Afrw core

Atrial Fibrillation Mechanismsand Management: Integrating Care for Better Outcomes

Contents

• The Cardiologist’s Perspective on AF Management• The Electrophysiologist’s Perspective on AF

Management• Case Presentation I: 65-Year-Old Man with Hypertension

and LVH• Case Presentation II: 72-Year-Old Woman with

Paroxysmal AF

The Cardiologist’s Perspective on AF Management

Managing patients with AF: The cardiologist’s perspective

AF can be present with, be affected by, and serve as a contributing factor in a wide range of CV conditions

As a marker of adverse outcomes, AF supports the need for prompt, aggressive management of all coexisting CV risk factors

Treatments directed at CV risk factors may also have beneficial effects on AF recurrence

AF is a complex disorder that is increasing in frequency

ATRIA: Prevalence of atrial fibrillation increases with age

<55 55-59 60-64 65-69 70-74 75-79 80-84 ≥85

Prevalence (%)

Age (years)

Go AS et al. JAMA. 2001;285:2370-5.

Men (n = 10,173)Women (n = 7801)

0

2

4

6

8

10

12

Total admissions/

year

Khairallah F et al. Am J Cardiol. 2004;94:500-4.

280,000

300,000

320,000

340,000

360,000

380,000

400,000

1996 1997 1998 1999 2000 2001

Increased ~34% over 6 years

Hospital admissions for AF have increased

ATRIA: AF projected to continue increasing

Adults with AF (millions)

7.0

2.1

5.65.45.2

4.84.3

3.83.3

2.92.72.42.3

6.0

5.0

3.0

4.0

2.0

1.0

01990 2000 2010 2020 2030 2040 2050

YearGo AS et al. JAMA. 2001;285:2370-5.

Projected numbers of adults with AF in the US, 1995 to 2050

CV conditions frequently associated with nonvalvular AF

• Hypertension • Obesity/metabolic syndrome/diabetes• Ischemic heart disease• Heart failure/diastolic dysfunction• Obstructive sleep apnea • Physical inactivity• Thyroid disease• Inflammation? Wattigney WA et al. Circulation. 2003.

Gersh BJ et al. Eur Heart J Suppl. 2005.Fuster V et al. J Am Coll Cardiol. 2006.

Mozaffarian D et al. Circulation. 2008.

Pathophysiology of AF and comorbiditiesInflammation?

• Left ventricular hypertrophy • Diastolic dysfunction

• Mitral regurgitation Atrial stretch

Inflammation?↑Stretch-activated channels↑Dispersion of refractoriness↑Pulmonary vein focal/discharges?

Increased vulnerability to AF?

↓Compliance

• HTN and/or vascular disease

Adapted from Gersh BJ et al. Eur Heart J Suppl. 2005;7(suppl C):C5-11.

VALUE: Impact of new-onset diabetes on development of AF

Aksnes TA et al. Am J Cardiol. 2008;101:634-8.

n = 5250 with DM at baseline n = 1298 initially nondiabetic patients developed DM during follow-up

N = 15,245 with hypertension at high risk

Proportion of patients with

1st event

0.04

0.03

0.02

0.01

00 500 1000 1500 2000

Time to persistent new-onset AF (days)

New-onset diabetes

Diabetesat baseline

No diabetes

Obstructive sleep apnea: Marker of incident AF

Gami AS et al. J Am Coll Cardiol. 2007;49:565-71.

N = 3542 undergoing diagnostic polysomnogram; mean follow-up 4.7 years

OSA = obstructive OSA = obstructive sleep apneasleep apnea

Cumulativefrequencyof AF (%)

0 2 4 6 8 10 12 14 15

OSA

No OSA0

5

10

15

20

1 3 5 7 9 11 13

Time (years)

High healthcare burden of AF

• 5 million office visits

• 234,000 outpatient department visits

• 276,000 emergency department visits

• 350,000 hospitalizations

• $6.65 billion in treatment costs

Coyne KS et al. Value Health. 2006;9:348-56.

Each year . . .

Impact on QoL: AF vs other CV illness

0

20

40

60

80

100

Physic

al fun

ction

Vitality

Genera

l hea

lthMen

tal hea

lthEmoti

onal

role

Social

functi

oning

General pop Recent MI AF HF

SF-36 scale*

*Higher numbers indicate higher QoL SF-36 = Medical Outcomes Study Short Form 36 Adapted from Dorian P et al. J Am Coll Cardiol. 2000;36:1303-9.

AF

AF AF

AF AFAF

Summary: AF burden

↑Prevalence

↑Hospitalizations

↑CV comorbidities

↑Economic costs

↓QoL

All contribute to ↑burden of disease

Possible “upstream” treatments and mechanisms for AF prevention

ACEIs/ARBs Statins Glucocorticoids Omega-3 fatty acids Physical activity

Courtesy of CJ Pepine, MD.

