Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial.
BACKGROUND
Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months.


METHODS
In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395.


RESULTS
Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840).


CONCLUSIONS
A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach.


BACKGROUND
Janssen Research & Development and Bayer AG.
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA. Electronic address: ohman001@mc.duke.edu.
E Magnus
EM
Ohman
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
Matthew T
MT
Roe
DHU FIRE, Université Paris-Diderot, AP-HP and Inserm U-1148, Paris, France; NHLI Royal Brompton Hospital, Imperial College London, London, UK.
P Gabriel
PG
Steg
Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
Stefan K
SK
James
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
Thomas J
TJ
Povsic
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
Jennifer
J
White
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
Frank
F
Rockhold
Janssen Research and Development, Raritan, NJ, USA.
Alexei
A
Plotnikov
Bayer AG, Wuppertal, Germany.
Hardi
H
Mundl
Janssen Research and Development, Raritan, NJ, USA.
John
J
Strony
Janssen Research and Development, Raritan, NJ, USA.
Xiang
X
Sun
Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
Steen
S
Husted
3rd Division of Cardiology, Medical University of Silesia, Katowice, Poland.
Michal
M
Tendera
Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Gilles
G
Montalescot
INECO Neurociencias Oroño, Rosario, Santa Fe, Argentina.
M Cecilia
MC
Bahit
Divisione di Cardiologia, Policlinico San Matteo, Pavia, Italy.
Diego
D
Ardissino
Spanish National Centre for Cardiovascular Research, Madrid, Spain.
Héctor
H
Bueno
University Hospital Antwerp, Edegem, Belgium.
Marc J
MJ
Claeys
Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
Jose C
JC
Nicolau
Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar and Dutch Network for Cardiovascular Research (WCN), Netherlands.
Jan H
JH
Cornel
Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan.
Shinya
S
Goto
Department of Cardiology, Military Hospital, Budapest, Hungary.
Róbert Gábor
RG
Kiss
Numune Education and Research Hospital, Department of Cardiology, Ankara, Turkey.
Ümit
Ü
Güray
Division of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Duk-Woo
DW
Park
University of Freiburg, Freiburg, Germany.
Christoph
C
Bode
Mazankowski Alberta Heart Institute and University of Alberta, Edmonton, AB, Canada.
Robert C
RC
Welsh
PERFUSE Study Group, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA, USA.
C Michael
CM
Gibson
D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000368:Aged; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D000077144:Clopidogrel; D017023:Coronary Angiography / Q000379:methods; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D004562:Electrocardiography / Q000379:methods; D065427:Factor Xa Inhibitors / Q000627:therapeutic use; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000069552:Rivaroxaban / Q000008:administration & dosage / Q000627:therapeutic use*; D015912:Thrombolytic Therapy / Q000379:methods; D000077486:Ticagrelor; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000069552:Rivaroxaban; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine; D001241:Aspirin