PREVENTING

Atrial Fibrillation Related

STROKES
with Anticoagulants

September 2012 - June 2013

 PREVENTING
Atrial Fibrillation Related
Disclosure of Commercial Support STROKES
with Anticoagulants

This activity is supported by educational grants from

Boehringer Ingelheim Pharmaceuticals, Inc. and Bristol-Myers
Squibb and Pfizer Inc.

This slide presentation and artwork was independently

developed by Boston University School of Medicine’s
Powerpoint designer.
Boston University School of Medicine’s Disclosure Policy
Boston University School of Medicine asks all individuals involved in the development
and presentation of Continuing Medical Education (CME) activities to disclose all
relationships with commercial interests. This information is disclosed to CME activity
participants. Boston University School of Medicine has procedures to resolve any
apparent conflicts of interest. In addition, faculty members are asked to disclose when
any unapproved use of pharmaceuticals and devices is being discussed.

2
 PREVENTING
Atrial Fibrillation Related

Accreditation Information STROKES

with Anticoagulants

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council
for Continuing Medical Education (ACCME) through the joint sponsorship of Boston University School of Medicine and
Anticoagulation Forum. Boston University School of Medicine is accredited by the ACCME to provide continuing medical education
for physicians.

Boston University School of Medicine designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™.
Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education Provider Unit, Boston University School of Medicine is accredited as a provider of continuing nursing
education by the American Nurses Credentialing Center’s Commission on Accreditation.

CNE Contact Hours: 1.00

Nurses will receive contact hours for those sessions attended, after completion of an evaluation and claim for credit form.

Continuing Pharmacy Education Credits

The University of Rhode Island College of Pharmacy is accredited by the Accreditation Council for
Pharmacy Education as a provider of continuing pharmacy education. Attendance and completion of
program evaluations at the conclusion of the program are required for a statement of credit. This
knowledge-based activity is approved for 1.0 Contact Hours (0.1 CEUs). UAN: 0060-9999-12- 040-L01-P.
Expiration date: September 5, 2013.

3
 PREVENTING
Atrial Fibrillation Related

Learning Objectives STROKES

with Anticoagulants

At the conclusion of this activity participants will be able to:

:

• Describe benefits of oral anticoagulants for stroke prevention in

atrial fibrillation
• Identify the population of patients who would be at risk of stroke with atrial
fibrillation
• Compare current and new oral anticoagulants with regards to safety,
efficacy, pharmacology, cost and convenience
• Compare the benefits and risks of oral anticoagulant therapy for reducing
the risk of stroke in atrial fibrillation patients
• Utilize available decision making tools to stratify the risks and benefits of
anticoagulation therapy in patients with atrial fibrillation

4
 PREVENTING
Atrial Fibrillation Related

Highlights STROKES
with Anticoagulants

• Prevalence and incidence of AF

• Risk stratification for stroke and bleeding
• New oral anticoagulants
• Guidelines
• Practical considerations for choosing an anticoagulant
 PREVENTING
Atrial Fibrillation Related

Highlights STROKES
with Anticoagulants

• Prevalence and incidence of AF

• Risk stratification for stroke and bleeding
• New oral anticoagulants
• Guidelines
• Practical considerations for choosing an anticoagulant
Question #1
An 82 year old man is in your office for an annual
Medicare physical. What is the chance he has atrial
fibrillation?
1. 1%
2. 5%
3. 10%
4. 25%

7
Prevalence of Diagnosed AF
Stratified by Age and Sex

12.0
Women 11.1
Men 10.3
10.0
9.1

8.0 7.3 7.2

6.0
5.0 5.0
x-axis = %
4.0 3.4 y-axis = # of
3.0 men/women
2.0 1.7 1.7
0.9 1.0
0.1 0.2 0.4
0.0
<55 55-59 60-64 65-69 70-74 75-79 80-84 > 85
# Women 530 310 566 896 1498 1572 1291 1132
# Men 1529 634 934 1426 1907 1886 1374 759

Go AS, JAMA. 2001 May 9;285(18):2370-5. Pub Med PMID: 11343485 8

Question #2
A 46 year old male patient is in for an annual physical
exam. What is his lifetime risk of developing AF?
1. 1%
2. 5%
3. 10%
4. 25%