↓Inflammation ↓Oxidative stress ↓RAAS activity ↑Endothelial function

↓Autonomic nervous system activity↑Vascular stability ↓Atrial remodeling Stabilize left atrial endocardium

↓Atrial fibrillation

*Random-effects model

Trials of RAAS inhibition in AF prevention

Salehian O et al. Am Heart J. 2007;154:448-53. Healey JS et al. J Am Coll Cardiol. 2005;45:1832-9.

ACEIsCAPPGISSIHOPESOLVDSTOP-H2TRACEUengVan den Berg

Subtotal

ARBsCHARMLIFEMadridValHeFT

Subtotal

Total

RR* (95% CI)0.1 0.2 0.5 2.0 5.01.0

Favors treatment Favors control

CaptoprilLisinoprilRamiprilEnalaprilEnalaprilTrandolaprilEnalaprilLisinopril

CandesartanLosartanIrbesartanValsartan

Subtotal

Total

AF prevention with ACEI or ARB plus antiarrhythmic drug

Yin Y et al. Eur Heart J. 2006;27:1841-6.Time after randomization (days)

Amiodarone

Amiodarone + perindopril

Amiodarone + losartan

Group 1 vs 2: P = 0.006Group 1 vs 3: P = 0.04Group 2 vs 3: P = 0.47

N = 177 with lone paroxysmal AF

0 90 180 270 360 450 540 630 720 8100.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

AF recurrence-free survival

Group 1

Group 3

Group 2

Statins in prevention of AF (1st episode or AF recurrence)

Fauchier L et al. J Am Coll Cardiol. 2008;51:828-35.

Favors treatment Favors control

OR (random)95% CI

0.1 0.2 0.5 1 2 5 10

Study Statin Controlor subcategory n/N n/M

MIRACL 93/1539 96/1548Tveit 18/51 17/51Dernellis 14/40 36/40ARMYDA 3 35/101 56/99Chello 2/20 5/20Ozaydin 3/24 11/24

Total (95% CI) 1775 1782

Total events: 165 (Statin), 221 (Control)Test for heterogeneity: Chi2 = 29.47, df = 5 (P < 0.0001), I2 = 83.0%Test for overall effect: Z = 2.35 (P = 0.02)

Not assessed in this meta-analysis: • Degree of ↓LDL-C• Statin dose

Inflammation and AF: Methylprednisolone to prevent AF recurrence

Dorian P, Singh BN. Eur Heart J Suppl. 2008;10(suppl H):H11-31.

Primary endpoint

Glucocorticoid

Placebo

P < 0.001

Free

of r

ecur

rent

AF

1.0

0.8

0.6

0.4

0.2

0.00 8 16 24 32

hsCRP

40-90

PlaceboP = NS

GlucocorticoidP < 0.001

0 8 16 24 32

10

0

-10

-30

-50

-70

Cha

nge

from

bas

elin

e (%

)Time (months)

Free

of p

erm

anen

t AF

Expanded endpoint

1.0

0.8

0.6

0.4

0.2

0.0

Glucocorticoid

Placebo

P < 0.001

0 8 16 24 32 40

Omega-3 fatty acids in AF prevention: Conflicting results in clinical trials

No effectFish/PUFA consumption

N = 5184Mean age 67 yo

Population-based Prospective

cohort6.4-y mean FU

Rotterdam Study, 2006

No effect ?↑Risk for AF as

age and HTN increased

Fish consumptionN = 47,949Mean age 56 yo


cohort5.7-y mean FU

Danish Diet, Cancer and Health Study, 2005

Postop AF risk ↓65%P = 0.013

PUFAs ≥5 daysN = 160CABGMean age 65 yo

Randomized Open-label

Calo et al, 2005

AF risk:↓28% (1 vs 3)

P = 0.005↓31% (2 vs 3)

P = 0.008

Fish consumption1. 1-4x per week2. ≥5x per week3. <1x per month

N = 4815≥65 yo


cohort12-y FU

Cardiovascular Health Study, 2004

Main findingsInterventionPatientsDesignStudy, year

Adapted from Dorian P, Singh BN. Eur Heart J Suppl. 2008;10(suppl H):H11-31; Nodari S et al. Eur Heart J. 2006;27(suppl 1):887.

Nodari et al, 2005 Placebo-controlled N = 70Persistent AFCardioversionMean age 70 yo

PUFAs 1 g/d x 6 mos AF recurrence:13.3% (PUFA) vs 40% (placebo), P < 0.0001

Adjusted for age, gender, race, site, education, smoking (statusand pack-yrs), CHD, COPD, diabetes, alcohol use, beta-blocker use

Mozaffarian D et al. Circulation. 2008;118:800-7.

