1. Denise Sutter, PharmD, BCPS
Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI [PIONEER AF-PCI]
Brandon Martinez, PharmD, BCPS PGY-2 Cardiology Pharmacy Resident
Abbott Northwestern Hospital/Minneapolis Heart Institute
Minneapolis, MN
Denise Sutter, PharmD, BCPS
Clinical Pharmacist Specialist, Cardiology/Internal Medicine
Detroit Receiving Hospital
Detroit, MI

2. Disclosure
I have nothing to disclose

3. Background Clotting Bleeding
Stent Thrombosis
Ischemic Stroke
5-8% of patients who undergo percutaneous coronary intervention (PCI) have atrial fibrillation
N Engl J Med 2016; 375:

4. Impact of Major Bleeding in ACS
JACC 2007; 49:1362-8

5. Dual Antiplatelet Therapy (DAPT)
Primary Outcome
Death, Revascularization of Target Lesion, Angiographically Evident Thrombosus, MI within 30 days
N Engl J Med 1998;339:

6. Stroke Reduction in Atrial Fibrillation
Primary Outcome
First occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death
Cumulative Risk of Stroke
Lancet 2006;367:

7. Triple Therapy ESC 2016 AF Guidelines WOEST Circulation 2010
Circulation 2010;121: Lancet 2013;381:
Eur Heart J 2016;37:

8. Triple Therapy ESC 2016 AF Guidelines WOEST Circulation 2010
Circulation 2010;121: Lancet 2013;381:
Eur Heart J 2016;37:

9. Triple Therapy ESC 2016 AF Guidelines WOEST Circulation 2010
Circulation 2010;121: Lancet 2013;381:
Eur Heart J 2016;37:

10. Composite of stroke (ischemic or hemorrhagic) and systemic embolism
Rivaroxaban
ROCKET AF
Composite of stroke (ischemic or hemorrhagic) and systemic embolism
N Engl J Med 2011;365:883-91

11. Composite of death from cardiovascular causes, MI, or stroke
Rivaroxaban
ATLAS ACS 2 TIMI-51
Composite of death from cardiovascular causes, MI, or stroke
N Engl J Med 2012;366:9-19

12. How did we get here?

13. PIONEER AF-PCI Inclusion Exclusion Study Design
International, multicenter, randomized, open-label trial
Inclusion
Men and women at least 18 years of age
Paroxysmal, persistent, or permanent nonvalvular AF
Undergone PCI with stent placement
Documented AF that occurred within 1 year before screening
Exclusion
History of stroke or TIA
Clinically significant GI bleeding within 12 months before randomization
CrCl<30 mL/min
Anemia of an unknown cause with a Hgb <10 g/dL
Any other condition known to increase the risk of bleeding
N Engl J Med 2016; 375:

14. End Points Safety Primary Safety Secondary Efficacy Exploratory
Clinically Significant Bleeding
TIMI Minor Bleeding
TIMI Major Bleeding
Bleeding Requiring Medical Attention
Each component of the primary safety endpoint
Safety
Major cardiovascular event composite*
Stent thrombosis
Efficacy
ISTH Major bleeding
GUSTO severe bleeding
Exploratory
*Death from cardiovascular cause, MI, Stroke
Each component of the composite
N Engl J Med 2016; 375:

15. Treatment Subgroups 12 Months
≤72 hours
After sheath removal
Rivaroxaban 15 mg Daily + Clopidogrel 75 mg
Randomizat
ion
GROUP 1
NVAF
No Prior Stroke/TIA
PCI with Stent Placement
Rivaroxaban 2.5 mg BID + DAPT
GROUP 2
1 month
Rivaroxaban 15 mg + ASA mg
6 months
Rivaroxaban 15 mg + ASA mg
Warfarin (INR ) + DAPT
GROUP 3
1 month
Warfarin + ASA mg
6 months
Warfarin + ASA mg
*Rivaroxaban 10 mg daily if CrCl 30-<50 mL/min
†Prasugrel 10 mg daily or Ticagrelor 90 mg BID in <15% of patients
N Engl J Med 2016; 375:

16. Statistical Analysis
Analysis based on pooled data across all strata of DAPT duration (1, 6, or 12 months)
Modified intention-to-treat analysis based on data for all participants who underwent randomized and received at least 1 dose of trial drug
Intention-to-treat based on data obtained through follow-up of all participants who underwent randomization
Comparisons of group 1 vs group 3 and group 2 vs group 3 were performed simultaneously with no adjustment for type I error at a rate of 0.05
N Engl J Med 2016; 375:

17. Patient Characteristics
N Engl J Med 2016; 375:

18. P<0.001 For both comparisons
Results
Participants who received at least one dose of the trial treatment permanently discontinued the treatment before the scheduled termination date
Group 1: 21.0%
Group 2: 21.1%
Group 3: 29.4%
P<0.001 For both comparisons
N Engl J Med 2016; 375:

19. N Engl J Med 2016; 375:

20. Results Group 1 Rivaroxaban 15 mg Daily + P2Y12 12 Months
Primary Safety % HR:0.59;CI: ; P<0.001
Major Adverse Cardiovascular Event % HR:1.08;CI: ; P=0.75
Group Rivaroxaban 2.5 mg BID + DAPT 1,6,12 Month(s)
Primary Safety % HR:0.63;CI: ; P<0.001
Major Adverse Cardiovascular Event % HR:0.93;CI: ; P=0.76
Group Warfarin DAPT 1,6,12 Month(s)
Primary Safety 26.7%
Major Adverse Cardiovascular Event %
N Engl J Med 2016; 375:

21. Results
N Engl J Med 2016; 375:

22. Results
N Engl J Med 2016; 375:

23. Authors’ Conclusion
Low-dose and very-low-dose rivaroxaban was associated with lower risk of clinically significant bleeding than standard triple therapy with warfarin
The rates of major adverse cardiovascular events were similar
Broad confidence intervals make efficacy difficult to assess
Cannot truly assess stroke prevention of 15 mg or 2.5 mg BID rivaroxaban doses
N Engl J Med 2016; 375:

24. Critique
Shorter duration of triple therapy (22% of patients) as compared to the WOEST trial (66% of patients)
More reflective of current clinical practice
Limitations
Trial not powered to establish superiority or inferiority of secondary endpoints
Rivaroxaban 15 mg daily dose not currently approved for ACS or AF for patients with normal renal function
Rivaroxaban 2.5 mg BID currently only approved in Europe for ACS
Overall trial is underpowered and individual efficacy end points within subgroups are even more underpowered
Stratification to 1, 6, or 12 months of DAPT was based on physician choice creating an imbalance of patient characteristics
Broad confidence intervals of efficacy endpoints make it difficult to draw reliable conclusions regarding efficacy

25. Impact on Clinical Practice
Difficult to make definitive recommendations based solely off this study
Recommend stratification strategy similar to ESC 2016 AF guidelines
Shortest duration of triple therapy possible
Important to assess patient risks regarding bleeding vs stroke
Patients at higher risk of bleeding may benefit from lower dose rivaroxaban treatment strategy
Additional Considerations
Tighter INR control with warfarin ( ) in high risk patients
Procedural considerations
Stent choice
Glycoprotein IIb/IIIa inhibitor exposure
Ongoing trials
RE-DUAL PCI™
Dabigatran 150 mg or 110 mg + Clopidogrel or Ticagrelor vs Triple Therapy
AUGUSTUS
Apixaban 5 mg BID ± ASA vs Warfarin ± ASA in addition to a P2Y12 inhibitor for 6 months
ENTRUST AF-PCI
Edoxaban 60 mg daily + P2Y12 vs Warfarin plus P2Y12 + ASA x 1-12 months

26. Acknowledgements Journal Club Mentor: Program Director:
Denise Sutter, PharmD, BCPS
Program Director:
Matthew Lillyblad, PharmD, BCPS-AQ Cardiology
ACCP Cardiology PRN Journal Club Coordinators:
Genevieve Hale, PharmD, BCPS
Ted Berei, PharmD, MBA
Zachary Noel, PharmD, BCPS