atrial fibrillation and stroke prevention - Continuing Medical ...

Essentials in Primary Care Conference 

Wednesday, July 31, 2013 

ATRIAL FIBRILLATION AND 

STROKE PREVENTION 

4 th Annual Essentials in Primary Care Summer Conference 

Kiawah Island, South Carolina 

July 31, 2013 

Jan Basile, MD 

Seinsheimer Cardiovascular Health Program 

Professor of Medicine 

Medical University of South Carolina 

Charleston, South Carolina 

DISCLOSURE OF FINANCIAL RELATIONSHIPS 

Jan N. Basile, MD 

Grant/Research support: NHLBI (SPRINT) 

Consultant: 

Daiichi-Sankyo, Forest, Takeda 

Speakers Bureau: 

Major stock shareholder: 

Other: 

Daiichi-Sankyo, Forest, Takeda, 

Boehringer Ingelheim, Lilly 

None 

None 


Atrial Fibrillation & Stroke Prevention



Educational Objectives 

• Understand the 3 important clinical strategies to 

consider when treating the patient with Atrial 

Fibrillation 

• Be familiar with the evidence for rate vs rhythm 

control in patients with Atrial Fibrillation 

• Understand the CHADS 2 and CHA 2 DS 2 -VASc 

score to assess stroke risk in patients with atrial 

fibrillation (AF) 

• Recognize the benefits versus risks of 

antithrombotic therapy for stroke risk reduction in 

AF patients 

• Be familiar with the new oral anticoagulants and the 

evidence-based studies that allowed them to be 

FDA approved 

Atrial Fibrillation: 

The Most Common Cardiac Arrhythmia 

• The prevalence of AF roughly doubles with 

each decade of age: 

– 0.5% at age 50–59 years 

– 9.0% at age 80–90 years 

• Present in 3–6% of acute hospital admissions 

• Prevalence of 4.7% of people aged 65 years or 

over in general practice 

• More common in men (regardless of age) 

• Greater risk in women 

• More common in whites than blacks, obese, 

those with alcohol use, metabolic syndrome 

Roger VL. et al. Circulation 2011; 123:e18—e209. 





Prevalence of Atrial Fibrillation 

Stratified by Age and Sex 

x-axis = % 

with AF 

y-axis = 

age of 

person 

# 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. 

AF Accounts For An Increasing 

Number of Hospitalizations 

(National Hospital Discharge Survey) 

Prevalence per 10,000 Persons 

140 

120 

100 

80 

60 

40 

20 

Principal Diagnosis 

of AF 

0 

1985 1987 1989 1991 1993 1995 1997 1999 

Year 

Per 10,000 Persons 

1400 

1200 

1000 

800 

600 

400 

200 

Any Diagnosis 

of AF 

0 

1985 1987 1989 1991 1993 1995 1997 1999 

Year 

Age (y) 85+ 75-84 65-74 55-64 35-54 

Wattigney WA, et al. Circulation. 2003;108:711-716. 





Atrial Fibrillation Adversely Affects 

Quality of Life (QoL) Even When 

Stroke is Not Involved 

Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309. 

Kalantarian S, et al. Ann Int Med 2013:158:338-346. 

Atrial Fibrillation Management: 

3 Important Clinical Strategies 

RATE 

CONTROL 

BB 

CCB 

Digoxin 

STROKE 

PREVENTION 

Warfarin 

Dabigatran 

Rivaroxaban 

Apixaban 

Asa + Clopidogrel 

Asa 

Anti-arrythmics 

Cardioversion 

Non- 

Pharmacologic 

strategies 

RHYTHM 

CONTROL 





Classifying AF 

Classification of AF 

ACC/AHA/ESC Guidelines 

< 7 days 

First 

Detected 

> 7 days 

Paroxysmal 

(Self-terminating) 

May be recurrent 

Persistent 

(not self-terminating ) 

1 year or longer 

Permanent 

(cardioversion failed 

or not attempted) 

1 year or longer 

Fuster et al. J Am Coll Cardiol. 2006;48:854. 





Who Develops Atrial Fibrillation 

Etiology/Risk factors 

• Structural heart disease (valvular disease) 

• Age (the older the more likely) 

• Hypertension 

• Pericarditis 

• Pulmonary Embolism 

• Chronic Lung Disease 

• Hyperthyroidism 

• Pneumonia 

• Others 

Bosiak M et al. Cardiol J. 2010;17:437-442. 

Approaches To Atrial Fibrillation 

1. Identify and treat reversible causes 

(pneumonia, hyperthyriodism, holiday 

heart, etc.) 

2. Workup with TSH, Metabolic Panel, Echo 

(LV function, rule out valvular disease), 

Consider Ischemia as an etiology 

3. Evaluate for rate vs rhythm control 

4. Stroke Prevention-Anticoagulation therapy 





Case… Rate vs Rhythm control? 

