Direct oral anticoagulants in patients with atrial fibrillation undergoing percutaneous coronary intervention

– PIONEERing the way for a new paradigm?

Sarah Alexis Hallowell, Pharm.D. PGY1 Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health San Antonio

October 6th, 2017

Learning Objectives: 1. Describe the significance and management of concomitant atrial fibrillation and acute

coronary syndromes requiring percutaneous coronary intervention 2. Provide a basic overview of atrial fibrillation, acute coronary syndromes, percutaneous

coronary intervention, and direct oral anticoagulants 3. Discuss the literature pertaining to the use of direct oral anticoagulants in patients with atrial

fibrillation undergoing percutaneous coronary intervention 4. Recommend optimal antithrombotic regimens in patients with atrial fibrillation undergoing

percutaneous coronary intervention

SARAH HALLOWELL 2

Acute Coronary Syndromes Requiring Percutaneous Coronary Intervention in Patients with Atrial Fibrillation

I. Significance

a. Atrial fibrillation (AF) – most common arrhythmia, affecting approximately 2.7-6.1 million Americans (~1-2 % of the general population)1,2 i. Expected to double by 2030 ii. Contributes significantly to mortality

1) Underlying cause of death on ~21,000 death certificates in United States (US) in 2013 2) High risk of death in first four months after diagnosis 3) Many fatal complications: non-cardiovascular (CV) death, sudden cardiac death,

progressive heart failure (HF), and stroke b. Acute coronary syndromes (ACS) – acute manifestations of coronary heart disease (CHD), which

affect an estimated 15.5 million Americans over age 201,3 i. Estimated 18% increase by 2030 ii. Responsible for greater than 1 million hospitalizations annually in the US – approximately

~660,000 Americans with a new event and ~305,000 with recurrent events iii. Most common cause of CV disease death

1) Decreased mortality in the last 10 years due to: a) Primary and secondary prevention b) Initial treatment for ACS events or HF c) Coronary artery revascularization d) Shift in the incidence of different ACS event types

II. Overlap a. 20-30% of patients with AF have concomitant CHD4

i. Incidence of both AF and ACS increases with age1,2,4 1) Average age of patients with AF: 66.8 years for men and 74.6 years for women 2) Average age of patients with ACS: 65.1 years for men and 72 years for women

ii. AF associated with increased mortality in patients with myocardial infarctions (MI)1,2 III. Management

a. Antithrombotic therapy is a core component of management of both AF and ACS after revascularization with percutaneous coronary intervention (PCI)4 i. Purposes of antithrombotic therapy

1) AF: prevent cerebrovascular ischemia or systemic embolism2,4 2) ACS post-PCI: prevent recurrence of coronary ischemic events and stent thrombosis 4

b. Triple Therapy: dual antiplatelet therapy (DAPT) + oral anticoagulant4 i. Guiding principles

1) Anticoagulant used to decrease risk of stroke or thromboembolic events in AF 2) DAPT used to decrease coronary ischemia and thrombosis after PCI for ACS

a) DAPT = aspirin + P2Y12 inhibitor 3) DAPT + anticoagulant – 2-3x increased risk of bleeding complications4,5

ii. Historical standard of care for triple therapy: warfarin + clopidogrel + aspirin4 iii. Direct oral anticoagulants (DOACs) have evidence and indications for use in nonvalvular AF6-10

1) Until recently, relatively little literature about the use of DOACs in AF after PCI 2) Guideline recommendations regarding use of DOACs in patients with AF undergoing PCI

are inconsistent

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c. Obstacle and objective of antithrombotic therapy: balance risk of clot with risk of bleed

d. Guideline recommendations:

Table 1: Summary of Various Guideline Recommendations for Antithrombotic Therapy in Patients with AF Undergoing PCI2,5,11-13

Antithrombotic therapy

• Triple therapy with warfarin + aspirin + clopidogrel for 1 month after bare metal stent (BMS) placement and 3-6 months after drug-eluting stent placement (DES) warfarin + single antiplatelet agent for total of 12 months, then warfarin targeted to international normalized ratio (INR) 2.0-3.011

• Risk stratification based on stroke, bleed, and ACS mortality or repeat MI risks5,12 o Use validated scoring tools – CHA2DS2-VASc and HAS-BLED (appendix A)5

• Warfarin targeted to INR 2.0-2.5 may be used as anticoagulant with new AF2,5,12 o Goal time in therapeutic range > 70%12

• Direct oral anticoagulant may be used as anticoagulant with new AF2 o Lower stroke prevention dose from AF trials may be considered12

• Dual therapy with clopidogrel + oral anticoagulant may be considered5,12,13 o Initial therapy option in patients with high bleed risk (HAS-BLED score ≥ 3)12 or

patients with CHA2DS2-VASc score ≥ 22 Antiplatelet

Agents • Clopidogrel is P2Y12 inhibitor of choice5,12

o Ticagrelor and prasugrel not part of triple therapy – used in special circumstances12 • Aspirin doses ≤ 100 mg5

Stent Type • Consider BMS to minimize required duration of DAPT2 • May prefer newer generation DES in patients with low HAS-BLED scores (0-2)12

Duration • Triple therapy duration should be limited5,13 – based on risks of coronary events vs. risk of bleeding 13 o High bleed risk – triple therapy for 1 month12,13 up to 12 months of dual therapy12 o High risk of stroke or low bleed risk relative to thrombosis risk – consider triple

therapy for 1-6 months13 o Moderate-high ACS risk + low bleed risk – triple therapy for 6 months regardless of

stent type, may continue 6-12 months12

Thrombosis Bleeding

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e. Proposed DOAC-based strategy14 i. Rationale

