Download GP AF talk

Stroke Prevention in AF – A
new Paradigm
ROHAN JAYASINGHE
Professor of Cardiology
Gold Coast Hospital
Learning Objectives
1.
To assess stroke risk in patients with non-valvular atrial fibrillation
(NVAF)
2.
To assess bleeding risk in patients with NVAF
3.
To comprehend and apply the current evidence regarding choice
and use of antithrombotic
therapy to reduce stroke risk in NVAF
4.
To evaluate the efficacy and safety of contemporary antithrombotic
therapies in the reduction of stroke risk in NVAF
Aetiology of AF
Age
Hypertension
Valvular heart disease (esp. mitral valve disease)
Coronary Disease / MI
CHF
Obesity / OSA
Diabetes
Alcohol/Caffeine/Drugs
Thyrotoxicosis
Acute illness (e.g. infections / surgery)
Myocarditis / Infiltration
Pericardial disease (e.g. pericarditis)
Electrolyte abnormalities
Anaemia
The Ageing Population of Australia
25
65-84 yrs
> 85 yrs
20
Per cent
15
10
5
0
1970
1990
2010
2030
2050
Consequently, the prevalence of AF will increase
Intergenerational Report 2010. Commonwealth of Australia
AF is a Frequent and Increasing Cause of
Hospitalisation in Australian Public
Hospitals
AIHW separations statistics
148 Atrial fibrillation and flutter
45,619
67% increase
27, 245
Australian Institute of Health and Welfare. Interactive national hospital morbidity data. Principal diagnosis data cubes.
Available at: http://d01.aihw.gov.au/cognos/cgi-bin/ppdscgi.exe?DC=Q&E=/ahs/pdx0607
Goals of Management in AF
 Management of AF has two broad objectives:
1.
Relief of symptoms
2. Prevention of complications, including thromboembolism (particularly stroke) and
heart failure
 These objectives can be achieved by:
1.
Rate control
2.
Rhythm control
3. Risk-stratified antithrombotic therapy
Goals of Management in AF
 Management of AF has two broad objectives:
1.
Relief of symptoms
2. Prevention of complications, including thromboembolism (particularly stroke)
and heart failure
 These objectives can be achieved by:
1.
Rate control
2.
Rhythm control
3. Risk-stratified antithrombotic therapy
AF Increases Stroke Risk by Nearly 500%
Risk ratio = 4.8
P < 0.001
Wolf PA, et al. Stroke. 1991;22:983-988. Adapted with permission.
Strokes Due to AF:
…are due to large artery cerebral occlusion and are
associated with a doubling of poor outcome
(death or non-fatal stroke) two weeks after ischaemic stroke
International Stroke Trial. Lancet 1997; 349: 1569-1581
Higher Mortality After Stroke,
at 2 Weeks and 6 Months, in AF Patients
45%
without AF
40%
with AF
35%
Mortality
30%
25%
20%
15%
10%
5%
0%
Dead at 2 weeks
Dead at 6 months
International Stroke Trial, Lancet 1997; 349: 1569-81
Patients With AF Are More Likely to
Die Within 1 Year of a Stroke
P < 0.001
Kaarisalo MM ,et al. Stroke. 1997;28:311-315
Severe Disability Is Increased in Patients
With Stroke due to AF
Lin HJ, et al. Stroke. 1996;27:1760-1764
Stroke Risk Persists
Even in Asymptomatic/Intermittent AF
 The risk of stroke with asymptomatic or intermittent AF is comparable to that with
permanent AF1,2
Observed rate of ischaemic stroke1
Annual risk of stroke, %
14
12
Intermittent AF
Sustained AF
10
8
6
4
2
0
Low
Moderate
High
Stroke risk category
1. Hart RG, et al. J Am Coll Cardiol 2000;35:183–7
2. Flaker GC, et al. Am Heart J 2005;149:657–63
The Cost of AF to the Australian Economy
 $1.25 billion every year
 $5,200 per person with AF
 64% of this cost arises as a direct result
