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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

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slide1

Antistolling in AF

Het begin van een nieuw tijdperk?

Dr RG Tieleman

Martini Ziekenhuis Groningen

slide2

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
Warfarin superior in reducing the stroke risk in AF patients

Control worse

Control better

RRR 64%

(95% CI: 4974%)

Warfarin vs Placebo

RRR = 19%(95% CI: –1 to 35%)

Aspirin vs Placebo

RRR 38%(95% CI: 18–52%)

Warfarin vs Aspirin

100

50

0

–50

–100

RRR (%)†

Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)

Hart RG et al. Ann Intern Med 2007;146:857–67

vkas have a narrow therapeutic window
VKAs have a narrow therapeutic window

Therapeuticrange

20

15

Stroke

10

Intracranial bleed

Odds ratio

5

1

0

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

sportif v inr values warfarin group

100

80

60

40

20

0

3

6

9

12

15

18

21

24

26

Treatment Duration (months)

SPORTIF VINR Values – Warfarin Group

68%

Time in Range (%)

2.0-3.0

Circulation 2003;108:2723

bleeding risk with warfarin compared with aspirin
Bleeding risk with warfarin compared with Aspirin

Aspirin

Intracranial bleeds

5.0

Warfarin

Major bleeds

4.0

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

most strokes occurred in patients who were under anticoagulated
Most strokes occurred in patients who were under-anticoagulated

Target range for study

4.0

INR at which stroke event occurred

3.0

INR

2.0

1.0

AFASAK

CAFA

SPAF

BAATAF

SPINAF

Association of stroke events with intensity of anticoagulation for patientswith AF treated with warfarin in major randomized trials

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

targets for novel antithrombotic agents in the coagulation cascade
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 126517 (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. 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
Dabigatran RE-LY®: study design

R

AF with 1 risk factor

Absence of contraindications

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
Phase III RE-LY®: time to first stroke or systemic embolism

Warfarin

Dabigatran 110 mg BID

Dabigatran 150 mg BID

RRR

34%

RR 0.91

(95% CI: 0.74–1.11)

P<0.001 (NI)

P=0.34 (Sup)

0.05

0.04

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

phase iii re ly major bleeding
Phase III RE-LY®: major bleeding

3.36

3.11

2.71

RR 0.80 (95% CI: 0.69–0.93)

P=0.003 (Sup)

RR 0.93 (95% CI: 0.81–1.07)

3.5

P=0.31 (Sup)

RRR

20%

3.0

2.5

2.0

Major bleeding (%/yr)

1.5

1.0

0.5

0.0

Dabigatran110 mg BID

Dabigatran150 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

phase iii re ly intracranial bleeding
Phase III RE-LY®: intracranial bleeding

0.74

0.30

0.23

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

0.6

RRR

60%

0.5

Intracranial bleeding (%/yr)

RRR

69%

0.4

0.3

0.2

0.1

0

Dabigatran110 mg BID

Dabigatran150 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

phase iii re ly conclusions
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 inhibition
Direct and indirect factor Xa (FXa) inhibition

Direct FXa inhibitor

FXa

DIRECT

Binds directly to the active site of FXa, blocking substrate interactions (e.g. apixaban, rivaroxaban, edoxaban, betrixaban)

INDIRECT

Binds to antithrombin (AT) and potentiates the activity of AT against FXa (e.g. idraparinux, SSR 126517)

FXa

AT

AT

AT

Indirect FXa inhibitor

II

Thrombin

Fibrinogen

Fibrin clot

Adapted from Turpie AG et al. N Engl J Med 2001;344:619–25

phase iii averroes study design
Phase III AVERROES: study design

R

AF with 1 risk factor and

demonstrated or expected unsuitable for VKA

Apixaban

5 mg BID

(2.5 mg BID in selected patients)

Aspirin81–324 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 708005-708006.Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx

VKA = vitamin K antagonist; BID = twice daily

averroes stroke or syst embolic event
AVERROES: stroke or syst embolic event

Aspirin

Apixaban

0.07

0.06

0.05

RR 0.4695% CI: 0.33–0.64P<0.001

0.04

Cumulative risk

0.03

0.02

0.01

0

0

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 708005-708006.Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

phase iii averroes major bleeding
Phase III AVERROES: major bleeding

Aspirin

Apixaban

0.025

0.020

RR 1.1495% CI: 0.74–1.75P=0.56

0.015

Cumulative risk

0.010

0.005

0

0

3

6

9

12

18

21

Months

No. at risk

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 708005-708006.Available at: http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

slide18
Ongoing Phase III trials with direct factor Xa inhibitors for the prevention of stroke in patients with AF

*Adjusted based on renal function; BID = twice daily; INR = international normalized ratio; OD = once daily

slide19

Who should we treat with what?

