hours Dual mode of elimination: One third of drug excreted unchanged by the kidneys Two thirds of drug metabolized by the liver: half excreted renally; half excreted via the hepatobiliary route Phase II dose finding studies indicated that for VTE prophylaxis a regimen consisting of rivaroxaban 10mg once daily, and for VTE treatment a regimen consisting of rivaroxaban 15 mg twice daily for 3 weeks followed by rivaroxaban 20 mg once daily for the subsequent period, appeared most optimal

33 Site of Action for anti coagulant drugs Intrinsic XII Extrinsic XI Tissue Factor UH, LMWHs & Indirect Xa Inhibitors -parinux AT IX VIII X V VII Direct Xa Inhibitors Rivaroxaban Warfarin II Fibrinogen Direct Thrombin Inhibitors -gatran Fibrin Clot

34 VTE: a leading cause of death worldwide Rivaroxaban in VTE treatment Phase III studies

35 Rivaroxaban EINSTEIN studies design Confirmed acute symptomatic DVT without symptomatic PE Confirmed acute symptomatic PE with or without symptomatic DVT N=3,449 R EINSTEIN DVT 1 and EINSTEIN PE 2* (non-inferiority studies) Treatment period of 3, 6 or 12 months Rivaroxaban 15 mg bid Rivaroxaban 20 mg od Enoxaparin 1.0 mg/kg bid for at least 5 days, followed N=4,845 by VKA to start 48 hours, target INR range Day 1 Day day observation after treatment cessation Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA N=1,197 R Day 1 EINSTEIN Extension 1 (superiority study) Treatment period of 6 or 12 months Rivaroxaban 20 mg od Placebo 30-day observation after treatment cessation 1. The EINSTEIN Investigators. N Engl J Med 2010;363: ; 2. EINSTEIN PE. Available at: Trial ID: NCT Accessed August 2011

36 EINSTEIN studies: inclusion criteria EINSTEIN DVT 1 Confirmed acute symptomatic proximal DVT without symptomatic PE EINSTEIN PE 2 Confirmed acute symptomatic PE with or without symptomatic DVT 1. The EINSTEIN Investigators. N Engl J Med 2010;363: ; 2. EINSTEIN PE. Available at: Trial ID: NCT Accessed August 2011

37 EINSTEIN studies: exclusion criteria Thrombectomy, insertion of a caval filter or use of a fibrinolytic agent to treat current DVT and/or PE Indication for VKA other than DVT and/or PE >48 hours prerandomization treatment with therapeutic dosages of anticoagulant treatment or more than a single dose of VKA prior to randomization Creatinine clearance <30 ml/min Significant liver disease or ALT >3 ULN Life expectancy <3 months Active bleeding or high risk for bleeding Systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg Childbearing potential without proper contraceptive measures, pregnancy or breast feeding Bacterial endocarditis Participation in another pharmacotherapeutic study within 30 days before screening Concomitant use of strong CYP3A4 inhibitors or inducers The EINSTEIN Investigators. N Engl J Med 2010;363: ; EINSTEIN PE. Available at: Trial ID: NCT Accessed August 2011; EINSTEIN Integrated Protocol/Study number 11702/Version no 2.0/08Jun2009, incl. Amend 2, 3, 4

38 EINSTEIN studies: primary outcomes Primary efficacy outcome* Symptomatic recurrent VTE: composite of recurrent DVT, non fatal PE or fatal PE Principal safety outcome* Combination of major and non major clinically relevant bleeding *Adjudicated by a central independent and blinded adjudication committee 1. The EINSTEIN Investigators, N Engl J Med 2010;363: ; 2 2. EINSTEIN PE. Available at: Trial ID: NCT Accessed August 2011

39 EINSTEIN studies: secondary outcomes All cause mortality Vascular events Acute coronary syndrome, ischaemic stroke, transient ischaemic attack or systemic embolism Net clinical benefit The composite of the primary efficacy outcome or major bleeding The EINSTEIN Investigators. N Engl J Med 2010;363: ; EINSTEIN PE. Available at: Trial ID: NCT Accessed August 2011; EINSTEIN Integrated Protocol/Study number 11702/Version no 2.0/08Jun2009, incl. Amend 2, 3, 4

