Original Article
Apixaban versus Warfarin in Patients with Atrial Fibrillation
N Engl J Med 2011; 365:981-992September 15, 2011
Comments
open through September 21, 2011
- Abstract
Background
Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin.
Methods
In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.
Results
The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42).
Conclusions
In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.)
Media in This Article
Figure 1
Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes.Figure 2
Relative Risks of the Primary Efficacy and Safety Outcomes, According to Major Prespecified Subgroups.Article Activity
- Article
Patients with atrial fibrillation are at increased risk for stroke. Warfarin and other vitamin K antagonists are highly effective treatments, reducing the risk of stroke by about two thirds, but their use is limited by a narrow therapeutic range, drug and food interactions, required monitoring, and risk of bleeding.1 A randomized trial has confirmed the effectiveness of warfarin in the current era.2 Two new oral anticoagulants have recently been shown to be equivalent or superior to warfarin in preventing stroke or systemic embolism.3,4 Apixaban is a direct oral factor Xa inhibitor with rapid absorption, a 12-hour half-life, and 25% renal excretion. 5 In patients with atrial fibrillation who were not candidates for vitamin K antagonists, apixaban, as compared with aspirin, reduced the rate of stroke or systemic embolism by 55% without increasing the risk of major bleeding.6 In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial,7 we compared apixaban with warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor for stroke.
Methods
Study Oversight
The trial was designed and led by a steering committee that included academic investigators and representatives of the sponsors (Bristol-Myers Squibb and Pfizer). Approval by the appropriate ethics committees was obtained at all sites. All patients provided written informed consent. The primary analyses were performed both at Bristol-Myers Squibb and at the Duke Clinical Research Institute. All the authors participated in the design of the trial and the planning of the analyses. The first author wrote the first draft of the manuscript, and all the authors participated in subsequent revisions (with no writing assistance other than copy editing) and approved the final version of the manuscript. The trial protocol and statistical analysis plan are available with the full text of this article at NEJM.org. All the authors assume responsibility for the accuracy and completeness of the data and the analyses and for the fidelity of the study to the protocol.
Trial Design
The trial design has been reported previously.7 With the use of a double-blind, double-dummy design, we randomly assigned patients to treatment with apixaban or dose-adjusted warfarin. The primary objective was to determine whether apixaban was noninferior to warfarin in reducing the rate of stroke (ischemic or hemorrhagic) or systemic embolism among patients with atrial fibrillation and at least one other risk factor for stroke. The primary safety outcome was major bleeding, according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH). Key secondary objectives were to determine whether apixaban was superior to warfarin with respect to the primary outcome and to the rates of major bleeding and death from any cause. To control the overall type I error, prespecified hierarchical sequential testing was performed first on the primary outcome for noninferiority, then on the primary outcome for superiority, then on major bleeding, and finally on death from any cause.
Study Population
Eligible patients had atrial fibrillation or flutter at enrollment or two or more episodes of atrial fibrillation or flutter, as documented by electrocardiography, at least 2 weeks apart in the 12 months before enrollment. In addition, at least one of the following risk factors for stroke was required: an age of at least 75 years; previous stroke, transient ischemic attack, or systemic embolism; symptomatic heart failure within the previous 3 months or left ventricular ejection fraction of no more than 40%; diabetes mellitus; or hypertension requiring pharmacologic treatment. Key exclusion criteria were atrial fibrillation due to a reversible cause, moderate or severe mitral stenosis, conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve), stroke within the previous 7 days, a need for aspirin at a dose of >165 mg a day or for both aspirin and clopidogrel, and severe renal insufficiency (serum creatinine level of >2.5 mg per deciliter [221 μmol per liter] or calculated creatinine clearance of <25 ml per minute).7 Patients were classified as not having received warfarin previously if they had used warfarin or another vitamin K antagonist for no more than 30 consecutive days. Investigators at all study centers were encouraged to enroll a sizable proportion of patients (≥40%) who had not previously received warfarin.
