1

A Randomized Trial to Compare the Safety of Rivaroxaban versus Aspirin in

Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome:

The Design of the GEMINI-ACS-1 Phase II Study

Thomas J. Povsic, MD, PhD,*,† Matthew T. Roe, MD, MHS*,† E. Magnus Ohman, MD,*,†

Philippe Gabriel Steg, MD,‡ Stefan James, MD, PhD,§ Alexei Plotnikov, MD,||

Hardi Mundl, MD,¶ Robert Welsh, MD,# Christoph Bode, MD,**

C. Michael Gibson, MS, MD††

*Division of Cardiology, †Duke Clinical Research Institute, Duke Medicine, Durham, NC;

‡Université Paris-Diderot, Sorbonne Paris Cité, FACT, DHU-FIRE, AP-HP and INSERM

U-1148, Paris, France and NHLI, Royal Brompton Hospital, Imperial College, London,

UK; §Dept. of Medical Sciences, Cardiology, and Uppsala Clinical Research Center,

Uppsala University, Uppsala, Sweden; ||Janssen Research & Development, Raritan, NJ;

¶Bayer HealthCare, Wuppertal, Germany; #Mazankowski Alberta Heart Institute and

University of Alberta, Edmonton, Alberta, Canada; **9University of Freiburg, Freiburg,

Germany; ††Cardiovascular Division, Department of Medicine, Beth Israel Deaconess

Medical Center, Harvard Medical School, Boston, MA.

ClinicalTrials.gov: NCT02293395

Brief title: GEMINI-ACS-1 Design

Word count: 3316 (text only)

Funding: GEMINI-ACS-1 is funded by Janssen Research & Development and Bayer

HealthCare.

2

Disclosures: Povsic: Available at

https://www.dcri.org/about-us/conflict-of-interest/COI_Povsic-2014-15.pdf.

Roe: Available at https://dcri.org/about-us/conflict-of-interest/COI%20-Roe_2015.pdf.

Ohman: Available at https://dcri.org/about-us/conflict-of-interest/Ohman-COI_2014.pdf.

Steg: Research grant (to INSERM U1148) from Sanofi, and Servier; speaking or

consulting fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-

Squibb, CSL-Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer,

Regeneron, Roche, Sanofi, Servier, The Medicines Company; and owns stocks from

Aterovax.

James: Institutional research grants from AstraZeneca, Terumo Inc, Medtronic,

Vascular Solutions, The Medicines Company; honoraria from The Medicines Company,

AstraZeneca; consultancy/advisory board fees from AstraZeneca, Daiichi Sankyo,

Janssen.

Plotnikov: Employee of Janssen Research & Development, a subsidiary of Johnson &

Johnson.

Mundl: Employee of Bayer HealthCare

Welsh: Research grants from Abbott Vascular, Alere, AstraZeneca, Bayer, Bristol-Myers

Squibb, Boehringer Ingelheim, CIHR, CSL Behring LLC, Edwards Lifesciences, Eli Lilly,

Janssen, Johnson & Johnson, Matrizyme Pharma, Pfizer, Population Health Research

Institute, University of Alberta Hospital Foundation; honoraria from AstraZeneca, Bristol-

Myers Squibb/Pfizer, and Bayer.

Bode: Consulting/Honoraria from Bayer, Daiichi Sankyo, and Bristol-Myers Squibb.

Gibson: Research grants from Angel Medical Corporation, Bayer, CSL Behring, Ikaria

3

Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, Portola

Pharmaceuticals, Stealth Peptides Inc., St. Jude Medical; Consulting fees from Boston

Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly and Co.,

Gilead Sciences Inc., The Medicines Company, Novo Nordisk, Pfizer, St. Jude Medical,

WebMD; Consultant (no fees received) for Bayer Corporation, Janssen

Pharmaceuticals, Johnson & Johnson Corporation, Ortho-McNeil.

Address for correspondence: Thomas J. Povsic, MD, PhD, Box 103208, DUMC,

Durham, NC 27708. Phone: 919-681-5821; Fax: 919-681-9607. Email:

Thomas.povsic@duke.edu.

4

Abstract

Dual antiplatelet therapy (DAPT), the combination of aspirin and a P2Y12 inhibitor,

given for 12 months remains the standard of care after presentation with acute coronary

syndrome (ACS) because it has been shown to be associated with a significant

reduction in ischemic events compared with aspirin monotherapy. The factor Xa

inhibitor rivaroxaban was shown to be associated with a significant reduction in the

composite of cardiovascular death, myocardial infarction (MI), and stroke, and resulted

in a nominal reduction in cardiovascular death, when added to background DAPT in the

ATLAS ACS 2-TIMI 51 trial; however, there was excessive bleeding with this “triple

therapy” approach. The combination of rivaroxaban with P2Y12 inhibition in a “dual

pathway” approach may be an effective therapeutic regimen for the treatment of ACS,

given the known importance of P2Y12 inhibition post-stenting and intriguing data that

the combination of an anticoagulant with clopidogrel post-stenting in patients with atrial

fibrillation appears an attractive option to this patient population. GEMINI-ACS-1 is a

prospective, randomized, double-dummy, double-blind, active-controlled trial that will

assess the safety of dual antithrombotic therapy (rivaroxaban [2.5 mg twice daily] +

P2Y12 inhibitor) as compared with DAPT (aspirin [100 mg] + P2Y12 inhibitor) within 10

days of an ACS event in 3000 patients. Patients will be randomized in a 1:1 ratio

stratified by intended P2Y12 inhibitor use (clopidogrel 75 mg daily or ticagrelor 90 mg

twice daily), with 1500 patients expected in each P2Y12 inhibitor strata. The primary

endpoint is Thrombolysis in Myocardial Infarction (TIMI) clinically significant bleeding

(major, minor, or requiring medical attention). The exploratory efficacy determination will

be a composite of cardiovascular death, MI, ischemic stroke, and stent thrombosis.

