Background, epidemiology and rationale for study
The PIONEER AF-PCI (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) trial addressed an important medical question, which is potentially relevant for the 20–45% of atrial fibrillation (AF) patients who also have coronary artery disease and are likely to undergo percutaneous coronary intervention (PCI). Prior to the PIONEER AF-PCI trial, there was an unmet need for evidence-based recommendations on the optimal regimen, dosage, and duration of antithrombotic strategies in these patients.1,2 The regimens studied in the PIONEER AF-PCI were selected based on the findings of several other trials. The PIONEER AF-PCI trial compared traditional vitamin K antagonist (VKA) triple therapy with two different rivaroxaban-based regimens that were similar to those that demonstrated favourable benefit/risk profiles in different patient populations in previous trials.
In the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) trial, clopidogrel monotherapy was compared with dual antiplatelet therapy (DAPT) among patients on long-term VKA therapy who underwent PCI. Clopidogrel monotherapy reduced the risk of bleeding, without an increase in thrombosis.3 These findings suggest that, compared with DAPT, P2Y12 inhibitor monotherapy may be a safer and equally effective choice in patients on long-term VKA who undergo PCI.
In the 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) trial, rivaroxaban (20 mg once daily [or 15 mg once daily, CrCl 30–49 ml/min]) was compared with VKA in the reduction of ischaemic stroke/systemic embolism in patients with non-valvular atrial fibrillation (NVAF). Rivaroxaban was non-inferior compared with VKA in reducing the risk of ischaemic stroke/systolic embolism.4 Following the presentation of the results of this and other clinical trials with non-vitamin K antagonist oral anticoagulants (NOACs), revisions to some clinical practice guidelines preferred the use of NOACs over VKA for stroke prevention in patients with NVAF.5-7 Similarly, in the J-ROCKET (Japanese Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial, a 15 mg (10 mg, CrCl 30–49 ml/min) once daily dose of rivaroxaban was shown to be non-inferior to VKA in both efficacy (thrombosis) and safety (bleeding) end points in Japanese patients with NVAF.8
The efficacy of the 2.5 mg twice daily dose of rivaroxaban was demonstrated in the ATLAS-ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome – Thrombolysis In Myocardial Infarction 51) trial. Acute coronary syndrome (ACS) patients who received this regimen, in addition to single or dual antiplatelet therapy, demonstrated a reduction in the risk of mortality and stent thrombosis, compared with those on antiplatelet therapy alone.9 This trial demonstrated that a very low 2.5 mg twice daily dose of rivaroxaban is an effective treatment option in the management of patients with ACS.
The results of these trials set the stage for the open-label, randomised, controlled, multi-centre study that evaluated the efficacy of two treatment strategies of rivaroxaban and a dose-adjusted oral VKA treatment (PIONEER AF-PCI) trial, which provided the most robust evidence at the time to guide the optimal administration of prophylaxis against stroke in patients with both ACS and NVAF.2
Study design
The PIONEER AF-PCI trial was an open-label, randomised, controlled, multi-centre trial that evaluated the safety of two different regimens of rivaroxaban compared with VKA in patients with NVAF who underwent PCI with stent placement (ClinicalTrials.gov Identifier: NCT01830543).2,10 PIONEER AF-PCI was a safety study. The primary safety end point was the occurrence of clinically significant bleeding. This end point was a composite of Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, or bleeding requiring medical attention (BRMA) and was evaluated throughout the 12-month treatment period. Bleeding was also assessed according to International Society on Thrombosis and Haemostasis (ISTH), Global Utilisation of Streptokinase and Tissue Plasminogen Factor for Occluded Coronary Arteries (GUSTO), and Bleeding Academic Research Consortium (BARC) classifications. The efficacy end point was secondary and was a composite of major adverse cardiovascular events including cardiovascular death, myocardial infarction, or stroke. The study also reported the individual components of the primary safety end point, the individual components of the secondary efficacy end point, and stent thrombosis. All safety events were adjudicated by a blinded independent clinical events committee.
