A. John Camm St. George’s University of London and Imperial College London, UK
Stroke prevention in AF: Insights from Clinical Trials and Real Life Experience
Approval Number G.MA.GM.XA.10.2015.0723
Disclosure Statement: John Camm
u Chairman: ESC Guidelines on Atrial Fibrillation 2012 and Update 2012, ACC/AHA/ESC Guidelines on VAs and SCD; 2012 NICE Guidelines on ACS and NSTEMI; 2008 NICE Guidelines on Heart Failure; 2006 NICE Guidelines on Atrial Fibrillation
u Steering Committees: multiple trials u DSMBs: multiple trials including AVERROES, SIGNIFY and INOVATE-
AF u Events Committees: one trial of novel oral anticoagulants and multiple
trials of miscellaneous agents with CV adverse effects u Consultant/Advisor/Speaker: AstraZeneca, ChanRX, Gilead, Merck,
Menarini, Otsuka, Sanofi, Servier, Xention, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion, GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi, Novartis, Takeda
Tolerability of Warfarin During First Year of Therapy: Elderly Patients in the US
u 58% time in therapeutic range u Major haemorrhage 7.2%; ICH 2.5% • Rates were 2.75× higher in patients ≥80 years
u 28% of patients discontinued warfarin at 1 year
CHADS2 score
Major bleeding event Taken off therapy Rate (per 100 person-years) Rate (per 100 person-years)
0 3.1 15.6 1 4.3 17.1 2 2.0 12.9 3 19.5 32.6 ≥4 23.4 35.1
Hylek EM et al, Circulation 2007;115:2689‒2696
GARFIELD AF: AF Patients Are Not Treated According to Current Guidelines
Undertreatment with anticoagulants in 38% of patients with CHADS2 score ≥2
0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
100%
Overall (n=10,607)
0 (n=857)
1 (n=3688)
2 (n=3302)
3 (n=1716)
4 (n=757)
5 (n=238)
6 (n=49)
Patie
nts
(%)
CHADS2 score
VKA + AP VKA FXa/DTI AP None
14.3 13.9 8.6 10.5 12.6 16.7 24.4
14.4
30.8
25.3
Bayer is supporting GARFIELD AF with an unrestricted educational grant
Kakkar AK et al, PLoS One 2013;8:e63479
27.9 23.4 21.9 22.2
26.1 22.4
43.2 47.8 50.1
42.4 32.7 45.7
35.1
45.2
14.7 16.3 16.2 8.4 7.1 10.6 11.5 12.2
7.3 2.9 14.3 3.9
4.6 5.2
4.5
2.6
NOACs vs. Warfarin: Overall Outcomes Risk ratio (95% CI)
Absolute risk
reduction, %
Risk ratio (95% CI) p-value
Ischaemic stroke 0.21 0.92 (0.83–1.02) p=0.10
Haemorrhagic stroke 0.46 0.49 (0.38–0.64) p<0.0001
Myocardial infarction 0.07 0.97 (0.78–1.20) p=0.77
All-cause mortality 0.78 0.90 (0.85–0.95) p=0.0003
0.2 0.5 1 2 Favours NOAC
Favours warfarin
Ruff CT et al, Lancet 2014;383:955–962
HR 0.79 (95% CI 0.66–0.96) p<0.001 (non-inferiority)
0 120 240 480 600 720 0
1
2
3
4
5
840 360
ROCKET AF: Effective Stroke Prevention in Patients With Non-valvular AF vs Warfarin (PPP)
Primary efficacy endpoint: stroke/SE
Rivaroxaban Warfarin
PPP, per-protocol population on-treatment (all ITT patients without major predefined protocol violations)
Patel MR et al, N Engl J Med 2011;365:883–891
Days since randomization
Cum
ulat
ive
even
t rat
e (%
)
Number of subjects at risk Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538
52%
48%
ENGAGE AF4 edoxaban
AF Patients in ROCKET AF Had a Higher Risk of Stroke than Patients in Other Phase III Trials
CHADS2 score patient distribution
13%
87%
ROCKET AF1 rivaroxaban
≤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.
