Anticoagulation for Atrial Fibrillation:
Who, When, and How?
August 17, 2013
Elaine M. Hylek, MD, MPH
Boston University School of Medicine
Disclosures
Disclosures of Elaine Hylek
Employment
No conflict of interest to disclose
Research support
NIH/NINDS, NIH/NHLBI; Bristol-Myers SquibbExecutive Steering Committee; ARISTOTLE trial;
Janssen-Executive Steering Committee; ORBITAF Registry
Scientific advisory board
Bayer, Boehringer-Ingelheim, Bristol-Myers
Squibb, Daiichi Sankyo, Johnson & Johnson,
Pfizer
Consultancy
No conflict of interest to disclose
Speakers bureau
No conflict of interest to disclose
Major stockholder
No conflict of interest to disclose
Patents
No conflict of interest to disclose
Honoraria
Bayer, Boehringer-Ingelheim, Pfizer
Travel support
No conflict of interest to disclose
Other
No conflict of interest to disclose
TEE depicting a large LAA thrombus attached to the lateral wall
Hesse, B. et al. Circulation 2006;113:e456-457e
Stanford Stroke Center, Albers G
Prevalence of AF by Age
Feinberg WM. Arch Intern Med. 1995;155(5):469–473
HAZARDS OF WARFARIN
Budnitz D et al. N Engl J Med 2011;365:2002–12
HAZARDS OF WARFARIN
Budnitz D et al. N Engl J Med 2011;365:2002–12
Efficacy and Safety
Data for
Target-Specific Oral
Anticoagulants
RE-LY: Time to First Stroke/SEE
RR 0.91
(95% CI: 0.74–1.11)
p<0.001 (noninferiority)
p=0.34 (superiority)
Cumulative hazard rates
0.05
0.04
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
0.03
RRR
34%
1.69%
1.53%
0.02
RR 0.66
(95% CI:
0.53–0.82)
p<0.001
(superiority)
1.11%
0.01
0.0
0
0.5
1.0
Years
1.5
Connolly SJ et al. N Engl J Med 2009; 361:1139–51
2.0
2.5
RE-LY Primary Efficacy Outcome
Stroke and non-CNS Embolism
Connolly SJ., et al. NEJM Aug 30th 2009. DOI 10.1056/NEJMoa0905561
Hemorrhagic stroke
RR 0.31 (95% CI: 0.17–0.56)
p<0.001 (sup)
RR 0.26 (95% CI: 0.14–0.49)
50
p<0.001 (sup)
45
40
0.38%
RRR
74%
RRR
69%
Number of events
30
20
14
10
12
0.12%
0.10%
0
D110 mg BID
D150 mg BID
6,015
6,076
Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561
Warfarin
6,022
Dabigatran Etexilate vs Warfarin
(RE-LY)
October 19, 2010
FDA Approves Pradaxa to Reduce the Risk of
Stroke in Patients with Non-Valvular Atrial
Fibrillation
PRADAXA 150 mg BID-higher rate of major (GI)
bleeds and any GI bleeds compared to warfarin.
In patients ≥75 years of age, the risk of major
bleeding may be greater with PRADAXA than with
warfarin.
ROCKET-AF Primary Efficacy Outcome
Stroke and non-CNS Embolism
Rivaroxaban Warfarin
Event
Event
Rate
Rate
On
Treatment
N= 14,171
Rivaroxaban
better
P-value
1.70
2.15
0.79
(0.65,0.95)
0.015
2.12
2.42
0.88
(0.74,1.03)
0.117
N= 14,143
ITT
HR
(95% CI)
Warfarin
better
Event Rates are per 100 Patient-years
Based on Safety on Treatment or Intention-to-Treat thru Site Notification
Populations
Patel et al. NEJM 2011;365:883-91
Key Secondary Efficacy Outcomes
Rivaroxaban
Warfarin
Event Rate
Event Rate
HR (95% CI)
P-value
3.11
3.63
0.86 (0.74, 0.99)
0.034
Hemorrhagic
0.26
0.44
0.59 (0.37, 0.93)
0.024
Ischemic
1.34
1.42
0.94 (0.75, 1.17)
0.581
Unknown Type
0.06
0.10
0.65 (0.25, 1.67)
0.366
Non-CNS Embolism
0.04
0.19
0.23 (0.09, 0.61)
0.003
Myocardial Infarction
0.91
1.12
0.81 (0.63, 1.06)
0.121
All Cause Mortality
1.87
2.21
0.85 (0.70, 1.02)
0.073
Vascular
1.53
1.71
