2. 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
4. Managing patients with AF: The cardiologist’s
perspective
AF is a complex disorder that is increasing in frequency
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
5. ATRIA: Prevalence of atrial fibrillation increases
with age
12
10
8
Prevalence
6
(%)
4
2
0
<55 55-59 60-64 65-69 70-74 75-79 80-84 ≥85
Age (years)
Women (n = 7801) Men (n = 10,173)
Go AS et al. JAMA. 2001;285:2370-5.
6. Hospital admissions for AF have increased
400,000
380,000
Increased ~34% over 6 years
360,000
Total
admissions/ 340,000
year
320,000
300,000
280,000
1996 1997 1998 1999 2000 2001
Khairallah F et al. Am J Cardiol. 2004;94:500-4.
7. ATRIA: AF projected to continue increasing
Projected numbers of adults with AF in the US, 1995 to 2050
7.0
6.0
5.4 5.6
5.0
5.2
4.8
4.0 4.3
Adults with 3.8
AF (millions)
3.0 3.3
2.9
2.4 2.7
2.0 2.3
2.1
1.0
0
1990 2000 2010 2020 2030 2040 2050
Year
Go AS et al. JAMA. 2001;285:2370-5.
8. 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.
9. Pathophysiology of AF and comorbidities
Inflammation?
• HTN and/or
vascular disease
↓Compliance
• Mitral regurgitation • Left ventricular hypertrophy
Atrial stretch
• Diastolic dysfunction
↑Stretch-activated channels Inflammation?
↑Dispersion of refractoriness
↑Pulmonary vein focal/discharges?
Increased vulnerability to AF?
Adapted from Gersh BJ et al. Eur Heart J Suppl. 2005;7(suppl C):C5-11.
10. VALUE: Impact of new-onset diabetes on
development of AF
N = 15,245 with hypertension at high risk
New-onset
0.04 diabetes
0.03
Proportion of Diabetes
patients with 0.02 at baseline
1st event
No diabetes
0.01
0
0 500 1000 1500 2000
Time to persistent new-onset AF (days)
n = 5250 with DM at baseline Aksnes TA et al. Am J Cardiol.
n = 1298 initially nondiabetic patients developed DM during follow-up 2008;101:634-8.
11. Obstructive sleep apnea: Marker of incident AF
N = 3542 undergoing diagnostic polysomnogram; mean follow-up 4.7 years
20
15
Cumulative OSA
frequency 10
of AF (%)
5
No OSA
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (years)
OSA = obstructive sleep apnea Gami AS et al. J Am Coll Cardiol. 2007;49:565-71.
12. High healthcare burden of AF
Each year . . .
• 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.
13. Impact on QoL: AF vs other CV illness
100
AF AF
AF AF
80
AF
AF
SF-36 60
scale*
40
20
0
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n
ng
lth
e
th
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al
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ra
io
ta
al
en
e
ot
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en
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So
General pop Recent MI AF HF
*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.
15. Possible “upstream” treatments and
mechanisms for AF prevention
ACEIs/ARBs Statins Glucocorticoids Omega-3 fatty acids Physical activity
↓Inflammation ↓Oxidative stress ↓RAAS activity ↑Endothelial function
↓Autonomic nervous system activity
↑Vascular stability ↓Atrial remodeling Stabilize left atrial endocardium
↓Atrial fibrillation
Courtesy of CJ Pepine, MD.
16. Trials of RAAS inhibition in AF prevention
Favors treatment Favors control
ACEIs
CAPP Captopril
GISSI Lisinopril
HOPE Ramipril
SOLVD Enalapril
STOP-H2 Enalapril
TRACE Trandolapril
Ueng Enalapril
Van den Berg Lisinopril
Subtotal
ARBs
CHARM Candesartan
LIFE Losartan
Madrid Irbesartan
ValHeFT Valsartan
Subtotal Subtotal
Total Total
0.1 0.2 0.5 1.0 2.0 5.0
RR* (95% CI)
Salehian O et al. Am Heart J. 2007;154:448-53.
*Random-effects model Healey JS et al. J Am Coll Cardiol. 2005;45:1832-9.