Cardiovascular Health Study: Risk of incident AF during 12-year follow-up

P trend < 0.001

Multivariable-adjusted RR of new-onset AF

1.2

1

0.8

0.6

0.4

0.2Q1 Q2 Q3 Q4

Combined distance and pace of usual walking (quartiles)

N = 5446 age ≥65 years

Summary and conclusions

• Complex disorder, increasing in frequency

• Cardiac functional/structural alterations related to AF may reflect “end stages” of CV diseases in general

• Early and aggressive pursuit of sinus rhythm may prevent clinical consequences of AF while improving QoL

• Therapies without primary antiarrhythmic properties seem to modify risk for and recurrence of AF

The Electrophysiologist’s Perspective on AF Management

Prognostic impact of AF

Sudden cardiac death (SCD)• AF is independent risk factor

for SCD among patients with structural heart disease (RR 1.20, P = 0.02) (AVID)1,2

Post-myocardial infarction mortality• Those with AF had ↑post-MI mortality

vs those without AF (RR 1.50, P < 0.001) (TRACE)3

Heart failure• Those with AF had significantly ↑mortality from HF progression vs those without AF (RR 1.95, P < 0.001) (SOLVD)4

1. AVID Investigators. N Engl J Med. 1997. 2. Wyse G et al. J Interv Card Electrophysiol. 2001.

3. Pedersen OD et al. Eur Heart J. 1999.4. Dries DL et al. J Am Coll Cardiol. 1998.

Atrial fibrillation: Framingham study

Wolf PA et al. Stroke. 1991;22:983-8.

50-59 0.5 6.5

60-69 1.8 8.5

70-79 4.8 18.8

80-89 8.8 30.7

StrokesAge AF prevalence attributable

(years) (%) to AF (%)

Severity of stroke with AF

• N = 1061 admitted with acute ischemic stroke– 20.2% had AF

• Bedridden state– With AF 41.2%– Without AF 23.7%

• Odds ratio for bedridden state following stroke due to AF = 2.23 (95% CI 1.87-2.59, P < 0.0005)

P < 0.0005

Dulli DA et al. Neuroepidemiology. 2003;22:118-23.

Arya A et al. Pacing Clin Electrophysiol. 2007;30:458-62.

AF: The more you look, the more you findEstimated correlation between follow-up technique and AF recurrence following catheter ablation

100%

Detection of AF

recurrences

*During 3-month follow-up†As the theoretical gold standard Tele = transtelephonic

Implanted device†

Daily Tele-ECG

7-day-ECG*

24-day-ECG*

Tele-ECG*

ECG*

Detection of recurrent AF

Israel CW et al. J Am Coll Cardiol. 2004;43:47-52.

Cumulative incidence

(%)

100

80

60

40

20

Baseline 1 3 6 12 18 4842363024

n = 110 110 110 110 85 73 1525394860

P < 0.0001

Implanted device

ECG

Device: AF detected in 88% of patientsECG: AF detected in 46% of patients

Time (months)

Electrocardiographic vs implanted device recording

Cumulative incidence of asymptomatic AF recurrence >48 hours*

*Not detected by serial ECG recordings during follow-up

110110

2020

1515

1010

55

BaselineBaseline 11 33 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

38% of patients with AF >48 hours were asymptomatic

Time (months)Time (months)Israel CW et al. J Am Coll Cardiol. 2004;43:47-52.


(%)

Anticoagulation for nonvalvular AF

*Compared with control 35 more minor bleeds occurred with warfarin Intention-to-treat analysis

Pooled data from AFASAK, SPAF, and BAATAF

Benefit Risk31 fewer thromboembolic events* 1 more intracranial or major bleed*

Adapted from Albers GW et al. Ann Neurol. 1991;30:511-8.

For every 1000 patients with nonvalvular AF in clinical trials treated with warfarin for 1 year:

Bleeding risk and age

• Categories– Minor: No costs or

consequences– Serious: Require testing

or treatment– Life-threatening/fatal

• Events (812)– 553 minor– 222 serious– 33 life-threatening– 4 fatal

Fihn SD et al. Ann Internal Med. 1996;124:970-9.Age not determinant of risk except possibly ≥80 years

N = 2376 receiving warfarin; Combined & retrospective cohort studies

0 1 2 3 4 5 6 7 8 9 18

Life-threatening or fatal bleedingReferent category

Serious bleedingReferent category

Minor bleedingReferent category

Adjusted relative risk (95% CI)

Age group(years)

<5050-5960-6970-79

>80

<5050-5960-6970-79

>80

<5050-5960-6970-79

>80

Survival following ischemic stroke: Warfarin vs aspirin*

Probability of survival

1.0

0.9

0.8

0.7

0.6

0.00 5 10 15 20 25 30

Time after admission (days)

P = 0.002†

Warfarin, INR ≥2Aspirin

Warfarin, INR <2

None

*Warfarin/aspirin therapy administered before or during stroke †Overall difference among groups Hylek EM et al. N Engl J Med. 2003;349:1019-26.

Noheria A et al. Arch Intern Med. 2008;168:581-6.

