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AHA/ASA Science Advisory
Oral Antithrombotic Agents for the Prevention of Stroke in
Nonvalvular Atrial Fibrillation
A Science Advisory for Healthcare Professionals From the American
Heart Association/American Stroke Association
The American Academy of Neurology affirms the value of this statement as an educational
tool for neurologists.
Karen L. Furie, MD, MPH, FAHA, Co- Chair; Larry B. Goldstein, MD, FAAN, FAHA, Co- Chair;
Gregory W. Albers, MD; Pooja Khatri, MD, MSc, FAHA; Ron Neyens, PharmD, BCPS;
Mintu P. Turakhia, MD, MAS; Tanya N. Turan, MD, MS, FAHA; Kathryn A. Wood, RN, PhD; on
behalf of the American Heart Association Stroke Council, Council on Quality of Care and Outcomes
Research, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Council on
Peripheral Vascular Disease
The rate of stroke among adults with atrial fibrilla- American College of Cardiology's methods of classifying
tion (AF) varies widely, ranging between 1% and 20%
the level of certainty of the treatment effect and the class of
annually (mean 4.5% per year) depending on comorbidi-
evidence (Table 1).
ties and a patient's history of prior cerebrovascular events.1 Stratification of stroke risk is important, because the major
Summary of Current AHA/ASA Guidelines
risk of antithrombotic medications used to lower the incidence
for Vitamin K Antagonists/Antithrombotics in
of AF- related stroke is bleeding. For warfarin, this involves
Patients With AF
balancing a bleeding risk of 1% to 12% per year against the risk of ischemic events, with its use generally reserved for
individuals at greatest thromboembolic risk.1–3 The advent of
The absolute risk of stroke varies 20-fold among AF patients
several new antithrombotic agents offers alternatives to warfa-
according to age and associated vascular comorbidities.
rin and may lower the threshold for thromboembolic risk for
Several stroke risk stratification schemes have been devel-
initiating therapy in patients with AF.
oped and validated.6–8 These, however, can yield differing
In this update to the American Heart Association/
results.9 Current AHA guidelines use the CHADS stratifica-
American Stroke Association (AHA/ASA) "Guidelines for
tion scheme7 (CHADS is an acronym for Congestive heart
the Primary Prevention of Stroke"4 and the prevention of
failure, Hypertension, Age ≥75 years, Diabetes mellitus,
stroke in patients with stroke or transient ischemic attack
and prior Stroke or TIA). The CHADS score was derived
(TIA),5 we review recent trials testing the safety and effi-
from independent predictors of stroke risk in patients with
cacy of a thrombin inhibitor (dabigatran) and 2 factor Xa
nonvalvular AF.7 The score assigns 1 point each for conges-
inhibitors (rivaroxaban and apixaban) in preventing stroke
tive heart failure, hypertension, age ≥75 years, and diabetes
in patients with AF, and we revise management recom-
mellitus and 2 points for prior stroke or TIA.7 The score was
mendations.4,5 Recommendations follow the AHA's and the
validated in a large cohort study and in clinical trials.6,10 For
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship
or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on June 1, 2012. A copy of the
document is available at http://my.americanheart.org/statements by selecting either the "By Topic" link or the "By Publication Date" link. To purchase additional reprints, call 843-216-2533 or e-
The American Heart Association requests that this document be cited as follows: Furie KL, Goldstein LB, Albers GW, Khatri P, Neyens R, Turakhia
MP, Turan TN, Wood KA; on behalf of the American Heart Association Stroke Council, Council on Quality of Care and Outcomes Research, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association.
Stroke. 2012;43:3442-3453.
Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines
development, visit http://my.americanheart.org/statements and select the "Policies and Development" link.
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(Stroke. 2012;43:3442-3453.)
2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
Furie et al Oral Agents for Stroke Prevention in Nonvalvular AF 3443
Table 1. Applying Classification of Recommendations and Level of Evidence
Oral Antithrombotic Agents for the Prevention of Stroke in
Nonvalvular Atrial Fibrillation
A Science Advisory for Healthcare Professionals From the American
Heart Association/American Stroke Association
The American Academy of Neurology affirms the value of this statement as an educational
tool for neurologists.
Karen L. Furie, MD, MPH, FAHA, Co- Chair; Larry B. Goldstein, MD, FAAN, FAHA, Co- Chair;
Gregory W. Albers, MD; Pooja Khatri, MD, MSc, FAHA; Ron Neyens, PharmD, BCPS;
Mintu P. Turakhia, MD, MAS; Tanya N. Turan, MD, MS, FAHA; Kathryn A. Wood, RN, PhD; on
behalf of the American Heart Association Stroke Council, Council on Quality of Care and Outcomes
Research, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Council on
Peripheral Vascular Disease
A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do
not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.
*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior
myocardial infarction, history of heart failure, and prior aspirin use.
†For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve
direct comparisons of the treatments or strategies being evaluated.
example, in one cohort study,10 those with a CHADS score of
but in validation studies of the CHADS score, patients with
0 had a thromboembolic rate of 0.49 (95% confidence interval
prior stroke or TIA averaged 7.40 strokes10 to 10.8 strokes6 per
[CI], 0.30–0.78) per 100 person- years versus 1.52 (95% CI,
100 patient- years. The CHA DS VASc index further refines
1.19–10.94) for CHADS score=1, 2.50 (95% CI, 1.98–3.15)
the risk calculation of CHADS by including additional vari-
for CHADS score=2, 5.27 (95% CI, 4.15–6.70) for CHADS
ables.11 Hemorrhage risk can also vary among individuals.
score=3, 6.02 (95% CI, 3.90–9.29) for CHADS score=4, and
Bleeding risk tools such as the HAS- BLED (Hypertension,
6.88 (95% CI, 3.42–13.84) CHADS score=5 or 6. A limitation
Abnormal renal/liver function, Stroke, Bleeding history or
of the CHADS scheme that applies to secondary prevention
predisposition, Labile INR, Elderly, Drugs/Alcohol concomi-
involves patients with prior stroke or TIA and no other risk
tantly), RIETE (Registro Informatizado de la Enfermedad
factors.2 These patients score 2 on the CHADS scale (point
Tromboemb´olica), and ATRIA (Anticoagulation and Risk
estimate of thromboembolic risk 2.50 per 100 person-years),
Factors in Atrial Fibrillation) scores have been developed
3444 Stroke December 2012
to estimate the likelihood of hemorrhage, but they have low
Current AHA/ASA Recommendations for Vitamin
K Antagonists/Antithrombotics for the Prevention
of a First Stroke
The following are the current AHA/ASA recommendations
Data from multiple clinical trials indicate the superiority of
for vitamin K antagonists/antithrombotics for prevention of
vitamin K antagonists over antiplatelet therapies for stroke
prevention in AF patients. Pooled data from 5 primary pre-
Adjusted-
dose warfarin (target INR, 2.0–3.0) is
vention trials show a consistent benefit of warfarin across
recommended for all patients with nonvalvular AF
studies (overall relative risk [RR] reduction, 68%; 95% CI,
deemed to be at high risk and many deemed to be
50%–79%), which reflects an absolute reduction in annual
at moderate risk for stroke who can receive it safely
stroke rate from 4.5% for control patients to 1.4% in patients
(Class I; Level of Evidence A).
