1. Stroke prevention in atrial fibrillation: current limitations and novel antithrombotic agents
Module 5

2. Limitations of current antithrombotic agents

3. Limitations of current treatment options for stroke prevention in AF
Many patients with AF do not receive effective thromboprophylaxis due to limitations of currently available agents
Aspirin is convenient to use but provides insufficient protection for stroke prevention in high-risk patients1
Vitamin K antagonists have greater efficacy but a range of limitations make them challenging agents to use:2,3
Narrow therapeutic window
Variable and unpredictable pharmacokinetics and pharmacodynamics
Wide variety of drug–drug and drug–food interactions
Need for regular anticoagulation monitoring and dose adjustments
Slow onset and offset of action
1. ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030; 2. Turpie AG. Eur Heart J 2008;29:155–65; 3. Khoo CW et al. Int J Clin Pract 2009;63:630–41

4. Intracerebral haemorrhage: the most feared complication of antithrombotic therapy
>10% of intracerebral haemorrhages occur in patients on antithrombotic therapy
Intracerebral haemorrhages during anticoagulation can be life-threatening
Compared with placebo, antithrombotic therapy increases the risk of intracerebral haemorrhage:
~40% with Aspirin
~200% with warfarin (INR 2.0–3.0; increases to 0.3–0.6%/year)
INR = international normalized ratio
Hart RG et al. Stroke 2005;36:1588–93

5. The VKA, warfarin, is used in only half of eligible patients with AF
Warfarin use in eligible patients (%)
Overall use = 55%
Age (yrs)
100
<55 80 60 40 20
55–64
65–74
75–84
85
61%
58%
57%
Figure reproduced with permission: ©2007, American College of Physicians
44%
35%
Graph reproduced with permission:
Go A et al. Ann Intern Med 1999;131:927
Under-use of warfarin is greatest in elderly patients who are at the highest risk of stroke
VKA = vitamin K antagonist
Go A et al. Ann Intern Med 1999;131:927

6. VKAs have a narrow therapeutic window1
International normalized ratio
Odds ratio 2 15 8 10 5 3 4 6 7 20
Therapeutic range
Stroke
Graph reproduced with permission: ©2010 American College of Chest Physicians
Intracranial bleed
Figure: Reprinted with permission
Circulation 2006;114:e257-e354
©2006, American Heart Association, Inc.
VKAs = vitamin K antagonists
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354 & Eur Heart J 2006;27:1979–2030

7. Management of AF in clinical practice: prescription of VKAs in eligible patients
Treatment received:
64%
n =
Medicare cohort, USA1
No anticoagulation
VKAs
67%
n = 5333
EuroHeart survey2
55%
n =
ATRIA cohort (managed care system, California, USA)3
VKAs = vitamin K antagonists; ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation
1. Birman-Deych E et al. Stroke 2006;37:1070–4; 2. Nieuwlaat R et al. Eur Heart J 2005;26:2422–34; 3. Go AS et al. JAMA 2003;290:2685–92

8. Time in target range (%)
The INR for VKAs is often outside the therapeutic range: international study of anticoagulation management
Time in target range (%) 20 40 60 80
100
USA
Canada
France
Italy
Spain
INR <2.0
INR 2.0–3.0
INR >3.0
The predominant vitamin K antagonist (VKA) in use was warfarin in the US, Canada and Italy; acenocoumarol in Spain; and fluindione in France; INR = international normalized ratio
Ansell J et al. J Thromb Thrombolysis 2007;23:83–91

9. Drug and food interactions associated with an increased potency of VKAs
Drug/food
Examples
Analgesics
Acetaminophen, propoyphene, salicylates
Anti-arrhythmics
Amiodarone, propafenone, quinidine
Antibiotics
Ciprofloxacin, erythromycin, metronidazole
Antifungals
Fluconazole, itraconazole, miconazole
Beta-blockers
Propranolol
H2-receptor antagonists/PPIs
Cimetidine, omeprazole
Lipid-lowering agents
Lovastatin, atorvastatin
Herbal products/dietary supplements
Vitamin E, garlic, devil’s claw
Miscellaneous
Alcohol (if concomitant liver disease)
PPIs = proton pump inhibitors; VKAs = vitamin K antagonists
Holbrook AM et al. Arch Intern Med 2005;165:1095–106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:1031–42

10. Drug and food interactions associated with a reduced potency of VKAs
Drug/food
Examples
Antibiotics
Dicloxacillin, nafcillin, rifampicin
Antifungals
Griseofulvin
Immunosupressants
Azathioprine, cyclosporine
Lipid-lowering agents
Cholestyramine
Herbal products/dietary supplements
Coenzyme Q10, ginseng, St John’s wort
Foods
Green tea, avocados (large amounts), food with high vitamin K content including broccoli and spinach
Miscellaneous
Carbamazepine, sucralfate, trazodone
VKAs = vitamin K antagonists
Holbrook AM et al. Arch Intern Med 2005;165:1095–106; du Breuil AL & Umland EM. Am Fam Physician 2007;75:1031–42

