Confidence from Evidence and Real World

Experience in NVAF Patients

Yoga Yuniadi

Department of Cardiology and Vascular Medicine

Faculty of Medicine, Universitas Indonesia, and
National Cardiovascular Center Harapan Kita

L.ID.MKT.07.2017.0387
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 0.660.96); 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 20 mg od Rivaroxaban 15 mg od
Prospectively tested (and approved)
Consistent benefits across all
dose in patients with moderate renal
subgroups
impairment

Significant reduction in critical bleeding Stroke/systemic

Critical organ events Fatal embolism
bleeding ICH bleeding (PP analysis)

RRR 31% 33% 50% 21%

Significantly lower event rates

while on rivaroxaban treatment
(ITT analysis)
Patel MR et al, N Engl J Med 2011;365:883891
ROCKET AF: Reduction of Stroke/SE vs. Warfarin
in NVAF Patients When On-Treatment
Primary efficacy endpoint: Stroke/SE

Rivaroxaban Warfarin HR and p-value

Parameter
(%/yr) (%/yr) 95% CIs Non-inf. Sup.

Per-protocol, on-treatment 1.7 2.2 <0.001

Safety, on-treatment 1.7 2.2 0.02

ITT 2.1 2.4 <0.001 0.12

On-treatment 1.7 2.2 0.02

Off-treatment 4.7 4.3 0.58

0.5 1 2
Favours Favours
rivaroxaban warfarin

Patel MR et al. N Engl J Med. 2011;365(10):883-891

ROCKET AF: Significant Reduction in Critical
Bleedings vs. Warfarin

Rivaroxaban Warfarin
Hazard ratio
Parameter (N=7,111) (N=7,125)
(95% CI)
n (%/year) n (%/year)

Principal safety endpoint 1,475 (14.9) 1,449 (14.5) 1.03 (0.961.11)

Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.901.20)

Haemoglobin drop (2 g/dL) 305 (2.8) 254 (2.3) 1.22 (1.031.44)*

Transfusion 183 (1.6) 149 (1.3) 1.25 (1.011.55)*

Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.530.91)*

Intracranial haemorrhage 55 (0.5) 84 (0.7) 0.67 (0.470.93)*

Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.310.79)*

Non-major clinically
1,185 (11.8) 1,151 (11.4) 1.04 (0.961.13)
relevant bleeding
0.2 0.5 1 2 5
Major bleeding and non-major clinically relevant bleeding;
*Statistically significant, p<0.05 Favours Favours
Safety on-treatment population rivaroxaban warfarin
Patel MR et al. N Engl J Med. 2011;365(10):883-891
ROCKET AF: Conclusions
Based on the pre-specified primary efficacy outcome:
A once-daily fixed-dose regimen of rivaroxaban was non-inferior to warfarin
for prevention of stroke or non-CNS systemic embolism
Rivaroxaban was superior to warfarin while patients were taking study drug
A sensitivity analysis in the ITT population that followed all patients in the
trial until completion suggested a benefit for rivaroxaban, but did not reach
superiority
Safety:
Similar overall incidence of bleeding and adverse events
Increase in gastrointestinal bleeds but fewer intracranial haemorrhages
and less fatal bleeding with rivaroxaban
Implication:
Rivaroxaban, administered once daily, has demonstrated non-inferiority
to warfarin in the prevention of stroke or systemic embolism, with similar
overall bleeding and fewer intracranial haemorrhages and fatal bleeds

Patel MR et al. N Engl J Med. 2011;365(10):883-891

Are Phase III Clinical Trials the Final Word?
At its best a trial shows what can be accomplished with a medicine
under careful observation and certain restricted conditions. The
same results will not invariably or necessarily be observed when
the medicine passes into general use.
Austin Bradford Hill father of the modern RCT

Between measurements based on RCTs and benefit in the

community there is a gulf which has been much under-estimated
A. L. Cochrane cataloguer of RCTs

Rothwell PM, Lancet 2005;365:8293

Randomized Clinical Trial Versus Real-World
Evidence

RCTs: controlled
patient population
Post-approval use includes more
Approval varied medical settings and more
diverse patient populations

RWE clarifies whether results observed under RCTs are

also observed in everyday clinical practice
Nallamothu BK et al, Circulation 2008;118:12941303
In essence, a clinical trial can tell us what a drug does, while RWE
can provide the context that tells us whether what it does
1
actually matters.