9
Incidence of AF
Lifetime Risk for AF at Selected Index Ages by Sex

Index Age, yrs Men Women

40 26.0% (24.0 – 27.0) 23.0% (21.0 – 24.0)
50 25.9% (23.9 – 27.0) 23.2% (21.3 – 24.3)
60 25.8% (23.7 – 26.9) 23.4% (21.4 – 24.4)
70 24.3% (22.1 – 25.5) 23.0% (20.9 – 24.1)
80 22.7% (20.1 – 24.1) 21.6% (19.3 – 22.7)

1 in 4
Men & women Lifetime risk if
>40 Years currently free
will develop AF of AF

Lloyd-Jones DM, et al. Circulation. 2004 Aug 31;110(9):1042-6. Pub Med PMID: 15313941. 10
 PREVENTING
Atrial Fibrillation Related

Highlights STROKES
with Anticoagulants

• Prevalence and incidence of AF

• Risk stratification for stroke and bleeding
• New oral anticoagulants
• Guidelines
• Practical considerations for choosing an anticoagulant
Question #3
68 year old female with atrial fibrillation and no other co-
morbidities. How would you classify her stroke risk?
1. Low
2. Moderate
3. High

12
Scoring Systems in Atrial Fibrillation
• Given that anticoagulant therapy has both risks
(principally bleeding) and benefits (a reduced risk of
thrombosis) many authors have attempted to produce
scoring systems which estimate the risks of these
outcomes

• No one scoring system is universally accepted or highly

predictive (in individual patients)

13
Scoring Systems in Stroke Risk
• A variety of systems have been published
– Outlined on next slide

• All use selected clinical characteristics to predict the risk

of stroke
• Most widely used is the CHADS2 score

• All scores provide a rough estimate of risk of thrombosis

in a population at similar risk as patient being reviewed

14
Atrial Fibrillation Risk Stratification
12 Schemes applied to 1000 patients from SPAF III study
High Moderate Low

Stroke Risk in Atrial Fibrillation Working Group. Stroke. 2008 Jun;39(6):1901-10. Pub Med PMID: 18420954. 15
CHADS2: Risk of Stroke
National Registry of Atrial Fibrillation Participants (NRAF)
NRAF Crude NRAF Adjusted
CHADS2 # Patients # Strokes Stroke Rate per Stroke Rate
Score (n = 1733) (n = 94) 100 Patient-yrs (95% CI)†
0 120 2 1.2 1.9 (1.2-3.0)
1 463 17 2.8 2.8 (2.0-3.8)
2 523 23 3.6 4.0 (3.1-5.1)
3 337 25 6.4 5.9 (4.6-7.3)
4 220 19 8.0 8.5 (6.3-11.1)
5 65 6 7.7 12.5 (8.2-17.5)
6 5 2 44.0 18.2 (10.5-27.4)
Scoring:
1 point: Congestive heart failure, HTN, < 75 years, and DM
2 points: Stroke history or transient ischemic attack
† Expected stroke rate per 100 pt-yrs from the exponential survival model, assuming aspirin not taken

Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. JAMA. 2001 Jun 13;285(22):2864-70. 16
Pub Med PMID: 11401607.
CHA2DS2-VASc
2009 Birmingham Schema Expressed as a Point-Based Scoring System

Risk Factor Score

Congestive heart failure/LV dysfunction 1
Hypertension 1
Age ≥ 75 y 2
Diabetes mellitus 1
Stroke/TIA/TE 2
Vascular disease 1
(prior myocardial infarction, peripheral artery disease, or aortic plaque)
Age 65-74 y 1
Sex category 1
(i.e. female gender)
LV = left ventricular; TE = thromboembolism

Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest. 2010 Feb;137(2):263-72. Pub Med PMID: 19762550. 17
CHA2DS2-VASc
Stroke or Other TE at One Year