5

GEMINI-ACS-1 will assess the safety and feasibility of dual antithrombotic therapy with

rivaroxaban and a P2Y12 inhibitor compared with conventional DAPT for the treatment

of patients with recent ACS.

ClinicalTrials.gov: NCT02293395

Key words: acute coronary syndrome; dual antithrombotic therapy; rivaroxaban

6

Background and Scope

Treatment of Acute Coronary Syndrome

Dual antiplatelet therapy (DAPT) is central to European Society of Cardiology (ESC)1,2

and American Heart Association/American College of Cardiology (AHA/ACC)3,4 practice

guidelines for the treatment of patients with acute coronary syndrome (ACS).

Despite the use and development of novel more potent P2Y12 inhibitors , the

residual risk of recurrent ischemic events remains unacceptably high, especially in the

medically-managed patient population.10,11 To mitigate this risk, a variety of “triple”

therapy approaches have been explored; however, the addition of either an additional

anti-platelet agent (the protease-activated receptor-1 inhibitor Vorapaxar ) or oral

anticoagulants at therapeutic doses (Apixaban13 dabigatran14, or darexaban15) were

associated with higher bleeding risk and modest non-statistically significant impacts on

ischemic events.12

In contrast, the addition of rivaroxaban, at comparatively lower doses, to DAPT as

explored in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin

with or without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome

(ATLAS) program was associated with a 31% RRR in the primary composite endpoint of

cardiovascular death, MI, and stroke in the phase II ATLAS ACS-TIMI 46 trial.16 A clear

dose-response relationship between the total daily dose of rivaroxaban and bleeding,

coupled with a lack of greater efficacy at higher doses on ischemic events led to the

selection of lower doses (2.5 mg and 5 mg twice daily) for assessment in a phase III trial

(ATLAS ACS 2-TIMI 51), which demonstrated a RRR of 16% on ischemic events (24-

month Kaplan-Meier rate of 8.9 and 10.7, respectively) in the combined rivaroxaban

7

groups.17 In addition, a ~35% reduction in cardiovascular (2.7% vs. 4.1%; p=0.002) and

all-cause (2.9% vs. 4.5%; p=0.002) mortality was observed in the 2.5 mg arm. Given a

dose-dependent bleeding hazard and preservation of ischemic effectiveness in the

lowest dose rivaroxaban arm (Table 1), the ESC guidelines for ST segment elevation MI

(STEMI),2 non-ST segment elevation (NSTE)-ACS,1 and myocardial revascularization18

suggest (level IIB) that low-dose rivaroxaban (2.5 mg twice daily) may be considered in

addition to clopidogrel and aspirin in appropriate patients.1

Alternative Strategies: Removing Aspirin

Aspirin has been the cornerstone of treatment of antithrombotic events since the initial

demonstration of a highly significant effect on mortality in patients with both NSTEMI

and STEMI.19-22

Both theoretical and clinical findings suggest that alternative dual antithrombotic

approaches combining a P2Y12 inhibitor with low-dose oral anticoagulation might retain

effectiveness against ischemic events while reducing the bleeding risk observed with

triple or DAPT therapies. First, while the use of a P2Y12 inhibitor post-stenting appears

important to reduce acute ischemic complications,23 the risks and benefits of aspirin in

this setting have never been fully tested.

Second, the addition of a second antiplatelet agent adds significant bleeding risk,

and aspirin, with direct gastrointestinal toxicity, leads directly to increased bleeding. In

the STent Anticoagulation Restenosis Study (STARS), the addition of ticlopidine post-

PCI resulted in a 3-fold increase in hemorrhagic complications with rates of bleeding

similar to a strategy using full-dose warfarin,23 while the CURE trial demonstrated a 30%

8

increase in major and a 2-fold increase in minor bleeding with aspirin and clopidogrel

compared with aspirin alone. 5

Third, the benefit of aspirin in addition to P2Y12 inhibition remains unproven. The

Management of ATherothrombosis with Clopidogrel in High-risk patients (MATCH) trial

showed marked increases in minor, major, and life-threatening bleeding with relatively

small improvements in ischemic events when aspirin was added to clopidogrel in

patients with prior stroke.31

Finally, DAPT targets the action of products released on platelet activation via

interaction with collagen, but does not inhibit direct platelet activation by potent agonists

such as thrombin, which is generated in prothrombotic conditions such as MI (Figure

