Trial Design
Apixaban for Reduction In Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial: Design and rationale

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Atrial fibrillation (AF) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists (VKAs). Vitamin K antagonist use is limited, in part, by the high incidence of complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor, apixaban, is noninferior to warfarin at reducing the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine treatment duration. The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38; apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with apixaban is >1.38 times higher than with warfarin. ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism; whether apixaban has particular benefits in the warfarin-naïve population; whether it reduces the combined rate of stroke, systemic embolism, and death; and whether it impacts bleeding.

Section snippets

Warfarin

Warfarin, a vitamin K antagonist (VKA), reduces the risk of stroke by approximately 62%6; however, VKAs have major limitations and are underused in clinical practice.7 Patients are frequently outside the optimal target anticoagulation range when VKAs are prescribed, exposing them to the risk of thrombosis or bleeding.8, 9 Clinical trial data show that among patients receiving warfarin or other VKAs, even in the highly structured setting of a trial, the international normalized ratio (INR) is

Apixaban

Factor Xa occupies a pivotal role in the clotting cascade because it promotes conversion of prothrombin to thrombin. Developed as an anticoagulant agent, apixaban is an orally active selective inhibitor of the coagulation factor Xa. The direct mechanism of this drug does not require the presence of antithrombin. It has a predominantly nonrenal (75%) clearance and a half-life around 12 hours in healthy volunteers. The effect is independent of vitamin K intake, and with the exception of strong

Primary objective

The primary objective of this study is to determine whether apixaban is noninferior to warfarin (INR target range 2.0-3.0) at reducing the combined outcome of stroke (ischemic or hemorrhagic) and systemic embolism in subjects with AF and at least 1 additional risk factor for stroke.

Secondary objectives

The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested

Study population

In this double-blind study, we have randomized 18,206 patients with AF from over 1,000 centers in about 40 countries. Eligible subjects were randomly assigned in a 1:1 ratio to receive either apixaban or warfarin titrated to a target INR range of 2.0 to 3.0. Both warfarin-naïve and warfarin-experienced patients are being recruited, with a special emphasis on the former. Our aim is for 40% of patients to be warfarin naïve. The inclusion and exclusion criteria are summarized in Table I.

Randomization and study drug

Subjects who were on warfarin before randomization discontinued the drug 72 hours before randomization and were not dosed with study drug until the INR was <2.0. Randomization is stratified by investigative site and prior warfarin use status (experienced or naïve). Patients are classified as warfarin naïve if they have never used warfarin (or other VKAs) or if they have used it for ≤30 consecutive days. Otherwise, patients are considered warfarin experienced.

To maintain blinding, study

Study design and duration

The trial is event driven, thus, the number of subjects required and length of treatment were estimated based on event rates in similar trials. The final duration of the trial will be determined by the time required to accrue at least 448 primary efficacy events (see statistical methods). All subjects will be followed from randomization until the study end date.

The study includes a screening period of up to 14 days. Subjects with AF and at least ≥1 risk factors for stroke will be evaluated for

Efficacy outcomes

The primary efficacy outcome is the time to first occurrence of stroke (ischemic or hemorrhagic) or systemic embolism.

In this study, stroke is defined as a nontraumatic abrupt onset of a focal neurologic deficit lasting at least 24 hours. A retinal ischemic event (embolism or thrombosis) will be considered a stroke. A cerebral imaging study (computed tomographic scan or magnetic resonance imaging) is recommended for all suspected strokes. Strokes will be classified as ischemic, ischemic with

Clinical Events Committee adjudication

An independent, blinded, clinical events committee (CEC) adjudicates all suspected hemorrhagic and non-hemorrhagic strokes, TIAs, systemic emboli, major and clinically relevant non-major bleeding, myocardial infarction, and cause of death.

Using prespecified event definitions and agreed upon event adjudication criteria, the CEC adjudicates suspected events based on the preponderance of the evidence and the clinical knowledge and experience of the physician reviewers. Event adjudication in

Statistical analysis and sample size calculation

A meta-analysis of 6 AF studies estimated a relative reduction in the risk of stroke or systemic thromboembolism of 62% for warfarin versus placebo.6 Based on historical trials, the primary noninferiority hypothesis of ARISTOTLE is that apixaban will preserve at least 50% of the benefit of warfarin in preventing stroke and systemic embolism. This gives an upper CI of 1.88 of the apixaban versus warfarin relative risk (Figure 2A). To be more certain that apixaban is noninferior to warfarin based

Pharmacokinetic biomarkers

The main objectives of the biomarker and genetic substudy program are to correlate genetic polymorphisms and levels of biomarkers with clinical outcomes, to improve risk stratification for stroke among patients with AF, and to relate the effects of apixaban and warfarin to these disease biomarkers. Several biomarkers will be analyzed at baseline for as many of the 18,206 patients as possible (Table II), and a second blood sample will be collected for approximately 5,000 patients at 2 months.

Organizational structure

The ARISTOTLE trial is led by an academic steering committee composed of 2 cochairs, national coordinators from each participating country, and a representative from the trial sponsor. This committee provides scientific direction and input, addresses policy issues regarding the protocol, and meets periodically to assess the trial progress.

The ARISTOTLE executive committee, composed of a subset of senior leaders from the steering committee, is responsible for evaluating the progress and safety

Discussion

Atrial fibrillation is a very common arrhythmia and is associated with an increased risk of mortality and morbidity, particularly stroke, which is the third most common cause of death in developed countries and the leading cause of serious long-term disability worldwide.28

The ACTIVE-W study included 6,706 patients with AF and at least ≥1 risk factors for stroke.18 ACTIVE-W was designed to compare oral anticoagulation therapy with aspirin plus clopidogrel for prevention of vascular events in

Conclusion

In conclusion, the ARISTOTLE trial will answer many important questions related to stroke prevention in AF. Most importantly, it will compare apixaban with warfarin for stroke prevention in a wide range of patients with AF. It will provide information about the efficacy of apixaban both in warfarin-experienced and warfarin-naïve patients. Finally, it will generate a better understanding of this common disease and the risks of stroke and bleeding based on large scale substudies on genetic and

References (35)

  • LairikyengbamS.K. et al.

    Present treatment options for atrial fibrillation

    Postgrad Med J

    (2003)
  • HartR.G. et al.

    Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis

    Ann Intern Med

    (1999)
  • HylekE.M. et al.

    Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation

    Circulation

    (2007)
  • GotoS. et al.

    Prevalence, clinical profile, and cardiovascular outcomes of atrial fibrillation patients with atherothrombosis

    Am Heart J

    (2008)
  • WanY. et al.

    Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review

    Circulation Cardiovascular Quality and Outcomes

    (2008)
  • AlbersG.W. et al.

    Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial

    JAMA

    (2005)
  • OlssonS.B.

    Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial

    Lancet

    (2003)
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