1) DOACs have lower intracranial hemorrhage risk and noninferior to lower risk of non-gastrointestinal (GI) major bleeding vs. warfarin

2) Clopidogrel – key to prevention of stent thrombosis and has lower bleed risk than newer P2Y12 inhibitors

3) Stopping aspirin does not appear to increase risk of stent thrombosis ii. Algorithm:

1) 0-1 months: aspirin + clopidogrel + DOAC 2) 1-6 months: clopidogrel + DOAC 3) 6+ months: DOAC

iii. Use lower dosage ranges than approved for clinical use

Atrial Fibrillation

I. Definition & Classifications2 a. Type of supraventricular tachycardia characterized by rapid atrial rate, disorganized atrial

activation, and irregularly irregular pulse b. Types:

i. Valvular AF – associated with mechanical or bioprosthetic heart valve, mitral valve stenosis, or mitral valve repair

ii. Nonvalvular AF (NVAF) – absence of above valvular complications II. Pathophysiology2

a. Mechanisms i. Atrial structural abnormalities – extracardiac factors, oxidative stress, tachycardic

remodeling, genetics, and renin-angiotensin-aldosterone system (RAAS) activation ii. Atrial electrical abnormalities – RAAS activation, atrial tachycardic remodeling, genetics, and

autonomic nervous system I. Presentation2

a. Symptoms i. Rapid heartbeat, palpitations ii. Worsening HF symptoms – dyspnea or fatigue iii. Asymptomatic

b. Signs i. Irregularly irregular rhythm without P waves – ventricular rate of 120-180 beats per minute

III. Risk factors & Complications a. Predictors of new onset AF1, 2

i. Patient factors – advanced age, greater height and body mass index, genetic variants, family history, moderate to heavy alcohol use, and smoking

ii. CV factors – left ventricular hypertrophy, left atrial enlargement, hypertension, and CV disease including CHD, HF, and valvular heart disease

iii. Other factors – hyperthyroidism, chronic kidney disease (CKD), diabetes

Rapid Atrial Rate

Desynchronized Atrial

Contraction

Variable Atrioventricular Node Impulse Penetration

Irregular Ventricle

Activiation

Irregularly Irregular Pulse

SARAH HALLOWELL 5

b. Complications1

i. Self-perpetuating arrhythmia ii. Ischemic stroke and other thromboembolic events iii. Increased risk of MI and HF

IV. Management

a. Antiarrhythmic Therapy – refer to guidelines for acute management, including discussion of rate vs. rhythm control strategies 2,11,13

b. Prevention of Thromboembolism 2,13 i. Individualized based on risk of stroke and bleeding2

1) Stroke risk assessed by CHA2DS2-VASc score (appendix A) a) Score of 0 – reasonable to omit oral antithrombotic medications b) Score of 1 – consider antiplatelet therapy, oral anticoagulant, or aspirin c) Score ≥ 2 – anticoagulant recommended

2) Bleed risk assessed by HAS-BLED score (appendix A) a) Score ≥ 3 – “high risk” for bleeding

ii. Vitamin K antagonist2,11 1) Historical standard of care – has the most evidence and a reversal agent

2) Limitations: genomics, interactions, monitoring, and narrow therapeutic index iii. DOACs

1) Four approved for NVAF10 (appendix B) 2) Increased use due to evidence of efficacy in reducing stroke and systemic embolism

(SSE), as well as noninferior or lower risk of bleeding6-9 3) More predictable anticoagulation and no INR monitoring11

4) Limitations: only one has reversal agent and limited evidence with renal dysfunction2,10

Table 2. Summary of Atrial Fibrillation Guideline Recommendations 2,11,13 Valvular AF Warfarin recommended anticoagulant2

NVAF Patients with prior stroke or transient ischemic attack (TIA) or CHA2DS2-VASc score ≥ 2 – warfarin, dabigatran, rivaroxaban,2 and edoxaban13 all options • 2016 European Society of Cardiology guidelines recommend DOACs over warfarin13 • 2012 CHEST guidelines suggest dabigatran rather than warfarin based on individual

patient factors and preferences11 * • DOAC recommended in patients unable to maintain therapeutic INR on warfarin • Selection based on renal function2 **

o Moderate to severe CKD – may consider reduced doses of DOACs (no established safety and efficacy), or use warfarin

o End-stage CKD or dialysis – warfarin recommended

*Dabigatran only DOAC approved for NVAF at time of publication ** Reassessed when clinically indicated and at least annually when DOACs selected

SARAH HALLOWELL 6

Direct Oral Anticoagulants

Figure 1: Clotting Cascade with Oral Anticoagulant Targets

http://www.nature.com/nrcardio/journal/v10/n7/fig_tab/nrcardio.2013.73_F1.html?foxtrotcallback=true

Table 3: Overview of DOACs Approved for NVAF10

Name (Brand)

Approved Doses Mechanism of Action

Monitoring Adjustments for Renal Function

Reversal

Apixaban (Eliquis®)

5 mg BID or 2.5 mg BID if any 2: age ≥ 80, weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL

Factor Xa inhibitor

Renal and hepatic function, bleeding

Avoid use with CrCl <25 mL/min

No specific reversal agent Not dialyzable

Dabigatran (Pradaxa®)

150 mg BID Direct thrombin inhibitor

Complete blood count (CBC), renal function, bleeding

CrCl 15-30 mL/min: 75 mg BID Per CHEST: contraindicated in CrCl ≤ 30 mL/min

Idarucizumab (Praxbind®) Dialysis removes ~57% over 4 hours

Edoxaban (Savaysa®)

