1. Matthew W. Sherwood, Anne Hellkamp, Manesh R. Patel, Jonathan P. Piccini, Yuliya Lokhnygina, James Douketis, Richard C. Becker, Kenneth W. Mahaffey, Keith A. A. Fox, and Robert M. Califf on behalf of the ROCKET AF Investigators Outcomes of Temporary Interruption of Rivaroxaban Compared with Warfarin in Patients with Nonvalvular Atrial Fibrillation

2. Disclosures  Matthew W. Sherwood – ACCF/BMS travel award

3. Background  Oral anticoagulation (OAC) attenuates the risk of stroke in atrial fibrillation (AF)  Interruption of OAC is common in clinical practice  In ROCKET AF, rivaroxaban was non-inferior to warfarin for the prevention of stroke and systemic embolism  There are very few data on the management and outcomes of temporary interruption (TI) in the current era of oral anticoagulation Patel MR. N Engl J Med. 2011; 365:883-891

4. Objectives  To describe the population who required temporary interruption of anticoagulation for any reason  To describe patterns of bridging therapy used in these patients  To describe the clinical outcomes of patients with TI

5. RivaroxabanWarfarin Primary endpoint: Stroke or non-CNS systemic embolism INR target: 2.5 (2.0–3.0 inclusive) 20 mg daily 15 mg for CrCl 30–49 ml/min Atrial fibrillation Randomize Double Blind / Double Dummy (n ~ 14,000) Monthly monitoring Adherence to standard of care guidelines Study Design *Enrollment of patients without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10% Risk factors CHF Hypertension Age  75 Diabetes OR Stroke, TIA, or systemic embolism At least 2 or 3 required* Rationale and design of the rocket af study. Am Heart J. 2010;159:340-347

6. Outcomes and definitions  Temporary Interruption (TI) – Defined as ≥3 days ending with resumption of study drug Median TI duration 5 days At risk period – 3 days after interruption until 3 days after resumption  Outcomes: Composite of all stroke (ischemic & hemorrhagic) and non-central nervous system (CNS) embolism Death and MI ISTH major bleeding (fatal, involving a critical site, Hb drop 2 g/dL or more, or transfusion ≥2 units RBC) Clinically relevant non-major (CRNM) bleeding  All events were adjudicated by a blinded multispecialty adjudication committee

7. Methods and Analyses  TI Study population  4693/14236 patients (33%) Included  All patients randomized who received at least 1 dose of study drug Excluded  interruptions with (1) transition to open-label warfarin or (2) permanent cessation of study drug  Baseline characteristics of TI patients and bridging therapy described  Clinical outcomes analyzed as events/# patients Stratified by treatment group Stratified by use of bridging therapy

8. Patient Characteristics Characteristic All patients in ROCKET AF (N=14236) Patients with temporary interruption (N=4693) Age73 (65, 78)73 (66, 78) Female5645 (39.7)1715 (36.5) Prior ASA5194 (36.5)1728 (36.8) Prior VKA8889 (62.4)3030 (64.6) CHADS 2 mean (SD) 3.47 (0.9)3.41 (0.95) Hx of Stroke/TIA7794 (54.7)2358 (50.2) CrCl (Cockcroft-Gault) 67 (52, 87)68 (53, 88)

9. Reasons for Temporary Interruption Reason for Interruption All TIs (N=7557) TIs among Riva pts (N=3393) TIs among Warf pts (N=4164) Surgical/Invasive procedure 2997 (39.7)1309 (38.6)1688 (40.5) Adverse event – non-bleeding 1874 (24.8)816 (24.0)1058 (25.4) Adverse event – Bleeding 995 (13.2)540 (15.9)455 (10.9) Subject Error1366 (18.1)624 (18.4)742 (17.8) Site Error48 (0.6)22 (0.6)26 (0.6) Logistic Difficulty449 (5.9)163 (4.8)286 (6.9) Duration of interruption (days) 5 (4, 9)6 (4, 10)5 (4, 9)