17. AF prevention with ACEI or ARB plus
antiarrhythmic drug
N = 177 with lone paroxysmal AF
1.0
0.9 Group 2 Amiodarone +
0.8 losartan
Group 3 Amiodarone +
0.7
perindopril
0.6
Amiodarone
AF recurrence- Group 1
0.5
free survival
0.4
0.3
0.2
Group 1 vs 2: P = 0.006
Group 1 vs 3: P = 0.04
0.1 Group 2 vs 3: P = 0.47
0.0
0 90 180 270 360 450 540 630 720 810
Time after randomization (days)
Yin Y et al. Eur Heart J. 2006;27:1841-6.
18. Statins in prevention of AF (1st episode or AF
recurrence)
Study Statin Control
or subcategory n/N n/M Favors treatment Favors control
MIRACL 93/1539 96/1548
Tveit 18/51 17/51
Dernellis 14/40 36/40
ARMYDA 3 35/101 56/99
Chello 2/20 5/20
Ozaydin 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%
0.1 0.2 0.5 1 2 5 10
Test for overall effect: Z = 2.35 (P = 0.02)
OR (random)
95% CI
Not assessed in this meta-analysis:
• Degree of ↓LDL-C
• Statin dose
Fauchier L et al. J Am Coll Cardiol. 2008;51:828-35.
19. Inflammation and AF: Methylprednisolone to
prevent AF recurrence
Primary endpoint Expanded endpoint hsCRP
Glucocorticoid 1.0 Glucocorticoid
1.0 10
0
Change from baseline (%)
0.8 Free of permanent AF 0.8 -10 Placebo
Free of recurrent AF
P = NS
Placebo
0.6 0.6 -30
Placebo
0.4 0.4 -50
P < 0.001 P < 0.001 Glucocorticoid
0.2 0.2 -70 P < 0.001
0.0 0.0 -90
0 8 16 24 32 0 8 16 24 32 40 0 8 16 24 32 40
Time (months)
Dorian P, Singh BN. Eur Heart J Suppl. 2008;10(suppl H):H11-31.
20. Omega-3 fatty acids in AF prevention: Conflicting
results in clinical trials
Study, year Design Patients Intervention Main findings
Cardiovascular Population-based N = 4815 Fish consumption AF risk:
Health Study, 2004 Prospective ≥65 yo 1. 1-4x per week ↓28% (1 vs 3)
cohort 2. ≥5x per week P = 0.005
12-y FU 3. <1x per month ↓31% (2 vs 3)
P = 0.008
Calo et al, 2005 Randomized N = 160 PUFAs ≥5 days Postop AF risk ↓65%
Open-label CABG P = 0.013
Mean age 65 yo
Nodari et al, 2005 Placebo-controlled N = 70 PUFAs 1 g/d x 6 mos AF recurrence:
Persistent AF 13.3% (PUFA) vs 40%
Cardioversion (placebo), P < 0.0001
Mean age 70 yo
Danish Diet, Population-based N = 47,949 Fish consumption No effect
Cancer and Health Prospective Mean age 56 yo ?↑Risk for AF as
Study, 2005 cohort age and HTN
5.7-y mean FU increased
Rotterdam Study, Population-based N = 5184 Fish/PUFA No effect
2006 Prospective Mean age 67 yo consumption
cohort
6.4-y mean FU
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.
21. Cardiovascular Health Study: Risk of incident AF
during 12-year follow-up
1.2 N = 5446 age ≥65 years
1
0.8
Multivariable-
adjusted RR of
new-onset AF 0.6
0.4
P trend < 0.001
0.2
Q1 Q2 Q3 Q4
Combined distance and pace of usual walking (quartiles)
Adjusted for age, gender, race, site, education, smoking (status Mozaffarian D et al.
and pack-yrs), CHD, COPD, diabetes, alcohol use, beta-blocker use Circulation. 2008;118:800-7.