N = 432 with AF; Meta-analysis of 4 randomized clinical trials

Catheter ablation vs antiarrhythmic drug therapy for AF

ADT = antiarrhythmic drug therapy CPVA = circumferential pulmonary vein ablation

0.04 0.20 1.00 5.00 25.00

CPVA more effective

ADT more effective

Risk ratio

Risk ratio(95% CI) % WeightSource

Pappone et al, 2006 3.86 (2.65-5.63) 37.5

Stabile et al, 2006 6.43 (2.91-14.21) 18.1

Wazni et al, 2005 4.22 (2.14-8.32) 22.0

Krittayaphong et al, 2003 2.00 (1.02-3.91) 22.4

Overall (95% CI) 3.73 (2.47-5.63)

A4 study: Catheter ablation vs antiarrhythmic drug therapy for AF

Jaïs P et al. Circulation. 2008;118:2498-505.

N = 112 with paroxysmal AF resistant to ≥1 AAD

ADT

RF = radiofrequency catheter ablation

Follow-up (days)200 250 300 350 400150100500

0.0

20.0

Freedom from

recurrent AF (%) 40.0

60.0

80.0

100.0

Logrank P < 0.0001

RF

Worldwide survey of catheter ablation

• 12,830 procedures, with 27% of patients undergoing >1 procedure

• 6% major complication rate– 4 deaths (0.05%)– 107 tamponade (1.22%)– 20 strokes (0.28%)– 47 TIA (0.66%)– 94 PV stenosis (1.3%)

Cappato R et al. Circulation. 2005;111:1100-5.

N = 8745 with AF treated at 90 centers

US experience with catheter ablation

• 641 procedures

• 32 major complications (5%)– 7 CVA (1.1%)– 8 cardiac tamponade (1.2%)– 1 PV occlusion (0.16%)– 11 vascular injury (1.7%) – No deaths or esophageal injury

• Complication rate 9% 1st 100 patients, 4% thereafter

• Predictors of complications– Female gender– Age >70 years

Spragg DD et al. J Cardiovasc Electrophysiol. 2008;19:627-31.

N = 517 with AF undergoing catheter ablation treated at 1 US institution

No (or minimal)heart disease

Amiodarone Dofetilide

HFCADHypertension

AmiodaroneFlecainidePropafenone

Sotalol

Yes

Maintenance of SR

Substantial LVH

No

FlecainidePropafenone

Sotalol

Catheterablation

Amiodarone Dofetilide

Catheterablation

Catheterablation

Amiodarone Catheterablation

DofetilideSotalol

AmiodaroneDofetilide

Catheterablation

Fuster V et al. Circulation. 2006;114:e257-e354.

ACC/AHA/ESC 2006 AF rhythm-control guidelines

HRS/EHRA/ECAS Expert Consensus Statement: Indications for catheter ablation of AF

• Indications– Symptomatic AF refractory or intolerant to ≥1 Class 1 or 3

antiarrhythmic drug– Selected symptomatic patients with HF and/or ↓EF

• Should not be considered as 1st line therapy, except in rare clinical situations

• Repeat procedures should be delayed for ≥3 months, if symptoms can be controlled with medical therapy

Calkins H et al. Heart Rhythm. 2007;4:816-61.

Morbidity with AF following CABG

<0.0126Minor (%) <0.0127Major (%)

Neurologic injury 0.0458Renal failure (%)0.01710CHF (%)

<0.0110.212.8Post-op LOS (days)1648617N

PWithout AFWith AF

Mathew JP et al. JAMA 1996;276:300-6.

MultiCenter Study of Perioperative Ischemia; Prospective, observational study

LOS = length of stay

Summary and conclusions

• AF is not benign

• Assess treatment efficacy by reduction in arrhythmia burden, not merely reduction in symptoms

• Anticoagulation may be considered in the elderly

• Ablation should generally be considered only after a trial of antiarrhythmic drug therapy

• Postoperative AF should be treated

Case Presentation:65-Year-Old-Man with Hypertension and LVH

Are rate and rhythm control mutually exclusive?

65-Year-old man

• History of hypertension for 23 years• Negative history for dyslipidemia or diabetes• Develops AF with severe symptoms despite

treatment with beta-blockers• Referred by PCP for further management of

his AF and assessment of CV risk• BMI: 27 kg/m2

• BP: 155/98 mm Hg both arms • Peripheral pulses

– R: DP and PT 2+– L: DP1 and PT 0

• ECG: AF at ~98/min• Cr: 1.3 mg/dL; eGFR: 48 mL/min per 1.73 m2

65-Year-old man: Echocardiography

Courtesy of AP Selwyn, MD.

E’A’

Courtesy of AP Selwyn, MD.

65-Year-old man: Doppler imaging

Primary care preferences: Rate vs rhythm control as optimal strategy for AF

60

2218

0

20

40

60

80

Respondents(%)

McCabe JM et al. Am J Cardiol. 2009;103:535-9.

