� Director of Cardiology Dept, Asklepeion General Hospital, Athens Greece.

� Adj. Ass. Professor, Hypertension Section, Boston University, MA, USA

� Adj. Professor of Medicine, Emory University, Atlanta, USA

Anticoagulation in Atrial Fibrillationand Hypertension

Athanasios J. Manolis MD, FACC, FESC, FAHA

AF is an increasingly common disorder

� The overall prevalence of AF is increasing, driven by:

� Ageing of populations worldwide

� Rising prevalence of chronic heart disease

� Rising prevalence of AF risk factors, e.g.

hypertension, obesity, diabetes mellitus

� Hospital admissions for AF have increased by 60%

over the past 20 years 2

1. Benyoucef S et al. Atrial fibrillation. 2008; av ailable at: http://www.decisionresources.com; accessed Feb 2010 ; 2. Friberg J et al.

Epidemiology 2003;14:666–72

What are the consequences of AF?

Over Time AF Causes Atrial Remodelling

�Contractile remodelling- Reduced atrial contractility- Sets the stage for thrombus

formation- May lead to atrial dilation

further altering electrophysiologic properties

- Occurs rapidly

�Structural remodelling- Histologic changes- Left atrium and left atrial

appendage enlargement- Decrease in cardiac output- Occurs after a period of

weeks to months

Shortened refractory

period

-80 mV

�Electrical remodelling- Shortening of atrial

refractory periods- Occurs rapidly (within

several days) and contributes to the increased stability of AF

Van Gelder et al. Europace 2006;8:943-949

AF is an Independent Risk Factor for Stroke

�AF patients have a near 5-fold increased risk of stroke 1

� 1 in every 6 strokes occurs in a patient with AF

� Ischemic stroke associated with AF is typically more severe than stroke due to other etiologies 3

� Stroke risk persists evenin asymptomatic AF 4

1. Wolf et al. Stroke 1991;22:983-9882. Fuster V et al. Circulation 2006;114:e257-e354 3. Dulli DA et al. Neuroepidemiology 2003;22:118-12 34. Page RL et al. Circulation 2003;107:1141-1145

CHA2DS2 VaSc Score and Annual Risk of StrokeRisk Factors Score

C Recent congestive heart failure 1

H Hypertension 1

A Age ≥ 75 y 2

D Diabetes mellitus 1

S History of stroke or transient ischemic attack 2

V Vascular disease (prior MI, PAD, or aortic plaque) 1

A Age 65-74 1

S Sex category (female sex) 1

CHADS2 Score

Str

oke

Rat

e %

20

15

10

5

0

1.92.8

4.0 5.98.5

12.5

18.2

1 2 30 4 5 6

Relationship between CHADS2 score and annual risk of stroke

Current Treatment Strategies for AF

�Prevention of

thrombo-embolism

�Rhythm control

�Rate control

ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006; 48:854-906

Camm AJ et al. Eur Heart J. 2010;31:2369-2429

Risk Category CHA 2DS2-VASc Score

Recommended Antithrombotic Therapy

1 ‘major’ risk factor or

≥ 2 ‘clinically relevant

nonmajor’ risk factors

≥ 2 OAC*

1 ‘clinically relevant

nonmajor’ risk factor

1 Either OAC* or aspirin75-325 mg daily.Preferred: OAC rather than aspirin

No risk factor 0 Either aspirin 75-325 mg daily or no antithrombotic therapy.Preferred: No antithrombotic therapy rather than aspirin.

*OACs such as a VKA, adjusted to an intensity range of INR 2.0-3.0 (target 2.5).New OAC drugs, which may be viable alternatives to a VKA, may ultimately be considered.

AF-related stroke is preventable

� 2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-K-antagonist (INR 2-3) 1

� Anticoagulation with a vitamin-K-antagonist (VKA) is recommended for patients with more than 1 moderate risk factor (age,HBP, CHF or LVD, Diabetes)

� A meta-analysis of 29 trials in 28,044 patients showed that adjusted-dose warfarin results in a reduction in ischaemic stroke and in all-cause mortality 1

Stroke Death

67% 26%

1. Hart RG et al. Ann Intern Med. 2007;146:857-867 2. Fuster V, et al. JACC. 2006; 48: 854-906

Effect of VKA compared to placebo

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

VKAs = vitamin K antagonists; ATRIA = Anticoagulati on and Risk Factors in Atrial Fibrillation

Management of AF in clinical practice:prescription of VKAs in eligible patients

n = 11 409ATRIA cohort (managed care system, California, USA) 3

n = 5333EuroHeart survey 2

n = 23 657Medicare cohort, USA 1

VKAs

No anticoagulation

Treatment received:64%

67%

55%

Underuse of oral anticoagulants in AF:A Systematic Review

Ogilvie I et al Am J Med 2010;123:638

� Underuse of oral anticoagulants for high-risk atria l fibrillation patients was found in most of the 54 studies (1998-2008) reporting both patient stroke risk and patients treated.

