Antithrombotic agents for secondary prevention after acute coronary syndromes: A systematic review and network meta-analysis.
BACKGROUND
Nine oral antithrombotic medications currently available in the United States and Europe have been studied in clinical trials for secondary prevention of cardiac events following acute coronary syndrome (ACS). Few combinations of these medications have been directly compared, and studies have used multiple different comparator regimens.


METHODS
We performed a systematic review and network meta-analysis of randomized controlled trials evaluating one or more available oral antithrombotic therapies in patients with ACS or prior myocardial infarction (MI). Co-primary outcomes were all-cause and cardiovascular mortality compared with imputed placebo and aspirin monotherapy.


RESULTS
Forty-seven studies (196,057 subjects) met inclusion criteria and were included in the systematic review. Almost all studies tested either aspirin monotherapy compared with placebo or a combination of antithrombotic agents that included aspirin. Nearly all regimens reduced all-cause and cardiovascular mortality compared with imputed placebo. However, compared with imputed aspirin monotherapy, only combination therapy with aspirin plus ticagrelor was associated with lower cardiovascular mortality (OR 0.80, 95% CI 0.68-0.93), and triple therapy with aspirin, clopidogrel, and very low dose rivaroxaban was associated with lower all-cause mortality (OR 0.67, 95% CI 0.49-0.90). Major bleeding was increased 45-95% with dual antithrombotic therapy, and 2-6-fold with triple therapy.


CONCLUSIONS
Few combinations of antithrombotic therapy were associated with a reduction in mortality compared with aspirin monotherapy, highlighting the difficulty in clinical interpretation of composite ischemic endpoints. Future studies may need to focus on limiting the number of antithrombotic therapies tested in combination to best balance ischemic event reduction and bleeding.
Division of Cardiology, Duke University, Durham, NC, USA; Duke Clinical Research Institute, Duke University, Durham, NC, USA. Electronic address: alexander.fanaroff@duke.edu.
Alexander C
AC
Fanaroff
Duke Clinical Research Institute, Duke University, Durham, NC, USA.
Vic
V
Hasselblad
Division of Cardiology, Duke University, Durham, NC, USA; Duke Clinical Research Institute, Duke University, Durham, NC, USA.
Matthew T
MT
Roe
Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, MA, USA.
Deepak L
DL
Bhatt
Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
Stefan K
SK
James
FACT (French Alliance for Cardiovascular Clinical Trials), DHU FIRE, INSERM Unité 1148, Université Paris-Diderot, Hôpital Bichat, Assistance-Publique-Hôpitaux de Paris, France; NHLI, Imperial College, Royal Brompton Hospital, London, UK.
Ph Gabriel
PG
Steg
Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
C Michael
CM
Gibson
Division of Cardiology, Duke University, Durham, NC, USA; Duke Clinical Research Institute, Duke University, Durham, NC, USA.
E Magnus
EM
Ohman
D054058:Acute Coronary Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D000284:Administration, Oral; D002986:Clinical Trials as Topic / Q000379:methods; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006470:Hemorrhage / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology; D006801:Humans; D055502:Secondary Prevention / Q000379:methods*
D005343:Fibrinolytic Agents
Acute coronary syndrome; Acute myocardial infarction; Antiplatelet agents, antithrombotic agents; Network meta-analysis