60 mg daily Factor Xa inhibitor

Bleeding, renal function prior to initiation

Do not use if CrCl > 95 mL/min Dose reduce if CrCl 15-50 mL/min: 30 mg daily Not recommended: CrCl < 15 mL/min

No specific reversal agent Not dialyzable

Rivaroxaban (Xarelto®)

20 mg daily with evening meal

Factor Xa inhibitor

CBC, renal and hepatic function

Dose reduce if CrCl 15-50 mL/min: 15 mg daily Avoid with CrCl < 15-30 mL/min

No specific reversal agent Not dialyzable

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Acute Coronary Syndromes

I. Definitions & Classification a. ACS – acute manifestations of CHD classified according to changes seen on electrocardiogram

(ECG) and presence or absence of biomarkers for cardiac necrosis3

i. ST segment elevation myocardial infarction (STEMI) – ischemic injury to full thickness of myocardial wall 1) Symptoms of myocardial ischemia 2) ST segment elevation on ECG 3) Elevated troponin T or I or creatinine kinase-myocardial band (CK-MB)

ii. Non-ST segment elevation myocardial infarction (NSTEMI) – injury to subendocardial myocardium, usually smaller than STEMI 1) Symptoms of myocardial injury 2) Elevated troponin T or I or CK-MB

iii. Unstable angina (UA) – ischemia that does not produce tissue injury 1) Symptoms of myocardial ischemia

II. Etiology & Pathophysiology3,15 a. Disruption of atherosclerotic plaque is the cause of ACS in 90% of patients

1) STEMI – large plaque fissures fixed, persistent thrombus abrupt cessation of myocardial perfusion transmural myocardium necrosis16

2) NSTEMI – plaque damage persistent thrombotic occlusion without complete cessation of myocardial perfusion16

3) UA – nonocclusive plaque thrombus, vasoconstriction, mechanical obstruction, inflammation/infection, or secondary UA17

III. Presentation15

a. Substernal chest pain or pressure, may radiate to jaw, neck, left arm or shoulder b. May be accompanied by nausea, vomiting, diaphoresis, fatigue, or shortness of breath

IV. Risk Factors & Complications

a. Risk factors: smoking, hypertension, diabetes, hyperlipidemia, obesity, lack of physical activity, family history of heart disease, and prior atherosclerotic ischemic stroke1,18

b. Complications19 i. Ischemic – angina, reinfarction, or infarct extension ii. Mechanical – cardiogenic shock, HF, valve dysfunction, aneurysm, myocardium rupture iii. Arrhythmic – node dysfunction, atrial or ventricular arrhythmias iv. Embolic – stroke and systemic embolism v. Inflammatory – pericarditis

V. Management a. Choice of reperfusion therapy by ACS type

i. STEMI 1) Primary PCI – treatment of choice within 12 hours of symptom onset and 90-120 minutes

of first medical contact20 2) PCI reasonable with ongoing ischemia 12-24 hours after symptom onset21

ii. UA/NSTEMI

Atherosclerosis Plaque Progression

Plaque Disruption

Thrombus Formation ACS

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1) Choice of therapy based on risk assessment21,22 2) Primary PCI – refractory angina, hemodynamic or electrical instability, absence of major

comorbidities or contraindications, and higher risk patients21 b. Pharmacotherapy 5,20,22

i. Aspirin given immediately and continued indefinitely, clopidogrel if patient aspirin intolerant ii. Parenteral anticoagulation regardless of treatment strategy iii. DAPT started upon presentation in patients in whom early invasive strategy selected

1) P2Y12 inhibitor loading dose + aspirin loading dose maintenance doses 2) Reasonable to use ticagrelor over clopidogrel, and prasugrel reasonable over clopidogrel

in patients at low bleed risk without history of stroke or TIA

Percutaneous Coronary Intervention

I. PCI & Stents a. PCI goal: open narrowed or blocked coronary arteries due to atherosclerotic plaques to restore

blood flow to the heart, relieve symptoms, and reduce ischemia23,24 i. Performed during cardiac catheterization ii. Tube with balloon or another device inserted into vessel, deployed, and stent placed

b. Stenting – insertion of a metallic mesh tube to keep the artery open i. Stent types: BMS and DES24 ii. Potential complications: bleeding, vessel damage, thrombosis, arrhythmias, and stroke

II. DAPT Duration Debate – Guideline Recommendations a. Older guidelines recommend P2Y12 inhibitor for 12 months21

i. ≤ 12 months BMS, at least 30 days ii. ≥ 12 months DES

b. Newer guidelines provide guidance for shortening or extending DAPT duration 5 i. Shorter duration in patients with higher risk of bleeding ii. Longer duration in patients with higher risk of clot and ischemia

c. In patients on DAPT with high bleed risk, such as those on oral anticoagulation, reasonable to discontinue P2Y12 inhibitor after 6 months 5

Clinical Controversy: DOACs in Patients with AF Undergoing PCI

Past Literature Review

Table 4: Subgroup Analyses of DOAC AF Trials25-28

Study Summary Conclusions Apixaban – ARISTOTLE25

Analyzed apixaban vs. warfarin with concomitant aspirin in patients with AF

Higher major bleed rates overall, but even with concomitant aspirin, apixaban showed significantly less bleeding and retained beneficial effects on SSE vs. warfarin • Aspirin + apixaban vs. warfarin – nonsignificantly higher MI