Randomization and Study Drugs
Randomization was stratified according to whether patients had received warfarin previously and according to clinical site. Apixaban or matching placebo was administered twice daily, with apixaban given in 5-mg doses; 2.5-mg doses were used in a subset of patients with two or more of the following criteria: an age of at least 80 years, a body weight of no more than 60 kg, or a serum creatinine level of 1.5 mg per deciliter (133 μmol per liter) or more. Warfarin (or matching placebo) was provided as 2-mg tablets and was adjusted to achieve a target international normalized ratio (INR) of 2.0 to 3.0. Patients who were receiving a vitamin K antagonist before randomization were instructed to discontinue the drug 3 days before randomization, and the study drug was initiated when the INR was less than 2.0. INRs were monitored with the use of a blinded, encrypted, point-of-care INR device. An algorithm was provided to guide the adjustment of the warfarin dose. The time that patients' INRs were within the therapeutic range was calculated by the Rosendaal method.8 A program was implemented to improve the quality of INR control through education and feedback at the site and country levels.
An algorithm was provided to manage temporary discontinuations of the study drug around the time of interventional procedures while maintaining concealment of the group assignments. At the end of the trial, when patients discontinued the study drug, guidance was provided in making the transition to open-label warfarin while maintaining concealment of the treatment assignments and ensuring appropriate anticoagulation. In addition to monthly study visits focusing on control of the INR, visits every 3 months included an assessment of clinical outcomes and adverse events. For each patient who was lost to follow-up or who withdrew consent, attempts were made to determine vital status at the end of the trial.
Study Outcomes
The primary efficacy outcome was stroke or systemic embolism. Stroke was defined as a focal neurologic deficit, from a nontraumatic cause, lasting at least 24 hours and was categorized as ischemic (with or without hemorrhagic transformation), hemorrhagic, or of uncertain type (in the case of patients who did not undergo brain imaging or in whom an autopsy was not performed). The key secondary efficacy outcome was death from any cause. The rate of myocardial infarction was also assessed as a secondary efficacy outcome.
The primary safety outcome was major bleeding, which was defined, according to the ISTH criteria,9 as clinically overt bleeding accompanied by a decrease in the hemoglobin level of at least 2 g per deciliter or transfusion of at least 2 units of packed red cells, occurring at a critical site, or resulting in death. The secondary safety outcome was a composite of major bleeding and clinically relevant nonmajor bleeding, which was defined as clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to hospital admission, physician-guided medical or surgical treatment, or a change in antithrombotic therapy. Other safety outcomes included any bleeding, other adverse events, and liver-function abnormalities.
The primary and secondary efficacy and safety outcomes were adjudicated on the basis of prespecified criteria by a clinical-events committee whose members were not aware of study-group assignments. For details, see the Supplementary Appendix, available at NEJM.org.
Statistical Analysis
The primary noninferiority hypothesis required that apixaban preserve at least 50% of the relative reduction in the risk of stroke or systemic embolism associated with warfarin (62%) in six previous, major randomized, controlled trials.10 This hypothesis provided a lower 95% confidence interval of 1.88 for the relative risk with placebo as compared with warfarin, and one half of this value was 1.44 (or 1.38 on a log scale). We estimated that with the occurrence of the primary outcome in 448 patients, the study would have 90% power to ensure that the upper boundary of the 99% confidence interval for the relative risk would be less than 1.44 and that the upper boundary of the 95% confidence interval for the relative risk would be less than 1.38, on the assumption that apixaban and warfarin had identical effects. On the basis of the overall event rate during the trial, we planned to recruit 18,000 patients in order to reach this number of events with approximately 2 years of follow-up. An independent data and safety monitoring committee reviewed the accumulating trial data, with one prespecified interim analysis for efficacy.
The primary and key secondary analyses were performed with the use of the Cox proportional-hazards model, with previous warfarin status and geographic region (North America, South America, Europe, or Asian Pacific) used as strata in the model. The primary and secondary efficacy analyses included all patients who underwent randomization (intention-to-treat population) and included all events from the time of randomization until the cutoff date for efficacy outcomes (predefined as January 30, 2011). The analyses of bleeding events included all patients who received at least one dose of a study drug and included all events from the time the first dose of a study drug was received until 2 days after the last dose was received. In a modified intention-to-treat sensitivity analysis, we analyzed bleeding events that occurred in patients who received at least one dose of a study drug and included all events from the time of randomization until January 30, 2011. All reported P values for noninferiority are one-sided, and all reported P values for superiority are two-sided. All statistical analyses were performed with the use of SAS software, version 9.0 (SAS Institute).
