Transcript No Slide Title

Antistolling in AF
Het begin van een nieuw tijdperk?
Dr RG Tieleman
Martini Ziekenhuis Groningen
CVA en Atriumfibrilleren: de feiten

CVA is de belangrijkste complicatie van AF

AF is geassocieerd met een 5x verhoogde kans op CVA

AF verdubbeld het risico op CVA wanneer gecorrigeerd voor
andere risico factoren

Zonder behandeling is de incidentie van CVA in AF 5%
 (incl
TIAs en stille CVAs > 7%)

AF is verantwoordelijk voor 1/3 van alle CVAs

AF geassocieerd CVA is 2x vaker dodelijk en meer
invaliderend
Warfarin superior in reducing the stroke risk in AF patients
Control worse
Control better
RRR 64%
Warfarin vs Placebo
(95% CI: 4974%)
RRR = 19%
Aspirin vs Placebo
(95% CI: –1 to 35%)
Warfarin vs Aspirin
RRR 38%
100
(95% CI: 18–52%)
50
0
RRR (%)†
Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
Hart RG et al. Ann Intern Med 2007;146:857–67
–50
–100
VKAs have a narrow therapeutic window
20
Therapeutic
range
Odds ratio
15
Stroke
10
Intracranial bleed
5
1
0
1
2
3
4
5
International normalized ratio
VKAs = vitamin K antagonists
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354
& Eur Heart J 2006;27:1979–2030
6
7
8
SPORTIF V
INR Values – Warfarin Group
Time in Range (%)
100
80
60
68%
2.0-3.0
40
20
0
3
6
9
12
15
18
21
24
26
Treatment Duration (months)
Circulation 2003;108:2723
Bleeding risk with warfarin compared with Aspirin
5.0
Warfarin
Aspirin
Major bleeds
Annual rate (%)
4.0
Intracranial bleeds
3.0
2.0
1.0
0.0
Age 75 yrs Age >75 yrs
AFASAK I
AFASAK II
PATAF
SPAF II
Major bleeds = transfusion or hospitalization required, or critical anatomic location (e.g. intracranial, perispinal);
Within trial differences not statistically significant
Albers GW et al. Chest 2001;119:194S–206S
Most strokes occurred in patients who were
under-anticoagulated
Association of stroke events with intensity of anticoagulation for patients
with AF treated with warfarin in major randomized trials
Target range
for study
4.0
INR
INR at which stroke
event occurred
3.0
ACC/AHA/ESC
recommended
INR (2.0–3.0)
2.0
1.0
AFASAK
CAFA
SPAF
BAATAF
SPINAF
ACC = American College of Cardiology; AHA = American Heart Association;
ESC = European Society of Cardiology; INR = international normalized ratio
Levi M et al. Semin Thromb Haemost 2009;35:527–42
Targets for novel antithrombotic agents in
the coagulation cascade
Vitamin K antagonist:
Tecarfarin (Ph II completed)2
Tissue factor/VIIa
X
IX
VIIIa
Indirect factor Xa inhibitors:
Idraparinux (Ph III terminated)3
SSR 126517 (withdrawn 2009)4
IXa
Direct factor Xa inhibitors:
Apixaban (Ph III ongoing)5,6
Rivaroxaban (Ph III ongoing)7
