1. Het begin van een nieuw tijdperk?
Antistolling in AF
Het begin van een nieuw tijdperk?
Dr RG Tieleman
Martini Ziekenhuis Groningen

2. 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

3. Warfarin superior in reducing the stroke risk in AF patients
Control worse
Control better
Warfarin vs Placebo
RRR 64%
(95% CI: 4974%)
RRR = 19% (95% CI: –1 to 35%)
Aspirin vs Placebo
Warfarin vs Aspirin
RRR 38% (95% CI: 18–52%)
100 50
–50
–100
RRR (%)†
Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
Hart RG et al. Ann Intern Med 2007;146:857–67 3

4. VKAs have a narrow therapeutic window20
Therapeutic range 15
Stroke 10
Intracranial bleed
Odds ratio 5 1 1 2 3 4 5 6 7 8
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 4

5. SPORTIF V INR Values – Warfarin Group20 40 60 80
100
68%
Time in Range (%)
In the group assigned to warfarin, the mean INR was 2·4 across all measurements taken over the course of the study. Anticoagulation intensity fell within the target range for 68% of the entire follow-up period and 83% of the time was within the extended range of 1·8 to 3·2. This high quality of anticoagulation control with warfarin is seldom achieved in clinical practice but quite comparable to performance in the open-label SPORTIF III trial.
Treatment Duration (months) 3 6 9 12 15 18 21 24 26
Circulation 2003;108:2723

6. Bleeding risk with warfarin compared with Aspirin
5.0
Warfarin
Aspirin
Major bleeds
4.0
Intracranial bleeds
3.0
Annual rate (%)
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 6

7. 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
AFASAK
SPINAF
INR
1.0
2.0
3.0
4.0
BAATAF
CAFA
SPAF
INR at which stroke event occurred
ACC/AHA/ESC recommended INR (2.0–3.0)
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 7

8. Targets for novel antithrombotic agents in the coagulation cascade
Vitamin K antagonist:
Tecarfarin (Ph II completed)2
Tissue factor/VIIa X IX
Indirect factor Xa inhibitors:
Idraparinux (Ph III terminated)3
SSR (withdrawn 2009)4
VIIIa
IXa Va
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 Xa AT
Direct thrombin inhibitors:
Dabigatran etexilate (Ph III completed)10
Ximelagatran (withdrawn 2006)11,12
AZD0837 (Ph II completed)13 II
Thrombin
Fibrinogen
Fibrin
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. NCT ; available at 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. NCT ; available at accessed Sept 09; 9. NCT ; available at 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 8

9. 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 9

10. Phase III RE-LY®: time to first stroke or systemic embolism
RR 0.91
(95% CI: 0.74–1.11)
P<0.001 (NI)
P=0.34 (Sup)
0.05
Warfarin
Dabigatran 110 mg BID
RRR
34%
0.04
Dabigatran 150 mg BID
0.03
Cumulative hazard rates
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 10

11. Phase III RE-LY®: major bleeding
RR 0.80 (95% CI: 0.69–0.93)
P=0.003 (Sup)
RR 0.93 (95% CI: 0.81–1.07)
3.5
RRR
20%
P=0.31 (Sup)
3.36
3.0
3.11
2.5
2.71
2.0
Major bleeding (%/yr)
1.5
1.0
0.5
0.0
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin
Events/n:
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 11

12. Phase III RE-LY®: intracranial bleeding
RR 0.31 (95% CI: 0.20–0.47)
P<0.001 (Sup)
RR 0.40 (95% CI: 0.27–0.60)
0.9
P<0.001 (Sup)
0.8
0.7
0.74
0.6
RRR
60%
0.5
Intracranial bleeding (%/yr)
RRR
69%
0.4
0.3
0.30
0.2
0.23
0.1
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin
Events/n:
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 12

13. 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; 13

14. Direct and indirect factor Xa (FXa) inhibition
Current methods of thromboprophylaxis
Direct and indirect factor Xa (FXa) inhibition
INDIRECT
Binds to antithrombin (AT) and potentiates the activity of AT against FXa (e.g. idraparinux, SSR )
DIRECT
Binds directly to the active site of FXa, blocking substrate interactions (e.g. apixaban, rivaroxaban, edoxaban, betrixaban)
FXa
Direct FXa inhibitor AT AT AT
FXa
Indirect FXa inhibitor II
Thrombin
Fibrinogen
Fibrin clot
Adapted from Turpie AG et al. N Engl J Med 2001;344:619–25 14 14 14