of stroke, heart failure or death
Pricewaterhouse Coopers, 2010
CHADS2 Score Helps Predict Stroke Risk
in Patients With AF
CHADS2 criteria
0
CHADS2 score
1
2
3
Score
Congestive heart failure
1
Hypertension
1
Age >75 yrs
1
Diabetes mellitus
1
Stroke/transient ischaemic attack
2
4
5
6
0
5
10
15
20
25
30
Annual stroke rate (%)*
Error bars = 95% CI; *Adjusted stroke rate = expected stroke rate per 100 patient-years
based on exponential survival model, assuming Aspirin not taken
Gage BF, et al. JAMA 2001;285:2864–70
Summary of Canadian Cardiology Society
Guidelines for Thromboembolic Management in
AF
Assess Thromboembolic Risk (CHADS2)
and Bleeding Risk (HAS-BLED)
CHADS2 = 0
CHADS2 = 1
CHADS2 ≥ 2
Aspirin
OAC
OAC
No antithrombotic may be
appropriate in selected
young patients with no
stroke risk factors
Aspirin is a reasonable
alternative in some as
indicated by risk-benefit
Novel agents preferred OAC over warfarin in most patients
Cairns JA, et al. Canadian Journal of Cardiology. 2011;27:74-90
AF – Warfarin compared with Placebo:
Effect on Stroke/Systemic
6 trials, 2,900 patients
Relative Risk Reduction
95% CI
Absolute RR
% / year
AFASAK I
2.6
SPAF
4.7
BAATAF
2.4
CAFA
1.2
SPINAF
3.3
EAFT
8.4
2.7 PP
8.4 SP
All trials
All Trials
RRR = 64 %
(49 to 74%)
100%
50%
0
-50%
-100%
Hart RG, et al. Ann. Intern Med 2007; 146: 857-67
AF – Related Stroke is Preventable
 2/3 of strokes due to AF are preventable
with appropriate anticoagulant therapy
with a vitamin-K-antagonist (VKA) (INR
2-3)1
 Anticoagulation with a VKA is
recommended for patients with more than
1 moderate risk factor2
Effect of VKA compared to placebo
Stroke
Stroke
Death
Death
67%
67%
26%
26%
 A meta-analysis of 29 trials in 28,044
patients showed that adjusted-dose
warfarin results in a reduction in ischaemic
stroke and in all-cause mortality1
1. Hart RG, et al. Ann Intern Med. 2007;146:857-867
2. Fuster V, et al. JACC. 2006; 48: 854-906
Questions?
Rivaroxaban Once-daily oral direct factor Xa inhibition
Compared with vitamin K antagonism for prevention
of stroke and Embolism Trial in Atrial Fibrillation
Rivaroxaban
 Selective, direct Factor Xa
inhibitor1
 High oral bioavailability2
TF/VIIa
X
IX
 Rapid onset of action3
VIIIa
 Half-life:2–4
IXa
Rivaroxaban
Va
 5–9 hours in young individuals
 11–13 hours in the elderly
Xa
 Dual mode of elimination:5
 1/3 of active drug excreted
unchanged by the kidneys
 2/3 of drug metabolized by the
liver; half of which is excreted
renally,
half excreted via the
hepatobiliary route
1. Perzborn et al, 2005; 2. Kubitza et al, 2005a; 3. Kubitza et al, 2005b;
4. Kubitza et al, 2008; 5. Weinz et al, 2009
II
IIa
Fibrinogen
Fibrin
Adapted from
Weitz et al, 2005; 2008
New Anticoagulants
Coagulation
cascade
Initiation
Drug
TF/VIIa
X
IX
IXa
VIIa
Propagation
Xa
Va
II
TFPI
NAPc2
Fondaparinux
Idraparinux
Razaxaban
Rivaroxaban
Apixiban
Thrombin activity
IIa
Fibrinogen
Fibrin
Ximelagatran
Dabigatran
Adapted with permission from Weitz J,, Hirsh J. Chest. 2001;119:95S-107S.
ROCKET AF – study design
Randomized, double-blind, double-dummy, event-driven
Non-valvular AF
N=14,264
OR
≥2* of the following:




R
CHF
Hypertension
Age ≥75 years
Diabetes
30-day follow-up
Rivaroxaban 20 mg once daily#
End of study
 History of stroke,
TIA or non-CNS SE
Warfarin target INR 2–3
~14 – 40 months‡
*Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%.
#Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily.
‡Duration of therapy varied for each patient as study was event-driven.
Patel MR et al. N Engl J Med 2011;365:883–891
25
ROCKET AF – study design
Atrial fibrillation
Rivaroxaban
20 mg once daily
(15 mg once daily
for CrCl 30–49 ml/min)
Randomized
double blind /
double dummy
Risk factors
• Stroke, TIA or
systemic embolus
OR
• CHF
At least 2
• Hypertension or 3
• Age  75
required*
• Diabetes
Warfarin
INR target: 2.5
(2.0–3.0 inclusive)
Monthly monitoring
Adherence to standard-of-care guidelines
Primary endpoint: stroke or non-CNS systemic embolism
*Enrolment of patients without prior stroke, TIA or SE and only two factors capped at 10%
Patel MR et al. N Engl J Med 2011;365:883–891
26
ROCKET AF – study endpoints
Primary efficacy endpoint
 Composite of stroke and sytemic embolism (SE)
Secondary efficacy endpoints
 Composite of stroke, SE and cardiovascular death
 Composite of stroke, SE, cardiovascular death and MI
 Individual components of the above endpoints
Principal safety endpoint
 Composite of major and non-major clinically relevant bleeding
Patel MR et al. N Engl J Med 2011;365:883–891
27
ROCKET AF – patient flow
Rivaroxaban
Warfarin
Randomized
(n=14,264)
7131
7133
–50
–43
7081
ITT population:
all patients randomized (n=14,171)
7090
–20
–8
7061
Safety population:
all ITT patients who received ≥1 dose of
study drug (n=14,143)
7082
–103
–78
Per-protocol population:
6958
all ITT patients without major predefined
protocol violations (n=13,962)
Patel MR et al. N Engl J Med 2011;365:883–891
7004
28
Rationale for the rivaroxaban
dose in ROCKET AF
 20 mg once daily was chosen as the rivaroxaban dose for the phase III
ROCKET AF trial based on the phase II dose-finding programme for DVT
treatment
 EINSTEIN DVT1 and ODIXa DVT2 both demonstrated:
 Efficacy of rivaroxaban did not increase with increasing total daily dose
(20, 40, 60 mg in ODIXa-DVT; 20, 30, 40 mg in EINSTEIN DVT)
 Major bleeding was similar irrespective of total daily dose and
comparable to the standard of care
– Supports 20 mg total daily dose (as lowest effective dose evaluated)
 Early clinical pharmacology studies showed that rivaroxaban inhibited
thrombin generation (and thereby continued to prevent coagulation)
beyond 24 hours after administration3
– Supports once-daily dosing
1. Büller HR et al, 2008; 2. Agnelli G et al, 2007; 3. Harder S et al, 2004.
29
ROCKET AF – baseline characteristics (1)
Rivaroxaban
(N=7,131)
Warfarin
(N=7,133)
73 (65, 78)
73 (65, 78)
Female, %
39.7
39. 7
Body mass index, median, kg/m2
28.3
28.1
Systolic
130
130
Diastolic
80
80
Persistent
5,786 (81.1)
5,762 (80.8)
Paroxysmal
1,245 (17.5)
1,269 (17.8)
100 (1.4)
102 (1.4)
Previous ASA use
2,586 (36.3)
2,619 (36.7)
Previous VKA use
4,443 (62.3)
4,461 (62.5)
Characteristic
Age, median (25th, 75th), years
Blood pressure, median, mmHg
Clinical presentation, n (%)
Type of atrial fibrillation
Newly diagnosed/new onset
ITT population
Patel MR et al. N Engl J Med 2011;365:883–891
30
ROCKET AF – baseline characteristics (2)
Rivaroxaban
(N=7,131)
Warfarin
(N=7,133)
