Prospects for improving thrombosis management in atrial fibrillation

Prospects for improving thrombosis management in atrial fibrillation

M. Duytschaever, P. Debonnaire, Y.Vandekerckhove and R. Tavernier

St Jan Hospital, Bruges EHRA Training Centre for Electrophysiology

University Hospital Ghent

Lessons from Large Randomised Trials

Presenter Disclosure Information of Mattias Duytschaever

Biosense Webster Consultant

Medtronic Consultant

Sanofi Advisory Board

5

10

15

40 50 60 70 80Age (yrs)

Prevalence (%)

Framingham StudyMayo Clinic StudyCHSRotterdam Study

Prevalence and Incidence of AF

Epidemiology of Atrial Fibrillation

20

40

60

40 50 60 70 80Age (yrs)

Incidence/1000 person-years

Miyasaka et al, Circ 2006;114:119-125

Framingham Study (men)

CHS (men)

Mayo Clinic (men)

90

At 55y Life time risk for AF = 23.8%

Heeringa et al, EHJ 2006;27:949-953

17.8%

1 to 1.5%

Impact of Atrial Fibrillation on Stroke

• Yearly Risk of Stroke in Non-Yearly Risk of Stroke in Non-valvular AF is valvular AF is 5%5%

• AF is Associated with a AF is Associated with a 6-fold6-fold Increased Risk for StrokeIncreased Risk for Stroke

• Over Over 87% of strokes87% of strokes are are ThromboembolicThromboembolic

• 40%40% of Patients with AF have of Patients with AF have Silent Brain Infarction Silent Brain Infarction

• In Patients with AF there is In Patients with AF there is TwiceTwice as much Cognitive Dysfunction or as much Cognitive Dysfunction or DementiaDementia

• Strokes by AF are Strokes by AF are TwiceTwice as Fatal as Fatal or Disabling, and are more Likely or Disabling, and are more Likely to Recur compared to other causesto Recur compared to other causes

Miyasaka et al, European Heart J 2007;28:1962-1967

40

60

80

50 60 70 80

Age (yrs)

Incidence of Dementia/1000 person-years

90

20 General Men

Men with AF

Stroke Prevention in AF is a Pressing Health Concern

Impact of Atrial Fibrillation on Stroke

Marini et al , Stroke 2005

Stroke due to AF is more Severe

Mortality after Stroke (%)

60

0

25%

30 days After 1 year

14%

63%

34%

Stroke due to AF

Other Stroke

40

20

• Atrial Fibrillation and StrokeAtrial Fibrillation and Stroke– Risk Factors for Stroke in AFRisk Factors for Stroke in AF

– Warfarin and AspirinWarfarin and Aspirin

– Dual Antiplatelet StrategyDual Antiplatelet Strategy

• Novel Antithrombotic Strategies Novel Antithrombotic Strategies – Control of Risk FactorsControl of Risk Factors

– Non-pharmacological StrategiesNon-pharmacological Strategies

– New Oral Anti-thrombotic DrugsNew Oral Anti-thrombotic Drugs


Endothelial injury

Hypercoagulable state

Circulatory stasis

Virchow’s Triad*

Atrial Fibrillation on Stroke

Thrombosis*>90% of thrombus *>90% of thrombus

accumulation accumulation originates in the Left originates in the Left

Atrial Appendage Atrial Appendage (LAA)(LAA)

Risk Factors for Stroke in Non-valvular AF: CHADS Criteria

Fuster et al, Circulation 2006;114:257-354

Risk Factors for Stroke in Pts with Afib

1.92.8

4

5.9

8.5

12.5

18.2

0

5

10

15

20

0 1 2 3 4 5 6

C—CHF 1H—Hypertension 1A—Age >75 1D—Diabetes mellitus 1S2—TIA/stroke 2

Str

oke

rate

(%

per

yea

r)

n=120 n=463 n=523 n=337 n=220 n=65 n=5

CHADS2 score

Risk Factors for Stroke in Non-valvular AF: CHADS2 Score


•Overall Yearly Risk of Stroke in Non-valvular AF is Overall Yearly Risk of Stroke in Non-valvular AF is 5%5%


How to Improve Risk Stratification?