Edoxaban (Ph III ongoing)8
Betrixaban (Ph II ongoing)9
Va
Xa
AT
II
Thrombin
Fibrinogen
Fibrin
Direct thrombin inhibitors:
Dabigatran etexilate
(Ph III completed)10
Ximelagatran
(withdrawn 2006)11,12
AZD0837 (Ph II completed)13
AT= antithrombin; Ph = Phase
1. Adapted from Turpie AG. Eur Heart J 2008;29:155–65; 2. Ellis DJ et al. Circulation 2009;22:120:1029–35; 3. Bousser MG et al. Lancet
2008;371:315–21; 4. NCT00580216; available at www.ClinicalTrials.gov; accessed Sept 09; 5. Lopes RD et al. Am Heart J
2010;159:331–9; 6. Eikelboom JW et al. Am Heart J 2010;159:348–53; 7. ROCKET-AF Study Investigators. Am Heart J 2010;159:340–
47; 8. NCT00781391; available at www.ClinicalTrials.gov; accessed Sept 09; 9. NCT00742859;
available at www.ClinicalTrials.gov; accessed Sept 09; 10. Connolly SJ et al. N Engl J Med 2009;361:1139–51;
11. Olsson SB et al. Lancet 2003;362:1691–8; 12. Albers GW et al. JAMA 2005;293:690–8;
13. Lip GY et al. Eur Heart J 2009;30:2897–907
Dabigatran RE-LY®: study design
AF with 1 risk factor
Absence of contraindications
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0–3.0)
n=6000
Dabigatran
110 mg BID
n=6000
Dabigatran
150 mg BID
n=6000
Primary objective: to establish the non-inferiority of dabigatran to warfarin
Minimum 1 year follow-up, maximum of 3 years and median of 2 years of follow-up
Primary Endpoint: All Strokes (ischemic and hemorrhagic) and systemic embolism
Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51
Phase III RE-LY®: time to first stroke or
systemic embolism RR 0.91
Cumulative hazard rates
0.05
(95% CI: 0.74–1.11)
P<0.001 (NI)
P=0.34 (Sup)
Warfarin
Dabigatran 110 mg BID
Dabigatran 150 mg BID
0.04
RRR
34%
0.03
RR 0.66
(95% CI: 0.53–0.82)
P<0.001 (NI)
P<0.001 (Sup)
0.02
0.01
0.00
0.0
0.5
1.0
1.5
2.0
2.5
Years
BID = twice daily; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2009;361:1139–51
Phase III RE-LY®: major bleeding
RR 0.80 (95% CI: 0.69–0.93)
P=0.003 (Sup)
3.5
RRR
20%
Major bleeding (%/yr)
3.0
2.5
RR 0.93 (95% CI: 0.81–1.07)
P=0.31 (Sup)
3.36
3.11
2.71
2.0
1.5
1.0
0.5
0.0
Events/n:
Dabigatran
110 mg BID
Dabigatran
150 mg BID
Warfarin
322/6015
375/6076
397/6022
BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2009;361:1139–51
Phase III RE-LY®: intracranial bleeding
RR 0.31 (95% CI: 0.20–0.47)
P<0.001 (Sup)
Intracranial bleeding (%/yr)
0.9
RR 0.40 (95% CI: 0.27–0.60)
P<0.001 (Sup)
0.8
0.7
0.74
0.6
0.5
RRR
60%
RRR
69%
0.4
0.3
0.2
0.1
0
Events/n:
0.23
0.30
Dabigatran
110 mg BID
Dabigatran
150 mg BID
Warfarin
27/6015
36/6076
87/6022
BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2009;361:1139–51
Phase III RE-LY®: conclusions