• A 68 year old currently asx male is in 

your office with a history of AF, 

hypertension and diabetes 

• BP 134/82 mmHg; pulse of 95 bpm 

with an irregularly irregular pattern. 

• Medications include: 

–Diltiazem CD 300 mg daily* 

–Lisinopril 40 mg daily 

–Metformin 500 mg twice daily 

–Aspirin 81 mg daily 

Ulimoen SR et al. Am J Cardiol. 2013:111-225-230. 

Rhythm Strip of A Fib with RVR 

RVR=rapid ventricular response 





Questions to answer 

• Would this patient benefit more 

from rate control or rhythm 

control with acute cardioversion 

or medical (anti-arrhythmic) 

conversion?-AFFIRM, AF-CHF 

• What is the target heart rate in a 

patient with asx or minimally 

symptomatic AF-(lenient vs strict 

rate control)?-RACE II 

AFFIRM 

Atrial Fibrillation Follow-up Investigation 

of Rhythm Management 

Primary Endpoint: All-Cause Mortality 

Mortality (%) 

Time (Y) 

25 

20 

15 

10 

5 

0 

p = 0.08 

•4080 pts, 

• mean age 70 yrs 

• 40% female 

•paroxysmal or persistent atrial fibrillation 

•All treated with coumadin 

Rhythm 

Rate 

Rhythm-guideline based anti-arrythmia Rx 

Rate-80 at rest,110 with exercise 

0 1 2 3 4 5 

Rate N 2027 1925 1825 1328 774 236 

Rhythm N 2033 1932 1807 1316 780 255 

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





The Atrial Fibrillation and Congestive Heart Failure 

(AF-CHF) [EF < 35%, clinical HF] Trial: Results 

(n=1376;1 endpoint=time to death from CV causes 

Rhythm Control 

Rate 

Control 

p-value 

Cardiovascular 

Mortality 

26.7 % 25.2 % NS 

Total Mortality 31.8 % 32.9 % NS 

Stroke 2.6 % 3.6 % NS 

Hospitalization 46 % 39 % 0.001 

Worsening CHF 27.6 % 30.8 % NS 

Roy et al. N Engl J Med. 2008;358:2667-2677. 

RAte Control Efficacy in Permanent 

Atrial Fibrillation II (RACE II) 

• Since rate control is as good as rhythm 

control, then let’s test 311 patients 

randomized to lenient (resting HR < 110 

BPM) vs 303 strict rate control (resting HR 

< 80 BPM, with exercise < 110 BPM) 

• Mean follow-up 2 years, max 3 years 

• BB alone (45%), CCB alone (6%), digoxin 

alone (6%), BB + dig (17%), BB + 

dilt/verap (3%), sotalol (5%), amiod (1.3%) 

Van Gelder IC, et al. RACE II trial. NEJM 2010;362:1363-73. 





RACE-II Trial 

• Primary outcome (composite of death from 

CV causes, hospitalization for heart failure, 

stroke, systemic embolism, bleeding, lifethreatening 

arrhythmias) 

–12.9% lenient control vs 14.9% strict (NS) 

• No difference in any individual outcome 

• No difference in hospitalizations or adverse 

effects 

• Conclusion: lenient rate control (resting HR 

< 110) is as effective and easier to achieve 

Van Gelder IC, et al. RACE II trial. NEJM 2010;362:1363-73. 

2011 ACCF/AHA/HRS Focused Update: 

Strict vs Lenient Control 

• Class III-No Benefit 

- Treatment to achieve strict rate control (HR < 80 

bpm at rest or < 110 bpm during 6-min walk) is not 

beneficial compared to achieving a resting HR < 

110 bpm in patients with persistent AF who have 

stable ventricular function and no or acceptable 

symptoms related to the arrhythmia 

Wann LS et al. Circulation 2011;123:11144-1150. 





Regardless of your Decision to 

Achieve Rhythm vs. Rate Control 

Choice of therapeutic strategy does 

not affect your decision regarding 

anticoagulation, i.e., achieving normal 

sinus rhythm does not allow one to 

stop anticoagulation-be it by 

-Antiarrythmic Rx 

-RF ablation 

-Cardioversion 

Asymptomatic Episodes More Common After 

Catheter Ablation for Atrial Fibrillation 

(DISCERN)* 

• Implantable Cardiac Monitor (ICM) placed 

3 months before and for a mean of 18 

months after RF ablation for AF in 50 pts 

• The ratio of asymptomatic to symptomatic 

AF episodes increased from 1.1 to 3.7 

(p=0.002) 

• Post-ablation state is the strongest 

predictor of asymptomatic AF with 12% of 

patients having asx recurrences only 

(DISCERN) Discerning Symptomatic and Asymptomatic Episodes Pre and Post Radiofrequency Ablation of 

Atrial Fibrillation 

Verma A et al. Jama Internal Medicine 2013;173 (2):149-156. 