Rate control* Rhythm control† Strategies are equal

N = 148 PCPs from 36 US states

*With anticoagulation †With or without anticoagulation

AFFIRM Investigators. N Engl J Med. 2002;347:1825-33.

AFFIRM: Primary outcome

• N = 4060 with AF– Age ≥65 years or ≥1 risk

factor for stroke or death– 1st AF episode: 36%– No contraindications for

warfarin

• Follow-up 3.5 years

• Predominant diagnosis Hypertension 51%, CAD 26%

• n = 2033 rhythm control

• n = 2027 rate control

0 1 2 3 4 5Time (years)

05

1015202530

Cum

ulat

ive

mor

talit

y (%

)

P = 0.08

Rhythm control

Rate control

Paroxysmal Persistent

Newly discovered AF

Accept permanent AF

Rate control and anticoagulation

as needed


ACC/AHA/ESC 2006 AF guidelines

Consider antiarrhythmic

therapy

Cardioversion

Long-term antiarrhythmic drug therapy unnecessary

Rate control and anticoagulation

as needed

No therapy needed unless

significant symptoms

Anticoagulation as needed

Antiarrhythmic drugsNew and old

New Class III agents Novel drugs

Dofetilide Azimilide

DronedaroneTedisamil Adenosineagonist

Connexinmodulators

5-HT4 antagonist

SAC blockers

ARDAs

Na+/Ca2+

inhibitor

Na+/H+

inhibitor

Upstream therapies

Amiodarone

Sotalol

ClassIII

Propafenone

Flecainide

ClassIC

Multi-channel blockers Celivarone

Antiarrhythmic medical therapies

Courtesy of J Camm, MD.

Dronedarone

• Amiodarone-like compound lacking the iodine moiety

• Similar electrophysiologic properties to amiodarone

• Side effects are minor, generally GI, and infrequent

• No evidence of thyroid or pulmonary toxicity

• 24-hour half-life

• Treatment may be initiated in outpatient setting

Wegener FT et al. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S17-S20.

EURIDIS, ADONIS: Primary endpoint

Dronedarone 400 mg bidPlacebo

EURIDIS ADONIS

Singh BN et al. N Engl J Med. 2007;357:987-99.


0 60 120 180 240 300 360

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Time (days)

P = 0.01

P = 0.002

0 60 120 180 240 300 360

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

First recurrence of AF/AFL

ERATO: Dronedarone added to rate-lowering drugs

-11.7

-14.9

-11.5

-5.1

-16

-12

-8

-4

0

Mean change (bpm)

Davy J-M et al. Am Heart J. 2008;156:527.e1-9.

All patients Beta-blockers DigoxinCalcium

antagonists

P < 0.0001

P < 0.0001

P < 0.0001

P = 0.10

Mean 24-hour Holter heart rate

ATHENA: Time to primary outcomeN = 4628 ≥75 yrs with AF or 70-74 yrs with AF + ≥1 CV risk factor

0

25

50

75

100

0 6 12 18 24 30

Cumulative incidence (%)

HR 0.76 (0.69-0.84)P < 0.001

Time (months)

Placebo Dronedarone

Primary outcome: First hospitalization due to CV events or death; Mean follow-up 21 ± 5 months Hohnloser SH et al. N Engl J Med. 2009;360:668-78.

ATHENA: All-cause mortality

Hohnloser SH et al. N Engl J Med. 2009;360:668-78.

HR 0.84 (0.66-1.08)P = 0.18

0

24

50

75

100

0 6 12 18 24 30


Time (months)

Placebo Dronedarone

10.0

7.5

5.0

2.5

0.00 6 12 18 24 30

Placebo

Dronedarone

ATHENA: CV mortality


HR 0.71 (0.51-0.98)P = 0.03

0

24

50

75

100

0 6 12 18 24 30


Time (months)

Placebo Dronedarone

0 6 12 18 24 300.0

2.5

5.0

7.5Placebo

Dronedarone

ATHENA: CV hospitalization


HR 0.74 (0.67-0.82)P < 0.001

0

24

50

75

100

0 6 12 18 24 30


Time (months)

Placebo Dronedarone

ATHENA: Primary outcome according to selected baseline characteristics

Hohnloser SH et al. N Engl J Med. 2009;360:668-78.*Not prespecified

0.1 1.0 10.0Hazard ratio (95% CI)

Dronedaronebetter

Placebobetter

Patients(no./total no.)Characteristic*

Age<75 yr 942/2703≥75 yr 709/1925

GenderMale 850/2459Female 801/2169

Presence of atrial fibrillation or flutterYes 396/1155No 1255/3473

Structural heart diseaseYes 1115/2732No 524/1853

Any congestive HFYes 603/1365No 1048/3263

LVEF<35% 86/17935 to <45% 145/361≥45% 1387/4004

Use of ACEI or ARBYes 1175/3216No 476/1412

Use of beta-blockerYes 1226/3269No 425/1359

ATHENA post hoc analysis: Stroke reduction

Connolly SJ. Circulation. 2009;120:1174-80.