assigned to adjusted- dose warfarin.1 This absolute risk reduc-
2. Antiplatelet therapy with aspirin is recommended for
tion translates to 31 ischemic strokes prevented each year for
low- risk and some moderate- risk patients with AF
every 1000 patients treated.
on the basis of patient preference, estimated bleeding
Anticoagulation is recommended for patients with AF with
risk if anticoagulated, and access to high- quality anti-
a CHADS score ≥2, but there has been more variability in
coagulation monitoring (Class I; Level of Evidence A).
the choice of antithrombotic agent in patients at lower risk
3. For high- risk patients with AF deemed unsuitable for
(CHADS score=1).4 Aspirin or no treatment is recommended
anticoagulation, dual- antiplatelet therapy with clopi-
for patients at very low risk (CHADS score=0).
dogrel and aspirin offers more protection against
Overall, warfarin is relatively safe (annual rate of major
stroke than aspirin alone but with an increased risk
of major bleeding and might be reasonable (Class
bleeding of 1.3% compared with 1% for placebo or aspirin).
IIb; Level of Evidence B).
Results from a large case- control study15 and 2 randomized controlled trials16,17 suggest that the efficacy of oral anticoagu-
Existing AHA/ASA Recommendations for Vitamin
lation declines below an international normalized ratio (INR)
K Antagonists/Antithrombotics for the Prevention of
of 2.0. The optimal intensity of oral anticoagulation for stroke
Stroke in Patients With a History of Stroke or TIA
prevention in patients with AF appears to be an INR of 2.0 to
The following are existing AHA/ASA recommendations for
3.0. Higher INRs are associated with increased risk of bleed-
vitamin K antagonists/antithrombotics for the prevention of
ing, as is the combination of an anticoagulant and an antiplate-
stroke in patients with a history of stroke or TIA5:
let agent.18 Similarly, decreased time in INR therapeutic range (TTR) reduces the safety and effectiveness of warfarin.19
1. For patients with ischemic stroke or TIA with parox-
There are no data showing that increasing the intensity of anti-
ysmal (intermittent) or permanent AF, anticoagulation
coagulation or adding an antiplatelet agent provides additional
with a vitamin K antagonist (target INR, 2.5; range,
protection against future ischemic cerebrovascular events for
2.0–3.0) is recommended (Class I; Level of Evidence A).
2. For patients unable to take oral anticoagulants, as-
patients with AF who have an ischemic stroke or TIA while
pirin alone (Class I; Level of Evidence A) is recom-
undergoing therapeutic anticoagulation.
mended. The combination of clopidogrel plus aspirin
Evidence supporting the efficacy of aspirin is substantially
carries a risk of bleeding similar to that of warfarin
weaker than for warfarin. A pooled analysis of data from
and therefore is not recommended for patients with a
3 trials reported an RR reduction (RRR) of 21% (95% CI,
hemorrhagic contraindication to warfarin (Class III;
0%–38%) compared with placebo.20 A national effectiveness
Level of Evidence B).
study found no benefit with aspirin and an overall risk reduc-tion with warfarin.21 At present, there are sparse data regarding
New Alternative Antithrombotic Agents for
the efficacy of alternative antiplatelet agents or combina-
Stroke Prevention in Patients With AF
tions for stroke prevention in AF patients who are allergic to
The Atrial fibrillation Clopidogrel Trial with Irbesartan
for prevention of Vascular Events (ACTIVE W) trial found
Dabigatran etexilate is an oral prodrug that is rapidly con-
that a vitamin K antagonist was superior to the combination
verted by a serum esterase to dabigatran, a direct, competitive
of clopidogrel and aspirin in AF patients with at least 1 risk
inhibitor of factor IIa (thrombin). The absolute bioavailability
factor for stroke23; however, a TTR <58% showed no benefit
is 6.5%, and the serum half- life is 12 to 17 hours.25 Because of
of vitamin K antagonist over combination antiplatelet ther-
predictable pharmacokinetics, dabigatran can be administered
apy.19 An additional arm of this study (ACTIVE A) compared
at a fixed dose and does not require coagulation monitoring.
aspirin alone versus clopidogrel plus aspirin in AF patients
Dabigatran pharmacokinetics are affected by renal function,
who were considered "unsuitable for vitamin K antagonist
because 80% is excreted renally. In contrast to warfarin, dabi-
therapy."24 Although there was a small reduction in the rate of
gatran is not metabolized by the cytochrome P450 (CYP3A4)
stroke with the combination of clopidogrel plus aspirin versus
system25; however, p- glycoprotein inhibitors such as drone-
aspirin alone, major bleeding occurred in a higher percentage
darone, ketoconazole, amiodarone, verapamil, and quinidine
of the patients undergoing combination therapy, resulting in
can increase dabigatran concentrations, whereas rifampin can
no net benefit.23,24
decrease its effects.
Furie et al Oral Agents for Stroke Prevention in Nonvalvular AF 3445
Clinical Trial Summary
per year).26 The rate of gastrointestinal bleeding was higher
The Randomized Evaluation of
Term Anticoagulation
with dabigatran 150 mg twice daily (1.51% per year) than
Therapy (RE-LY) compared open- label warfarin with 2 fixed,
with warfarin (1.02% per year) or dabigatran 110 mg twice
blinded doses of dabigatran (110 or 150 mg twice daily) in
daily (1.12% per year;
P<0.05). Rates of life- threatening and
patients with AF and at least 1 additional stroke risk factor (previ-
intracranial bleeding, respectively, were higher with warfarin
ous stroke or TIA, left ventricular ejection fraction <40%, New
(1.80% and 0.74%) than with either dabigatran 110 mg twice
York Heart Association heart failure classification of II or higher,
daily (1.22% and 0.23%) or dabigatran 150 mg twice daily
age ≥75 years, or age 65–74 years plus diabetes mellitus, hyper-
(1.45% and 0.30%). In patients aged ≥75 years, intracranial
tension, or coronary artery disease). Patients with stroke within
bleeding risk was lower with dabigatran than with warfarin, but
14 days or those with severe stroke within 6 months, increased
extracranial bleeding risk was increased with the 150-mg dose
bleeding risk, a creatinine clearance (CrCl) <30 mL/min, or
(5.10% versus 4.37%;
P=0.07;
P for interaction <0.001).28
active liver disease were excluded.26 Low- dose aspirin or other
The rate of MI was higher with dabigatran 150 mg twice
antiplatelet therapy was permitted. Although dabigatran dose
daily (0.74% per year) than with warfarin (0.53% per year; RR,
was concealed, patients randomized to dabigatran did not receive
1.38; 95% CI, 1.00–1.91).26 After readjudication for silent MI
sham INR testing. Target INR for warfarin was 2.0 to 3.0.
