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

Antistolling in AFAntistolling in AFHet begin van een nieuw tijdperk?Het begin van een nieuw tijdperk?

Dr RG TielemanDr RG TielemanMartini Ziekenhuis GroningenMartini Ziekenhuis Groningen

CVA en Atriumfibrilleren: de feiten

CVA is de belangrijkste complicatie van AFCVA is de belangrijkste complicatie van AF

AF is geassocieerd met een 5x verhoogde kans op CVAAF is geassocieerd met een 5x verhoogde kans op CVA

AF verdubbeld het risico op CVA wanneer gecorrigeerd voor AF verdubbeld het risico op CVA wanneer gecorrigeerd voor andere risico factorenandere risico factoren

Zonder behandeling is de incidentie van CVA in AF 5%Zonder behandeling is de incidentie van CVA in AF 5%

(incl TIAs en stille CVAs > 7%)(incl TIAs en stille CVAs > 7%)

AF is verantwoordelijk voor 1/3 van alle CVAs AF is verantwoordelijk voor 1/3 van alle CVAs

AF geassocieerd CVA is 2x vaker dodelijk en meer AF geassocieerd CVA is 2x vaker dodelijk en meer invaliderendinvaliderend

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

Warfarin superior in reducing the stroke risk in AF patients

Control worse Control better

RRR (%)†

100 –10050 0 –50

Warfarin vs Placebo RRR 64%(95% CI: 4974%)

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

RRR = 19%(95% CI: –1 to 35%)

RRR 38%(95% CI: 18–52%)

Aspirin vs Placebo

Warfarin vs Aspirin

Therapeuticrange

1International normalized ratio

Odds

rati

o

2

15

8

10

5

01

3 4 5 6 7

20

VKAs have a narrow therapeutic window

ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354& Eur Heart J 2006;27:1979–2030

Stroke

Intracranial bleed

VKAs = vitamin K antagonists

SPORTIF VINR Values – Warfarin Group

Circulation 2003;108:2723

0

20

40

60

80

100

Tim

e in

Ra

ng

e (

%)

Treatment Duration (months)

3 6 9 12 15 18 21 24 26

68%68%2.0-3.02.0-3.0

AFASAK I

Annual ra

te (

%)

5.0

4.0

3.0

2.0

1.0

0.0

AFASAK II PATAF SPAF II

Age 75 yrsAge >75 yrs

Bleeding risk with warfarin compared with Aspirin

Albers GW et al. Chest 2001;119:194S–206S

Major bleeds = transfusion or hospitalization required, or critical anatomic location (e.g. intracranial, perispinal); Within trial differences not statistically significant

Warfarin

Major bleeds

Aspirin

Intracranial bleeds

AFASAK SPINAF

INR

1.0

2.0

3.0

4.0

BAATAFCAFA SPAF

Most strokes occurred in patients who were under-anticoagulated

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

ACC = American College of Cardiology; AHA = American Heart Association;ESC = European Society of Cardiology; INR = international normalized ratio

Target range for study

ACC/AHA/ESC recommended INR (2.0–3.0)

INR at which stroke event occurred

Levi M et al. Semin Thromb Haemost 2009;35:527–42

Targets for novel antithrombotic agents in the coagulation cascade

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

AT= antithrombin; Ph = PhaseFibrin

IX

IXa

X

VIIIa

Thrombin

Fibrinogen

Direct factor Xa inhibitors:Apixaban (Ph III ongoing)5,6

Rivaroxaban (Ph III ongoing)7

Edoxaban (Ph III ongoing)8

Betrixaban (Ph II ongoing)9

Va

Xa

II

AT

Direct thrombin inhibitors: Dabigatran etexilate (Ph III completed)10

Ximelagatran (withdrawn 2006)11,12

AZD0837 (Ph II completed)13

Indirect factor Xa inhibitors: Idraparinux (Ph III terminated)3

SSR 126517 (withdrawn 2009)4

Vitamin K antagonist: Tecarfarin (Ph II completed)2

Tissue factor/VIIa

Dabigatran RE-LY®: study design

Ezekowitz MD et al. Am Heart J 2009;157:805–10; Connolly SJ et al. N Engl J Med 2009;361:1139–51

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-upPrimary Endpoint: All Strokes (ischemic and hemorrhagic) and systemic embolism

AF with 1 risk factorAbsence of contraindications

R

Dabigatran110 mg BID

n=6000

Warfarin1 mg, 3 mg, 5 mg

(INR 2.0–3.0)n=6000


n=6000

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

Connolly SJ et al. N Engl J Med 2009;361:1139–51

BID = twice daily; NI = non-inferiority; RR = relative risk; RRR = relative risk reduction; Sup = superiority

