PIONEER AF-PCI

Published

Gibson CM, et al. "Prevention of bleeding in patients with AF undergoing PCI". The New England Journal of Medicine. 2016. epub 2016-11-14:1-12.
PubMed • Full text • PDF

Clinical Question

Among patients with nonvalvular AF undergoing PCI with stent placement, does low-dose rivaroxaban plus either single or dual antiplatelet therapy reduce risk of bleeding when compared to warfarin plus dual antiplatelet therapy?

Bottom Line

Among patients with nonvalvular AF undergoing PCI with stent placement, the use of low dose rivaroxaban plus either single or dual antiplatelet therapy reduces the risk of bleeding when compared to warfarin plus DAPT at 1 year.

Major Points

Up to 1 in 10 patients undergoing PCI have AF. Prior to the publication of WOEST (2013) and ISAR-TRIPLE (2015), clinical practice guidelines suggested that this particular patient population should be placed on a triple therapy anticoagulation strategy post-PCI with warfarin and dual antiplatelet therapy (DAPT). However, since WOEST and ISAR-TRIPLE, current AHA/ACC guidelines suggest that in patients with nonvalvular AF undergoing PCI, it is reasonable to maintain patients on oral anticoagulation (typically warfarin) and clopidogrel without ASA. Based on data from RE-LY (2009), ARISTOTLE (2011), and ROCKET AF (2011), there is accumulating evidence supporting the use of direct oral anticoagulants (DOACs) in patients with AF compared to warfarin. However, prior to the publication of PIONEER AF-PCI, there were no clinical trials to support the use of DOACs in patients with nonvalvular AF undergoing PCI with stent placement.

Published in 2016, the PIONEER AF-PCI trial randomized 2,214 patients with nonvalvular AF who had just undergone PCI with stent placement to one of three treatment groups:

1. Rivaroxaban 10-15 mg daily+P2Y₁₂ inhibitor x12 mo
2. Rivaroxaban 2.5 mg BID+DAPT x1, 6, or 12 mo
3. Warfarin+DAPT x1, 6, or 12 mo

At 12 months, the primary outcome of clinically significant bleeding was lower in the rivaroxaban groups than the warfarin groups (16.8% vs. 18.0% vs. 26.7%). There was no significant difference in the rate of major adverse cardiovascular events (CV mortality, MI, or stroke) between the three groups but the trial. However, this trial was not powered to detect a difference between the groups.

It should be noted that both of the dosing regimens of rivaroxaban (15 mg daily or 2.5 mg twice daily) used in the trial have not been formally investigated and are not FDA approved for AF or acute coronary syndromes. And, while lower than approved doses of rivaroxaban were used in this trial, a lower INR target was not tested.

Guidelines

As of November 2016, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, open-label, 3-parallel-group, randomized, controlled trial
• N=2,124
  • Group 1: Rivaroxaban 10-15 mg daily+P2Y₁₂ inhibitor x12 mo (n=709)
  • Group 2: Rivaroxaban 2.5 mg BID+DAPT x1, 6, or 12 mo (n=709)
  • Group 3: Warfarin+DAPT x1, 6, or 12 mo (n=706)
• Setting: 426 sites in 26 countries
• Enrollment: 2013-2015
• Follow-up: 3 years
• Analysis: Modified Intention-to-treat
• Primary outcome:
  • Clinically significant bleeding (a composite of TIMI major/or minor bleeding or bleeding requiring medical attention)

Population

Inclusion Criteria

• Age ≥18 years
• PCI with stent placement for atherosclerotic disease
• History of AF

Exclusion Criteria

• Contraindication or high risk of bleeding with AC (e.g., active or recent clinically-significant bleeding, thrombocytopenia, prior ICH)
• Stroke/TIA
• Cardiogenic shock
• Ventricular arrhythmias refractory to treatment
• Renal dysfunction (CrCl <30 mL/min), liver disease/elevated LFTs, unexplained anemia, HIV infection, recent substance abuse issues, active malignancy
• Stent thrombosis during enrollment PCI or stent-within-a-stent in prior 12 mo
• Incomplete PCI or planned CABG
• Contraindications to study meds
• Transient AF from a reversible conditions (e.g., PE, recent surgery, thyroid abnormalities)
• Other indication for long-term AC with VKA
• CYP 3A4 and P-glycoprotein inhibitor use
• Likely to need NSAIDS >4 weeks
• Life expectancy <1 year
• Women capable of pregnancy not on birth control

Baseline Characteristics

From group 1.