Dabigatran etexilate has been shown to
concurrently reduce both thrombotic and
haemorrhagic events

Both doses of dabigatran provide different and
complementary advantages over warfarin
 150
mg BID has superior efficacy with similar
bleeding
 110
mg BID has significantly less bleedings
with similar efficacy
BID = twice daily; INR = international normalized ratio
Connolly SJ et al. N Engl J Med 2009;361:1139–51;
Direct and indirect factor Xa (FXa)
DIRECT
INDIRECT
inhibition
Binds directly to the active site of
Binds to antithrombin (AT) and
FXa, blocking substrate
interactions (e.g. apixaban,
rivaroxaban, edoxaban,
betrixaban)
potentiates the activity of AT
against FXa
(e.g. idraparinux, SSR 126517)
Direct FXa
inhibitor
AT
AT
AT FXa
FXa
Indirect FXa
inhibitor
II
Fibrinogen
Adapted from Turpie AG et al. N Engl J Med 2001;344:619–25
Thrombin
Fibrin clot
Phase III AVERROES: study design
AF with 1 risk factor and
demonstrated or expected unsuitable for VKA
R
Apixaban
5 mg BID
(2.5 mg BID in
selected patients)
Aspirin
81–324 mg/d
Primary objective: to establish the superiority of apixaban over Aspirin
36 countries, 522 centres, double-blind study. N=5600 pts
Study was stopped after interim analysis
VKA = vitamin K antagonist; BID = twice daily
Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.
Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx
AVERROES: stroke or syst embolic event
0.07
Aspirin
Apixaban
Cumulative risk
0.06
0.05
RR 0.46
95% CI: 0.33–0.64
P<0.001
0.04
0.03
0.02
0.01
0
0
3
6
9
12
Months
Aspirin
2791
2720
2541
2124
Apixaban
2809
2761
2587
2127
18
21
1541
626
329
1523
617
352
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.
Available at: http://www.escardio.org/congresses/esc-2010/congressreports/Pages/708-3-AVERROES.aspx [Accessed September 2010]
Phase III AVERROES: major bleeding
0.025
Aspirin
Apixaban
Cumulative risk
0.020
RR 1.14
95% CI: 0.74–1.75
P=0.56
0.015
0.010
0.005
0
0
3
6
Aspirin
2791
2744
2572
2152
Apixaban
2809
2763
2567
2123
No. at risk
9
12
Months
18
21
1570
642
340
1521
622
357
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.
Available at: http://www.escardio.org/congresses/esc-2010/congressreports/Pages/708-3-AVERROES.aspx [Accessed September 2010]
Ongoing Phase III trials with direct factor Xa inhibitors for
the prevention of stroke in patients with AF
Expected
CHADS2
completion
score
date
Trial
acronym
Drug
Dose
Comparator
N
ARISTOTLE
Apixaban
5 mg
BID
Warfarin
(INR 2.0–3.0)
18 000
≥1
Apr 2011
AVERROES
Apixaban
5 mg
BID
Aspirin
(81–324 mg
OD)
6000
≥1
Aug 2010
ROCKET-AF
Rivaroxaban
20 mg*
OD
Warfarin
(INR 2.0–3.0)
14 000
≥2
May 2010
30 mg OD
60 mg OD
Warfarin
(INR 2.0–3.0)
16 500
≥2
Mar 2011
ENGAGE-AF TIMI 48 Edoxaban
*Adjusted based on renal function; BID = twice daily; INR = international normalized ratio; OD = once daily
Who should we treat with what?
Individual
‘cost-benefit analysis’
to determine
therapeutic strategy
Stroke risk assessment with CHA2DS2-VASc
CHA2DS2-VASc criteria
Score
Congestive heart failure/
left ventricular dysfunction
1
Hypertension
1
Age 75 yrs
CHA2DS2VASc
total score
Rate of stroke/other
TE (%/year) (95% CI)*
0
0
1
0.6
(0.0–3.4)
2
2
1.6
(0.3–4.7)
Diabetes mellitus
1
3
3.9
(1.7–7.6)
Stroke/transient ischaemic
attack/TE
2
4
1.9
(0.5–4.9)
Vascular disease (prior
myocardial infarction,
peripheral artery disease or
aortic plaque)
5
3.2
(0.7–9.0)
1
6
3.6
(0.4–12.3)
7
8.0
(1.0–26.0)
Age 65–74 yrs
1
8
11.1
(0.3–48.3)
9
100
(2.5–100)
Sex category (i.e. female
gender)
TE = thromboembolism
Lip GYH et al. Chest 2010;137:263-72
(0–0)
1
*Theoretical rates without therapy corrected for the % of
patients receiving Aspirin within each group,
assuming 22% reduction in risk with Aspirin
2010 ESC guidelines on antithrombotic
therapy in AF