RCT*
Pre-selected patient population
Strict inclusion and exclusion criteria
Strict study protocol
Objectively adjudicated event rates
Provide a good understanding of how the product
performs in a certain group of people, but not necessarily
reflective of the real-world

RWE** Data collected outside of a RCT setting

More diverse patient population treated in everyday
practice
Data collected prospectively (real-time) or retrospectively
(using past data)
Treatment recommendations through guidelines and at
the discretion of the physician, not strict study protocol
Over- and under-reporting of events is possible

1. PMLiVE. Get Real! The Rise of Observational Data In Healthcare. Available at:
http://www.pmlive.com/pharma_intelligence/get_real!_the_rise_of_observational_data_in_healthcare_705710
Accessed May 2016.
EP
Rivaroxaban Tested in Different Populations in
Randomized Clinical Trials and the Real World
XANTUS1 Baseline ROCKET AF2
Rivaroxaban1 2.0 CHADS2 3.5 Rivaroxaban2

41% 01 0%

30% 2 13%
13%
29% 3 87%
29% 41%
19% Heart failure 63%

75% Hypertension 90% 87%

30%
37% Age >75 years 44%

20% Diabetes 40%

19% Prior stroke# 55%

CHADS2 score
1 10% Prior MI 17%

2 Results are not intended for direct

36 comparison

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

1. Camm AJ et al, Eur Heart J 2016;37:11451153; 2. Patel MR et al, N Engl J Med 2011;365:883891
 Rivaroxaban is Highly Effective in Both
Randomised Clinical Trials and Real World

XANTUS1 Baseline ROCKET AF2

Rivaroxaban Rivaroxaban
2.0 CHADS2 3.5
XANTUS1 ROCKET AF2
1.9 2 1.9
2 41% 0-1 0%
1.7
Event rate, %/year*

Event rate, %/year*

30% 2 13%

29% 3 87%

1 0.8 19% Heat Failure 63% 1

75% Hypertension 91%

Age:
37% 44%
>75 years
0 0
Stroke/ Death 20% Diabetes 40% Stroke/ Death
SE Prior SE
19% 55%
On-treatment analysis Stroke# On-treatment analysis
10% Prior MI 17%

Results are not intended for direct comparison

#Includes. prior stroke, SE or TIA; *Events per 100 patient-years
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;
2. Patel MR et al, N Engl J Med 2011;365:883891
 Rivaroxaban Provides Reassuring Safety,
Reaffirmed in the Real World

XANTUS1 Baseline ROCKET AF2

Rivaroxaban Rivaroxaban
2.0 CHADS2 3.5
XANTUS1 ROCKET AF2
4 41% 0-1 0% 4
3.6
Event rate, %/year*

Event rate, %/year*

30% 2 13%
3 3
29% 3 87%
2.1 2.0
2 2
19% Heat Failure 63%

0.9 75% Hypertension 91%

1
1
0.4 0.5
Age:
37% 44%
>75 years
0 0
Major ICH GI 20% Diabetes 40% Major ICH GI
Bleeding Bleeding 19%
Prior
55% Bleeding Bleeding
On-treatment analysis Stroke# On-treatment analysis
10% Prior MI 17%

Results are not intended for direct comparison

.
#Includes
prior stroke, SE or TIA; *Events per 100 patient-years
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466;
2. Patel MR et al, N Engl J Med 2011;365:883891
 Safety Profile of Rivaroxaban Confirmed through Real World
Evidence Data Regardless of Data Source

ROCKET AF1 Dresden Registry2 US DoD PMSS3 XANTUS4

Clinical trial Retrospective
Prospective Registry Observational
Database
Study

CHADS2-Score 3.5 CHADS2-Score 2.4 CHADS2-Score 2.2 CHADS2-Score 2.0

Rivaroxaban
n=7,111 n=1,200 n=27,476 n=6,784
4 4 4
4
Event rate (%/year)