34%
30%
36%
ARISTOTLE3 apixaban
32%
32%
36%
RE-LY2 dabigatran
CHADS2 score
Older Age: Stroke and Systemic Embolism Intention-to-Treat Analysis
HR 0.95 (0.76–1.19) HR 0.80 (0.63–1.02)
Interaction p=0.3131
Halperin JL et al, Circulation 2014;130:138–146
0
1
2
3
4
5
6
0 180 360 540 720 St
roke
or S
E (%
) Days following randomization
Age ≥75 years n=6229
0
1
2
3
4
5
6
0 180 360 540 720
Stro
ke o
r SE
(%)
Days following randomization
Age <75 years n=8035
2.10%/year
2.00%/year
2.85%/year
2.29%/year
Warfarin Rivaroxaban
0
1
2
3
4
5
6
<75 years ≥75 years
Even
t rat
e (%
per
yea
r)
Older Age: Major Bleeding On-Treatment Analysis
Halperin JL et al, Circulation 2014;130:138–146
Major bleeding
interaction p=0.336
Haemorrhagic
stroke interaction p=0.365
HR 1.1 (95% CI 0.92–1.34)
HR 0.96 (95% CI 0.78–1.19)
Major bleeding Haemorrhagic stroke
Major bleeding Haemorrhagic stroke
0.49 0.41 0.34 0.20
2.69 2.79
4.40 4.86
ROCKET AF: Primary Efficacy Endpoint: Patients with Stroke or non-CNS Embolism and CrCl 30–49 ml/min vs ROCKET AF overall
Days since randomization 0 120 240 480 600 720
0
1
2
3
4
5
6
840 360
Cum
ulat
ive
even
t rat
e (%
)
*HR 0.79 (95% CI 0.66‒0.96) p<0.001 (non-inferiority)
Warfarin, overall*1
Rivaroxaban overall*1
Warfarin, renally impaired#2
Rivaroxaban renally impaired#2
#Among patients with CrCl 30–49 ml/min: HR 0.84 (95% CI 0.57‒1.23)
Per-protocol population on-treatment
1. Fox KA et al, Eur Heart J 2011;32:2387–2394; 2. Patel MR et al, N Engl J Med 2011;365:883–891
ROCKET AF: Safety Outcomes among AF Patients with CrCl 30–49 ml/min
Clinical endpoint (% per year)
Rivaroxaban (N=7111)
Warfarin (N=7116)
HR (95% CI) rivaroxaban vs warfarin
p-value (interaction)
Principal safety outcome*
14.24 17.82
13.67 18.28
1.04 (0.96‒1.13) 0.98 (0.84‒1.14) 0.45
Major bleeding 3.39 4.49
3.17 4.70
1.07 (0.91‒1.26) 0.95 (0.72‒1.26) 0.48
Haematocrit or haemoglobin drop
2.54 3.76
2.03 3.28
1.25 (1.03‒1.52) 1.14 (0.83‒1.58) 0.65
Transfusion 1.49 2.34
1.16 2.00
1.28 (0.99‒1.65) 1.17 (0.77‒1.76) 0.71
Critical organ 0.83 0.76
1.13 1.39
0.74 (0.55‒0.99) 0.55 (0.30‒1.00) 0.39
Fatal bleeding 0.23 0.28
0.43 0.74
0.55 (0.32‒0.93) 0.39 (0.15‒0.99) 0.53
Intracranial haemorrhage
0.44 0.71
0.71 0.88
0.62 (0.42‒0.92) 0.81 (0.41‒1.60) 0.51
GI bleeding (upper, lower, rectal)
1.79 2.88
1.12 1.77 not reported
CrCl ≥50 ml/min# CrCl 30–49 ml/min‡
Based on safety population on treatment. *Composite of major plus non-major clinically relevant bleeding; #rivaroxaban 20 mg od; ‡rivaroxaban 15 mg od
Fox KAA et al, Eur Heart J 2011;32:2387–2394
0.01 0.1 1 10
Favours warfarin Favours rivaroxaban
ROCKET AF: Rivaroxaban in Patients with AF and Prior Myocardial Infarction
Mahaffey KW et al, Eur Heart J 2014;35:233–241
u 17% had prior MI u Primary efficacy and safety
outcomes in patients with prior MI were consistent with overall ROCKET AF results
u OveralI: 14% reduction in CV death, MI or UA with rivaroxaban vs warfarin (p=0.051)
With prior MI (%/year)
Without prior MI (%/year)
p-value (int.) Riva. Warf. Riva. Warf.
Major/NMCR bleeding 18.84 15.51 14.20 14.31 0.035
Major bleeding 4.75 3.61 3.38 3.42 0.112
CV death, MI, UA
0
3
6
9
12
15
18
0 900 180 360 540 720 Days from randomization
6.80%/yr
1.94%/yr
6.57%/yr
2.45%/yr
HR (95% CI) rivaroxaban vs. warfarin:
With prior MI: 1.04 (0.81–1.33); Without prior MI: 0.79 (0.65–0.96)
Cum
ulat
ive
even
t rat
e (%
)
Warf. with prior MI
Warf. without prior MI Riva. without prior MI
Riva. with prior MI Results
Conclusions
u Many high-risk patients remain untreated or inadequately treated with anticoagulants
u NOACs are recommended by guidelines as they reduce the rate of stroke and intracranial haemorrhage vs. VKAs
u NOACs are effective in high-risk cohorts with favourable benefits compared with risks
u Rivaroxaban once daily is an effective treatment option in many higher-risk cohorts, including in those with moderate renal dysfunction, older age, prior MI etc.