The intended duration of DAPT (one, six or 12 months) and the specific P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) was determined by the investigators prior to randomisation. Patients were stratified according to the clinician-determined DAPT duration and a total of 2,124 subjects were randomised in a 1:1:1 ratio to one of the three treatment groups. Patients were eligible for randomisation within 72 hours after sheath removal and when international normalised ratio (INR) was 2.5 or lower.
Patients in group 1 were administered rivaroxaban 15 mg (10 mg, CrCl 30–49 ml/min) once daily plus a P2Y12 inhibitor for a fixed duration of 12 months, a regimen similar to the one used in the WOEST trial. Patients in group 2 received an ‘ATLAS-like regimen’ consisting of rivaroxaban 2.5 mg twice daily in addition to DAPT for the pre-randomisation clinician-specified duration of one, six or 12 months. Patients in group 2 who were stratified to one or six months of study treatment continued on rivaroxaban 15 mg (10 mg, CrCl 30–49 ml/min) once daily, in addition to low-dose aspirin once daily, for the remainder of the 12-month treatment period. Patients in group 3 received a traditional ‘triple therapy’ regimen with dose-adjusted VKA plus DAPT for the pre-randomisation clinician-determined duration of one, six or 12 months. Patients in group 3 stratified to receive study treatment for one or six months switched to a regimen of VKA and low-dose aspirin for the remaining duration of the 12-month treatment period (figure 1).
Key results from PIONEER AF-PCI (figure 2)
All of the subjects in group 1 were administered a thienopyridine for 12 months. In the remaining two groups, 224 subjects (15.8%) were allocated to one month of DAPT, 494 subjects (34.9%) were allocated to six months of DAPT, and 697 subjects (49.2%) were allocated to 12 months of DAPT. Over 90% of patients were prescribed clopidogrel as the investigator’s choice of P2Y12 inhibitor. No subjects were lost to follow-up.10
![Figure 2. Cumulative incidence of the primary safety end point and a secondary efficacy end point. Panel A shows the cumulative incidence of the primary safety end point of clinically significant bleeding (a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding requiring medical attention), and Panel B shows the cumulative incidence of the secondary efficacy end point of major adverse cardiovascular events (a composite of death from cardiovascular causes, myocardial infarction, or stroke) during the treatment period (from the time of the first administration of a trial drug up to 2 days after the trial treatment was discontinued) in the three treatment groups. In each panel, the inset shows the same data on an expanded y-axis](https://bjcardio.co.uk/wp-content/uploads/2018/04/PIONEER-2-fig-2.png)
The rivaroxaban-based regimens reduced the occurrence of the primary safety end point at 12 months. Clinically significant bleeding occurred in 16.8% (n=109) of patients in group 1, 18.0% (n=117) of patients in group 2, and 26.7% (n=167) of patients in group 3 (group 1 vs. group 3 hazard ratio [HR] = 0.59; 95% confidence interval [CI] 0.47 to 0.76, p<0.001; and group 2 vs. group 3 HR=0.63; 95% CI 0.50 to 0.80, p<0.001).
Overall, 393 patients experienced the primary safety end point of clinically significant bleeding. Among those bleeds, 46 were TIMI major bleeds (11.3%), 27 were TIMI minor (6.6%), and 334 were BRMA (82.1%). Rivaroxaban-based regimens significantly reduced BRMA compared with the VKA-based regimen (rivaroxaban vs. VKA HR=0.64; 95% CI 0.51 to 0.800, p<0.001). TIMI major and TIMI minor bleeds occurred less frequently in patients who received a rivaroxaban-based strategy compared with the VKA strategy (rivaroxaban vs. VKA major bleeding HR=0.61; 95% CI 0.34 to 1.09, p=0.09; and rivaroxaban vs. VKA minor bleeding HR=0.51; 95% CI 0.24 to 1.08, p=0.07).