Years

0.0 0.5 1.0 1.5 2.0 2.5

0.01

0.02

0.03

0.05

0.04

Cum

ula

tive h

aza

rd r

ate

s

0.00

Warfarin

Dabigatran 110 mg BID

Dabigatran 150 mg BID

RR 0.91(95% CI: 0.74–1.11)P<0.001 (NI)P=0.34 (Sup)

RR 0.66(95% CI: 0.53–0.82)P<0.001 (NI)P<0.001 (Sup)

RRR34%

Phase III RE-LY®: major bleeding


BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority

Events/n: 322/6015 375/6076 397/6022

2.71

3.113.36



Warfarin0.0

1.0

2.0

3.5

Majo

r ble

edin

g (

%/y

r)

3.0

2.5

1.5

0.5

RR 0.80 (95% CI: 0.69–0.93)

P=0.003 (Sup)RR 0.93 (95% CI: 0.81–1.07)

P=0.31 (Sup)RRR20%

Phase III RE-LY®: intracranial bleeding


BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority

Events/n: 27/6015 36/6076 87/6022



Warfarin0

0.6

0.9

Intr

acr

ania

l ble

edin

g (

%/y

r) 0.8

0.7

0.5

0.4

0.3

0.2

0.10.23

0.30

0.74

RR 0.31 (95% CI: 0.20–0.47)

P<0.001 (Sup)RR 0.40 (95% CI: 0.27–0.60)

P<0.001 (Sup)

RRR69%

RRR60%

Phase III RE-LY®: conclusions

Dabigatran etexilate has been shown to Dabigatran etexilate has been shown to concurrently reduce both thrombotic and concurrently reduce both thrombotic and haemorrhagic events haemorrhagic events

Both doses of dabigatran provide different and Both doses of dabigatran provide different and complementary advantages over warfarincomplementary advantages over warfarin

150 mg BID has superior efficacy with similar 150 mg BID has superior efficacy with similar bleedingbleeding

110 mg BID has significantly less bleedings 110 mg BID has significantly less bleedings with similar efficacywith similar efficacy

Connolly SJ et al. N Engl J Med 2009;361:1139–51;BID = twice daily; INR = international normalized ratio

ThrombinII

Fibrinogen Fibrin clot

Direct and indirect factor Xa (FXa) inhibition

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

AT

Indirect FXa inhibitor

AT ATFXa

FXa

Direct FXa inhibitor

INDIRECT Binds to antithrombin (AT) and potentiates the activity of AT

against FXa (e.g. idraparinux, SSR 126517)

DIRECT Binds directly to the active

site of FXa, blocking substrate interactions (e.g. apixaban,

rivaroxaban, edoxaban, betrixaban)

Phase III AVERROES: study design

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

Primary objective: to establish the superiority of apixaban over Aspirin36 countries, 522 centres, double-blind study. N=5600 ptsStudy was stopped after interim analysis

AF with 1 risk factor anddemonstrated or expected unsuitable for VKA

R

Apixaban5 mg BID

(2.5 mg BID in selected patients)

Aspirin81–324 mg/d

VKA = vitamin K antagonist; BID = twice daily

AVERROES: stroke or syst embolic event

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]

RR = relative risk; CI = confidence interval

Cu

mu

lati

ve r

isk

0.02

0.04

0.05

0.06

0.07

0

0.01

0.03

0Months

3 6 9 12 18 21

2791 2720 2541 2124 1541 626 329

2809 2761 2587 2127 1523 617 352

Aspirin

Apixaban

RR 0.4695% CI: 0.33–0.64P<0.001

AspirinApixaban

Phase III AVERROES: major bleeding


2791 2744 2572 2152 1570 642 340

2809 2763 2567 2123 1521 622 357

Aspirin

Apixaban

Cu

mu

lati

ve r

isk

0.005

0.015

0.020

0.025

0

0.010

0Months

3 6 9 12 18 21No. at risk

RR 1.1495% CI: 0.74–1.75P=0.56

AspirinApixaban


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

TrialTrialacronymacronym DrugDrug DoseDose ComparatorComparator NN

CHADSCHADS22

scorescore

Expected Expected completion completion

datedate

ARISTOTLEARISTOTLE ApixabanApixaban5 mg5 mg

BIDBID

WarfarinWarfarin

(INR 2.0–3.0)(INR 2.0–3.0)1818 000000 ≥≥11 Apr 2011Apr 2011

AVERROESAVERROES ApixabanApixaban5 mg5 mg

BIDBIDAspirin Aspirin

((81–324 mg OD)81–324 mg OD) 60006000 ≥≥11 Aug 2010Aug 2010

ROCKET-AFROCKET-AF RivaroxabanRivaroxaban20 mg*20 mg*

ODOD

WarfarinWarfarin

(INR 2.0–3.0)(INR 2.0–3.0)1414 000000 ≥≥22 May 2010May 2010

ENGAGE-AF TIMI 48ENGAGE-AF TIMI 48 EdoxabanEdoxaban30 mg OD30 mg OD

60 mg OD60 mg OD

WarfarinWarfarin

(INR 2.0–3.0)(INR 2.0–3.0)1616 500500 ≥≥22 Mar 2011Mar 2011

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

Who should we treat with what?Who should we treat with what?

