Background: Acute Coronary Syndrome (ACS) patients, despite treatment with Dual Anti-
Platelet Therapy (DAPT), have up to 10% risk of recurrent Major Adverse Cardiac Events (MACE) in
the short term.
Methods: Here we review studies using more potent antithrombotic agent combinations to reduce this
risk, namely Triple Therapy (TT) with the addition of an oral anticoagulant, PAR-1 antagonist, or
cilostazol to DAPT (mainly aspirin and clopidogrel), and discuss the limitations of trials to date.
Results: Generally speaking, TT leads to an increase in bleeding. Vorapaxar showed a signal for reducing
ischaemic events, but increased intracranial haemorrhage 3-fold in the subacute phase of ACS, although
remains an option for secondary prevention beyond the immediate subacute phase, particularly if
prasugrel or ticagrelor are not available. Non-Vitamin K Oral Anticoagulants (NOACs) all increased
bleeding, with only modest reduction in MACE noted with low dose rivaroxaban. Rivaroxaban can be
considered combined with aspirin and clopidogrel in ACS patients at high ischaemic and low bleeding
risk, without prior stroke/TIA. The combination of P2Y12 inhibitor and NOAC, without aspirin, looks
promising. DAPT may be replaced, not by TT, but by dual therapy comprising a NOAC with a P2Y12
Conclusion: More potent antithrombotic regimens increase bleeding and should only be considered on
an individual basis, after careful risk stratification. Accurate risk stratification of ACS patients, for both
ischaemic and bleeding risk, is essential to allow individualised treatment.