10. Distribution of procedures causing TI

11. Clinical Outcomes by Treatment Arm RivaroxabanWarfarin Event Events (Events/100 pt-yrs) N=2165 Events (Events/100 pt-yrs) N=2528 Stroke/SE5 (6.0)5 (5.2) Death01 (1.0) MI5 (6.0)3 (3.1) Major/NMCR bleed32 (38.2)39 (41.1) Major bleeding15 (17.9)18 (18.9)

12. Patterns of bridging anticoagulation Bridging Therapy All TIs (N=7557) TIs among Riva pts (N=3393) TIs among Warf pts (N=4164) Any Bridging555 (7.3)308 (9.1)247 (5.9) ASA53 (9.5)23 (7.5)30 (12.1) Clopidogrel19 (3.4)8 (2.6)11 (4.5) Fondaparinux7 (1.3)6 (1.9)1 (0.4) LMWH476 (85.8)271 (88.0)205 (83.0)

13. Patients characteristics of those bridged Characteristic Bridging therapy at least once Yes (N=495 pts) No (N=4198 pts) P-value Age74 (68, 78)73 (65, 78)0.08 Female165 (33.3)1550 (36.9)0.12 Prior chronic ASA157 (31.7)1571 (37.4)0.01 Prior VKA373 (75.4)2657 (63.3)<.0001 CHADS 2 mean (SD)3.52 (0.9)3.39 (1.0)0.01 Hx of stroke/TIA254 (51.3)2104 (50.1)0.62 CrCl (Cockcroft-Gault) 67 (53, 85)68 (53, 88)0.93

14. Clinical Outcomes and Bridging Bridging therapyNo bridging therapy Event Events (Events/100 pt-yrs) (N=555) Events (Events/100 pt-yrs) (N=7002) Stroke/SE1 (6.1)9 (5.4) Death0 (0)1 (0.6) MI0 (0)8 (4.8) Major/NMCR bleed (any)12 (76.9)59 (36.3) Major bleeding3 (18.8)30 (18.2)

15. Limitations  Post-hoc analysis  Fairly small number of events in the setting of temporary interruption  Granularity of data not available for all TIs, including urgency and relationship of study drug restart to events

16. Conclusions  In a moderate to high risk population of patients with atrial fibrillation, temporary interruption of anticoagulation is common  Use of bridging therapy was infrequent despite the high risk population  Rates of stroke/embolism and clinically significant bleeding were moderate but comparable between rivaroxaban and warfarin

17. Clinical Implications  Temporary Interruptions of oral anticoagulation are associated with increased risk and should be minimized if possible  More investigation is needed to determine the optimal management of temporary interruption and bridging for warfarin and new oral anticoagulants

18. Freedom from TI by treatment group

19. Event Rate (per 100 pt yrs) RivaroxabanWarfarinHR (95% CI)P-value All discontinuations and interruptions (prior to end of study) 16.4914.05 1.21 (0.81, 1.81) 0.35 Temporary interruptions 6.005.20 1.28 (0.49, 3.31) 0.62 Permanent discontinuations 25.6023.28 1.10 (0.71, 1.72) 0.66 After end of study 6.421.73 3.72 (1.51, 9.16) 0.0044 All discontinuations and interruptions (prior to end of study) + After end of study events 11.207.57 1.50 (1.05, 2.15) 0.026 Rivaroxaban better Warfarin better Stroke or non-CNS embolism after any interruption or discontinuation

20. Cumulative proportion of subjects with INR ≥2 who completed the study Safety/Days 3 to 30 after the last dose Rivaroxaban Warfarin 48.8 81.3

21. Clinical Outcomes and Bridging Bridging therapyNo bridging therapy Rivaroxaban Warfarin Rivaroxaban Warfarin Event Event rate per TI (N=308 TIs) Event rate per TI (N=247 TIs) Event rate per TI (N=3085 TIs) Event rate per TI (N=3917 TIs) Stroke/SE0% (0)0.40% (1)0.16% (5)0.10% (4) Death0% (0) 0.03% (1) MI0% (0) 0.16% (5)0.08% (3) Major/NMCR bleed (any) 2.27% (7)2.02% (5)0.81% (25)0.87% (34) Major bleeding0.32% (1)0.81% (2)0.45% (14)0.41% (16)