CHA2DS2- TE Rate During 1 yr,

VASc #TE TE Rate During Adjusted for
Score # Events 1 yr (95% CI) Aspirin RX
0 103 0 0% (0-0) 0%
1 162 1 0.6% (0.0-3.4) 0.7%
2 184 3 1.6% (0.3-4.7) 1.9%
3 203 8 3.9% (1.7-7.6) 4.7%
4 208 4 1.9% (0.5-4.9) 2.3%
5 95 3 3.2% (0.7-9.0) 3.9%
6 57 2 3.6% (0.4-12.3) 4.5%
7 25 2 8.0% (1.0-26.0) 10.1%
8 9 1 11.1% (0.3-48.3) 14.2%
9 1 1 100% (2.5-100) 100%
Total 1,084 25 P Value for trend 0.003

Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest. 2010 Feb;137(2):263-72. Pub Med PMID: 19762550. 18
CHA2DS2-VASc and CHADS2 Score 0–1
Refines stroke risk stratification in AF patients: nationwide cohort
1 Year Follow-up 12 Years Follow-up
Person Yrs Events Stroke rate (95%CI) Person Yrs Events Stroke rate (95%CI)

CHADS2 score 0–1 40,272 1,405 3.49 (3.31–3.68) 187,200 4,599 2.46 (2.39–2.53)

CHA2DS2-VASc = 0 6,919 58 0.84 (0.65–1.08) 39,500 299 0.76 (0.68–0.85)

CHA2DS2-VASc = 1 8,880 159 1.79 (1.53–2.09) 45,926 662 1.44 (1.34–1.56)

CHA2DS2-VASc = 2 11,863 435 3.67 (3.34–4.03) 51,595 1,489 2.89 (2.74–3.04)

CHA2DS2-VASc = 3 11,473 660 5.75 (5.33–6.21) 45,799 1,933 4.22 (4.04–4.41)

CHA2DS2-VASc = 4 1,137 93 8.18 (6.68–10.02) 4,380 216 4.93 (4.32–5.64)

CHADS2 score = 0 17,327 275 1.59 (1.41–1.79) 92,531 1182 1.28 (1.21–1.35)

CHA2DS2-VASc = 0 6,919 58 0.84 (0.65–1.08) 39,500 299 0.76 (0.68–0.85)

CHA2DS2-VASc = 1 6,811 119 1.75 (1.46–2.09) 35,079 504 1.44 (1.32–1.57)

CHA2DS2-VASc = 2 3,347 90 2.69 (2.19–3.31) 16,710 353 2.11 (1.90–2.34)

CHA2DS2-VASc = 3 250 8 3.20 (1.60–6.40) 1,242 26 2.09 (1.43–3.07)

CHADS2 Score = 1 22,945 1,130 4.92 (4.65–5.22) 94,669 3417 3.61 (3.49–3.73)

CHA2DS2-VASc = 1 2,069 40 1.93 (1.42–2.64) 10,847 158 1.46 (1.25–1.70)

CHA2DS2-VASc = 2 8,516 345 4.05 (3.65–4.50) 34,885 1136 3.26 (3.07–3.45)

CHA2DS2-VASc = 3 11,223 652 5.81 (5.38–6.27) 44,557 1907 4.28 (4.09–4.48)

CHA2DS2-VASc = 4 1,137 93 8.18 (6.68–10.02) 4,380 216 4.93 (4.32–5.64)

Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. Thromb Haemost. 2012 Jun;107(6):1172-9. Pub Med PMID: 22473219. 19
Question #4
78 year old male with atrial fibrillation and hypertension
(CHADS2 score = 2 [4% stroke rate per year]). What is his
annual major bleeding rate?
1. 1%
2. 2%
3. 3%
4. 5%
5. 10%

20
Bleeding Risk Scores
• Variety of scoring systems developed to predict risk of
bleeding in patients initiating anticoagulants, as with
stroke risk
• Less predictive than stroke risk scores, in general

• Each score incorporates clinical characteristics and

provides estimate of risk of bleeding in a population
similar to patients being considered
• Unclear whether to include risk scores in decision making
for individual patients