during study site closure, 28 additional events were identified,
The primary outcome was stroke or systemic embolism;
and differences in rate of MI between treatment arms were no
secondary outcomes included stroke, systemic embolism, and
longer significant.27 Post hoc analysis including these events
death, although several additional outcomes were also pre-
found that MI occurred at annual rates of 0.82% per year with
specified, including myocardial infarction (MI). The primary
dabigatran 110 mg twice daily and 0.81% per year with dabi-
safety outcome was major hemorrhage, and the trial was pow-
gatran 150 mg twice daily compared with 0.64% with warfarin
ered to demonstrate noninferiority versus warfarin with respect
(hazard ratio [HR], 1.29; 95% CI, 0.96–1.75;
P=0.09; and HR,
to the primary outcome. A net clinical benefit was defined as
1.27; 95% CI, 0.94–1.71;
P=0.12, respectively).29 Net clinical
an unweighted composite of stroke, systemic embolism, pul-
benefit favored treatment with dabigatran. Patients with MI had
monary embolism, MI, death, or major hemorrhage.
higher baseline rates of aspirin and clopidogrel use. The interac-
A total of 18 113 patients were enrolled from 44 countries;
tion with on- treatment concomitant antiplatelet therapy and the
the median follow- up was 2.0 years, and only 20 patients were
risk of MI has not been evaluated. A meta- analysis of noninfe-
lost to follow- up. Patients were elderly (71.6±8.7 years; 36%
riority trials that included 30 514 subjects found that dabiga-
women) and had moderate to high risk of stroke (CHADS
tran was associated with a higher risk of MI or acute coronary
syndromes (odds ratio, 1.33; 95% CI, 1.03–1.71;
P=0.01), with
2.1±1.1; 20% with prior stroke, 32% with heart failure, and
similar results when the revised RE- LY data were included.30 In
23% with diabetes mellitus). Half of the patients were receiv-
RE- LY, discontinuation rates for dabigatran were higher than
ing warfarin before randomization.
for warfarin (16% dabigatran versus 10% warfarin at 1 year)
For the primary outcome of stroke or systemic embolism,
and concordant with rates of dyspepsia (12% versus 6%).26
both dabigatran 110 mg twice daily (1.53% per year) and
Higher baseline CHADS scores were associated with
dabigatran 150 mg twice daily (1.11% per year) were nonin-
an increased risk of stroke and systemic embolism in all 3
ferior to warfarin (1.69% per year); dabigatran 150 mg twice
treatment arms.31 The risk reduction with dabigatran 150 mg
daily was also superior to warfarin (RR, 0.66; 95% CI, 0.53–
twice daily (compared with warfarin) was consistent across
0.82). Compared with warfarin, the risk of hemorrhagic stroke
CHADS categories. Similarly, bleeding risk increased across
was lower with both dabigatran 110 mg twice daily (RR, 0.31;
CHADS categories, although both doses of dabigatran had
95% CI, 0.17–0.56) and dabigatran 150 mg twice daily (RR,
lower rates of intracranial bleeding than with warfarin.
0.26; 95% CI, 0.14–0.49).
There are limited data from RE- LY on patients with prior
For the outcome of net clinical benefit, dabigatran 150 mg
stroke or TIA. A subgroup analysis of 3623 subjects with stroke
twice daily (6.91% per year) was marginally superior to warfa-
or TIA before randomization showed higher overall event rates
rin (7.09% per year; RR, 0.91; 95% CI, 0.82–1.00) but not dabi-
than for those without stroke or TIA (2.38% versus 1.22% per
gatran 110 mg twice daily (7.09% per year; RR, 0.98; 95% CI,
year) but similar rates of stroke or systemic embolism with
0.89–1.08). There was a trend toward lower all- cause mortal-
warfarin (2.78% per year), dabigatran 150 mg twice daily
ity with dabigatran 150 mg twice daily (3.64% year) compared
(2.07% per year), and dabigatran 110 mg twice daily (2.32%
with warfarin (4.13% per year; RR, 0.88; 95% CI, 0.80–1.03)
per year).32 Dabigatran at either dose was superior to warfa-
but not dabigatran 110 mg twice daily (3.75%; RR, 0.91; 95%
rin for the primary outcome (RR, 0.34 and 0.65, respectively;
CI, 0.80–1.03). No racial or ethnic subgroup analyses were
P for interactions=NS). The rate of major bleeding was lower
included in the primary report on RE- LY.26 Additional events
in patients taking 110 mg dabigatran twice daily and similar in
were identified after the RE-LY trial database was locked.
those taking 150 mg dabigatran twice daily compared with those
Based on the updated results, the net clinical benefit for dabigi-
taking warfarin. Results in patients with prior stroke or TIA were
tran 110 mg twice daily was 7.34 per 100 person years versus
consistent with the overall RE- LY result, except that dabigatran
7.11 for dabigitran 150 mg twice daily and 7.91 for warfarin.27
150 mg was noninferior to warfarin for the primary outcome
Major bleeding in RE- LY was lower with dabigatran 110
rather than superior to it.
mg twice daily (2.71% per year; RR, 0.80; 95% CI, 0.69–0.93)
TTR is a potent predictor of warfarin effectiveness
but similar for dabigatran 150 mg twice daily (3.11% per year;
and safety.33,34 A
level secondary analysis of the
RR, 0.93; 95% CI, 0.81–1.07) compared with warfarin (3.36%
LY trial compared the efficacy of dabigatran versus
3446 Stroke December 2012
warfarin, stratified by quartiles of mean TTR of the enrolling
projected drug price of $13 per dose, dabigatran 150 mg twice
center.35 The median TTR in the warfarin arm was 64%, with
daily compared with warfarin had increased quality- adjusted
significant patient- and site- level variation (44%–77%). In the
life- years (QALYs; 10.84 versus 10.28 QALYs) and an incre-
warfarin arm, the rate of stroke or systemic embolism decreased
mental cost- effectiveness ratio (ICER) of $45 372 per QALY
with higher center TTR. Compared with warfarin, dabigatran
gained with dabigatran.39 The model was highly sensitive to
150 mg twice daily had a lower risk of stroke and dabigatran
dabigatran price and risk of stroke or intracranial hemorrhage
110 mg twice daily had a lower risk of bleeding across all
while taking dabigatran or warfarin. When dabigatran pricing
quartiles of TTR. Intracranial bleeding did not vary by center
was announced to be significantly lower than this projected
TTR but was lower for both doses of dabigatran. A major limi-
price, the ICER of dabigatran 150 mg twice daily decreased to
tation of this facility- level analysis is that it did not evaluate
$12 386 per QALY gained.44 Sensitivity analyses demonstrated
patient- level differences in outcomes by TTR using a multilevel
that for patients at higher risk for stroke (based on CHADS 2
model that accounted for site- level effects, because correlation
score), the QALYs and ICER for dabigatran improved rela-
between individual patient TTR and facility TTR was modest
tive to warfarin. These results were robust over a wide range
(
r2=0.588). Moreover, TTR could not be estimated in 5% of
of model assumptions. A subsequent
centers, with these patients being excluded from the analysis.