3.48±0.94
3.46±0.95
2, n (%)
925 (13.0)
934 (13.1)
3, n (%)
3,058 (42.9)
3,158 (44.3)
4, n (%)
2,092 (29.3)
1,999 (28.0)
5, n (%)
932 (13.1)
881 (12.4)
6, n (%)
123 (1.7)
159 (2.2)
Previous stroke/TIA or SE
3,916 (54.9)
3,895 (54.6)
Congestive heart failure
4,467 (62.6)
4,441 (62.3)
Hypertension
6,436 (90.3)
6,474 (90.8)
Diabetes mellitus
2,878 (40.4)
2,817 (39.5)
Previous MI
1,182 (16.6)
1,286 (18.0)
Peripheral vascular disease
401 (5.6)
438 (6.1)
Chronic obstructive pulmonary disease
754 (10.6)
743 (10.4)
67 (52, 88)
67 (52, 86)
Characteristic
CHADS2 score, mean ± SD
Co-existing conditions, n (%)
CrCl, median (25th, 75th), ml/min
ITT population
Patel MR et al. N Engl J Med 2011;365:883–891
31
ROCKET AF – primary efficacy endpoint
Stroke or systemic embolism
Cumulative event rate (%)
6
HR=0.79 (0.66, 0.96)
5
Warfarin
p<0.001 (non-inferiority)
4
3
Rivaroxaban
2
1
0
0
Number of subjects at risk
Rivaroxaban
6,958
Warfarin
7,004
120
240
480
600
360
Days since randomization
720
840
6,211
6,327
5,786
5,911
2,472
2,539
1,496
1,538
5,468
5,542
4,406
4,461
3,407
3,478
Per-protocol population – as treated
Patel MR et al. N Engl J Med 2011;365:883–891
32
ROCKET AF – primary efficacy endpoint
Stroke or systemic embolism
p-value
Rivaroxaban
(% per year)
Warfarin
(% per year)
Non-inf.
Per-protocol,
on treatment
1.7
2.2
<0.001
Safety,
on treatment
1.7
2.2
ITT
2.1
2.4
Hazard ratio
and 95% CIs
Sup.
0.02
<0.001
0.12
0.5
Favours
rivaroxaban
Patel MR et al. N Engl J Med 2011;365:883–891
1
2
Favours
warfarin
33
ROCKET AF – primary efficacy endpoint
ITT
6
Stroke or systemic embolism
Warfarin
Cumulative event rate (%)
5
HR=0.88 (0.75, 1.03)
p<0.001 (non-inferiority)
p=0.12 (superiority)
4
Rivaroxaban
3
2
1
0
0
Number of subjects at risk
Rivaroxaban
7,081
Warfarin
7,090
120
240
360
480
600
Days since randomization
720
840
6,879
6,871
6,683
6,656
2,951
2,944
1,785
1,783
6,470
6,440
5,264
5,225
4,105
4,087
ITT population
Patel MR et al. N Engl J Med 2011;365:883–891
34
ROCKET AF – primary efficacy
endpoint components
Hazard ratio
and 95% CIs
Rivaroxaban
(N=7,061)
Warfarin
(N=7,082)
n
(% per year)
n
(% per year)
Hazard ratio
(95% CI)
189 (1.7)
243 (2.2)
0.79 (0.65, 0.95)*
184 (1.7)
221 (2.0)
0.85 (0.70,1.03)
Haemorrhagic stroke
29 (0.3)
50 (0.4)
0.59 (0.37,0.93)*
Ischaemic stroke
149 (1.3)
161 (1.4)
0.94 (0.75,1.17)
7 (0.1)
11 (0.1)
0.65 (0.25,1.67)
5 (0.04)
22 (0.2)
0.23 (0.09, 0.61)*
Endpoints
Primary efficacy endpoint
All-cause stroke
Unknown stroke type
Non-CNS SE
0.2
Safety population – on-treatment analysis
*Statistically significant
Patel MR et al. N Engl J Med 2011;365:883–891
0.5
Favours
rivaroxaban
1
2
5
Favours
warfarin
35
ROCKET AF – bleeding analysis
Rivaroxaban
(N=7,111)
Parameter
Warfarin
(N=7,125)
n (% per year) n (% per year)
Hazard ratio
(95% CI)
Principal safety
endpoint
1,475 (14.9)
1,449 (14.5)
1.03 (0.96,1.11)
Major bleeding
395 (3.6)
386 (3.4)
1.04 (0.90,1.20)
Haemoglobin drop
(≥2 g/dl)
305 (2.8)
254 (2.3)
1.22 (1.03,1.44)*
Transfusion
183 (1.6)
149 (1.3)
1.25 (1.01,1.55)*
Critical organ
bleeding
91 (0.8)
133 (1.2)
0.69 (0.53,0.91)*
55 (0.5)
84 (0.7)