21
Bleeding Risk Scores Widely Used in AF
• HAEMORRHAGES1
• HASBLED2
• ATRIA Score3

1. Gage BF, et al. Am Heart J. 2006 Mar;151(3):713-9. PMID: 16504638. Pub Med PMID:16504638.
2. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. Chest. 2010 Nov;138(5):1093-100. PMID:20299623.
3. Fang MC, et al. J Am Coll Cardiol. 2011 Jul 19;58(4):395-401. Pub Med PMID:21757117. 22
Bleeding Risk Scores in AF
ATRIA HAS-BLED HEMORR2HAGES

Anemia1 3 Hypertension4 1 Hepatic10 or 1

Renal disease2 1

Severe renal disease2 3 Abnormal Renal5 or 1

Ethanol abuse 1
Liver function6 1
Age ≥75 yrs 2 Stroke 1 Malignancy 1
Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1

Hypertension3 1 Labile INR8 1 Reduced platelet number 1

or function11
Elderly (>65 yrs) 1 Rebleeding12 2
Drugs9 or 1
Hypertension4 1
1.
2.
Hemoglobin <13 g/dl men; <12 g/dl women
Estimated glomerular filtration rate <30 ml/min or dialysis-dependent Alcohol 1
3. Diagnosed hypertension
4. Systolic blood pressure >160 mmHg
5.
6.
Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 mmol/L
Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal,
Anemia13 1
in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)
8.
9.
Unstable/high INRs or poor time in therapeutic range (eg <60%)
Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc.
Genetic factors14 1
10. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl
11.
12.
Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia
Prior hospitalization for bleeding
Excessive fall risk15 1
13. Most recent hematocrit <30 or hemoglobin <10 g/dl
14.
15.
CYP2C9*2 and/or CYP2C9*3
Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls Stroke 1
Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] 23
Online Appendix. PMID: 22858389.
AMADEUS Cohort
Stratified by the HEMORR2HAGES, HAS-BLED, and ATRIA Schemes

Clinically
Relevant Major
Scheme All Patients Bleeding Bleeding
HEMORR2HAGES
Low (≤1) Risk 1,738 (76.6) 182 (10.5) 25 (1.4)
Intermediate Risk (2–3) 517 (22.8) 63 (12.2) 13 (2.5)
High Risk (>3) 13 (0.5) 3 (23.1) 1 (7.7)
TOTAL 2,268 248 (10.9) 39 (1.7)
HAS-BLED
Low Risk (<3) 1,739 (75.9) 159 (9.1) 22 (1.3)
High Risk (≥3) 553 (24.1) 92 (16.6) 17 (3.1)
TOTAL 2,292 251 (11.0) 39 (1.7)
ATRIA
Low Risk (<4) 2,038 (90) 220 (10.8) 31 (1.5)
Intermediate Risk (4) 102 (4.4) 13 (12.7) 3 (2.9)
High Risk (>4) 128 (5.6) 18 (14.1) 5 (3.9)
TOTAL 2,268 248 (10.9) 39 (1.7)

Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] 24
Online Appendix. PMID: 22858389.
Risks of Bleeding with Warfarin or
Dabigatran in AF

Oldgren J, et al. Ann Intern Med. 2011 Nov 15;155(10):660-7, W204. Pub Med PMID: 22084332. 25
Adjusted HR for Death After Stroke,
MI, or Major Hemorrhage
In Patients Who Received Antiplatelet Therapy in the ACTIVE Trials
Event Pts With Subsequent HR for Death Relative
Event, n Deaths, n (95% CI)† Weights‡
(Adjusted Rate)
Ischemic stroke 785 362 (36.4) 5.74 1.00
(5.10 – 6.47) (reference)

Hemorrhage stroke 59 48 (81.4) 17.67 3.08

(13.15 – 23.75)
Subdural 42 15 (32.4) 3.44 0.60
hemorrhage (2.06 – 5.74)
Major extracranial 435 162 (31.6) 3.82 0.67
bleeding event (3.24 – 4.51)
Myocardial 260 120 (38.9) 5.44 0.95
infarction (4.51 – 6.56)
† Compared to no event
‡ ratio of hazard ratios

Connolly SJ, et al. Ann Intern Med. 2011 Nov 1;155(9):579-86. Pub Med PMID: 22041946. 26
 PREVENTING
Atrial Fibrillation Related