1).24,25 .26,27 Rivaroxaban, by directly inhibiting factor Xa and prothrombinase complex

activity, prolongs the time and suppresses the maximal extent of thrombin generation. In

the ATLAS ACS-TIMI 46 trial, treatment with rivaroxaban was associated with reduced

thrombin generation both acutely and at 6-month follow-up.28 In an in vivo rat shunt

thrombosis model, rivaroxaban and clopidogrel was as effective as triple therapy and

more effective in suppressing thrombus formation than any single agent, DAPT, or

rivaroxaban and aspirin, while demonstrating lower bleeding times than DAPT or triple

therapy.29 Finally, rivaroxaban and ticagrelor may act synergistically to reduce platelet

aggregation. In an in vitro model, either agent alone resulted in 31–37% inhibition of

tissue factor-induced platelet aggregation; however, the combination, even at sub-

maximal dosing, resulted in >90% inhibition.29 These observations suggest that

suppression of thrombin generation might be particularly effective at limiting ischemic

9

events via both an anticoagulation effect as well as inhibition of thrombin-mediated

platelet activation.

Clinical Trial Results with Dual Pathway Inhibition

Clinical findings support the hypothesis that dual antithrombotic approaches warrant

additional study. The What is the Optimal antiplatElet and anticoagulant therapy in

patients with oral anticoagulation and coronary StenTing (WOEST) study compared the

use of oral anticoagulation and clopidogrel alone with triple therapy in patients with an

indication for oral anticoagulation after PCI. A dual pathway approach was associated

with a 64% RRR in bleeding (HR 0.36, 95% CI 0.26–0.50; p<0.001), and a lower rate of

ischemic endpoints (11.1% vs. 17.6; HR 0.60, 95% CI 0.38–0.94; p=0.025).30 These

findings have spurred a variety of trials exploring the utility of a dual pathway strategy

without aspirin in patients with atrial fibrillation undergoing PCI (Table 2). To date, no

safety concerns have been raised in these trials.34 In addition, two other ongoing post-

PCI studies are comparing a Ticagrelor alone approach to DAPT, starting either 1-

month35 or 3-months36 after PCI. While these trials will build on our understanding of

the utility of long-term DAPT,37,38 they do not address the addition of alternative

therapies after cessation of aspirin.

The GEMINI-ACS-1 clinical trial builds on these pre-clinical and clinical

observations to explore the feasibility and safety of a dual antithrombotic strategy

(rivaroxaban 2.5 twice daily with a P2Y12 inhibitor) in comparison with conventional

DAPT (aspirin 100 mg daily with a P2Y12 inhibitor) for secondary prevention in patients

with recent ACS.

10

METHODS

Study Overview

GEMINI-ACS-1 (NCT02293395) is a phase II, randomized, double-blind, double-

dummy, active-controlled study assessing the safety and feasibility of rivaroxaban (2.5

mg twice daily) and a P2Y12 inhibitor compared with conventional DAPT (aspirin [100

mg] + P2Y12 inhibitor) in patients within 10 days of an ACS event. The study will be

conducted at approximately 370 sites in 22 countries with proportional geographic

representation (Figure 2).

GEMINI-ACS-1 was designed by an academic executive committee (Appendix)

comprising international experts in interventional cardiology and thrombosis/hemostasis

and representatives from each of the sponsors. The executive committee will oversee

the medical, scientific, and operational conduct of the study, and review and approve

analyses for publication. A steering committee (Appendix) comprising the executive

committee and individual country leaders will provide feedback on country-specific

issues related to applicability of the trial and regional practices, and formulate substudy

analysis initiatives.

GEMINI-ACS-1 adheres fully to the ethical principles of the Declaration of

Helsinki, the specifications of the International Conference on Harmonization, and Good

Clinical Practice, including the requirement for each subject's informed consent before

initiating any study procedure.

Study Population

11

GEMINI-ACS-1 will enroll approximately 3000 patients with recent (<10 days) ACS.

Patients with unstable angina, NSTEMI, and STEMI treated with medical therapy alone,

PCI, or coronary artery bypass graft (CABG) surgery are eligible. Key inclusion and

exclusion criteria are shown in Table 3. Notably, patients <55 years old must have

diabetes or have had an MI prior to the index presentation, and patients with NSTEMI or

unstable angina must fulfill enrichment criteria to ensure a population at risk for future

events.

Patients will receive at least 1 dose of DAPT with aspirin and a P2Y12 inhibitor

prior to randomization, and, in those undergoing PCI, an additional dose after PCI. All

patients should be intended to be treated with DAPT for their ACS event and agree to

provide a genetic sample for CYP2C19 testing.

Randomization and Treatment

Randomization will be 1:1 stratified by intended P2Y12 inhibitor use (clopidogrel 75 mg

daily or ticagrelor 90 mg twice daily) with approximately1500 patients in each P2Y12

inhibitor strata. The study will use a double-blind, double-dummy design. Patients will be

provided with drug packs containing either aspirin (100 mg) or matching placebo taken

once daily and rivaroxaban or matching placebo, taken twice daily. Dosing of aspirin

was based on analyses indicating either greater39 or identical ischemic benefit but a

bleeding hazard associated with higher aspirin dosing.40 All patients must receive a

dose of DAPT prior to randomization. Patients undergoing PCI must receive 2 doses of

DAPT, including a minimum of 1 dose post-PCI. Patients post-CABG surgery may be

enrolled once able to tolerate DAPT, but not within 12 hours of CABG surgery. Study

12

drug will be started on the day of randomization and will be taken on a 12-hour

schedule. All study drug and P2Y12 inhibitor will be provided by the sponsor for the

duration of the study.