Dabigatran – RE-LY26

Assessed efficacy and safety of dabigatran vs. warfarin in patients who did and did not

Antiplatelet therapy had little effect on dabigatran’s advantages over warfarin; similar increase in bleed risk seen with dabigatran and warfarin

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receive concomitant antiplatelet therapy

• Dabigatran 110 mg – safer for major bleed and equally effective in lowering SSE risk vs. warfarin regardless of antiplatelet therapy

• Dabigatran 150 mg – similar major bleed risk vs. warfarin, but benefit in SSE possibly attenuated by concomitant antiplatelet use

Edoxaban – ENGAGE AF-TIMI 4827

Evaluated effects of single antiplatelet agent on edoxaban efficacy and safety

• Antiplatelet therapy + edoxaban – significantly greater bleed risk but no alteration in relatively increased safety and efficacy of edoxaban over warfarin

Rivaroxaban – ROCKET AF28

Assessed DAPT use and associated outcomes in patients who underwent PCI

Increased event rates of SSE, MI, and bleeding in patients on DAPT + rivaroxaban compared with warfarin

Table 5: DOACs in ACS Trials29-33

Study Summary Conclusions Apixaban

APPRAISE29 Phase II, placebo-controlled, apixaban dose-ranging study in patients with recent ACS on concomitant single or DAPT

Dose dependent increase in major or clinically relevant nonmajor bleeding – not significant for 2.5 mg BID only • More bleeding and ischemic event reduction on DAPT vs.

aspirin alone APPRAISE-2 30

Phase III, placebo-controlled trial of apixaban 5 mg BID vs. placebo + DAPT in high risk recent ACS patients

Discontinued prematurely due to significantly increased major bleeding without a reduction in ischemic events – more intracranial and fatal bleeding with apixaban vs. placebo

Dabigatran RE-DEEM31 Double blind, placebo

controlled, dose escalation trial of dabigatran + DAPT vs. placebo post-ACS

Linear increase in major or clinically relevant bleeding with dose, and numerically lower incidence of CV death, nonfatal MI, or non-hemorrhagic stroke composite endpoint with dabigatran vs. placebo • Higher incidence of non-fatal MI with dabigatran • Highest incidence of severe recurrent ischemia with

dabigatran 150 mg, and highest incidence of major or clinically relevant bleeding with dabigatran 110 mg

Rivaroxaban ATLAS ACS-TIMI 4632

Phase II, double-blind, multicenter, dose-escalation trial of rivaroxaban in patients post-ACS

Dose dependent increase in clinically significant bleeding but significant reduction in death, MI, or stroke with rivaroxaban • Lowest bleeding with 2.5 mg BID + single or DAPT • Lowest event rates with 2.5 mg BID and 5 mg BID + DAPT

ATLAS ACS-2-TIMI-5133

Phase III, placebo-controlled trial of DAPT + rivaroxaban 2.5 mg or 5 mg BID or placebo in patients with recent ACS

Significant reduction in CV death, MI, and stroke, significant increase in major bleed and intracranial hemorrhage rates, and nonsignificant increase in fatal and minor bleeding with rivaroxaban vs. warfarin • Significant decrease in fatal bleeds, minor bleeding, and

bleeding requiring medical attention with 2.5 mg BID

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Major Trials

I. Rivaroxaban

PIONEER AF-PCI: Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016; 375(25): 2423-34. doi: 10.1056/NEJMoa1611594.34

Purpose Compare the safety and efficacy of different treatment strategies after PCI with stent placement in patients with paroxysmal, persistent, or permanent NVAF

Study Design Open-label, randomized, controlled, multicenter, international trial • Duration of DAPT and P2Y12 inhibitor prespecified by investigator prior to randomization • Patients randomized 1:1:1 to groups

Group 1 – Low Dose Group 2 – Very Low Dose Group 3 – Standard Therapy

Rivaroxaban 15 mg daily* + P2Y12

inhibitor • P2Y12 inhibitor

for 12 months

Rivaroxaban 2.5 mg BID + DAPT • Low dose aspirin for 12 months • P2Y12 inhibitor for specified

DAPT duration • Patients in 1 and 6 month

groups switched to 15 mg daily for remainder of 12 months*

Warfarin daily + DAPT • Adjusted to INR 2.0-3.0 • Low dose aspirin for 12

months • P2Y12 inhibitor for

specified DAPT duration

• P2Y12 inhibitors: clopidogrel 75 mg daily, ticagrelor 90 mg BID, or prasugrel 10 mg daily** given for DAPT durations of 1, 6, or 12 months in groups 2 and 3

*10 mg if patient’s CrCl between 30-50 mL/min ** Ticagrelor and prasugrel used in ≤ 15% of patients

Patient Population

Inclusion: patients age ≥ 18 years with NVAF who had undergone PCI • AF documented within 1 year prior to

screening or documented > 1 year prior if patient receiving oral anticoagulation 3 months before PCI

Exclusion: • History of stroke/TIA • Clinically significant GI bleed within 12 months • CrCl < 30 mL/min • Unknown cause anemia, hemoglobin < 10 g/dL • Condition with increased risk for bleeding

Endpoints Primary endpoint: clinically significant bleeding – composite of Thrombolysis in Myocardial Infarction (TIMI) criteria major and minor bleeding and bleeding requiring medical attention Secondary endpoints: • Incidence of individual primary endpoint components • Efficacy endpoints: composite major adverse CV events (composite of death from CV

causes, stroke, or MI), individual components of CV event endpoint, and stent thrombosis Statistics Analyses performed on pooled data including all DAPT durations within treatment groups