15. 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
Connolly SJ et al. Presented at ESC 2010; session number Available at:
VKA = vitamin K antagonist; BID = twice daily

16. AVERROES: stroke or syst embolic event
0.07
Aspirin
0.06
Apixaban
0.05
RR % CI: 0.33–0.64 P<0.001
0.04
Cumulative risk
0.03
0.02
0.01 3 6 9 12 18 21
Months
Aspirin
2791
2720
2541
2124
1541
626
329
Apixaban
2809
2761
2587
2127
1523
617
352
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010]

17. Phase III AVERROES: major bleeding
0.025
Aspirin
Apixaban
0.020
RR % CI: 0.74–1.75 P=0.56
0.015
Cumulative risk
0.010
0.005 3 6 9 12 18 21
No. at risk
Months
Aspirin
2791
2744
2572
2152
1570
642
340
Apixaban
2809
2763
2567
2123
1521
622
357
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010]

18. Expected completion date
Ongoing Phase III trials with direct factor Xa inhibitors for the prevention of stroke in patients with AF
Trial acronym
Drug
Dose
Comparator N
CHADS2 score
Expected completion date
ARISTOTLE
Apixaban
5 mg
BID
Warfarin
(INR 2.0–3.0)
18 000 ≥1
Apr 2011
AVERROES
Aspirin (81–324 mg OD)
6000
Aug 2010
ROCKET-AF
Rivaroxaban
20 mg* OD
14 000 ≥2
May 2010
ENGAGE-AF TIMI 48
Edoxaban
30 mg OD
60 mg OD
16 500
Mar 2011
*Adjusted based on renal function; BID = twice daily; INR = international normalized ratio; OD = once daily

19. ‘cost-benefit analysis’
Who should we treat with what?
Individual
‘cost-benefit analysis’
to determine
therapeutic strategy

20. Stroke risk assessment with CHA2DS2-VASc
CHA2DS2-VASc criteria
Score
Congestive heart failure/ left ventricular dysfunction 1
Hypertension
Age 75 yrs 2
Diabetes mellitus
Stroke/transient ischaemic attack/TE
Vascular disease (prior myocardial infarction, peripheral artery disease or aortic plaque)
Age 65–74 yrs
Sex category (i.e. female gender)
CHA2DS2-VASc total score
Rate of stroke/other TE (%/year) (95% CI)*
0 (0–0) 1
0.6 (0.0–3.4) 2
1.6 (0.3–4.7) 3
3.9 (1.7–7.6) 4
1.9 (0.5–4.9) 5
3.2 (0.7–9.0) 6
3.6 (0.4–12.3) 7
8.0 (1.0–26.0) 8
11.1 (0.3–48.3) 9
100 (2.5–100)
*Theoretical rates without therapy corrected for the % of patients receiving Aspirin within each group, assuming 22% reduction in risk with Aspirin
TE = thromboembolism
Lip GYH et al. Chest 2010;137:263-72

21. 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 21

22. Bleeding risk assessment with HAS-BLED
HAS-BLED risk criteria
Score
Hypertension 1
Abnormal renal or liver function (1 point each)
1 or 2
Stroke
Bleeding
Labile INRs
Elderly (e.g. age >65 yrs)
Drugs or alcohol (1 point each)
HAS-BLED total score N
Number of bleeds
Bleeds per 100 patient-yrs*
798 9
1.13 1
1286 13
1.02 2
744 14
1.88 3
187 7
3.74 4 46
8.70 5 8
12.5 6
0.0 –
INR=international normalized ratio
*P value for trend = 0.007
Pisters R et al. Chest. 2010; ESC guidelines: Camm J et al. Eur Heart J 2010

23. Percutane Left Atrial Appendage Closure Devices
PLAATO
WATCHMAN
AMPLATZER
CARDIAC PLUG

24. 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 No therapy
HAS-Bled Score of ≥ 4: LAA Closure device?
No indication for vitamin K antagonists or Aspirin
R.G. Tieleman, (personal opinion) GetRhythm Symposium Utrecht 2010 24