Results
Patients and Follow-up
From December 19, 2006, through April 2, 2010, we recruited 18,201 patients at 1034 clinical sites in 39 countries. A total of 9120 were assigned to the apixaban group and 9081 to the warfarin group. The two groups were well balanced with respect to baseline characteristics (Table 1Table 1
Baseline Characteristics of the Patients.). The median age was 70 years; 35.3% of the patients were women, and the mean CHADS2 score was 2.1. (The CHADS2 score, an index of the risk of stroke in patients with atrial fibrillation, ranges from 1 to 6, with higher scores indicating a greater risk of stroke.) Approximately 57% of the patients had previously received a vitamin K antagonist, and 19% had had a previous stroke, transient ischemic attack, or systemic embolism.Data on vital status at the end of the trial were missing for 380 patients (2.1%). The absence of data on vital status was due to withdrawal of consent in the case of 92 patients in the apixaban group (1.0%) and 107 patients in the warfarin group (1.2%) and was due to loss to follow-up in the case of 35 patients in the apixaban group (0.4%) and 34 in the warfarin group (0.4%).
Study Drugs
A reduced dose of apixaban (2.5 mg twice daily) or placebo was administered in 428 patients in the apixaban group (4.7%) and 403 in the warfarin group (4.4%). Fewer patients in the apixaban group than in the warfarin group discontinued a study drug before the end of the study: 25.3% of the patients in the apixaban group, with 3.6% of the discontinuations due to death, versus 27.5% of patients in the warfarin group, with 3.8% due to death (P=0.001). Patients in the warfarin group had an INR in the therapeutic range (2.0 to 3.0) for a median of 66.0% of the time and a mean of 62.2% of the time, after the exclusion of INR values during the first 7 days after randomization and during study-drug interruptions.
Primary Outcome
The primary outcome of stroke or systemic embolism occurred in 212 patients in the apixaban group (1.27% per year) as compared with 265 patients in the warfarin group (1.60% per year) (hazard ratio in the apixaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority and P=0.01 for superiority) (Table 2Table 2
Efficacy Outcomes. and Figure 1AFigure 1Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes.). The rate of hemorrhagic stroke was 49% lower in the apixaban group than in the warfarin group, and the rate of ischemic or uncertain type of stroke was 8% lower in the apixaban group than in the warfarin group (Table 2). Fatal or disabling stroke occurred in 84 patients in the apixaban group (0.50% per year) as compared with 117 patients in the warfarin group (0.71% per year) (hazard ratio, 0.71; 95% CI, 0.54 to 0.94). Ischemic stroke occurred in 149 patients in the apixaban group and in 155 patients in the warfarin group, and an unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group. Among the patients with ischemic strokes, hemorrhagic transformation occurred in 12 patients in the apixaban group and 20 patients in the warfarin group. Fatal stroke occurred in 42 patients in the apixaban group and 67 patients in the warfarin group.Key Secondary and Other Efficacy Outcomes
The rate of death from any cause was lower in the apixaban group than in the warfarin group (3.52% per year vs. 3.94% per year; hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of death from cardiovascular causes (including death from hemorrhagic stroke) was 1.80% per year in the apixaban group and 2.02% per year in the warfarin group (hazard ratio, 0.89; 95% CI, 0.76 to 1.04), and the rate of death from noncardiovascular causes (including fatal bleeding other than that from hemorrhagic stroke) was 1.14% per year in the apixaban group and 1.22% per year in the warfarin group (hazard ratio, 0.93; 95% CI, 0.77 to 1.13). The rate of myocardial infarction was lower in the apixaban group than in the warfarin group, but the difference was not significant (Table 2).