Atrial Fibrillation Management: 

3 Important Clinical Strategies 

STROKE 

PREVENTION 

Warfarin 

Dabigatran 

Rivaroxaban 

Apixaban 

Asa + Clopidogrel 

Asa 

Atrial Fibrillation: 

A Major Contibutor to Stroke in the Elderly 

Framingham Study, 30-Year Follow-Up, n=5184 Men + Woman* 

Age 

Group 

Preval 

ence 

AF 

Stroke per 

1000 py O 

Stroke per 

1000 py AF 

IDR 

Pop. 

AR % † 

60 - 69 1.8% 4.5 21.2 4.7 8.1 

70 - 79 4.7% 9.0 48.9 5.4 21.3 

80 - 89 10.2% 14.3 71.4 5.0 36.2 

† Pop AR=% of all strokes attributed to atrial fibrillation;adjusted for BP 

* Wolf PA, Abbott RD, Kannel WB. Arch Intern Med 1987;147:1561-1564. 





NVAF ASA Trials: 

Dubious Stroke Reduction 

AFASAK I 

SPAF I 

EAFT 

ESPS II 

LASAF 

UK-TIA 

Relative Risk Reduction (95% CI) 

All trials 

22% (2%-38%) 

Hart et al. Ann Intern Med. 1999;131:492-501. 

100 50 0 -50 -100 

Favors ASA Favors Placebo 

NVAF Warfarin Trials: 

Stroke & Mortality Reduction 

All cause mortality RRR = 26% 

AFASAK 

SPAF 

BAATAF 

CAFA 

SPINAF 

•N=2900 

• mean age 69 

•20% > 70 yrs old 

EAFT 

All Trials 62% (48%-72%) 

100% 50% 0 -50% -100% 

Favors Warfarin Favors Placebo 

Hart et al. Ann Intern Med. 1999;131:492-501. 





Current Use of Warfarin in Preventing 

Stroke: A Recent Meta-Analysis 

• Previous Hart Meta-analysis (Ann Int Med 1999) with Warfarin 

revealed stroke or systemic embolism event rate at 2.09% per 

year with only 2 of 6 trials with time in therapeutic range (TTR) 

above 60% 

• This updated meta-analysis included 8 Randomized trials 

(including RE-LY, ROCKET-AF, ARISTOTLE) with 32,053 patients 

• Overall INR was in therapeutic range (TTR) in 7 of the 8 trials 

more than 60% of the time 

• Incidence of stroke or systemic embolism now at 1.66% per year 

(down from 2.09% per year) with warfarin Rx with better TTR. 

TAKE AWAY POINT: 

• There has been a significant improvement using warfarin in the 

proportion of time spent in therapeutic anticoagulation with a 

resultant decline in observed stroke rates. 

Agarwal S, et al. Archives Intern Med 2012;172:623-631 

Can We Make Warfarin Use 

Easier for the Patient? 

• Study: VKA patients on stable dose of warfarin for 6 

months currently on monthly f/u (n=226) with stable 

INR 

• Intervention: f/u Q4 weeks vs Q 12 weeks 

• Outcome : 

TTR (4 wk vs 12 wk): 74.1% vs 72.6% (non inferior) 

Major bleeding, VTE, death: No difference 

Intervention: f/u Q4 weeks vs Q 12 weeks 

• Conclusion: 

Q 3 months f/up of warfarin monitoring is 

acceptable in a patient with a stable and 

therapeutic INR 

Schulman S, Ann Intern Med 2011;155:653-659 





Antithrombotic Paradox in AF: 

The Greater The Stroke Risk, The Less The 

Anticoagulant Use 

Wolf PA. Arch Intern Med 1987;147:1561-4 

White RH. Am J Med 1999;106:165-71 

Why Warfarin Is Underutilized in Clinical Practice 

for Non-Valvular Atrial Fibrillation (NVAF) 

• Narrow Therapeutic Index Drug (INR 2.0-3.0 range; 

target 2.5) [Mechanical valves INR 3.0-4.0 range; 

target 3.5] 

• Drug-Drug Interactions 

• Food-Drug Interactions (Vit K containing foods) 

• Has Required frequent laboratory monitoring 

• Bleeding risk 

Bottom Line: 

• Up to 50% of NVAF patients are not taking an oral 

anticoagulant 





Balancing the Risk of Stroke Vs Bleeding: 

Risk of ICH is Very Low when INR Between 2 and 3 

20 

Ischemic stroke 

Odds Ratio 

15 

10 

5 

IDEAL 

Intracranial hemmorhage (ICH) 

1 

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 

INR 

Fuster et al. J Am Coll Cardiol. 2001;38:1231-1265. 

Hylek et al. Ann Intern Med. 1994;120:897-902. 