Highlights STROKES
with Anticoagulants

• Prevalence and incidence of AF

• Risk stratification for stroke and bleeding
• New oral anticoagulants
• Guidelines
• Practical considerations for choosing an anticoagulant
Pharmacokinetics of NOACs
Apixaban Dabigatran Rivaroxaban
Direct factor inhibition Xa IIa Xa
Bioavailability (Frel) 80% 6% 80%
Peak action (tmax) 1–3 hr 1–3 hr 1–3 hr
Protein binding 84% 35% 92–95%
Renal clearance 25% 80% 33%
Elimination half life with creatinine 15.1 hr 13.8 hr 8.3 hr
clearance > 80 ml/min
Elimination half life with creatinine 14.6 hr 16.6 hr 8.7 hr
clearance 50–79 ml/min
Elimination half life with creatinine 17.6 hr 18.7 hr 9.0 hr
clearance 30–49 ml/min
Elimination half life with creatinine 17.3 hr 27.5 hr 9.5 hr
clearance < 30 ml/min

Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649. 28
Measuring the Effect of NOACs
Coagulation Assays Apixaban Rivaroxaban Dabigatran
PT Not useful Qualitative Not useful
-dilute PT Data n/a Data n/a Data n/a
-modified PT Qualitative Data n/a Data n/a

aPTT Not useful Not useful Qualitative

TT No effect No effect Qualitative

-dTT/HEMOCLOT No effect No effect Quantitative

Chromogenic Assays
-Anti-Xa Quantitative Quantitative No effect
-Anti-Iia No effect No Effect Quantitative
n/a = not available

Garcia DA, et al. In review. 29

Reversal of NOACs
Types of Studies Evaluating Reversal of New Oral Anticoagulants

Apixaban Dabigatran Rivaroxaban

Oral activated No data In vitro No data
charcoal

Hemodialysis No data Human volunteers No data

Hemoperfusion with No data In vitro No data
activated charcoal
Fresh frozen plasma No data Mouse model No data

Activated factor VIIa No data Rat model Rat and baboon

model
3-factor PCC No data No data No data

4-factor PCC No data Human volunteers Human volunteers

and rat model

Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649. 30
Reversal of NOACs
Suggestions for Reversal of New Oral Anticoagulants

Apixaban Dabigatran Rivaroxaban

Oral activated Yes Yes Yes
charcoal

Hemodialysis No Yes No
Hemoperfusion with Possible Yes Possible
activated charcoal
Fresh frozen plasma No No No

Activated factor VIIa Unclear Unclear Unclear

3-factor PCC Unclear Unclear Unclear

4-factor PCC Possible Possible Possible

Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649. 31
Meta-analysis of Efficacy and Safety of
New Oral Anticoagulants
Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients

All cause stroke/SEE

Ischemic and unspecified stroke

Hemorrhagic stroke

32
Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354..
Meta-analysis of Efficacy and Safety of
New Oral Anticoagulants
Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients

Major bleeding

Intracranial bleeding

GI Bleeding

Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.33
 PREVENTING
Atrial Fibrillation Related

Highlights STROKES
with Anticoagulants

• Prevalence and incidence of AF

• Risk stratification for stroke and bleeding
• New oral anticoagulants
• Guidelines
• Practical considerations for choosing an anticoagulant
Question #5
78 year old female with atrial fibrillation, hypertension and
CHF.
CHADS2 = 3
CHA2DS2-VASc = 5
HAS-BLED = 2
What would you use for stroke prevention?
1. No anti-thrombotics
2. Aspirin
3. Aspirin + clopidogrel
4. VKA antagonist
5. Dabigatran or Rivaroxaban

35
European Society of Cardiology Guidelines
CHA2DS2-VASc and Stroke Rate
Risk Factors
For Stroke and Thrombo-embolism in Non-valvular AF
Risk Factor Score
Congestive heart failure/LV dysfunction* 1
Hypertension* 1
Age >75** 2
Diabetes Mellitus* 1
Stroke / TIA / Thrombo-embolism** 2
Vascular Disease* 1
Age 65-74* 1
Sex category (i.e. female sex)* 1
Maximum Score 9
Note: maximum score is 9 since age may contribute 0,1, or 2 points
* ‘Clinically relevant non-major’ risk factor
** “Major” risk factor