All patients will be treated for 12 months or until the study treatment end date,

defined as 180 days after the last subject is randomized. At the end of the treatment

phase, or on permanent discontinuation of study drug, all patients will be instructed to

receive treatment with aspirin (unless contraindicated) starting on the day following the

last dose of study drug. The duration of continued background treatment with a P2Y12

inhibitor will be left to the discretion of the managing physician, but it is preferred that

the P2Y12 treatment continues at least until the end of study (EOS) visit.

All outcomes (bleeding, death, MI, stroke, and stent thrombosis) will be collected

at days 30, 90, 180, 270, 360, and at a study visit 30 days after permanent cessation of

study drug, either during or at the conclusion of the study.

Genomic Evaluation

A pharmacogenomics sample for assessment of CYP2C19 metabolizer status will be

obtained from all participants. The principal investigator will be informed of genotyping

results for all subjects regardless of P2Y12 inhibitor choice (clopidogrel or ticagrelor)

and any prior CYP2C19 genotype testing, and will inform subjects of the results. No

instructions or guidelines will be provided from study leadership on how to interpret or

utilize these results; however, investigators will be asked to pre-specify what actions

they expect to take with regard to P2Y12 inhibitor choice, and actual action will

subsequently be tracked.

13

Endpoints

The primary endpoint is Thrombolysis in Myocardial Infarction (TIMI) clinically significant

bleeding (major, minor, or requiring medical attention). The primary exploratory efficacy

determination will be a composite of cardiovascular death, MI, ischemic stroke, and

stent thrombosis. All ischemic and bleeding outcomes after randomization will be

adjudicated by an independent clinical events committee (CEC) (Appendix) blinded to

treatment assignment using previously published criteria and recommended event

definitions.41-45 Bleeding events will be adjudicated based on TIMI, Bleeding Academic

Research Consortium (BARC), Global Use of Strategies to Open Occluded Coronary

Arteries (GUSTO), and International Society on Thrombosis and Haemostasis (ISTH)

criteria. Undetermined deaths will be categorized as cardiovascular deaths. Importantly,

for this trial, all hemorrhagic deaths will be categorized as cardiovascular deaths. Event

definitions are shown in Table 4.

Alterations in Study Treatment During Conduct of the Trial

Study treatment may be temporarily held if the patient:

a. undergoes PCI, CABG, or any other surgical procedure;

b. experiences a significant bleeding event;

c. develops a new neurological deficit or alteration in mental status;

d. develops a platelet count <50,000/μL;

e. has an adverse event related to or exacerbated by study drug; or

f. requires anticoagulation or prohibited therapy on a temporary basis.

14

In these cases, study drug can be resumed when deemed safe by the investigator. If

appropriate, open-label aspirin may be used during this period. Patients should

discontinue treatment if they require open-label long-term anticoagulation, suffer a TIA

or stroke, become pregnant, develop critical bleeding or other adverse event precluding

further use, develop renal insufficiency (CrCl <15 mL/min), or request to stop study

drug.

In rare cases, it may be necessary to unblind treatment assignment to allow

proper medical treatment to be administered (for instance, to dose other anticoagulants

during urgent procedures or thrombolysis). In such cases, the investigator may contact

the interactive web response system (IWRS) vendor to determine individual patient

assignments. It is recommended that the investigator contact the sponsor or its

designee, if possible, to discuss the particular situation before breaking the blind, and

the sponsor must be informed as soon as possible after unblinding has occurred.

Investigators will not disclose treatment assignment to the subject whenever possible;

subjects who have had their treatment assignment unblinded may continue on study

drug if appropriate.

Concern Over Stent Thrombosis and Safety Review

DAPT with aspirin and a P2Y12 inhibitor is the standard for prevention of acute

thrombotic complications since a series of trials compared ticlopidine and aspirin with

other anticoagulation strategies.23,46-49 Several developments have altered this

landscape, including the development of novel oral anticoagulants which reach

therapeutic levels within hours of administration and are not accompanied by an initial

prothrombotic state. In addition, the development of more potent P2Y12 inhibitors, their

15

routine earlier administration in the treatment of ACS patients, and newer less

thrombogenic stent technologies have continued to impact post-PCI care since the

completion of the ATLAS trials.16,17 GEMINI-ACS-1 differs from many trials in the early

transition (1–10 days post-presentation) to a dual pathway strategy using a single

antiplatelet agent post-ACS. Given that early cessation of DAPT has been associated

with a significant risk of stent thrombosis,50 the safety of this approach has yet to be

established; although, it is reassuring that several studies incorporating similar

strategies have either completed enrollment or are ongoing without evident safety

concerns raised.34

To monitor and protect patient safety, GEMINI-ACS-1 will actively engage and

utilize an independent data monitoring committee (DMC), coordinated out of Stanford

University, including experts in clinical trials, interventional cardiology, thrombosis, and

biostatistics. The DMC chairman will review each definite and probable stent

thrombosis, death, and major bleeding event as they are reported. The DMC is

scheduled to review data every 4 months throughout the enrollment period. In addition,

a DMC meeting may be convened without notification of the sponsor or trial leadership.

