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David Putney, PharmD, BCPS
Cardiology Specialist II
The Methodist Hospital
Houston, TX
Stroke Prevention with Atrial
Fibrillation
Objectives
• Review trials on antiplatelet and
anticoagulation in atrial fibrillation
• Apply literature to case based
discussion
• Describe the pharmacokinetic
properties of newer oral anticoagulants
2
Atrial Fibrillation
Atrial Fibrillation
http://heartstrong.files.wordpress.com/2009/06/atrial-fibrillation-lg.jpg
4
Atrial Fibrillation
Prevalence
• Affects nearly 2.5 million people in the US
– Uncommon among individuals < 50 years of
age (risk < 0.5%)
– Nearly 10% in those > 80 years of age
– Men > women
– Lifetime risk of AF for an individual at 40
years of age is 25%
Singer D, et al. Chest. 2008;133:546S-592S.
Gage BF, et al. Circulation. 2004;110:2287-92.
5
2010 US Census
25,000,000
20,000,000
15,000,000
10,000,000
5,000,000
0
http://www.census.gov/population/www/socdemo/age/age
_sex_older.html. Last accessed 3/8/2012.
6
Atrial Fibrillation
Atrial electrical remodeling
• “Atrial fibrillation begets atrial fibrillation”
• Repeated episodes of induced atrial
tachycardia
– Marked shortening of atrial refractory period
• Normal function occurs 2 to 4 weeks after
normalization of sinus rhythm (SR)
Camm AJ, et al. Eur Heart J. 2010;31:2369-2439.
Singer D, et al. Chest. 2008;133:546S-592S.
7
Stroke Risk
Go SA. N Engl J Med. 2009;360: 2127-29.
8
Atrial Fibrillation
Stroke Risk
• Loss of coordinated atrial contractions
– Predisposition for thrombus formation within the atria
• Flow abnormalities
– Reduced left atrial appendage flow velocity
• Endocardial abnormalities
– Progressive atrial dilation and edematous/fibrolastic
infiltration of extracellular matrix
• Abnormalities of blood constituents
– Hemostatic and platelet activation
– Inflammation and growth factor abnormalities
Camm AJ, et al. Eur Heart J. 2010;31:2369-2439.
Rockson S, et al. J Am Coll Cardiol. 2004;43:929-35.
9
Case
• CC: “fluttering heart”
• HPI: AJ is a 60 yo female who presents with a
2 day history of fluttering feeling in chest. No
SOB, syncope, or chest pain noted.
• PMH: HTN x 20 yrs (well controlled)
• Medication: HCTZ 25 mg daily and Ramipril
10 mg daily
• ECG: Atrial fibrillation with a ventricular
response of 128 BPM
• Significant Events: Pt spontaneously
cardioverted back into NSR
10
What to do?
• Do we anticoagulate?
• What if pt has had previous TIA/CVA?
• What if pt has hx of CAD and is taking
ASA and clopidogrel?
• What if pt has ESRD?
11
Stroke Risk
CHADS2
CHADS2 Risk
Criteria
Score
Congestive
Heart Failure
1
HTN
1
Age >75y
1
DM
1
Prior stroke or
TIA
2
Singer D, et al. Chest. 2008;133:546S-592S.
12
CHA2DS2-VASc
Camm AJ, et al. Eur Heart J. 2010;31:2369-2439.
13
HAS BLED Scale
Pisters R, et al. Chest 2010;138;1093-1100.
14
Guideline Recommendations
CHEST Guidelines
• CHADS2 score 0
– No therapy or long-term aspirin 75-325mg
daily
• CHADS2 score 1
– Long-term antithrombotic therapy
• CHADS2 score ≥ 2
– Long-term antithrombotic therapy
You J, et al. Chest. 2012;141:531S-575S.
15
Guideline Recommendations
European Society of Cardiology
(ESC) Guidelines
Camm AJ, et al. Eur Heart J. 2010;31:2369-2439.
16
Coagulation Cascade
Accessed 8 October 2010. URL: http://picasaweb.google.com/lh/photo/GCMu-PcRpUhwQS9538eKYw
New Agents
18
Weitz J, et al. Chest. 2012;141:120S-151S.
RCTs
Drug Interactions
Special Populations
Reversibility
19
Adverse Effects in the Elderly
Agents Utilized
60%
50%
40%
30%
20%
10%
Hospitalization
ED Encounter
0%
Budnitz D, et al. NEJM. 2012;365:2002-12.
20
Latest Trial Information
SPAF III
Hart R, et al. Stroke. 1999;30:1223-1229.