IndividualIndividual‘‘cost-benefit analysis’ cost-benefit analysis’

to determine to determine therapeutic strategytherapeutic strategy

Stroke risk assessment with CHA2DS2-VASc

CHACHA22DSDS22-VASc criteria-VASc criteria ScoreScore

CCongestive heart failure/ongestive heart failure/left ventricular dysfunctionleft ventricular dysfunction

11

HHypertensionypertension 11

AAge ge 75 yrs75 yrs 22

DDiabetes mellitusiabetes mellitus 11

SStroke/transient ischaemic troke/transient ischaemic attack/TEattack/TE

22

VVascular disease (prior ascular disease (prior myocardial infarction, myocardial infarction, peripheral artery disease or peripheral artery disease or aortic plaque)aortic plaque)

11

AAge 65–74 yrsge 65–74 yrs 11

SSex ex ccategory (i.e. female ategory (i.e. female gender)gender)

11

CHACHA22DSDS22--

VASc VASc total scoretotal score

Rate of stroke/other Rate of stroke/other TE (%/year) (95% CI)*TE (%/year) (95% CI)*

00 00 (0–0)(0–0)

11 0.60.6 (0.0–3.4)(0.0–3.4)

22 1.61.6 (0.3–4.7)(0.3–4.7)

33 3.93.9 (1.7–7.6)(1.7–7.6)

44 1.91.9 (0.5–4.9)(0.5–4.9)

55 3.23.2 (0.7–9.0)(0.7–9.0)

66 3.63.6 (0.4–12.3)(0.4–12.3)

77 8.08.0 (1.0–26.0)(1.0–26.0)

88 11.111.1 (0.3–48.3)(0.3–48.3)

99 100100 (2.5–100)(2.5–100)

*Theoretical rates without therapy corrected for the % of patients receiving Aspirin within each group,assuming 22% reduction in risk with Aspirin

Lip GYH et al. Chest 2010;137:263-72

TE = thromboembolism

2010 ESC guidelines on antithrombotic therapy in AF

recommendations based on the CHArecommendations based on the CHA22DSDS22-VASc score:-VASc score:

Score of ≥2:Score of ≥2: Oral anticoagulation Oral anticoagulation (INR 2.0–3.0) (INR 2.0–3.0)

Score of 1:Score of 1: Oral anticoagulationOral anticoagulation (INR 2.0–3.0) (INR 2.0–3.0)(preferred option) (preferred option) oror

Aspirin (81–325 mg/day)Aspirin (81–325 mg/day)

Score of 0:Score of 0: Aspirin (81–325 mg/day) Aspirin (81–325 mg/day) oror no therapy (preferred option)no therapy (preferred option)

ESC = European Society of Cardiology; INR = international normalized ratioESC guidelines: Camm J et al. Eur Heart J 2010

Bleeding risk assessment with HAS-BLED

HAS-BLED risk criteriaHAS-BLED risk criteria ScoreScore

HHypertensionypertension 11

AAbnormal renal or liver bnormal renal or liver function (1 point each)function (1 point each)

1 or 21 or 2

SStroketroke 11

BBleeding leeding 11

LLabile INRsabile INRs 11

EElderlylderly(e.g. age >65 yrs)(e.g. age >65 yrs)

11

DDrugs or alcoholrugs or alcohol(1 point each)(1 point each)

1 or 21 or 2

Pisters R et al. Chest. 2010; ESC guidelines: Camm J et al. Eur Heart J 2010

INR=international normalized ratio

HAS-BLED HAS-BLED total scoretotal score NN

NumberNumberof bleedsof bleeds

Bleeds per 100 Bleeds per 100 patient-yrs*patient-yrs*

00 798798 99 1.131.13

11 12861286 1313 1.021.02

22 744744 1414 1.881.88

33 187187 77 3.743.74

44 4646 44 8.708.70

55 88 11 12.512.5

66 22 00 0.00.0

77 00 –– ––

88 00 –– ––

99 00 –– ––

*P value for trend = 0.007

Percutane Left Atrial Appendage Closure Devices

PLAATO WATCHMANAMPLATZER

CARDIAC PLUG

Future guidelines on Antithrombotic therapy in Atrial Fibrillation

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

Male lone AF patients < 65 yrsMale lone AF patients < 65 yrs No therapyNo therapy

HAS-Bled Score of ≥ 4:HAS-Bled Score of ≥ 4: LAA Closure device?LAA Closure device?