22. 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
24. Prognostic impact of AF
Sudden cardiac death (SCD) Heart failure
• AF is independent risk factor • Those with AF had significantly
for SCD among patients with ↑mortality from HF progression
structural heart disease vs those without AF
(RR 1.20, P = 0.02) (AVID)1,2 (RR 1.95, P < 0.001) (SOLVD)4
Post-myocardial infarction mortality
• Those with AF had ↑post-MI mortality
vs those without AF
(RR 1.50, P < 0.001) (TRACE)3
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.
25. Atrial fibrillation: Framingham study
Strokes
Age AF prevalence attributable
(years) (%) to AF (%)
50-59 0.5 6.5
60-69 1.8 8.5
70-79 4.8 18.8
80-89 8.8 30.7
Wolf PA et al. Stroke. 1991;22:983-8.
26. Severity of stroke with AF
• N = 1061 admitted with acute ischemic stroke
– 20.2% had AF
• Bedridden state
– With AF 41.2% P < 0.0005
– 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)
Dulli DA et al. Neuroepidemiology. 2003;22:118-23.
27. AF: The more you look, the more you find
Estimated correlation between follow-up technique and AF recurrence
following catheter ablation
100%
Implanted
Daily Tele-ECG device†
7-day-ECG*
Detection 24-day-ECG*
of AF
Tele-ECG*
recurrences
ECG*
*During 3-month follow-up
†As the theoretical gold standard
Tele = transtelephonic Arya A et al. Pacing Clin Electrophysiol. 2007;30:458-62.
28. Detection of recurrent AF
Electrocardiographic vs implanted device recording
100
80
Device: AF detected in 88% of patients P < 0.0001
ECG: AF detected in 46% of patients
Cumulative 60
incidence
(%)
40
Implanted device
20
ECG
Baseline 1 3 6 12 18 24 30 36 42 48
Time (months)
n = 110 110 110 110 85 73 60 48 39 25 15
Israel CW et al. J Am Coll Cardiol. 2004;43:47-52.
29. Cumulative incidence of asymptomatic AF
recurrence >48 hours*
110
20
Cumulative
15
incidence
(%)
10
38% of patients with AF >48 hours were asymptomatic
5
Baseline 1 3 6 12 18 24 30 36 42 48 54 60 66
Time (months)
*Not detected by serial ECG recordings during follow-up Israel CW et al. J Am Coll Cardiol. 2004;43:47-52.
30. Anticoagulation for nonvalvular AF
Pooled data from AFASAK, SPAF, and BAATAF
For every 1000 patients with nonvalvular AF in clinical trials
treated with warfarin for 1 year:
Benefit Risk
31 fewer thromboembolic events* 1 more intracranial or major bleed*
*Compared with control
35 more minor bleeds occurred with warfarin
Intention-to-treat analysis Adapted from Albers GW et al. Ann Neurol. 1991;30:511-8.
31. Bleeding risk and age
N = 2376 receiving warfarin; Combined & retrospective cohort studies
Minor bleeding
• Categories <50
50-59
Referent category
– Minor: No costs or 60-69
70-79
consequences >80
– Serious: Require testing Serious bleeding
or treatment Age group
<50
50-59
Referent category
– Life-threatening/fatal (years) 60-69
70-79
>80
• Events (812)
Life-threatening or fatal bleeding
– 553 minor <50 Referent category
– 222 serious 50-59
60-69
– 33 life-threatening 70-79
>80
– 4 fatal
0 1 2 3 4 5 6 7 8 9 18
Adjusted relative risk (95% CI)
Age not determinant of risk except possibly ≥80 years Fihn SD et al. Ann Internal Med. 1996;124:970-9.
32. Survival following ischemic stroke:
Warfarin vs aspirin*
1.0
Warfarin, INR ≥2
Aspirin
0.9 Warfarin, INR <2
0.8
Probability
of survival None
0.7
0.6
P = 0.002†
0.0
0 5 10 15 20 25 30
Time after admission (days)
*Warfarin/aspirin therapy administered before or during stroke
†Overall difference among groups Hylek EM et al. N Engl J Med. 2003;349:1019-26.