Individual

‘cost-benefit analysis’

to determine

therapeutic strategy

stroke risk assessment with cha 2 ds 2 vasc
Stroke risk assessment with CHA2DS2-VASc

*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

2010 esc guidelines on antithrombotic therapy in af
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
Bleeding risk assessment with HAS-BLED

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

percutane left atrial appendage closure devices
Percutane Left Atrial Appendage Closure Devices

PLAATO

AMPLATZER

CARDIAC PLUG

WATCHMAN

future guidelines on antithrombotic therapy in atrial fibrillation
Future guidelines on Antithrombotic therapy in Atrial Fibrillation

All AF pts receive Direct Thrombin Inhibitor or Direct Factor Xa Inhibitorexcept:

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

dabigatran etexilate
Dabigatran etexilate

Oral prodrug, converted to dabigatran, which is a potentand 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

slide27
Dabigatran etexilate has key features that make it an effective antithrombotic for stroke prevention

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
Phase III RE-LY®: largest AF outcomes trial

18113 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

RE-LY®:Randomized Evaluation of Long-term anticoagulant therapy

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
Baseline characteristics

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
Phase III RE-LY®: study inclusion and exclusion criteria

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
Phase III RE-LY®: risk of stroke or systemic embolism

Non-inferiority

P value

Superiority

P value

Dabigatran110 mg BID

vs. warfarin

<0.001

0.34

Margin = 1.46

Dabigatran150 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

warfarin reduces the risk of stroke in patients with af
Warfarin reduces the risk of stroke in patients with AF

Warfarin better

Placebo better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trials

100

50

0

–50

–100

RRR (%)†

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

limited efficacy of aspirin in reducing the risk of stroke in patients with af
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

0

–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

warfarin compared with aspirin for stroke prevention in af
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

0

–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

slide35
Congestive heart failure (1 point)

(History of) Hypertension (1 point)

Age > 75 years (1 point)

Diabetes Mellitus (1 point)

Prior Stroke/TIA (2 points)

Risk factors for stroke in AF: CHADS2

OAC in case

score > 1

Cage et al JAMA 2001

stroke risk assessment with chads 2
Stroke risk assessment with CHADS2

0

1

2

3

CHADS2 score

4

5

6

0

5

10

15

20

25

30

Annual stroke rate (%)*

  • Congestive heart failure (1 point)
  • (History of) Hypertension (1 point)
  • Age > 75 years (1 point)
  • Diabetes Mellitus (1 point)
  • Prior Stroke/TIA (2 points)

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

2010 esc guidelines for antithrombotic rx in af
2010 ESC guidelines for antithrombotic Rx in AF

ESC guidelines: Camm J et al. Eur Heart J 2010

2010 esc guidelines for antithrombotic therapy in af
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]

spaf iii adjusted dose warfarin compared with low intensity warfarin plus aspirin
SPAF III: adjusted-dose warfarin compared with low-intensity warfarin plus Aspirin

n=

521

378

265

166

61

n=

523

397

273

173

65

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 warfarinWarfarin (INR 2.0–3.0)

0

0

0.5

1.0

1.5

2.0

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
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 A

Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)

vs.

Aspirin (75–100 mg/d)

ACTIVE W

Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)

vs.

VKA (target INR = 2.0–3.0)

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

active w dual antiplatelet therapy inferior to oral anticoagulation for stroke prevention in af
ACTIVE W: dual antiplatelet therapy inferior to oral anticoagulation for stroke prevention in AF

n=

3335

3168

2419

941

n=

3371

3232

2466

930

Stroke

0.05

Dual antiplatelet therapy

Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)

0.04

RR 1.72(95% CI: 1.242.37)

P=0.001

0.03

Oral anticoagulationVKA (target INR = 2.0–3.0)

Cumulative hazard rates

0.02

0.01

0.00

0

0.5

1.0

1.5

Years

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
ACTIVE A: dual antiplatelet therapy superior to Aspirin alone for stroke prevention in AF

3772

3491

3229

2570

1203

n=

n=

3782

3458

3155

2517

1186

Stroke

0.15

Aspirin aloneAspirin (75–100 mg/d)

Dual antiplatelet therapy

Clopidogrel (75 mg/d) + Aspirin (75–100 mg/d)

0.10

But 1.5-2.0x more bleeding

Cumulative incidence

HR 0.72(95% CI: 0.62–0.83)

P<0.0001

0.05

0.00

0

1

2

3

4

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
Safety and efficacy of idraparinux for stroke prevention in AF: Phase III AMADEUS

Idraparinux (n=2283)

Warfarin (n=2293)

19.7%

20

1.5

1.3%

15

0.9%

1.0

11.3%

10

Incidence (%)

Incidence (%)

0.5

5

0

0

Clinically relevant bleeding

Stroke and embolism

P<0.0001

P=0.007 (for non-inferiority)

Bousser MG et al. Lancet 2008;371:315–21

rivaroxaban
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
Rivaroxaban and stroke prevention in AF: Phase III ROCKET-AF

Randomized, double-blind, non-inferiority study1

Approximately 14000 patients with AF

Comparing the efficacy and safety of rivaroxaban 20 mg ODwith 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
Phase III ROCKET-AF: study inclusion criteria

ECG = electrocardiogram; LVEF = left ventricular ejection fraction

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

rocket af study exclusion criteria
ROCKET-AF: study exclusion criteria

VTE = venous thromboembolism

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

summary direct factor xa inhibitors
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 Aspirinwith 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/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

biotinylated version of idraparinux ssr 126517
Biotinylated version of idraparinux: SSR 126517

No antidote for idraparinux to reverse its anticoagulant activity

SSR 126517 developed to offer the same pharmacological featuresas 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
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
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

phase iii re ly haemorrhagic stroke
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%

0

Dabigatran110 mg BID

Dabigatran150 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

warfarin reduces the risk of stroke in both primary and secondary prevention
Warfarin reduces the risk of stroke in both primary and secondary prevention

Meta-analysis of trials comparing dose-adjusted warfarin with placebo

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
Phase III AVERROES: bleeding

Outcome

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

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/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]

phase iii averroes conclusions
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/congress-reports/Pages/708-3-AVERROES.aspx [Accessed September 2010]