40 EINSTEIN studies: bleeding definitions Major bleeding: overt bleeding associated with: 2 g/dl fall in haemoglobin, or Transfusion of 2 units of packed red blood cells or whole blood, or Occurrence at a critical site,* or Death Non major clinically Relevant bleeding: overt bleeding not meeting the criteria for major bleeding, but associated with: Medical intervention, or Unscheduled contact (visit or telephone call) with a physician, or Temporary cessation of study treatment, or Discomfort such as pain, or impairment of activities of daily life *Intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal The EINSTEIN Investigators. N Engl J Med 2010;363: ; EINSTEIN Integrated Protocol/Study number 11702/Version no 2.0/08Jun2009, incl. Amend 2, 3, 4

41 EINSTEIN DVT study Randomized, open label, eventdriven, non inferiority study 3449 patients The EINSTEIN Investigators. N Engl J Med 2010;363:

42 EINSTEIN DVT Treatment period: 3, 6 or 12 months Day 1 Day 21 Confirmed symptomatic DVT without symptomatic PE N=3,449 R Rivaroxaban Rivaroxaban 15 mg bid 20 mg od Enoxaparin (1.0 mg/kg) bid for at least 5 days, plus VKA target INR 2.5 (INR range ) 30-day observation after treatment cessation The EINSTEIN Investigators. N Engl J Med 2010;363: ; EINSTEIN DVT.

43 EINSTEIN DVT primary efficacy outcome analysis Rivaroxaban (n=1,731) Enoxaparin/VKA (n=1,718) n (%) n (%) First symptomatic recurrent VTE 36 (2.1) 51 (3.0) Recurrent DVT 14 (0.8) 28 (1.6) Recurrent DVT + PE 1 (<0.1) 0 (0.0) Non-fatal PE 20 (1.2) 18 (1.0) Fatal PE/unexplained death where PE cannot be ruled out 4 (0.2) 6 (0.3) Rivaroxaban superior HR p=0.08 for superiority (two-sided) 1.00 Rivaroxaban non-inferior 2.00 p<0.001 for non-inferiority (one-sided) Rivaroxaban inferior The EINSTEIN Investigators. N Engl J Med 2010;363:

44 EINSTEIN DVT primary efficacy outcome analysis Cumulative event rate (%) 4.0 Enoxaparin/VKA (n=1,718) 3.0 Rivaroxaban (n=1,731) 2.0 HR=0.68; p<0.001, RR=32% Time to event (days) Number of subjects at risk Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1, Enoxaparin/ VKA 1,718 1,616 1,581 1,553 1,368 1,358 1, The EINSTEIN Investigators. N Engl J Med 2010;363:

45 EINSTEIN DVT primary safety outcome analysis Cumulative event rate (%) 14 Enoxaparin/VKA (n=1,711) Rivaroxaban (n=1,718) Time to event (days) Number of subjects at risk Rivaroxaban 1,718 1,585 1,538 1,382 1,317 1, Enoxaparin/ VKA 1,711 1,554 1,503 1,340 1,263 1, The EINSTEIN Investigators. N Engl J Med 2010;363:

46 EINSTEIN DVT: Conclusions In patients who had acute symptomatic proximal DVT, without symptomatic PE, rivaroxaban showed: Non inferiority to LMWH/VKA for efficacy (HR=0.68; 95% CI ; p<0.001) Similar findings for principal safety outcome between the two groups (HR=0.97; 95% CI ; p=0.77) Consistent efficacy and safety results irrespective of age, body weight, gender, creatinine clearance and cancer No evidence of liver toxicity Oral rivaroxaban, 15 mg bid for 3 weeks followed by rivaroxaban 20 mg od, could provide clinicians and patients with a simple, single drug approach for the acute treatment of DVT The EINSTEIN Investigators. N Engl J Med 2010;363:

47 EINSTEIN PE study Randomized, open label, eventdriven, non inferiority study 4832 patients The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

48 EINSTEIN PE Objectively confirmed PE ± DVT Predefined treatment period of 3, 6, or 12 months Day 1 Day 21 N=4833 R Rivaroxaban 15 mg bid Rivaroxaban 20 mg od Enoxaparin bid for at least 5 days, plus VKA INR 2.5 (range ) 30-day post-study treatment period Primary efficacy outcome: first recurrent VTE Principal safety outcome: first major or non-major clinically relevant bleeding The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

49 EINSTEIN PE primary efficacy outcome analysis Rivaroxaban (N=2419) Enoxaparin/VKA (N=2413) n (%) n (%) First symptomatic recurrent VTE 50 (2.1) 44 (1.8) Recurrent DVT 18 (0.7) 17 (0.7) Recurrent DVT + PE 0 2 (<0.1) Non-fatal PE 22 (0.9) 19 (0.8) Fatal PE/unexplained death where PE cannot be ruled out 10 (0.4) 6 (0.2) HR * Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferior p=0.57 for superiority (two-sided) p= for non-inferiority (one-sided) The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

50 EINSTEIN PE primary efficacy outcome analysis Cumulative event rate (%) Time to event (days) Rivaroxaban N=2419 Enoxaparin/VKA N=2413 HR=1.12; p= (non-inferiority), TTR=62.7% Number of patients at risk Rivaroxaban Enoxaparin/VKA The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

51 EINSTEIN PE primary safety outcome analysis Cumulative event rate (%) Enoxaparin/VKA N= Rivaroxaban N= Rivaroxaban Enoxaparin/VKA HR (95% CI) 5 n/n (%) n/n (%) p-value / / ( ) 2 (10.3) (11.4) p= Time to event (days) Number of patients at risk Rivaroxaban Enoxaparin/VKA The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

52 EINSTEIN PE major bleeding 3.0 Rivaroxaban n/n (%) Enoxaparin/VKA n/n (%) HR (95% CI) p-value Cumulative event rate (%) /2412 (1.1) 52/2405 (2.2) 0.49 ( ) p= Enoxaparin/VKA N=2405 Rivaroxaban N= Time to event (days) Number of patients at risk Rivaroxaban Enoxaparin/VKA The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

53 EINSTEIN PE: Conclusions In patients with acute symptomatic PE with or without DVT, rivaroxaban showed: Non inferiority to LMWH/VKA for efficacy: HR=1.12 ( ); pnon inferiority = for non inferiority margin of 2.0 Similar findings for principal safety outcome: HR=0.90 ( ); p=0.23 Superiority for major bleeding: HR=0.49 ( ) p= Consistent efficacy and safety results irrespective of age, body weight, gender, kidney function and cancer No evidence for liver toxicity Oral rivaroxaban, 15 mg bid for 3 weeks followed by rivaroxaban 20 mg od, could provide clinicians and patients with a simple, single drug approach for the acute treatment of PE that potentially improves the benefit risk profile of anticoagulation The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

54 EINSTEIN DVT and PE pooled analysis Primary efficacy outcomes in 8281 patients Rivaroxaban (N=4150) Enoxaparin/VKA (N=4131) n (%) n (%) First symptomatic recurrent VTE 86 (2.1) 95 (2.3) Recurrent DVT 32 (0.8) 45 (1.1) Recurrent DVT + PE 1 (<0.1) 2 (<0.1) Non-fatal PE 43 (1.0) 38 (0.9) Fatal PE/unexplained death where PE cannot be ruled out 15 (0.4) 13 (0.3) HR Rivaroxaban superior p=0.41 for superiority (two-sided) Rivaroxaban non-inferior p< for non-inferiority (one-sided) Rivaroxaban inferior The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