16

Statistical ConsiderationsThe primary objective of the study is to estimate bleeding risk of rivaroxaban 2.5 mg

twice daily compared with aspirin 100 mg daily when added to background of P2Y12

inhibition. A Cox proportional hazards model from time of randomization to the first non-

CABG surgery-related TIMI clinically significant bleeding event will be used for the

primary analysis. Bleeding rates were modeled based on the ATLAS ACS 2-TIMI 51

trial, assuming 85 primary events per stratum, an incidence rate of 4.5% at day 180 and

6.5% at day 360 in the aspirin (DAPT) arm, and a discontinuation rate of 10% by day

360; an observed HR of 1.0 will result in an upper bound of the 2-sided 95% CI of 1.5,

while an observed HR of 1.3 will define an upper bound of 95% CI at 2.0. With 170 total

events, an observed HR of 1.0 results in an upper bound of the 95% CI of 1.4. The

primary analysis will be performed on the intention-to-treat (ITT) population and will

include data through the EOS visit. The analysis will be repeated on the as-treated

population as the primary safety analysis. All analyses will use data adjudicated by the

CEC. An exploratory efficacy analysis will investigate the time to occurrence of the

composite of cardiovascular death, MI, stroke, and stent thrombosis, and each of these

components individually.

As a sensitivity analysis of the primary endpoint, a P2Y12-stratified Cox

proportional hazards model will be conducted based on the intention-to-treat analysis

set and on-treatment analysis phase across strata. Homogeneity of treatment effects

between the clopidogrel and ticagrelor strata will be explored via a test for treatment-by-

stratum interaction using the Cox proportional hazards model with treatment, stratum,

and the treatment-by-stratum interaction as the covariates at a 2-sided significance level

17

of 0.05. If there is a statistically significant interaction, clinical interpretations will be

explored.

Additional post-hoc analyses may be conducted to investigate unexpected

results, including the impact of differential study drug discontinuations and/or differential

discontinuation of P2Y12 between the 2 treatment groups and between the 2 strata.

Summary

GEMINI-ACS-1 will assess the bleeding risk of a dual antithrombotic therapy compared

with conventional DAPT in an ACS population, a substantial proportion of which are

expected to undergo PCI for their index event, while monitoring for concerning signals

around ischemic events, specifically stent thrombosis.

Acknowledgements

The authors thank Elizabeth Cook for her editorial support for this manuscript.

18

REFERENCES

1. Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of

acute coronary syndromes in patients presenting without persistent st-segment

elevation. Eur Heart J 2015;pii: ehv320 [Epub ahead of print]. PMID: 26320110.

2. Steg PG, James SK, Atar D, et al. ESC guidelines for the management of acute

myocardial infarction in patients presenting with st-segment elevation. Eur Heart

J 2012;33:2569-619.

3. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the

management of patients with non–st-elevation acute coronary syndromes: A

report of the American College of Cardiology/American Heart Association task

force on practice guidelines. Circulation 2014;130:e344-426.

4. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the

management of st-elevation myocardial infarction: a report of the American

College of Cardiology Foundation/American Heart Association task force on

practice guidelines. J Am Coll Cardiol 2013;61:e78-140.

5. Effects of clopidogrel in addition to aspirin in patients with acute coronary

syndromes without st-segment elevation. N Engl J Med 2001;345:494-502.

6. Steinhubl SR, Berger PB, Mann IJ, et al. Early and sustained dual oral

antiplatelet therapy following percutaneous coronary intervention: A randomized

controlled trial. JAMA 2002;288:2411-20.

7. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in

patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.

19

8. Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with

clopidogrel in patients with a planned invasive strategy for acute coronary

syndromes (PLATO): A randomised double-blind study. Lancet 2010;375:283-93.

9. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute

coronary syndromes without revascularization. N Engl J Med 2012;367:1297-

309.

10. Chan MY, Mahaffey KW, Sun LJ, et al. Prevalence, predictors, and impact of

conservative medical management for patients with non–st-segment elevation

acute coronary syndromes who have angiographically documented significant

coronary disease. JACC Cardiovasc Interv 2008;1:369-78.

11. Cohen MG, Filby SJ, et al. The paradoxical use of cardiac catheterization in

patients with non–st-elevation acute coronary syndromes: Lessons from the can

rapid stratification of unstable angina patients suppress adverse outcomes with

early implementation of the ACC/AHA guidelines (CRUSADE) quality

improvement initiative. Am Heart J 2009;158:263-70.

12. Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist vorapaxar in

acute coronary syndromes. N Engl J Med 2012;366:20-33.

13. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after

acute coronary syndrome. N Engl J Med 2011;365:699-708.

14. Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with

acute coronary syndromes on dual antiplatelet therapy: A randomized, double-

blind, phase II trial. Eur Heart J 2011;32:2781-9.

20

15. Steg PG, Mehta SR, Jukema JW, et al. Ruby-1: A randomized, double-blind,

placebo-controlled trial of the safety and tolerability of the novel oral factor xa

inhibitor darexaban (ym150) following acute coronary syndrome. Eur Heart J

2011;32:2541-54.

16. 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.

17. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent

acute coronary syndrome. N Engl J Med 2012;366:9-19.

18. Windecker S, Kolh P, Alfonso F, et al. ESC/EACTS guidelines on myocardial

revascularization. The Task Force on Myocardial Revascularization of the

European Society of Cardiology (ESC) and the European Association for Cardio-

Thoracic Surgery (EACTS). Eur Heart J 2014;35:2541-619.