Fang et al, JACC 2008;51:810-5


CHADS2 criteria and other mild risk

factors (female, diastolic

dysfunction, LA dilatation, mild VHD, PAOD,

CAD, renal failure)

Is there a critical value of daily burden that raises stroke risk?

Glotzer et al, TRENDS Study, Circulation Arrhythmia Electrophysiol 2009;2:474

Zero burden 1.1%

burden Annual TE Rate (unadjusted)

Low burden <5.5hrs 1.1%

(0.8-1.6)

(0.4-2.8)

Hazard Ratio

0.98

High burden >5.5hrs 2.4% (1.2-4.5) 2.2

0.97

0.06

device detetecd AF/AT burden >5.5hrs on any day doubles the risk for TE

95% CI

P- value


• Atrial Fibrillation and StrokeAtrial Fibrillation and Stroke– Risk Factors for Stroke in AFRisk Factors for Stroke in AF







50%

AFASAK

SPAF

BAATAF

CAFA

SPINAF

Warfarin Better Warfarin Worse

EAFT

All Trials (6)

0 -50%

RR Reduction (95% CI)

Hart et al, Arch Intern Med 1999;131:492

Warfarin in Non-valvular AF Risk Patients (Pooled 1° RCT)

Antithrombotic Therapies in AF

•Relative Risk Reduction 68% (to placebo)

•Absolute Risk Reduction 3.1% per year

•Annual Rate of Major Bleeding 2%

•Annual Rate of ICH 0.3%


Cooper: Arch Int Med 166, 2006Cooper: Arch Int Med 166, 2006Lip: Thromb Res 118, 2006Lip: Thromb Res 118, 2006

• Assuming 51 ischemic strokes/1000 pt-yrAssuming 51 ischemic strokes/1000 pt-yr

• Adjusted standard dose warfarin prevented 28 Adjusted standard dose warfarin prevented 28

strokes at expense of 11 fatal bleedsstrokes at expense of 11 fatal bleeds

Net Clinical Benefit of Warfarin Anticoagulation in AF

• TEs prevented minus ICHs inducedTEs prevented minus ICHs induced

• (TE rate off warfarin – TE rate on warfarin) minus (TE rate off warfarin – TE rate on warfarin) minus 1.5 1.5

(ICH rate off warfarin – ICH rate on warfarin)(ICH rate off warfarin – ICH rate on warfarin)

Singer et al Annals of Int Med 2009;151:298-305

Net Clinical Benefit of Warfarin Anticoagulation in AF


50%

AFASAK (75mg)

SPAF I (325mg)

EAFT (300mg)

ESPS II

LASAF

Aspirin Better Aspirin Worse

UK-TIA

All Trials (6)

0 -50%

RR Reduction (95% CI)


JACC 2001;38(4):1-70

Aspirin in Non-valvular AF Risk Patients

•Relative Risk Reduction 21% (to placebo)

•Aspirin prevented 16 strokes at expense of 6 fatal bleeds

• Warfarin vs ASA: Relative Risk Reduction 41%

Antithrombotic Therapies in AFACC/AHA/ESC Practice Guidelines for the management of AF


(CHADS2 0)

(CHADS2 1)

(CHADS2 2 or more)

Warfarin Treatment in European Countries (Euro Heart Survey)

Despite the Guidelines:

•Over-utilisation (49%)

•Under-utilisation (33%)


% of Patients

Non Eligible (N=517)

Eligible (N=4736)

100

75

50

25

67%

49%

OAC

Nieuwlaat et al, Eur Heart J 2005;26:2422 (Euro Heart Survey)