11. VKAs require regular anticoagulation monitoring
Careful monitoring of patients being treated with VKAs is critical due to the:
Narrow therapeutic window
Unpredictable relationship between VKA dose and the anticoagulant response
Influence of the quantity of vitamin K in the diet that can change over time
Availability of small devices capable of measuring INR enables patients to self-monitor
Reduces risk of thromboembolism and bleeding complications1
Increases time in the therapeutic range2
Improves patient compliance, treatment satisfaction and quality of life2,3
Conflicting evidence on whether it may be more cost-effective2–4
INR = international normalized ratio; VKAs = vitamin K antagonists
1. Heneghan C et al. Lancet 2006;367:404–11; 2. Levi M. Expert Rev Cardiovasc Ther 2008;6:979–85; 3. Braun S et al. Anal Bioanal Chem 2009;393:1463–71; 4. Connock M et al. Health Technol Assess 2007;11:iii–66

12. Contraindications to VKA treatment
Pregnancy
Frequent falls or seizures
Coagulation factor abnormalities
Poor drug or clinic compliance
Thrombocytopenia
(< /mL)
Poorly controlled hypertension (>180/110 mmHg)
Haemorrhagic stroke
Severe hepatic or renal disease
Excessive alcohol intake
Threatened abortion (eclampsia, pre-eclampsia)
Dementia
Non-steroidal agents
Recent or contemplated surgery of the CNS or the eye
Gastrointestinal or urinary bleeding in the previous 6 months
CNS = central nervous system; VKA = vitamin K antagonist
ACCP Guidelines, 2008: Signer DE et al. Chest 2008;133;546S–92S; Coumadin: SmPC, 2009; Sudlow M et al. Lancet 1998;352:1167–71; Brass LM et al. Stroke 1997;28:2382–9; Kalra L et al. Stroke 1999;30:1218–22; Go AS et al. Ann Intern Med 1999;131:927–34

13. Many patients with AF are unsuitable for treatment with VKAs
The contraindications that make patients unsuitable for VKAs are found most frequently in elderly patients who are often at the greatest risk of stroke
Patients unsuitable for VKAs (%) 50
>65 yrs1
>65 yrs2
>75 yrs3
All ages4 40 30 20 10
43%
38%
37%
17%
VKAs = vitamin K antagonists
1. Sudlow M et al. Lancet 1998;352:1167–71; 2. Brass LM et al. Stroke 1997;28:2382–9; 3. Kalra L et al. Stroke 1999;30:1218–22; 4. Go AS et al. Ann Intern Med 1999;131:927–34

14. VKAs have a slow onset and offset of action
VKAs inhibit the vitamin K-dependent synthesis of clotting factors
Takes several days for functional clotting factors to be cleared from the circulation as well as new factors to be synthesized
The initial effect of warfarin administration is to briefly promote clot formation
Warfarin initially decreases the levels of protein S, which is a cofactor for the natural anticoagulant, protein C, resulting in a paradoxical increase in the tendency of the blood to clot
The time lag between dosing and the anticoagulant response complicates dose titration to achieve a therapeutic INR
Slow offset of action presents a problem if patients experience trauma or require emergency surgery
Persistent anticoagulant activity may increase the risk of bleeding complications
INR = international normalized ratio; VKAs = vitamin K antagonists
Connolly SJ et al. Circulation 2007;116:449–55; Connock M et al. Health Technol Assess 2007;11:iii–66

15. Requirements of new antithrombotic agents
At least as effective as warfarin
Predictable response
Wide therapeutic window
Low incidence and severity of adverse effects
Oral fixed dose
No need for routine anticoagulation monitoring
Low potential for food or drug interactions
Fast onset and offset of action
Cost-effective
Adapted from Lip GY et al. EHJ Suppl 2005;7:E21–5

16. Summary: VKAs have many limitations
Many AF patients (~50%) do not receive thromboprophylaxis due to the contraindications and limitations associated with current agents, particularly warfarin
VKAs have a narrow therapeutic range, requiring regular anticoagulation monitoring for adequate stroke protection, while minimizing the risk of bleeding complications
 New antithrombotic therapies are needed, which do not share the limitations of warfarin, to deliver reliable stroke protection to a greater proportion of patients with AF
VKAs = vitamin K antagonists

17. Mechanism of action of new antithrombotic agents

18. Targets for novel antithrombotic agents in the coagulation cascade1
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

