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Anticoagulation in Atrial
Fibrillation
Roger Kerzner, MD
Christiana Care Cardiology Consultants
March 28th, 2014
Disclosures

None
Objectives
Atrial fibrillation basics, and why we use
anticoagulation
 Who should be anticoagulated
 Risk calculators and how to apply to
clinical decision making
 How to address fall risk
 Agents available for anticoagulation
 When and when not to hold
anticoagulation for procedures

Anticoagulation in Atrial Fibrillation
ATRIAL FIBRILLATION
BASICS
Atrial Fibrillation Basics: Definitions

Paroxysmal
◦ Spontaneous termination within 7 days

Persistent
◦ Episodes lasting longer than 7 days
◦ Generally require cardioversion to restore
sinus rhythm

Permanent or Chronic
Atrial Fibrillation Basics: Epidemiology
2.2 million Americans have atrial
fibrillation.
 Median age is 75 years
 Lifetime risk of developing atrial
fibrillation is 1:6, and increases to 1:4 in
men and women older than 40 years
 The mortality rate of patients with atrial
fibrillation is about double that of patients
in normal rhythm, and linked to the
severity of underlying heart disease.

J Am Coll Cardiol, 2011; 57:101-198
Atrial Fibrillation Basics: Morbidity
Common symptoms include
palpitations,chest pain, dyspnea, fatigue,
lightheadedness, or syncope.
 In many patients, particularly the elderly,
atrial fibrillation is asymptomatic.
 It is the most common arrhythmia in
clinical practice, accounting for
approximately one-third of
hospitalizations for cardiac rhythm
disturbances

J Am Coll Cardiol, 2011; 57:101-198
Atrial Fibrillation Basics:
Morbidity : Stroke
The rate of ischemic stroke among
patients with atrial fibrillation averages 5%
per year, which is 2 to 7 times that of
people without atrial fibrillation.
 One of every 6 strokes occurs in a patient
with atrial fibrillation.
 Strokes in patients with atrial fibrillation
tend to be more debilitating.

J Am Coll Cardiol, 2011; 57:101-198
Atrial Fibrillation Basics:
Morbidity : Stroke
 The
risk of stroke is present
regardless of the type, duration, or
symptoms related to atrial
fibrillation.
◦ In the AFFIRM trial, there we more strokes in
the arm of the trial in which patients were
thought to be in sinus rhythm, and their
anticoagulation was stopped.
J Am Coll Cardiol, 2011; 57:101-198, N Engl J Med. 2002 Dec 5;347(23):1825-33.
Anticoagulation in Atrial Fibrillation
WHY WE USE
ANTICOAGULATION
Anticoagulation: Randomized Trials





Approximately 20,000 patients enrolled in
trials of warfarin versus placebo.
Target INR approximately 2.0-3.0
Often >90% of patients with AF excluded
from trials
Mean follow-up 1.6 years
Average age of 69 years
◦ Average age of AF patients in clinical practice is
75 years

Meticulous monitoring of INRs
Hart RG, et al. Ann Intern Med 1999;131:492-501
Fuster V, et al. J Am Coll Cardiol 2006;48:854-906
Birman-Deych E, et al. Stroke 2006;37:1070-4
Randomized Trials : Warfarin vs.
Placebo for prevention of stroke
62% reduction in risk
of stroke
2.7% absolute reduction
per year for primary
prevention
8.4% absolute reduction
per year for secondary
prevention
26% reduction in all
cause mortality
Hart RG, et al. Ann Intern Med 1999;131:492-501
Randomized Trials : Aspirin
~20% reduction in
risk of stroke
Hart RG, et al. Ann Intern Med 1999;131:492-501 Eur
Heart J 2007; 28; 926-8
Anticoagulation: Failed Strategies

Plavix and Aspirin vs. Warfarin
◦ Randomized Trial (n=6706) [ACTIVE Trial.
2006;367:1903-12]

Low-intensity Warfarin (INR 1.2-1.5) vs.
Aspirin
◦ Randomized Trial (n=1044)
1996;348:633-8]

Lancet
[SPAF III. Lancet
Rhythm Control
◦ Eliminate the atrial fibrillation with antiarrhythmic
medications
◦ Randomized Trial (n=4060) [AFFIRM. NEJM
2002:347:1825-33]
Anticoagulation in Atrial Fibrillation
WHO SHOULD BE
ANTICOAGULATED
Who should be anticoagulated?

Patients with valvular heart disease.
◦ Valvular atrial fibrillation = Patients with atrial
fibrillation and rheumatic mitral valve disease,
a prosthetic heart valve, or valve repair.
◦ The risk of stroke in patients with rheumatic
mitral valve disease is very high.
J Am Coll Cardiol, 2011; 57:101-198
Who should be anticoagulated?