Rivaroxaban significantly reduced bleeding evaluated according to ISTH, GUSTO, and BARC classifications. Fifty-two subjects in groups 1 and 2 experienced ISTH major bleeding, compared with 48 subjects in group 3 (3.7% vs. 6.9%, p=0.001). Among those that received a rivaroxaban strategy, 1.2% (n=17) experienced GUSTO severe bleeding compared with 2.9% (n=20) of subjects who received the VKA strategy (p=0.007). BARC definitive fatal bleeds (type 5b bleeding) occurred in 0.2% of patients on the rivaroxaban-based regimens compared with 1.0% in the VKA-based regimen (p=0.019).
Similar risks of the secondary efficacy outcome (death from cardiovascular causes, myocardial infarction, stroke), its individual components, and stent thrombosis were observed across all groups. The secondary efficacy end point occurred in 6.5% (n=41) of patients in group 1, 5.6% (n=36) of patients in group 2, and 6.0% (n=36) of patients in group 3 (group 1 vs. group 3 HR=1.08; 95% CI 0.69 to 1.68, p=0.75; and group 2 vs. group 3 HR=0.93; 95% CI 0.59 to 1.48, p=0.76).
Mortality and rehospitalisation for adverse events
The occurrence of all-cause death or rehospitalisation for an adverse event was assessed in a post-hoc analysis of the PIONEER AF-PCI data.11 This end point occurred in 34.9% (n=228) of subjects in group 1, 31.9% (n=213) of subjects in group 2, and 41.9% (n=261) of those in group 3 (group 1 vs. group 3 HR=0.79; 95% CI 0.66 to 0.94, p=0.008; and group 2 vs. group 3 HR=0.75; 95% CI 0.62 to 0.90, p=0.002). The risk of all-cause rehospitalisation was 34.1% in group 1, 34.2% in group 2, and 41.5% in group 3 (group 1 vs. group 3 HR=0.77; 95% CI 0.65 to 0.92, p=0.005; and group 2 vs. group 3 HR=0.74; 95% CI 0.61 to 0.88, p=0.001).
Additionally, rivaroxaban reduced the risk of all-cause death and bleeding as a cause of rehospitalisation (group 1 vs. group 3 HR=0.69; 95% CI 0.48 to 0.97, p=0.032; and group 2 vs. group 3 HR=0.64; 95% CI 0.45 to 0.91, p=0.012) and the risk of all-cause death and cardiovascular rehospitalisation (group 1 vs. group 3 HR=0.70; 95% CI 0.56 to 0.87, p=0.001; and group 2 vs. group 3 HR=0.75; 95% CI 0.60 to 0.94, p=0.011), compared with the VKA regimen.
Discussion
The primary results of the PIONEER AF-PCI study demonstrated that, among participants with AF who underwent PCI with stent placement, rivaroxaban-based regimens were associated with reductions in clinically significant bleeding compared with standard VKA triple therapy with similar risks of major adverse cardiovascular events (MACE). In a post-hoc analysis, compared with the VKA regimen, the rivaroxaban regimens reduced risk of all-cause mortality or recurrent hospitalisation for adverse events.
Although the administration of rivaroxaban 20 mg once daily has previously demonstrated non-inferiority to VKA in the prevention of stroke/systemic embolism and a reduced incidence of fatal and intracranial bleeding in patients with NVAF (albeit with increased risk of major gastrointestinal bleeding),4 this dose was associated with an increased risk of bleeding in patients with ACS receiving DAPT.12 The subsequent evaluation of a rivaroxaban 2.5 mg twice daily dose in patients with ACS who were receiving DAPT demonstrated lower risk of a MACE end point (which included fatal thrombotic events) compared to DAPT alone, at the cost of an increased risk of major, but not fatal, bleeding.9
Patients with AF who undergo PCI are at an increased risk of thrombosis, which seems to necessitate the administration of a combination antiplatelet/anticoagulant therapy that, in turn, increases the risk of fatal and non-fatal bleeding. With the intensification of antiplatelet/anticoagulant regimens successfully reducing thrombotic events, the focus has shifted to the reduction of bleeding. A bleeding event often results in discontinuation of the antithrombotic regimen, which subsequently increases the risk of thrombosis.13 The clinical implications of an inappropriately administered antithrombotic regimen present a ‘catch-22’ for clinicians managing these patients in the absence of robust evidence.