33. Catheter ablation vs antiarrhythmic drug
therapy for AF
N = 432 with AF; Meta-analysis of 4 randomized clinical trials
ADT more CPVA more Risk ratio
Source effective effective (95% CI) % Weight
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)
0.04 0.20 1.00 5.00 25.00
Risk ratio
ADT = antiarrhythmic drug therapy
CPVA = circumferential pulmonary vein ablation Noheria A et al. Arch Intern Med. 2008;168:581-6.
34. A4 study: Catheter ablation vs antiarrhythmic
drug therapy for AF
N = 112 with paroxysmal AF resistant to ≥1 AAD
100.0
80.0
Freedom 60.0
from
recurrent
AF (%) 40.0
20.0
Logrank P < 0.0001
0.0
0 50 100 150 200 250 300 350 400
Follow-up (days)
RF ADT
RF = radiofrequency catheter ablation Jaïs P et al. Circulation. 2008;118:2498-505.
35. Worldwide survey of catheter ablation
N = 8745 with AF treated at 90 centers
• 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.
36. US experience with catheter ablation
N = 517 with AF undergoing catheter ablation treated at 1 US institution
• 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.
37. ACC/AHA/ESC 2006 AF rhythm-control guidelines
Maintenance of SR
No (or minimal) Hypertension CAD HF
heart disease
Flecainide Substantial LVH Dofetilide Amiodarone
Propafenone
Sotalol Dofetilide
Sotalol
No Yes
Amiodarone Catheter Catheter
Amiodarone
Dofetilide ablation ablation
Flecainide Catheter
Amiodarone ablation
Propafenone
Sotalol
Catheter
ablation
Amiodarone Catheter
Dofetilide ablation
Fuster V et al. Circulation. 2006;114:e257-e354.
38. 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.
39. Morbidity with AF following CABG
MultiCenter Study of Perioperative Ischemia; Prospective, observational study
With AF Without AF P
N 617 1648
Post-op LOS (days) 12.8 10.2 <0.01
CHF (%) 10 7 0.01
Renal failure (%) 8 5 0.04
Neurologic injury
Major (%) 7 2 <0.01
Minor (%) 6 2 <0.01
LOS = length of stay Mathew JP et al. JAMA 1996;276:300-6.
40. 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
42. 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
45. Primary care preferences: Rate vs rhythm control
as optimal strategy for AF
N = 148 PCPs from 36 US states
80
60
60
Respondents
40
(%)
22
18
20
0
Rate control* Rhythm control† Strategies are
equal
*With anticoagulation
†With or without anticoagulation McCabe JM et al. Am J Cardiol. 2009;103:535-9.
46. AFFIRM: Primary outcome
Cumulative mortality (%)
30 P = 0.08
• N = 4060 with AF 25
– Age ≥65 years or ≥1 risk Rhythm control
20
factor for stroke or death
– 1st AF episode: 36% 15
10 Rate control
– No contraindications for
warfarin 5
• Follow-up 3.5 years 0
0 1 2 3 4 5
• Predominant diagnosis Time (years)
Hypertension 51%, CAD 26%
• n = 2033 rhythm control
• n = 2027 rate control
AFFIRM Investigators. N Engl J Med. 2002;347:1825-33.
47. ACC/AHA/ESC 2006 AF guidelines
Newly discovered AF
Paroxysmal Persistent
Rate control and
Accept
No therapy anticoagulation
permanent AF
needed unless as needed
significant
symptoms
Rate control and Consider
anticoagulation antiarrhythmic
as needed therapy
Anticoagulation
as needed Cardioversion
Long-term
antiarrhythmic
drug therapy
unnecessary
Fuster V et al. Circulation. 2006;114:e257-e354.
48. Antiarrhythmic medical therapies
Amiodarone Propafenone
Class Class
III Antiarrhythmic drugs IC
Sotalol New and old Flecainide
New Upstream
Novel drugs
Class III agents therapies
SAC Connexin
blockers modulators
Dofetilide Azimilide
5-HT4 Na+/H+
antagonist inhibitor
Tedisamil Dronedarone Adenosine
Na+/Ca2+
Multi-channel inhibitor agonist
blockers Celivarone
ARDAs
Courtesy of J Camm, MD.