55 EINSTEIN DVT and PE pooled analysis: bleeding and overall conclusion First major or non major clinically relevant bleeding HR=0.93 (95% CI: ), p=0.27 Major bleeding HR=0.54 (95% CI: ), p= Oral rivaroxaban, 15 mg twice daily for 3 weeks followed by 20 mg once daily provides patients and clinicians with a simple, single drug approach for the acute and continued treatment of both DVT and PE with a potential improvement in the benefit risk profile The EINSTEIN PE Investigators. N Engl J Med Apr 5;366(14):

56 EINSTEIN Extension: study background Treatment for index venous thromboembolic event 6 or 12 months anticoagulation Continue anticoagulation Equipoise Should anticoagulation be stopped or continue? Stop treatment Routine coagulation monitoring, with dose adjustment and attendant risk of bleeding The EINSTEIN Investigators. N Engl J Med 2010;363:

57 EINSTEIN Extension: study objective and design Primary objective To evaluate whether rivaroxaban is superior to placebo in the long term prevention of recurrent symptomatic VTE in patients with symptomatic DVT or PE who completed 6 or 12 months of treatment with a VKA or rivaroxaban Study design Multicentre, randomized, double blind, placebo controlled, eventdriven, superiority study for efficacy The EINSTEIN Investigators. N Engl J Med 2010;363:

58 EINSTEIN Extension study Multicenter, randomized, double blind, placebo controlled, event driven, superiority study for efficacy 1196 patients The EINSTEIN Investigators. N Engl J Med 2010;363:

59 EINSTEIN Extension Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA in EINSTEIN VTE programme Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA ~53% N=1,197 ~47% Day 1 R Treatment period of 6 or 12 months Rivaroxaban 20 mg od Placebo 30-day observation period The EINSTEIN Investigators. N Engl J Med 2010;363: ; EINSTEIN DVT.

60 EINSTEIN Extension Primary efficacy outcome analysis Cumulative event rate (%) NNT=15 Placebo (n=594) HR=0.18; p<0.001, RRR=82% Rivaroxaban (n=602) Time to event (days) Number of subjects at risk Rivaroxaban Placebo The EINSTEIN Investigators. N Engl J Med 2010;363:

61 EINSTEIN Extension major bleeding Rivaroxaban (n=598) Placebo (n=590) n (%) n (%) Major bleeding 4 (0.7)* 0 Bleeding contributing to death 0 0 Bleeding in a critical site 0 0 Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units 4 0 Gastrointestinal bleeding 3 (0.5) 0 Menorrhagia 1 (0.2) 0 Safety population; *p=0.11 The EINSTEIN Investigators. N Engl J Med 2010;363:

62 EINSTEIN Extension non major clinically relevant bleeding Rivaroxaban (n=598) Placebo (n=590) n (%) n (%) Non-major clinically relevant bleeding 32 (5.4) 7 (1.2) Urogenital/uterus 12 (2.0) 2 (0.3) Nasal 8 (1.3) 1 (0.2) Rectal/anal 6 (1.0) 2 (0.3) Skin 4 (0.7) 2 (0.3) Ear 1 (0.2) 0 Gastrointestinal 1 (0.2) 0 Surgical site 1 (0.2) 0 Safety population; some patients experienced more than one event The EINSTEIN Investigators. N Engl J Med 2010;363:

63 EINSTEIN Extension: Conclusions In patients who had completed 6 or 12 months of anticoagulation, rivaroxaban showed: An 82% RRR in the recurrence of VTE (HR=0.18; p<0.001) Absolute risk reduction 5.8%; hence 15 patients need to be treated to prevent one recurrent venous thromboembolic event Low incidence of major bleeding (0.7%; p=0.11; NNH approximately 139) Modest increase in non major clinically relevant bleeding (5.4% versus 1.2%) Efficacy and safety results were consistent irrespective of bodyweight and creatinine clearance No signal for liver toxicity Oral rivaroxaban 20 mg od could provide clinicians and patients with a simple and effective option for continued anticoagulant treatment The EINSTEIN Investigators. N Engl J Med 2010;363:

64 European Medicines Agency (EMA) US Food and Drug Administration (FDA) Current Approved Indications Rivaroxaban Prevention of VTE in patients undergoing hip or knee replacement Acute treatment of DVT/PE Secondary prevention of DVT/PE Stroke prevention in patients with non valvular atrial fibrillation