recommendations based on the CHA2DS2-VASc score:
 Score
of ≥2:
Oral anticoagulation (INR 2.0–3.0)
 Score
of 1:
Oral anticoagulation (INR 2.0–3.0)
(preferred option) or
Aspirin (81–325 mg/day)
 Score
of 0:
Aspirin (81–325 mg/day) or
no therapy (preferred option)
ESC = European Society of Cardiology; INR = international normalized ratio
ESC guidelines: Camm J et al. Eur Heart J 2010
Bleeding risk assessment with HAS-BLED
HAS-BLED risk criteria
Hypertension
Abnormal renal or liver
function (1 point each)
Stroke
Score
HAS-BLED
total score
N
1
0
798
9
1.13
1
1286
13
1.02
2
744
14
1.88
3
187
7
3.74
4
46
4
8.70
5
8
1
12.5
6
2
0
0.0
7
0
–
–
8
0
–
–
9
0
–
–
1 or 2
1
Bleeding
1
Labile INRs
1
Elderly
(e.g. age >65 yrs)
Drugs or alcohol
(1 point each)
1
1 or 2
INR=international normalized ratio
Pisters R et al. Chest. 2010;
ESC guidelines: Camm J et al. Eur Heart J 2010
*P value for trend = 0.007
Number Bleeds per 100
of bleeds
patient-yrs*
Percutane Left Atrial Appendage Closure Devices
PLAATO
WATCHMAN
AMPLATZER
CARDIAC PLUG
Future guidelines on Antithrombotic
therapy in Atrial Fibrillation

All AF pts receive Direct Thrombin Inhibitor or
Direct Factor Xa Inhibitor
except:
Male
lone AF patients < 65 yrs
HAS-Bled

Score of ≥ 4:
No therapy
LAA Closure device?
No indication for vitamin K antagonists or Aspirin
R.G. Tieleman, (personal opinion) GetRhythm Symposium Utrecht 2010
Back-up Slides
Dabigatran etexilate







Oral prodrug, converted to dabigatran, which is a potent
and reversible direct thrombin inhibitor (DTI)
Inhibits both clot-bound and free thrombin
6.5% bioavailability
Peak plasma levels of dabigatran achieved within 2 hours
after administration in healthy volunteers
Half-life of 12–17 hours
~80% renal excretion
Most advanced DTI in Phase III development for stroke
prevention in patients with AF
 Recently demonstrated superiority to warfarin in the
Phase III RE-LY® study
Pradaxa: SmPC, 2009; Connolly SJ et al. N Engl J Med 2009;361:1139–51
Dabigatran etexilate has key features that make it
an effective antithrombotic for stroke prevention
Twice-daily dosing1
Predictable and consistent pharmacokinetic profile2,3
Rapid onset/offset of action2
No requirement for anticoagulation monitoring4
Low potential for drug–drug interactions1,5
Not metabolized by CYP450 enzymes, and does not affect the
metabolism of other drugs that utilize this system1,5
No food–drug interactions, with dosing independent of meals
or dietary restrictions6
1. Pradaxa: SmPC, 2009; 2. Stangier J et al. Clin Pharmacokinet 2008;28:47–59; 3. Stangier J Clin Pharmacokinet
2008;47:285–95; 4. Stangier J et al. Br J Pharmacol 2007;64:292–303; 5. Blech S et al. Drug Metab Dispos
2008;36:386–99; 6. Stangier J et al. J Clin Pharmacol 2005;45:555–63
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation.
This information is provided for medical education purposes only.
Phase III RE-LY®: largest AF outcomes trial
RE-LY®:
Randomized Evaluation of Long-term anticoagulant therapy