• Modified intention to treat analyses based on data for all patients who underwent randomization and received at least one dose of trial drug during treatment period

• Cox proportional hazards model: analyze time from first dose to first occurrence of primary safety event, provide hazard ratio (HR) and two-sided 95% confidence interval (CI)

• Kaplan-Meier method: cumulative event rates estimated at 360 days, P values calculated using two-sided log-rank test

SARAH HALLOWELL 11

Results Baseline Characteristics: 2124 patients stratified between May 2013 through July 2015 • Predominantly white males, average age 70 years, most common CHA2DS2-VASc scores 3-5

for all groups – no major between group differences o Fewer than 10% enrolled in North America o P2Y12 inhibitors: clopidogrel used in ~93-96% o Warfarin mean percentage of time in the therapeutic range: 65.0%

Outcomes: Safety Outcomes: % of Participants with Events, HR (95% CI)

Low dose (n=696) vs. Standard

(n=697) P value Very low dose (n=706)

vs. Standard (n=697) P value

Primary: Clinically Significant Bleeding

16.8 vs. 26.7 0.59 (0.47-0.76) <0.001* 18.0 vs. 26.7

0.63 (0.50-0.80) <0.001*

Major Bleeding 2.1 vs. 3.3 0.66 (0.33-1.31) 0.23 2.0 vs. 3.3

0.57 (0.28-1.16) 0.11

Minor Bleeding 1.1 vs. 2.2 0.51 (0.20-1.28) 0.14 1.1 vs. 2.2

0.50 (0.20-1.26) 0.13

Bleeding Requiring Medical Attention

14.6 vs. 22.6 0.61 (0.47-0.80) <0.001* 15.8 vs. 22.6

0.67 (0.52-0.86) <0.001*

Efficacy: no significance difference for any events with either rivaroxaban group vs. warfarin • Power to detect 15% lower risk in rivaroxaban group = 11.4%

DAPT: Clinically Significant Bleeding by Duration of DAPT:

Event Rates, HR (95% CI) Very low dose vs. Standard P value

Patients assigned to 1 month DAPT 19.4 vs. 25.7, 0.68 (0.38-1.23) 0.20 Patients assigned to 6 months DAPT 17.5 vs. 31.2, 0.51 (0.34-0.75) <0.001*

Patients assigned to 12 months DAPT 17.9 vs. 23.9, 0.74 (0.52-1.04) 0.08 • Efficacy composite event remained nonsignificant across all DAPT stratifications

o 12-month DAPT group: narrowest CIs MI – 2.3 vs. 4.8, 0.44 (0.18-1.10), P=0.07

o 6-month DAPT group: % patients with events higher across all endpoints Stroke – 2.7 vs. 0, P=0.02

Additional Findings: significantly lower permanent discontinuation rate prior to scheduled termination date with both rivaroxaban groups vs. warfarin (P<0.001, both comparisons)

Author’s Conclusions

Administration of either low dose rivaroxaban + P2Y12 inhibitor for 12 months or very low dose rivaroxaban + DAPT for 1, 6, 12 months was associated with lower rate of clinically significant bleeding vs. standard therapy warfarin + DAPT for 1, 6, 12 months, with similar efficacy rates Limitations: • Few secondary efficacy endpoints – not powered for noninferiority or superiority, broad CIs • Trial underpowered – individual efficacy outcomes power between 5.4-13%, would need

~40,794 patients total to detect 15% event difference • 2.5 BID ACS CV event prevention indication only in some countries, 15 mg and 10 mg in

renal dysfunction daily doses not approved in ACS or AF • DAPT stratification by clinician choice – baseline characteristics unbalanced

SARAH HALLOWELL 12

Critique Strengths: • First trial directly comparing DOAC

with standard therapy in patient with NVAF undergoing PCI

• Well-designed trial evaluating multiple dosing strategies of rivaroxaban

Limitations: • Little insights regarding efficacy • No insight on DAPT duration • Dosages not available or indicated in US • Excluded high risk patients and those with

decreased renal function • Few US patients

Take Away Sheds light on bleeding-related safety of two dosing strategies of rivaroxaban with antiplatelet agents, but questions of efficacy of these non-FDA approved dosing strategies remain

PIONEER Post-hoc: 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. doi:

10.1161/CIRCULATIONAHA.116.025783.35

Purpose Assess whether low dose rivaroxaban + P2Y12 inhibitor or very low dose rivaroxaban + DAPT could reduce bleeding and, therefore, favorably impact all-cause mortality or rehospitalization

Study Design

Non-prespecified, post-hoc analysis of patients in the PIONEER AF-PCI trial Group 1 – Low Dose Group 2 – Very Low Dose Group 3 – Standard

Rivaroxaban 15 mg daily + P2Y12 inhibitor

Rivaroxaban 2.5 mg BID + DAPT Warfarin daily + DAPT

Patient Population

Same as PIONEER AF-PCI trial – patients with NVAF who had undergone PCI

Endpoints Primary endpoint: all-cause mortality or recurrent hospitalization for an adverse event (AE) • AEs classified by investigators using International Conference on Harmonization guidelines • Those leading to hospitalization included in study and classified as a result of bleeding, CV

cause, or other cause blinded to treatment assignment Statistics Patients receiving ≥ 1 dose of study drug included – analyzed as-treated, DAPT strata pooled

• Groups compared via two specific, simultaneous pair-wise comparisons without adjustment • Cox proportional hazard model: HR and 95% CI to compare time from first study drug dose to

first occurrence of all-cause death or hospitalization for AE – treatment group covariate • Kaplan-Meier method: summarize cumulative event rates at 360 days

Results Baseline characteristics: 2124 patients – well-matched, no significant between group differences Outcomes:

Risk of All-Cause Mortality or Rehospitalization: % risk, HR (95% CI)

Low dose vs. Standard P value Very low dose vs.