19. Elwood PC, Cochrane AL, Burr ML, et al. A randomized controlled trial of acetyl

salicyclic acid in the secondary prevention of mortality from myocardial infarction.

Br Med J 1974;1:436-40.

20. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither

among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet

1988;332:349-60.

21. Risk of myocardial infarction and death during treatment with low dose aspirin

and intravenous heparin in men with unstable coronary artery disease. Lancet

1990;336:827-30.

21

22. Wallentin LC. Aspirin (75 mg/day) after an episode of unstable coronary artery

disease: Long-term effects on the risk for myocardial infarction, occurrence of

severe angina and the need for revascularization. J Am Coll Cardiol

1991;18:1587-93.

23. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three

antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med

1998;339:1665-71.

24. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and

atherothrombosis. Eur Heart J 2010;31:17-28.

25. Sugidachi A, Asai F, Ogawa T, et al. The in vivo pharmacological profile of cs-

747, a novel antiplatelet agent with platelet adp receptor antagonist properties. Br

J Pharmacol 2000;129:1439-46.

26. Ardissino D, Merlini PA, Bauer KA, et al. Coagulation activation and long-term

outcome in acute coronary syndromes. Blood 2003;102:2731-5.

27. Merlini PA, Bauer KA, Oltrona L, et al. Persistent activation of coagulation

mechanism in unstable angina and myocardial infarction. Circulation 1994;90:61-

8.

28. Gibson CM, Mega JL, Jennings LH, et al. Effect of rivaroxaban on markers of

coagulation in patients with acute coronary syndromes: An ATLAS ACS-TIMI 46

substudy. Circulation 2009;120:S1035.

29. Perzborn E, Heitmeier S, Laux V. Effects of rivaroxaban on platelet activation

and platelet–coagulation pathway interaction: In vitro and in vivo studies. J

22

Cardiovasc Pharmacol Ther 2015;pii:1074248415578172 [Epub ahead of print].

PMID: 25848131.

30. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without

aspirin in patients taking oral anticoagulant therapy and undergoing

percutaneous coronary intervention: An open-label, randomised, controlled trial.

Lancet 2013;381:1107-15.

31. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared

with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack

in high-risk patients (MATCH): Randomised, double-blind, placebo-controlled

trial. Lancet 2004;364:331-7.

32. Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy with Warfarin in

Patients with AF that Undergo a PCI with Stenting (REDUAL-PCI):

NCT02164864. ClinicalTrials.gov Web site.

https://clinicaltrials.gov/ct2/show/NCT02164864. Updated September 15, 2015.

Accessed October 5, 2015.

33. Study Apixaban to Vitamin K Antagonist for the Prevention of Stroke or Systemic

Embolism and Bleeding in Patients with Non-valvular Atrial Fibrillation and Acute

Coronary Syndrome/Percutaneous Coronary Intervention (AUGUSTUS):

NCT02415400. ClinicalTrials.gov Web site.

https://clinicaltrials.gov/ct2/show/NCT02415400?term=NCT02415400&rank=1.

Updated October 1, 2015. Accessed October 5, 2015.

34. Gibson CM, Mehran R, Bode C, et al. An open-label, randomized, controlled,

multicenter study exploring two treatment strategies of rivaroxaban and a dose-

23

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.

35. GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet

Therapy After Stent Implantation: NCT01813435. ClinicalTrials.gov Web site.

https://clinicaltrials.gov/ct2/show/NCT01813435?term=NCT01813435&rank=1.

Updated July 21, 2015. Accessed October 5, 2015.

36. Ticagrelor with Aspirin or Alone in High-risk Patients after Coronary Intervention

(TWILIGHT): NCT02270242. ClinicalTrials.gov Web site.

https://clinicaltrials.gov/ct2/show/NCT02270242?term=nct02270242&rank=1.

Updated September 8, 2015. Accessed October 5, 2015.

37. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet

therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.

38. Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy

after drug-eluting stent implantation: A systematic review and meta-analysis

of randomized controlled trials. J Am Coll Cardiol 2015;65:1298-310.

39. Collaborative meta-analysis of randomised trials of antiplatelet therapy for

prevention of death, myocardial infarction, and stroke in high risk patients. BMJ

2002;324:71-86.

40. Campbell CL, Smyth S, Montalescot G, et al. Aspirin dose for the prevention of

cardiovascular disease: A systematic review. JAMA 2007;297:2018-24.

41. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent

trials: A case for standardized definitions. Circulation 2007;115:2344-51.

24

42. ROCKET AF Study Investigators. Rivaroxaban—once daily, oral, direct factor xa

inhibition compared with vitamin k antagonism for prevention of stroke and

embolism trial in atrial fibrillation: Rationale and design of the ROCKET AF

study. Am Heart J 2010;159:340-7.

43. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for

cardiovascular clinical trials: A consensus report from the bleeding academic

research consortium. Circulation 2011;123:2736-47.

44. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial

infarction. Circulation 2012;126:2020-35.

45. Hicks KA, Tcheng JE, Bozkurt B, et al. 2014 ACC/AHA key data elements and

definitions for cardiovascular endpoint events in clinical trialsa report of the

American College of Cardiology/American Heart Association task force on clinical

data standards (writing committee to develop cardiovascular endpoints data

standards). J Am Coll Cardiol 2015;66:403-69.

46. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of

antiplatelet and anticoagulant therapy after the placement of coronary-artery

stents. N Engl J Med 1996;334:1084-9.

47. Schömig A, Neumann FJ, Walter H, et al. Coronary stent placement in patients

with acute myocardial infarction: Comparison of clinical and angiographic

outcome after randomization to antiplatelet or anticoagulant therapy. J Am Coll

Cardiol 1997;29:28-34.

48. Bertrand M, Legrand V, Boland J, et al. Randomized multicenter comparison of

conventional anticoagulation versus antiplatelet therapy in unplanned and

25

elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine

(FANTASTIC) study. Circulation 1998;98:1597-603.

49. Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of

anticoagulation versus antiplatelet therapy after coronary stent implantation in

high-risk patients: The multicenter aspirin and ticlopidine trial after intracoronary

stenting (MATTIS). Circulation 1998;98:2126-32.

50. Généreux P, Rutledge DR, Palmerini T, et al. Stent thrombosis and dual

antiplatelet therapy interruption with everolimus-eluting stents: Insights from the

Xience V coronary stent system trials. Circ Cardiovas Interv 2015;8:pii:e001362.

doi: 10.1161/CIRCINTERVENTIONS.114.001362. PMID: 25940520.

26

Figure Legends

Figure 1: Sites of action of current antithrombotic therapies in patients with ACS.

Figure 2: GEMINI-ACS-1 trial design.

27

Figure 1: Sites of action of current antithrombotic therapies in patients with ACS.

ASA and P2Y12 inhibitors inhibit the action of effectors released from activated

platelets. Inhibition of factor Xa prevents both direct thrombin activation of platelets as

well as intracoronary thrombus formation.

ADP indicates adenosine diphosphate; ASA, aspirin; P2Y12 Inh, P2Y12 receptor inhibitor; Plt, platelet; TXA2, thromboxane A2.

28

Figure 2: GEMINI-ACS-1 Trial Design.

ACS indicates acute coronary syndrome; ASA, aspirin; bid, twice daily; CV, cardiovascular; MI, myocardial infarction; qd, once daily; TIMI, Thrombolysis in Myocardial Infarction.

29

Table 1: Comparison of ischemic and bleeding events in the ATLAS ACS 2-TIMI 51 trial

by treatment group.

Rivaroxaban 2.5 mg

Twice Daily

Rivaroxaban 5 mg

Twice Daily

Placebo

Composite of CV death, MI, stroke 9.1 8.8 10.7

Death, MI, stroke 9.3 9.1 11.0

CV death 2.7 4.0 4.1

Stent thrombosis 2.2 2.3 2.9

Non-CABG TIMI major bleeding 1.8 2.4 0.6

TIMI minor bleeding 0.9 1.6 0.5

TIMI bleeding requiring medical attention 12.9 16.2 7.5

Intracranial hemorrhage 0.4 0.7 0.2

Fatal bleeding 0.1 0.4 0.2

CABG indicates coronary artery bypass graft surgery; CV, cardiovascular; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

30

Table 2: Clinical trials exploring non-aspirin approaches to ACS or post-PCI treatments

Trial Indication N Arm 1 Arm 2 Arm 3

WOEST30 AF + PCI 573 warfarin + clopidogrel warfarin + clopidogrel +

aspirin

---

REDUAL-PCI32 AF + PCI 8520 dabigatran 110 mg

BID + P2Y12 inhibitor

dabigatran 150 mg BID

+ P2Y12 inhibitor

VKA + P2Y12

inhibitor + aspirin

AUGUSTUS33 AF + PCI 4600 apixaban + P2Y12

inhibitor ± aspirin*

warfarin + P2Y12

inhibitor ± aspirin

---

PIONEER AF-PCI34 AF + PCI 2125 rivaroxaban 15 mg QD

+ P2Y12 inhibitor

rivaroxaban 2.5 BID +

aspirin + P2Y12

inhibitor

VKA + aspirin +

P2Y12 inhibitor

GLOBAL LEADERS35 PCI 16000 DAPT x 1-month

ticagrelor only

DAPT x 12 months ---

TWILIGHT36 PCI 9000 DAPT x 3-months

ticagrelor only

DAPT x 12 months ---

*Study employs a 2x2 factorial design with randomization to apixaban vs. warfarin and aspirin vs. placebo. AF indicates atrial fibrillation; BID, twice daily; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention; QD, once daily; VKA, vitamin K antagonist.

31

Table 3: Key inclusion and exclusion criteria.