25. Back-up Slides 25

26. 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 26

27. 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. 27

28. Phase III RE-LY®: largest AF outcomes trial
RE-LY®: Randomized Evaluation of Long-term anticoagulant therapy
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 28

29. Baseline characteristics
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)
2.1
2.2
0/1 (%)
32.6
32.2
30.9
2 (%)
34.7
35.2
37.0
3+ (%)
32.7
32.1
Prior stroke/TIA (%)
19.9
20.3
19.8
Prior MI (%)
16.8
16.9
16.1
CHF (%)
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 29

30. Phase III RE-LY®: study inclusion and exclusion criteria
Inclusion criteria
Documented AF
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
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
Patients enrolled in the RE-LY® study had documented atrial fibrillation and at least one additional risk factor for stroke. Risk factors for stroke included a history of thromboembolism, a left ventricular ejection fraction less than 40%, symptomatic heart failure, age of 75 years or more, and age of 65 years or more in combination with diabetes mellitus, coronary artery disease or hypertension.
Exclusion criteria in the RE-LY® study included a severe heart-valve disorder, recent stroke, any condition associated with an increased risk of bleeding, renal impairment associated with a creatinine clearance of less then 30 mL per minute, active liver disease or pregnancy.
Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51 30

31. Phase III RE-LY®: risk of stroke or systemic embolism
Non-inferiority
P value
Superiority
P value
Dabigatran 110 mg BID
vs. warfarin
<0.001
0.34
Margin = 1.46
Dabigatran 150 mg BID
vs. warfarin
<0.001
<0.001
0.50
0.75
1.00
1.25
1.50
Hazard ratio
Error bars = 95% CI; BID = twice daily
Connolly SJ et al. N Engl J Med 2009;361:1139–51 31

32. Warfarin reduces the risk of stroke in patients with AF
Warfarin better
Placebo better
RRR (%)†
100
–100 50
–50
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
All trials
RRR 64%* (95% CI: 4974%)
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 32

33. 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%* (95% CI: –1 to 35%)
All trials
100 50
–50
–100
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 33

34. 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% (95% CI: 18–52%)
All trials
100 50
–50
–100
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 34

35. Risk factors for stroke in AF: CHADS2
Congestive heart failure (1 point)
(History of) Hypertension (1 point)
Age > 75 years (1 point)
Diabetes Mellitus (1 point)
Prior Stroke/TIA (2 points)
OAC in case
score > 1
Cage et al JAMA 2001

36. Stroke risk assessment with CHADS2
Congestive heart failure (1 point)
(History of) Hypertension (1 point)
Age > 75 years (1 point)
Diabetes Mellitus (1 point)
Prior Stroke/TIA (2 points)
Annual stroke rate (%)*
CHADS2 score 30 2 3 4 5 6 10 15 20 25 1
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

37. 2010 ESC guidelines for antithrombotic Rx in AF
Risk category
CHA2DS2-VASc score
Recommended therapy
No risk factors
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
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†
Previous stroke, TIA, or systemic embolism
Age ≥75 years
ESC guidelines: Camm J et al. Eur Heart J 2010 37

38. 2010 ESC guidelines for antithrombotic therapy in AF
CHADS2 score ≥2†
†Congestive heart failure, Hypertension, Age ≥75 yrs, Diabetes, Stroke/TIA/thrombo-embolism (doubled)
*Other clinically relevant non-major risk factors: age 65–74 yrs, female sex, vascular disease No
Yes
Consider other risk factors*
Age ≥75 years No
Yes
≥2 other risk factors* No
Yes
OAC
1 other risk factor*
Yes
OAC (or Aspirin) No
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]

39. Cumulative event rate (% per year)
SPAF III: adjusted-dose warfarin compared with low-intensity warfarin plus Aspirin
Ischaemic stroke or systemic embolism 15
Similar Bleeding Risk
Combination therapy
Fixed-dose warfarin (INR 1.2–1.5)* + Aspirin (325 mg/d) 10
Cumulative event rate (% per year)
RRR 74% (95% CI: 5087%)
P<0.0001 5
Adjusted-dose warfarin Warfarin (INR 2.0–3.0)
0.5
1.0
1.5
2.0
Years n=
521
378
265
166 61 n=
523
397
273
173 65
*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 39