18 113 patients randomized during 2 years1,2

50% of enrolled patients are naïve to previous oral anticoagulant

Median treatment duration: 2 years

951 centres in 44 countries

December 2005 to March 2009

Results first presented at ESC congress 2009 and published
online in New England Journal of Medicine on 30 Aug 2009
ESC = European Society of Cardiology
1. Ezekowitz MD et al. Am Heart J 2009;157:805–10;
2. Connolly SJ et al. N Engl J Med 2009;361:1139–51
Baseline characteristics
Characteristic
Dabigatran
110 mg BID
Dabigatran
150 mg BID
Warfarin
Randomized (n)
6015
6076
6022
Mean age (yrs)
71.4
71.5
71.6
Male (%)
64.3
63.2
63.3
CHADS2 score (mean)
0/1 (%)
2
(%)
3+ (%)
2.1
32.6
34.7
32.7
2.2
32.2
35.2
32.6
2.1
30.9
37.0
32.1
Prior stroke/TIA (%)
19.9
20.3
19.8
Prior MI (%)
16.8
16.9
16.1
CHF (%)
32.2
31.8
31.9
Baseline ASA (%)
40.0
38.7
40.6
Warfarin-naïve (%)
49.9
49.8
51.4
ASA = acetylsalicylic acid (aspirin); BID = twice daily; CHF = congestive heart failure; MI = myocardial infarction;
TIA = transient ischaemic attack
Connolly SJ et al. N Engl J Med 2009;361:1139–51
Phase III RE-LY®: study inclusion and
exclusion criteria
Inclusion criteria
1.
Documented AF
2.
One additional risk factor for stroke:
•
•
•
•
•
History of previous stroke, transient ischaemic attack or systemic embolism
LVEF less than 40%
Symptomatic heart failure, NYHA Class II or greater
Age of 75 yrs or more
Age of 65 yrs or more and one of the following additional risk factors: diabetes
mellitus, coronary artery disease or hypertension
Exclusion criteria
1.
2.
3.
4.
5.
6.
Severe heart-valve disorder
Stroke within 14 days or severe stroke within 6 months before screening
Any condition that increases the risk of haemorrhage
Creatinine clearance <30 mL per min
Active liver disease
Pregnancy
Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al.
N Engl J Med 2009;361:1139–51
Phase III RE-LY®: risk of stroke or
systemic embolism
Non-inferiority Superiority
P value
P value
Dabigatran
110 mg BID
vs. warfarin
0.34
Margin = 1.46
<0.001
Dabigatran
150 mg BID
vs. warfarin
<0.001
0.50
0.75
1.00
Hazard ratio
Error bars = 95% CI; BID = twice daily
Connolly SJ et al. N Engl J Med 2009;361:1139–51
1.25
1.50
<0.001
Warfarin reduces the risk of stroke in patients with AF
Warfarin better
Placebo better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
RRR 64%*
All trials
(95% CI: 4974%)
100
50
0
RRR (%)†
Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity;
†Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
Hart RG et al. Ann Intern Med 2007;146:857–67
–50
–100
Limited efficacy of Aspirin in reducing the risk of
stroke in patients with AF
Aspirin better
Placebo better
AFASAK
SPAF
EAFT
ESPS II
LASAF
125 mg/d
125 mg QOD
UK-TIA
300 mg/d
1200 mg/d
JAST
RRR = 19%*
All trials
(95% CI: –1 to 35%)
100
50
0
–50
RRR (%)†
Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR)
for all strokes (ischaemic and haemorrhagic); QOD = every other day
Hart RG et al. Ann Intern Med 2007;146:857–67
–100
Warfarin compared with Aspirin for stroke prevention in AF
Warfarin better
Aspirin better
AFASAK I
AFASAK II
Chinese ATAFS
EAFT
PATAF
SPAF II
Age 75 yrs
Age >75 yrs
RRR 38%
All trials
(95% CI: 18–52%)
100
50
0
–50
RRR (%)*
Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR)
for all strokes (ischaemic and haemorrhagic)
Hart RG et al. Ann Intern Med 2007;146:857–67
–100
Risk factors for stroke in AF: CHADS2
• Congestive heart failure
• (History of) Hypertension
• Age > 75 years
• Diabetes Mellitus
• Prior Stroke/TIA
(1 point)
(1 point)
(1 point)
(1 point)
(2 points)
OAC in case
score > 1
Cage et al JAMA 2001
Stroke risk assessment with CHADS2
•
•
•
•
•
0
CHADS2 score
1
2
3
Congestive heart failure
(History of) Hypertension
Age > 75 years
Diabetes Mellitus
Prior Stroke/TIA
(1 point)
(1 point)
(1 point)
(1 point)
(2 points)
4
5
6
0
5
10
15
20
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
25
30
2010 ESC guidelines for antithrombotic Rx in AF