HR 0.66 (95% CI 0.46-0.96)P = 0.027 Placebo

(n = 70, annual rate = 1.8%)

Dronedarone(n = 46, annual rate = 1.2%)


Months

0 6 12 18 24 30

5

4

3

2

1

0

ATHENA post hoc analysis: Reduction in stroke, ACS, or CV death

Connolly SJ. Circulation. 2009;120:1174-80.

HR 0.68 (95% CI 0.55-0.84)P < 0.001 Placebo

(n = 216, annual rate = 5.5%)

Dronedarone(n = 147, annual rate = 3.8%)


Months

0 6 12 18 24 30

15

10

5

0

Atrial-selective drugs

• Effect on IKur (KV 1.5) or INa currents

• Theoretical selective atrial effect

• Will likely see ventricular effects at highest concentrations

Savelieva I, Camm J. Europace. 2008;10:647-65.

Vernakalant (RSD1235)

• Unique ion channel-blocking profile– Frequency- and voltage-dependent INa block– Early activating K+ channel block – Blocks IKACh

• Rate-enhanced activity on conduction

• Atrial-selective APD/ERP prolongation

• Activity confirmed in several species

• No adverse hemodynamic effects

• Novel aminocyclohexyl ether drug

Beatch GN et al. Circulation. 2003;108(suppl IV):IV-85.

Conversion to sinus rhythm with IV vernakalant in patients who experienced AF for <7 days

0

10

20

30

40

50

60

Placebo Vernakalant

ACT I (n = 220)*

ACT II(N = 150)

ACT III(n = 170)*

ACT IV†

(n = 170)*

Patients(%)

Savelieva I, Camm J. Europace. 2008;10:647-65.*Subgroup analysis; †Not placebo-controlled

Antiarrhythmic drugs

PropafenoneFlecainideSotalolAmiodaroneDofetilideDisopyramideQuinidineProcainamideNew drugs

AF

Beta-blocker + DigoxinCa channel blocker + DigoxinAV node ablation+ Pacer

Surgery

Pulmonary veinsLA linear lesionsRA linear lesions

Focal lesions

Maze procedure

Catheter ablation

DC or chemical cardioversion to reestablish SR as needed

Anticoagulation for all patients with risk factors for stroke

AF treatment strategies

Anticoagulation for all patients with risk factors for stroke

Atrial defibrillator

Rate control Rhythm control

Courtesy of KA Ellenbogen, MD.

Clinical pearls

• Rate and rhythm control are not mutually exclusive strategies

• Rhythm control has a role in highly symptomatic patients

• Since many AF episodes are asymptomatic, symptom-guided treatment will result in suboptimal control of the arrhythmia

• Therapy should be directed at reducing AF burden– New agents with potentially improved safety profiles are under

investigation

• Attention should also be paid to reducing global cardiovascular risk

Courtesy of AE Epstein, MD and AP Selwyn, MD.

Case Presentation: 72-Year-Old Woman with Paroxysmal AF

Meeting the challenge of effective anticoagulation

72-Year-old woman

• Paroxysmal AF for 5 years– Events have lasted 8-23 hours and have occurred every

3-5 months– Episodes are minimally symptomatic and tolerable on

rate-control therapy

• History of hypertension, controlled on diet and medications

• No history of diabetes, heart failure, or embolic events

• No history of heart murmur or bleeding disorder

Diagnostic studies

• Echocardiogram– Normal LV and RV size and function; normal LA and RA size; no significant valvular

disorders. LV wall thickness 1.0 cm

• Chest x-ray– Normal heart size, clear lung fields

• Blood studies– CBC, chemistry profile, lipid profile, TSH, Mg all within normal limits

ECG rhythm strip ECG rhythm strip during an episodeduring an episode

Courtesy of JA Reiffel, MD.

CHADS2 risk stratification scheme

Prior stroke or TIA

Diabetes mellitus

Age ≥75 years

Hypertension

Congestive heart failure

2S2

CHADS2 risk criteria ScoreC 1

H 1

A 1

D 1


Warfarin risk/benefit balance

Odds ratio

20

15

10

5

1

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

International normalized ratio

Ischemic stroke Intracranial bleeding


Misconceptions about rhythm-control strategy

55

64

73

0

20

40

60

80

Respondents(%)

McCabe JM et al. Am J Cardiol. 2009;103:535-9.