22
ACTIVE A
Atrial Fibrillation with At Least One
Additional Risk Factors for Stroke
Randomized
Double-blind
N = 7,554
Clopidogrel 75mg daily
+
ASA 75 – 100mg daily
Risk Factors
• Prior stroke or TIA, or SE
• Age ≥ 75yo
• HTN
• DM
• HF or EF ≤ 35%
ASA 75 – 100mg daily
+
Placebo
Primary outcome: Any major vascular event
Connolly S, et al. N Engl J Med. 2009;360:2066-78.
23
ACTIVE A
Results: Primary and Secondary Outcomes
Clopidogrel + ASA
ASA
P-value
Composite of stroke, nonCNS embolus, MI, vascular
death
6.8
7.6
0.01
Ischemic stroke
1.9
2.8
<0.05
Total mortality
6.4
6.6
0.69
Major Bleeding
2
1.3
<0.001
Connolly S, et al. N Engl J Med. 2009;360:2066-78.
24
ACTIVE W
Atrial Fibrillation with At Least One
Additional Risk Factor for Stroke
Randomized
Blinded
N = 6,706
Clopidogrel 75mg daily
+
ASA 75 – 100mg daily
Risk Factors
• Prior stroke or TIA, or SE
• Age ≥ 75yo
• HTN
• DM
• HF or EF ≤ 35%
Warfarin (INR 2 – 3)
Primary outcome: First occurrence of stroke, non-CNS systemic
embolism, MI, or vascular death
Connolly S, et al. Lancet. 2006;367:1903-12.
25
ACTIVE W
Results: Primary and Secondary Outcomes
Clopidogrel + ASA
Warfarin
P-value
Composite of stroke, nonCNS embolus, MI, vascular
death
5.60
3.93
0.0003
Ischemic stroke
2.39
1.40
<0.0001
Total mortality
3.80
3.76
0.91
Major Bleeding
2.42
2.21
0.53
Primary outcome and
major bleed
7.56
5.45
<0.0001
Connolly S, et al. Lancet. 2006;367:1903-12.
26
RE-LY
Atrial Fibrillation with At Least One
Additional Risk Factor for Stroke
Risk Factors
• Prior stroke or TIA, or SE
• Age ≥ 75yo
• HTN
• DM
• HF or EF ≤ 35%
Randomized
Blinded
N = 18,113
Dabigatran 110 or 150mg twice daily
Warfarin (INR 2 – 3)
Primary outcome: Stroke or systemic embolism
Safety outcome: Major hemorrhage
Conolly S, et al. N Engl J Med. 2009;361:1139-51.
27
RE-LY
RE-LY: Results
Conolly S, et al. N Engl J Med. 2009;361:1139-51.
28
RE-LY
RE-LY: Adverse Effects
• Major bleeding:
– Warfarin 3.36% per year
– Dabigatran 110mg, 2.71% per year (p = 0.003)
– Dabigatran 150mg, 3.11% per year (p = 0.31)
• Elevation in LFTs:
– Warfarin 2.2%
– Dabigatran 110mg, 2.1% and 150mg, 1.9%
• Dyspepsia:
– Warfarin 5.8%
– Dabigatran 110mg, 11.8% and 150mg, 11.3% (p<0.001)
Conolly S, et al. N Engl J Med. 2009;361:1139-51.
29
ROCKET AF
Atrial Fibrillation with At Least Two
Additional Risk Factors for Stroke
Randomized
Double-blind
N = ~14,000
Rivaroxaban 20mg daily
(15 mg if CrCL 20 – 49 mL/min)
Risk Factors
• Prior stroke or TIA, or SE
• Age ≥ 75yo
• HTN
• DM
• HF or EF ≤ 35%
Warfarin (INR 2 – 3)
Primary outcome: Stroke or non-CNS systemic embolism
Maffey K, et al. Am Heart J. 2010;159:340–7.
ROCKET AF
Results
Maffey K, et al. Am Heart J. 2010;159:340–7.
Patel MR, et al. NEJM 2011;365:883-91.
31
ROCKET AF
Safety
Rivaroxaban
Warfarin
P-value
Primary Safety Endpoint:
Major and nonmajor
clinically relevant bleeding
14.9
14.5
0.44
Any Major Bleeding
3.6
3.4
0.58
Intracranial Hemorrhage
0.5
0.7
0.02
Fatal Bleeding
0.2
0.5
0.003
Patel MR, et al. NEJM 2011;365:883-91.
32
AVERROES
Atrial Fibrillation with At Least One
Additional Risk Factor for Stroke
Risk Factors
• Prior stroke or TIA, or SE
• Age ≥ 75yo
• HTN
• DM
• HF or EF ≤ 40%
Randomized
Double-blind
N = 5,599
Apixaban 5mg twice daily
(2.5 mg if 2 or more of the following
were present:
Age > 80, ABW < 60kg or Scr > 1.5
mg/dL)
Aspirin (81-325 mg) daily
Primary outcome: Stroke or systemic embolism
Safety outcome: Major hemorrhage
Connolly SJ , et al. N Engl J Med. 2011;364:806-17.