Why is Real World Evidence Needed Given the Positive Outcomes of Phase III trials?
u Phase III studies • Gold standard for evaluating efficacy and safety against the current
standard of care • Support marketing approval by regulatory authorities
u However… • Strict protocols and inclusion/exclusion criteria may exclude some patients
– Limit translation of results from phase III studies to real world populations – Event rates, patient characteristics (i.e. co-morbidities), and adherence/
persistence may not fully reflect real world settings
u Real world studies • Unselected patient populations typical of those seen in routine
clinical practice • Observational design with little interference in patient management • Provide additional information on rare safety events or routine clinical
practice such as management of serious bleeding
XANTUS: Study Objective and Design
u To collect real world data on adverse events in patients with NVAF treated with rivaroxaban to determine the safety profile of rivaroxaban across the broad range of patient risk profiles encountered in routine clinical practice • Primary outcomes: major bleeding (ISTH definition), all-cause mortality,
any other adverse events
Final visit: 1 year#
Data collection at initial visit, hospital discharge
(if applicable) and quarterly*
Population: Adult patients with NVAF receiving rivaroxaban for stroke/non-CNS SE prevention
Rivaroxaban; treatment
duration and dose at
physician’s discretion
*Exact referral dates for follow-up visits not defined (every 3 months recommended); #for rivaroxaban discontinuation ≤1 year, observation period ends 30 days after last dose. Observational design means no interference with clinical practice was allowed
1. Camm AJ et al, Vasc Health Risk Manag 2014;10:425–434; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature
1 year
N=6,784
. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
XANTUS: Baseline Demographics – Clinical Characteristics
Rivaroxaban (N=6784)
Age (years) Mean ± SD 71.5±10.0 Age <65, n (%) 1478 (21.8) Age ≥65–≤75, n (%) 2782 (41.0) Age >75, n (%) 2524 (37.2)
Gender (male): n (%) 4016 (59.2) Weight (kg): mean ± SD 83.0±17.3
BMI (kg/m2): mean ± SD 28.3±5.0 BMI >30 kg/m2, n (%) 1701 (25.1)
AF, n (%) First diagnosed 1253 (18.5) Paroxysmal 2757 (40.6) Persistent 923 (13.6) Permanent 1835 (27.0) Missing 16 (0.2)
Rivaroxaban (N=6784)
Creatinine clearance, n (%) <15 ml/min 20 (0.3) ≥15–<30 ml/min 75 (1.1) ≥30–<50 ml/min 545 (8.0) ≥50–≤80 ml/min 2354 (34.7) >80 ml/min 1458 (21.5) Missing 2332 (34.4)
Existing co-morbidities, n (%) Hypertension 5065 (74.7) Diabetes mellitus 1333 (19.6) Prior stroke/non-CNS SE/TIA 1291 (19.0)
Congestive HF 1265 (18.6) Prior MI 688 (10.1)
Baseline hospitalization, n (%) 1226 (18.1)
XANTUS: Cumulative Rates (Kaplan–Meier) for Treatment-Emergent Primary Outcomes
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
XANTUS: Event-Free Rate (Kaplan–Meier) for Treatment-Emergent Primary Outcomes
u In total, 6522 (96.1%) patients did not experience any of the outcomes of treatment-emergent all-cause death, major bleeding or stroke/SE
1. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
Comparison of Main Outcomes: XANTUS versus ROCKET AF
0,8 0,7
1,9 2,1
0,4
0,9
0,0
0,5
1,0
1,5
2,0
2,5
Stroke/SE All strokes
Death Major bleeding
ICH GI bleeding
XANTUS
Xarelto
CHADS2 Prior stroke#
ROCKET AF1 3.5 55%
XANTUS2 2.0 19%
#Includes prior stroke, SE or TIA; *Events per 100 patient-years
1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466
1,7 1,7 1,9
3,6
0,5
2,0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
Stroke/SE All strokes
Death Major bleeding
ICH GI bleeding
ROCKET AF
Xarelto
Rivaroxaban Safety Profile in Real Life was Consistent with Findings from ROCKET AF
0
1
2
3
4
Major bleeding*
Rivaroxaban
ROCKET AF1 Mean CHADS2 score 3.5
Even
t rat
e (%
/yea
r)
Results are not intended for direct comparison *Major bleeding definitions according to ISTH; #major bleeding was defined by the Cunningham algorithm3 1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Tamayo S et al, Clin Cardiol 2015;38:63-68; 3. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20:560–566