No indication for vitamin K antagonists or AspirinNo indication for vitamin K antagonists or Aspirin

R.G. Tieleman, (personal opinion) GetRhythm Symposium Utrecht 2010

Back-up Slides

Dabigatran etexilate OralOral prodrug, converted to dabigatran, which is a potent prodrug, converted to dabigatran, which is a potent

and reversible direct thrombin inhibitor (DTI)and reversible direct thrombin inhibitor (DTI) Inhibits both clot-bound and free thrombinInhibits both clot-bound and free thrombin 6.5% bioavailability 6.5% bioavailability Peak plasma levels of dabigatran achieved Peak plasma levels of dabigatran achieved within 2 hours within 2 hours

after administration in healthy volunteers after administration in healthy volunteers Half-life of 12–17 hoursHalf-life of 12–17 hours ~~80% renal excretion80% renal excretion

Most advanced DTI in Phase III development for stroke Most advanced DTI in Phase III development for stroke prevention in patients with AFprevention in patients with AF Recently demonstrated superiority to warfarin in the Recently demonstrated superiority to warfarin in the

Phase III RE-LYPhase III RE-LY®® study study

Pradaxa: SmPC, 2009; Connolly SJ et al. N Engl J Med 2009;361:1139–51

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

Twice-daily dosingTwice-daily dosing11

Predictable and consistent pharmacokinetic profilePredictable and consistent pharmacokinetic profile2,32,3

Rapid onset/offset of actionRapid onset/offset of action22

No requirement for anticoagulation monitoringNo requirement for anticoagulation monitoring44

Low potential for drug–drug interactionsLow potential for drug–drug interactions1,51,5

Not metabolized by CYP450 enzymes, and does not affect the Not metabolized by CYP450 enzymes, and does not affect the metabolism of other drugs that utilize this systemmetabolism of other drugs that utilize this system1,51,5

No food–drug interactions, with dosing independent of mealsNo food–drug interactions, with dosing independent of mealsor dietary restrictionsor dietary restrictions66

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;45:555–63Disclaimer: 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

1818 113 patients randomized during 2 years113 patients randomized during 2 years1,21,2

50% of enrolled patients are naïve to previous oral anticoagulant50% of enrolled patients are naïve to previous oral anticoagulant

Median treatment duration: 2 yearsMedian treatment duration: 2 years

951 centres in 44 countries951 centres in 44 countries

December 2005 to March 2009December 2005 to March 2009

Results first presented at ESC congress 2009 and published Results first presented at ESC congress 2009 and published online in online in New England Journal of MedicineNew England Journal of Medicine on 30 Aug 2009 on 30 Aug 2009

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

therapy

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

ESC = European Society of Cardiology

Baseline characteristics


CharacteristicCharacteristic Dabigatran Dabigatran 110 mg BID110 mg BID

Dabigatran Dabigatran 150 mg BID150 mg BID WarfarinWarfarin

Randomized (n)Randomized (n) 60156015 60766076 60226022

Mean age (yrs)Mean age (yrs) 71.471.4 71.571.5 71.671.6

Male (%)Male (%) 64.364.3 63.263.2 63.363.3

CHADSCHADS22 score (mean) score (mean) 2.12.1 2.22.2 2.12.10/10/1 (%)(%) 32.632.6 32.232.2 30.930.922 (%)(%) 34.734.7 35.235.2 37.037.03+3+ (%)(%) 32.732.7 32.632.6 32.132.1

Prior stroke/TIA (%)Prior stroke/TIA (%) 19.919.9 20.320.3 19.819.8

Prior MI (%)Prior MI (%) 16.816.8 16.916.9 16.116.1

CHF (%)CHF (%) 32.232.2 31.831.8 31.931.9

Baseline ASA (%)Baseline ASA (%) 40.040.0 38.738.7 40.640.6

Warfarin-naïve (%)Warfarin-naïve (%) 49.949.9 49.849.8 51.451.4

ASA = acetylsalicylic acid (aspirin); BID = twice daily; CHF = congestive heart failure; MI = myocardial infarction; TIA = transient ischaemic attack

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

Exclusion criteriaExclusion criteria

1.1. Severe heart-valve disorder Severe heart-valve disorder

2.2. Stroke within 14 days or severe stroke within 6 months before screeningStroke within 14 days or severe stroke within 6 months before screening

3.3. Any condition that increases the risk of haemorrhageAny condition that increases the risk of haemorrhage

4.4. Creatinine clearance <30 mL per minCreatinine clearance <30 mL per min

5.5. Active liver diseaseActive liver disease

6.6. PregnancyPregnancy

Inclusion criteriaInclusion criteria

1.1. Documented AFDocumented AF

2.2. One additional risk factor for stroke:One additional risk factor for stroke:

• History of previous stroke, transient ischaemic attack or systemic embolismHistory of previous stroke, transient ischaemic attack or systemic embolism• LVEF less than 40%LVEF less than 40%• Symptomatic heart failure, NYHA Class II or greaterSymptomatic heart failure, NYHA Class II or greater• Age of 75 yrs or moreAge of 75 yrs or more• Age of 65 yrs or more and one of the following additional risk factors: diabetes Age of 65 yrs or more and one of the following additional risk factors: diabetes

mellitus, coronary artery disease or hypertensionmellitus, coronary artery disease or hypertension