OAC+ antiplatelet

antiplateletNo antithrombotic

• Warfarin is cornerstone of therapyWarfarin is cornerstone of therapy

• Anticoag at INR 2.0-3.0 very effective – generally safe

– moderately burdensome

• Aspirin is much less effective

• Under-utilisation of Warfarin:– Narrow therapeutic spectrum

– Need for monitoring (with 65% TTR to 50% real-life)

– Drug and Diet Interactions

– Study Pts vs Real World Pts (elderly, warfarin naieve)

Core Findings


• Atrial Fibrillation and StrokeAtrial Fibrillation and Stroke– Clinical Relevance of AF and Stroke Clinical Relevance of AF and Stroke







Rationale for dual antiplatelet therapy

Antiplatelet Therapies in AF

•Increased platelet activation in AF

•Aspirin reduces stroke in AF by 22%

•Addition of clopidogrel to aspirin achieves greater suppression of platelet activity

•Addition of clopidogrel to aspirin reduces vascuclar events in ACS with acceptable risk of bleeding

Dose-adjusted OAC (INR 2.0–3.0)

Clopidogrel (75 mg/d) + ASA (75–100 mg/day)

Clopidogrel (75 mg/day) + ASA (75–100 mg/day)

Placebo + ASA (75–100 mg/day)

Placebo

n = 14.500

ACTIVE W

ACTIVE A #

ACTIVE I

R

R

R

Patients Patients

with documented with documented AFAF

Irbesartan (150–300 mg/day)

Re-randomisation (if RRs >=110mmHg)Re-randomisation (if RRs >=110mmHg)

with 1:

•EF<45%

•AHT

•>75yrs

•Diabetes

•Stroke/TIA/emboli

•CAD

•PAOD Yusuf et al, ESC 2009

ACTIVE W and A Study


#patients with AF unable to receive VKAs

#Stopped after complete enrolment because of warfarin superiority; ‡Composite of stroke, non CNS embolism, MI and vascular death

Warfarin (INR 2.0–3.0) vs ASA (75–100 mg) + clopidogrel (75 mg)

Ann

ual i

ncid

ence

(%

)

RR 1.44

p=0.0003

RR 1.10

p=0.53

10

8

6

4

2

0

5.60

3.93

2.42 2.21

Primary endpoint‡ Major bleeding

Clopidogrel/ASA (n=3,335)

Warfarin (n=3,371)

Warfarin vs ASA+clopidogrel

Active W Study

ACTIVE Investigators, Lancet 2006;367:1903-1912

‡Composite of stroke, non CNS embolism, MI and vascular death

Ann

ual i

ncid

ence

(%

)

RR 0.89

p=0.01

RR 1.57

p<0.001

10

8

6

4

2

0

6.87.6

2.0

1.3

Connolly et al. N Engl J Med 2009

Primary endpoint‡ Major bleeding

Clopidogrel/ASA (n=3,772)

ASA (n=3,782)

ASA vs ASA+clopidogrel

Active A Study

ASA (75-100mg) vs ASA (75–100 mg) + clopidogrel (75 mg)

Apsirine and clopidogrel: 1000pts treated for 3 years will prevent 28 strokes at a

cost of 20 major bleeds

ACTIVE W and A Study: Stroke Rates

Antiplatelets vs Anticoagulants in AF

Active W (rate per year) 1.4%

Treatment VKA

Active A (rate per year) -

2.4%

A+C

2.4%

-

A

3.3%

ACTIVE W and A Study: Major Bleeding Rates

Active W (rate per year) 2.2%

Active A (rate per year) -

2.4%

2.0%

-

1.3%

• Warfarin is the treatment of choice for pts with AF at higher risk

• In pts unsuited for warfarin, addition of clopidogrel to ASA reduces stroke by 28%