0.89 (0.73, 1.10)
0.289
Non-vascular
0.19
0.30
0.63 (0.36, 1.08)
0.094
Unknown Cause
0.15
0.20
0.75 (0.40, 1.41)
0.370
Vascular Death,
Stroke, Embolism
Stroke Type
Patel et al. NEJM 2011;365:883-91
Safety Outcomes Rivaroxaban
Rivaroxaban
Warfarin
Event Rate
or N (Rate)
Event Rate
or N (Rate)
HR
(95% CI)
Pvalue
3.60
3.45
1.04 (0.90, 1.20)
0.576
>2 g/dL Hgb drop
2.77
2.26
1.22 (1.03, 1.44)
0.019
Transfusion (> 2 units)
1.65
1.32
1.25 (1.01, 1.55)
0.044
Critical organ bleeding
0.82
1.18
0.69 (0.53, 0.91)
0.007
Bleeding causing death
0.24
0.48
0.50 (0.31, 0.79)
0.003
55 (0.49)
84 (0.74)
0.67 (0.47, 0.94)
0.019
Intraparenchymal
37 (0.33)
56 (0.49)
0.67 (0.44, 1.02)
0.060
Intraventricular
2 (0.02)
4 (0.04)
Subdural
14 (0.13)
27 (0.27)
0.53 (0.28, 1.00)
0.051
Subarachnoid
4 (0.04)
1 (0.01)
Major
Intracranial Hemorrhage
Event Rates are per 100 patient-years Based on Safety on Treatment Population
Primary Outcome
Stroke (ischemic or hemorrhagic) or systemic embolism
P (non-inferiority)<0.001
21% RRR
Apixaban 212 patients, 1.27% per year
Warfarin 265 patients, 1.60% per year
HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011
No. at Risk
Apixaban
Warfarin
9120
9081
8726
8620
8440
8301
Granger C et al. NEJM 2011;365:981–92
6051
5972
3464
3405
1754
1768
Efficacy Outcomes
Outcome
Stroke or systemic embolism*
Apixaban
Warfarin
(N=9120)
(N=9081)
Event Rate Event Rate
(%/yr)
(%/yr)
HR (95% CI)
P
Value
1.27
1.60
0.79 (0.66, 0.95)
0.011
1.19
1.51
0.79 (0.65, 0.95)
0.012
Ischemic or uncertain
0.97
1.05
0.92 (0.74, 1.13)
0.42
Hemorrhagic
0.24
0.47
0.51 (0.35, 0.75)
<0.001
0.09
0.10
0.87 (0.44, 1.75)
0.70
All-cause death*
3.52
3.94
0.89 (0.80, 0.998)
0.047
Stroke, SE, or all-cause death
4.49
5.04
0.89 (0.81, 0.98)
0.019
Myocardial infarction
0.53
0.61
0.88 (0.66, 1.17)
0.37
Stroke
Systemic embolism (SE)
* Part of sequential testing sequence preserving the overall type I error
Granger C et al. NEJM 2011;365:981–92
Bleeding Outcomes
Outcome
Primary safety outcome:
ISTH major bleeding*
Apixaban
Warfarin
(N=9088)
(N=9052)
Event Rate Event Rate
(%/yr)
(%/yr)
HR (95% CI)
P Value
2.13
3.09
0.69 (0.60, 0.80)
<0.001
Intracranial
0.33
0.80
0.42 (0.30, 0.58)
<0.001
Gastrointestinal
0.76
0.86
0.89 (0.70, 1.15)
0.37
Major or clinically relevant
non-major bleeding
4.07
6.01
0.68 (0.61, 0.75)
<0.001
GUSTO severe bleeding
0.52
1.13
0.46 (0.35, 0.60)
<0.001
TIMI major bleeding
0.96
1.69
0.57 (0.46, 0.70)
<0.001
Any bleeding
18.1
25.8
0.71 (0.68, 0.75)
<0.001
* Part of sequential testing sequence preserving the overall type I error
ACCP Recommendations for Stroke
Prevention Therapy
CHADS
2
score = 0
No therapy rather than
antithrombotic
therapy (Grade 2B)
CHADS
2
score = 1
Oral anticoagulation
rather than no therapy
or antiplatelet therapy
(Grade 1B)
CHADS
2
score = 2
Oral anticoagulation
rather than no therapy
or other therapies
(Grade 1A)
For recommendations in favor of oral AC, we
suggest dabigatran 150 mg twice daily rather
than VKA therapy (Grade 2B)
You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: 22315271
ESC 2012
UPDATE
GUIDELINES
For
ATRIAL
FIBRILLATION
Camm J et al. Eur Heart J 2012;33:2719–47
2011 ACCF/AHA/HRS
Focused Update
Dabigatran is useful as an alternative to warfarin for the
prevention of stroke in patients with AF.