Risk category
CHA2DS2-VASc score Recommended therapy
No risk factors
0
Either Aspirin 75–325 mg daily or no
antithrombotic therapy
Preferred choice is no antithrombotic
therapy
One clinically relevant
non-major risk factor
1
Either OAC* or Aspirin 75–325 mg daily
Preferred choice is OAC
One major risk factor
or ≥2 clinically
relevant non-major
risk factors
2
OAC*
Clinically relevant non-major risk
factors
Heart failure or moderate to
severe LV systolic dysfunction
(e.g. LV ejection fraction ≤40%)
Hypertension – Diabetes mellitus
Female sex – Age 65–74 yrs
Vascular disease†
ESC guidelines: Camm J et al. Eur Heart J 2010
Major risk factors
Previous stroke, TIA, or systemic
embolism
Age ≥75 years
2010 ESC guidelines for antithrombotic therapy in AF
†Congestive heart failure,
Hypertension, Age ≥75 yrs,
Diabetes, Stroke/TIA/thromboembolism (doubled)
CHADS2 score ≥2†
No
Yes
Consider other risk factors*
*Other clinically relevant nonmajor risk factors: age 65–74 yrs,
female sex, vascular disease
Age ≥75 years
No
Yes
≥2 other risk factors*
No
Yes
OAC
1 other risk factor*
Yes
No
OAC (or Aspirin)
Nothing (or Aspirin)
ESC = European Society of Cardiology; OAC = oral anticoagulation; TIA = transient ischaemic attack
ESC guidelines: Camm J et al. Eur Heart J 2010; [Epub ahead of print]
SPAF III: adjusted-dose warfarin compared with
low-intensity warfarin plus Aspirin
Ischaemic stroke or systemic embolism
Cumulative event rate
(% per year)
15
Similar Bleeding Risk
Combination therapy
Fixed-dose warfarin (INR 1.2–1.5)*
+ Aspirin (325 mg/d)
10
RRR 74%
(95% CI: 5087%)
P<0.0001
5
Adjusted-dose warfarin
Warfarin (INR 2.0–3.0)
0
n=
n=
0
0.5
521
523
378
397
1.0
1.5
2.0
265
273
166
173
61
65
Years
*Warfarin dose adjusted between 0.5 and 3.0 mg/day to achieve international normalized ratio (INR) 1.21.5
when initiating therapy and then fixed for rest of study; RRR = relative risk reduction
SPAF Investigators. Lancet 1996;348:633–8
ACTIVE trials: dual antiplatelet therapy for
stroke prevention in AF
Documented AF
and 1 risk factor*for stroke
Suitable for VKA
Unsuitable for VKA
ACTIVE W
ACTIVE A
Clopidogrel (75 mg/d)
+ Aspirin (75–100 mg/d)
vs.
VKA (target INR = 2.0–3.0)
Clopidogrel (75 mg/d)
+ Aspirin (75–100 mg/d)
vs.
Aspirin (75–100 mg/d)
No exclusion criteria for ACTIVE I
ACTIVE I
Irbesartan (300 mg/d) vs. placebo
Connolly SJ et al. Am Heart J 2006;151:1187–1193
Partial factorial design
ACTIVE W: dual antiplatelet therapy inferior to oral
anticoagulation for stroke prevention in AF
Stroke
Cumulative hazard rates
0.05
Dual antiplatelet therapy
0.04
Clopidogrel (75 mg/d) +
Aspirin (75–100 mg/d)
RR 1.72
0.03
(95% CI: 1.242.37)
Oral anticoagulation
P=0.001
VKA (target INR = 2.0–3.0)
0.02
0.01
0.00
n=
n=
0
0.5
3335
3371
3168
3232
Years
1.0
1.5
2419
2466
941
930
INR = international normalized ratio; RR = relative risk; VKA = vitamin K antagonist
ACTIVE Investigators. Lancet 2006;151:1903–12
ACTIVE A: dual antiplatelet therapy superior
to Aspirin alone for stroke prevention in AF
Stroke
0.15
Aspirin alone
Cumulative incidence
Aspirin (75–100 mg/d)
Dual antiplatelet therapy
0.10
Clopidogrel (75 mg/d) +
Aspirin (75–100 mg/d)
But 1.5-2.0x more bleeding
HR 0.72
0.05
(95% CI: 0.62–0.83)
P<0.0001
0.00
n=
n=
0
1
3772
3782
3491
3458
2
3
4
3229
3155
2570
2517
1203
1186
Years
Reasons for considering patients inappropriate for vitamin K antagonist included specific risk of bleeding (22.9%),
physician’s judgement in absence of specific bleeding risk (49.7%) and patient preference alone (26.0%);
HR = hazard ratio
ACTIVE Investigators. N Engl J Med 2009;360:2066–78
Safety and efficacy of idraparinux for stroke
prevention in AF: Phase III AMADEUS
Idraparinux (n=2283)
20
19.7%
Warfarin (n=2293)
P<0.0001
1.5
P=0.007 (for non-inferiority)
1.3%
11.3%
10
Incidence (%)
Incidence (%)
15
1.0
0.9%
0.5
5
0
0
Clinically relevant bleeding
Bousser MG et al. Lancet 2008;371:315–21
Stroke and embolism
Rivaroxaban