Helps avoid long-term

anticoagulation

Decreases mortality

Decreases stroke

N = 148 PCPs from 36 US states

Rate control n (%)

Rhythm control n (%)

Ischemic stroke 77 (5.5)* 80 (7.1)*

INR 2.0 25 19INR <2.0 27 17

Not taking warfarin 25 44AF at time of event 42 25

Regardless of treatment strategy, majority of strokes occurred in patients with subtherapeutic INR or not taking warfarin

However, some strokes occurred despite therapeutic INR and sinus rhythm

N = 4060 with AF and ≥65 years or with additional stroke risk factors

AFFIRM Investigators. N Engl J Med. 2002;347:1825-33.

AFFIRM: Incidence of stroke and anticoagulation status at time of stroke

*Percentages derived from Kaplan-Meier analysis

Inadequate warfarin treatment in patients with AF

65%: No warfarin

4%: INR above target 26%: INR

within target

5%: INR below target

Samsa GP et al. Arch Intern Med. 2000;160:967-73.

N = 660 with AF in primary care practices

Adequacy of anticoagulation

• Even with intentions to follow the guidelines, and with patient cooperation, effective anticoagulation is erratic at best

• INR often deviates outside of the therapeutic range– Dietary fluctuations– Changes in bowel flora– Interactions– Formulation substitution– Lab errors– Other

• Time that INR is in therapeutic range is variable … even when patients are managed carefully


Why patients do not like warfarin

• Concerns about bleeding• Inconvenience and costs of prothrombin time testing

– Home check units not yet in widespread use

– Physicians still have doubts about accuracy of home testing methods, which are conveyed to patients

• Dietary interactions• Drug interactions (including OTCs and herbals)• Concerns about travel• Concerns about procedures (eg, dental)


Proposed algorithm for warfarin initiation in elderly patients

Measure INR daily and omit dose until INR <2.5, then give 1 mg

INR ≥2.51†1.9 ≤ INR < 2.52†1.7 ≤ INR < 1.93†1.5 ≤ INR < 1.74†1.3 ≤ INR < 1.55†<1.3Day 34Do not measureDay 24Do not measureDay 14Do not measureDay 0

Warfarin dose (mg)*INR value at 10 AM

Siguret V et al. Am J Med. 2005;118:137-42.

*Given at 6 PM †Predicted maintenance dose Elderly: ≥70 years

Make the regimen as easy as possible for your patients and yourself

• Try to use 1 size tablet

• Try to link varying doses to days of week (ie, MWF, TTSS) or to odd/even days on calendar

• Remember drug interactions and their time course when you change any other therapy

• Remember to tell patient to contact you if there are any changes in concomitant medications by another physician, OTC agents, or GI status (eg, bowel prep, gastroenteritis)

• Give patient list of Vit K-containing foods and instruct to keep diet constant

• Give patient Vit K Rx to keep for emergenciesCourtesy of JA Reiffel, MD.

Other important considerations with warfarin

• What dose should be used to initiate it?

• Do you use genetic pattern testing?

• When might you need to cover the period of initiation with LMWH or ASA?

• What regimen do you use when warfarin has to be held for a procedure and how do you reinitiate it?

• How often do you check the INR?

• Do you use home INR monitoring?

• What do you do if the patient is also taking ASA and clopidogrel?


Coagulation cascade

Brass LF. Chest. 2003;124(suppl):18S-25S.Mann KG. Chest. 2003;124(suppl):4S-10S.Nesheim M. Chest. 2003;124(suppl):33S-39S.

Thrombin Inhibitors

Intrinsic system

XII XIIa

XI XIa

XI XIa + VIIIa

Extrinsic system

XII VIIa + Tissue factor

X Xa + Va

Prothrombin Thrombin

Fibrinogen Fibrin

Stable fibrin clotXIIIaXIII

Factor Xa Inhibitors

Future directions in anticoagulant therapy

• Indirect Factor Xa inhibitors– Idraparinux (BOREALIS-AF)

• Direct Factor Xa inhibitors– YM150 (ONYX-2)– Apixaban (ARISTOTLE)– Betrixaban (EXPERT)– Rivaroxaban (ROCKET AF)

• Alternative DTIs – Dabigatran (RE-LY)

• Indirect thrombin inhibitors (eg, odiparcil)

Courtesy of JA Reiffel, MD and PR Kowey, MD.

Rivaroxaban

• Factor Xa inhibitor with once-daily dosing

• Superior to enoxaparin in preventing VTE after knee replacement surgery and THA (Phase III studies–the RECORD trials) and effective in preventing DVT and PE after other orthopedic surgery (Phase IIb trials)

• No “liver signal” in VTE trials

• No significant drug interactions

• Excess bleeding in early trials with doses ≥30 mg/d

• Approved for marketing for VTE in the European Union in 2008

• Being studied for stroke prevention in AF and for ACS


Apixaban

• Direct Xa inhibitor (follow-up to razaxaban, halted due to excess bleeding)

• BID dosing• Under development for VTE prevention, VTE treatment,

and stroke prevention in AF – AVERROES being conducted in patients who failed or are

unsuitable for vitamin K therapy

• ACS trial (APPRAISE-1) showed increased risk of bleeding and only a trend towards increased efficacy when added to ASA or clopidogrel


Dabigatran

• Direct thrombin inhibitor

• Active moiety of the prodrug dabigatran etexilate

• Onset of action <1 hr; T ½ 12-15 hrs; no food interaction

• Renally excreted (80%), the rest biliary

• Dialyzable

• Increases aPTT, PT, TT, ECT but these are not used to monitor therapy– ECT and TT are sensitive to dabigatran effect

• Being developed for VTE prevention, VTE treatment, and AF


PETRO: Dabigatran in AF phase II clinical trial

Ezekowitz MD et al. Am J Cardiol. 2007;100:1419-26.