Standard P value

All-Cause Mortality or

Rehospitalization for Any Cause

34.9 vs. 41.9 0.79 (0.66-0.94)

0.008*, NNT = 15

31.9 vs. 41.9 0.75 (0.62-0.90)

0.002*, NNT = 10

• Significance retained for all-cause mortality or rehospitalization due to bleeding or CV cause, due to bleeding alone, and due to CV cause alone

• No difference in other all-cause death or recurrent hospitalization, all-cause death alone • No significant differences between low dose or very low dose rivaroxaban groups

SARAH HALLOWELL 13

II. Dabigatran

RE-DUAL PCI: Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after

PCI in atrial fibrillation. [Epub ahead of print August 27, 2017]. N Engl J Med. 2017. doi: 10.1056/NEJMoa1708454.36

Purpose Compare use of two regimens of dual antithrombotic therapy with dabigatran etexilate (DE) with warfarin triple antithrombotic therapy among patients with AF undergoing PCI

Study Design

Randomized, open-label, multicenter, international, controlled noninferiority trial • Patients randomized by permuted blocks, stratified by age and region 1:1:1 ratio to:

Group 1 – DE 110 Dual Therapy

Group 2 – DE 150 Dual Therapy

Group 3 – Triple Therapy

DE 110 mg BID + P2Y12 inhibitor* ≥ 12

months

DE 150 mg BID + P2Y12 inhibitor* ≥ 12 months

Warfarin** daily + P2Y12 inhibitor for ≥ 12 months + aspirin discontinued after 1

month with BMS and 3 months with DES • Continued until patients had ≥ 6 month of follow up, target number of events reached

* Clopidogrel 75 mg daily or ticagrelor 90 mg BID ** Adjusted to INR 2.0-3.0

First Recurrent Hospitalization: % events, HR (95% CI)

Low dose vs. Standard P value Very low dose vs. Standard P value

Overall Rehospitalization

34.1 vs. 41.5 0.77 (0.65-0.92) 0.005* 31.2 vs. 41.5

0.74 (0.61-0.88) 0.001*

• Significance retained for rehospitalization for bleeding or CV cause, bleeding, or CV cause

AEs: severe bleeding adverse events reduced in low dose (P=0.021) and very low dose (P=0.003) Author’s Conclusions

Administration of either strategy of rivaroxaban associated with reduced risk of all-cause mortality or recurrent hospitalization for adverse events compared with standard of care • Results added strength to PIONEER AF-PCI trial and suggests potential for improved value • Rehospitalization greater sensitivity, less specificity than original efficacy endpoints – greater

power (90%) to observe 20% difference between groups • All-cause death and rehospitalization as endpoints are objective, comprehensive endpoints Limitations: • Post-hoc analysis, no multiplicity testing adjustment, method of event allocation not a priori • Only generalizable to PIONEER AF-PCI population and clopidogrel • Rivaroxaban 2.5 mg not available/indicated in all countries, including US • Bias to admit more patients on open-label warfarin therapy

Critique Strengths: • Adequately powered, more sensitive

endpoints • Analyzed relevant rehospitalization causes • Sought to demonstrate clinical significance

of previous findings

Limitations: • Non-prespecified analysis, inclusion of

DAPT analysis questionable • Justification for lack of original efficacy and

new endpoints • Limited generalizability

Take Away Provides insight into clinical relevance of bleeding reduction with rivaroxaban but little in the way of understanding efficacy of these lower doses of rivaroxaban in reducing thrombosis risk –

true balance in bleeds vs. clots remains uncertain

SARAH HALLOWELL 14

Patient Population

Inclusion – patients ≥ 18 years with NVAF who underwent PCI in previous 120 hours • Eligible regardless of whether or not on

oral anticoagulant prior to PCI • ACS or stable CAD as PCI indications

Exclusion • NVAF due to reversible disorder without

anticipated long-term anticoagulation • Severe renal insufficiency (CrCl < 30 mL/min) • Other major coexisting conditions

Endpoints Primary Safety Endpoint: first major or clinically relevant nonmajor International Society on Thrombosis and Haemostasis (ISTH) bleeding event Secondary: • Composite efficacy: thromboembolic events (MI, SSE), death, unplanned revascularization • Combined endpoint of thrombotic events or death, individual events, and stent thrombosis

Statistics Primary analysis: intention-to-treat for all patients randomized • Noninferiority margin: upper limit (UL) of 95% confidence interval = 1.38 • Estimated sample size: 2500 patients – assumed primary endpoint 14% event rate per group,

83.6% power for noninferiority, one-sided alpha of 0.025 • Cox proportional-hazards model for primary endpoint Initial protocol: planned for coprimary endpoint comparison of thromboembolic event rates • Changed to secondary, sample size changed from 8520 to 2500

Results Baseline characteristics: 2725 patients randomized between July 2014 through October 2016 • Mean age 70.8, predominantly male, average CHA2DS2-VASc score 3.6 and HAS-BLED 2.7

o Warfarin group – higher rate of previous stroke o P2Y12 inhibitor: 88% clopidogrel o Warfarin mean percentage of time with therapeutic INR: 64%

Outcomes: Safety: Event Rate %, HR (95% CI)

DE 110 (n=981) vs. Triple (n=981) P value DE 150 (n=763) vs.