Event rate (%/year)

Event rate (%/year)

Event rate (%/year)

3 3.6 3 3 3
3.1 2.9
2 2 2 2
2.1
1 1 1 1

0 0 0 0
Major bleeding* Major bleeding# Major bleeding** Major bleeding*

Results are not intended for direct comparison

.
*Major bleeding definitions according to ISTH; **Major bleeding was defined by the Cunningham algorithm 5; # modified ISTH definition (additionally
included surgical revision from bleeding)
1. Patel MR et al. N Engl J Med 2011; 2. Beyer-Westendorf J et al, Blood 2014;124;955962; 3. Tamayo S et al. Clin Cardiol 2015; 4 Camm AJ et al,
Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 5. Cunningham A et al. Pharmacoepidemiol Drug Saf 2011;
Meta-Analysis Reported No Significant Increase in
Gastrointestinal Bleeding Risk for Rivaroxaban vs Warfarin

Meta-analysis of observational cohort studies (N=8) to examine the link

between NOACs and real-world GI bleeding events1
Rivaroxaban: n=10,713 patients, of whom 184 had experienced GI bleeding

Study or Rivaroxa Warfa Weig Risk ratio Risk ratio

subgroup ban total rin ht IV, random IV, random (95% CI)
total (95% CI)
Abraham 5166 5166 35.3 0.93 (0.69
2015 % 1.25)
Chan 2015 244 8064 12.1 0.96 (0.58
% 1.59)
Chang 2015 1649 39,60 3.0% 0.98 (0.36
7 2.69)
Lalibert 3654 14,61 49.6 1.27 (0.99
2014 6 % 1.63)
Subtotal 10,713 67,45 100.0 1.09 (0.92 0.1 0.2 0.5 1 2 5 10
(95% CI) 3 % 1.30) Favours rivaroxaban Favours warfarin

1. He Y et al, Br J Clin Pharmacol 2016;82:285300

Fewer ICH and Comparable GI Bleeding Events in AF
Patients Treated with Rivaroxaban Versus Warfarin

Patients (N=5,165) diagnosed with AF (3/10/201231/12/2014)

identified from the National Swedish Patient Register
Mean SD follow-up: 1.20.6 years (warf) versus 0.80.6 years (riva);
p<0.001
4
Warfarin (n=4,395)
3.5 HR (95% CI)
Events (%/year)

Rivaroxaban (n=5,165)
3
Major
2.5 bleeding
2 ICH*
1.5 GI bleeding
1
Urogenital
0.5 bleeding
0 0.1
Major ICH GI Urogenital Favours 1 Favours 10
bleeding bleeding bleeding rivaroxaba warfarin
*p<0.05 vs warfarin n

Friberg L et al, presented at ESC 2016: O2067. Available at: http://congress365.escardio.org Slide
REVISIT-US Study Design
Characteristics of included patients
(matched cohorts)

Newly initiated on rivaroxaban Parameter Rivaroxaban VKA

or VKA meeting selection (n=11,411) (n=11,411)
criteria
N=38,831
Age, years, mean
70.7 (11.0) 70.7 (11.4)
(SD)

Sex, % male 53.6 53.9

Rivaroxaban VKA
n=12,748 n=26,083 CHADS2 score, Day
180, 1.92 (1.08) 1.94 (1.08)
mean (SD)
Following propensity-score
matching stratified by exposure CHA2DS2-VASc score,
3.46 (1.37) 3.48 (1.35)
status, mean (SD)
11,411 VKA and 11,411
rivaroxaban users were HAS-BLED bleeding
selected for analysis score, Day 180, mean 1.62 (0.69) 1.62 (0.71)
(SD)
15 mg od;
Lower dose NOAC N/A
17.3%
Coleman CI et al, presented at ESC 2016
 REVISIT-US Study Design

Newly initiated on Newly initiated on apixaban Newly initiated on dabigatran

rivaroxaban or VKA meeting or VKA meeting selection or VKA meeting selection
selection criteria criteria criteria
N=38,831 N=18,591 N=56,039