• there is a risk of major haemorrhage

• Anticoagulation is the preferred mechanism to prevent stroke

Conclusion

Antiplatelets vs Anticoagulants in AF








Decreasing Stroke Rates on Warfarin in Large AF Trials in High Risk Patients

Connolly et al, Circulation 2007;116:449-455

SPAF III 1996

ACTIVE W 2006

Trial Year

SPORTIF V 2005

SPORTIF III 2003

61%

64%

Therapeutic INR

68%

66%

56%

23%

Warfarin at entry

84%

73%

1.9%

1.0%

Annual Ischemic Stroke Rate

1.1%

1.9%

0.5%

0.4%

Annual Hemorrh Stroke Rate

0.1%

0.4%

140

133

Syst BP (mmHg)

132

139

Indirect Antithrombotic Therapies in AF

Dose-adjusted OAC (INR 2.0–3.0)

Clopidogrel (75 mg/d) + ASA (75–100 mg/day)

Clopidogrel (75 mg/day) + ASA (75–100 mg/day)

Placebo + ASA (75–100 mg/day)

Placebo

n = 14.500

ACTIVE W

ACTIVE A

ACTIVE I

R

R

R

Patients Patients

with documented with documented AFAF

Irbesartan (150–300 mg/day)

Re-randomisation (if RRs >=110mmHg)Re-randomisation (if RRs >=110mmHg)

with 1:

•EF<45%

•AHT

•>75yrs

•Diabetes

•Stroke/TIA/emboli

•CAD

•PAOD

Effect of BP lowering by ARB on Vascular Events (ACTIVE-I)

Yusuf et al, ESC 2009

Indirect Antithrombotic Therapies in AF

Irbesartan in Atrial Fibrillation

Yusuf et al, ESC 2009

• Primary composite end point of stroke, MI, and cardiovascular death

• Treatment with ARBs reduced systolic and diastolic blood pressure 6.84 mm Hg and 4.51 mm Hg (vs 3.93 mm Hg and 2.63 mm Hg).

• No overall benefit in primary endpoint

• 14% reduction in heart-failure hospitalizations alone (secondary end point)

• More aggressive BP lowering???

Effect of ARB and BP Lowering on Vascular Events (ACTIVE-I)








Non Pharmacological StrategiesNon Pharmacological Strategies

Oral et al Circulation 2006;114:759

• Observational Cohort Study in 755 patients, 2 y FU, Stop A/C

• In 256 pts with successful ablation and no RF for stroke: no T.E.

• In 180 pts with successful ablation and >1 RF for stroke: no T.E.

• Observational Multic Study in 2436 patients, 31 m FU, Stop A/C

• In 1508 pts with successful ablation and no RF for stroke: 1 T.E.

• In 928 pts with successful ablation and >1 RF for stroke: no T.E.

Corrado et al Heart Rhythm 2007;abstract

Freedom of Stroke after Catheter Ablation for AF (PVI)

Freedom of Stroke after percutaneous closure of the LAA

WATCHMAN LAA Closure Device in situWATCHMAN LAA Closure Device in situ


PROTECT-AF, Lancet 2009;374:534-542

PROTECT-AF, Lancet 2009;374:534-542

Freedom of Stroke after percutaneous closure of the LAA









FondaparinuxIdraparinux

RivaroxabanApixabanEndoxaban

XimelagatranDabigatran

ORAL PARENTERAL

IIa (Thrombin)

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

Adapted from Weitz & Bates, J Thromb Haemost 2005

New Oral Antithrombotic TherapiesMany Targets for Novel Anticoagulants in The Coagulation Pathway

“Direct IIa” Inhibitors

“Direct Xa” Inhibitors

“Indirect Xa” Inhibitors

Xa

HOHO

NHNH

NNNNHH

OOOO NNHHOO

NHNH22

melagatranmelagatran

Oral precursor of Melagatran

Effective Direct Thrombin Inhibitor

No coagulation monitoring required

Fixed dosing and predictable response

Does not involve CYP450 system

Renal excretion

Dosing is fixed

Direct Oral FIIa InhibitorsXimelagatran: Key Characteristics

•Exantha (Astra Zeneca)

Annual Event Rate (%)