Intracranial Hemorrhage During Long- 

Term Anticoagulation With Warfarin 

ICH %/Year 

2.0 

1.8 

1.6 

1.4 

1.2 

1.0 

0.8 

0.6 

0.4 

0.2 

INR 



Predicting Stroke Risk in NVAF: 

Scoring Systems 

• A variety of systems have been published 

• No single scoring system is universally accepted 

• Most widely used in the US is the CHADS 2 score 

• All scores have been derived from groups of 

Non- Valvular AF patients who were not 

anti-coagulated 

• Europeans recommend using the CHA 2 DS 2 - 

VASc score especially when the CHADS 2 

score is 0-1. 

Why CHADS 2 In AT9 Chest 

Guidelines 2012? 

“The CHADS 2 score is the most 

validated risk scheme, having been 

independently tested in at least 10 

separate cohorts after its original 

derivation.” 

You JJ, et al. CHEST 2012;141(2)(Suppl):e531S-e575S 





CHADS 2 

Score 

CHADS 2 : Risk of Stroke 

National Registry of Atrial Fibrillation Participants (NRAF) 

# Patients 

(n = 1733) 

# Strokes 

(n = 94) 

NRAF Crude 

Stroke Rate per 

100 Patient-yrs 

NRAF Adjusted 

Stroke Rate 

(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: History of stroke or transient ischemic attack 

† Expected stroke rate per 100 pt-yrs, assuming aspirin not being taken 

Gage BF, et al. JAMA. 2001 Jun 13;285(22):2864-70. 

AF Rx as Per CHADS 2 Score: 

AT9 (2012) 

CHADS 2 

Rx 

0 

1 

>2 

No Rx (2B) 

Oral Anticoagulant 

(1B) 


(1A) 

If patient chooses treatment, 

then ASA 81-325 mg/d (2B) 

If patient unwilling or unsuitable, then 

ASA + clopidogrel (2B) 

If patient unwilling or unsuitable, then 

ASA + clopidogrel (1B) 






CHADS 2 Limitations 

• CHF: independent predictive role inconsistent 

• HTN: stroke risk may vary with degree or 

method of HTN control 

• AGE: even at age 65, risk increases 

• GENDER: risk in women > men and women 

not accounted for 

• VASCULOPATHY: MI, PAD, AORTIC 

PLAQUE associated with increased stroke risk 


CHA 2 DS 2 -VASc-Total Points 9 

2009 Birmingham England 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 

(prior myocardial infarction, peripheral artery disease, or aortic plaque) 

Age 65-74 y 1 

Sex category 

(i.e. female gender) 

LV = left ventricular; TE = thromboembolism 

How different from CHADS2 score 

1 

1 

Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest. 2010 Feb;137(2):263-72. 





Stroke Risk Stratification in AF 

Total Score 

0 

1 

2 

3 

4 

5 

6 

7 

8 

9 

NRAF Adjusted Stroke 

Rate (%)* 

CHADS 2 

1.9 

2.8 

4.0 

5.9 

8.5 

12.5 

18.2 

CHA 2 DS 2 -VASc 

0 

1.3 

2.2 

3.2 

4.0 

6.7 

9.8 

9.6 

6.7 

15.2 

*The adjusted stroke rate is the expected stroke rate 

per 100 patient-years from the exponential survival 

model, assuming that aspirin was not taken. 

NRAF = National Registry of Atrial Fibrillation. 

Lip GY, et al. Am J Med. 2010;123(6):484-488. 

Camm AJ, et al. Eur Heart J. 2010;31(19):2369-2429. 

Gage BF, et al. JAMA. 2001;285(22):2864-2870. 

Risk Factor 

CHF 

HTN 

Age 75 years 

Diabetes mellitus 

Stroke 

CHADS 2 


Score 

1 

1 

1 

1 

2 

Risk Factor 

Score 

CHF 1 

HTN 1 

Age 75 years 2 

Diabetes mellitus 1 

Stroke 2 

Vascular disease (MI, peripheral 

arterial disease, aortic atherosclerosis) 

1 

Age 65-74 years 1 

Sex category (female) 1 

Where 


Might Help? 