19. Thrombin is the central player in the coagulation cascade
Thrombin has several properties that make it an excellent target for anticoagulation1
Thrombin:
Converts soluble fibrinogen to fibrin – the essential step in thrombus (clot) formation
Activates factor XIII to favour the formation of cross-linked bonds among fibrin molecules
Triggers additional thrombin generation by activating factors V and VIII
Stimulates thrombus-activated fibrinolysis inhibitor (TAFI) resulting in inhibition of fibrinolysis
Is the single most potent stimulus for platelet activation
1. Di Nisio M et al. N Engl J Med 2005;353:1028–40

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

21. 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 21 21

22. Summary: targets of novel antithrombotic agents
Thrombin is the central player in the blood-clotting process and has several key properties that make it an excellent target for inhibition
Direct thrombin inhibitors (e.g. dabigatran, ximelagatran and AZD0837) act directly on free and clot-bound thrombin, blocking its substrate interactions and thereby preventing fibrin formation
Factor Xa (FXa) can be inhibited by antithrombotics either:
Indirectly, through binding to antithrombin (e.g. idraparinux and SSR )
Directly, by interacting with the active site of FXa and blocking its substrate interactions (e.g. apixaban, rivaroxaban and edoxaban)

23. Direct thrombin inhibitors

24. Direct thrombin inhibitors (DTIs): past and present
A well-established approach to antithrombotic therapy1
Characteristic
Hirudin
Bivalirudin
Argatroban
Ximelagatran* and melagatran
Dabigatran etexilate
AZD0837
Route of administration
IV, SC IV
IV, SC, oral
Oral
Half-life
60–120 min
25 min
45 min
2–5 hrs
12–17 hrs
9–14 hrs
Clearance
Kidney (100%)2
Kidney (50%), endogenous peptidases (50%)3
Liver (65%), kidney (20%)4
Kidney (70%)5
Kidney (80%)6
Kidney, intestine7
*Withdrawn in IV = intravenous; SC = subcutaneous
1. Data from Di Nisio M et al. N Engl J Med 2005;353:1028–40; 2. Markwardt F et al. Thromb Haemost 1984;52:160–3; 3. Markwardt F et al. Biomed Biochim Acta 1987;46:237–44; 4. Novastan: SmPC, 2009; 5. Erikkson UG et al. Drug Metab Dispos 2003;31:294–305; 6. Pradaxa: SmPC, 2009; 7. Lip GY et al. Eur Heart J 2009;30:2897–907

25. 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
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

26. 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 outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

27. 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
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 27 27

28. Phase III 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
*Severe heart-valve disorder, stroke ≤14 days or severe stroke ≤6 months before screening, increased haemorrhage risk, creatinine clearance <30 mL/min, active liver disease, pregnancy; BID = twice daily; INR = international normalized ratio
Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 28 28

29. 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 29

30. Phase III RE-LY®: outcome measures
Primary efficacy endpoint
Secondary efficacy endpoints
Safety criteria include
All stroke (ischaemic + haemorrhagic) and systemic embolism
All stroke (ischaemic + haemorrhagic)
Systemic embolism
All death
All stroke (ischaemic + haemorrhagic)
Pulmonary embolism
Acute MI
Vascular death (including deaths from bleeding)
Net clinical benefit: composite of stroke, systemic embolism, PE, MI, death, major bleeding
Primary safety outcome: major bleeding events
Intracranial haemorrhage
Cerebral haemorrhage
Subdural haematoma
Subarachnoid haemorrhage
Elevations in liver enzymes or hepatic dysfunction
MI = myocardial infarction; PE = pulmonary embolism
Connolly SJ et al. N Engl J Med 2009;361:1139–51
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 30 30

31. Phase III RE-LY®: 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
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 31 31

32. Phase III RE-LY®: risk of stroke or systemic embolism
0.50
0.75
1.00
1.25
1.50
<0.001
Superiority
P-value
0.30
Non-inferiority
Hazard ratio
Margin = 1.46
Dabigatran 110 mg BID
vs. warfarin
Dabigatran 150 mg BID
vs. warfarin
Error bars = 95% CI; BID = twice daily
Connolly SJ et al. N Engl J Med 2010;363:1875–6
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 32 32

33. Phase III RE-LY®: time to first stroke or systemic embolism
RR 0.90
(95% CI: 0.74–1.10)
P<0.001 (NI)
P=0.30 (Sup)
Years
0.0
0.5
1.0
1.5
2.0
2.5
0.01
0.02
0.03
0.05
0.04
Cumulative hazard rates
0.00
Warfarin
Dabigatran 110 mg BID
RRR
35%
Dabigatran 150 mg BID
RR 0.65
(95% CI: 0.52–0.81)
P<0.001 (NI)
P<0.001 (Sup)
BID = twice daily; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2010;363:1875–6
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 33 33

34. 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)
Haemorrhagic stroke (no. of events) n:
6015
6076
6022
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin 10 20 30 40 50
P<0.001 (Sup) 45
0.38%
RRR
69%
RRR
74% 14
0.12% 12
0.10%
BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 34 34

