Trial DesignAn open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin k antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI)
Section snippets
Background
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia of clinical significance,1 with a prevalence ranging from less than 1% among people younger than 60 years to approximately 10% among those older than 80 years.2 More than 6 million patients in Europe and approximately 2.3 million patients in the United States have been diagnosed as having AF, and this number continues to grow rapidly due to the aging of the population.2 Atrial fibrillation is an independent risk factor for
Study operations
The trial is funded by Johnson and Johnson and Bayer. The authors, members of the Executive Steering Committee, are responsible for the design and conduct of the study, the drafting and editing of this manuscript, as well as the analysis and reporting of the final results. The executive committee consists of members of the academic leadership of the trial and members from each sponsoring company. The executive committee appointed an independent Data Monitoring Committee (DMC) Chair, identified
Study objectives
The primary objective of the PIONEER AF-PCI study is to assess the safety of 2 rivaroxaban treatment strategies as compared with the current standard of care (a dose-adjusted VKA treatment strategy) in subjects with paroxysmal, persistent, or permanent nonvalvular AF undergoing PCI with stent placement, based on the composite of Thrombolysis in Myocardial Infarction (TIMI) major bleeding, minor bleeding, and bleeding requiring medical attention events (known collectively as clinically
Study population and patient selection
Approximately 2,100 men and women at least 18 years of age who have electrocardiographically documented paroxysmal, persistent, or permanent nonvalvular AF (defined as AF not considered to be caused by a primary valve stenosis) and have undergone a PCI procedure (with stent placement) are being enrolled.
The principal inclusion and exclusion criteria a provided in the online Appendix Supplementary Table I and include conditions that contraindicate OAC or confer an unacceptable risk of bleeding,
Randomization and treatment protocol
Randomization in equal proportion to 1 of 3 treatment strategies is stratified by the intended duration of DAPT (1, 6, or 12 months) and balanced by randomly permuted blocks (Figure):
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“Arm 1” rivaroxaban 15-mg once-daily treatment strategy (12 months) (WOEST-like strategy): rivaroxaban 15 mg (or 10 mg for subjects with moderate renal impairment [creatinine clearance: 30-50 mL/min]) once daily plus background single antiplatelet therapy with clopidogrel 75 mg (or alternate P2Y12 inhibitor) daily
Primary and secondary safety end points
The primary safety end point is the percentage of subjects experiencing either TIMI major bleeding, minor bleeding, or bleeding requiring medical attention events (known collectively as clinically significant bleeding) by the end of 12 months of randomized therapy, assessed according to intention-to-treat (ITT) for all patients receiving at least one dose of the randomized study medications. Secondary safety end points include the incidence of each component of the TIMI clinically significant
Safety outcomes and definitions
Safety evaluations performed throughout the study include monitoring of clinical events (cardiovascular death, MI, stroke, bleeding events, and stent thrombosis), adverse events, and performing clinical laboratory tests. Investigators will be required only to classify bleeding events by the TIMI scale. An independent Clinical Endpoints Committee assesses bleeding events according to the TIMI scale and alternative scales, including clinically insignificant bleeding events to the extent these are
Exploratory secondary analyses
Blood samples for pharmacokinetic and pharmacodynamic analyses will be collected from 120 subjects at selected participating sites.
Statistical considerations
This is an open-label, randomized controlled multicenter study; the study team will remain blinded to treatment information until database lock. All reported bleeding events will be adjudicated, and analyses of the primary safety end point and other bleeding end points will be based on adjudicated events. The primary safety end point is the percent of subjects developing the composite of TIMI major bleeding, minor bleeding, and bleeding requiring medical attention (clinically significant
Analysis data sets
Two analysis sets are to be used: the ITT analysis set and the safety analysis set. All primary analyses in the trial will be based on the safety analysis set, which consists of all randomized subjects who receive at least 1 dose of study drug. The ITT analysis set includes all randomized subjects. Subjects will be analyzed in the treatment groups on an “as randomized” basis. The safety analysis set includes all ITT subjects who received at least one dose of study medication.
Methods of analysis
The primary safety analysis will describe percentages of cumulative treatment-emergent end point events observed from the time of the first study drug administration up to 2 days after discontinuation of the study drug. The primary analysis will be based on pooled data across all strata within each randomized treatment strategy group. The time from administration of the first dose of study drug to the first occurrence of the primary safety end point event, major bleeding, will be analyzed using
Interim analysis
Two formal interim reviews of the safety data will be performed by the DMC when approximately 10% and 50% of subjects have completed at least 1 month of the allocated treatment. The data review will include adverse events (specifically, clinically significant bleeding, adverse cardiovascular events, stent thrombosis), dosing information, completion/withdrawal information, demographic and baseline characteristics, laboratories, and treatment assignment information. The following summaries will
Conclusion
The PIONEER AF-PCI exploratory trial evaluates the safety of 3 treatment strategies among a broad group of patients with paroxysmal, persistent, or permanent nonvalvular AF after PCI with stenting. The trial provides an assessment of the safety of rivaroxaban when added to current guidelines-based medical therapy for AF.
Acknowledgements
We would like to acknowledge statistical support from C.V. Damaraju, PhD, and help with the protocol development process from Dereck Wentworth, Pharm D.
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Stuart J. Connolly, MD, served as guest editor for this article.
RCT No. NCT01830543.