Triple (n=764) P value

First major or clinically relevant

nonmajor bleeding event

15.4 vs. 26.9 0.52 (0.42-0.63)

<0.001* noninferiority

and superiority

20.2 vs. 25.7 0.72 (0.58-0.88)

<0.001* noninferiority,

<0.002* superiority

Intracranial hemorrhage

0.3 vs. 1.0 0.30 (0.08-1.07) 0.06 0.1 vs. 1.0

0.12 (0.02-0.98) 0.047*

Efficacy: Event Rate %, HR (95% CI) Main composite efficacy endpoint: DE 110 and DE 150 (n=1744) vs. triple (n=981): 13.7 vs. 13.4, 1.04 (0.84-1.29), P=0.005 for noninferiority, P=0.74 for superiority Secondary composite efficacy endpoint: thromboembolic events or death – DE 110 and DE 150 vs. triple: 9.6 vs. 8.5, 1.17 (0.90-1.53), P=0.11 for noninferiority, P=0.25 superiority

DE 110 (n=981) vs. Triple (n=981) P value DE 150 (n=763) vs.

Triple (n=764) P value

Composite efficacy endpoint

15.2 vs. 13.4 1.13 (0.90-1.43) 0.30 11.8 vs. 12.8

0.89 (0.67-1.19) 0.44

Thromboembolic events or death

11.0 vs. 8.5 1.30 (0.98-1.73) 0.07 7.9 vs. 7.9

0.97 (0.68-1.39) 0.88

MI 4.5 vs. 3.0 1.51 (0.94-2.41) 0.09 3.4 vs. 2.9

1.16 (0.66-2.04) 0.61

Trend favoring triple therapy • No significant difference in DE groups for death, stroke, or definite stent thrombosis

SARAH HALLOWELL 15

Other findings: • Serious AEs: 42.7% DE 110, 39.6% DE 150, and 41.8% triple therapy • Fatal serious AEs: 3.9% DE 110, 3.2% DE 150, and 4.3% triple therapy • Premature discontinuation: 13.3% DE 110, 13% DE 150, and 16.6% triple therapy

Author’s Conclusions

Risk of bleeding lower with dual therapy with dabigatran + P2Y12 vs. triple therapy with warfarin + P2Y12 + aspirin; dual therapy noninferior for risk of thromboembolic events – reaffirms safety and net clinical benefit of DE regimens and supports changes in guidelines • DE 110 significantly lower major bleeding, nonsignificantly higher thromboembolic events • DE 150 significantly lower major bleeding, nonsignificantly lower thromboembolic events Limitations: • Not powered for individual endpoints and amended protocol • Combined DE groups for efficacy to get 83.6% power • Noninferiority margin used for SSE in AF trials • Can only speculate on impact of aspirin omissions in safety and efficacy outcomes

Critique Strengths: • Tested multiple dosing strategies with

NVAF approved doses • Tested omission of aspirin and found

higher bleeding rates even with shortened duration of aspirin

• Slightly more efficacy insight to be gleamed vs. PIONEER AF-PCI

Limitations: • Combined DE groups to show composite

efficacy endpoint noninferiority • MI rates higher with DE, especially DE 110 • Lack of power for individual endpoints • Questionable claims about DE 110 clinical

benefit, effectiveness, and safety

Take Away DE dual therapy superior to classic triple therapy with warfarin for bleeding Questions about effectiveness and even safety of DE 110 dual therapy

Ultimately favors DE 150 dual therapy for superior bleeding and noninferior efficacy

Future Studies – Apixaban and Edoxaban Trial Design & Endpoints

Apixaban – AUGUSTUS37

An open-label, 2 x 2 factorial, randomized controlled trial evaluating safety of apixaban 5 mg or 2.5 mg BID vs. warfarin, as well as aspirin vs. placebo in patients with AF and ACS or PCI Primary: time to first occurrence of major or clinically relevant nonmajor bleeding with apixaban vs. warfarin, with no aspirin vs. aspirin Secondary: apixaban vs. warfarin superiority for major and clinically relevant nonmajor bleeding, composite endpoints of death and ischemic events, and first any cause rehospitalization

Apixaban – SAFE-A38

Multicenter, prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative study of safety and efficacy of 1-month and 6 months of P2Y12 inhibitor plus 12 months of aspirin and apixaban 5 mg BID in patients with NVAF undergoing PCI with DESs Primary: incidence of bleeding occurrences in 12 months Secondary: composite of all-cause death, MI, SSE, net clinical benefit, and individual endpoints

Edoxaban – ENTRUST-AF-PCI39

Open-label, randomized clinical trial to evaluate safety and efficacy of edoxaban-based antithrombotic regimen (60 mg daily) vs. warfarin-based antithrombotic regimen in patients with AF post-PCI with stent placement Primary: incidence of major or clinically relevant nonmajor ISTH-defined bleeding Secondary: composite of CV death, SSE, MI, and stent thrombosis events

SARAH HALLOWELL 16

Summary, Conclusion, and Recommendations

I. Summary: a. In patients with AF undergoing PCI, goal is balance between thrombosis and bleed risk b. Triple therapy with warfarin + aspirin + clopidogrel is the historical standard of care c. Triple therapy holds an inherently increased risk of bleeding d. Shifting paradigms are increasing the use of DOACs in the management of NVAF – ease of use

and reduction in risk of bleeding compared to warfarin i. Increasing number of patients coming into the hospital on a DOAC requiring PCI ii. Increased push from clinicians to utilize these newer medications as literature accumulates