35. Phase III RE-LY®: major bleeding
RR 0.80 (95% CI: 0.70–0.93)
P=0.003 (Sup)
RR 0.93 (95% CI: 0.81–1.07)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Major bleeding (%/yr)
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin
Events/n:
342/6015
399/6076
421/6022
RRR
20%
P=0.32 (Sup)
3.57
3.32
2.87
BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2010;363:1875–6
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 35 35

36. Phase III RE-LY®: intracranial bleeding
RR 0.30 (95% CI: 0.19–0.45)
P<0.001 (Sup)
RR 0.41 (95% CI: 0.28–0.60)
Events/n:
27/6015
38/6076
90/6022
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Warfarin
0.6
0.9
Intracranial bleeding (%/yr)
0.8
0.7
0.5
0.4
0.3
0.2
0.1
P<0.001 (Sup)
0.76
RRR
59%
RRR
70%
0.32
0.23
BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority
Connolly SJ et al. N Engl J Med 2010;363:1875–6
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 36 36

37. Cumulative hazard rates
Phase III RE-LY®: cumulative risk of ALT or AST >3xULN after randomization
Years
0.0
0.5
1.0
1.5
2.0
2.5
0.01
0.02
0.03
0.04
Cumulative hazard rates
0.00
Warfarin
Dabigatran 110 mg BID
Dabigatran 150 mg BID
ALT = alanine transaminase; AST = aspartate transaminase; BID = twice daily; ULN = upper limit of normal
Connolly SJ et al. N Engl J Med 2009;361:1139–51
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 37 37

38. 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;
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details. 38 38

39. Ximelagatran: proof-of-concept for direct thrombin inhibition
First oral direct thrombin inhibitor (DTI) to launch in Europe for stroke prevention in AF
At least as effective as dose-adjusted warfarin for the prevention of stroke in high-risk patients with AF1,2
Associated with lower bleeding rates than warfarin
Wider therapeutic index than warfarin
Fixed dosing without the need for anticoagulation monitoring
BUT, associated with serious liver toxicity in a significant proportion of patients
Approximately 1 in 200 patients treated with long-term ximelagatran had severe liver injury3
 Withdrawn from clinical development and all markets in 2006
1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; Integrated Executive Summary of FDA Review for NDA Exanta (Ximelagatran), 2004; available at accessed Feb 2010

40. Study design of SPORTIF III and V trials
Stroke Prevention using an ORal direct Thrombin Inhibitor in atrial Fibrillation
Patients with non-valvular AF and risk factors for stroke N=7329
Adjusted-dose warfarin (target INR 2.0–3.0)
Fixed-dose ximelagatran (36 mg BID)
SPORTIF III: nations Open-label (n=3407)
SPORTIF V: US, Canada Double-blind (n=3922)
BID = twice daily; INR = international normalized ratio
1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8

41. SPORTIF trials: study inclusion and exclusion criteria
Inclusion criteria
Age 18 yrs
Persistent/paroxysmal AF plus 1 of the following:
Hypertension
Age 75 yrs
Previous stroke, transient ischaemic attack or systemic embolism
LVEF <40% or congestive heart failure
Age 65 yrs with coronary artery disease or diabetes
Exclusion criteria
Mitral stenosis or prior heart valve surgery
Major surgery or trauma within 30 days
Recent gastrointestinal bleeding
Percutaneous coronary intervention within 30 days
Endocarditis
Active liver disease or elevated liver enzymes 2xULN
Renal insufficiency with a calculated creatinine clearance <30 mL/min
LVEF = left ventricular ejection fraction; ULN = upper limit of normal
Akins PT et al. Stroke 2007;38:874–80

42. Non-inferiority of ximelagatran compared with warfarin in patients with AF
Difference in absolute event rates (ximelagatran – warfarin) –4
SPORTIF III1
SPORTIF V2
Pooled3 4 –3 2
Ximelagatran better
Warfarin better –2 –1 1 3
Stroke and systemic embolism
–0.66
P=0.10
+0.45
P=0.13
–0.03
P=0.94
Non-inferiority
1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; Albers GW. Am J Manag Care 2004;10(14 Suppl):S462–9; discussion S469–73

43. Major bleeding events (% patients/yr)
Ximelagatran was associated with a trend for fewer major bleeding events in patients with AF
Warfarin
Ximelagatran
Major bleeding events (% patients/yr) 4
SPORTIF III1
SPORTIF V2
Pooled3 3 2 1
P=0.150
3.1%
P=0.054
2.5%
2.4%
P=0.228
1.9%
1.8%
1.3%
1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; 3. Albers GW. Am J Manag Care 2004;10(14 Suppl):S462–9; discussion S469–73

