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 RivaroxabanCompared with Warfarin in Patients with Nonvalvular Atrial Fibrillation

Disclosures

Matthew W. Sherwood – ACCF/BMS travel award

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

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

Rivaroxaban

Warfarin

Primary endpoint: Stroke or non-CNS systemic embolism

INR target: 2.5 (2.0–3.0 inclusive)

20 mg daily15 mg for CrCl 30–49 ml/min

Atrial fibrillation

RandomizeDouble Blind / Double Dummy

(n ~ 14,000)

Monthly monitoringAdherence 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

Outcomes and definitions

Temporary Interruption (TI) – Defined as ≥3 days ending with resumption of study drug

Median TI duration 5 daysAt risk period – 3 days after interruption until 3 days after resumption

Outcomes: Composite of all stroke (ischemic & hemorrhagic)

and non-central nervous system (CNS) embolismDeath 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

Methods and Analyses

TI Study population 4693/14236 patients (33%) Included All patients randomized who received at least 1 dose of

study drugExcluded 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

Patient Characteristics

CharacteristicAll patients in ROCKET

AF

(N=14236)

Patients with temporary interruption

(N=4693)

Age 73 (65, 78) 73 (66, 78)

Female 5645 (39.7) 1715 (36.5)

Prior ASA 5194 (36.5) 1728 (36.8)

Prior VKA 8889 (62.4) 3030 (64.6)

CHADS2

mean (SD)3.47 (0.9) 3.41 (0.95)

Hx of Stroke/TIA 7794 (54.7) 2358 (50.2)

CrCl

(Cockcroft-Gault)67 (52, 87) 68 (53, 88)

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 Error 1366 (18.1) 624 (18.4) 742 (17.8)

Site Error 48 (0.6) 22 (0.6) 26 (0.6)

Logistic Difficulty 449 (5.9) 163 (4.8) 286 (6.9)

Duration of interruption (days)

5 (4, 9) 6 (4, 10) 5 (4, 9)

Distribution of procedures causing TI

CABG surgery

Urologic procedure

Angiography/PCI

Other procedure

Eye surgery

EP Procedure

Dermatology/Tissue bx

Unknown

Abd/Thora/Ortho surgery

Dental work

Colonoscopy/GI endoscopy

0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20%

1%

4%

6%

8%

8%

9%

11%

11%

13%

17%

17%

Clinical Outcomes by Treatment Arm

Rivaroxaban Warfarin

EventEvents

(Events/100 pt-yrs) N=2165

Events(Events/100 pt-yrs)

N=2528

Stroke/SE 5 (6.0) 5 (5.2)

Death 0 1 (1.0)

MI 5 (6.0) 3 (3.1)

Major/NMCR bleed 32 (38.2) 39 (41.1)

Major bleeding 15 (17.9) 18 (18.9)

Patterns of bridging anticoagulation

Bridging Therapy

All TIs

(N=7557)

TIs among Riva pts

(N=3393)

TIs among Warf pts

(N=4164)

Any Bridging 555 (7.3) 308 (9.1) 247 (5.9)

ASA 53 (9.5) 23 (7.5) 30 (12.1)

Clopidogrel 19 (3.4) 8 (2.6) 11 (4.5)

Fondaparinux 7 (1.3) 6 (1.9) 1 (0.4)

LMWH 476 (85.8) 271 (88.0) 205 (83.0)

Patients characteristics of those bridged

CharacteristicBridging therapy at least once

Yes

(N=495 pts)

No

(N=4198 pts)P-value

Age 74 (68, 78) 73 (65, 78) 0.08

Female 165 (33.3) 1550 (36.9) 0.12

Prior chronic ASA 157 (31.7) 1571 (37.4) 0.01

Prior VKA 373 (75.4) 2657 (63.3) <.0001

CHADS2 mean (SD) 3.52 (0.9) 3.39 (1.0) 0.01

Hx of stroke/TIA 254 (51.3) 2104 (50.1) 0.62

CrCl

(Cockcroft-Gault)67 (53, 85) 68 (53, 88) 0.93

Clinical Outcomes and Bridging

Bridging therapy No bridging therapy

Event

Events (Events/100 pt-yrs)

(N=555)

Events(Events/100 pt-yrs)

(N=7002)

Stroke/SE 1 (6.1) 9 (5.4)

Death 0 (0) 1 (0.6)

MI 0 (0) 8 (4.8)

Major/NMCR bleed (any) 12 (76.9) 59 (36.3)

Major bleeding 3 (18.8) 30 (18.2)

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

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

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

Freedom from TI by treatment group

0 6 12 18 240.5

0.6

0.7

0.8

0.9

1

WarfarinRivaroxaban

Months from study drug startPro

po

rtio

n w

ith

ou

t te

mp

ora

ry i

nte

rru

p-

tio

n

  Event Rate (per 100 pt yrs)  

Rivaroxaban Warfarin HR (95% CI) P-value

All discontinuations and interruptions (prior to end of study)

16.49 14.05 1.21(0.81, 1.81) 0.35

Temporary interruptions 6.00 5.20 1.28(0.49, 3.31) 0.62

Permanent discontinuations 25.60 23.28 1.10

(0.71, 1.72) 0.66

After end of study 6.42 1.73 3.72(1.51, 9.16) 0.0044

All discontinuations and interruptions (prior to end of study) + After end of study events

11.20 7.57 1.50(1.05, 2.15) 0.026

Rivaroxabanbetter

Warfarinbetter

Stroke or non-CNS embolism after any interruption or discontinuation

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