II. Conclusions & Recommendations: a. Is it time to change our paradigm?

i. No overall, definitive conclusion to move to utilization of DOACs in all patients with NVAF undergoing PCI can be made based on evidence available to date 1) Good evidence for decreased bleeding, noninferior efficacy with single strategy of single

DOAC – dabigatran 150 dual therapy a) Requires additional research into trend towards increased MI b) Only generalizable to patient population used in RE-DUAL

2) Insufficient evidence to recommend any other DOAC ii. Certain situations exist in which a DOAC, specifically dabigatran, should be considered

b. Recommendations i. Patients admitted therapeutic on warfarin – consider patient’s lifestyle, compliance,

preferences, and bleed risk and history 1) Patient prefers warfarin, no compliance or lifestyle barriers, and has lower bleed risk –

continue warfarin targeting INR between 2.0-2.5 2) Patient would prefer less monitoring, has lifestyle barriers, and has higher bleed risk –

dabigatran 150 dual therapy ii. Patients not therapeutic on warfarin or with difficulty complying with INR monitoring –

dabigatran 150 dual therapy iii. Patients admitted on DOAC for PCI – depends on DOAC

1) Edoxaban: not enough data to recommend continuation – change anticoagulant 2) Apixaban: increased risk of bleeding with apixaban + DAPT in ACS trials and questionable

trend towards increased MI in patients on aspirin + apixaban in ARISTOTLE subgroup analysis leaves questions of safety – change anticoagulant

3) Rivaroxaban: based on lack of efficacy conclusions from PIONEER – change anticoagulant 4) Dabigatran: based on RE-DUAL’s safety and noninferior efficacy – continue dabigatran

150 mg and start clopidogrel iv. Initiating new anticoagulant post-PCI

1) Assess patient’s stroke, bleed, and ACS event risks, as well as preference, likely compliance, and lifestyle a) Patient with higher bleed risk – dabigatran 150 dual therapy or warfarin + clopidogrel

with decision based on patient factors and preference b) Patient with lower bleed risk – dabigatran 150 dual therapy or warfarin triple therapy

with decision based on patient factors and preference v. Patients with renal dysfunction, either stable or recent onset – warfarin triple therapy

targeting INR between 2.0-2.5

SARAH HALLOWELL 17

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Appendices Appendix A – CHA2DS2-VASc13 and HAS-BLED scores

http://www.acc.org/latestincardiology/articles/2014/07/18/11/38/which-risk-score-best-predicts-bleeding-with-warfarin-in-atrial-fibrillation

SARAH HALLOWELL 20

Appendix B – DOACs in AF Table 1: Summary of Direct Oral Anticoagulant NVAF Trials6-9

Study Endpoints Results Apixaban ARISTOTLE6 Double blind, double dummy noninferiority trial of apixaban 5 mg BID vs. warfarin (N=18,2011)

Primary efficacy: SSE Primary safety: major bleeding Other: death from any cause, MI UL 95% CI for noninferiority: 1.38

Primary efficacy outcome: apixaban superior Major bleeding: apixaban superior Death from any cause: apixaban superior MI: numerically lower event rate with apixaban

Dabigatran RE-LY7 Blinded noninferiority trial of DE 110 mg or 150 mg vs. warfarin in SSE prevention (N=18,113)

Primary efficacy: SSE Primary safety: major hemorrhage Secondary: SSE and death Other: MI, bleeding Upper limit 95% CI for noninferiority: 1.46

Primary efficacy outcome: DE 110 mg noninferior, DE 150 mg superior Major hemorrhage: DE both doses superior MI: DE 110 mg nonsignificantly and DE 150 mg significantly higher Bleeding: significantly lower rate of major bleed with DE 110 mg, and significantly lower rates of life-threatening bleeding, intracranial bleeding, and major or minor bleeding with DE Dose comparison: Greater SSE reduction with DE 150 mg

Edoxaban ENGAGE AF-TIMI 488 Double-blind, double-dummy noninferiority trial of edoxaban 60 mg or 30 mg daily vs. warfarin (N=21,105)

Primary efficacy: SSE Principle safety: major bleeding Other: death from CV cause, ischemic stroke, GI bleeding UL 97.5% CI for noninferiority: 1.38

Primary efficacy outcome: edoxaban 60 mg superior, edoxaban 30 mg noninferior Major bleeding: significantly lower in both edoxaban groups Death from CV causes: lower rates with edoxaban Ischemic stroke: equal with edoxaban 60 mg, significantly higher with edoxaban 30 mg GI bleeding: significantly higher with edoxaban 60 mg Comparison of doses: edoxaban 60 mg lower primary outcome

Rivaroxaban ROCKET AF9 Double blind noninferiority trial of rivaroxaban 20 mg daily vs. warfarin (N=14,264)

Primary efficacy: SSE Principle safety: composite of major and nonmajor clinically relevant bleeding events Other: other bleeding measures UL 95% CI for noninferiority: 1.46

Primary efficacy outcome: per protocol annual event rate with rivaroxaban noninferior ITT efficacy: rivaroxaban noninferior, not superior Safety population efficacy for superiority: rivaroxaban superior Principle safety: rivaroxaban numerically higher than warfarin Other: similar rates of major bleeding, significant reductions in intracranial hemorrhage and fatal bleeding, significantly more major GI bleeding, significantly greater decrease in hemoglobin ≥2 g/dl, and significantly higher transfusion rates with rivaroxaban