Bleeding
Major bleeding, as defined according to ISTH criteria, occurred in 327 patients in the apixaban group (2.13% per year), as compared with 462 patients in the warfarin group (3.09% per year) (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001) (Table 3Table 3
Bleeding Outcomes and Net Clinical Outcomes. and Figure 1B). There appeared to be an even greater reduction in the rate of serious bleeding as defined according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria for severe bleeding and according to the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding (Table 3). The rate of intracranial hemorrhage was 0.33% per year in the apixaban group and 0.80% per year in the warfarin group (hazard ratio, 0.42; 95% CI, 0.30 to 0.58; P<0.001), and the rate of any bleeding was 25.8% per year in the warfarin group and 18.1% per year in the apixaban group, an absolute reduction of 7.7 percentage points (P<0.001). In a modified intention-to-treat sensitivity analysis that included the entire treatment period, there was a consistent 27% relative reduction in the rate of major bleeding in the apixaban group, as compared with the warfarin group (P<0.001). Fatal bleeding (including fatal hemorrhagic stroke), as evaluated in the intention-to-treat analysis, occurred in 34 patients in the apixaban group and 55 patients in the warfarin group.Subgroups
The reduction in the primary outcome with apixaban was consistent across all major subgroups (Figure 2Figure 2
Relative Risks of the Primary Efficacy and Safety Outcomes, According to Major Prespecified Subgroups.), and statistical tests for interaction were not significant (P>0.10) for all of the 21 predefined subgroups. With respect to the outcome of major bleeding, the only baseline characteristics for which the interaction was significant were diabetes status and renal function, with a greater reduction in bleeding among patients who did not have diabetes (P=0.003 for interaction) and among patients with moderate or severe renal impairment (P=0.03 for interaction).Overall Safety Outcomes
Adverse events occurred in almost equal proportions of patients in the apixaban group and in the warfarin group (81.5% of the patients in the apixaban group and 83.1% of patients in the warfarin group), as did serious adverse events (35.0% and 36.5% in the two groups, respectively) (for details, see the Supplementary Appendix). The rates of abnormalities on liver-function testing and liver-related serious adverse events were similar in the two groups.
Discussion
In patients with atrial fibrillation and at least one additional risk factor for stroke, the use of apixaban, as compared with warfarin, significantly reduced the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death by 11%. For every 1000 patients treated for 1.8 years, apixaban, as compared with warfarin, prevented a stroke in 6 patients, major bleeding in 15 patients, and death in 8 patients. The predominant effect on stroke prevention was on hemorrhagic stroke, with prevention of a hemorrhagic stroke in 4 patients per 1000 and prevention of an ischemic or unknown type of stroke in 2 patients per 1000.
The results were consistent in subgroups according to geographic region, status with respect to previous warfarin exposure, age, sex, level of renal impairment, and risk factors for stroke, as well as in other predefined subgroups. Apixaban had an acceptable side-effect profile, with no unexpected side effects, and the rate of discontinuation of the study drug was lower in the apixaban group than in the warfarin group.
Warfarin is highly effective in preventing stroke in patients with atrial fibrillation but is associated with a variable response, has drug and food interactions, requires regular monitoring for dose adjustment, and carries a risk of bleeding (including intracranial hemorrhage). In part because of these limitations, only about half of patients who would benefit from warfarin therapy actually receive the drug.11 The alternative treatment regimen with apixaban (at a dose of 5 mg twice daily), which does not require anticoagulation monitoring, not only is more effective than warfarin for stroke prevention but also accomplishes this goal at a substantially lower risk of bleeding and with lower rates of discontinuation. These findings are supported by the results of the Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment trial (AVERROES; ClinicalTrials.gov number, NCT00496769),6 in which the same apixaban regimen, as compared with low-dose aspirin, was shown to substantially reduce the risk of stroke without any difference in the rates of major bleeding and with lower rates of discontinuation. Although major bleeding was less common with apixaban, at a dose of 5 mg twice daily, than with warfarin in patients with atrial fibrillation, the use of the same dose of apixaban, as compared with placebo, resulted in more bleeding in patients with acute coronary syndromes who were receiving both aspirin and clopidogrel.12 The significant reduction in mortality observed in our study was consistent with trends toward lower rates of death among patients receiving apixaban than among those receiving aspirin in the AVERROES trial.