49. 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.
50. EURIDIS, ADONIS: Primary endpoint
First recurrence of AF/AFL
EURIDIS ADONIS
0.8 0.8
0.7 0.7
0.6 0.6
0.5 0.5
Cumulative
0.4 0.4
incidence P = 0.01
0.3 0.3
P = 0.002
0.2 0.2
0.1 0.1
0.0 0.0
0 60 120 180 240 300 360 0 60 120 180 240 300 360
Time (days)
Placebo Dronedarone 400 mg bid
Singh BN et al. N Engl J Med. 2007;357:987-99.
51. ERATO: Dronedarone added to rate-lowering
drugs
Mean 24-hour Holter heart rate
Calcium
All patients Beta-blockers Digoxin antagonists
0
-4
-5.1
Mean change P = 0.10
-8
(bpm)
-12 -11.5
-11.7
P < 0.0001 P < 0.0001
-16 -14.9
P < 0.0001
Davy J-M et al. Am Heart J. 2008;156:527.e1-9.
52. ATHENA: Time to primary outcome
N = 4628 ≥75 yrs with AF or 70-74 yrs with AF + ≥1 CV risk factor
100 HR 0.76 (0.69-0.84)
P < 0.001
75
Cumulative
50
incidence (%)
25
0
0 6 12 18 24 30
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.
53. ATHENA: All-cause mortality
10.0
HR 0.84 (0.66-1.08)
100 7.5
P = 0.18 Placebo
5.0
75
2.5
Dronedarone
Cumulative
50 0.0
incidence (%) 0 6 12 18 24 30
24
0
0 6 12 18 24 30
Time (months)
Placebo Dronedarone
Hohnloser SH et al. N Engl J Med. 2009;360:668-78.
54. ATHENA: CV mortality
7.5
Placebo
100 HR 0.71 (0.51-0.98)
P = 0.03 5.0
75 2.5
Dronedarone
Cumulative 0.0
50
incidence (%) 0 6 12 18 24 30
24
0
0 6 12 18 24 30
Time (months)
Placebo Dronedarone
Hohnloser SH et al. N Engl J Med. 2009;360:668-678.
55. ATHENA: CV hospitalization
HR 0.74 (0.67-0.82)
100
P < 0.001
75
Cumulative
50
incidence (%)
24
0
0 6 12 18 24 30
Time (months)
Placebo Dronedarone
Hohnloser SH et al. N Engl J Med. 2009;360:668-78.
56. ATHENA: Primary outcome according to
selected baseline characteristics
Patients Dronedarone Placebo
Characteristic* (no./total no.) better better
Age
<75 yr 942/2703
≥75 yr 709/1925
Gender
Male 850/2459
Female 801/2169
Presence of atrial fibrillation or flutter
Yes 396/1155
No 1255/3473
Structural heart disease
Yes 1115/2732
No 524/1853
Any congestive HF
Yes 603/1365
No 1048/3263
LVEF
<35% 86/179
35 to <45% 145/361
≥45% 1387/4004
Use of ACEI or ARB
Yes 1175/3216
No 476/1412
Use of beta-blocker
Yes 1226/3269
No 425/1359
0.1 1.0 10.0
Hazard ratio (95% CI)
*Not prespecified Hohnloser SH et al. N Engl J Med. 2009;360:668-78.
58. ATHENA post hoc analysis: Reduction in stroke,
ACS, or CV death
15 HR 0.68 (95% CI 0.55-0.84)
P < 0.001
Placebo
(n = 216, annual rate = 5.5%)
10
Cumulative Dronedarone
incidence (%) (n = 147, annual rate = 3.8%)
5
0
0 6 12 18 24 30
Months
Connolly SJ. Circulation. 2009;120:1174-80.
59. 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.
60. 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.
61. Conversion to sinus rhythm with IV vernakalant in
patients who experienced AF for <7 days
60
50
40
Patients
30
(%)
20
10
0
ACT I ACT II ACT III ACT IV†
(n = 220)* (N = 150) (n = 170)* (n = 170)*
Placebo Vernakalant
*Subgroup analysis; †Not placebo-controlled Savelieva I, Camm J. Europace. 2008;10:647-65.
