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ACS is a major public health challenge

ACS is a major public health challenge. In the US: Over 1.5 million people experience ACS annually 1 In the EU: ACS is the most common cause of death, accounting for more than 741,000 deaths each year 2 The 6-month post-discharge mortality rate is: 3 3.6% in patients with UA

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ACS is a major public health challenge

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  1. ACS is a major public health challenge In the US: • Over 1.5 million people experience ACS annually1 In the EU: • ACS is the most common cause of death, accounting for more than 741,000 deaths each year2 • The 6-month post-discharge mortality rate is:3 • 3.6% in patients with UA • 4.8% in patients with STEMI • 6.2% in patients with NSTEMI 1. American Heart Association, 2008; 2. British Heart Foundation Health Promotion Research Group, 2008; 3. Goldberg et al, 2004

  2. Event rate of CV death, MI or stroke at 12 months post event remains ~10% 25 CV death, MI or stroke Major bleeding 20 –25% 15 –20% Event rate (%) –16% –19% 10 5 1.3 0.8 20.0 15.0 12.1 1.8* 9.9 2.4* 11.7 2.2* 9.8 2.8* 0 None ASA1,2 ASA + ASA + ASA + ASA + clopidogrel3 prasugrel3 clopidogrel4 ticagrelor4 *Major bleeding: non-CABG-related TIMI major bleeding 1. Antiplatelet Trialists' Collaboration, 1994; 2. Antithrombotic Trialists' Collaboration, 2002; 3. Wiviott et al, 2007; 4. Wallentin et al, 2009

  3. Anticoagulants and antiplatelets have different yet complementary mechanisms of action Coagulationcascade Platelets Anticoagulants Collagen + other mediators Antiplatelets RivaroxabanApixabanEdoxaban ASA FactorXa Thromboxane ClopidogrelPrasugrelTicagrelor ADP InflammationCellular proliferation Thrombin Thrombin Activatedplatelet GPIIb/IIIa inhibitors Fibrinogen GPIIb/IIIa Platelet aggregation Fibrin Clot Mackman, 2008

  4. Rivaroxaban has the potential to further improve secondary prevention of ACS Oral administration Predictable pharmacology Rapid onset of action Fixed dose Balanced dual mode of elimination Low potential for drug–drug or food–drug interactions* No routine coagulation monitoring Rivaroxaban Rivaroxaban binds directly to the active site of Factor Xa (Ki 0.4 nM) *For full details, see the rivaroxaban Summary of Product Characteristics, available at http://www.xarelto.com Roehrig et al, 2005; Perzborn et al, 2005; Kubitza et al, 2005; 2006a,b,c; 2007a,b

  5. 2.5 and 5 mg bid rivaroxaban doses were chosen for phase III based on data from ATLAS ACS TIMI 46 Rivaroxaban 2.5 and 5 mg TIMI major bleeding Rivaroxaban 2.5 and 5 mg death, MI, stroke Placebo TIMI major bleeding Placebo death, MI, stroke 5 15 ASA ASA plus thienopyridine 11.9% 12 4 3.8% HR=0.54(0.27–1.08) HR=0.55(0.27–1.11) 3 9 Incidence (%) 6.6% 2.0% 2 6 p=0.17 1.2% 1 3 p=0.03 1.2% 0.2% 0 0 0.0% 0 90 180 0 90 180 Time after start of treatment (days) Gibson, 2008; Data on file at Johnson & Johnson; Mega et al, 2009

  6. ATLAS ACS 2 TIMI 51 N=15,526* Physician's decision to add thienopyridine or not Stratum 2: ASA +thienopyridine (93%) Stratum 1: ASA alone (7%) ASA dose =75–100 mg/day Placebo n=355 Rivaroxaban 2.5 mg bid n=349 Rivaroxaban 5 mg bid n=349 Placebo n=4821 Rivaroxaban 2.5 mg bid n=4825 Rivaroxaban 5 mg bid n=4827 Event-driven study – 1002 events *184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct at three sites Mega et al, 2011

  7. Inclusion criteria Diagnosis of STEMI, NSTEMI, or UA with at least one of the following: ≥0.1 mV ST-segment deviation TIMI risk score ≥4 Patients aged ≥18 years; <55 years only with either: Diabetes mellitus or Prior MI Patients received ASA 75–100 mg/day alone or ASA plus a thienopyridine Based on national/local dosing guidelines Exclusion criteria Increased bleeding risk, e.g. Low platelet count History of intracranial haemorrhage Active internal bleeding Prior stroke or TIA in stratum 2 patients Atrial fibrillation: except single episodes >2 years previously in patients aged <60 years with no evidence of cardiopulmonary disease Main inclusion and exclusion criteria Gibson et al, 2011

  8. Study endpoints/analyses • Primary efficacy endpoint:composite of cardiovascular death, MI and stroke (ischaemic, haemorrhagic or uncertain) • Main safety endpoint: incidence of major bleeding not associated with CABG surgery (according to TIMI bleeding definition) • Primary analysis: log-rank test stratified by thienopyridine use in mITT population with confirmation in an ITT analysis • mITT: all randomized patients and events from randomization up to earliest date of completion of treatment period (i.e. global treatment end date), 30 days after early discontinuation of study drug, or 30 days after randomization (patients randomized but not treated) • ITT: all randomized patients and events observed from randomization up to global treatment end date Gibson et al, 2011