Rivaroxaba
VKA Apixaban VKA Dabigatran VKA
n
n=26,083 n=4332 n=14,259 n=15,908 n=40,131
n=12,748

Following propensity-score
matching stratified by
exposure status, 11,411
VKA and
11,411 rivaroxaban users
were selected for analysis
Following propensity-score Following propensity-score
matching, 4083 VKA and matching, 15,679 VKA and
4083 apixaban users were 15,679 dabigatran users
selected for analysis were selected for analysis

Coleman CI et al, presented at ESC 2016

Association Between NOAC Use (Versus Warfarin)
and Ischaemic Stroke or ICH
Ischaemic stroke, ICH and combined outcomes

HR (95% CI)
Rivaroxaban vs warfarin 0.71 (0.471.07)
Ischaemic
Apixaban vs warfarin 1.13 (0.492.63)
stroke
Dabigatran vs warfarin 0.87 (0.631.22)
Rivaroxaban vs warfarin 0.53 (0.350.79)
ICH Apixaban vs warfarin 0.38 (0.170.88)
Dabigatran vs warfarin 0.71 (0.491.02)
Rivaroxaban vs warfarin 0.61 (0.450.82)
Ischaemic
stroke and Apixaban vs warfarin 0.63 (0.351.12)
ICH
Dabigatran vs warfarin 0.79 (0.621.02)
0.1 Favours 1 Favours 10
NOAC warfarin
Coleman CI et al, presented at ESC 2016
Stroke Rate with Rivaroxaban Is Consistently Low
Across Real-World Studies
Randomized Prospective Observational
clinical trial registry study
ROCKET AF1 Dresden NOAC2 XANTUS3
n=7111 n=1204 n=6784
Stroke/SE
event 1.7% 1.7%*
rate/year 0.8%

Mean 2.0
CHADS2 2.4
score 3.5
Results are not intended for direct comparison

*Includes transient ischaemic attack

1. Patel MR et al, N Engl J Med 2011;365:883891; 2. Hecker J et al, Thromb Haemost 2016 Jan 21;115:939949; 3. Camm AJ et al, Eur Heart J 2016;37:1145
1153
Major Bleeding with Rivaroxaban Is Consistently
Low Across Real-World Studies
Randomized Prospective Retrospective Observational
clinical trial registry database study
ROCKET AF1* Dresden NOAC2# US DoD PMSS3 XANTUS4*
n=7111 N=1204 N=27,467 N=6784

Major bleeding 3.6%

3.0% 2.9%
event rate/year
2.1%

Mean CHADS2 2.4 2.2 2.0

score 3.5
Results are not intended for direct comparison

*Major bleeding definition according to ISTH; #modified ISTH definition (additionally included surgical revision from bleeding);
major bleeding defined by the Cunningham algorithm 5; no major bleeding cohort (representative of >98% of the patient population)

1. Patel MR et al, N Engl J Med 2011;365:883891; 2. Hecker J et al, Thromb Haemost 2016;115:939949; 3. Tamayo S et al, Clin Cardiol 2015;38:6368;
4 Camm AJ et al, Eur Heart J 2016;37:11451153; 5. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20:560566
XANAP: Real-World, Prospective,
Observational Study of Patients Treated
with Rivaroxaban for Stroke Prevention in
Atrial Fibrillation
Background: The Asia-Pacific Perspective

Prevalence of NVAF is growing rapidly in Asia1

Higher overall risk of stroke in

Challenges in using VKAs in
Asian patients with AF compared
Asian versus Caucasian patients2
with Caucasian counterparts2

NOACs have the potential to address the challenges associated with VKA use
in Asian patients3

1. Kodani E & Atarashi H. J Arrhythmia 2012;2012:330337; 2. Sabir I et al, Nat Rev Cardiol 2014;11:290303; 3. Ogawa S et al, J Arrhythmia 2013;29:190200
The XANAP Study
XANAP is the first real-world, prospective, observational study to describe rivaroxaban
use in a broad patient population with NVAF in ten countries of the Asia-Pacific region
(10 countries)
Study period was from 9th January 2013 until 12th October 2015