62. AF treatment strategies
AF
DC or chemical
cardioversion to
reestablish SR as
Rate control Rhythm control needed
Antiarrhythmic Catheter Atrial
Beta-blocker Surgery
+ Digoxin drugs ablation defibrillator
Ca channel blocker
+ Digoxin Propafenone Maze
Pulmonary veins
AV node ablation Flecainide procedure
LA linear lesions
+ Pacer Sotalol RA linear lesions
Amiodarone Focal lesions
Dofetilide
Anticoagulation Disopyramide
for all patients Quinidine
with risk factors Procainamide Anticoagulation for all patients with risk
for stroke New drugs factors for stroke
Courtesy of KA Ellenbogen, MD.
63. 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.
65. 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
66. Diagnostic studies
ECG rhythm strip
during an episode
• 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
Courtesy of JA Reiffel, MD.
67. CHADS2 risk stratification scheme
CHADS2 risk criteria Score
C Congestive heart failure 1
H Hypertension 1
A Age ≥75 years 1
D Diabetes mellitus 1
S2 Prior stroke or TIA 2
Fuster V et al. Circulation. 2006;114:e257-e354.
68. Warfarin risk/benefit balance
20
15
Odds ratio 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
Fuster V et al. Circulation. 2006;114:e257-e354.
69. Misconceptions about rhythm-control strategy
N = 148 PCPs from 36 US states
80 73
64
60 55
Respondents
40
(%)
20
0
Helps avoid Decreases Decreases
long-term mortality stroke
anticoagulation
McCabe JM et al. Am J Cardiol. 2009;103:535-9.
70. AFFIRM: Incidence of stroke and anticoagulation
status at time of stroke
N = 4060 with AF and ≥65 years or with additional stroke risk factors
Rate control Rhythm control
n (%) n (%)
Ischemic stroke 77 (5.5)* 80 (7.1)*
INR 2.0 25 19
INR <2.0 27 17
Not taking warfarin 25 44
AF 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
*Percentages derived from Kaplan-Meier analysis AFFIRM Investigators. N Engl J Med. 2002;347:1825-33.
71. Inadequate warfarin treatment in patients with AF
N = 660 with AF in primary care practices
4%: INR
above target 26%: INR
within target
5%: INR
below target
65%: No
warfarin
Samsa GP et al. Arch Intern Med. 2000;160:967-73.
72. 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
Courtesy of JA Reiffel, MD.
73. 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)
Courtesy of JA Reiffel, MD.
74. Proposed algorithm for warfarin initiation in
elderly patients
INR value at 10 AM Warfarin dose (mg)*
Day 0 Do not measure 4
Day 1 Do not measure 4
Day 2 Do not measure 4
Day 3 <1.3 5†
1.3 ≤ INR < 1.5 4†
1.5 ≤ INR < 1.7 3†
1.7 ≤ INR < 1.9 2†
1.9 ≤ INR < 2.5 1†
INR ≥2.5 Measure INR daily and
omit dose until INR <2.5,
then give 1 mg
*Given at 6 PM
†Predicted maintenance dose
Elderly: ≥70 years Siguret V et al. Am J Med. 2005;118:137-42.
75. 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 emergencies
Courtesy of JA Reiffel, MD.
76. 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?
Courtesy of JA Reiffel, MD.
77. Coagulation cascade
Intrinsic system Extrinsic system
XII XIIa XII VIIa + Tissue factor
XI XIa
rs
ibito
XI XIa + VIIIa nh
a I
X rs
c tor bi to
Fa i
X Xa + Va n Inh
m bi
r o
Th
Prothrombin Thrombin
Fibrinogen Fibrin
XIII XIIIa
Brass LF. Chest. 2003;124(suppl):18S-25S. Stable fibrin clot
Mann KG. Chest. 2003;124(suppl):4S-10S.
Nesheim M. Chest. 2003;124(suppl):33S-39S.
78. 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.
79. 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
Courtesy of JA Reiffel, MD.
