BUDI YULI SETIANTO

DEPARTMENT OF CARDOLOGY AND VASCULAR MEDICINE FACULTY OF

MEDICINE UGM – SARDJITO HOSPITAL, YOGYAKARTA.
DISCLAIMER

• NO CONFLICT OF INTEREST
INTRODUCTION

• AF IS DIVIDED INTO:
• VALVULAR AF
• NON VALVULAR AF
• OAC FOR PREVENTION OF SE IN AF PATIENTS:
• VITAMIN K ANTAGONIST (WARFARIN)
• NON VITAMAIN K ANTAGONIST (NOAC)
 ROCKET AF: Effective Stroke Prevention in
Patients with Non-Valvular AF Versus Warfarin
Primary efficacy endpoint: stroke/SE

ITT population PPP population

Cumulative event rate (%)

Cumulative event rate (%)

5 5
Rivaroxaban Rivaroxaban
4 Warfarin 4 Warfarin

3 3

2 2

1 1

0 0
0 120 240 360 480 600 720 840 0 120 240 360 480 600 720 840

Days since randomization Days since randomization

HR=0.88 (95% CI 0.75–1.03)

HR=0.79 (95% CI 0.66–0.96)
p<0.001 (non-inferiority)
p<0.001 (non-inferiority)
p=0.12 (superiority)
ITT population = all patients randomized
PPP = all ITT patients without major predefined protocol violations
Patel MR et al, N Engl J Med 2011;365:883–891
ROCKET AF: Significant Reduction in Critical
Organ, ICH and Fatal Bleeding Versus Warfarin
HR=0.69 HR=0.67 HR=0.50
(95% CI 0.53–0.91) (95% CI 0.47–0.93) (95% CI 0.31–0.79)
p=0.007 p=0.02 p=0.003
1.2% 0.8% 0.7% 0.5% 0.5% 0.2%
Warfarin Rivaroxaban
Event rate (%/year)

31%
RRR

33%
RRR

50%
RRR

Fatal
Critical organ bleeding ICH
bleeding

Safety on-treatment analysis

Patel MR et al, N Engl J Med 2011;365:883–891
AF Patients in ROCKET AF Had a Higher Risk of
Stroke than Patients in Other Phase III Trials
CHADS2 score patient distribution

ROCKET AF1 RE-LY2 ARISTOTLE3 ENGAGE AF4

rivaroxaban dabigatran apixaban edoxaban

13%

36% 32% 36% 34%

48% 52%

87% 32% 30%

CHADS2 score ≤1 2 3–6

1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Connolly SJ et al, N Engl J Med 2009;361:1139–1151;
3. Granger CB et al, N Engl J Med 2011;365:981–992; 4. Giugliano RP et al, N Engl J Med 2013;369:2093–2104
ROCKET AF: Consistent Benefit Across Different
Co-Morbidities for the Challenging AF Patients
Primary efficacy endpoint: stroke/SE (N=14,171)

Co-morbidity/
Patient (%) HR (95% CI)
risk factor

C CHF 62% 0.91 (0.74–1.13)

H Hypertension 91% 0.87 (0.73–1.03)

A Age ≥75 years 43% 0.80 (0.63–1.02)

D Diabetes 40% 0.74 (0.54–1.01)

S2 Prior stroke or TIA 55% 0.94 (0.77–1.16)

Mean CHADS2 score 3.5% 0.1 1 1.5 2.0

Favours Favours
rivaroxaban warfarin

Per-protocol population
Patel MR et al, N Engl J Med 2011;365:883–891
ROCKET AF: Effective and Safe Stroke Prevention
in Patients with Non-Valvular AF Versus Warfarin
Mean CHADS2 score: 3.5

Double-blind, double-dummy Rivaroxaban: non-inferior to warfarin

international study of AF patients HR=0.79 (95% CI 0.66–0.96); p<0.001 (non-inferiority)
with two or more risk factors
for stroke Similar rates of major bleeding: significantly lower
rate of critical bleeding events with rivaroxaban

Rivaroxaban 15 mg od
Rivaroxaban 20 mg od
Prospectively tested (and
Consistent benefits across
approved) dose in patients with
all subgroups
moderate renal impairment

Significant reduction in critical bleeding events

Stroke/systemic embolism
Critical organ bleeding ICH Fatal bleeding (PP analysis)

RRR 31% 33% 50% 21%

Patel MR et al, N Engl J Med 2011;365:883–891

Significantly lower event rates
while on rivaroxaban treatment
(ITT analysis)
STADIUM GAGAL GINJAL

Laju filtrasi glomerulus

Stadium Penjelasan
(ml/menit/1,73m2)
Kerusakan ginjal ringan dengan filtrasi
1 Lebih dari 90
normal atau meningkat
2 Penurunan ringan fungsi ginjal 60-89
3 Penurunan sedang fungsi ginjal 30-59
4 Penurunan berat fungsi ginjal 15-29
Kurang dari 15 (atau
5 Gagal ginjal
dialisis)
 Rivaroxaban is the Only NOAC with a Prospectively
Tested,Specific Renal Dose
Primary efficacy endpoint: Stroke/SE

