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

Disclosure I have nothing to disclose

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; 375:2423-34

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

Dual Antiplatelet Therapy (DAPT) Primary Outcome Death, Revascularization of Target Lesion, Angiographically Evident Thrombosus, MI within 30 days N Engl J Med 1998;339:1665-71

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;367:1903-12

Triple Therapy ESC 2016 AF Guidelines WOEST Circulation 2010 Circulation 2010;121:2067-70 Lancet 2013;381:1107-15 Eur Heart J 2016;37:2893-2962

Triple Therapy ESC 2016 AF Guidelines WOEST Circulation 2010 Circulation 2010;121:2067-70 Lancet 2013;381:1107-15 Eur Heart J 2016;37:2893-2962

Triple Therapy ESC 2016 AF Guidelines WOEST Circulation 2010 Circulation 2010;121:2067-70 Lancet 2013;381:1107-15 Eur Heart J 2016;37:2893-2962

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

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

How did we get here?

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; 375:2423-34

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; 375:2423-34

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 75-100 mg 6 months Rivaroxaban 15 mg + ASA 75-100 mg Warfarin (INR 2.0-3.0) + DAPT GROUP 3 1 month Warfarin + ASA 75-100 mg 6 months Warfarin + ASA 75-100 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; 375:2423-34

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; 375:2423-34

Patient Characteristics N Engl J Med 2016; 375:2423-34

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; 375:2423-34

N Engl J Med 2016; 375:2423-34

Results Group 1 Rivaroxaban 15 mg Daily + P2Y12 12 Months Primary Safety 16.8% HR:0.59;CI:0.47-0.76; P<0.001 Major Adverse Cardiovascular Event 6.5% HR:1.08;CI:0.69-1.68; P=0.75 Group 2 Rivaroxaban 2.5 mg BID + DAPT 1,6,12 Month(s) Primary Safety 18.0% HR:0.63;CI:0.5-0.8; P<0.001 Major Adverse Cardiovascular Event 5.6% HR:0.93;CI:0.59-1.48; P=0.76 Group 3 Warfarin + DAPT 1,6,12 Month(s) Primary Safety 26.7% Major Adverse Cardiovascular Event 6.0% N Engl J Med 2016; 375:2423-34

Results N Engl J Med 2016; 375:2423-34

Results N Engl J Med 2016; 375:2423-34

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; 375:2423-34

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

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 (2.0-2.5) 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

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