analysis performed a 4-way comparison of aspirin, warfarin,
Among 8989 RE- LY subjects who had been receiving
aspirin- clopidogrel, and dabigatran using networked analysis
long- term vitamin K antagonist therapy before randomization,
to derive efficacy estimates across treatments that have never
efficacy was similar for the primary outcome with dabigatran
been compared in clinical studies.41 Dabigatran 150 mg and
150 mg twice daily and 110 mg twice daily (RR, 0.81 and
110 mg twice daily were associated with higher QALYs than
0.72, respectively;
P for interactions=NS).26 There are no pub-
warfarin, aspirin, or aspirin- clopidogrel combination therapy.
lished data on bleeding events, tolerability, or stratification by
QALYs and ICERs varied by stroke risk and bleeding risk. A
prerandomization TTR in this subgroup.
low risk of stroke favored aspirin, a moderate risk of stroke
There are very limited data on safety and efficacy in
favored warfarin, and a high risk of stroke or hemorrhage
patients taking aspirin or other antiplatelet therapy, alone or
favored dabigatran 150 mg twice daily. In this analysis, results
in combination.26 Aspirin was used continuously in only 20%
were very sensitive to warfarin TTR, and dabigatran 150 mg
of patients in all 3 treatment arms, and there are no published
twice daily was not cost- effective if warfarin anticoagulation
on- treatment data evaluating the safety or efficacy of combi-
quality was in the highest TTR quartile. Studies from Canada
nation therapy.
and the United Kingdom, using country- specific costs, have
An important limitation of the RE- LY study is the short
also found increased QALYs with dabigatran and ICERs well
median follow- up (2.0 years) relative to the time horizon for
within the range of willingness- to- pay thresholds for their
anticoagulation in patients with AF. Measuring the anticoagu-
lant effect of the drug is also challenging in clinical practice.
Cost- effectiveness analyses can have several major limita-
The effects of dabigatran can be detected in the activated partial
tions. The analyses cannot overcome limitations of the pri-
thromboplastin time, endogenous thrombin potential lag time,
mary efficacy data, which in this case are drawn from a single
thrombin time, and ecarin clotting time.36 Ecarin clotting time
trial with a short follow- up relative to the patient's lifetime
correlates best with plasma concentrations; however, activated
horizon of anticoagulation use. Minor alterations in the dura-
partial thromboplastin time is an alternative and is generally
bility of drug effect or changes in drug adherence could have
prolonged in patients receiving dabigatran. Factors that affect
large effects on real QALYs and costs. Additional costs or
clearance and plasma concentrations (kidney function, body
harms may become apparent with ongoing use outside of ran-
mass index, or volume of distribution) could lead to variation
domized trials. For example, none of these studies evaluated
of anticoagulation effect, safety, and efficacy. Use of activated
cost, utility, or harm related to periprocedural anticoagulation
recombinant factor VIIa or purified factor replacement products
management. A patient may have several major procedures
has been proposed for reversal of dabigatran36; however, both
over the lifetime of anticoagulation use. Differences in hospi-
are costlier than vitamin K or fresh- frozen plasma.37 The US
tal utilization or costs and harms of anticoagulation bridging
package insert for dabigatran recommends emergency dialysis
for warfarin or short half- life (dabigatran) could dramatically
for rapid reversal of the antithrombotic effect, which may not
impact ICERs. In addition, dabigatran was
be feasible in unstable patients.38 None of the reversal strategies
but not cost- saving. Because of the high prevalence of AF
have been evaluated adequately for efficacy.
and long time horizon of anticoagulation, widespread use of
Cost- Effectiveness Analyses
dabigatran instead of warfarin could lead to marked esca-lations in healthcare expenditures. Finally, these studies
Several rigorous
effectiveness analyses of dabigatran
assessed cost- effectiveness from a healthcare system or soci-
in different healthcare systems have compared dabigatran to
etal perspective. Infrastructural costs, such as anticoagulation
warfarin using decision analysis with efficacy inputs from the
clinics, and indirect costs, such as lost wages and productivity,
RE- LY trial and quality of life and cost data from the medical
were not considered.
literature or public reimbursement data.39–43 There are minor differences in model structure across these studies, but signifi-
cant differences in the base case patient risk profile and age,
In the United States, dabigatran 150 mg twice daily but not
cost of complications, and time horizon. In the first published
110 mg twice daily was approved by the US Food and Drug
study, using a base case of a 65- year- old with CHADS ≥1 and
Administration (FDA). The FDA's justification for approving
Furie et al Oral Agents for Stroke Prevention in Nonvalvular AF 3447
only the high- dose formulation was that superiority for stroke
with CYP3A4 inhibitors or inducers. Clearance is both renal
prevention with dabigatran 150 mg twice daily is a more desir-
(≈36% unchanged) and fecal (≈7% unchanged).
able outcome than decreased nonfatal bleeding with dabi-
Clinical Trial Summary
gatran 110 mg twice daily.45,46 A dose of 75 mg twice daily
The Rivaroxaban versus Warfarin in Nonvalvular Atrial
was approved for patients with low CrCl (15–30 mL/min),
Fibrillation (ROCKET AF) Trial52 was a double- blind nonin-
although these patients were excluded from enrollment in
feriority trial that randomized 14 264 patients with nonval-
RE- LY.47 There are no published comparative data on safety
vular AF who were at moderate to high risk of stroke (prior
events for dabigatran in patients with chronic kidney disease.
history of TIA, stroke, or systemic embolization or ≥2 addi-
Postmarketing surveillance reports of fatal bleeding events in
tional risk factors) to rivaroxaban (20 mg/d) or dose- adjusted
patients treated with dabigatran have led to advisories from reg-
warfarin (target INR 2.0–3.0). The mean CHADS score
ulatory agencies. By November 2011, 256 case reports of bleed-
was 3.5, higher than the mean scores in the RE- LY and
ing events that resulted in death in association with dabigatran
ARISTOTLE (Apixaban for Reduction In STroke and
were recorded in a pharmacovigilance database of the European
Other ThromboemboLic Events in atrial fibrillation) trials.