44. Primary events* + major bleeding + death
Ximelagatran has greater net clinical benefit compared with warfarin in patients with AF 10
SPORTIF III1
SPORTIF V2,3
Pooled4 8 6 4 2
Primary events* + major bleeding + death
(% patients/yr)
Warfarin
Ximelagatran
RRR 26% P=0.019
RRR 7% P=0.527
RRR 16% P=0.038
6.3%
6.1%
6.2%
5.8%
5.2%
4.6%
Net clinical benefit: composite outcome of stroke, systemic embolic events, major bleeding and all-cause mortality; RRR = relative risk reduction
1. Olsson SB et al. Lancet 2003;362:1691–8; 2. Albers GW et al. JAMA 2005;293:690–8; Lip GY et al. EHJ Suppl 2005;7:E21–5; 4. Albers GW. Am J Manag Care 2004; (14 Suppl):S462–9; discussion S469–73

45. Incidence of ALT >3xULN (n)
Time-dependent elevation of liver enzymes (ALT >3xULN): pooled analysis of SPORTIF III and V trials 50 40 30 20 10
Month 27 21 18 16 15 13 12 11 9 1 3 4 5 6 7 8
Incidence of ALT >3xULN (n)
Warfarin
Ximelagatran
ALT >3xULN
Event rate (%) 10 8 6 4 2
6.1%
Figures reproduced with permission: ©2004, Managed Care & Healthcare Communications, LLC
0.8%
Figures reproduced with permission:
Albers GW. Stroke prevention in atrial fibrillation: pooled analysis of SPORTIF III and V trials.
The American Journal of Managed Care 2004;10(14 Suppl):S462–9
©2004, Managed Care & Healthcare Communications, LLC
ALT = alanine transaminase; ULN = upper limit of normal
Albers GW. Am J Manag Care 2004;10(14 Suppl):S462–9; discussion S469–73

46. AZD0837
Prodrug converted to the selective and reversible direct thrombin inhibitor, AR-H067637
Half-life of AR-H is 9–14 hours in healthy subjects
Excreted in the urine and faeces
Phase II, randomized, double-blind, dose-guiding study completed in patients with AF to assess safety, tolerability, pharmacokinetics and pharmacodynamics
AF patients (n=955) with 1 additional risk factors for stroke were randomized to receive AZD0837 (150, 300 or 450 mg OD or 200 mg BID) or a VKA for 3–9 months
~30% of patients were naïve to VKA treatment
BID = twice daily; OD = once daily; VKA = vitamin K antagonist
Lip GY et al. Eur Heart J 2009;30:2897907

47. Lower doses of AZD0837 are associated with less bleeding than VKA
Any bleeding (% patients) 20 15 10 5
150 mg OD
300 mg OD
450 mg OD
200 mg BID
INR 2.0–3.0
AZD0837
VKA
14.1%
14.5%
11.0%
10.6%
5.3%
BID = twice daily; INR = international normalized ratio; OD = once daily; VKA = vitamin K antagonist
Lip GY et al. Eur Heart J 2009;30:2897–907

48. Preliminary clinical results with AZD0837
AZD0837 was generally well tolerated at all doses
Most commonly reported adverse events were gastrointestinal disorders (e.g. diarrhoea, flatulence or nausea)
While the study was not powered to compare stroke and systemic embolic events associated with AZD0837 and VKAs, few events were reported in either treatment arm:
Ischaemic stroke (two on AZD mg OD, one on VKA)
Transient ischaemic attack (one on AZD mg BID, one on VKA)
Systemic embolus (one on AZD mg OD)
Frequency of serum ALT >3xULN was similar for AZD0837 and VKA treatment
 AZD mg OD provides similar suppression of thrombogenesis (based on levels of D-dimer) to dose-adjusted VKA, with a lower risk of bleeding
BID = twice daily; OD = once daily; ULN = upper limit of normal; VKA = vitamin K antagonist
Lip GY et al. Eur Heart J 2009;30:2897–907

49. Summary: direct thrombin inhibitors (DTIs)
Proof-of-concept for direct thrombin inhibition has been provided with ximelagatran
Withdrawn from clinical development and all markets in 2006 due to liver toxicity
Landmark studies have shown clinical effectiveness for DTIs in large Phase III trials
The pivotal Phase III trial (RE-LY®) recently demonstrated superiority of dabigatran to warfarin in the prevention of stroke in patients with AF
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
This information is provided for medical education purposes only. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses, so please check local prescribing information for further details.