N = 502 with AF, treatment duration 12 weeks

ALT >3x ULN in 0.9% of patients

04 (5.7%)0070Warfarin (INR 2-3)

06 (20%)3 (10%)32530300

05 (14.7%)1 (2.9%)8134300

06 (5.7%)00105300

02 (6.1%)032533150

02 (5.6%)08136150

09 (9%)00100150

01 (3.7%)03252750

1 (4.8%)1 (4.8%)0812150

1 (1.7%)0005950TE events

Relevant bleed

Major bleedASA (mg)n

Dabigatran dose(mg, twice daily)

Design of RE-LY: A non-inferiority trial

R

Warfarin(Adjusted INR

2.0-3.0)n = 6022

Dabigatran etexilate

110 mg bidn = 6015

Dabigatran etexilate

150 mg bidn = 6076

Blinded event adjudication

Blinded

Follow up: 1-yr minimum, 2-yr median, 3-yr maximum

Atrial fibrillation 1 Stroke risk factors

Absence of contraindications

Open

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

Randomized Evaluation of Long-Term Anticoagulation Therapy

Primary outcome: Stroke or systemic embolism

RE-LY: Stroke or systemic embolism

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs warfarin


P for non-inferiority

<0.001

<0.001

P for superiority

0.34

<0.001

Non-inferiority margin = 1.46

HR (95% CI)

Warfarin better

Dabigatranbetter

Primary outcome


RE-LY: Stroke or systemic embolism


↓34% P < 0.001

Dabigatran 150Dabigatran 110Warfarin

Months18 24 301260

0.0

0.2

0.4

0.6

0.8

1.0 0.05

0.04

0.03

0.02

0.01

0.000 6 12 18 24 30

Cumulative hazard rate

RE-LY: MI, hospitalization, death

Dabigatran 110

Dabigatran 150 Warfarin



Annual rate (%)

Annual rate (%)

Annual rate (%)

RR(95% CI) P

RR(95% CI) P

Myocardial infarction

0.72 0.74 0.53 1.35(0.98-1.87)

0.07 1.38(1.00-1.91)

0.048

Hospitalization 19.4 20.2 20.8 0.92(0.87-0.97)

0.003 0.97(0.92-1.03)

0.34

Death 3.75 3.64 4.13 0.91(0.80-1.03)

0.13 0.88(0.77-1.00)

0.051


Dabigatran 110

Dabigatran 150 Warfarin



Annual rate (%)

Annual rate (%)

Annual rate (%)

RR(95% CI) P

RR(95% CI) P

Major bleeding

2.71 3.11 3.36 0.80(0.69-0.93)

0.003 0.93(0.81-1.07)

0.31

Minor bleeding

13.16 14.84 16.37 0.79(0.74-0.84)

<0.001 0.91(0.85-0.97)

0.005

Net clinical benefit*

7.09 6.91 7.64 0.92(0.84-1.02)

0.10 0.91(0.82-1.00)

0.04

*Composite of stroke, systemic embolism, pulmonary embolism, MI, death, or major bleeding

RE-LY: Bleeding and net clinical benefit


RE-LY: Liver function test abnormalities

n (%)n (%)n (%)

Dabigatran 110 Dabigatran 150 Warfarin

ALT or AST >3x ULN 124 (2.1) 117 (1.9) 132 (2.2)

ALT or AST >3x ULN with concurrent bilirubin >2x ULN(Potential Hy’s Law case)

13 (0.2) 13 (0.2) 21 (0.3)

ALT = alanine aminotransferaseAST = aspartate aminotransferaseULN = upper limit of normal Connolly SJ et al. N Engl J Med. 2009;361:1139-51.

Clinical pearls

• Minimum burden of AF that can promote atrial clot is uncertain

• AF patients with high-risk markers for thromboembolism should receive anticoagulation, in the absence of a clear contraindication

• Based on recent clinical trials, anticoagulation in such patients should be continued regardless of whether (and how) sinus rhythmis restored

• Improved physician and patient education and compliance is required to maximize efficacy and safety of anticoagulation

• New alternatives to warfarin appear to be on the horizon; they appear likely to be easier to use and are eagerly awaited


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