33
AVERROES
Connolly SJ , et al. N Engl J Med. 2011;364:806-17.
34
AVERROES
Apixaban
Aspirin
P-value
Primary Safety Endpoint:
Major Bleeding
1.4 %
1.2 %
0.57
Fatal Bleeding
0.1 %
0.2 %
0.53
Intracranial Hemorrhage
0.4 %
0.4 %
0.69
Gastrointestinal
0.4 %
0.4 %
0.71
Connolly SJ , et al. N Engl J Med. 2011;364:806-17.
35
ARISTOTLE
Atrial Fibrillation with At Least One
Additional Risk Factor for Stroke
Risk Factors
• Prior stroke or TIA, or SE
• Age ≥ 75yo
• HTN
• DM
• HF or EF ≤ 40%
Randomized
Double-blind
N = 18,201
Apixaban 5mg twice daily
(2.5 mg if 2 or more of the following
were present:
Age > 80, ABW < 60kg or Scr > 1.5
mg/dL)
Warfarin (INR 2 – 3)
Primary outcome: Stroke or systemic embolism
Safety outcome: Major hemorrhage
Granger C, et al. N Engl J Med. 2011;365:981-992.
36
ARISTOTLE
Granger C, et al. N Engl J Med. 2011;365:981-992.
37
ARISTOTLE
Apixaban
Warfarin
P-value
Primary Safety Endpoint:
ISTH major bleeding
2.13
3.09
<0.001
Any Major Bleeding
4.07
6.01
<0.001
Intracranial Hemorrhage
0.33
0.8
<0.001
Gastrointestinal
0.76
0.86
0.37
ISTH=International Society on Thrombosis and Haemostasis
Granger C, et al. N Engl J Med. 2011;365:981-992.
38
Summary
Agent Studied
Stroke or
Systemic
Embolism
Primary
Safety
Endpoint
Aspirin
Aspirin & Clopidogrel
Warfarin
7.6 %
6.8 %
5.6 %
1.3 %
2.0 %
2.2 %
Dabigatran 110
Dabigatran 150
Warfarin
1.54 %
1.11 %
1.71 %
2.87 %
3.32 %
3.57 %
ROCKET AF
Rivaroxaban
Warfarin
1.7 %
2.2 %
14.9 %
14.5%
AVERROES
Apixiban
Aspirin
1.6 %
3.7 %
1.4 %
1.2 %
ARISTOTLE
Apixiban
Warfarin
1.27 %
1.6 %
2.13 %
3.09 %
Trial Acronym
ACTIVE
RE-LY
39
Patient Specific Factors
Warfarin Control Across Trials
RE-LY
ROCKET AF
ARISTOTLE
Time in Therapeutic INR
64 %
55 %
66 %
Subtherapeutic
23 %
NA
NA
Supratherapeutic
2%
NA
NA
Conolly S, et al. N Engl J Med. 2009;361:1139-51.
Patel MR, et al. NEJM 2011;365:883-91.
Granger C, et al. N Engl J Med. 2011;365:981-992.
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/dru
gs/cardiovascularandrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed
3/12/12
41
RE-LY Analysis
42
Wallentin L, et al. Lancet 2010;376:975-83.
RE-LY Analysis
Time in Therapeutic
Target
(%)
Dabigatran
110
Dabigatran
150
Warfarin
< 57.1
1.91
1.10
1.92
57.1 - 65.5
1.67
1.04
2.06
65.5 – 72.6
1.34
1.04
1.51
> 72.6
1.23
1.27
1.34
Improved time within therapeutic range
was associated with a decrease in stroke
and systemic embolism
43
Wallentin L, et al. Lancet 2010;376:975-83.
RE-LY Analysis
Time in Therapeutic
Target
(%)
Dabigatran
110
Dabigatran
150
Warfarin
< 57.1
2.36
2.54
3.59
57.1 - 65.5
3.38
3.33
4.13
65.5 – 72.6
2.82
3.80
3.40
> 72.6
2.81
3.60
3.11
Major bleeding was associated with
poorer control of warfarin therapy
44
Wallentin L, et al. Lancet 2010;376:975-83.