Connolly SJ et al. N Engl J Med 2009;361:1139–51Error bars = 95% CI; BID = twice daily

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

Dabigatran110 mg BIDvs. warfarin

Dabigatran150 mg BIDvs. warfarin

<0.001

<0.001

0.34

<0.001

0.50 0.75 1.00 1.25 1.50

SuperiorityP value

Non-inferiorityP value

Hazard ratioM

arg

in =

1.4

6

Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity;†Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)

Warfarin reduces the risk of stroke in patients with AF

Warfarin better Placebo better

RRR (%)†

100 –10050 0 –50

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

All trials RRR 64%*(95% CI: 4974%)


RRR (%)†100 –10050 0 –50

AFASAK

SPAF

EAFT

ESPS II

Aspirin better Placebo better

LASAF125 mg/d

125 mg QOD

UK-TIA300 mg/d

1200 mg/d

JAST

All trials

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

Limited efficacy of Aspirin in reducing the risk of stroke in patients with AF

RRR = 19%*(95% CI: –1 to 35%)


Warfarin compared with Aspirin for stroke prevention in AF


RRR (%)*

100 –10050 0 –50

AFASAK I

AFASAK II

EAFT

PATAF

Warfarin better Aspirin better

Chinese ATAFS

SPAF IIAge 75 yrsAge >75 yrs

All trials

Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR)for all strokes (ischaemic and haemorrhagic)

RRR 38%(95% CI: 18–52%)

Risk factors for stroke in AFRisk factors for stroke in AF: CHADS: CHADS22

• CCongestive heart failureongestive heart failure (1 point)(1 point)

• (History of) (History of) HHypertensionypertension (1 point)(1 point)

• AAge >ge > 7 75 year5 yearss (1 point)(1 point)

• DDiabetes Mellitusiabetes Mellitus (1 point)(1 point)

• Prior Prior SStroke/TIAtroke/TIA ((22 points) points)

OAC in case

score > 1

Cage et al JAMA 2001Cage et al JAMA 2001

Stroke risk assessment with CHADS2

Gage BF et al. JAMA 2001;285:2864–70

Error bars = 95% CI; *Adjusted stroke rate = expected stroke rate per 100 patient-years based on exponential survival model, assuming Aspirin not taken

Annual stroke rate (%)*

CH

AD

S2 s

core

30

0

2

3

4

5

6

0 5 10 15 20 25

1

• CCongestive heart failureongestive heart failure (1 point)(1 point)

• (History of) (History of) HHypertensionypertension (1 point)(1 point)

• AAge >ge > 7 75 year5 yearss (1 point)(1 point)

• DDiabetes Mellitusiabetes Mellitus (1 point)(1 point)

• Prior Prior SStroke/TIAtroke/TIA ((22 points) points)

2010 ESC guidelines for antithrombotic Rx in AFRisk categoryRisk category CHACHA22DSDS22-VASc score-VASc score Recommended therapyRecommended therapy

No risk factorsNo risk factors 00

Either Aspirin 75–325 mg daily Either Aspirin 75–325 mg daily oror no noantithrombotic therapyantithrombotic therapyPreferred choice is no antithrombotic Preferred choice is no antithrombotic therapytherapy

One clinically relevantOne clinically relevantnon-major risk factornon-major risk factor 11 Either OAC* Either OAC* oror Aspirin 75–325 mg Aspirin 75–325 mg

daily Preferred choice is OACdaily Preferred choice is OAC

One major risk factorOne major risk factoror ≥2 clinicallyor ≥2 clinicallyrelevant non-majorrelevant non-majorrisk factorsrisk factors

22 OACOAC**

Clinically relevant non-major risk Clinically relevant non-major risk factorsfactors Major risk factorsMajor risk factors

Heart failure or moderate toHeart failure or moderate tosevere LV systolic dysfunctionsevere LV systolic dysfunction(e.g. LV ejection fraction ≤40%)(e.g. LV ejection fraction ≤40%)Hypertension – Diabetes mellitusHypertension – Diabetes mellitusFemale sex – Age 65–74 yrsFemale sex – Age 65–74 yrsVascular disease†Vascular disease†

Previous stroke, TIA, or systemic Previous stroke, TIA, or systemic embolismembolismAge ≥75 yearsAge ≥75 years

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

2010 ESC guidelines for antithrombotic therapy in AF

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]

CHADS2 score ≥2†

No Yes

Age ≥75 years

No Yes

≥2 other risk factors*

No Yes

1 other risk factor*

No

Yes

†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

OAC

OAC (or Aspirin)