• Demographics: Age 70 years, female sex 25%, White race 93%, Black race 1%, Asian 3.5%
• PMH: HF 25%, HTN 73%, DM 29%, HLD 43%, prior MI 20%, PVD 4%, GIB 1%, active smoker 5%
• CrCl: Mean 78 mL/min; 30-60 mL/min 29%
• Medications: ASA 1%, B-blocker 83%, ACE-inhibitor or ARB 80%, statin 84%, omprazole/esomeprazole 10% (other PPI 28%)
  • P2Y₁₂ inhibitor at baseline: Clopidogrel 93%, prasugrel 2%, ticagrelor 5%
• Index event: NSTEMI 18%, STEMI 12%, UA 21%
• Stent type: DES 65%, BMS 33%, DES and BMS 2%
• AF type: Persistent 21%, permanent 37%, paroxysmal 42%
• CHA₂DS₂-VASc score: Zero 2%, one 9%, two 16%, three 18%, four 20%, five 20%, six 13%, seven 3%
• HAS-BLED score: Zero <1%, one 4%, two 23%, three 45%, four 23%, five 4% six <1%

Interventions

• Participants were randomized to a group:
  • Group 1: Rivaroxaban 10-15 mg daily+P2Y₁₂ inhibitor x12 mo (n=709)
  • Group 2: Rivaroxaban 2.5 mg BID+DAPT x1, 6, or 12 mo (n=709)
    • After the 1, 6, or 12 months, members of this group received rivaroxaban 15 mg daily and ASA
  • Group 3: Warfarin+DAPT x1, 6, or 12 mo (n=706)
    • After the 1, 6, or 12 months, member were treated with warfarin and ASA
• Antiplatelet therapy:
  • P2Y₁₂ inhibitor - Preferentially with clopidgrogrel, though ticagrelor or prasugrel was also used
  • ASA at 75-100 mg/day
• Warfarin targeted an INR of 2-3

Outcomes

Comparisons are group 1 vs. group 2 vs. group 3 except where stated. See details on these groups in the Interventions section above.

Primary Outcome

Clinically-significant bleeding

TIMI major/or minor bleeding or bleeding requiring medical attention

16.8% vs. 18.0% vs. 26.7%

Group 1 vs. 3: HR 0.59; 95% CI 0.47-0.76; P<0.001

Assigned to DAPT for 1 mo: 19.4% vs. 25.7% (HR 0.68; 95% CI 0.38-1.23; P=0.20)

Assigned to DAPT for 6 mo: 17.5% vs. 31.2% (HR 0.51; 95% CI 0.34-0.75; P<0.001)

Assigned to DAPT for 12 mo: 17.9% vs. 23.9% (HR 0.74; 95% CI 0.52-1.04; P=0.08)

Group 2 vs. 3: HR 0.63; 95% CI 0.50-0.80; P<0.001

Secondary Outcomes

TIMI major bleeding

2.1% vs. 1.9% vs. 3.3%

Group 1 vs. Group 3: HR 0.66; 95% CI 0.33-1.31; P=0.23

Group 2 vs. Group 3: HR 0.57; 95% CI 0.28-1.16; P=0.11

TIMI minor bleeding

1.1% vs. 1.1% vs. 2.2%

Group 1 vs. Group 3: HR 0.51; 95% CI 0.20-1.28; P=0.14

Group 2 vs. Group 3: HR 0.50; 95% CI 0.20-1.26; P=0.13

Bleeding requiring medical attention

14.6% vs. 15.8% vs. 22.6%

Group 1 vs. Group 3: HR 0.61; 95% CI 0.47-0.80; P<0.001

Group 2 vs. Group 3: HR 0.67; 95% CI 0.52-0.86; P=0.002

CV mortality, MI, or stroke

6.5% vs. 5.6% vs. 6.0%

Group 1 vs. Group 3: HR 1.08; 95% CI 0.69-1.68; P=0.75

Group 2 vs. Group 3: HR 0.93; 95% CI 0.59-1.48; P=0.76

There were no differences between the outcomes when assessed individually, see Table 3 in the main paper for details.

Stent thrombosis

0.8% vs. 0.9% vs. 0.7%

Group 1 vs. Group 3: HR 1.20; 95% CI 0.32-4.45; P=0.79

Group 2 vs. Group 3: HR 1.44; 95% CI 0.40-5.09; P=0.57

Subgroup Analysis

There were no significant differences for the primary outcome when assessing by sex, age, race, duration of DAPT, stent type, event type, AF stroke risk scores, or HAS-BLED scores.

Adverse Events

Details on non-CV adverse events are lacking in this publication except in adverse events leading to discontinuation, which were 12.5% vs. 10.6% vs. 10.9% (P=NS).

Criticisms

• Not blinded
• Not powered for efficacy
• Little ethnic/racial diversity, which is problematic considering the high incidence of polymorphisms leading to "clopidogrel resistance" in Asian populations
• Small number of patients compared to previous trials of DOACs
• Limited presentation of adverse events

Funding

The study was funded by Janssen Scientific Affairs (makers of Xarelto, the brand name of rivaroxaban) and Bayer Pharmaceuticals.