CHA 2 DS 2 -VASc When CHADS 2 Score 0 

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) 

CHADS 2 score 0–1 40,272 1,405 3.49 (3.31–3.68) 187,200 4,599 2.46 (2.39–2.53) 

CHA 2DS 2-VASc = 0 6,919 58 0.84 (0.65–1.08) 39,500 299 0.76 (0.68–0.85) 

CHA 2DS 2-VASc = 1 8,880 159 1.79 (1.53–2.09) 45,926 662 1.44 (1.34–1.56) 

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

CHA 2DS 2-VASc = 3 11,473 660 5.75 (5.33–6.21) 45,799 1,933 4.22 (4.04–4.41) 

CHA 2DS 2-VASc = 4 1,137 93 8.18 (6.68–10.02) 4,380 216 4.93 (4.32–5.64) 

CHADS 2 score = 0 17,327 275 1.59 (1.41–1.79) 92,531 1182 1.28 (1.21–1.35) 

CHA 2DS 2-VASc = 0 6,919 58 0.84 (0.65–1.08) 39,500 299 0.76 (0.68–0.85) 

CHA 2DS 2-VASc = 1 6,811 119 1.75 (1.46–2.09) 35,079 504 1.44 (1.32–1.57) 

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

CHA 2DS 2-VASc = 3 250 8 3.20 (1.60–6.40) 1,242 26 2.09 (1.43–3.07) 

CHADS 2 Score = 1 22,945 1,130 4.92 (4.65–5.22) 94,669 3417 3.61 (3.49–3.73) 

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

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

CHA 2DS 2-VASc = 3 11,223 652 5.81 (5.38–6.27) 44,557 1907 4.28 (4.09–4.48) 

CHA 2DS 2-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 June;107(6):1172-9. 

Bleeding Risk Scores 

• Variety of scoring systems have been developed to 

predict risk of bleeding in patients initiating 

anticoagulants. 

• In general, less predictive than stroke risk scores 

• Unclear whether to include risk scores in decision 

making process for individual patients as the greater 

the need for stroke prevention, the more comorbidities 

that increase the risk of bleeding 

• Score predicts risk of ‘major bleeding’ as defined by: 

2 units PRBC OR 

Intracranial hemorrhage 





Bleeding Risk Scores Widely 

Used in Atrial Fibrillation 

• HEMORR 2 HAGES-2006 1 

• HAS-BLED-2010 2 

• ATRIA Score-2011 3 

1.Gage BF, et al. Am Heart J. 2006 Mar;151(3):713-9. PMID: 16504638. 

2.Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. Chest. 2010 Nov;138(5):1093-100. 

3.Fang MC, et al. J Am Coll Cardiol. 2011 Jul 19;58(4):395-401. 

Bleeding Risk Scores in AF 

ATRIA HAS-BLED HEMORR 2 

HAGES 

Anemia 1 3 Hypertension 4 1 

Severe renal disease 2 3 

Abnormal Renal 5 or 1 

Liver function 6 1 

Hepatic 10 or 

1 

Renal disease 2 1 

Ethanol abuse 1 

Age 75 yrs 2 Stroke 1 Malignancy 1 

Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1 

Hypertension 3 1 Labile INR 8 1 

Reduced platelet number 

or function 11 1 

Elderly (>75 yrs) 1 Rebleeding 12 2 

Drugs 9 or 

Alcohol abuse 

1. Hemoglobin



HASBLED 

Risk #points Major Bleeding 

High Risk 

(>4%/yr) 

Moderate Risk 

(2-4%/yr) 

Low Risk 

( 4 pts 6-16%/yr 

2-3 pts 2- 4%/yr 

0-1 pts 0-1%/yr 

Pisters R, et al. Chest 2010: 138: 1093 

Lip GY, et al J Am Coll Cardiol. 2011;57(2):173-180. 

Roldan V et al. Chest 2013 Jan; 143: 179. 

Bleeding Risk Prediction Generally Poor: 

The HAS-BLED Score Best Improves The 

Reclassification of One’s Bleeding Risk 

• Investigators compared the HAS-BLED, ATRIA, and older 

HEMORRHAGES score in A Fib cohort 

• Independent predictors of bleeding were age > 75, and 

age > 65, alcohol excess, anemia, and heart failure 

• Bleeding Risk Estimations by Clinicians is Poor and 

Anticoagulant Prescribing Does Not Reflect Bleeding Risk 

• HAS-BLED score performed well and helped reclassify 

bleeding risk over other bleeding risk scores tested. 

Lip GY et al. Circ Arrhythm Electrophysiol. 2012; 5:941-948. 

Roldan V et al. Chest 2013 Jan; 143: 179. 





Warfarin 

first used 

Timeline of Antithrombotic 

Therapies for Atrial Fibrillation 

Unfractionated heparin 

for PE 

Efficacy of warfarin 

to prevent AF-related stroke 

demonstrated 

Fondaparinux, bivalirudin 

and argatroban 

approved 

LMWHs approved 

For VTE 

FDA rejects ximelagatran: 

possible liver toxicity 

FDA approves 

dabigatran 

Dabigatran and 

rivaroxaban 

Europe and Canada 

FDA approves 

rivaroxaban 

FDA 

approves 

apixaban 

1950’s 

1960 

Early 

1990’s 

Mid- 

1990’s 

2000-1 

2004 

2009 Oct 2010 

Nov 2011 

Dec 2012 

XII 

Unfractionated 

Heparin 

XI 

IX 

Low 

Molecular 

Weight 

Heparin 

VIII 

X 

V 

II 

I 

Fibrin Clot 

Ericksson BI et al. Clinical Pharmacokinetics 2009;48:1-22 

Anticoagulants 

FDA Approved* and In Development** 

VII 

New Oral Xa 

Inhibitors 

Rivaroxaban* 

Apixaban* 

Edoxaban** 

Warfarin 

New Oral IIa 

(Direct 

Thrombin) 

