I nuovi anticoagulanti orali ed il dilemma delle copatologie

1. I nuovi anticoagulanti orali ed il dilemma delle copatologie Bruno Trimarco Dipartimento di Scienze Biomediche Avanzate Università degli Studi di Napoli “Federico II”

3. New Oral Anticoagulants Pathophysiology of thrombosis in heart failure. Adapted from Weitz J. J Thromb Haemost 2005

4. -New Oral Anticoagulants- An Overview Adapted from Piccini et al. Curr Opin Cardiol 2010

5. -New Oral Anticoagulants- Stroke and Systemic emboli

6. -New Oral Anticoagulants- Intracranial Hemorrhage

7. Study Design • Risk Factors • Stroke, TIA or Systemic embolus • OR • CHF • Hypertension • Age  75 • Diabetes Atrial Fibrillation At least 2 or 3 required* Rivaroxaban Warfarin Randomized Double Blind / Double Dummy (n ~ 14,000) 20 mg daily 15 mg for Cr Cl 30-49 ml/min INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

8. Pathophysiology of thrombosis in heart failure. Pathophysiology of thrombosis in heart failure Lip G Y et al. Eur J Heart Fail 2012;14:681-695

9. Anticoagulants in heart failure The beginning

10. Anticoagulants in heart failure in the New Millennium

11. Methods - Definitions • HF was defined as a history of HF or left ventricular ejection fraction (LVEF) <40% • Pre-specified secondary HF sub-group analyses • LVEF ≥40% vs. <40% • New York Heart Association (NHYA) class • CHADS2 score • Implantable cardioverter defibrillator (ICD) or biventricular-ICD (BiV-ICD)

12. Methods - Outcomes • Efficacy endpoints (intention-to-treat population) • Primary: Stroke or systemic embolism • Secondary • All-cause death • Stroke, systemic embolism, or vascular death • Safety endpoints (safety population) • Primary : Major or non-major clinically relevant (NMCR) bleeding • Secondary • Intracranial hemorrhage (ICH) • Hemorrhagic stroke *All outcomes reported as adjusted hazard ratios (HR) per 100 patient-years (pt-yrs)

13. Results – HF vs. No HF • 9033 (63.7%) of patients were defined as having HF

14. Results - HF vs. No HF

15. Results – HF Status and Treatment Assignment

18. Results – HF Subgroups

19. Results – Heart Failure Subgroups

21. Available now online from European Heart Journal http://eurheartj.oxfordjournals.org/cgi/content/full/ehr342

22. Baseline demographics ASA, acetylsalicylic acid; IQR, interquartile range; VKA, vitamin K antagonist Safety population (minus 9 pts in warfarin arm with no CrCl data)

23. Baseline demographics (continued) SD, standard deviation; TIA, transient ischaemic attack Safety population (minus 9 pts in warfarin arm with no CrCl data)

24. ROCKET AF: stroke or non-CNS embolism among patients with CrCl 30–49 ml/min Warfarin Rivaroxaban Cumulative event rate (%) HR (95% CI): 0.84 (0.57, 1.23) Days since randomization No. at risk: Rivaroxaban 1,434 1,226 1,103 1,027 806 621 442 275 Warfarin 1,439 1,261 1,140 1,052 832 656 455 272 Event rates are % per year; Based on Protocol Compliant on Treatment Population Fox KA et al.Eur Heart J 2011; 32 (19): 2387-2394

25. 6 5 4 Cumulative event rate (%) 3 2 1 0 0 120 240 480 600 720 840 360 ROCKET AF: Primary efficacy endpoint: stroke or non-CNS embolism patients with CrCl 30–49 ml/min vs. ROCKET AF overall Warfarin, renally impaired*,1 Rivaroxabanrenally impaired*,1 Warfarin, overall**,2 Rivaroxaban overall**,2 * among patients with CrCl 30-49 ml/min:HR 0.84 (95% CI: 0.57-1.23) ** HR 0.79 (95% CI: 0.66-0.96) p<0.001 (non-inferiority) Days since randomization Per-protocol population on-treatment 1Fox KA et al.Eur Heart J 2011; 32 (19): 2387-2394; 2Patel MR et al. N Engl J Med 2011;365:883–891

26. Safety outcomes CrCl ≥50 ml/min†CrCl 30–49 ml/min‡ 0.01 0.1 1 10 Based on safety population on treatment *Composite of major plus non-major clinically relevant bleeding. †Rivaroxaban 20 mg od. ‡Rivaroxaban 15 mg od

27. Bleeding sites † p=0.02 (riva vs. warf in CrCl 30–49 ml/min); p=0.0002 (riva vs. warf in CrCl ≥50 ml/min) ‡ p=0.02 (riva vs. warf in CrCl ≥50 ml/min)

28. ROCKET AF – PREVENZIONE SECONDARIA

29. Secondary prevention cohortkey demographics *‘Prior stroke’ includes TIA, ischaemic stroke, stroke of unknown type, and haemorrhagic stroke. #Mean±SD. IQR, interquartile range; TTR, time in therapeutic INR range

30. Results: Primary efficacy endpoint Kaplan–Meier survival curve showing time to the primary endpoint (stroke or systemic embolism) 7 Prior stroke/TIA, warfarin 6 Prior stroke/TIA, rivaroxaban 5 No prior stroke/TIA, warfarin 4 Cumulative event rate – stroke or systemic embolism (%) 3 No prior stroke/TIA, rivaroxaban 2 1 0 0 6 12 18 24 30 Months from randomization Per protocol population, on-treatment

31. Results: Efficacy analysis No prior stroke or TIA Prior stroke or TIA Per protocol population, on-treatment

32. Results: Principal safety outcome Safety population, on-treatment †Principal safety outcome No prior stroke or TIA Prior stroke or TIA

33. ROCKET AF – subanalysis elderly patients - Rationale • To determine the efficacy and safety of rivaroxaban compared with warfarin among elderly patients (>75 years old) with AF compared with patients <75 years • 6,229 patients were ≥75 years • Mean CHADS2 3.7 vs 3.3 • Female 46% vs. 35% • Prior stroke/TIA 42% vs 65% Halperin JL et al. presentedat AHA 2012

34. ROCKET AF - subanalysis elderly patients - Results Major Bleeding (n=14.236) Stroke/SE (n=14.171) Age (Years) <75 ≥75 HR 0.95 (0.76-1.19) HR 0.80 (0.63-1.02) p*=0.31 HR 0.96 (0.78-1.19) HR 1.11 (0.92-1.34) p*=0.34 Rivaroxaban better Warfarin better Rivaroxaban better Warfarin better * p-value for interaction Halperin JL et al. presented at AHA 2012

35. ROCKET AF - subanalysis elderly patients - Results R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage; CRNMB=clinically relevant non-major bleeding 1ITT population, 2 safety population excluding a GCP violating site, 3safety population Halperin JL et al. presented at AHA 2012

36. ROCKET AF - subanalysis elderly patients - Results R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage; CRNMB=clinically relevant non-major bleeding 1ITT population, 2 safety population excluding a GCP violating site, 3safety population Halperin JL et al. presented at AHA 2012