Patients with non-valvular heart disease,
and risk factors for stroke in atrial
fibrillation.
◦ Basically all patients with atrial fibrillation, but
without rheumatic heart disease
◦ Patients with lone atrial fibrillation should not
be anticoagulated.
 Lone atrial fibrillation = individuals younger than 60
years, without clinical or echocardiographic
evidence of cardiopulmonary disease, including
hypertension, or other risk factors for stroke
J Am Coll Cardiol, 2011; 57:101-198
Anticoagulation in Atrial Fibrillation
RISK CALCULATORS AND
HOW TO APPLY TO
CLINICAL DECISION
MAKING
The Problem with Anticoagulation =
Bleeding

Risk of
intracerebral
hemmorhage is
between 0.1-0.6%
Oden A, et al. Thromb Res 2006;117:493-9
Fuster V, et al. J Am Coll Cardiol 2006;48:854-906
The Problem with Anticoagulation =
Bleeding

The answer to the problem of bleeding
risk = risk calculators.
◦ Use calculators of stroke and bleeding risk to
determine the risk/benefit ratio of starting a
patient on a strong blood thinner.
◦ For each calculator, one adds up the number
of points a patient has, and this correlates
with the risk of a stroke or bleeding event.
Estimating the Risk of Stroke
CHADS2 Score
CHADS2 Risk Criteria
Score
C – Cardiac
Heart failure or
structural heart disease
1
H – Hypertension
1
A – Age > 75 years
1
D – Diabetes
1
S2 – Stroke
Prior ischemic CVA /TIA
2
Gage BF, et al. JAMA 2001;285:2864-70
Estimating the Risk of Stroke
CHADS2 Score
CHADS2 Score
% Adjusted Stroke Risk/Year
0
1.9
1
2.8
2
4.0
3
5.9
4
8.5
5
12.5
6
18.2
Gage BF, et al. JAMA 2001;285:2864-70
Estimating the Risk of Stroke
CHA2DS2-VASc Score
CHA2DS2-VASc Risk Criteria
Score
C – Cardiac
Heart failure or
structural heart disease
1
H – Hypertension
1
A2 – Age > 75 years
2
D – Diabetes
1
S2 – Stroke
Prior ischemic CVA /TIA
2
V – Vascular disease (CAD/PAD)
1
A – Age > 65 years
1
S – Sex (Female)
1
Gage BF, et al. JAMA 2001;285:2864-70
Estimating the Risk of Stroke
CHA2DS2-VASc Score
CHA2DS2-VASc Score % Adjusted Stroke Risk/Year
0
0
1
1.3
2
2.2
3
3.2
4
4.0
5
6.7
6
9.8
7
9.6
8
6.7
9
15.2
Eur Heart J 2010; 31:2369
Estimating the Risk of Stroke

Examples
◦ 80 year old male with a history of heart
failure with an ejection fraction of 40%,
hypertension, and a prior stroke
 CHADS2 Score = 5 -> stroke risk 12.5%/year
◦ 70 year old female with a prior myocardial
infarction
 CHA2DS2-VASc Score = 3 -> stroke risk 3.2%/year
Modified 2011 Guidelines Approach
CHA2DS2-VASc Score
or CHADS2 Score
Recommended Therapy

0

Aspirin, 81 to 325 mg daily

1

Aspirin or Anticoagulation

2 or more

Anticoagulation
CHA2DS2-VASc score is preferred as it has better
discrimination of risk at a low CHADS2 score.
J Am Coll Cardiol, 2011; 57:101-198
Estimating the Risk of Bleeding
HAS-BLED Score
HAS-BLED Risk Criteria
H – Hypertension
A – Abnormal renal or liver
function
Score
1
1 for each
S – Stroke
1
B – Bleeding tendancy or
disposition
1
L – Labile INRs
1
E – Elderly (Age > 65)
1
D – Drug or Alcohol
1 for each
Chest. 2010 Nov;138(5):1093-100
Estimating the Risk of Bleeding
HAS-BLED Score
HAS-BLED Score
% Major Bleeding Risk/Year
0
1
0.7
2
1.9
3
2.4
4
3.4
5
5.7
6
15.5
7
8
9
Eur Heary J 2012; 33; 1500-10
Balancing the Risk of Stroke and
Bleeding

Example
◦ 80 year old male with a history of heart
failure with an ejection fraction of 40%,
hypertension, a prior stroke, and chronic
kidney disease
 CHADS2 Score = 5 -> stroke risk 12.5%/year
 HAS-BLED Score = 4 -> major bleeding risk
3.4%/year
Anticoagulation in Atrial Fibrillation
HOW TO ADDRESS
FALL RISK
How to address fall risk

Analysis of 1245 Medicare patients with AF at high
risk for falls
◦ Data accumulated as part of a quality improvement
initiative.