0.67 (0.47,0.93)*
27 (0.2)
55 (0.5)
0.50 (0.31,0.79)*
1,185 (11.8)
1,151 (11.4)
1.04 (0.96,1.13)
Intracranial
haemorrhage
Fatal bleeding
Non-major clinically
relevant bleeding
Major bleeding from gastrointestinal site (upper, lower and rectal):
rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001*
Safety population – on-treatment analysis; *Statistically significant
Patel MR et al. N Engl J Med 2011;365:883–891
Hazard ratio
and 95% CIs
0.2
0.5 1
2
5
Favours
Favours
rivaroxaban
warfarin
36
ROCKET AF – secondary efficacy endpoints
Rivaroxaban
(N=7,061)
Warfarin
(N=7,082)
n (% per year)
n (% per year)
Hazard ratio
(95% CI)
Composite of stroke, nonCNS SE,
vascular death
346 (3.1)
410 (3.6)
0.86 (0.74, 0.99)*
Composite of stroke, non-CNS
SE, vascular death and MI
433 (3.9)
519 (4.6)
0.85 (0.74, 0.96)*
All-cause stroke
184 (1.7)
221 (2.0)
0.85 (0.70, 1.03)
Non-CNS SE
5 (0.04)
22 (0.2)
0.23 (0.09, 0.61)*
MI
101 (0.9)
126 (1.1)
0.81 (0.63, 1.06)
Vascular death
170 (1.5)
193 (1.7)
0.89 (0.73, 1.10)
208 (1.9)
250 (2.2)
0.85 (0.70, 1.02)
Endpoints
Components of major secondary
endpoints
All-cause mortality
Safety population – on-treatment analysis. *Statistically significant
Patel MR et al. N Engl J Med 2011;365:883–891
37
ROCKET AF – primary efficacy endpoint
subgroup analysis#
Rivaroxaban
Overall
Sex
Male
Female
Age (years)
<75
≥75
Weight (kg)
≤70
70–≤90
>90
CrCl (ml/min)
<50
50–80
>80
n/N
189/7,061
(%)
2.7
Hazard ratio and 95% CIs
Warfarin
n/N
243/7,082
(%)
3.4
p-value*
0.92
103/4,270
86/2,791
2.4
3.1
136/4,283
107/2,799
3.2
3.8
0.11
107/3,988
82/3,073
2.7
2.7
119/4,005
124/3,077
3.0
4.0
0.78
63/2,004
92/3,022
34/2,033
3.1
3.0
1.7
78/2,008
129/3,133
36/1,940
3.9
4.1
1.9
0.72
50/1,485
91/3,290
47/2,278
3.4
2.8
2.1
60/1,456
128/3,396
54/2,221
Safety population – on-treatment analysis
*p-value for interaction
#Stroke or systemic embolism
Patel MR et al. N Engl J Med 2011;365:883–891
4.1
3.8
2.4
0.1
0.2
0.5
Favours
rivaroxaban
1
2
5
Favours
warfarin
10
38
ROCKET AF – primary efficacy endpoint
subgroup analysis#
Rivaroxaban
n/N
189/7,061
Overall
CHADS2
2
21/922
3
56/3,025
4
71/2,073
5
35/918
6
6/122
Congestive heart failure
Yes
106/4,428
No
83/2,632
Hypertension
Yes
174/6,372
No
15/689
Diabetes
Yes
70/2,842
No
119/4,219
Previous MI
Yes
25/1,169
No
164/5,892
Previous stroke/TIA/Non-CNS
Yes
136/3,881
No
53/3,180
(%)
2.7
Hazard ratio and 95% CIs
Warfarin
n/N
243/7,082
(%)
3.4
p-value*
0.74
2.3
1.9
3.4
3.8
4.9
24/931
87/3,131
88/1,988
36/875
8/155
2.6
2.8
4.4
4.1
5.2
0.66
2.4
3.2
141/4,409
102/2,672
3.2
3.8
0.85
2.7
2.2
223/6,429
20/653
3.5
3.1
0.60
2.5
2.8
94/2,793
149/4,289
3.4
3.5
0.25
2.1
2.8
SE
3.5
1.7
46/1,269
197/5,813
3.6
3.4
0.04
151/3,869
92/3,213
Safety population – on-treatment analysis
*p-value for interaction
#Stroke or systemic embolism
Patel MR et al. N Engl J Med 2011;365:883–891
3.9
2.9
0.1
0.2
0.5
Favours rivaroxaban
1
2
5
10
Favours warfarin
39
ROCKET AF – primary efficacy endpoint
subgroup analysis#
Rivaroxaban
Overall
Hazard ratio and 95% CIs
Warfarin
n/N
(%)
n/N
189/7,061
2.7
243/7,082
p(%) value*
3.4
Race
0.49
White
151/5,856
2.6
194/5,909
3.3