Two alternative oral anticoagulants, the direct thrombin inhibitor dabigatran3 and the factor Xa inhibitor rivaroxaban,4 have recently been shown in randomized clinical trials to be at least as effective as warfarin in preventing stroke. Each of these agents, like apixaban, has the major advantage of convenience, since there is no need for anticoagulation monitoring. In the Randomized Evaluation of Long-Term Anticoagulation Therapy trial (RE-LY, NCT00262600) the oral direct thrombin inhibitor dabigatran administered in two doses per day was compared with open-label warfarin. The 150-mg dose of dabigatran administered twice daily, as compared with warfarin, was shown to reduce the rate of stroke, including ischemic or unspecified stroke, with a similar overall rate of bleeding, although the rate of gastrointestinal bleeding was increased. The 110-mg dose administered twice daily was associated with a rate of stroke that was similar to that with warfarin but with a lower rate of major bleeding. Both doses resulted in lower rates of intracranial hemorrhage. In our study, apixaban at a dose of 5 mg twice daily (with the recommendation to use a reduced dose in patients with a predicted higher drug exposure) appears to combine the advantages of each of the two doses of dabigatran, with both a greater overall reduction in the rate of stroke and a lower rate of bleeding than the rates with warfarin. As compared with warfarin, apixaban is also associated with a reduction in the rate of gastrointestinal bleeding and with consistently lower bleeding rates across age groups13 and all other major subgroups. Fewer patients receiving apixaban had a myocardial infarction than those receiving either warfarin (in our study) or aspirin (in the AVERROES trial).
Rivaroxaban, the second new alternative, was shown to be noninferior to warfarin for the prevention of stroke and systemic embolism in the intention-to-treat analysis in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF, NCT00403767).4 The rates of intracranial hemorrhage and fatal bleeding were lower with rivaroxaban than with warfarin, but there was no advantage with respect to other major bleeding. The differences between our findings and those of other trials comparing novel anticoagulants with warfarin may be related to differences in the doses of drugs, the pharmacokinetic and pharmacodynamic properties of the drugs,14 patient populations, or other features of the clinical-trial design. The lower risk of hemorrhagic stroke associated with all three novel anticoagulants suggests that there is a specific risk associated with warfarin, possibly related to its inhibition of multiple coagulation factors or interaction between warfarin and tissue factor VIIa complexes in the brain.15
In conclusion, in patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
Supported by Bristol-Myers Squibb and Pfizer.
Dr. Granger reports receiving grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, the Medtronic Foundation, Merck, Sanofi-Aventis, Astellas, and the Medicines Company, consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Otsuka Pharmaceutical, Sanofi-Aventis, and the Medicines Company, and support from the Medtronic Foundation and Merck for travel, accommodations, or meeting expenses; Dr. Alexander, receiving grants from Merck/Schering-Plough and Regado Biosciences and consulting fees from Merck/Schering-Plough, AstraZeneca, Boehringer Ingelheim, Ortho-McNeil-Janssen, PolyMedix, Regado Biosciences, and Bayer; Dr. Lopes, receiving grants from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo and consulting fees from Bristol-Myers Squibb; Dr. Hylek, receiving consulting fees from Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck, Pfizer, and Ortho-McNeil-Janssen and lecture fees from Boehringer Ingelheim; Dr. Hanna, being an employee of Bristol-Myers Squibb and receiving stock as part of his compensation; Dr. Ansell, being a member of Bristol-Myers Squibb's data and safety monitoring boards, receiving consulting fees from Ortho-McNeil-Janssen, Daiichi Sankyo, Boehringer Ingelheim, and Bristol-Myers Squibb, and receiving payments from Daiichi Sankyo for developing educational presentations; Dr. Atar, receiving consulting fees or honoraria from Bristol-Myers Squibb; Dr. Avezum, receiving consulting fees from Boehringer Ingelheim and GlaxoSmithKline; Dr. Bahit, receiving consulting fees or honoraria and other research support from Bristol-Myers Squibb; Dr. Diaz, receiving consulting fees or honoraria and other research support from