Risk of intracranial hemmorhage in patients at high
risk for falls = 2.8 per 100 patient-years
Risk of stroke in falls vs. non-falls patients = 13.7 vs.
6.9 per 100 patient-years
Despite a high risk for falls, patients with 2 or more
risk factors for stroke benefit from anticoagulation
therapy
Gage BF, et al. Am J Med 2005;118:612-7
Anticoagulation in Atrial Fibrillation
AGENTS AVAILABLE
FOR
ANTICOAGULATION
Warfarin
Vitamin K antagonist, which prevents the
creation of Vitamin K dependent elements
of the coagulation cascade.
 Adjusted to a trial-proven level of
anticoagulation.

◦ INR = 2.0-3.0
Limitations of Warfarin
Limitation
Consequence
Slow onset of action
Overlap with parenteral anticoagulation
Genetic variation
in metabolism
Variable dose requirements
Multiple food and drug
interactions
Frequent coagulation monitoring
Narrow theraputic range
Frequent coagulation monitoring
JI Weitz Presentation, Boston Atrial Fibrillation Symposium, Boston, MA, Jan 14 2011.
Limitations of Warfarin

Risk of
intracerebral
hemmorhage is
between 0.1-0.6%

Close monitoring
of INRs is critical
Oden A, et al. Thromb Res 2006;117:493-9
Fuster V, et al. J Am Coll Cardiol 2006;48:854-906
Warfarin Monitoring


Warfarin monitoring and dose adjust should
be coordinated through an anticoagulation
management service (anticoagulation clinic)
On average, patients followed in community
physician practices are in the theraputic
range only 57% of the time, and this
increases by approximately 8% in
anticoagulation clinic.
◦ Christiana cardiology practice clinic = TTR ~ 72%
CHEST 2008; 133:160S–198S, Chest. 2006 May;129(5):1155-66
Anticoagulation in Atrial Fibrillation
THE NOVEL
ANTICOAGULANTS
(NOACS)
Mechanisms of New Agents
Warfarin
Rivaroxiban
Apixaban
Edoxaban
Dabigatran
http://commons.wikimedia.org/wiki/File:Coagulation_simple.svg
Comparison of warfarin vs
newer agents
Warfarin
Newer Agents
Onset
Slow
Rapid
Dosing
Variable
Fixed
Yes
No
Many
Few
Yes
No
Half-life
Long
Short
Antidote
Yes
No
Food affect
Drug interactions
Monitoring
JI Weitz Presentation, Boston Atrial Fibrillation Symposium, Boston, MA, Jan 14 2011.
Dabigatran : RELY Trial

A noninferiority trial of 18,113 patients with
atrial fibrillation randomized to:
◦ In a blinded fashion, fixed doses of dabigatran 110 mg
or 150 mg twice daily
or
◦ In an unblinded fashion, adjusted-dose warfarin



Mean age 71 years; 64% male; Mean CHADS2
score of 2.1.
The median follow-up was 2 years.
The primary outcome was stroke or systemic
embolism.
Connolly SJ et al. N Engl J Med 2009;361:1139-1151.
Dabigatran : RELY Trial : Stroke
110mg dose noninferior,
& 150mg dose superior
to warfarin for reduction
in stroke or systemic
embolism.
Benefit present regardless of age, CHADS2 score, renal function,
or time with INRs in theraputic range.
Schirmer, S. H. et al. J Am Coll Cardiol 2010;56:2067-2076
Dabigatran : RELY Trial : Bleeding
Reduction in total
bleeding with both
doses compared
to warfarin
In the elderly, lower risk of stroke and intracranial bleeding,
But higher risk of extracranial (mostly GI) bleeding.
JI Weitz Presentation, Boston Atrial Fibrillation Symposium, Boston, MA, Jan 14 2011.
Schirmer, S. H. et al. J Am Coll Cardiol 2010;56:2067-2076
Apixaban: AVERROES Trial
A double blind, controlled trial of 5599
patients with atrial fibrillation, but not
candidates for warfarin, randomized to:
 A fixed dose of apixaban 5mg twice daily
or aspirin (81-324mg) daily
 Mean age 71 years; 58% male; Mean
CHADS2 score of 2.1.
 The mean follow-up was only 1.1 years, as
the trial was stopped earlier.
 The primary outcome was stroke or
systemic embolism.