Black
5/94
5.3
5/85
5.9
Asian
27/894
3.0
41/887
4.6
Other
6/217
2.8
3/201
1.5
Region
0.62
North America
20/1,334
1.5
36/1,339
2.7
Latin America
33/939
3.5
37/938
3.9
West Europe
28/1,040
2.7
34/1,049
3.2
East Europe
78/2,696
2.9
91/2,704
3.4
Asia-Pacific
30/1,052
2.9
45/1,052
4.3
Safety population – on-treatment analysis
*p-value for interaction
#Stroke or systemic embolism
Patel MR et al. N Engl J Med 2011;365:883–891
0.1
0.2
0.5
Favours rivaroxaban
1
2
5
10
Favours warfarin
40
ROCKET AF – conclusions
 Based on the prespecified 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
 Safety:
 Similar overall incidence of bleeding and adverse events
 Increase in gastrointestinal bleeds but importantly fewer intracranial
haemorrhages and less fatal bleeding with rivaroxaban
 Implication:
 Rivaroxaban, once approved in the indication, is a once-daily, proven
alternative to warfarin with superior efficacy ‘on treatment’, similar overall
bleeding and fewer intracranial haemorrhages
41
New Oral Anticoagulants
dabigatran
(Pradaxa)
rivaroxaban
(Xarelto)
apixaban
80%
66%
25%
T1/2
12-14 hours
9-13 hours
8-15 hours
Tmax
1.25-3 hours
2-4 hours
1-4 hours
P-gp inhibitors
CYP3A4 /
P-gp inhibitors
CYP3A4 /
P-gp inhibitors
6.5%
(human)
67-86% (animals)
49%
(human)
Protein binding
35%
92-95%
87%
Prodrug
Yes
No
No
Renal excretion
Drug-drug
interactions
Bioavailability
Eriksson BI, et al. Clin. Pharmacokinet. 2009; 48(1): 1-22
ROCKET AF some additional points of
value
ROCKET AF: principal inclusion criteria
 Age ≥18 years
 Persistent or paroxysmal AF documented on ≥2 episodes (one of
which is electrocardiographically documented within 30 days of
enrollment)
 Risk for future stroke, including the history of stroke/TIA or
systemic embolism OR ≥2 of the following:
 Congestive heart failure or left ventricular ejection fraction ≤35%
 Hypertension (systolic blood pressure ≥180 mmHg or diastolic blood
pressure ≥100 mmHg)
 Age ≥75 years
 Diabetes mellitus
Patel MR et al: Am Heart J 2010;159:340-347.e1
ROCKET AF: principal exclusion criteria 1
 Cardiovascular-related conditions






Prosthetic heart valve
Planned cardioversion
AF secondary to reversible disorders (ie, thyrotoxicosis)
Known presence of atrial myxoma or left ventricular thrombus
Active endocarditis
Hemodynamically significant mitral stenosis
Patel MR et al: Am Heart J 2010;159:340-347.e1
ROCKET AF: principal exclusion criteria 2
 Hemorrhage risk-related criteria
 Active internal bleeding
 History of, or condition associated with, increased bleeding risk,
including
– Major surgical procedure or trauma within 30 days before
randomization
– Clinically significant gastrointestinal bleeding within 6 months
– before randomization
– History of intracranial, intraocular, spinal, or atraumatic
– intraarticular bleeding
– Chronic hemorrhagic disorder
– Known intracranial neoplasm, arteriovenous malformation, or
aneurysm
– Planned invasive procedure with potential for uncontrolled bleeding,
including major surgery
Patel MR et al: Am Heart J 2010;159:340-347.e1
ROCKET AF: principal exclusion criteria 3
 Concomitant conditions:
 Any stroke within 14 days before randomization
 TIA within 3 days before randomization
 Indication for anticoagulant therapy for a condition other than AF (eg,
VTE)
 Anemia (hemoglobin level b10 g/dL) at the screening visit
 Pregnancy or breastfeeding
 Known HIV infection at time of screening
 Calculated creatinine clearance b30 mL/min at the screening visit
 Known significant liver disease (eg, acute clinical hepatitis, chronic
active hepatitis, cirrhosis) or alanine aminotransferase N3× the upper
limit of normal
Patel MR et al: Am Heart J 2010;159:340-347.e1
Comparison of phase III studies of
new oral anticoagulants for stroke
prevention in atrial fibrillation
Study design and inclusion
ROCKET AF1
RE-LY2
ARISTOTLE3,6
AVERROES4
ENGAGE AFTIMI 485
14,264
18,113
18,201
5,599
20,500
Statistical
objective
Non-inferiority
Non-inferiority
Non-inferiority
Superiority
Non-inferiority
No. study
arms
2
3
2
2
3
Study
drug
Double-blind
rivaroxaban
Two doses of
double-blind
dabigatran
Double-blind
apixaban
Double-blind
apixaban
Two doses of
double-blind
edoxaban
Control
Double-blind
warfarin
(INR 2–3)
Open-label
warfarin
(INR 2–3)
Double-blind
warfarin
(INR 2–3)
Double-blind
ASA
Double-blind
warfarin
(INR 2–3)
Non-valvular
Non-valvular
All except
mechanical valves
Non-valvular
Non-valvular
No. of
patients
AF type
of pts
included
1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011;
5. Ruff CT et al, 2010; 6.Granger CB et al, 2011.
49
Dosing and dose evaluation for
special populations
ROCKET AF1
RE-LY2
ARISTOTLE3
& AVERROES4
ENGAGE AF-TIMI 485
Rivaroxaban
Dabigatran
Apixaban
Edoxaban
20 mg od (15 mg od)
110 mg bid
or
150 mg bid
5 mg bid (2.5 mg bid)
(randomized to
two separate
arms)
Dose adjustment for
patients with:
Moderate
renal
impairment CrCl 3049
ml/min
No dose
adjustment
30 mg od (15 mg od)
or
60 mg od (30 mg od)
(randomized to two
separate arms)
Dose adjustment for
patients fulfilling 2
of the following criteria
at baseline:
 Age 80 years
Dose adjustment for
patients fulfilling ≥1 of
the following criteria at
baseline:

Body weight 60 kg
verapamil or quinidine

Serum creatinine
1.5mg/dl (133 µmol/l)
Body
Concomitant
CrCl
1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011;
5. Ruff CT et al, 2010.
weight 60 kg
3050 ml/min
50
Cross-trial comparisons
 Cross-trial comparisons
are hazardous
 ROCKET AF and others:
 Different drugs
 Different trial designs
 Different patient populations
 The best method to compare
drugs is head-to-head,
randomization in large
populations
51
ROCKET AF vs RE-LY (150 mg)
Rivaroxaban 20/15 mg vs warfarin in
ROCKET AF1
Dabigatran 150 mg vs warfarin in
RE-LY2,3
Design
Double blind
Open label
Efficacy
Non-inferior to warfarin
Non-inferior to warfarin
Superior to warfarin on treatment
Superior to warfarin
Safety
Similar rates of major haemorrhage
Similar rates of major haemorrhage
Less ICH
Less ICH
*Data from initial publication,2 in a post hoc analysis published 2010 the addition of newly identified MIs
led to the loss of significance for MI3
1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Connolly SJ et al, 2010.
52