50. Direct factor Xa inhibitors

51. 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
ARISTOTLE1,2
Apixaban
5 mg
BID
Warfarin
(INR 2.0–3.0)
18 000 ≥1
Apr 2011
AVERROES3,4
Aspirin (81–324 mg OD)
6000
Aug 2010
ROCKET-AF5,6
Rivaroxaban
20 mg* OD
14 000 ≥2
May 2010
ENGAGE-AF TIMI 487
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
1. NCT at accessed Sept 09; 2. Lopes RD et al. Am Heart J 2010;159:331–9; 3. NCT at accessed Sept 09; 4. Eikelboom JW et al. Am Heart J 2010;159:348–53; 5. NCT at accessed Sept 09; 6. ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477; 7. NCT ; available at accessed Sept 09

52. Apixaban Highly selective and potent inhibitor of factor Xa
Bioavailability of >50%
Half-life of between 9 and 14 hours
Metabolized in the liver via CYP3A4
Eliminated through renal (~25%) and intestinal routes (~70%)
Two Phase III studies are currently underway to investigate stroke prevention in AF
ARISTOTLE (vs. warfarin)
AVERROES (vs. Aspirin)
Khoo CW et al. Int J Clin Pract 2009;63:630–41

53. Apixaban and stroke prevention in AF: Phase III ARISTOTLE
Randomized, double-blind, non-inferiority trial1
Investigating the safety and efficacy of apixaban 5 mg BID compared with dose-adjusted warfarin
Approximately patients with non-valvular AF
Primary outcome:
Stroke or systemic embolism
Secondary outcomes:
Ischaemic stroke, haemorrhagic stroke, systemic embolism and all causes of death
1. Lopes RD et al. Am Heart J 2010;159:331–9

54. Phase III ARISTOTLE: study inclusion criteria
Males and females aged 18 yrs with documented AF
Presence of at least one of the following risk factors for stroke (CHADS2 1):
Age 75 yrs
Previous stroke, transient ischaemic attack or systemic embolism
Symptomatic congestive heart failure or left ventricular dysfunction with LVEF 40%
Diabetes mellitus or hypertension requiring pharmacological treatment
LVEF = left ventricular ejection fraction
Lopes RD et al. Am Heart J 2010;159:331–9

55. Phase III ARISTOTLE: study exclusion criteria
AF or flutter due to reversible causes (e.g. thyrotoxicosis, pericarditis)
Clinically significant (moderate or severe) mitral stenosis
Increased bleeding risk
Conditions other than AF that require chronic anticoagulation
Persistent, uncontrolled hypertension
Active infective endocarditis
Planned major surgery (e.g. AF or flutter ablation procedure)
Use of an unapproved, investigational drug or device within the past 30 days
Required treatment with Aspirin >165 mg/day
Simultaneous treatment with both Aspirin and a thienopyridine (e.g. clopidogrel, ticlopidine)
Severe comorbid condition with life expectancy of <1 yr
Active alcohol or drug abuse
Recent stroke (within 7 days)
Severe renal insufficiency
Platelet count < /mm3
Haemoglobin <9 g/dL
Inability to comply with INR monitoring
INR = international normalized ratio
Lopes RD et al. Am Heart J 2010;159:331–9

56. Apixaban and stroke prevention in AF: Phase III AVERROES
Randomized, double-blind, superiority trial1
Investigating the safety and efficacy of apixaban 5 mg BID compared with Aspirin (81–324 mg OD)
Approximately 6000 patients with AF at high-risk of developing stroke who are either unsuitable for or have failed prior warfarin treatment
Primary objective:
Determine whether apixaban is superior to Aspirin for preventing the composite outcome of stroke or systemic embolism
Secondary objective:
Determine whether apixaban is superior to Aspirin for preventing the composite outcome of stroke, systemic embolism, myocardial infarction or vascular death (major vascular events)
Study halted following a predefined interim analysis by an independent data monitoring committee, which revealed “clear evidence of a clinically important reduction in stroke and systemic embolism”
BID = twice daily; OD = once daily
1. Eikelboom JW et al. Am Heart J 2010;159:348–53

57. 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
VKA = vitamin K antagonist; BID = twice daily 57
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010] 57

58. Phase III AVERROES: study inclusion criteria
Minimal eligible age for the study is 50 yrs
Permanent, persistent or paroxysmal AF documented by 12-lead ECG on the day of screening
Presence of at least one of the following risk factors for stroke (CHADS2 1):
Prior stroke or transient ischaemic attack
Age 75 yrs
Arterial hypertension on treatment
Diabetes mellitus
Heart failure: NYHA Class II or greater at time of enrolment
LVEF 35% documented within 6 months of enrolment
Documented peripheral arterial disease (previous arterial revascularization, limb or foot amputation, or current intermittent claudication with ankle–arm systolic blood pressure ratio <0.9)
ECG = electrocardiogram; LVEF = left ventricular ejection fraction; NYHA = New York Health Association
Eikelboom JW et al. Am Heart J 2010;159:348–53