80. 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
Courtesy of JA Reiffel, MD.
81. 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
Courtesy of JA Reiffel, MD.
82. PETRO: Dabigatran in AF phase II clinical trial
N = 502 with AF, treatment duration 12 weeks
Dabigatran dose Major Relevant
(mg, twice daily) n ASA (mg) bleed bleed TE events
50 59 0 0 0 1 (1.7%)
50 21 81 0 1 (4.8%) 1 (4.8%)
50 27 325 0 1 (3.7%) 0
150 100 0 0 9 (9%) 0
150 36 81 0 2 (5.6%) 0
150 33 325 0 2 (6.1%) 0
300 105 0 0 6 (5.7%) 0
300 34 81 1 (2.9%) 5 (14.7%) 0
300 30 325 3 (10%) 6 (20%) 0
Warfarin (INR 2-3) 70 0 0 4 (5.7%) 0
ALT >3x ULN in 0.9% of patients Ezekowitz MD et al. Am J Cardiol. 2007;100:1419-26.
83. Design of RE-LY: A non-inferiority trial
Randomized Evaluation of Long-Term Anticoagulation Therapy
Atrial fibrillation
1 Stroke risk factors
Absence of contraindications
Primary outcome:
Blinded event adjudication R Stroke or systemic embolism
Open Blinded
Warfarin Dabigatran Dabigatran
(Adjusted INR etexilate etexilate
2.0-3.0) 110 mg bid 150 mg bid
n = 6022 n = 6015 n = 6076
Follow up: 1-yr minimum, 2-yr median, 3-yr maximum Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
84. RE-LY: Stroke or systemic embolism
Primary outcome
Dabigatran Warfarin
better better P for non- P for
inferiority superiority
Dabigatran 110 vs warfarin <0.001 0.34
Dabigatran 150 vs warfarin <0.001 <0.001
Non-inferiority margin = 1.46
0.50 0.75 1.00 1.25 1.50
HR (95% CI)
Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
86. RE-LY: MI, hospitalization, death
Dabigatran Dabigatran Dabigatran 110 Dabigatran 150
110 150 Warfarin vs warfarin vs warfarin
Annual Annual Annual RR RR
rate (%) rate (%) rate (%) (95% CI) P (95% CI) P
Myocardial 0.72 0.74 0.53 1.35 0.07 1.38 0.048
infarction (0.98-1.87) (1.00-1.91)
Hospitalization 19.4 20.2 20.8 0.92 0.003 0.97 0.34
(0.87-0.97) (0.92-1.03)
Death 3.75 3.64 4.13 0.91 0.13 0.88 0.051
(0.80-1.03) (0.77-1.00)
Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
87. RE-LY: Bleeding and net clinical benefit
Dabigatran Dabigatran Dabigatran 110 Dabigatran 150
110 150 Warfarin vs warfarin vs warfarin
Annual Annual Annual RR RR
rate (%) rate (%) rate (%) (95% CI) P (95% CI) P
Major 2.71 3.11 3.36 0.80 0.003 0.93 0.31
bleeding (0.69-0.93) (0.81-1.07)
Minor 13.16 14.84 16.37 0.79 <0.001 0.91 0.005
bleeding (0.74-0.84) (0.85-0.97)
Net clinical 7.09 6.91 7.64 0.92 0.10 0.91 0.04
benefit* (0.84-1.02) (0.82-1.00)
*Composite of stroke, systemic embolism,
pulmonary embolism, MI, death, or major bleeding Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
88. RE-LY: Liver function test abnormalities
Dabigatran 110 Dabigatran 150 Warfarin
n (%) n (%) n (%)
ALT or AST >3x ULN 124 (2.1) 117 (1.9) 132 (2.2)
ALT or AST >3x ULN with 13 (0.2) 13 (0.2) 21 (0.3)
concurrent bilirubin >2x ULN
(Potential Hy’s Law case)
ALT = alanine aminotransferase
AST = aspartate aminotransferase
ULN = upper limit of normal Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
89. 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 rhythm
is 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
Courtesy of JA Reiffel, MD.