Dabigatran Steady State
• Mean concentration of dabigatran 150 mg twice daily in
patients with normal renal function
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara
ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12
45
Effects of Renal Dysfunction
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara
ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12
46
75 mg Twice Daily Dosing
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara
ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12
47
Dabigatran Drug Interactions
Dabigatran Concentration
48
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara
ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12
Renal Function Update
• When to assess renal function:
– Prior to starting therapy
– Annually in patients greater than 75 years old and those with a creatinine
clearance (CrCl) less than 50 mL per minute
• Recommended dosing guidelines in renal impairment
CrCl (mL per minute)
Dose
Greater than 30
150mg twice daily
15-30
75mg twice daily
Less than 15
Use not recommended
Dabigatran [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc; 2011.
Connolly SJ, et al. N Engl J Med. 2009;361:1139-51.
49
Package Insert Update
• Dabigatran is a substrate of the P-glycoprotein (P-gP) metabolism
pathway
• P-gP inhibitors
– Dronedarone (antiarrhythmic)
– Ketoconazole (antifungal)
• Recommended dosing adjustments
Concomitant Medication
CrCl (mL per minute)
Dose
(dabigatran)
Dronedarone
30-50
75mg twice daily
Ketoconazole
30-50
75 mg twice daily
Dronedarone
15-30
Use not recommended
Ketoconazole
15-30
Use not recommended
Dabigatran [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc; 2011.
50
Dabigatran Monitoring?
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara
ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12
51
Stroke Reduction vs. Bleeding
52
Real World Effects
• New Zealand Data
• European Data
• FDA warnings
Dabigatran: Australia issues Dabigatran: 260 fatal bleeds
bleeding warning
since approval worldwide
October 7, 2011
November 17, 2011
http://www.theheart.org/article/1291757.doc. Last accessed 3/12/12
53
Rivaroxaban Effect on PT
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/Cardiova
scularandRenalDrugsAdvisoryCommittee/ucm270796.pdf. Last accessed 3/12/12
54
Rivaroxaban Major Bleeding
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/Cardiova
scularandRenalDrugsAdvisoryCommittee/ucm270796.pdf. Last accessed 3/12/12
55
Kinetic Profiles
Dabigatran
Rivaroxaban
Apixaban
12 – 18 hours
5 – 9 hours
12 hours
CYP 450 Substrate
No
Yes
(3A4/3A5 & 2J2)
Yes
(3A4/3A5)
Renal Elimination
80 %
66%
30%
Twice Daily
Once Daily
Twice Daily
< 30 mLs/min
< 25 mLs/min or
Scr > 2.5 mg/dL
Half Life
Dosing
Minimum Renal
Function During
Major Trial
< 30 mLs/min
56
Acute Reversal
Eerenberg, ES, et al. Circulation. ePub online Sept. 2011.
57
Cardioversion
• Electrical or pharmacological
• Systemic embolism is the most serious
complication
• “Atrial stunning”
– Further depression of left atrial appendage ejection
velocities
– Increased left atrial spontaneous echocardiographic
contrast
– New thrombus formation
You J, et al. Chest. 2012;141:531S-575S.
58
Guideline recommendations
CHEST Guidelines
• AF duration ≥ 48 hours or unknown
– Warfarin (INR 2-3) for 3 weeks before and at least 4
weeks after cardioversion
• AF duration known <48 hours
– Cardioversion may be performed without prolonged
anticoagulation
• Emergency cardioversion
– Immediate IV UFH (PTT 50-60) or LMWH (full
treatment dose)
– Follow with 4 weeks of therapeutic anticoagulation
You J, et al. Chest. 2012;141:531S-575S.
59
Transesophageal Echocardiography
(TEE) Guided Cardioversion
• Biplane and
multiplane TEE used
to detect thrombi
• Offers opportunity to
perform early
cardioversion if no
thrombi observed
You J, et al. Chest. 2012;141:531S-575S.
http://www.yale.edu/imaging/techniques/echo_tee/graphics/unlabelled.gif
60
Case
• CC: “fluttering heart”
• HPI: AJ is a 60 yo female who presents with a
2 day history of fluttering feeling in chest. No
SOB, syncope, or chest pain noted.
• PMH: HTN x 20 yrs (well controlled)
• Medication: HCTZ 25 mg daily and Ramipril
10 mg daily
• ECG: Atrial fibrillation with a ventricular
response of 128 BPM
• Significant Events: Pt spontaneously
cardioverted back into NSR
61
What to do?
• Do we anticoagulate?
• What if pt has had previous TIA/CVA?
• What if pt has hx of CAD and is taking
ASA and clopidogrel?
• What if pt has ESRD?
62
In Summary
• Atrial fibrillation and stroke prevention
is an increasing epidemic
• Newer oral anticoagulants offer
alternatives to traditional warfarin
therapy
• Tailoring regiments to specific factors
helps to minimize the risk of major
bleeding events
63
Suggested Readings
• CHEST Guidelines on antithrombotic therapy
for atrial fibrillation
You JJ, et al. Chest. 2012;141:531S-575S.
65
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