  9. Patient characteristics Mega et al, 2011

  10. Primary efficacy endpoint (CV death/MI/stroke)Both rivaroxaban doses, both strata 12 2-year Kaplan–Meier estimate 10.7% 10 Placebo 8.9% 8 HR=0.84 (0.74–0.96) ARR=1.7% mITT p=0.008 ITT p=0.002 NNT=56 Rivaroxaban Estimated cumulative rate (%) 6 4 2 0 24 16 8 0 4 12 20 Months after randomization Mega et al, 2011

  11. Primary efficacy analysis: patient subgroupsBoth rivaroxaban doses, both strata P HR (95% CI) interaction Overall 0.96) 0.84 (0.74 ASA ASA + thienopyridine 0.69 (0.45 -1.05) 0.34 0.86 (0.75 -0.98) 0.94 <65 years 0.83 (0.70 - 0.99) ≥65 years 0.84 (0.70 - 1.01) STEMI 0.96 0.85 (0.70 - 1.03) NSTEMI 0.85 (0.68 - 1.06) UA 0.82 (0.62 - 1.07) Male 0.87 (0.75 - 1.01) 0.40 Female 0.77 (0.60 - 0.99) 0.98 0.83 (0.56 - 1.25) Weight <60 kg Weight 60 to <90 kg 0.85 (0.72 - 0.99) Weight ≥90 kg 0.83 (0.64 - 1.08) Prior MI 0.83 (0.68 - 1.01) 0.80 No prior MI 0.85 (0.72 - 1.01) Diabetes mellitus 0.96 (0.77 - 1.20) 0.14 No diabetes mellitus 0.78 (0.67 - 0.92) CrCl <50 ml/min 0.88 (0.62 - 1.26) 0.82 CrCl ≥50 ml/min 0.84 (0.73 - 0.96) North America 0.57 (0.33 - 0.97) 0.80 South America 0.89 (0.59 - 1.34) Western Europe 0.90 (0.59 - 1.37) Eastern Europe 0.83 (0.69 - 1.00) Asia 0.86 (0.63 - 1.17) Other 0.92 (0.60 - 1.39) 1.0 0.8 2.0 0.5 1.25 Mega et al, 2011 Favoursrivaroxaban Favours placebo

  12. Primary efficacy endpointSeparate rivaroxaban doses, both strata Mega et al, 2011

  13. Components of primary endpointRivaroxaban 2.5 mg bid, both strata CV death/MI/stroke Cardiovascular death All-cause death 13 5 5 HR=0.84 mITT p=0.02ITT p=0.007 HR=0.66 mITT p=0.002 ITT p=0.005 HR=0.68 mITT p=0.002 ITT p=0.004 Placebo Placebo Placebo 4.1% 4.5% 10.7% 9.1% 2.9% 2.7% Cumulative incidence (%) Rivaroxaban 2.5 mg bid Rivaroxaban 2.5 mg bid Rivaroxaban 2.5 mg bid NNT=63 NNT=71 NNT=63 0 0 0 0 6 12 18 24 0 6 12 18 24 0 6 12 18 24 Months Months Months Mega et al, 2011; Gibson et al, 2011

  14. Stent thrombosis*Both rivaroxaban, both strata 2-year Kaplan–Meier estimate 3 2.9% Placebo 2.3% HR=0.69(0.51–0.93) RRR=31% mITT p=0.02 ITT p=0.008 2 Rivaroxaban Estimated cumulative incidence (%) 1 0 0 4 8 12 16 20 24 Months after randomization *Stent thrombosis events: definite, probable or possible (Academic Research Consortium definitions) Mega et al, 2011

  15. Principal safety endpointSeparate rivaroxaban doses, both strata Mega et al, 2011

  16. Treatment-emergent fatal bleeding events and ICHSeparate rivaroxaban doses, both strata Rivaroxaban vs placebop=NS Rivaroxaban vs placebop=0.009 Rivaroxaban vs placebop=NS 2-year Kaplan–Meier estimate (%) Mega et al, 2011

  17. Other safety endpointsSeparate rivaroxaban doses, both strata *CV death/MI/stroke (ischaemic, haemorrhagic, uncertain) events occurring 1–10 days after last rivaroxaban dose; #Abnormal values from first dose to 2 days post last dose in patients with normal baseline values Mega et al, 2011

  18. ATLAS ACS 2 TIMI 51: summary • Compared with placebo, rivaroxaban (2.5 or 5 mg bid) on top of ASA or ASA plus clopidogrel showed: • Significant reductions in the rates of death, MI , and stroke • Benefits in all types of ACS  patients (UA, NSTEMI and STEMI ) • More than a 30% reduction in risk of both CV and all-cause mortality (2.5 mg bid) • No increase in fatal bleeding and fatal ICH  • A non-bleeding safety profile similar to placebo • The addition of anticoagulation with rivaroxaban may represent a new treatment strategy in patients after recent ACS Mega et al, 2011

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