Inhibitor 

Dabigatran * 





Antithrombotic Therapies for AF 

• Warfarin 1960’s 

• Dabigatran (Pradaxa) September 2010 

• Rivaroxaban (Xarelto) November 2011 

• Apixaban (Eliquis) December 2012 

RE-LY 

Dabigatran vs Warfarin for NV AF 

BASELINE CHARACTERISTICS 

• 18,311 subjects 

• Mean age = 72 

• Previous long-term warfarin: 50% 

• 64% men 

• Mean CHADS 2 = 2.1 

• ASA (



RE-LY 

Time to First Stroke/Systemic Embolism 

0.05- 

Warfarin 

Dabigatran 110 mg 

Dabigatran 150 mg 

H 

R 

RR = 0.91 

p < 0.001 (NI) 

P< 0.034 

(Sup) 

RR = 0.66 

(95% CI: 0.53- 

0.82) 

p < 0.001 (NI) 

P< 0.001 

(Sup) 

0.04- 

0.03- 

0.02- 

0.01- 

0.00- 

0 6 12 18 24 30 

Months 

Connolly SJ et al. NEJM 2009;361:1139-51 

RE-LY: Major Bleeding 

p=0.31 

% 

major 

bleed 

3.5- 

3.0- 

2.5- 

2.0- 

1.5- 

1.0- 

0.5- 

p=0.003 

3.36% 

2.71% 

3.11% 

warfarin 

dabigatran 

110 mg bid 

dabigatran 

150 mg bid 

Connolly SJ et al. NEJM 2009;361:1139-51 





% 

CNS 

bleed 

RE-LY: Hemorrhagic Stroke 

0.4- 

- 

0.3- 

- 

0.2- 

- 

0.1- 

- 

0.38% 

N=45 

p



Dabigatran Dosing 

• Dosing with normal renal function 

150mg PO b.i.d with or without food. 

swallow capsules whole 

• Renal impairment: 

• CrCL 15-30 mL/min : 75mg b.i.d. 

• CrCL 30 Start parenteral anticoagulant 12 hrs after the 

last dose of dabigatran 

< 30 Start parenteral anticoagulant 24 hours after 

the last dose of dabigatran 

Dabigatran Package Insert 





Time to Stroke or Systemic Embolism: 

Dabigatran vs. warfarin, stratified by center-based 

time-in-range (TTR) 

Wallentin et al. Lancet 2010. 376:975-83 

Differences in Major Outcomes 

in RE-LY and RELY-ABLE 

RE-LY patients 

(n=18,113) 

Dabigatran Dabigatran HR p-value 

150 mg bid 110 mg bid 

stroke (/yr) 1.0% 1.4% 0.70 (0.56–0.89) 0.003 

major bleeding (/yr) 3.1 % 2.7 % 1.16 (1.00-1.34) 0.05 

RELY-ABLE patients 

(N=5,671 

stroke (/yr) 1.2 % 1.4 % 0.89 (0.66-1.21) n.a. 

major bleeding (/yr) 3.8 % 3.0 % 1.26 (1.04-1.53) n.a. 

Connolly SJ, et al.The long term multi-center observational study of dabigatran treatment in 

patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128:XX-XXX. 





ROCKET AF Trial: 

Rivaroxaban vs Warfarin 

Nonvalvular AF, 

history of stroke, 

TIA, or embolism, 

or at least 2 of the 

following: HF, 

HTN, age 75 

years, or diabetes 

mellitus 

R 

Day 1 

Treatment period 12-32 months 

Rivaroxaban 20 mg QD 

Rivaroxaban 15 mg QD 

(CrCl 30-49 mL/min at entry) 

N = 14,269 

Warfarin target INR, 2.5 

(INR range, 2.0-3.0) 

End of treatment 

Follow-up 

Day 30 

after last dose 

• Primary study endpoint: composite of all-cause stroke and non-CNS 

systemic embolism 

• Primary safety endpoint: composite of major and clinically relevant 

nonmajor bleeding events 

ROCKET = Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K 

Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; CNS = central 

nervous system. 

Patel MR, et al. N Engl J Med. 2011;365(10):883-891. 