Camm AJ. Europace. 2010 Oct;12(10):1360-420. Pub Med PMID: 20876603. 36

European Society of Cardiology Guidelines
Approach to Thromboprophylaxis in Patients with AF
CHA2DS2-VASc Recommended
Risk Category Score Antithrombotic Therapy1
One ‘major’ risk factor
or > 2 ‘clinically relevant >2 OAC
non-major’ risk factors
One ‘clinically relevant • Either OAC or aspirin 75-325 mg daily
1
non-major’ risk factor’ • Preferred: OAC rather than aspirin
• Either aspirin 75-325 mg daily or no
antithrombotic therapy
No risk factors 0
• Preferred: no antithrombotic therapy
rather than aspirin

Risk of Bleeding HAS-BLED Score Dabigatran Dosage2

Low risk 0–2 150 mg b.i.d.
Measurable risk, or 1 clinically- ≥3 110 mg b.i.d.
relevant non-major risk factor

1. Camm AJ. Europace. 2010 Oct;12(10):1360-420. Pub Med PMID: 20876603.

2. Connolly SJ, et al. N Engl J Med 2009;361:1139–1151. PMID: 19717844. 37
2011 ACCF/AHA/HRS Guidelines
Antithrombotic Therapy for Patients with Atrial Fibrillation
1
Risk Category Recommended Therapy
No risk factors Aspirin, 81 to 325 mg daily
One moderate risk factor Aspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5)
Any high risk factor or
Warfarin (INR 2.0 to 3.0, target 2.5)*
> 1 moderate-risk factor

Less Validated / 1
Weaker Risk Factors Moderate Risk Factors High Risk Factors
Female gender Age >75 years Previous stroke, TIA or embolism
Age 65 to 74 years Hypertension Mitral stenosis
Coronary artery disease Heart failure Prosthetic heart valve*
* If mechanical valve, target international normalized ratio (INR) > 2.5
Thyrotoxicosis LV ejection fraction <35%
Diabetes mellitus
2
2011 Focused Update Recommendation Class I Comments

Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic New Recommendation
thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or
systemic embolization who do not have a prosthetic heart valve or hemodynamically significant
valve disease, severe renal failure (creatinine clearance <15 mL/min) or advanced liver disease
(impaired baseline clotting function). (Level of Evidence: B)
1. Fuster V. Circulation. 2011 Mar 15;123(10): Pub Med PMID: 21382897. 38
2. Wann LS, et al. J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7. Pub Med PMID: 21324629.
ACCP Guidelines
For patients with Nonrheumatic AF, including those with Paroxysmal AF

ACCP
Level of Risk Recommendation Alternative* Not Recommended
Low Risk No Therapy Aspirin Oral anticoagulation
(CHADS2 = 0) or combination
therapy with aspirin
and clopidogrel
Intermediate Risk Oral anticoagulation Aspirin with Aspirin
(CHADS2 = 1) clopidogrel
High Risk Oral anticoagulation Aspirin with Aspirin
(CHADS2 = 2) (dabigatran 150 mg clopidogrel
b.i.d. vs. VKA**)

*For patients with AF unsuitable for, or who refuse, oral anticoagulant (for reasons other than concerns about major bleeding)
**VKA = adjusted-dose vitamin K antagonist

You JJ, et al. Chest. 2012 Feb;141(2 Suppl):e531S-75S. Pub Med PMID: 22315271. 39
Canadian Cardiovascular Society
Guidelines
Assess Thromboembolic Risk
(CHADS2)

CHADS2 = 0 CHADS2 = 1 CHADS2 = 2

Increasing stroke risk

No anti-
thrombotic ASA OAC* OAC* OAC

Age > 65 yrs When OAC therapy is indicated,

Either Age >or65 yrs *ASA is a most patients receive:
No female sex or
combination reasonable • Dabigatran, rivaroxaban,
additional or combination
female sex alternative or apixaban (after Health
risk factors female sex for some as Canada approval)
for stroke vascular and
and vascular indicated by • In preference to warfarin
disease vascular
disease risk/benefit • Conditional Recommendation,
disease High-Quality Evidence

