Elsevier

American Heart Journal

Volume 169, Issue 4, April 2015, Pages 472-478.e5
American Heart Journal

Trial Design
An 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)

https://doi.org/10.1016/j.ahj.2014.12.006Get rights and content

Background

Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes.

Design

PIONEER AF-PCI (ClinicalTrials.gov NCT01830543) is an exploratory, open-label, randomized, multicenter clinical study assessing the safety of 2 rivaroxaban treatment strategies and 1 vitamin K antagonist (VKA) treatment strategy in subjects who have paroxysmal, persistent, or permanent nonvalvular AF and have undergone PCI with stent placement. Approximately 2,100 subjects will be randomized in a 1:1:1 ratio to receive either rivaroxaban 15 mg once daily plus clopidogrel 75 mg daily for 12 months (a WOEST trial–like strategy), or rivaroxaban 2.5 mg twice daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, an ATLAS trial–like strategy), or dose-adjusted VKA once daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, traditional triple therapy). All patients will be followed up for 12 months for the primary composite end point of Thrombolysis in Myocardial Infarction major bleeding, bleeding requiring medical attention, and minor bleeding (collectively, clinically significant bleeding).

Conclusion

The PIONEER AF-PCI study is the first randomized comparison of VKA vs novel oral anticoagulant therapy in patients with NVAF receiving antiplatelet therapy after PCI to assess the relative risks of bleeding complications.

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):

  • “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.

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