59. Phase III AVERROES: study exclusion criteria
AF due to reversible causes (e.g. thyrotoxicosis, pericarditis)
Valvular disease requiring surgery
Planned AF ablation procedure within 3 months
Conditions other than AF that require chronic anticoagulation
Patients with serious bleeding in the past 6 months or at high risk of bleeding:
Active peptic ulcer disease
Platelet count < /mm3 or haemoglobin <10 g/dL
Recent stroke (within 10 days)
Documented haemorrhagic tendencies or blood dyscrasias
Current alcohol or drug abuse, or psychosocial reasons that make study participation impractical
Severe comorbid condition with life expectancy <1 yr
Severe renal insufficiency
Serum creatinine >2.5 mg/dL or a calculated creatinine clearance <25 mL/min
ALT or AST >2xULN or a total bilirubin 1.5xULN (unless an alternative causative factor [e.g. Gilbert's syndrome] is identified)
Women who are pregnant or breastfeeding
ALT = alanine transferase; AST = aspartate transferase; ULN = upper limit of normal
Eikelboom JW et al. Am Heart J 2010;159:348–53

60. Phase III AVERROES: baseline characteristics
Apixaban
Aspirin
Randomized
2809
2791
Age (mean±SD)
70±10 yrs
Male
59%
58%
CHADS2 score (mean±SD)
2.1±1.1
0–1
36%
37% 2
34% 3+
27%
29%
Prior stroke/TIA
14%
13%
Diabetes
19%
20%
Hypertension
86%
87%
CHF
40%
38%
Baseline ASA
76%
74%
Unsuitable for VKA
VKA used and discontinued
39%
VKA expected unsuitable
61%
60%
TIA = transient ischaemic attack; CHF = congestive heart failure; VKA = vitamin K antagonist
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010] 60

61. Phase III AVERROES: stroke or systemic embolic event
Cumulative risk
0.02
0.04
0.05
0.06
0.07
0.01
0.03
Months 3 6 9 12 18 21
Aspirin
Apixaban
RR % CI: 0.33–0.64 P<0.001
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] 61

62. Phase III AVERROES: secondary efficacy outcomes
Apixaban
Aspirin
Apixaban vs. Aspirin
Events
Annual rate RR
95% CI
P value
Stroke, SEE, MI or vascular death
129
4.1
193
6.2
0.66
0.53–0.83
<0.001 MI 22
0.7 26
0.8
0.85
0.48–1.50
0.57
Vascular death 81
2.5 94
2.9
0.86
0.64–1.16
0.33
Cardiovascular hospitalization
346
11.8
432
14.9
0.79
0.68–0.91
Total death
110
3.4
139
4.4
0.62–1.02
0.07
RR = relative risk; CI = confidence interval; SEE = systemic embolic event; MI = myocardial infarction
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010] 62

63. Phase III AVERROES: major bleeding
Cumulative risk
0.005
0.015
0.020
0.025
0.010
Months 3 6 9 12 18 21
No. at risk
Aspirin
Apixaban
RR % CI: 0.74–1.75 P=0.56
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] 63

64. Phase III AVERROES: bleeding
Outcome
Apixaban
Aspirin
Apixaban vs. Aspirin
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
0.84
0.26–2.75
0.77
Intracranial 13
0.4 12
0.3
1.09
0.50–2.39
0.83
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010] 64

65. Phase III AVERROES: permanent discontinuation of study medication
Months 3 6 9 12 18 21
No. at risk
Cumulative risk
0.05
0.15
0.20
0.25
0.30
0.10
Aspirin
Apixaban
RR % CI: 0.78–1.00 P=0.04
Aspirin
2791
2567
2325
1906
1365
534
266
Apixaban
2809
2624
2356
1909
1328
521
299
RR = relative risk; CI = confidence interval
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010] 65

66. 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 (ARISTOTLE trial)
VKA = vitamin K antagonist
Connolly SJ et al. Presented at ESC 2010; session number Available at: [Accessed September 2010] 66 66

67. 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
1. Khoo CW et al. Int J Clin Pract 2009;63:630–41; 2. FDA Advisory Committee Briefing Document: Rivaroxaban, 2009; available at Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm htm, accessed Feb 2010; 3. Xarelto: SmPC, 2009; 4. Perzborn E et al. J Thromb Haemost 2005;3:514–21; 5. Kubitza D et al. Clin Pharmacol Ther 2005;78:412–21; 6. Kubitza D et al. Eur J Clin Pharmacol 2005;61:873–80

68. Rivaroxaban has clinical potential for drug–drug interactions with the CYP450 system
Metabolized by CYP450 enzymes in the liver
Approximately two-thirds of administered rivaroxaban is metabolically degraded by CYP3A4, CYP2J2 and CYP-independent mechanisms1
Not recommended as concomitant treatment with CYP3A4 inhibitors:1
Azole antimycotics (e.g. ketoconazole, itraconzole, voriconazole and posaconazole)
HIV protease inhibitors (e.g. ritonavir)
Co-administration with strong CYP3A4 inducers should be performed with caution:1
Rifampicin, phenytoin, carbmazepine, phenobarbital, St John’s wort
HIV = human immunodeficiency virus
1. Xarelto: SmPC, 2009