Economic Area.48 The Therapeutic Goods Administration of
Approximately 55% of subjects had a stroke, TIA, or systemic
Australia reported 209 adverse bleeding events associated
embolism before enrollment. Slightly more than one third of
with dabigatran, most commonly of gastrointestinal origin.49
subjects also took aspirin at some time during the study. The
Some of the bleeding events occurred from the transition from
median follow- up was 707 days.
warfarin to dabigatran. As a result, the Therapeutic Goods
The primary end point was the composite of ischemic and
Administration,50 European Medicines Agency,48 and FDA47
hemorrhagic stroke and systemic embolism, which occurred
have issued advisories or revised product labeling advising phy-
in 1.7% of subjects per year in the rivaroxaban group and 2.2%
sicians to assess renal function before prescribing and in clini-
per year in the warfarin group (HR, 0.79; 95% CI, 0.66–0.96;
cal situations in which declines in kidney function could occur.
P<0.001 for noninferiority). In the intention- to- treat analysis,
In contrast to the FDA, the Therapeutic Goods Administration
the primary end point occurred in 2.1% of subjects per year in
and European Medicines Agency recommend that dabigatran
the rivaroxaban group and 2.4% per year in the warfarin group
not be prescribed if CrCl is <30 mL/min.
(HR, 0.88; 95% CI, 0.74–1.03;
P<0.001 for noninferiority and
Revised FDA labeling recommends reducing the dose of
P=0.12 for superiority). The primary safety end point was a
dabigatran to 75 mg twice daily when dronedarone or systemic
composite of major and nonmajor clinically relevant bleeding,
ketoconazole is coadministered in patients with moderate
which occurred in 14.9% of patients per year in the rivaroxa-
renal impairment (CrCl 30–50 mL/min). The use of dabi-
ban group and 14.5% in the warfarin group (HR, 1.03; 95%
gatran and P- glycoprotein inhibitors in patients with severe
CI, 0.96–1.11;
P=0.44). Lower rates of intracranial hemor-
renal impairment (CrCl 15–30 mL/min) should be avoided.
rhage (0.5% versus 0.7%,
P=0.02) and fatal bleeding (0.2%
As of the time of publication of the present statement, the
versus 0.5%,
P=0.003) occurred in the rivaroxaban group than
FDA was analyzing postmarketing reports of adverse events
in the warfarin group.
for evidence of inappropriate dosing, use of interacting drugs,
There was a trend toward an interaction between presence
and other clinical factors that may be associated with bleed-
or absence of a prior stroke, TIA, or systemic embolism for
ing events.47 Postmarketing advisories have not indicated an
the primary end point and in the intention- to- treat analysis
increased risk of MI.
(
P=0.072) and a significant interaction for safety (
P=0.039).
Existing AHA Recommendations
Among subjects without a history of stroke, TIA, or systemic
The existing AHA recommendation for use of dabigatran is
embolism, the primary end point (efficacy) occurred in 2.57%
reported below51:
of subjects in the rivaroxaban group and 3.61% of subjects in the warfarin group (HR, 0.71; 95% CI, 0.54–0.94), which
1. Dabigatran is useful as an alternative to warfarin for
suggests superiority of rivaroxaban for primary prevention of
the prevention of stroke and systemic thromboembo-
stroke or systemic embolism. The primary safety end point
lism in patients with paroxysmal to permanent AF
occurred in 1.67% of subjects with a prior history of stroke,
and risk factors for stroke or systemic embolization
TIA, or systemic embolism in the rivaroxaban group compared
who do not have a prosthetic heart valve or hemo-
dynamically significant valve disease, severe renal
with 2.86% in the warfarin group (HR, 0.59; 95% CI, 0.42–
failure (CrCl <15 mL/min), or advanced liver disease
0.83). Among subjects with a history of prior stroke, TIA, or
(impaired baseline clotting function) (Class I; Level
systemic embolism, the primary end point (efficacy) occurred
of Evidence B).
in 4.8% in the rivaroxaban group and 4.9% in the warfarin group (HR, 0.98; 95% CI, 0.8–1.2), with no difference for the
secondary prevention of stroke or systemic embolism. The primary safety end point occurred in 3.5% of subjects with a
history of prior stroke, TIA, or systemic embolism who were
Rivaroxaban is a direct factor Xa inhibitor. It has ≈70%
taking rivaroxaban versus 3.9% taking warfarin (HR, 0.91;
bioavailability, with a serum half- life of 5 to 9 hours. It has
95% CI, 0.72–1.14).
predictable pharmacokinetics and is administered as a fixed
Although there was no standardized definition of "warfa-
dose without coagulation monitoring. Rivaroxaban is metabo-
rin naiveté" across the trials, 38% of subjects in ROCKET AF
lized by the CYP3A4 system, and there can be interactions
lacked exposure to vitamin K antagonists at enrollment. There
3448 Stroke December 2012
was no interaction between prior history of vitamin K antago-
nist use and either efficacy or safety. Subjects näive to vitamin
K antagonists had a lower rate of the primary end point while taking rivaroxaban (3.79%) than those taking warfarin (4.94%)
Apixaban is a direct and competitive factor Xa inhibitor.56 It has
in the intention- to- treat analysis (HR, 0.76; 95% CI, 0.59–0.98).
≈50% bioavailability. Apixaban has a short half- life of 8 to 15
J- ROCKET AF (Japanese Rivaroxaban Once daily oral direct
hours. It has predictable pharmacokinetics and is administered
factor Xa inhibition Compared with vitamin K antagonism for
as a fixed dose without coagulation monitoring. Apixaban is
prevention of stroke and Embolism Trial in Atrial Fibrillation)
metabolized by the CYP3A4 system, and there can be interac-
was a prospective, randomized, double- blind phase 3 study
tions with CYP3A4 inhibitors or inducers. Clearance is both
in which 1280 Japanese subjects with AF were enrolled from
renal (≈25% unchanged) and fecal (≈50% unchanged).