Highly selective and potent inhibitor of factor Xa

Bioavailability of 60–80%1

Half-life of up to 9 hours in healthy young subjects and
11–13 hours in the elderly2

Approved in Europe and Canada for the prevention of
venous blood clots in patients undergoing elective hip- or
knee-replacement surgery3

Compound has no direct effect on platelet aggregation4

Well-tolerated in healthy human subjects5,6

Rapid onset of action5,6

Dose-proportional
pharmacokinetics/pharmacodynamics5,6
Rivaroxaban and stroke prevention in AF:
Phase III ROCKET-AF

Randomized, double-blind, non-inferiority study1

Approximately 14 000 patients with AF

Comparing the efficacy and safety of rivaroxaban 20 mg OD
with warfarin for the prevention of stroke



Patients with moderate renal impairment (creatinine clearance 30–49
mL/min) will receive a fixed dose of 15 mg OD rivaroxaban
Primary outcomes:

Any stroke or non-CNS systemic embolism

Composite of major and clinically relevant non-major bleeding events
Secondary outcomes:

Each category of bleeding events and adverse events

Composite of stroke, non-CNS systemic embolism and vascular death
Phase III ROCKET-AF: study inclusion criteria
Inclusion criteria
1.
2.
3.
Male and female patients aged 18 yrs
Persistent or paroxysmal AF on 2 episodes (one of which is
documented by ECG within 30 days of enrollment)
History of stroke, transient ischaemic attack or systemic embolism,
or at least two of the following risk factors (CHADS2 2):
•
Congestive heart failure or LVEF 35%
•
Hypertension
•
Age 75 yrs
•
Diabetes mellitus
ECG = electrocardiogram; LVEF = left ventricular ejection fraction
ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477
ROCKET-AF: study exclusion criteria
Exclusion criteria
1.
Cardiovascular-related conditions:
•
Prosthetic heart valve
•
Planned cardioversion
•
AF secondary to reversible causes (i.e. thyrotoxicosis)
•
Active endocarditis
•
Haemodynamically significant mitral stenosis
2.
Haemorrhage risk-related factors:
•
Active internal bleeding
•
History of, or condition associated with, increased risk of bleeding , including intracranial
bleeding, major surgical procedure or trauma within 30 days, and clinically relevant
gastrointestinal bleeding within 6 months
3.
Concomitant conditions and therapies
•
Recent stroke (14 days) or transient ischaemic attack (3 days)
•
Indication for anticoagulant therapy for a condition other than AF (e.g. VTE)
•
Pregnancy or breastfeeding
•
Treatment with other therapies include Aspirin (>100 mg daily), intravenous antiplatelets
(5 days before randomization), fibrinolytics (10 days before randomization)
VTE = venous thromboembolism
ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477
Summary: direct factor Xa inhibitors

Apixaban, rivaroxaban and edoxaban are highly selective and potent
inhibitors of factor Xa

Several Phase III studies are comparing the efficacy and safety of
direct factor Xa inhibitors with warfarin for stroke prevention in AF:


ARISTOTLE (apixaban)

ROCKET-AF (rivaroxaban)

ENGAGE-AF TIMI-48 (edoxaban)
For patients with AF who are unsuitable or have failed warfarin
therapy, the efficacy and safety of direct factor Xa inhibitors have
been compared with those of Aspirin

AVERROES has reported that apixaban significantly reduces the
risk of stroke or systemic embolism over Aspirin with no
significant increase in risk of major haemorrhage1
1. Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.
Available at: http://www.escardio.org/congresses/esc-2010/congressreports/Pages/708-3-AVERROES.aspx [Accessed September 2010]
Biotinylated version of idraparinux: SSR 126517