HR 0.86 Warfarin
(95% CI 0.63–1.17) Rivaroxaban
4
3.44
HR 0.89
Events (%/year)

2.95
3 (95% CI 0.73–1.08)
2.16
1.92
2

0
30–49 ≥ 50
CrCl (mL/min)

Consistent efficacy of rivaroxaban vs. warfarin in NVAF patients with moderate renal
impairment
Intention-to-treat population
Fox KA et al. Eur Heart J. 2011;32(19):2387-2394
ROCKET AF: Consistent Safety Outcomes in NVAF Patients With
Moderate Renal Impairment
HR 0.55 Warfarin
(95% CI 0.30–1.00) Rivaroxaban 15 mg OD
1.5 1.4
HR 0.81
(95% CI 0.41–1.60) HR 0.39
Events (%/year)

1 (95% CI 0.15–0.99)
0.9
0.8 0.7
0.7

0.5
0.3

0
Critical organ bleeding ICH Fatal bleeding

Safety on-treatment population

Fox KA et al. Eur Heart J. 2011;32(19):2387-2394
Rivaroxaban Provides a Consistent and Unique
Dataset Covering the Full Patient-Risk Spectrum

Randomized clinical trial

Prospective
Prospective, Retrospective
registry1 databases2,3
non-interventional
study4 Dresden US PMSS
NOAC RELIEF
Registry
REVISIT-US

1. Beyer-Westendorf J et al, Blood 2014;124;955–962; 2. Tamayo S et al, Clin Cardiol 2015;38:63–68;

3. Coleman C et al, Int J Card Med 2015;203:882–884; 4. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466
 Rivaroxaban tested in different populations in
Randomized Clinical Trial and the Real World
XANTUS1 Baseline ROCKET AF2
Rivaroxaban1 Rivaroxaban2
2.0 CHADS2 3.5

41% 0–1 0%

30% 2 13%

29% ≥3 87% 13%

29%
41% 19% Heart failure 63%

75% 91%
Hypertension 87%
30%
37% Age >75 years 44%

20% Diabetes 40%

*Events per 100 patient-years; #includes prior stroke, SE or TIA

19% Prior stroke# 55%
1. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466;
2. Patel MR et al, N Engl J Med 2011;365:883–891
10% Prior MI 17%

Results are not intended for direct comparison

Rivaroxaban Is Highly Effective and Provides Reassuring
Safety in Clinical Trials
Baseline ROCKET AF
Efficacy1 CHADS2 3.5 Safety1,2

4 0–1 0% 4
3.6

On-treatment event rate, %/year*

On-treatment event rate, %/year*

2 13%

3 ≥3 87% 3

Heart failure 63%

2
2 1.7 Hypertension 90% 2

Age >75 years 44%

1 40%
1
Diabetes
0.5
Prior stroke# 55% 0.2
0 0
Stroke/SE Prior MI 17%
Major Fatal ICH GI
bleeding bleeding bleeding
*Events per 100 patient-years; #includes prior stroke, SE or TIA
1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Sherwood M et al, JACC 2015;66:2271–2281
Rivaroxaban Is Highly Effective and Provides Reassuring
Safety in the Real World
Baseline XANTUS

Effectiveness CHADS2 2.0 Safety

4 0–1 41% 4

On-treatment event rate, %/year*

On-treatment event rate, %/year*

2 30%

3 ≥3 29% 3

Heart failure 19%

2.1
2 Hypertension 75% 2

Age >75 years 37%

1 0.8 1 0.9
Diabetes 20%
0.4
Prior stroke# 19% 0.2
0 0
Prior MI 10%
Stroke/SE Major Fatal ICH GI
bleeding bleeding bleeding
*Events per 100 patient-years; #includes prior stroke, SE or TIA
Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466
 REVISIT-US
Study Design to Optimize “Internal Validity”

• Combined Endpoint of Ischemic Stroke and ICH

– Most likely to be coded accurately and with less variability in
claims data and of equal importance to allow for benefit/risk
assessment

– Used validated ICD-9 coding algorithms and restricted codes to

the primary diagnosis code position
– May miss cases, but greater robustness in those identified

Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States
(REVISIT-US) [Presentation at ECAS 2016] Available at: http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx
REVISIT-US:
Rivaroxaban vs warfarin and apixaban vs warfarin

HR (95% CI) HR (95% CI)

rivaroxaban vs. warfarin apixaban vs. warfarin

ICH ICH

Ischaemic stroke Ischaemic stroke

Combined Combined

0.125 0.25 0.5 1 2 4 0.125 0.25 0.5 1 2 4

Favours Favours Favours Favours
rivaroxaban warfarin apixaban warfarin

HR (95% CI) HR (95% CI)

rivaroxaban vs. warfarin apixaban vs. warfarin

ICH 0.53 (0.35–0.79)* ICH 0.38 (0.17–0.88)*

Ischaemic stroke 0.71 (0.47–1.07) Ischaemic stroke 1.13 (0.49–2.63)

Combined 0.61 (0.45–0.82)* Combined 0.63 (0.35–1.12)

*p<0.05 vs warfarin
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States
(REVISIT-US) [Presentation at ECAS 2016] Available at: http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx
MATUR NUWUN