165 centers across Japan.53 The primary objective of the study
Clinical Trial Summary
was to evaluate the safety of rivaroxaban 15 mg once daily (10
The Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in
mg daily in patients with moderate renal impairment) versus
Atrial Fibrillation Patients Who Have Failed or Are Unsuitable
dose- adjusted warfarin (target INR of 2.0–3.0 for patients <70
for Vitamin K Antagonist Treatment (AVERROES) trial was
years of age and 1.6–2.6 for those patients ≥70 years of age).
a randomized, double- blind trial comparing the efficacy and
The study was designed to evaluate the noninferiority of riva-
safety of apixaban to aspirin in 5599 subjects with nonvalvular
roxaban compared with warfarin for on- treatment bleeding.53
AF and ≥1 additional risk factor for stroke who were unsuit-
The primary safety end point in J- ROCKET was the time
able for vitamin K antagonist therapy primarily on the basis of
to first major or nonmajor clinically relevant bleeding event
physician judgment or patient preference.56 The dose of apixa-
in both the rivaroxaban and warfarin arms. There were 11 ver-
ban was 5 mg twice daily (94%) or 2.5 mg twice daily (6%),
sus 22 bleeding events in the rivaroxaban and warfarin arms,
with the lower dose used for patients who met ≥2 of the fol-
respectively (1.26 versus 2.61 events per 100 patients per year;
lowing criteria: Age ≥80 years, weight ≤60 kg, or serum cre-
HR, 0.48; 95% CI, 0.23–1.00).54 Rivaroxaban was shown to
atinine ≥1.5 mg/dL. The dose of aspirin was 81 mg (64%), 162
be noninferior to warfarin for the primary efficacy end point
mg (27%), 243 mg (2%), or 324 mg (7%) at the discretion of
(time to the first stroke or noncerebral systemic embolization).
the investigator. Subjects were a mean of 70 years old and had
The quality of warfarin anticoagulation management in the
a mean CHADS score of 2. Fourteen percent of patients had a
J- ROCKET trial is a concern. The TTR was lower than his-
prior stroke, and 9% reported concurrent aspirin use for more
torical values in other warfarin trials.54
than half of the study duration. The study was terminated when
Several issues regarding interpretation of the results of
an interim analysis found that apixaban was superior to aspirin
the ROCKET- AF trial were raised during the FDA regula-
for prevention of stroke or systemic embolism (1.6% per year
tory review.55 These included uncertainty about the constancy
versus 3.7% per year; HR, 0.45; 95% CI, 0.32–0.62; number
assumption (ie, in noninferiority trials, "the control treat-
needed to treat [NNT]=45; RRR=57%) with a similar rate of
ment, as administered in the new trial, must have the same
major bleeding (1.4% per year versus 1.2% per year; HR, 1.13;
magnitude of benefit relative to placebo as it had in the refer-
95% CI, 0.74–1.75). Apixaban was superior to aspirin in pre-
ence trials used to estimate its effect").55 The mean TTR for
venting a disabling or fatal stroke (1% per year versus 2.3% per
warfarin- arm subjects was only 55% (versus 62%–73% in
year; HR, 0.43; 95% CI 0.28–0.65; NNT=67; RRR=57%). The
other recent trials). The on- treatment analysis was truncated 2
benefit of apixaban remained when aspirin doses were grouped
days after discontinuation of the randomized treatment, with
(<162 mg or ≥162 mg). The net clinical benefit, a composite
higher rates of stroke or systemic embolization with rivaroxa-
outcome of stroke, systemic embolism, MI, death of a vascular
ban observed 2 to 7 days after discontinuation of the study
cause, or major bleeding, supported apixaban as being superior
medication. This highlights the importance of ensuring ade-
to aspirin (5.3% per year versus 7.2% per year; HR, 0.74; 95%
quate anticoagulation after temporary or permanent rivaroxa-
CI, 0.6–0.9; NNT=48; RRR=26%).
ban discontinuation for a reason other than bleeding. Finally,
AVERROES primarily enrolled subjects who had not had
once- daily dosing was not supported by pharmacokinetic or
a prior stroke or TIA (86%). Apixaban was superior to aspi-
pharmacodynamic data. Despite these concerns, rivaroxaban
rin for primary prevention of stroke or systemic embolism
received FDA regulatory approval.
(1.5% per year versus 3% per year; NNT=62; RRR=50%)
The effect of rivaroxaban is reflected in the prothrombin
with a similar rate of major bleeding (1.1% per year versus
time and endogenous thrombin potential. Prothrombin com-
1% per year).56 When analyzed by CHADS score, apixaban
plex concentrate has been reported to reverse the effect of
was superior to aspirin in patients with a CHADS score of 2
rivaroxaban37; however, no reversal strategies have been ade-
(2.1% per year versus 3.7% per year; NNT=56; RRR=43%)
quately evaluated for clinical efficacy.
and a CHADS score ≥3 (1.9% per year versus 6.3% per year;
Cost- Effectiveness Analyses, Postmarketing Surveillance,
NNT=21; RRR=70%),
and Existing AHA Recommendations
For those without prior stroke or TIA with a CHADS 2
effectiveness analyses have not been published.
score of 0 or 1, apixaban was equally safe and effective as
Rivaroxaban was recently approved for stroke prevention in
aspirin for preventing stroke or systemic embolism (0.9%
patients with AF in the United States. Postmarketing surveil-
per year versus 1.6% per year; NNT=143; RRR=44%).
lance data are not yet available. There are no existing AHA
Despite a greater number of patients, the CIs were wider for
recommendations with regard to the use of rivaroxaban.
this subgroup than for those with higher CHADS scores, so
Furie et al Oral Agents for Stroke Prevention in Nonvalvular AF 3449
further delineation of risk with the CHA DS VASc score may
bleeding with apixaban among those without diabetes mellitus
enable future investigations to identify a subset of patients
(
P=0.003 for interaction) and among those with moderate or
who may benefit from apixaban.57
severe renal impairment (
P=0.03 for interaction).
Study drug was initiated a minimum of 10 days after the
Cost- Effectiveness Analyses, Postmarketing Surveillance,
stroke in the small subgroup with prior stroke or TIA (14%).
and Existing AHA Recommendations
Apixaban was superior to aspirin for secondary prevention
Cost- effectiveness analyses have not been published.
of stroke or systemic embolism (2.5% per year versus 8.3%
Apixaban is not currently approved for stroke prevention in
per year; NNT=16; RRR=70%), with a similar rate of major
patients with AF in the United States; therefore, there are no
bleeding (3.5% per year versus 2.7% per year).56
postmarketing surveillance data. When apixaban is approved,
A vitamin K antagonist had been prescribed and discontin-
there may be additional data made available that would affect
ued in 40% of patients in the AVERROES study, with 14% dis-
the recommendations. No AHA recommendations regarding
continuing it within 30 days before screening. Apixaban was
apixaban currently exist.
superior to aspirin for reduction in stroke or systemic embolism in patients who had previously taken a vitamin K antagonist
(1.4% per year versus 4.2% per year; NNT=36; RRR=67%),
It is important to acknowledge several unresolved issues related
as well as in patients who were näive to a vitamin K antagonist
to the clinical use of dabigatran, rivaroxaban, and apixaban.