Nothing (or Aspirin)

Consider other risk factors*

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

*Warfarin dose adjusted between 0.5 and 3.0 mg/day to achieve international normalized ratio (INR) 1.21.5 when initiating therapy and then fixed for rest of study; RRR = relative risk reduction

Adjusted-dose warfarinWarfarin (INR 2.0–3.0)

Combination therapyFixed-dose warfarin (INR 1.2–1.5)*+ Aspirin (325 mg/d)

Cum

ula

tive e

vent

rate

(%

per

year)

Years

15

0

10

5

02.00.5 1.0 1.5

RRR 74%(95% CI: 5087%)

P<0.0001

n= 521 378 265 166 61n= 523 397 273 173 65

Ischaemic stroke or systemic embolism

SPAF Investigators. Lancet 1996;348:633–8

Similar Bleeding Risk

ACTIVE AClopidogrel (75 mg/d)

+ Aspirin (75–100 mg/d)vs.

Aspirin (75–100 mg/d)

Documented AF and 1 risk factor*for stroke

Unsuitable for VKA

No exclusion criteria for ACTIVE I

ACTIVE IIrbesartan (300 mg/d) vs.

placebo

ACTIVE trials: dual antiplatelet therapy for stroke prevention in AF

Partial factorial design

ACTIVE WClopidogrel (75 mg/d)

+ Aspirin (75–100 mg/d)vs.

VKA (target INR = 2.0–3.0)

Connolly SJ et al. Am Heart J 2006;151:1187–1193

Suitable for VKA

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

ACTIVE Investigators. Lancet 2006;151:1903–12INR = international normalized ratio; RR = relative risk; VKA = vitamin K antagonist

Oral anticoagulationVKA (target INR = 2.0–3.0)

Dual antiplatelet therapyClopidogrel (75 mg/d) + Aspirin (75–100 mg/d)

RR 1.72(95% CI: 1.242.37)

P=0.001

n= 3335 3168 2419 941n= 3371 3232 2466 930

Stroke

Cum

ula

tive h

aza

rd r

ate

s

Years

0.05

00.00

0.5 1.0 1.5

0.04

0.03

0.02

0.01

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

ACTIVE Investigators. N Engl J Med 2009;360:2066–78

Aspirin aloneAspirin (75–100 mg/d)

Dual antiplatelet therapyClopidogrel (75 mg/d) + Aspirin (75–100 mg/d)

HR 0.72(95% CI: 0.62–0.83)

P<0.0001

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

Stroke

Cum

ula

tive inci

dence

Years

0.15

00.00

1 2 4

0.10

0.05

3

n= 3772 3229 2570 12033491n= 3782 3458 3155 11862517

But 1.5-2.0x more bleeding

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

Idraparinux (n=2283) Warfarin (n=2293)

0.9%

1.3%

P=0.007 (for non-inferiority)19.7%

11.3%

P<0.0001

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

Inci

dence

(%

)

1.5

Stroke and embolism

1.0

0.5

0

Inci

dence

(%

)

20

Clinically relevant bleeding

15

10

5

0

Rivaroxaban

Highly selective and potent inhibitor of factor XaHighly selective and potent inhibitor of factor Xa Bioavailability of 60–80%Bioavailability of 60–80%11

Half-life of up to 9 hours in healthy young subjects and Half-life of up to 9 hours in healthy young subjects and 11–13 hours in the elderly 11–13 hours in the elderly22

Approved in Europe and Canada for the prevention of Approved in Europe and Canada for the prevention of venous blood clots in patients undergoing elective hip- or venous blood clots in patients undergoing elective hip- or knee-replacement surgeryknee-replacement surgery33

Compound has no direct effect on platelet aggregationCompound has no direct effect on platelet aggregation44

Well-tolerated in healthy human subjectsWell-tolerated in healthy human subjects5,65,6

Rapid onset of actionRapid onset of action5,65,6

Dose-proportional pharmacokinetics/pharmacodynamicsDose-proportional pharmacokinetics/pharmacodynamics5,65,6

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

Randomized, double-blind, non-inferiority studyRandomized, double-blind, non-inferiority study11

Approximately 14Approximately 14 000 patients with AF 000 patients with AF

Comparing the efficacy and safety of rivaroxaban 20 mg ODComparing the efficacy and safety of rivaroxaban 20 mg ODwith warfarin for the prevention of strokewith warfarin for the prevention of stroke

Patients with moderate renal impairment (creatinine clearance 30–49 Patients with moderate renal impairment (creatinine clearance 30–49 mL/min) will receive a fixed dose of 15 mg OD rivaroxabanmL/min) will receive a fixed dose of 15 mg OD rivaroxaban

Primary outcomes:Primary outcomes:

Any stroke or non-CNS systemic embolismAny stroke or non-CNS systemic embolism

Composite of major and clinically relevant non-major bleeding eventsComposite of major and clinically relevant non-major bleeding events