� Over two thirds of studies of atrial fibrillation p atients with prior stroke or transient ischemic attack repo rted treatment levels of under 60% of eligible patients.

� Most studies based on CHADS2 score reported oral anticoagulant treatment levels of high-risk subject s below 70%.

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

Therapeuticrange

1International normalized ratio

Odd

s ra

tio

2

15

8

10

5

01

3 4 5 6 7

20

Stroke

Intracranial bleed

VKAs = vitamin K antagonists

Gra

ph r

epro

duce

d w

ith p

erm

issi

on: ©

2010

Am

eric

an C

olle

ge o

f Che

st P

hysi

cian

s

VKAs have a narrow therapeutic window

Advantages and Diasadvantages of Current Antithrombotics

Advantages

�Used for many years

�Well studied/experience

�Effective if INR kept in therapeutic range

�Well known drug and food interactions

�Low cost

�Antidote/easy to recover

Disadvantages

�Erratic INR control / frequent monitoring

�Narrow therapeutic index�Medications adjustments

often required�Drug and food interactions�Risk of bleeding�Patients reluctance�Underuse in high risk

patients

Warfarin compared with Aspirin for stroke prevention in AF

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

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 f or homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haem orrhagic)

RRR 38%(95% CI: 18–52%)

Fig

ure

repr

oduc

ed w

ith p

erm

issi

on: ©

2007

, Am

eric

an

Col

lege

of P

hysi

cian

s

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

ACTIVE Investigators. Lancet 2006;151:1903–12

INR = 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: 1.24−2.37)

P=0.001

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

Stroke

Cum

ulat

ive

haza

rd r

ates

Years

0.05

00.00

0.5 1.0 1.5

0.04

0.03

0.02

0.01

Key features of a “new contender” in the prevention of CV events in AF

� Freedom from coagulation monitoring

� Simpler kinetic profile

� More rapid onset and offset

� Reduced or absent drug-drug and drug-food interactions

� More “user-friendly” than Warfarin

Targets for novel antithrombotic agents in the coagulation cascade1

AT= antithrombin; Ph = PhaseFibrin

IX

IXa

X

VIIIa

Thrombin

Fibrinogen

Direct Factor Xa inhibitors:Apixaban RivaroxabanEdoxaban 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

Apixaban

.

ROCKET

Rivaroxaban

RE-LYRELYABLE

Dabigatran

2009 2010 2011

AVERROES ARISTOTLE

Atrial Fibrillation Phase 3 Study Timelines

ENGAGE-AF TIMI 48

Edoxaban

RE-LY® – study design

Atrial fibrillation with ≥≥≥≥ 1 risk factorAbsence of contraindications

R

Warfarin1 mg, 3 mg, 5 mg

(INR 2.0-3.0)N=6000

Dabigatran etexilate

110 mg bidN=6000

Dabigatran etexilate

150 mg bidN=6000

� Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin

� Minimum 1 year follow-up, maximum of 3 years and m ean of 2 years of follow-up

Ezekowitz MD, et al. Am Heart J 2009;157:805-10Connolly SJ., et al. NEJM published online on Aug 3 0th 2009. DOI 10.1056/NEJMoa0905561

RE-LY Study: Time to first stroke / SSE

RR, relative risk; CI, confidence interval; NI, non -inferior; Sup, superiorConnolly SJ., et al. NEJM published online on Aug 3 0th 2009. DOI 10.1056/NEJMoa0905561

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

0.00

WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg

RRR34%

ROCKET AF Trial

Rivaroxaban

Primary Endpoint: Stroke or non-CNS systemic emboli smStatistics: non-inferiority, >95% power, 2.3% warfa rin event

rate

Atrial Fibrillation

RandomizeDouble blind / Double Dummy

(n ~ 14,000)

Risk Factors• CHF • Hypertension • Age ≥≥≥≥ 75 • Diabetes

OR• Stroke, TIA, or Systemic

embolus

At least 2 required

Monthly monitoring and adherence to standard of care guidelines

20 mg daily15 mg for Cr Cl 30-49

Warfarin

INR target - 2.5(2.0-3.0 inclusive)

Primary Efficacy OutcomeStroke and non -CNS Embolism

Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

0

1

2

3

4

5

6

0 120 240 360 480 600 720 840 960

No. at risk:Rivaroxaban 6958 6211 5786 5468 44 06 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cum

ulat

ive

even

t rat

e (%

)

Rivaroxaban

Rivaroxaban Warfarin

Event Rate

1.71 2.16

ARISTOTLE

APIXABAN Phase 3 Clinical Trial vs Warfarin to Prevent Stroke or Embolism in AF Pts

AF = atrial fibrillation; INR = international norma lized ratio.National Institutes of Health Clinical Trials.gov. www.clinicaltrials.gov/ct2/show/NCT00412984?term=ap ixaban&rank=4. Accessed January 16, 2008.