Bristol-Myers Squibb; Dr. Ezekowitz, receiving research support, honoraria, and payments for continuing medical education events from AstraZeneca, Amgen, Abbott, Servier, Johnson & Johnson, Pfizer, and Bristol-Myers Squibb; Dr. Flaker, receiving consulting fees from Boehringer Ingelheim and Sanofi-Aventis and grants from Boehringer Ingelheim and Sanofi-Aventis; Dr. Garcia, receiving consulting fees from Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Daiichi Sankyo and payments from Boehringer Ingelheim for developing educational presentations; Dr. Geraldes, being an employee of Bristol-Myers Squibb and receiving stock or stock options annually; Dr. Gersh, receiving consulting fees from Ortho-McNeil-Janssen, Amorcyte, Abbott Laboratories, GE Healthcare, St. Jude Medical, Medispec, Merck, and Boston Scientific; Dr. Goto, being a board member of Bristol-Myers Squibb and Sanofi-Aventis, receiving grants from Boehringer Ingelheim, Otuska, Eisai, Sanofi-Aventis, and Daiichi Sankyo, consulting fees from Eisai, lecture fees from Eisai, Otsuka, Daiichi Sankyo, Sanofi-Aventis, Bayer, Novartis, AstraZeneca, Asteras, Pfizer, Medtronics-Japan, Tanabe-Mitsubishi, Takeda, Mochida, and MSD, and payments from Bayer and Sanofi-Aventis for developing educational presentations; Dr. Hermosillo, receiving consulting fees or honoraria from Bristol-Myers Squibb; Dr. Hohnloser, receiving consulting fees from Sanofi-Aventis, St. Jude Medical, Boehringer Ingelheim, Cardiome, and Medtronic Vascular and lecture fees from Sanofi-Aventis, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and St. Jude Medical; Dr. Horowitz, receiving research support from Bristol-Myers Squibb; Dr. Mohan, being an employee of Bristol-Myers Squibb and receiving performance-based stock or stock options annually; Dr. Lewis, being an advisory board member for Bayer Healthcare; Dr. Lopez-Sendon, receiving grants from Bristol-Myers Squibb, Boehringer Ingelheim, and Bayer and consulting fees from Boehringer Ingelheim; Dr. Parkhomenko, receiving consulting fees and grants from Borshchiagovsky Chemical-Pharmaceutical Plant; Dr. Verheugt, receiving lecture fees from Bayer and AstraZeneca and consulting fees from Bayer and Daiichi Sankyo; and Dr. Wallentin, receiving grants from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck, consulting fees from Regado Biotechnologies, Portola, CSL Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline, and lecture fees from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
This article (10.1056/NEJMoa1107039) was published on August 28, 2011, and updated on August 30, 2011, at NEJM.org.
Source Information
The authors' affiliations are listed in the Appendix.
Address reprint requests to Dr. Granger at the Duke Clinical Research Institute, Duke University Medical Center, DUMC Box 3850, Durham, NC 27715, or at christopher.granger@duke.edu.
The members of the steering committee, as well as other committee members and investigators in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, are listed in the Supplementary Appendix, available at NEJM.org.
Appendix
The authors' affiliations are as follows: the Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (C.B.G., J.H.A., R.D.L., H.R.A.-K.); University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); Boston University Medical Center, Boston (E.M.H.); Bristol-Myers Squibb, Princeton, NJ (M.H., M.G., P.M.); Lenox Hill Hospital, New York (J.A.); Oslo University Hospital, Oslo (D.A.); Dante Pazzanese Institute of Cardiology, São Paulo (A.A.); ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina (M.C.B., R.D.); University of California San Francisco, San Francisco (J.D.E.); University of Alberta, Edmonton, Canada (J.A.E.); University of Missouri Health Care, Columbia (G.F.); University of New Mexico, Albuquerque (D.G.); Mayo Clinic, Rochester, MN (B.J.G.); Russian Cardiology Research Center, Moscow (S. Golitsyn); Tokai University School of Medicine, Kanagawa, Japan (S. Goto); Instituto Nacional de Cardiologia, Tlalpan CP, Mexico (A.G.H.); J.W. Goethe-University, Frankfurt, Germany (S.H.H.); University of Adelaide, Adelaide, Australia (J.H.); Motol University Hospital, Prague, Czech Republic (P.J.); Lady Davis Carmel Medical Center, Haifa, Israel (B.S.L.); Hospital Universitario La Paz, Madrid (J.L.L.-S.); St. John's Medical College, Bangalore, India (P.P.); Institute of Cardiology, Kiev, Ukraine (A.P.); Onze Lieve Vrouwe Gasthuis, Amsterdam (F.W.A.V.); Fuwai Hospital, Beijing (J.Z.); and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W.).