69. Rivaroxaban and stroke prevention in AF: Phase III ROCKET-AF
Randomized, double-blind, non-inferiority study
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
CNS = central nervous system; OD = once daily
ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

70. 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 70
ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

71. Phase III 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 71
ROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

72. Edoxaban Highly selective and potent inhibitor of factor Xa
Phase II dose-ranging study in patients with non-valvular AF completed1,2
The safety and tolerability of 30 and 60 mg OD edoxaban were similar to warfarin
Phase III ENGAGE-AF TIMI-48 trial to assess safety and efficacy of edoxaban compared with warfarin for stroke prevention in patients with AF is currently underway3
OD = once daily
1. Weitz JI et al. ASH 2008; abstr 33; 2. Giugliano R et al. ISTH 2009; abstr OC-WE-003; 3. NCT ; available at accessed Sept 09

73. Edoxaban and stroke prevention in AF: Phase III ENGAGE-AF TIMI-48
Randomized, double-blind study1
Approximately patients with AF
Comparing the efficacy and safety of edoxaban 30 mg and 60 mg OD with warfarin for the prevention of stroke
Primary outcome:
Composite of stroke and systemic embolic events
Secondary outcomes:
Composite of stroke, systemic embolic events and all-cause mortality
Major bleeding events
OD = once daily
1. NCT ; available at accessed Sept 09

74. Phase III ENGAGE-AF TIMI-48: study inclusion and exclusion criteria
Inclusion criteria
Male and female patients aged 21 yrs
Able to provide written informed consent
History of documented AF within the prior 12 months
A moderate to high risk of stroke, as defined by CHADS2 index score of 2
Exclusion criteria
Transient AF secondary to other reversible disorders
Patients with moderate or severe mitral stenosis, unresected atrial myxoma or a mechanical heart valve
Patients with any contraindication for anticoagulant agents
Patients with conditions associated with high risk of bleeding or with known or suspected hereditary or acquired bleeding disorders
Females of childbearing potential, including:
History of tubal ligation
<2 yrs postmenopausal
NCT ; available at accessed Sept 09

75. 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]

76. Indirect factor Xa inhibitors

77. Idraparinux
Bioavailability approaching 100% after subcutaneous administration1
Binds antithrombin with such high affinity that it has a similar half-life to antithrombin (80 hours)2
Given once-weekly and does not require anticoagulation monitoring2
Not metabolized; excreted unchanged via the kidneys2
Dose must be reduced in patients with renal insufficiency
Contraindicated in patients with creatinine clearance <30 mL/min
Phase III VAN GOGH trial assessed the safety and efficacy of idraparinux 2.5 mg once weekly in patients with DVT or PE3
Similar efficacy to standard therapy for DVT
Failed to demonstrate non-inferiority for PE
Phase III AMADEUS trial to assess safety and efficacy of idraparinux compared with warfarin for stroke prevention in patients with AF terminated due to excess bleeding4
DVT = deep vein thrombosis; PE = pulmonary embolism
1. Veyrat-Follet C et al. J Thromb Haemost 2009;7:559–65; 2. Gross PL & Weitz JI. Arterioscler Thromb Vasc Biol 2008;28:380–6; 3. Buller HR et al. N Engl J Med 2007;357:1094–104; 4. Bousser MG et al. Lancet 2008;371:315–21

78. Idraparinux is associated with clinically relevant bleeding
Phase III AMADEUS1
Randomized, open-label, non-inferiority study
Compared safety and efficacy of idraparinux 2.5 mg once weekly with dose-adjusted warfarin for the prevention of stroke in patients with AF
Primary efficacy outcome:
Cumulative incidence of all stroke and systemic embolism
Primary safety outcome:
Clinically relevant bleeding
Trial stopped after randomization of 4576 patients (2283 idraparinux; 2293 warfarin) and a mean follow-up of 10.7 months
Due to excess clinically relevant bleeding with idraparinux
1. Bousser MG et al. Lancet 2008;371:315–21

79. 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

80. 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
1. Gross PL & Weitz JI. Arterioscler Thromb Vasc Biol 2008;28:380–6; 2. NCT ; available at accessed Sept 09; 3. NCT ; available at accessed Sept 09;
4. Sanofi-aventis press release Dec 2009; available at accessed Feb 10

81. 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

82. Conclusions Current anticoagulants have numerous limitations
There is a clear and meaningful unmet clinical need for stroke prevention in patients with AF
A number of novel antithrombotic agents have been developed
Factor Xa inhibitors:
Direct: apixaban, rivaroxaban and edoxaban (in Phase III development)
Indirect: idraparinux and SSR (Phase III trials terminated)
Direct thrombin inhibitors
Ximelagatran: provided proof-of-concept but withdrawn from the market in 2006 due to liver toxicity
AZD0837: Phase II completed
Dabigatran: most advanced in clinical development with recent Phase III data (RE-LY®) demonstrating superiority to warfarin
Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.
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