40. 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
Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)
vs.
VKA (target INR = 2.0–3.0)
ACTIVE A
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
Partial factorial design
Connolly SJ et al. Am Heart J 2006;151:1187–1193 40

41. Cumulative hazard rates
ACTIVE W: dual antiplatelet therapy inferior to oral anticoagulation for stroke prevention in AF
Stroke
0.05
0.04
Dual antiplatelet therapy
Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)
RR 1.72 (95% CI: 1.242.37)
P=0.001
0.03
Oral anticoagulation VKA (target INR = 2.0–3.0)
Cumulative hazard rates
0.02
0.01
0.00
0.5
1.0
1.5
Years n=
3335
3168
2419
941 n=
3371
3232
2466
930
INR = international normalized ratio; RR = relative risk; VKA = vitamin K antagonist
ACTIVE Investigators. Lancet 2006;151:1903–12 41

42. ACTIVE A: dual antiplatelet therapy superior to Aspirin alone for stroke prevention in AF
0.15
Aspirin alone Aspirin (75–100 mg/d)
Dual antiplatelet therapy
Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)
0.10
But x more bleeding
Cumulative incidence
0.05
HR 0.72 (95% CI: 0.62–0.83)
P<0.0001
0.00 1 2 3 4
Years n=
3772
3229
2570
1203
3491 n=
3782
3458
3155
1186
2517
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 42

43. Safety and efficacy of idraparinux for stroke prevention in AF: Phase III AMADEUS
Idraparinux (n=2283)
Warfarin (n=2293)
19.7%
Incidence (%) 20
Clinically relevant bleeding 15 10 5
P<0.0001
Incidence (%)
1.5
Stroke and embolism
1.0
0.5
P=0.007 (for non-inferiority)
1.3%
0.9%
11.3%
Bousser MG et al. Lancet 2008;371:315–21

44. 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 –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

45. Rivaroxaban and stroke prevention in AF: Phase III ROCKET-AF
Randomized, double-blind, non-inferiority study1
Approximately 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

46. Phase III ROCKET-AF: study inclusion criteria
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

47. ROCKET-AF: study exclusion criteria
Cardiovascular-related conditions:
Prosthetic heart valve
Planned cardioversion
AF secondary to reversible causes (i.e. thyrotoxicosis)
Active endocarditis
Haemodynamically significant mitral stenosis
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
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

48. 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 Available at: [Accessed September 2010]

49. Biotinylated version of idraparinux: SSR 126517
No antidote for idraparinux to reverse its anticoagulant activity
SSR 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 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 with warfarin for the prevention of stroke in AF3
SSR was withdrawn from development for stroke prevention in AF in December 2009 as it did not appear to significantly improve the care of patients4

50. 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 , the biotinylated version of idraparinux, was withdrawn from development for stroke prevention in AF in December 2009 50

51. Direct thrombin inhibitors (DTIs) block both circulating and clot-bound thrombin
Thrombin generation
DTIs: dabigatran etexilate ximelagatran* AZD0837
Anti- thrombin
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 51

52. Phase III RE-LY®: haemorrhagic stroke
RR 0.31 (95% CI: 0.17–0.56)
P<0.001 (Sup)
RR 0.26 (95% CI: 0.14–0.49) 50
P<0.001 (Sup) 45
0.38% 40 30
Haemorrhagic stroke (no. of events)
RRR
69%
RRR
74% 20 14
0.12% 10 12
0.10%
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin n:
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 52

53. Warfarin reduces the risk of stroke in both primary and secondary prevention
Meta-analysis of trials comparing dose-adjusted warfarin with placebo
Primary prevention
Secondary prevention
All trials
Number of trials 5 1 6
Patients (n)
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
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 53

54. Phase III AVERROES: bleeding
Outcome
Major
Clinically relevant, non-major
Minor
Fatal
Intracranial
Apixaban
Events 44 95
159 5 13
Annual rate
1.4
3.0
5.2
0.1
0.4
Aspirin 39 81
126 6 12
1.2
2.6
4.1
0.3
Apixaban vs. Aspirin RR
1.14
1.18
1.27
0.84
1.09
95% CI
0.74–1.75
0.88–1.58
1.01–1.61
0.26–2.75
0.50–2.39
P value
0.56
0.28
0.04
0.77
0.83
Phase III AVERROES: bleeding
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010]

55. 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 Available at: [Accessed September 2010]