Inclusion criteria

Age ≥18 yrs

ACS within 48 hours of hospitalization or while hospitalized

Receiving DAPT and plan to continue DAPT

If age <55 yrs, must have diabetes or MI prior to index event

Enrichment criteria

A. STEMI

EKG criteria (1 of the following):

- ST-segment elevation >0.1 mV in 2 or more contiguous leads

- New LBBB

- ST-segment depression ≥0.1 mV in V1–V4 (posterior MI)

Elevated cardiac biomarkers

B. NSTEMI

Clinical symptoms of ACS + elevated cardiac biomarkers AND at least 1 of the following:

1. EKG criteria

- Transient ST-segment elevation ≥0.1 mV

- New horizontal or down-sloping ST depression ≥0.05 mV

- New T-wave inversions ≥0.1 mB in 2 leads with prominent R wave of t/s ratio >1

2. Identification of a culprit lesion by angiography

C. Unstable angina

Clinical symptoms of ACS + elevated cardiac biomarkers AND at least 1 of the following:

1. EKG criteria as listed above

2. Revascularization for the index event AND

3. TIMI risk score ≥4

32

Exclusion criteria

Prior stroke or TIA

Contraindication to anticoagulation including

Active bleeding

History of intracranial hemorrhage

Clinically significant GI bleeding within 12 mos

INR >1.5 or plt count <90,000/μL

Use of abciximab within 8 hours, or eptifibatide or tirofiban within 2 hours

Creatinine clearance <20 mL/min

Severe concomitant disease, including HIV, liver disease, life-limiting conditions

Fibrinolytic therapy precludes enrolment in the ticagrelor stratum

Use of omeprazole or esomeprazole in the clopidogrel stratum

Need for chronic anticoagulation

Need for chronic nonsteroidal anti-inflammatory drug use

Unwilling to take contraceptive measures to prevent pregnancy (both sexes)

ACS indicates acute coronary syndrome; DAPT, dual antiplatelet therapy; EKG, electrocardiogram; GI, gastrointestinal; HIV, human immunodeficiency virus; INR, international normalized ratio; LBBB, left bundle branch block; MI, myocardial infarction; NSTEMI, non-ST segment elevation myocardial infarction; plt, platelet; STEMI, ST segment elevation myocardial infarction; TIA, transient ischemic attack; TIMI, Thrombolysis in Myocardial Infarction.

33

Table 4: Bleeding and ischemic endpoints.

Bleeding endpoints

TIMI

Major

- ≥5 g/dL drop in Hgb

- Intracranial hemorrhage

- Fatal hemorrhage

Minor

- 3–4.9 g/dL drop in Hgb

Requiring medical attention

- Medical or surgical treatment

Life-threatening

- Fatal

- Need for IV inotropes

- Requires surgical intervention

- ≥4 U transfusion

- Symptomatic intracranial

ISTH

GUSTO

BARC

Ischemic endpoints

Death

Cardiovascular

- MI

34

- Sudden cardiac death

- Stroke

- Heart failure

- Cardiovascular procedure

- Any hemorrhagic death

- Other

- Undetermined

Non-cardiovascular

Stroke

Focal neurologic deficit >24 hours

Non-localizing or transient symptoms with imaging evidence of stroke

Categorized as hemorrhagic, ischemic, or unknown

MI (universal definition)

Stent thrombosis (ARC definition)

ARC indicates Academic Research Consortium; BARC, Bleeding Academic Research Consortium; GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries; Hgb, hemoglobin; ISTH, International Society on Thrombosis and Haemostasis; IV, intravenous; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

35

Appendix

Executive Committee: C. Michael Gibson (Harvard University, co-chair), E. Magnus Ohman (Duke Clinical Research Institute, co-chair), Matthew T. Roe (Duke Clinical Research Institute), Christoph Bode (University of Freiburg), Stefan James (Uppsala Clinical Research Center), Philippe Gabriel Steg (Université Paris-Diderot, Sorbonne Paris Cité), Robert Welsh (University of Alberta), Alexei Plotnikov (Janssen Research & Development), Hardi Mundl (Bayer HealthCare).

Steering Committee: Diego Ardissino (Parma, Italy), M. Cecilia Bahit (Buenos Aires, Argentina), Hector Bueno (Madrid, Spain), Marc Claeys (Antwerp, Belgium), Jan-Hein Cornel (Alkmaar, the Netherlands), Shinya Goto (Tokai, Japan), Umit Guray (Ankara, Turkey), Christopher Hammett (Brisbane, Australia), Steen Husted (Aarhus, Denmark), Julia Jorgova (Sophia, Bulgaria), Dean Kereiakes (Cincinnati, OH, US), Robert Gabor Kiss (Budapest, Hungary), Gilles Montalescot (Paris, France), Jose Nicolau (Sao Paulo, Brazil), Duk-Woo Park (Seoul, Korea), Alexander Parkhomenko (Kiev, Ukraine), Michael Ruda (Moscow, Russia), David Schneider (Burlington, VE, US), Jindrich Spinar (Brno, Czech Republic), Michal Tendera (Katowice, Poland)

Clinical Events Committee: Thomas J. Povsic (principal investigator), Kris Anderberg (project leader), Nikieia Hayden (chief research coordinator), Keith Dombrowski (neurologist), Christopher B. Fordyce, Patricia Oliveira Guimaraes, Robert W. Harrison, William S. Jones, Bradley J. Kolls (neurologist), Rajendra Mehta, Chiara Melloni, Robert J. Mentz, Sreekanth Vemulapalli, Amit Vora

Data Monitoring Committee: Robert A. Harrington (Stanford University, chair), Bernard J. Gersh (Mayo Clinic), David Faxon (Harvard University), Christian Hamm (Thorax Centre), David J. Moliterno (University of Kentucky), W. Douglas Weaver (Henry Ford Hospital), Janet Wittes (Statistics Collaborative, Inc., Independent Statistician).