(1.8% per year versus 3.3% per year; NNT=67; RRR=45%).56
There are no published data directly comparing dabigatran,
The ARISTOTLE trial was a phase 3 randomized trial
rivaroxaban, and apixaban to one another, only comparisons
comparing apixaban to warfarin for the prevention of stroke
to warfarin. The duration of follow- up in the clinical trials was
(ischemic or hemorrhagic) or systemic embolization among
limited. Factors relevant to long- term, real- world adherence are
patients with AF or atrial flutter and at least 1 additional risk
not known, especially if these new drugs are used outside of a
factor for stroke.58 To be eligible, AF had to be present at the
care structure designed to assess adherence, such as an antico-
time of enrollment or documented by ECG at 2 separate times
agulation clinic. Because of their short half- lives, patients who
at least 2 weeks apart within the prior 12 months. At least 1 of
are noncompliant and miss medication doses might be at risk
the following stroke risk factors was also required: Age ≥75
for thromboembolism. Treatment decisions should account for
years; prior stroke, TIA, or systemic embolism; symptomatic
differences in costs to patients, which could also affect com-
heart failure within 3 months or left ventricular ejection frac-
pliance. Drug activity of the newer agents presently cannot be
tion ≤40%; diabetes mellitus; or hypertension that required
assessed in routine clinical practice, which poses a potential
risk of undertreating or overtreating individuals. The transition
Study interventions were administered in a double- blind,
from warfarin must be managed carefully and may constitute a
double- dummy fashion. Subjects in the apixaban arm received
period of increased risk. It is not known whether patients receiv-
5 mg twice daily unless they met ≥2 of the following crite-
ing these agents but otherwise eligible for thrombolysis can be
ria for a lower 2.5-mg twice- daily dose: Age ≥80 years,
treated safely with a thrombolytic agent (ie, intravenous recom-
body weight ≤60 kg, or serum creatinine mt1.5 mg/dL (133
binant tissue- type plasminogen activator) for an acute ischemic
μmol/L). Subjects in the warfarin arm received 2-mg tablets
stroke. There are no antidotes to emergently reverse dabigatran,
initially, and dosing was adjusted to achieve a target INR of
apixaban, or rivaroxaban in the setting of hemorrhage. Apixaban is not currently approved for stroke prevention in patients with
2.0 to 3.0 in a blinded and algorithmic manner; therapeutic
AF in the United States (Table 2). Data reflecting clinical effec-
INRs were achieved a mean 62% of the time. Additionally,
tiveness (ie, the balance of benefits and risks of the newer agents
subjects in both arms were permitted to receive up to 162 mg
as used in real- world settings) are only beginning to emerge for
of aspirin daily if clinically indicated.
dabigatran and are unavailable for apixaban and rivaroxaban.
Among 18 201 randomized patients followed up for a
median of 1.8 years, 1.27% of apixaban- treated subjects expe-
1. Warfarin (Class I; Level of Evidence A), dabigatran
rienced the primary outcome of stroke or systemic emboliza-
(Class I; Level of Evidence B), apixaban (Class I;
tion compared with 1.60% of warfarin- treated subjects (HR,
Level of Evidence B), and rivaroxaban (Class IIa;
0.79; 95% CI, 0.66–0.95). In prespecified hierarchical test-
Level of Evidence B) are all indicated for the pre-
ing, both noninferiority (
P<0.001) and superiority (
P=0.01)
vention of first and recurrent stroke in patients
of apixaban were demonstrated. A greater proportion of the
with nonvalvular AF. The selection of an antithrom-
benefit appeared to be related to the reduction in hemorrhagic
botic agent should be individualized on the basis of
stroke (49% reduction) compared with ischemic or uncertain
risk factors, cost, tolerability, patient preference,
potential for drug interactions, and other clinical
types of stroke (8% reduction). Additional secondary end
characteristics, including time in INR therapeutic
points of death (3.52% versus 3.94%; HR, 0.89; 95% CI, 0.80–
range if the patient has been taking warfarin.
0.99;
P=0.047) and major bleeding (2.13% versus 3.09%; HR,
2. Dabigatran 150 mg twice daily is an efficacious al-
0.69; 95% CI, 0.60–0.80;
P<0.001) favored apixaban.
ternative to warfarin for the prevention of first and
Consistent treatment effects were seen across prespecified
recurrent stroke in patients with nonvalvular AF
subgroups, including those based on concurrent aspirin use at
and at least 1 additional risk factor who have CrCl
randomization, warfarin use before study enrollment, type of
>30 mL/min (Class I; Level of Evidence B).
AF (paroxysmal versus permanent), and prior stroke or TIA
3. On the basis of pharmacokinetic data, the use of
status. Subgroup analyses did suggest greater reduction in
dabigatran 75 mg twice daily in patients with AF
3450 Stroke December 2012
Table 2. Comparison of Key Studies of New Oral Antithrombotics
Dabigatran 150 mg BID
Rivaroxaban 20 mg QD
Apixaban 5 mg or 2.5 mg BID*
Apixaban 5 mg BID*
Aspirin 81–325 mg QD
Double blind, double dummy
Double blind, double dummy
Double blind, double dummy
Previous stroke, %
Event rate vs comparator, %†
1.1 vs 1.7 (P<0.001)
2.1 vs 2.4 (P=0.12‡)
1.3 vs 1.6 (P<0.001)
1.6 vs 3.7 (P<0.001)
HR vs comparator†
0.66 (0.53–0.82)
0.88 (0.74–1.03)‡
0.79 (0.66–0.95)
0.45 (0.32–0.62)
No. needed to treat
Major bleeding vs comparator, %
ICH vs comparator, %
RE- LY indicates Randomized Evaluation of Long- Term Anticoagulation Therapy; ROCKET- AF, Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With
Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; ARISTOTLE, Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation; AVERROES, Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; BID, twice per day; QD, every day; CHADS, Congestive heart failure, Hypertension, Age, Diabetes, prior Stroke or TIA; HR, hazard ratio; and ICH, intracerebral hemorrhage.
*Reduced dose used in select patients; refer to text.
†Stroke or systemic embolism.
‡P=NS for superiority in intention- to- treat analysis.
and at least 1 additional risk factor who have a low
8. Although its safety and efficacy have not been
CrCl (15–30 mL/min) may be considered, but its
established, apixaban 2.5 mg twice daily may be
safety and efficacy have not been established (Class
considered as an alternative to warfarin in pa-
IIb; Level of Evidence C).
tients with nonvalvular AF deemed appropriate
4. Because there are no data to support the use of dab-
for vitamin K antagonist therapy who have at
igatran in patients with more severe renal failure,
least 1 additional risk factor and ≥
2 of the fol-
dabigatran is not recommended in patients with a
lowing criteria: Age ≥
80 years, weight ≤
60 kg, or
CrCl <15 mL/min (Class III; Level of Evidence C).
serum creatinine ≥
1.5 mg/dL (Class IIb; Level of
5. Apixaban 5 mg twice daily is an efficacious alter-
native to aspirin in patients with nonvalvular AF
9. Apixaban should not be used if the CrCl is <25 mL/
deemed unsuitable for vitamin K antagonist ther-
min (Class III; Level of Evidence C).