The PIONEER AF-PCI study presented safety data that are critical in guiding clinicians through this paradox. PIONEER AF-PCI was the first trial to assess the safety of both low-dose and very-low-dose rivaroxaban regimens against VKA triple therapy in this patient population. Inherent to the PIONEER AF-PCI study design, prior to randomisation, clinicians had decided both the P2Y12 inhibitor to be used and the duration of DAPT administration. This individual patient-level decision reflected real-world clinical practice and improves the generalisability of the results. The primary safety findings were robust with a consistent reduction associated with rivaroxaban across TIMI, ISTH, GUSTO, and BARC classifications of bleeding. The reduction in mortality and rehospitalisation associated with adverse events represents a hard end point that is of particular importance to patients and also translates to reductions in costs to the healthcare system.
It is important to note that PIONEER AF-PCI was a safety study and was powered for safety end points. Efficacy end points were secondary and a small number of efficacy events occurred. In fact, it was estimated that in order to assess efficacy at a 90% power to detect a 15% difference in the efficacy end point between groups, this trial would require enrolment of approximately 41,000 participants (more than 20 times the number of subjects that were enrolled in PIONEER AF-PCI).10 Thus, efficacy observations from PIONEER AF-PCI should be interpreted with caution. Recurrent hospitalisation and mortality occurred more frequently and represents a more sensitive, but less specific end point than the secondary efficacy end point of MACE. Unlike the MACE end point, this end point achieved 90% power to detect a 20% difference between the treatment groups.11
VKA-based regimens can be difficult to administer. Variation in dosing due to genetic variability, dietary intake, and drug-drug interactions necessitate frequent INR monitoring and dose-adjustment to keep patients within therapeutic range. This monitoring is arduous for both patients and clinicians and is speculated to contribute to the underuse of VKA regimens in patients with AF.1,14-16 Unlike VKA, NOACs have a shorter half-life and a consistent treatment effect that eliminates the need for burdensome monitoring.
The rivaroxaban-based combination therapies were the first non-VKA regimens to demonstrate a superior safety profile in patients with AF and PCI, compared with a traditional VKA-based triple therapy. Indeed, in August 2017 there was an update to the SmPC (Summary of Product Characteristics) for the use of rivaroxaban 15 mg once daily in combination with a P2Y12 inhibitor, and the 2017 European Society of Cardiology (ESC) focused update on DAPT in coronary artery disease incorporated the results of PIONEER AF-PCI.17
Results from a second study, RE-DUAL PCI (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting),18 with another non-VKA dual therapy regimen demonstrate a lower risk of bleeding with dabigatran plus a P2Y12 inhibitor compared to triple therapy with warfarin plus DAPT; dual therapy was also non-inferior to triple therapy with respect to thromboembolic risk. Ongoing trials (AUGUSTUS19 and ENTRUST-AF PCI20 with apixaban and edoxaban, respectively), which are investigating other non-VKA-based regimens for the management of AF and ACS and/or PCI, may also add to the evidence base, leading to further updating of clinical practice guidelines in the European Union.
Summary
In the PIONEER AF-PCI trial, regimens that included both low-dose rivaroxaban (15 mg [10 mg, CrCl 30–49 ml/min] once daily) or very-low-dose rivaroxaban (2.5 mg twice daily) were associated with reduced risk of clinically significant bleeding when compared with VKA triple therapy in patients with AF who underwent PCI with coronary stenting. In these patients, the rivaroxaban regimens also reduced all-cause mortality and rehospitalisation associated with adverse events. Based on data from this trial, there was an update to the SmPC describing the use of rivaroxaban 15 mg once daily in combination with a P2Y12 inhibitor for these patients.
Further data on the safety of non-VKA anticoagulant/antiplatelet combination therapies in this patient population have also been shown in the recently reported RE-DUAL PCI study, which showed a significant reduction in bleeding complications in patients with non-valvular AF undergoing stent placement with dabigatran plus a P2Y12 inhibitor over those given traditional non-VKA-based triple therapy.18 More data are anticipated with the ongoing AUGUSTUS trial with apixaban19 and the ENTRUST-AF PCI study20 with edoxaban, which will add to the evidence base in this area.