Clinical endpoint % (n) ICH 0.8 (55)
Fatal bleeding 0.4 (27)
Major GI bleeding 3.2 (224)
Clinical endpoint % (n) ICH 0.1 (36)
Fatal bleeding <0.1 (14)
Major GI bleeding 1.5 (423)
0
1
2
3
4
Major bleeding
US DoD PMSS2
Mean CHADS2 score 2.2
Even
t rat
e (%
/yea
r)
Median duration of treatment exposure was 590 days Rivaroxaban users were followed for 455 days
#
3.6 2.9
N=7111
N=27,467
Similar Risk of Gastrointestinal Bleeding with Novel OACs Compared with Warfarin in Real Life
u Patients: 4907 dabigatran, 1649 rivaroxaban, 39,607 warfarin
u Results are similar to a recent observational study from the US that reported no statistically significant differences in real-life rates of bleeding between rivaroxaban and warfarin (HR for major bleeding 1.08, 95% CI 0.71–1.64)2
Analysis (reference group warfarin) Dabigatran Rivaroxaban
All patients:
Adjusted HR (95% CI) 1.21 (0.96–1.53) 0.98 (0.36–2.69)
Patients <65 years:
Adjusted HR (95% CI) 1.34 (0.98–1.83) 1.03 (0.33–3.18)
Patients >65 years:
Adjusted HR (95% CI) 1.07 (0.75–1.53) 0.62 (0.18–2.08)
Population based retrospective cohort study1
1. Chang HY et al, BMJ 2015;350:h1585; 2. Laliberté F et al, Curr Med Res Opin 2014;30:1317–1325
u Most MB cases could be treated conservatively, rarely requiring procoagulants1
0
10
20
30
40
50
60
70 C
onse
rvat
ive
Sur
g/In
terv
RB
C
Vit K
FFP
only
PC
C o
nly
FFP
+ P
CC
rFV
II
Conservative = no treatment/ compression/ tamponade/ transfusion
MB
Man
agem
ent A
ppro
ach
(%)
0
1
2
3
4
5
6
7
8
9
10
VKA Rivaroxaban
MB
Cas
e fa
talit
y ra
te (%
)
u With Rivaroxaban Case-fatality rate was 6.3% at day 90 after bleeding-related hospitalization compared to 9.1% with VKA
u Different studies report Case fatality rates of VKA-related major bleeding of 15% - 20%3–5
2 1
Dresden NOAC Registry: Outcomes of Major Bleedings May Be Better with Rivaroxaban than Those Reported for VKAs
1. Beyer-Westendorf J et al, Blood 2014;124:955–962; 2. Michalski F et al, Thromb Haemost 2015;114 [epub ahead of print]; 3. Gomes et al, CMAJ 2013;185:E121–E127: 4. Linkins et al, Ann Intern Med 2003;139:893–900; 5. Halbritter et al, J Thromb Haemost 2013;11:651–659
0% 1000% 2000% 3000% 4000% 5000% 6000% 7000% 8000% 9000%
10000%
0 30 60 90 120 150 180
HR 0.66 (95% CI 0.60–0.72)
p<0.0001
Rivaroxaban Warfarin
Time to non-persistence (days)
Patie
nt p
ersi
sten
ce (%
)
u Matched sample included 3654 rivaroxaban and 14,616 warfarin patients1
u 7259 rivaroxaban patients were matched 1:1 with warfarin patients2
In Real Life AF Patients Stayed Longer on Rivaroxaban Than on Warfarin
Two retrospective U.S. database analyses
Patients were significantly more persistent with Rivaroxaban than with Warfarin
0% 1000% 2000% 3000% 4000% 5000% 6000% 7000% 8000% 9000%
10000%
0 60 120 180 240 300 360
Patie
nt p
ersi
sten
ce (%
)
Time to non-persistence (days)
1. Laliberté F et al, Curr Med Res Opin 2014;30:1317–1325; 2. Nelson WW et al, Curr Med Res Opin 2014;30:2461–2469
HR 0.63 (95% CI 0.59–0.68)
p<0.001
Rivaroxaban Warfarin
Conclusion
u Real life evidence of novel OACs is important to delineate effectiveness and safety in patients with AF1-3
u In XANTUS, rivaroxaban demonstrated low rates of stroke/SE and major bleeding, including intracranial and GI bleeding4
u Major bleedings in Real Life can normally be conservatively managed3 u Rivaroxaban once daily in real life is associated with higher patient
persistence compared with warfarin 5–8
1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Tamayo S et al, Clin Cardiol 2015;38:63–68; 3. Beyer-Westendorf et al, Blood 2014;124;955–962; 4. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 5. Laliberté F et al, Curr Med Res Opin 2014;30:1317–1325; 6. Nelson WW et al, Curr Med Res Opin 2014;30:2461–2469; 7. Beyer-Westendorf J et al, Europace 2015;17:530–538; 8. Beyer-Westendorf J et al, Thromb Haemost 2015;113:1247–1257