65 Rivaroxaban for the treatment of VTE Phases of the disease Acute Intermediate Long term Rivaroxaban treatment for VTE Rivaroxaban 15 mg twice daily for the initial treatment of acute VTE for the first 3 weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE

66 Contraindications Hypersensitivity to the active substance or to any of the excipients Clinically significant active bleeding Lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities Concomitant treatment with any other anticoagulant agent e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.) except under the circumstances of switching therapy to or from rivaroxaban (see section 4.2) or when UFH is given at doses necessary to maintain a patent central venous or arterial catheter Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Pregnancy and breast feeding

67 Renal impairment Level of renal impairment Indication Dose Moderate (CrCl ml/min) Note: To be used with special caution in patients with moderate renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Severe (CrCl ml/min) VTE prevention after major orthopaedic surgery Prevention of stroke in patients with non valvular AF DVT, PE treatment and prevention of recurrent DVT and PE VTE prevention after major orthopaedic surgery Prevention of stroke in patients with non valvular AF DVT, PE treatment and prevention of recurrent DVT and PE in adults 10 mg once daily 15 mg once daily 15 mg twice daily for first 3 weeks 20 mg once daily for continuous treatment (reduction to 15 mg od if higher bleeding risk) 10 mg once daily. Use with caution 15 mg once daily. Use with caution 15 mg twice daily for first 3 weeks 20 mg once daily for continuous treatment. (reduction to 15 mg od if higher bleeding risk) Use with caution Renal failure (CrCl <15 ml/min) Use of rivaroxaban at the above doses is not recommended for patients with CrCl rates < 15 ml/min

68 Concomitant drugs Interactions Co-medications Macrolide antibiotics Clarithromycin Erthryomycin Non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, platelet aggregation inhibitors or other antithrombotic agents such as: Naproxen Acetylsalicylic acid Clopidogrel Enoxaparin Warfarin Acenocoumarol, etc Other commonly used medications: Midazolam (substrate of CYP3A4) Digoxin (substrate of P-gp) Atorvastatin (substrate of CYP3A4 and P-gp). Recommendation No clinical relevant interactions have been noted and rivaroxaban can be used in patients taking these medications Care is to be taken, due to the increased bleeding risk. Concomitant treatment with any other anticoagulant agent e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.) except under the circumstances of switching therapy to or from rivaroxaban or when UFH is given at doses necessary to maintain a patent central venous or arterial catheter. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with rivaroxaban when these drugs were coadministered

69 Concomitant drugs Interactions Co medications Strong CYP3A4 inducers Rifampicin Phenytoin Carbamazepine Phenobarbital St. John s Wort Strong CYP3A4 and P-gp inhibitors: Systemic use of azole-antimycotics Ketoconazole Itraconazole Voriconazole Posaconazole Or HIV protease inhibitors: e.g. Ritonavir Dronedarone Recommendation Medications in this class should be co-administered with caution. It is not recommended to co-administer these drugs with rivaroxaban due to an increased bleeding risk. BUT Fluconazole is expected to have less effect on rivaroxaban exposure and can be co-administered with caution Co-administration with rivaroxaban should be avoided due to limited clinical data

70 No antidote No antidote is currently available for rivaroxaban Activated charcoal to reduce absorption may be considered within the first hours after intake Should a bleeding complication arise in a patient on rivaroxaban, next dose should be delayed or treatment be interrupted as felt appropriate Individualized bleeding management may include: Symptomatic treatment (such as mechanical compression, surgical intervention, fluid replacement) Hemodynamic support (such as blood products or blood components) For life threatening bleeding, use of specific procoagulant agents should be considered such as: Prothrombin complex concentrate (PCC) apcc Factor VIIa note: there is currently limited clinical experience with these measures

71 Rivaroxaban profile with different doses in different populations Indication VTE prevention VTE treatment (first 3 weeks) VTE treatment (continued treatment) Stroke prevention in AF Stroke prevention in AF (with impaired renal function) Dose regimen 10 mg od 15 mg bid 20 mg od 20 mg od 15 mg od Ref: Summary of Product Characteristics Nov-2013.