Rivaroxiban vs Warfarin 

Event Rate (%/year) 

Efficacy Outcomes Rivaroxiban Warfarin 

Stroke or Systemic Embolism 

As-treated population 1.7 2.2 

Intention-to-treat population 2.1 2.4 

Hemorrhagic stroke 0.26 0.44 

MI 0.91 1.12 

Safety Outcomes 

Major bleeding (Fatal) 0.2 0.5 

ICH 0.5 0.7 

0 0.50 1.00 1.50 2.00 

Rivaroxiban Better Warfarin Better 

Patel MR, et al. N Engl J Med. 2011;365(10):883-891. 





Indications for Rivaroxaban in CV Disease 

• Reduce the risk of stroke and systemic 

embolism in patients with non-valvular AF 

• Prophylaxis of DVT, which may lead to 

PE, in patients undergoing knee or hip 

replacement surgery 

• Treatment of DVT and/or PE 

• To reduce the risk of recurrence of DVT 

and PE 

Rivaroxaban Dosing in CV Disease 

• 20 mg in A Fib if CrCl > 50 cc/min 

• 15 mg in A Fib if CrCl is 15 – 49 cc/min 

• Do not use if CrCl



Rivaroxaban: Dosage Conversion 

Agent 

Heparin 

Enoxaparin 

Fondaprinux 

Conversion Instructions 

Discontinue the heparin infusion when the first 

evening dose of rivaroxaban is administered 

Start rivaroxaban at the time the next evening 

dose of enoxaparin was to be administered 

Start dabigatran at the time the next dose of 

fondaparinux as to be administered 

Conversion 

From warfarin 

To warfarin 

Recommendation 

Discontinue warfarin and start rivaroxaban 

when INR < 3. 

No clinical trial data available 

May consider: Start warfarin and parenteral 

anticoagulant at the time the next dose of 

rivaroxaban would have been taken 

Rivaroxaban Package Insert 

Stroke prevention in Atrial Fibrillation 

Apixaban vs warfarin (ARISTOTLE) 

Apixaban 5 mg oral twice daily 

(2.5 mg twice daily if Age > 80, 

< 60 kg body wt, creat > 1.5 mg/dl 

+ 

Warfarin placebo 

Randomize 

Double blind 

(n = 18,201) 

Apixaban placebo twice daily 

+ 

Warfarin (target INR 2-3) 

Primary outcome: stroke and systemic embolism 

Other outcomes: Death, MI, bleeding 

Stratified by warfarin-naïve status 

• Age 75 years 

• Prior stroke, TIA or SE 

• CHF or LVEF 40% 

• Diabetes mellitus 

• Hypertension 

Warfarin/warfarin placebo adjusted by INR/sham INR 

based on encrypted point-of-care testing device 

Granger CB et al. N Engl J Med 2011; 365:981-992. 





ARISTOTLE: Primary Outcome 

Stroke (Ischemic or Hemorrhagic) or Systemic Embolism 

P (noninferiority)



ARISTOTLE: 

Apixaban vs Warfarin: Safety Outcomes 

OUTCOME 

Apixaban 

%/yr 

Warfarin 

%/yr 

HR 

P 

Value 

Major Bleeding 2.13 3.09 0.69



Apixaban Dosing in A Fib 

• 5 mg twice daily 

• 2.5 mg twice daily for either: 

-Age > 80 yrs of age 

-Body weight 60 Kg or less 

-Creatinine > 1.5 mg/dl 

-Dual inhibitors of cytochrome P450 3A4 and 

p-glycoprotein such as ketoconazole and 

clarithromycin 

Warfarin Comparison Trials in Atrial Fib 

TRIAL RE-LY ROCKET-AF ARISTOTLE 

n =18,113 (3 arms) n=14,264 n=18,201 

Drug (Brand name) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixiban (Eliquis) 

150 mg twice a day 20 mg once daily with 5 mg twice a day 

evening meal 

Trial design, randomized Open label Double blind, double dummy Double blind, double dummy 

Mean Age (yrs) 72 73 70 

Male ratio 63.6% 60.1% 65.3% 

Previous CVA 20% 55% 19% 

CHADS score mean 2.1 3.5 2.1 

% 0-1 32% 0% 34% 

% >3 33% 87% 30% 

TTR (%) median/mean ? / 64% 57.8% / 55% 66.0% / 62.2% 

Efficacy % vs warfarin 1.71 vs. 1.11 p



Recommended Antithrombotic for AF 

ACCP/CCS/AHA/ESC Guidelines 

New Antithrombotics 

“Preferred” to Warfarin 

New Antithrombotics 

are “Alternatives” to 

Warfarin 

ACCP, CCS 

AHA, ESC 

ACCP=American College of Chest Physicians 

CCS=Canadian Cardiovascular Society 

AHA=American Heart Association 

ESC=European Society of Cardiology 

Consensus of the Experts: 

New Antithrombotics May Be Considered Best in: 

• New Patients naive to oral 

anticoagulation. 

• New patients unwilling to take 

warfarin. 

• Those with unstable or nontargeted 

INR’s on warfarin. 





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 

Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. 

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. 