Secondary outcomes:Secondary outcomes:

Each category of bleeding events and adverse eventsEach category of bleeding events and adverse events

Composite of stroke, non-CNS systemic embolism and vascular deathComposite of stroke, non-CNS systemic embolism and vascular death

Phase III ROCKET-AF: study inclusion criteria

Inclusion criteriaInclusion criteria

1.1. Male and female patients aged Male and female patients aged 18 yrs18 yrs

2.2. Persistent or paroxysmal AF on Persistent or paroxysmal AF on 2 episodes (one of which is 2 episodes (one of which is documented by ECG within 30 days of enrollment) documented by ECG within 30 days of enrollment)

3.3. History of stroke, transient ischaemic attack or systemic embolism, History of stroke, transient ischaemic attack or systemic embolism, or at least two of the following risk factors (CHADS2 or at least two of the following risk factors (CHADS2 2):2):

• Congestive heart failure or LVEF Congestive heart failure or LVEF 35% 35%

• Hypertension Hypertension

• Age Age 75 yrs75 yrs

• Diabetes mellitus Diabetes mellitus

ECG = electrocardiogram; LVEF = left ventricular ejection fractionROCKET-AF Study Investigators. Am Heart J 2010;159:340–477

ROCKET-AF: study exclusion criteria

VTE = venous thromboembolism

Exclusion criteriaExclusion criteria

1.1. Cardiovascular-related conditions:Cardiovascular-related conditions:• Prosthetic heart valveProsthetic heart valve• Planned cardioversionPlanned cardioversion• AF secondary to reversible causes (i.e. thyrotoxicosis)AF secondary to reversible causes (i.e. thyrotoxicosis)• Active endocarditisActive endocarditis• Haemodynamically significant mitral stenosisHaemodynamically significant mitral stenosis

2.2. Haemorrhage risk-related factors:Haemorrhage risk-related factors:• Active internal bleedingActive internal bleeding• History of, or condition associated with, increased risk of bleeding , including intracranial History of, or condition associated with, increased risk of bleeding , including intracranial

bleeding, major surgical procedure or trauma within 30 days, and clinically relevant bleeding, major surgical procedure or trauma within 30 days, and clinically relevant gastrointestinal bleeding within 6 monthsgastrointestinal bleeding within 6 months

3.3. Concomitant conditions and therapiesConcomitant conditions and therapies• Recent stroke (14 days) or transient ischaemic attack (3 days)Recent stroke (14 days) or transient ischaemic attack (3 days)• Indication for anticoagulant therapy for a condition other than AF (e.g. VTE)Indication for anticoagulant therapy for a condition other than AF (e.g. VTE)• Pregnancy or breastfeedingPregnancy or breastfeeding• Treatment with other therapies include Aspirin (>100 mg daily), intravenous antiplatelets Treatment with other therapies include Aspirin (>100 mg daily), intravenous antiplatelets

(5 days before randomization), fibrinolytics (10 days before randomization)(5 days before randomization), fibrinolytics (10 days before randomization)

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

Summary: direct factor Xa inhibitors Apixaban, rivaroxaban and edoxaban are highly selective and potent Apixaban, rivaroxaban and edoxaban are highly selective and potent

inhibitors of factor Xainhibitors of factor Xa

Several Phase III studies are comparing the efficacy and safety of Several Phase III studies are comparing the efficacy and safety of direct factor Xa inhibitors with warfarin for stroke prevention in AF:direct factor Xa inhibitors with warfarin for stroke prevention in AF:

ARISTOTLE (apixaban) ARISTOTLE (apixaban)

ROCKET-AF (rivaroxaban)ROCKET-AF (rivaroxaban)

ENGAGE-AF TIMI-48 (edoxaban)ENGAGE-AF TIMI-48 (edoxaban)

For patients with AF who are unsuitable or have failed warfarin For patients with AF who are unsuitable or have failed warfarin therapy, the efficacy and safety of direct factor Xa inhibitors have therapy, the efficacy and safety of direct factor Xa inhibitors have been compared with those of Aspirinbeen compared with those of Aspirin

AVERROES has reported that apixaban significantly reduces the AVERROES has reported that apixaban significantly reduces the risk of stroke or systemic embolism over Aspirinrisk of stroke or systemic embolism over Aspirin with no with no significant increase in risk of major haemorrhagesignificant increase in risk of major haemorrhage11

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

No antidote for idraparinux to reverse its anticoagulant activityNo antidote for idraparinux to reverse its anticoagulant activity

SSR 126517 developed to offer the same pharmacological featuresSSR 126517 developed to offer the same pharmacological featuresas idraparinuxas idraparinux

Addition of biotin allows the rapid removal of the drug following Addition of biotin allows the rapid removal of the drug following intravenous injection of avidinintravenous injection of avidin11