• Selection of patients with AF and ≥1 risk factor for stroke who could
benefit from treatment with dabigatran as opposed to warfarin should
consider individual clinical features, including the ability to comply with
twice-daily dosing, availability of an anticoagulation management program,
patient preferences, cost, and other factors
Because of the twice-daily dosing and greater risk of non-hemorrhagic side
effects with dabigatran, patients already taking warfarin with excellent INR
control may have little to gain by switching to dabigatran.
Wann LS et al. Heart Rhythm 2011;8:e1–e8
Hylek, EM. J Cardiovasc Med 2009;10:605-09
Effect of TTR on Primary Endpoints
In RELY
0.54
0.59
0.91
1.21
Wallentin, et al. Lancet 2010
10% increase in center algorithm-consistent warfarin
dosing predicted a 6.12% increase in TTR (95% CI 5.656.59%), and an 8% decrease in rate of the composite
clinical outcome (HR 0.92, 95% CI 0.85-1.00).
Translating the Results of Clinical
Trials into Clinical Practice
 Patient selection
 Therapeutic implementation
 Environment of the healthcare delivery system
Nallamothu, et al. Circulation 2008;118:1294–303
Will we be able to translate trial results
to real-world practice?
New Oral Anticoagulants:
Summary
Property
Route of
admin
Dabigatran Rivaroxaban
Apixaban
Edoxaban
Oral
Oral
Oral
Oral
Target
Thrombin
FXa
FXa
FXa
Dosing
Twice daily
Once daily
Twice daily
Once daily
No
No
No
No
12–17
9–12
8–15
8–11
Renal 80%
Renal ~36%
Monitoring
required
Half-life
(hrs)
Mode of
elimination
Renal ~25% Renal ~35%
Definitions:
Chronic Kidney Disease and Renal Insufficiency
Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation
www.ckdsite.com
I
MILD
Slide courtesy of C Cove
I
MOD
I
SEVERE
Renal Insufficiency Classification
I
Randomized Trial
Age
Baseline
CrCl
Exclusion
CrCl
<25 ml/min
ARISTOTLE
Apixaban 5 mg bid
70
83% ≥50
Warfarin
70
83% ≥50
Rivaroxaban 20 mg qd
73
67 (median)
Warfarin
73
67 (median)
Dabigatran 150 mg bid
72
68 (median)
Warfarin
72
69 (median)
ROCKET AF
< 30 ml/min
RE-LY
<30 ml/min
Pharmacokinetics with Varying
Levels of Renal Dysfunction
Apixaban Dabigatran
Rivaroxaban
Elimination half life with
CrCl >80 ml/min
7.6 hr
13.8 hr
8.3 hr
Elimination half life with
CrCl 50–79 ml/min
7.3 hr
16.6 hr
8.7 hr
Elimination half life with
CrCl 30–49 ml/min
Elimination half life with
CrCl <30 ml/min
17.6 hr
18.7 hr
9.0 hr
17.3 hr
27.5 hr
9.5 hr
Kaatz S et al. Am J Hematol 2012 Suppl 1:S141-5. PMID: 22473649
JANUARY 2012 UPDATE
DABIGATRAN PACKAGE INSERT
Periodically assess renal function as clinically
indicated (i.e., more frequently in clinical situations
that may be associated with a decline in renal
function) and adjust therapy accordingly.
Discontinue dabigatran in patients who develop acute
renal failure and consider alternative therapy.
In patients with moderate renal impairment
(CrCl 30–50 mL/min), concomitant use of the
P-gp inhibitor dronedarone or systemic ketoconazole
can be expected to produce drug exposure similar to
that observed in severe renal impairment. Consider
reducing the dose.
New Oral Anticoagulants:
Summary
Property
Route of
admin
Dabigatran Rivaroxaban
Apixaban
Edoxaban
Oral
Oral
Oral
Oral
Target
Thrombin
FXa
FXa
FXa
Dosing
Twice daily
Once daily
Twice daily
Once daily
No
No
No
No
12–17
9–12
8–15
8–11
Renal 80%
Renal ~36%
Monitoring
required
Half-life
(hrs)
Mode of
elimination
Renal ~25% Renal ~35%
Polypharmacy and
Non-adherence
• Strongest predictor of non-adherence is
the # of medications
• Non-adherence rates estimated 25–50%
• Intentional about 75% of the time
Changes in regimen made
by patients to:
– increase convenience
– reduce adverse effects or
– decrease refill expense
Recommended Structured Follow-up
First month and subsequent 3 month intervals
Pradaxa (dabigatran etexilate
mesylate): Drug Safety Communication
– Safety Review of Post-Market
Reports of Serious Bleeding Events
UPDATED 11/02/2012.