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- Comments (8)
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8 Reader's Comments
Patrick Oben, MD | Physician | Disclosure: NoneChicago ILSeptember 14, 2011Was the Efficacy Outcome Data Correctly Interpreted?
The interpretation of the primary efficacy and safety data makes me uncomfortable. Firstly, I think hemorrhagic stroke in this clinical context is more of a safety than efficacy outcome. AF in itself does not cause hemorrhagic stroke, the anticoagulants do. Hemorrhagic stroke is NOT prevented by these drugs but associated with their use (see different usage of these words in first and last paragraph of discussion). In Table 2, the difference in the occurrence of ischemic stroke or uncertain type of stroke (p= 0.42) and systemic embolism( p=0.7) is insignificant with respect to the p values.The difference in hemorrhagic stroke is largely significant (<0.001) which doubtless has influenced the overall significant difference in stroke occurrence(p=0.01). Hemorrhagic stroke should not be up there in the primary outcome measure in Table 2 but below (primary safety outcome).
Therefore it seems to me that the remarkable safety profile of apixaban which this trial clearly shows has infiltrated the interpretation of its efficacy data with respect to warfarin.
I stand to be corrected.TAHIR AHMAD | Physician | Disclosure: NoneHALIFAX United KingdomSeptember 05, 2011Apixaban vs. Warfarin in patients with atrial fibrillation
It is very nice & interesting study. Should we assume that the era of Warfarin for nonvalvular atrial fibrillation is over? Has Apixaban been approved by the FDA or in Europe & the UK? What is the cost of Apixaban?
ERASTO GOMES, MD | Physician | Disclosure: NoneJUIZ DE FORA Bouvet IslandSeptember 01, 2011Apaxiban vs Warfarin in patients with atrio-ventricular mechanical valves
Though retired also, I`ve been asked about such patients. Does a patient with atrial fibrillation, on Warfarin for a mechanical valve, change the medication?
Andre Gabriel, MD | Physician | Disclosure: NoneNew York NYAugust 30, 2011Patients with more than 1 risk factor
Was there an effort to stratify the outcome data on patients with more than 1 risk factor for stroke? Although the trial shows promising results, how did the authors account for the patients randomized into the Warfarin treatment group with more than 1 stroke risk factor?
DAVID HINCHMAN, MD | Physician | Disclosure: NoneBOISE IDAugust 28, 2011Apixaban is well tolerated
The Supplementary Appendix shows that adverse events, serious adverse events, discontinuation due to adverse events, and LFT elevations >3 times normal were all higher on warfarin than apixaban.
Dr.Bader S Alshammari, MD | Physician | Disclosure: NoneToronto ON CanadaAugust 28, 2011Apixaban vs. Warfarin in patients with atrial fibrillation
Prophylaxis of stroke in atrial fibrillation is truly an unmet need because of the problematic nature of chronic anticoagulation with Warfarin. Again and in addition to AVERROES trial, Apixaban makes its debut on the scene of stroke prevention in Atrial Fibrillation.
ERNEST PICARD, MD | Physician | Disclosure: NoneNEWTON CENTER MAAugust 28, 2011Apaxiban vs Warfarin in Partients with Atrial Fibrillation
Though retired, I have a personal interest in this subject. Is it now a recommendation that patients on Warfarin with well-controlled INRs be switched to Apaxiban for less thrombosis and hemorrhage risk? Increasing age is clearly one additional risk for hemorrhagic stroke. What is the cost of Apaxiban therapy and what are the side effects?
- Letters
Compliance in Real World Versus Research World
It is definitely a welcome addition! But we should note that patients on warfarin are regularly seen on anticoagulation clinics by doctors or other health professionals to monitor their INR.That effectively serves to reinforce compliance and adherence to therapy. So, unlike in a study setting,the compliance and adherence to a medication that does not require monitoring may be less than ideal.The efficacy noted here may not translate into real world.So the health care providers should be vigilant in monitoring compliance.
Hopefully with the arrival of three very effective choices,the cost factor will not be a big problem.One can only hope!