Connolly SJ et al. N Engl J Med 2011;364:806-817
Apixaban: AVERROES Trial: Stroke
Apixaban was
superior to aspirin
with over a 50%
reduction
of stroke or
systemic
embolism.
Benefit present regardless of age, CHADS2 score, renal function,
or prior use of warfarin.
Connolly SJ et al. N Engl J Med 2011;364:806-817
Apixaban: AVERROES Trial: Bleeding
No statistically significant increase in the risk of major
bleeding or intracranial bleeding.
Connolly SJ et al. N Engl J Med 2011;364:806-817
Novel Anticoagulants
Equivalent, or superior efficacy to warfarin
for the reduction of stroke or systemic
embolism.
 Superior safety compared to warfarin for the
reduction of serious bleeding.
 Apixaban is superior to aspirin for the
reduction of stroke and systemic embolism,
with a similar risk of bleeding.
 None of the NOACs have been directly
compared, thus it is difficult to determine
which agent is the best agent.

N Engl J Med. 2009 Sep 17;361(12):1139-51, Connolly SJ et al. N Engl J Med 2011;364:806-817,
N Engl J Med. 2011 Sep 8;365(10):883-91, N Engl J Med. 2011 Sep 15;365(11):981-92
Novel Anticoagulants : Unique Traits

Dabigatran (Pradaxa)
◦ Twice daily
*Renal dose not included in RCT
◦ Superior to warfarin for stroke reduction

Rivaroxiban (Xarelto)
◦ Once daily
*Renal included in RCT
◦ Equivalent to warfarin for stroke reduction
 Higher CHADS score compared to other RCTs

Apixaban (Eliquis)
◦ Twice daily
*Renal included in RCT
◦ Superior to warfarin for stroke and mortality
reduction
◦ Only agent demonstrated superior to aspirin
N Engl J Med. 2009 Sep 17;361(12):1139-51, Connolly SJ et al. N Engl J Med 2011;364:806-817,
N Engl J Med. 2011 Sep 8;365(10):883-91, N Engl J Med. 2011 Sep 15;365(11):981-92
Practical points for using NOACs
Only approved for non-valvular atrial
fibrillation
 Start NOACs when INR < 2.0
 Contraindicated in patients with severe
renal insufficiency (CrCl < 15)

◦ Except apixaban
Normal aPTT indicates absent activity
 Potential cost issues

Practical points for using NOACs

Dabigatran (Pradaxa)
◦ Twice daily
◦ 150mg BID, or 75mg BID if CrCl 15-30
◦ Dyspepsia in 10% of pateints

Rivaroxiban (Xarelto)
◦ Once daily, with largest meal of the day
◦ 20mg daily, or 15mg daily if CrCl 15-50

Apixaban (Eliquis)
◦ Twice daily
◦ 5mg BID, or 2.5mg BID if at 2 of these items present
(>80 yo, <60 kg, Cr > 1.5)
Anticoagulation in Atrial Fibrillation
WHEN AND WHEN NOT
TO HOLD
ANTICOAGULATION FOR
PROCEDURES
Interruption of Anticoagulants for
Procedures

Christiana Care Guidelines for Interruption
of Anticoagulant/Antiplatelet Medications
prior to Outpatient Procedures
◦ Interruption should occur only if absolutely
necessary, and for as short a time period as
possible.
◦ Risk of stroke or systemic embolism
approximately 1% with brief interruption of
anticoagulants for procedures.
◦ Many procedures can be safely performed on
therapeutic, or minimally reduced anticoagulation.
Interruption of Anticoagulants for
Procedures

Christiana Care Guidelines Highlights
◦ Simple dental (including root canals) and
minor dermatologic procedures can be done
on therapeutic anticoagulation.
◦ Endoscopy can often be performed on
therapeutic anticoagulation.
◦ Pacemaker and defibrillator implants are now
standardly performed on therapeutic warfarin.

Commentary: Don’t just fill out the form;
speak to the proceduralist.
Interruption of Anticoagulants for
Bleeding Events

Christiana Care Guidelines for withholding
of antiplatelet and anticoagulant medications
in the setting of specific bleeding events
◦ Interruption should occur only if absolutely
necessary, and for as short a time period as
possible.
 For instance, in the setting of GI bleeding, holding
warfarin for 12 weeks as opposed to restarting
anticoagulation within 1-2 weeks, is associated with a
higher mortality risk.
◦ To determine the necessity of interruption, a
collaborative discussion between providers is
recommended.
Anticoagulation in Atrial Fibrillation
THANK YOU