Key messages
- The PIONEER AF-PCI trial addressed a critical unmet need for evidence-based recommendations on the optimal regimen, dosage, and duration of antithrombotic strategies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) with coronary stent placement
- Low-dose (15 mg) rivaroxaban once daily plus a P2Y12 inhibitor and very-low-dose (2.5 mg) rivaroxaban twice daily plus dual antiplatelet therapy (DAPT) both reduced clinically significant bleeding compared with vitamin K antagonist (VKA) triple therapy through 12 months
- Rivaroxaban-based regimens reduced the incidence of rehospitalisation and mortality due to adverse events
- Based on these data, the Summary of Product Characteristics (SmPC) was updated describing the use of rivaroxaban 15 mg once daily in combination with a P2Y12 inhibitor
Conflict of interest
The PERFUSE Study Group has received research grant funding from JnJ. The co-authors have no conflicts of interest of significant financial disclosures to report.
Articles in this supplement include:
Introduction
The PIONEER AF-PCI study: its implications for everyday practice in the UK
The potential for NOACs in cardiac ablation in the UK
Use of NOAC drugs in DC cardioversion for patients with non-valvular AF
References
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2. Gibson CM, Mehran R, Bode C et al. 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). Am Heart J 2015;169:472–8.e5. https://doi.org/10.1016/j.ahj.2014.12.006
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11. Gibson CM, Pinto DS, Chi G et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy. Circulation 2017;135:323–33. https://doi.org/10.1161/CIRCULATIONAHA.116.025783
12. Mega JL, Braunwald E, Mohanavelu S et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29–38. https://doi.org/10.1016/S0140-6736(09)60738-8
13. Bhatt DL. O PIONEERs! The beginning of the end of full-dose triple therapy with warfarin? Circulation 2017;135:334–7. https://doi.org/10.1161/CIRCULATIONAHA.116.025923
14. Nieuwlaat R, Olsson SB, Lip GY et al. Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation. The Euro Heart Survey on Atrial Fibrillation. Am Heart J 2007;153:1006–12. https://doi.org/10.1016/j.ahj.2007.03.008
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17. Valgimigli M, Bueno H, Byrne RA et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2017 (published online 26th August 2017). https://doi.org/10.1093/eurheartj/ehx419
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19. A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart (AUGUSTUS). https://clinicaltrials.gov/ct2/show/NCT02415400
20. Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF-PCI). https://clinicaltrials.gov/ct2/show/NCT02866175
Notes on dosing recommendations from Xarelto® ▼ (rivaroxaban) SmPC (Summary of Product Characteristics)
For the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) with one or more risk factors, the recommended dose is 20 mg once daily (15 mg once daily in patients with moderate [creatine clearance {CrCl} 30-49 ml/min] or severe [CrCl 15-29 ml/min] renal impairment). To be used with caution in severe renal impairment and use is not recommended in patients with CrCl <15 ml/min.
The above doses were studied in the pivotal ROCKET AF study in patients with non-valvular AF.
In the PIONEER AF-PCI study, participants with non-valvular AF who had undergone percutaneous coronary intervention (PCI) with stenting were randomly assigned to receive either rivaroxaban 15 mg once daily (10 mg once daily, CrCl 30-50 ml/min) plus a P2Y12 inhibitor for 12 months, or rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) for one, six, or 12 months, or dose-adjusted vitamin K antagonist once daily plus DAPT for one, six, or 12 months.
The Xarelto® (rivaroxaban) SmPC has been updated under ‘Special populations’ in the section on ‘Posology and method of administration’ following completion of the PIONEER AF-PCI study; the rivaroxaban 15 mg once daily regimen, but not the 2.5 mg twice daily regimen, has been included.
In summary, the SmPC update states that for patients with non-valvular AF who require oral anticoagulation and undergo PCI with stent placement, there is limited experience of a reduced dose of rivaroxaban 15 mg once daily (10 mg once daily, CrCl 30-49 ml/min) in addition to a P2Y12 inhibitor for a maximum of 12 months.