The bioequipotency of SSR 126517 compared with an equimolar The bioequipotency of SSR 126517 compared with an equimolar dose of idraparinux has been evaluated for the treatment of deep dose of idraparinux has been evaluated for the treatment of deep vein thrombosisvein thrombosis22

The Phase III BOREALIS-AF study compared SSR 126517 with The Phase III BOREALIS-AF study compared SSR 126517 with warfarin for the prevention of stroke in AFwarfarin for the prevention of stroke in AF33

SSR 126517 was withdrawn from development for stroke prevention SSR 126517 was withdrawn from development for stroke prevention in AF in December 2009 as it did not appear to significantly improve in AF in December 2009 as it did not appear to significantly improve the care of patientsthe care of patients44

Summary: indirect factor Xa inhibitors

Idraparinux has a long half-life of 80 hours that Idraparinux has a long half-life of 80 hours that subsequently enables weekly dosingsubsequently enables weekly dosing

The Phase III AMADEUS study was terminated The Phase III AMADEUS study was terminated due to excess bleedingdue to excess bleeding

SSR 126517, the biotinylated version of SSR 126517, the biotinylated version of idraparinux, was withdrawn from development idraparinux, was withdrawn from development for stroke prevention in AF in December 2009for stroke prevention in AF in December 2009

Direct thrombin inhibitors (DTIs) block both circulating and clot-bound thrombin

Thrombin generation

Clot-bound thrombin

Heparin

Conversion of fibrinogen to

fibrin

DTIs: dabigatran etexilate

ximelagatran*AZD0837

Amplification

Anti-thrombin

Adapted from Eikelboom J et al. J Am Coll Cardiol 2003;41:70S–8S

DTIs: dabigatran etexilate

ximelagatran*AZD0837

*Withdrawn from the market in 2006

Phase III RE-LY®: haemorrhagic stroke

Connolly SJ et al. N Engl J Med 2009;361:1139–51BID = twice daily; RR = relative risk; RRR = relative risk reduction; Sup = superiority

n: 6015 6076 6022

Haem

orr

hagic

str

oke

(no. of

events

)



Warfarin0

10

20

30

40

50

14

0.12%12

0.10%

45

0.38%

RR 0.31 (95% CI: 0.17–0.56)

P<0.001 (Sup)RR 0.26 (95% CI: 0.14–0.49)

P<0.001 (Sup)

RRR69%

RRR74%

Warfarin reduces the risk of stroke in both primary and secondary preventionMeta-analysis of trials comparing dose-adjusted warfarin with placebo

Primary Primary preventionprevention

Secondary Secondary preventionprevention All trialsAll trials

Number of trialsNumber of trials 55 11 66

Patients (n)Patients (n) 24612461 439439 29002900

ARR with warfarin vs. ARR with warfarin vs. placebo (%)placebo (%) 2.72.7 8.48.4 3.13.1

RRR with warfarin vs. RRR with warfarin vs. placebo (%)placebo (%) 6262 6868 6464

NNTNNT 3737 1212 3232

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

OutcomeOutcome

MajorMajor

Clinically Clinically relevant,relevant,non-majornon-major

MinorMinor

FatalFatal

IntracranialIntracranial

ApixabanApixaban

EventsEvents

4444

9595

159159

55

1313

Annual Annual raterate

1.41.4

3.03.0

5.25.2

0.10.1

0.40.4

AspirinAspirin

EventsEvents

3939

8181

126126

66

1212

Annual Annual raterate

1.21.2

2.62.6

4.14.1

0.10.1

0.30.3

Apixaban vs. AspirinApixaban vs. Aspirin

RRRR

1.141.14

1.181.18

1.271.27

0.840.84

1.091.09

95% CI95% CI

0.74–0.74–1.751.75

0.88–0.88–1.581.58

1.01–1.01–1.611.61

0.26–0.26–2.752.75

0.50–0.50–2.392.39

P valueP value

0.560.56

0.280.28

0.040.04

0.770.77

0.830.83



Phase III AVERROES: conclusions

Apixaban, in patients with atrial fibrillation who are at risk Apixaban, in patients with atrial fibrillation who are at risk of stroke and are unsuitable for VKA therapy:of stroke and are unsuitable for VKA therapy:

– Reduces the risk of stroke or systemic embolism by Reduces the risk of stroke or systemic embolism by 54% over an antiplatelet with no significant increase in 54% over an antiplatelet with no significant increase in risk of major haemorrhagerisk of major haemorrhage

– Offers an important advantage over Aspirin for Offers an important advantage over Aspirin for prevention of stroke prevention of stroke

– Data comparing apixaban with warfarin are expected Data comparing apixaban with warfarin are expected in 2011 (ARISTOTLE trial)in 2011 (ARISTOTLE trial)

VKA = vitamin K antagonist


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

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