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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.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart A link to the "Copyright Permissions Request Form" appears on the right side of the page.
(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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