South Korea
Pakistan
Hong Kong
Vietnam Taiwan
Thailand Philippines
Malaysia
Singapore
Indonesia

www.clinicaltrials.gov/ct2/show/NCT01750788
Recruitment by Country

Country Number of patients enrolled

South Korea 844
Taiwan 614
Philippines 178
Thailand 143
Indonesia 126
Vietnam 112
Malaysia 98
Singapore 79
Pakistan 40
Hong Kong 39
Total 2273
Patient Flow
XANAP Study Results
Overview of Rivaroxaban Trials: Clinical
Characteristics
XANAP XANTUS ROCKET ROCKET AF
(N=2273) (N=6784)1 AF (Asia)
(N=7111)2 (N=468)3

Mean weight, kg 66.1 (28.0% 83.0 - 67.3

missing)
CrCl <50, % 16.3 (48.5% 9.4 20.7
missing)
Prior stroke/SE/TIA, 33.0 19.0 54.9 65.0
%
Mean CHADS2 2.3 2.0 3.5 3.2
Mean CHA2DS2- 3.7 3.4 - 4.4
VASc
Mean HAS-BLED 2.1 2.0 - 2.9
Data not intended for direct comparison

The Asian population in XANAP was at higher risk of stroke and bleeding than
the European and Canadian population in XANTUS and at lower risk than
patients in the ROCKET AF trial and its East-Asian subanalysis
1. Camm AJ et al, Eur Heart J 2016;37:11451153; 2. Patel MR et al, N Engl J Med 2011;365:883891; 3. Wong KS et al, Stroke 2014;45:17391747.
Overview of Rivaroxaban Trials: Outcomes
Outcomes (% per XANAP XANTUS ROCKET AF ROCKET AF
year) (N=2273) (N=6784)1 (N=7111)2 (Asia)
(N=468)3

Major bleeding 1.5 2.1 3.6 3.4

Intracranial 0.7 0.4 0.5 0.6
haemorrhage
Stroke/systemic 1.9 0.8 1.7 2.6
embolism
Stroke 1.7 0.7 1.7 2.6
Ischaemic stroke 0.9* 0.5* 1.3 2.1
Haemorrhagic stroke 0.4* 0.2* 0.3 0.5
Myocardial infarction 0.4 0.4 0.9 1.0
*Shows incidence proportion not incidence rate
Data not intended for direct comparison

Despite the relative-risk profile of patients in XANAP, rates of major bleeding were
lower than in XANTUS, the ROCKET AF trial or its East-Asian subanalysis
1. Camm AJ et al, Eur Heart J 2016;37:11451153; 2. Patel MR et al, N Engl J Med 2011;365:883891; 3. Wong KS et al, Stroke 2014;45:17391747.
 Cumulative Rates of Treatment-Emergent
Outcomes
0.05
Major bleeding event
0.04 Death
Cumulative event rate

Symptomatic thromboembolic event

0.03

0.02

0.01

0
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420
Time to event (days)
Patients at risk: 2273 2169 2073 2000 1903 1840 1768 1707 1664 1606 1522 1370 958 359 165
2273 2170 2076 2002 1906 1844 1773 1715 1674 1617 1535 1385 970 361 166
2273 2170 2076 2001 1904 1845 1773 1713 1672 1614 1530 1379 969 361 166

Overall, very few patients experienced adjudicated treatment-emergent major bleeding,

death, stroke or non-central nervous system systemic embolism
Summary of XANAP
XANAP is the first real-world, prospective, observational study to
describe rivaroxaban use in a broad patient population with non-
valvular AF in ten countries of the Asia-Pacific region
Over 96% patients receiving rivaroxaban did not experience any of the
outcomes of stroke/systemic embolism, treatment-emergent major
bleeding or all-cause death
In XANAP, rivaroxaban demonstrated low rates of stroke/SE and major
bleeding, including intracranial and GI bleeding
Outcomes were broadly consistent with those from the phase III
ROCKET AF trial, its East Asian subanalysis and the XANTUS real-
world observational study, when differences in baseline risk factors
were taken into consideration