1. No category

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.
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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
10.0
Women
Men
11.1
10.3
9.1
8.0
7.3
6.0
5.0
4.0
3.0
1.7
2.0
0.0
0.1 0.2 0.4
<55
0.9
7.2
5.0
x-axis = %
y-axis = # of
men/women
3.4
1.7
1.0
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
>40 Years
will develop AF
Lifetime risk if
currently free
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 comorbidities. 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
Stroke Risk in Atrial Fibrillation Working Group. Stroke. 2008 Jun;39(6):1901-10. Pub Med PMID: 18420954.
Low
15
CHADS2: Risk of Stroke
National Registry of Atrial Fibrillation Participants (NRAF)
CHADS2
Score
# 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: 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.
Pub Med PMID: 11401607.
16
CHA2DS2-VASc
2009 Birmingham Schema Expressed as a Point-Based Scoring System
Risk Factor
Score
Congestive heart failure/LV dysfunction
Hypertension
Age ≥ 75 y
Diabetes mellitus
Stroke/TIA/TE
Vascular disease
(prior myocardial infarction, peripheral artery disease, or aortic plaque)
Age 65-74 y
Sex category
(i.e. female gender)
1
1
2
1
2
1
1
1
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
CHA2DS2VASc
Score
#
#TE
Events
TE Rate During
1 yr (95% CI)
TE Rate During 1 yr,
Adjusted for
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
disease2
1
1
Severe renal disease2
3
Abnormal Renal5 or
1
1
Ethanol abuse
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
Elderly (>65 yrs)
1
Rebleeding12
2
Drugs9 or
1
1
Hypertension4
1
Anemia13
1
Genetic factors14
1
Excessive fall risk15
1
Stroke
1
1.
2.
3.
4.
5.
6.
8.
9.
10.
11.
12.
13.
14.
15.
Liver
function6
Alcohol
Hemoglobin <13 g/dl men; <12 g/dl women
Estimated glomerular filtration rate <30 ml/min or dialysis-dependent
Diagnosed hypertension
Systolic blood pressure >160 mmHg
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,
in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)
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.
Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl
Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia
Prior hospitalization for bleeding
Most recent hematocrit <30 or hemoglobin <10 g/dl
CYP2C9*2 and/or CYP2C9*3
Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls
Renal
or function11
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]
Online Appendix. PMID: 22858389.
23
AMADEUS Cohort
Stratified by the HEMORR2HAGES, HAS-BLED, and ATRIA Schemes
All Patients
Clinically
Relevant
Bleeding
Major
Bleeding
1,738 (76.6)
182 (10.5)
25 (1.4)
517 (22.8)
63 (12.2)
13 (2.5)
13 (0.5)
3 (23.1)
1 (7.7)
2,268
248 (10.9)
39 (1.7)
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)
2,292
251 (11.0)
39 (1.7)
Scheme
HEMORR2HAGES
Low (≤1) Risk
Intermediate Risk (2–3)
High Risk (>3)
TOTAL
HAS-BLED
TOTAL
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)
2,268
248 (10.9)
39 (1.7)
TOTAL
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]
Online Appendix. PMID: 22858389.