No antidote for idraparinux to reverse its anticoagulant activity

SSR 126517 developed to offer the same pharmacological features
as idraparinux

Addition of biotin allows the rapid removal of the drug following
intravenous injection of avidin1

The bioequipotency of SSR 126517 compared with an equimolar
dose of idraparinux has been evaluated for the treatment of deep vein
thrombosis2

The Phase III BOREALIS-AF study compared SSR 126517 with
warfarin for the prevention of stroke in AF3

SSR 126517 was withdrawn from development for stroke prevention
in AF in December 2009 as it did not appear to significantly improve
the care of patients4
Summary: indirect factor Xa inhibitors

Idraparinux has a long half-life of 80 hours that
subsequently enables weekly dosing

The Phase III AMADEUS study was terminated
due to excess bleeding

SSR 126517, the biotinylated version of
idraparinux, was withdrawn from development
for stroke prevention in AF in December 2009
Direct thrombin inhibitors (DTIs) block both
circulating and clot-bound thrombin
Thrombin generation
DTIs:
dabigatran
etexilate
ximelagatran*
AZD0837
Antithrombin
Heparin
Conversion of
fibrinogen to
fibrin
Amplification
DTIs:
dabigatran
etexilate
ximelagatran*
AZD0837
Clot-bound thrombin
*Withdrawn from the market in 2006
Adapted from Eikelboom J et al. J Am Coll Cardiol 2003;41:70S–8S
Phase III RE-LY®: haemorrhagic stroke
RR 0.31 (95% CI: 0.17–0.56)
Haemorrhagic stroke (no. of events)
P<0.001 (Sup)
50
RR 0.26 (95% CI: 0.14–0.49)
P<0.001 (Sup)
45
40
0.38%
30
RRR
69%
20
10
14
0.12%
0
n:
RRR
74%
12
0.10%
Dabigatran
110 mg BID
Dabigatran
150 mg BID
Warfarin
6015
6076
6022
BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2009;361:1139–51
Warfarin reduces the risk of stroke in both
primary and secondary prevention
Meta-analysis of trials comparing dose-adjusted warfarin with placebo
Primary Secondary
prevention prevention
Number of trials
All trials
5
1
6
2461
439
2900
ARR with warfarin vs.
placebo (%)
2.7
8.4
3.1
RRR with warfarin vs.
placebo (%)
62
68
64
NNT
37
12
32
Patients (n)
ARR = absolute risk reduction; NNT = number need to treat for 1 year to prevent one stroke;
RRR = relative risk reduction
Hart RG et al. Ann Intern Med 1999;131:492–501 & Ann Intern Med 2007;146:857–67
Phase III AVERROES: bleeding
Apixaban
Aspirin
Apixaban vs. Aspirin
Events
Annual
rate
Events
Annual
rate
RR
95% CI
P value
Major
44
1.4
39
1.2
1.14
0.74–
1.75
0.56
Clinically
relevant,
non-major
95
3.0
81
2.6
1.18
0.88–
1.58
0.28
Minor
159
5.2
126
4.1
1.27
1.01–
1.61
0.04
Fatal
5
0.1
6
0.1
0.84
0.26–
2.75
0.77
Intracranial
13
0.4
12
0.3
1.09
0.50–
2.39
0.83
Outcome
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.
Available at: http://www.escardio.org/congresses/esc-2010/congressreports/Pages/708-3-AVERROES.aspx [Accessed September 2010]
Phase III AVERROES: conclusions

Apixaban, in patients with atrial fibrillation who are at risk
of stroke and are unsuitable for VKA therapy:
–
Reduces the risk of stroke or systemic embolism by
54% over an antiplatelet with no significant increase in
risk of major haemorrhage
–
Offers an important advantage over Aspirin for
prevention of stroke
–
Data comparing apixaban with warfarin are expected
in 2011 (ARISTOTLE trial)
VKA = vitamin K antagonist
Connolly SJ et al. Presented at ESC 2010; session number 708005-708006.
Available at: http://www.escardio.org/congresses/esc-2010/congressreports/Pages/708-3-AVERROES.aspx [Accessed September 2010]