1

2

3

Warfarin Ximelagatran

Stroke and Systemic Embolism

2,31,6

Annual Event Rate (%)

1

2

3

Warfarin Ximelagatran

Major Bleeding

1,8 1,3

SPORTIF III Investigators, Lancet 2003;362:1691-1698

AF and >=1 RF

Warfarin INR 2-3 vs Ximelagatran 2*36mg

Open Label phase III N=3407 (non-inferiority)

Stroke Prevention in AF: SPORTIF III

Direct Oral FIIa Inhibitor: Ximelagatran

11 Oct 2004 … Ximelagatran failed to receive approval from the US Food and Drug Administration

But novel anticoagulants work!!

4-6%: raised transaminase levels

Few cases of fulminant hepatic failure

http://www.medicalnewstoday.com/youropinions.php?associatednewsid=14775

http://www.medicalnewstoday.com/voiceyouropinion.php?associatednewsid=14775

Is an oral pro-drug, rapidly converted to dabigatran

Inhibits both clot-bound and free thrombin

Fast onset and offset of action

Weak bioavailability ~6.5 %

Predictable and reproducible PK/PD*

No Need for Monitoring – Fixed dose

Half life 12-17 hours (twice daily)

Renal excretion ~80%

Is not metabolized by CYP450 and does not induce nor inhibit CYP450

leading to a low potential for drug interactions

•PK/PD = pharmacokinetics and pharmacodynamics

•Pradaxa (Boehringer Ingelheim)

Direct Oral FIIa InhibitorsDabigatran Etexilate: Key Characteristics

Non-valvular atrial fibrillation at moderateto high risk of stroke or systemic embolism

(at least one high risk factor)

R

Warfarin1 mg, 3mg, 5 mg

(INR 2.0-3.0)N=6000

Dabigatran Etexilate 110 mg b.i.d.

N=6000

Dabigatran Etexilate 150 mg b.i.d.

N=6000

•Primary objective: Noninferiority to warfarin •Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up.•Primary end point: Stroke + systemic embolism

Stroke Prevention in AF: RELY Study (St Jan Bruges)

Direct Oral FIIa Inhibitor: Dabigatran

18.113

Connolly et al. NEJM 2009

0.01

0.02

0.03

0.05

0.04

Cum

ulat

ive

haza

rd r

ates

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)

Years0 0.5 1.0 1.5 2.0 2.5

0.0

WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg

RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superiorWarfarin (TTR 64%)

Time to first stroke / SSE

RRR34%

Connolly et al. NEJM 2009

RR 0.66 (95% CI: 0.53–0.82)

p<0.001 (sup)

1,53

1,11

1,69

0

0,3

0,6

0,9

1,2

1,5

1,8

D110 mg BID D150 mg BID Warfarin

RR 0.91 (95% CI: 0.74–1.11)

p<0.001 (NI)

% p

er y

ear

182 / 6,015 134 / 6,076 199 / 6,022

RRR34%

Stroke or systemic embolism (SSE)

RR 0.26 (95% CI: 0.14–0.49)

p<0.001 (sup)

Hemorrhagic strokeRR 0.31 (95% CI: 0.17–0.56)

p<0.001 (sup)

Num

ber

of e

vent

s

6,015 6,076 6,022

1412

45

0

10

20

30

40

50

D110 mg BID D150 mg BID Warfarin

0.10%

0.38%RRR69%

RRR74%

0.12%

Still Room for Improvement?

Direct Oral FIIa Inhibitor: Dabigatran

Gage et al. NEJM 2009

Unblinded warfarin administration

NNT to prevent 1 NHS (1.2% to 0.9%): 357

Outcome with dabigatran TTR 79% (unlikely even

with self monitoring)

Myocardial infarction (D 0.72% vs W 0.5%/yr)

Dyspepsia and abdominal pain (D 11% vs W 6%)

Hepatic risks after longer Follow-up?