72 Converting from VKA to rivaroxaban treatment Guidance VKA therapy should be stopped INR measurement has to continue Xarelto should be initiated when INR is 2.5 (DVT, PE treatment) Ref: Summary of Product Characteristics Nov-2013.

73 Converting from rivaroxaban to VKA treatment Guidance Important! Overlapping therapy is crucial to ensure proper anticoagulation VKA and Xarelto have to be given concomitantly Xarelto can be stopped once INR is >2.0 INR measurement should be done 24h after the last administration of Xarelto and prior to the next one Ref: Summary of Product Characteristics Nov-2013.

74 Converting from rivaroxaban to Heparin/LMWH and vice versa Guidance Patients who receive continuously administered parenteral drug such as i.v. heparin: Xarelto should be started at the time of discontinuation Patients who receive a parenteral drug on a fixed dosing scheme such as LMWH: Xarelto should be started 0 to 2 hours before the time of the next scheduled administration of the parenteral drug Patients who receive Xarelto and are converted to parenteral anticoagulation: The first dose of the parenteral drug should be administered instead of the next Xarelto dose at the planned time Ref: Summary of Product Characteristics Nov-2013.

75 INR measurement / lab testing Guidance Xarelto does not require routine coagulation monitoring INR was developed for measuring VKA-activity and is not an appropriate tool for Xarelto Anti-FXa chromogenic assays have been developed and are now commercialized Other coagulation tests (PT, appt, INR) are increased If necessary, heamostatic status can also be assessed with PT using Neoplastin only Ref: Summary of Product Characteristics Nov-2013.

76 Patients with hepatic impairment Guidance Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child-Pugh B and C Ref: Summary of Product Characteristics Nov-2013.

77 Populations potentially at higher risk of bleeding: AF and ACS dual indication Guidance There is currently very limited experience in patients with AF receiving rivaroxaban 20 mg once daily concomitantly with dual antiplatelet therapy Physicians should ensure appropriate anticoagulation by following current guideline recommendations Once dual antiplatelet therapy is stopped and single antiplatelet therapy is continued, rivaroxaban 20 mg once daily (15 mg once daily for patients with moderate or severe renal impairment) is the recommended dose to ensure adequate protection from AF related stroke Patients who receive dual antiplatelet therapy (e.g. coronary stenting) have a contraindication to receive rivaroxaban 15 and 20 mg The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology Eur Heart J 2010;31:

78 Patients with other hemorrhagic risk factors Guidance Xarelto is to be used with caution in patients with other hemorrhagic risk factors such as: congenital or acquired bleeding disorders uncontrolled severe arterial hypertension active ulcerative gastrointestinal disease vascular retinopathy bronchiectasis or history of pulmonary bleeding Xarelto is contraindicated during pregnancy. Women of child-bearing potential should avoid becoming pregnant during treatment with Xarelto Ref: Summary of Product Characteristics Nov-2013.

79 Today s Opportunity Rivaroxaban treatment for VTE Rivaroxaban 15 mg twice daily for the initial treatment of acute VTE for the first 3 weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE Phases of the disease Acute Intermediate Long term

80 Outpatient treatment of Venous Thromboembolism Improvement in patients satisfaction and quality of life Substantial cost reductions Matsagas, Int Angiol 2004

81 In Conclusion.. Rivaroxaban, has been proven effective and safe in the prevention and treatment of VTE at least in the phase III trials Rivaroxaban, could provide clinicians and patients with a simple, single-drug approach for the prevention and treatment of VTE that potentially improves the benefit risk profile of anticoagulation

82 In Conclusion.. It has to be seen if these results will be confirmed in the every day practice in terms of both efficacy and safety Phase IV studies with Rivaroxaban are on the way (Xalia study) and will give us data for the use of the drug in the every day practice

83