apy who have at least 1 additional risk factor and
10. In patients with nonvalvular AF who are at mod-
no more than 1 of the following characteristics: Age
erate to high risk of stroke (prior history of TIA,
≥
80 years, weight ≤
60 kg, or serum creatinine ≥
1.5
stroke, or systemic embolization or ≥
2 additional
mg/dL (Class I; Level of Evidence B).
risk factors), rivaroxaban 20 mg/d is reasonable
6. Although its safety and efficacy have not been es-
as an alternative to warfarin (Class IIa; Level of
tablished, apixaban 2.5 mg twice daily may be con-
sidered as an alternative to aspirin in patients with
11. In patients with renal impairment and nonvalvu-
nonvalvular AF deemed unsuitable for vitamin K
lar AF who are at moderate to high risk of stroke
antagonist therapy who have at least 1 additional
(prior history of TIA, stroke, or systemic emboli-
risk factor and ≥
2 of the following criteria: Age ≥
80
zation or ≥
2 additional risk factors), with a CrCl
years, weight ≤
60 kg, or serum creatinine ≥
1.5 mg/
of 15 to 50 mL/min, 15 mg of rivaroxaban daily
dL (Class IIb; Level of Evidence C).
may be considered; however, its safety and effi-
7. Apixaban 5 mg twice daily is a relatively safe and
cacy have not been established (Class IIb; Level of
efficacious alternative to warfarin in patients with
nonvalvular AF deemed appropriate for vitamin K
12. Rivaroxaban should not be used if the CrCl is <15
antagonist therapy who have at least 1 additional
mL/min (Class III; Level of Evidence C).
risk factor and no more than 1 of the following
13. The safety and efficacy of combining dabigatran,
characteristics: Age ≥
80 years, weight ≤
60 kg, or
rivaroxaban, or apixaban with an antiplatelet
serum creatinine ≥
1.5 mg/dL, (Class I; Level of
agent have not been established (Class IIb; Level of
Furie et al Oral Agents for Stroke Prevention in Nonvalvular AF 3451
Writing Group Disclosures
Consultant/Advisory
Massachusetts General
Abbott*; Bristol- Myers
Stanford University
Daiichi-Sankyo*;
Johnson & Johnson*;
University of Cincinnati
Medical University of
Palo Alto VA Health
Medical University of
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the
Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be "significant" if (1) the person receives $10 000 or more during any 12-month period, or 5% or more of the person's gross income; or (2) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.
Thomas Jefferson
Boehringer Ingelheim†; ARYX
Boehringer Ingelheim†;
Boehringer Ingelheim†; ARYX
Therapeutics†; Pfizer†;
ARYX Therapeutics†;
Therapeutics†; Pfizer†;
Sanofi†; Bristol Meyers
Pfizer†; Sanofi†; Bristol
Sanofi†; Bristol Myers
Squibb†; Portola†; Astra
Myers Squibb†;
Squibb†; Portola†; Astra
Zeneca & Eisai*; Daiichi-
Portola†; Astra Zeneca
Zeneca & Eisai*; Daiichi-
Sankyo†; Medtronic†; Merck
& Eisai*; Daiichi-
Sankyo†; Medtronic†; Merck
and Johnson & Johnson†;
Sankyo†; Medtronic†;
and Johnson & Johnson†;
Gilead†; Janssen Scientific
Merck and Johnson &
Gilead†; Janssen Scientific
Johnson†; Gilead†;
Janssen Scientific
Bayer HealthCare†;
Biotronik†; Boehringer
Ingelheim†; Johnson &
Janssen†; Sanofi-Aventis*;
RosenfeldLee Schwamm
Medtronic advisor on design
of studies to evaluate risk
of stroke during ablation for
atrial fibrillation*
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure
Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be "significant" if (1) the person receives $10 000 or more during
any 12-month period, or 5% or more of the person's gross income; or (2) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more
of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition.
3452 Stroke December 2012
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Key Words: AHA Scientific Statements ◼ atrial fibrillation ◼ antithrombotic
Goods Administration. Dabigatran (Pradaxa): risk of bleeding relating
therapy ◼ stroke prevention ◼ treatment
Source: http://www.insult-afib.ru/images/pages/%D1%80%D1%83%D0%BA%D0%BE%D0%B2%D0%BE%D0%B4%D1%81%D1%82%D0%B2%D0%B0%20%D0%BD%D0%B0%20%D1%81%D1%82%D1%80%D0%B0%D0%BD%D0%B8%D1%86%D1%83/2012%20%D0%90%D0%9D%D0%90-ASA%20%D0%9F%D0%B5%D1%80%D0%BE%D1%80%D0%B0%D0%BB%D1%8C%D0%BD%D0%B0%D1%8F%20%D0%B0%D0%BD%D1%82%D0%B8%D1%82%D1%80%D0%BE%D0%BC%D0%B1%D0%BE%D1%82%D0%B8%D1%87%D0%B5%D1%81%D0%BA%D0%B0%D1%8F%20%D1%82%D0%B5%D1%80%D0%B0%D0%BF%D0%B8%D1%8F%20%D0%B4%D0%BB%D1%8F%20%D0%BF%D1%80%D0%BE%D1%84%D0%B8%D0%BB%D0%B0%D0%BA%D1%82%D0%B8%D0%BA%D0%B8%20%D0%B8%D0%BD%D1%81%D1%83%D0%BB%D1%8C%D1%82%D0%B0.pdf
ARTICLE IN PRESS Medical Engineering & Physics xxx (2006) xxx–xxx Photoacoustic monitoring of the absorption of isotonic saline solution by human mucus F.L. Dumas , F.R. Marciano , L.V.F. Oliveira , P.R. Barja , D. Acosta-Avalos a Instituto de Pesquisa e Desenvolvimento (IP&D), Universidade do Vale do Paraiba, Av. Shishima Hifumi 2911, CEP 12244-000, S˜ao Jos´e dos Campos, SP, Brazil
Observatoire des Médicaments, des Dispositifs médicaux et des Innovations Thérapeutiques Prescription médicamenteuse chez la personne âgée Liste ATC des médicaments proposés par la Commission Gériatrie de la région Centre Préambule Ce livret thérapeutique regroupe la liste des médicaments pouvant être prescrits chez le sujet âgé, proposés par la Commission Gériatrie de la région Centre pilotée par l'OMéDIT. Il a pour objectif d'aider les médecins généralistes, principaux prescripteurs chez les personnes âgées1, dans l'élaboration de leur prescription, la thérapeutique gériatrique n'étant pas une priorité de la formation médicale initiale et continue. Sous le terme de « personnes âgées » sont concernés les sujets de 75 ans et plus, ainsi que ceux de plus de 65 ans polypathologiques. Ils représentent 16 millions de personnes au 1er Janvier 2011 (données INSEE)2. L'âge en soi ne contre-indique aucune thérapeutique, mais le vieillissement et les situations physiopathologiques associées peuvent modifier l'objectif des traitements et leur rapport bénéfice-risque.