Skanes AC, et al. Can J Cardiol. 2012 Mar-Apr;28(2):125-36. Pub Med PMID: 22433576. 40
 PREVENTING
Atrial Fibrillation Related

Highlights STROKES
with Anticoagulants

• Prevalence and incidence of AF

• Risk stratification for stroke and bleeding
• New oral anticoagulants
• Guidelines
• Practical considerations for choosing an anticoagulant
Optimal Candidates for New Drugs
Patients who:
• Find INR testing burdensome

• Despite adherence to provider recommendations,

have low ‘time-in-range’
• Can afford (or arrange to get) the new drugs

• Have normal renal function

42
Optimal Candidates for Warfarin
Patients who:
• Have (borderline) renal insufficiency

• Are taking stable dose of warfarin and do not find INR

testing burdensome
• Have access to self-testing machine

• Are concerned about the lack of an evidence-based

reversal strategy

43
 10
20
30
40
60
70
80
90

0
Taiwan
Mexico

50 44 47
Peru
Romania
India

48 49 49
Columbia
Russia
Brazil
China
Korea

53 53 54 55 55
Greece
Thailand
Malaysia
Poland
Japan
South Africa
56 56 56 57 58 58

France
Slocakia
Portugal
Israel
60 60 62 62

Czech Republic
Philippines
Bulgaria
Hungary
Hong Kong
64 64 64 64 64

Wallentin L, et al. Lancet. 2010 Sep 18;376(9745):975-83. PMID: 20801496.

Turkey
Belgium
Austria
USA
TTR per Country in RELY

USA: Spain

Needed
Germany
65 65 66 66 66 67

Improvement
Switzerland
Singapore
68 68

Argentina
Netherlands
Norway
Canada
Italy
Ukraine
UK
Denmark
70 70 70 71 71 72 72 72

Austrailia
Finland
74 74

Sweden
77

44
Stroke and Systemic Embolism
By Center TTR in RELY

• TTR=optimum
therapeutic
range

• cTTR=center's
mean TTR

Wallentin L, et al. Lancet. 2010 Sep 18;376(9745):975-83. Pub Med PMID: 20801496. 45
Major Bleeding
By Center TTR in RELY

• TTR=optimum
therapeutic
range

• cTTR=center's
mean TTR

Wallentin L, et al. Lancet. 2010 Sep 18;376(9745):975-83. PMID: 20801496. 46

Stroke and Systemic Embolization by
Center Proportion of INR in Therapeutic
Range in ROCKET AF
Rivaroxaban
Rivaroxaban Warfarin vs. Warfarin
Center TTR‡ Total Event Rate Total Event Rate Hazard Ratio
(100 Pt Yrs)§ (100 Pt Yrs)§ (95% CI)II
0.00-50.6% 45/1735 (2.59) 1.77 62/1689 (3.67) 2.53 0.70 (0.48, 1.03)

50.7%-58.5% 53/1746 (3.04) 1.94 63/1807 (3.49) 2.18 0.89 (0.62, 1.29)

58.6-65.7% 54/1734 (3.11) 1.90 62/1758 (3.53) 2.14 0.89 (0.62, 1.28)

65.7-100.0% 37/1676 (2.21) 1.33 55/1826 (3.01) 1.80 0.74 (0.49, 1.12)

N=7061 rivaroxaban N=7082 warfarin

P value for interaction=0.736
Time in therapeutic range-2-3 inclusive
‡Center TTR calculated using total INR values in target range from all warfarin subjects
within center, divided by total INR values from all warfarin subjects within center
§Number of events per 100 patient-years of follow-up
II Hazard ratio from Cox proportional hazard model with treatment as a covariate

Patel MR, et al. N Engl J Med. 2011 Sep 8;365(10):883-91. Pub Med PMID: 21830957. 47
 PREVENTING
Atrial Fibrillation Related

Summary STROKES
with Anticoagulants

• Prevalence and incidence of AF

• Risk stratification for stroke and bleeding
• New oral anticoagulants
• Guidelines
• Practical considerations for choosing an anticoagulant

48