24
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
Event, n
Subsequent
Deaths, n
(Adjusted Rate)
HR for Death
(95% CI)†
Relative
Weights‡
Ischemic stroke
785
362 (36.4)
5.74
(5.10 – 6.47)
1.00
(reference)
Hemorrhage stroke
59
48 (81.4)
17.67
(13.15 – 23.75)
3.08
Subdural
hemorrhage
42
15 (32.4)
3.44
(2.06 – 5.74)
0.60
Major extracranial
bleeding event
435
162 (31.6)
3.82
(3.24 – 4.51)
0.67
Myocardial
infarction
260
120 (38.9)
5.44
(4.51 – 6.56)
0.95
† 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
Xa
IIa
Xa
80%
6%
80%
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
clearance > 80 ml/min
Elimination half life with creatinine
clearance 50–79 ml/min
Elimination half life with creatinine
clearance 30–49 ml/min
15.1 hr
13.8 hr
8.3 hr
14.6 hr
16.6 hr
8.7 hr
17.6 hr
18.7 hr
9.0 hr
Elimination half life with creatinine
clearance < 30 ml/min
17.3 hr
27.5 hr
9.5 hr
Direct factor inhibition
Bioavailability (Frel)
Peak action (tmax)
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
-dilute PT
-modified PT
Not useful
Data n/a
Qualitative
Qualitative
Data n/a
Data n/a
Not useful
Data n/a
Data n/a
aPTT
Not useful
Not useful
Qualitative
TT
-dTT/HEMOCLOT
No effect
No effect
No effect
No effect
Qualitative
Quantitative
Quantitative
No effect
Quantitative
No Effect
No effect
Quantitative
Chromogenic Assays
-Anti-Xa
-Anti-Iia
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
charcoal
No data
In vitro
No data
Hemodialysis
No data
Human volunteers
No data
Hemoperfusion with
activated charcoal
No data
In vitro
No data
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
and rat model
Human volunteers
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
charcoal
Yes
Yes
Yes
Hemodialysis
No
Yes
No
Hemoperfusion with
activated charcoal
Possible
Yes
Possible
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
Score
Recommended
Antithrombotic Therapy1
>2
OAC
CHA2DS2-VASc
Risk Category
One ‘major’ risk factor
or > 2 ‘clinically relevant
non-major’ risk factors
One ‘clinically relevant
non-major’ risk factor’
No risk factors
Risk of Bleeding
Low risk
Measurable risk, or 1 clinicallyrelevant non-major risk factor
1
0
•
•
Either OAC or aspirin 75-325 mg daily
Preferred: OAC rather than aspirin
•
Either aspirin 75-325 mg daily or no
antithrombotic therapy
Preferred: no antithrombotic therapy
rather than aspirin
•
HAS-BLED Score
Dabigatran Dosage2
0–2
150 mg b.i.d.
≥3
110 mg b.i.d.
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
> 1 moderate-risk factor
Warfarin (INR 2.0 to 3.0, target 2.5)*
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*
Thyrotoxicosis
LV ejection fraction <35%
* If mechanical valve, target international normalized ratio (INR) > 2.5
Diabetes mellitus
2011 Focused Update Recommendation Class I
2
Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic
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.
2. Wann LS, et al. J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7. Pub Med PMID: 21324629.
Comments
New Recommendation
38
ACCP Guidelines
For patients with Nonrheumatic AF, including those with Paroxysmal AF
ACCP
Recommendation
Alternative*
Not Recommended
Low Risk
(CHADS2 = 0)
No Therapy
Aspirin
Oral anticoagulation
or combination
therapy with aspirin
and clopidogrel
Intermediate Risk
(CHADS2 = 1)
Oral anticoagulation
Aspirin with
clopidogrel
Aspirin
High Risk
(CHADS2 = 2)
Oral anticoagulation
(dabigatran 150 mg
b.i.d. vs. VKA**)
Aspirin with
clopidogrel
Aspirin
Level of Risk
*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
OAC
Increasing stroke risk
No antithrombotic
No
additional
risk factors
for stroke
ASA
OAC*
OAC*
Either
female sex
or
vascular
disease
Age > 65 yrs
Age >or65 yrs
or
combination
combination
female
sex
female sex
and
and vascular
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. 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
Taiwan
Mexico
Peru
Romania
India
Columbia
Russia
Brazil
China
Korea
Greece
Thailand
Malaysia
Poland
Japan
South Africa
France
Slocakia
Portugal
Israel
Czech Republic
Philippines
Bulgaria
Hungary
Hong Kong
Turkey
Belgium
Austria
USA
Spain
Germany
Switzerland
Singapore
Argentina
Netherlands
Norway
Canada
Italy
Ukraine
UK
Denmark
Austrailia
Finland
Sweden
TTR per Country in RELY
90
80
70
60
50 44 47
48 49 49
53 53 54 55 55
56 56 56 57 58 58
64 64 64 64 64
60 60 62 62
65 65 66 66 66 67
Wallentin L, et al. Lancet. 2010 Sep 18;376(9745):975-83. PMID: 20801496.
68 68
74 74
70 70 70 71 71 72 72 72
77
40
30
20
10
0
USA:
Improvement
Needed
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
Center TTR‡
Rivaroxaban
vs. Warfarin
Warfarin
Total
Event Rate
(100 Pt Yrs)§
Total
Event Rate
(100 Pt Yrs)§
Hazard Ratio
(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