Contrasting the 3 New Oral Agents 

• Apixaban prevents about 3 more strokes per 1000 patients 

per year than warfarin. Plus it leads to 10 FEWER bleeds 

and 4 FEWER deaths. 

• Rivaroxaban doesn’t prevent more strokes than 

warfarin...and has a similar risk of bleeding. But it’s the 

only new agent given just ONCE daily. 

• Dabigatran prevents about 5 more strokes per 1000 

patients per year than warfarin...with a similar overall 

bleeding risk. Dabigatran is also the only new agent that 

reduces ISCHEMIC strokes compared to warfarin...in 

addition to HEMORRHAGIC strokes. 

Pharmacists/Physicians Letter Feb 2013. 

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 or other 

reliable means of regular INR monitoring 

• Are concerned about the lack of an evidencebased 

reversal strategy 

• Has issues with out-of-pocket expense 





Optimal Candidates for New 

Oral Antithrombotic Drugs 

Patients who: 

• Find INR testing burdensome 

• Despite adherence to provider 

recommendations, have low INR ‘time-inrange’ 

(TTR) 

• Can afford (or arrange to get) the new drugs 

• Have normal and stable renal function 

AF Rx as Per CHADS 2 Score: 

AT8 (2008) vs AT9 (2012) 

CHADS 2 

0 

Rx Recommendation 

AT8 (2008) AT9 (2012) 

ASA 

No Rx (2B) 

1 

>2 

Warfarin or ASA 

Warfarin 


(1B) 


(1A) 






Canadian Cardiovascular Society 

Guidelines 

Assess Thromboembolic Risk 

(CHADS 2 ) 

CHADS 2 = 0 

CHADS 2 = 1 

CHADS 2 = 2 

Increasing stroke risk 

No antithrombotic 

ASA 

OAC* 

OAC* 

OAC 

No 

additional 

risk factors 

for stroke 

Either 

female sex 

or 

vascular 

disease 

Age 65 yrs 

Age > or 65 yrs 

combination 

or 

combination 

female 

female sex 

sex 

+ vascular and 

vascular disease 

disease 

*ASA is a 

reasonable 

alternative 

for some as 

indicated by 

risk/benefit 

When OAC therapy is 

indicated, most patients 

receive: 

• Dabigatran, rivaroxaban, 

or apixaban (after Health 

Canada approval) 

• In preference to warfarin 

• Conditional Recommendation, 

High-Quality Evidence 

Skanes AC, et al. Can J Cardiol. 2012 Mar-Apr;28(2):125-36.. 

Take-home Teaching Points: 

• Most patients with CHADS 2 > 2 will derive net benefit 

from anticoagulation, regardless of ‘bleeding score’ 

• For patients with CHADS 2 = 0 or 1 

Consider calculating CHA 2 DS 2 -VASc score 

If CHA 2 DS 2 -VASc score is 1 or higher, anticoagulate 

but…. 

Weigh absolute benefit of AC against best estimate 

of bleeding risk 

• Antiplatelet therapy (e.g. ASA and/or clopidogrel) is 

much less effective than anticoagulation (and not 

significantly safer!) 





Take Home Teaching Points 

• Stroke risk reduction with warfarin is substantial 

(±66%) 

• Risk of ICH with warfarin is low (



Question 1 

What are the major advantages of 

Dabigatran over Warfarin? 

1. It’s low price 

2. It is easier to reverse in the event of serious 

bleeding 

3. Compared with warfarin, it is associated with a 

lower risk of stroke in those with non-valvular 

atrial fibrillation 

4. The dose of dabigatran does not need to be 

adjusted for impaired renal function 

5. It is easy to check the adequacy of its 

antithrombotic effect 

Question 2 

What is the annual risk of stroke in a 72 year 

old man with hypertension and diabetes using 

the CHADS 2 scoring system 

1) Annual stroke risk is about 1-3% 




5) I am not sure what the CHADS2 scoring 

system is? 





Question 3 

What is the annual risk of Intracranial 

hemorrhage seen in clinical trials using 

Warfarin and the newer anticoagulation 

agents? 

1) 7% 

5) Not sure 

Question 4 

Which of the following has not been 

associated with a reduction in intracranial 

hemorrhage in clinical trials when 

compared to coumadin in those with nonvalvular 

atrial fibrillation? 

1.150 mg dabigatran bid 

2. 110 mg dabigatran bid 

3. 75 mg dabigatran bid 

4. 20 mg rivaroxaban qd 

5. None of the above 





Question 5 

You may stop anticoagulation which was 

being given because of the risk of stroke 

in which of the following non-valvular 

atrial fibrillation situations? 

1) Successful atrial fibrillation ablation 

2) Successful cardioversion 

3) Successful rate control 

4) All of the above 

5) None of the above

atrial fibrillation and stroke prevention - Continuing Medical ...

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