… bleeding rates associated with new use of Pradaxa
do not appear to be higher than bleeding rates
associated with new use of warfarin, which is consistent
with observations from the large clinical trial used to
approve Pradaxa (the RE-LY trial). FDA is continuing to
evaluate multiple sources of data in the ongoing safety
review of this issue.
HAS-BLED Bleeding Risk Score
– Hypertension
(SBP>160mmHg)
– Abnormal renal/liver fxn
(1 pt for each)
– Stroke
– Bleeding history or prone
– Labile INR (if on warfarin)
– Elderly (>65 years)
– Drugs (ASA, NSAIDS)/alcohol
(1 pt for each)
• Increasing score associated
with ISTH major bleeding
(C-index 0.72)
Pisters R et al. Chest 2010;138:1093–100
Optimizing Benefit and
Reducing Risk
Hemorrhage
Thrombosis
AF stroke associated with a 30-day mortality of 24%.
Swedish AF Cohort; Circulation 2011; 125: 2298-2307
2010
Q4
2011
Q1
2011
Q2
2011
Q3
2011
Q4
Atrial fibrillation
92
72
75
71
63
Venous
thromboembolism
0
4
8
3
5
Hypertensive heart
disease
8
13
5
15
14
Coronary artery disease
0
3
9
3
6
CVA/TIA
0
0
0
3
3
Valvular disorders
0
0
0
3
0
Dabigatran
visits,%
Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21
Effective Use of TSOACs in
Clinical Practice
1.
Patient selection – ADHERENCE
2.
Dose selection – creatinine clearance
3.
Determine interval follow-up
4.
Assess stability of renal function
5.
Blood pressure control
6.
Avoidance of concomitant antiplatelet therapy
7.
Package insert – avoid potent drug interactions,
guidance on transitions
Procedural Management based
on Bleeding Risk of Surgery
DABIGATRAN
APIXABAN/
RIVAROXABAN
Novel Anticoagulants
1. Dabigatran 150 mg BID reduced ischemic stroke
2. Dabigatran 80% renal clearance
3. Dabigatran is associated with small risk of MI, but
reduced cardiovascular mortality
4. Dabigatran and rivaroxaban increase GI bleeding
5. Rivaroxaban is once per day and approved Rx for
VTE
6. Apixaban reduced stroke, major hemorrhage, and
mortality
7. Well-controlled warfarin is associated with low
rate of adverse events
Gaps: Practical
Considerations
Translation across indication
Atrial fibrillation and valvular heart disease
Atrial fibrillation and ACS
Atrial fibrillation and DVT or PE
Select situations in which monitoring would be
desirable
Reversibility-trauma, urgent surgery, lifethreatening hemorrhage
Guide to the Management of
Bleeding in Patients Taking NOAC
Patients with bleeding on NOAC therapy
Moderate-Severe
bleeding
Mild bleeding
• Delay next dose or
discontinue treatment
as appropriate
•
•
•
•
•
•
•
Mechanical compression
Surgical intervention
Fluid replacement and
hemodynamic support
Blood product transfusion
Oral charcoal
Hemodialysis
? Prothrombin Complex
Concentrate?
(Circulation 2011;124:1573-9)
Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450
Life-threatening
bleeding
• Consideration of rFVIIa
or PCC
• Charcoal filtration
• ? Prothrombin Complex
Concentrate
(Circulation 2011;124:1573-9)
WILL THERE BE A CONTINUING
ROLE
FOR WARFARIN?
1. Mechanical heart valves
2.
3.
4.
5.
6.
7.
8.
9.
Cost
Pregnancy
Severe renal impairment
Drug Interactions
Lack of acceptance of no monitoring
Reversal?
Nonadherence
Intolerant of novel anticoagulant drug
47
• Novel anticoagulants may be safer in the elderly population
due to their wider therapeutic index, shorter t1/2, lack of dietary
interference, and fewer drug interactions.
• Older individuals with AF are at the highest risk of stroke, the
highest risk of hemorrhage, and the highest risk of stopping
therapy.
• Further research is needed to inform commonly encountered
clinical situations to optimize the effectiveness of these novel
agents in routine practice.