Apixaban 2.5 mg bid or 5 mg bid

Warfarin 2 mg qd, target INR 2.0-3.0

�Primary outcome measures: �Time to first occurrence of confirmed stroke or systemic

embolism�Time to major bleeding in treatment or follow-up

Patient characteristics

Ran

dom

izat

ion

≈≈≈≈ 1.8 years

• Aged ≥18 years

• Atrial fibrillation

• ≥1 additional risk factor for stroke

N=15,000

ARISTOTLE: Main Trial Results

21% RRR21% RRR 31% RRR31% RRR

ISTH major bleedingStroke or systemic embolism

Median TTR 66%

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P=0.011

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per yearHR 0.69 (95% CI, 0.60–0.80); P<0.001

Granger CB et al. N Engl J Med 2011; epub ahead of print, August 28

Apixaban(N=9120)

Warfarin(N=9081)

Outcome Event Rate%/yr

Event Rate%/yr

Hazard Ratio(95% CI)

P value

Primary outcome: stroke or systemic embolism

1.27 1.60 0.79 (0.66-0.95) .01

Stroke 1.19 1.51 0.79 (0.65-0.95) .01

Ischemic or uncertaintype of stroke

0.97 1.05 0.92 (0.74-1.13) .42

Hemorrhagic stroke 0.24 0.47 0.51 (0.35-0.75) <.001

Systemic embolism 0.09 0.10 0.87 (0.44-1.75) .70

Key secondary efficacyoutcome: death from any cause

3.52 3.94 0.89 (0.80-0.998)

.047

Conolly SJ et al. N Engl J Med 2010;364:806-816

Apixaban(N=2808)

Aspirin(N=2791)

HR with Apixaban

Outcome %/yr %/yr 95% CI P value

Stroke or systemic embolism

1.6 3.7 0.45 (0.32-0.62) <.001

Bleeding event

Major 1.4 1.2 1.13 (0.74-1.75) 0.57

Intracranial 0.4 0.4 0.85 (0.38-190) 0.69

Trials with new oral anticoagulants

Trial RELY ROCKET-AF ARISTOTLE

Drug used Dabigatran Vs Warfarin Rivaroxaban vs Warfa rin Apixaban vs Warfarin

Dose 150 or 110 mg BID

vs Warfarin (INR 2-3)

20 or 15mg QD

vs Warfarin (INR 2-3)

5mg BID vs Warfarin

(INR 2-3)

No. of Patients 18.113 14.000 18.201

Mean age (yrs) 71.5 73 70

Percentage of Hypertension

80% 90% 85%

Mean CHADS 2 Score 2.1 2.1 2.1

Conclusions: Dabigatran 110mg non-inferior to warfarin, with 20% less major bleedings Dabigatran 150 mg superior to warfarin with similar rate of major bleedings

Rivaroxaban non-inferior to warfarin on intention to treat analysis but superior in on treatment analysis Similar rate of major bleedings

Apixaban was superior to warfarin in the risk of stroke or systemic embolism, bleeding and all cause mortality

Approval FDA

Doses of 150 mg and 75mg

(if CI Cr 15-30 mL/min

FDA approved 9/11

EMA: under consideration

Manolis AJ et al. J Hypertens 2012

Bleeding Risk Assessment in AF:HAS-BLED Bleeding Risk Score

ClinicalCharacteristic* Points Awarded

H Hypertension 1

A Abnormal renal and liver function (1 point each )

1 or 2

S Stroke 1

B Bleeding 1

L Labile INRS 1

E Elderly 1

D Drugs or alcohol 1 or 2

Risk of bleeding >3

Letter

Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concetrate in Healthy Subjects

Circulation 2011 September 2011 on line

B

12.3%

0

5

10

15

20

R

15.8%

12.8%

PCP

Prothrombin time

B

92%

0

50

100

150

200

R

51%

114%

PCP

Endogenous thrombin

Position Paper of the ESH WG

“Hypertension, Arrhythmias and Thrombosis”

Manolis AJ et al. J Hypertens 2012

Box 3: AF and antithrombotic treatment

� VKAs have been proven effective for more than 50 years and are the standard anticoagulation treatment for AF. Howeve r they have disadvantages resulting in underutilization for different reasons.

� Patients with CHADS 2-VASc score >=1 should receive oral anticoagulation or aspirin treatment, although oral an ticoagulation is preferred. Since most hypertensive patients are over 65 years old, of which half of them are female and most of them have subclinical or clinical organ damage, it is concluded that they sh ould receive anticoagulation treatment.

Implementation of current guidelines in HTN patients with AF

200 ptsMean age 71 ± 12yrs

HTNTarget BP

72%

0

20%

40%

60%

80%

18%

48%

82%

50%

100%

CHAD2VASC2 >2 VKA INR 2-3DMTarget HbA 1C

Zamfir T. et al. ESH 2012 oral

Which Anticoagulant ?

WarfarinNew anticoagulants