Drug interactions (verapamil, amiodarone, quinidine)

FondaparinuxIdraparinux

RivaroxabanApixabanEndoxaban

XimelagatranDabigatran

ORAL PARENTERAL

IIa (Thrombin)

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

Adapted from Weitz & Bates, J Thromb Haemost 2005

New Antithrombotic Therapies in AF

“Direct IIa” Inhibitors

“Direct Xa” Inhibitors

“Indirect Xa” Inhibitors

Xa

Many Targets for Novel Anticoagulants in The Coagulation Pathway

• Position of FXa in the coagulation Pathway

• Arixtra > LMWH > UFH

• Inhibition of thrombin might have deleterious consequences

• Larger therapeutic window with Xa inhibition

New Antithrombotic Therapies in AFRationale for FXa Inhibitors

• Direct, oral, specific, competitive FXa inhibitor

• Inhibits both clot-bound and free factor Xa

• Predictable and reproducible PK/PD*

• No coagulation monitoring required

• High oral bioavailability (80%)

• Half life 5-9 hours

• Renal and feces excretion

• Fixed dosing, irrespective of

– Age, gender, body weight,…

– Mild/moderate renal impairment

N NO

NH

O

SCl

O

O

O Rivaroxaban

N NO

NH

O

SCl

O

O

O Rivaroxaban

N NO

NH

O

SCl

O

O

O Rivaroxaban

Direct Oral FXa InhibitorsRivaroxaban: Key Characteristics

•Xarelto (Bayer)

Rivaroxaban Warfarin

Primary Efficacy Endpoint: Stroke or non-CNS Systemic EmbolismPrimary Safety Endpoint: CE of Major Bleeding and Clinically Relevant Bleeding

Statistics: non-inferiority, >95% power, 2.3% warfarin event rate

INR target - 2.5 (2.0-3.0 inclusive)

20 mg once daily15 mg for Cr Cl 30-49

Atrial Fibrillation

RandomizeDouble blind / Double Dummy

(n ~ 14,000)

Risk FactorsRisk Factors• CHF CHF • Hypertension Hypertension • Age Age 75 75 • Diabetes Diabetes OROR• Stroke, TIA or Systemic Stroke, TIA or Systemic

embolus embolus

At least 2 At least 2 requiredrequired

Direct Oral FXa Inhibitor: RivaroxabanStroke Prevention in AF: ROCKET AF

Finished recruitment N=15.000

Camm J.: Oral presentation at ESC on Aug 30th 2009.

Meta-analysis of ischaemic stroke or systemic embolism

W vs placebo

W vs W low dose

W vs ASA

W vs ASA + clopidogrel

W vs ximelagatran

W vs dabigatran 150

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

Favours warfarin Favours other treatment


• AF is a Growing Public Health Problem which Has Reached Epidemic Proportions

• Stroke Prevention is a Pressing Health Concern, with Warfarin being the Single Most Effective Treatment

• Many AF Patienst at risk for Stroke Will Benefit from Novel Anticoagulants

• Goals in 2010 and Beyond:

Breaking the Warfarin Barrier

Head-to-head Comparisons of FIIa and FXa Inhibitors

True cure for AF (Ablation, Maze)


• Atrial Fibrillation and StrokeAtrial Fibrillation and Stroke– EpidemiologyEpidemiology

– WarfarinWarfarin

– Antiplatelet StrategyAntiplatelet Strategy

• Novel Antithrombotic Strategies Novel Antithrombotic Strategies – Indirect Antithrombotic DrugsIndirect Antithrombotic Drugs

– New Antithrombotic DrugsNew Antithrombotic Drugs


Atrial Fibrillation and Stroke

Antistollingsbeleid bij VKFAntistollingsbeleid bij VKF

• InnovatieInnovatie door nieuwe orale door nieuwe orale antistollingsmiddelen bij VKF : nog wat antistollingsmiddelen bij VKF : nog wat geduld…geduld…

• Kwaliteitsbewaking van coumarines : een Kwaliteitsbewaking van coumarines : een absolute prioriteit !absolute prioriteit !

• Alertheid peri-operatief mbt antitrombotica ! Alertheid peri-operatief mbt antitrombotica !

Warfarin vs placebo 0.33 [0.24, 0.45]

Warfarin vs ASA 0.59 [0.40, 0.86]

Warfarin vs all FLD warfarin

0.36 [0.23, 0.58]

Warfarin vs ximelagatran 1.04 [0.77, 1.40]

RR (fixed) [95% Cl]

Favours adjusted warfarin Favours other treatment

13 trials reviewed (n=14,423)

AF, atrial fibrillation; ASA, acetylsalicylic acid; CI, confidence interval; FLD, fixed low dose

0.1 1 10 1000.01

Comparison

Meta-analysis of ischaemic stroke/systemic embolism with adjusted-dose oral anticoagulants in AF

Challenges of Antithrombotic AF Therapies

AF ++ ACS +++

Endothelial injury

Hypercoagulable state

Circulatory stasis

+++ = Strong association++ = Possible association, due to ischaemia or underlying inflammation state + = Weak association, if at all

AF ++ ACS ++

AF +++ ACS +

Virchow’s Triad*

Atrial Fibrillation on Stroke

Thrombosis*Greater than *Greater than

90% of thrombus 90% of thrombus accumulation accumulation

originates in the originates in the Left Atrial Left Atrial

Appendage (LAA)Appendage (LAA)

Time under Therapautic INR (TTR)


White et al, Arch Int Med 2007;167:239

Do the right ting, do the right thing right

Factor Xa–Factor Va complex is resistant to inhibition by

antithrombin

Factor Xa sensitive to AT inhibition

Factor Xa–Factor Va resistant to AT inhibition

Esmon Thromb Haemost 2008

Maintaining Sinus Rhythm and Stroke

Conventional Antiarrhythmic Drugs for AF

Wyse et al. NEJM 2002

4060 patients, FU 5 year

Paroxysmal or Recurrent Persistent Asymptomatic AF

> 65 yr or Other RF for Stroke or Death

Rhythm Control : cardioversion, antiarrhythmic drugs, Stop coumadin if SR

Rate Control : heart rate from 80/’ en 110/’ ; continued coumadin

EP: Cumulative Mortality

ACTIVE Investigators, Lancet 2006;367:1903-1912

Challenges of New Antithrombotic Therapies in AF (ACTIVE W)

Warfarin (INR 2-3) vs Asprin (75mg) +Clopidogrel (75mg)

CRT (3371/3335)

Primary Outcome

- stroke, non CNS embols, myocardial infarction, vascular death

Study was Stopped Early


1020304050607080

PIAF

RACESTAF

HOT CAFE

AFFIRM

*

AFFIRM

**

* Hypertension as a predominant cardiac diagnosis** Overall prevalence of hypertension

Patients with Hypertension (%)

Paroxysmal persistent

Recurrentpersistent

Recurrentpersistent

Recurrentpersistent



Camm AJ et al. Dialog in Cardiov Med 2003

Indirect Antithrombotic Therapies in AFPrevalence of Arterial Hypertension

Glotzer et al, Circulation, 2003;107:1614

Proportion of Patients with

AF

AHRE No AHRE

125

100

75

50

25AF

Relation Between AF Burden and Stroke

• Half of all hospitalizations for Arrhythmias

• 2- to 3-fold increased risk for Hospitalizations

• 1.6-fold increased risk for developing HF

• 3-fold increased risk for worsening HF

• 5- to 7-fold increased risk for Stroke

• 10-fold increased risk for Stroke in hypertrophic CMP

• 1.8-fold increased risk for Mortality in population

• 4.2-fold increased risk for CV Mortality in lone AF

• 2.5-fold increased risk for Mortality in HF

• 4.5-fold increased risk for Mortality in ACS

Atrial Fibrillation begets Trouble

Documents

Prospects for improving thrombosis management in atrial fibrillation