Essence of this Article

The use of secondary prevention measures, including dual antiplatelet therapy, has reduced the rate of myocardial infarction (MI), stroke and death from cardiovascular causes. However, there is also a rationale for combining antiplatelets and anticoagulants in the secondary prevention of acute coronary syndrome (ACS). Novel oral anticoagulants (OACs) have been studied for secondary prevention of ACS, and of these, a low-dose regimen of rivaroxaban was the only novel OAC to show a positive benefit–risk profile. This has led to the approval of rivaroxaban in Europe (but not in the United States [US]) as an adjunct to standard antiplatelet therapy for prevention of atherothrombotic events in selected patients who have experienced a recent ACS event with elevated cardiac biomarkers and who do not have a history of stroke or transient ischaemic attack. In patients who have experienced an ACS event and have an indication for the use of long-term anticoagulation therapy, US and European guidelines recommend the addition of an OAC to existing antiplatelet therapy for limited time periods owing to the elevated risk of bleeding.

Anticoagulants in combination with antiplatelets in the secondary prevention of acute coronary syndrome

Anticoagulants and antiplatelets target different pathways in clot formation. ADP, adenosine diphosphate; ASA, acetylsalicylic acid; GP, glycoprotein; VKA, vitamin K antagonist.

The use of secondary prevention measures, including dual antiplatelet therapy, has reduced the rate of myocardial infarction (MI), stroke and death from cardiovascular causes to approximately 10% in the 12 months after an ACS event,231, 232 and strategies that further improve outcomes for patients are still an active area of research.

Parenteral anticoagulation in the acute ACS setting has contributed to improved survival. There is also a rationale for combining antiplatelets and anticoagulants in the secondary prevention of ACS.

The thrombus responsible for an ACS event forms via a dual pathway process:221

  • Platelet activation
  • Thrombin generation

Therapeutic strategies that include only antiplatelet agents target one mechanism involved in clot formation; a regimen that also involves anticoagulants will address both pathways.

Further support for the long-term use of anticoagulants after an ACS event comes from the fact that thrombin generation, which plays an important role in the final stage of fibrin production, is increased at the time of the event and remains at a high level for a long period of time.224

Bleeding events occur more frequently with dual antiplatelet therapy than with single antiplatelet therapy.229 Early trials of antiplatelet and anticoagulant therapy for the secondary prevention of ACS used the vitamin K antagonist warfarin, which further increased the risk of bleeding.245 As a result, although such regimens did decrease rates of thromboembolic events, they are not widely used for secondary prevention after an ACS event owing to an unclear benefit–risk profile.221, 222

Novel OACs, including dabigatran, apixaban, rivaroxaban and darexaban, have been studied for secondary prevention of ACS. The only one of these novel OACs to show a positive benefit–risk profile was a low-dose regimen of rivaroxaban. The results of the ATLAS ACS 2 TIMI 51 trial showed that in patients treated with standard antiplatelet therapy (thienopyridine plus ASA or ASA alone), treatment with rivaroxaban 2.5 mg twice daily led to a significant reduction in the composite of cardiovascular death, MI and stroke over 24 months compared with placebo (9.1% vs 10.7%; hazard ratio 0.84; p=0.02). As expected, the rate of major bleeding was significantly increased with rivaroxaban versus placebo (1.8% vs 0.6%; hazard ratio 3.46; p<0.001).246 However, in selected patients with elevated biomarkers and no history of stroke or transient ischaemic attack, the rate of fatal bleeding with rivaroxaban 2.5 mg twice daily was similar to placebo (0.1% vs 0.3%). Moreover, in this patient subgroup, treatment with rivaroxaban 2.5 mg twice daily significantly reduced cardiovascular mortality and all-cause mortality (by 45% and 42%, respectively) compared with placebo.547 Based on this, rivaroxaban 2.5 mg twice daily has been approved in Europe (but not in the US) as an adjunct to standard antiplatelet therapy with thienopyridine plus ASA or ASA alone, for prevention of atherothrombotic events in patients who have experienced a recent ACS event and have elevated cardiac biomarkers and no history of stroke or transient ischaemic attack.80

The management of patients who have experienced an ACS event and have an indication for the use of long-term anticoagulation therapy (e.g. atrial fibrillation, prior venous thromboembolism or mechanical heart valves) is challenging because combined anticoagulant and single or dual antiplatelet therapies are associated with incremental increases in the risk of major bleeding.32 US and European guidelines recommend the addition of an OAC (vitamin K antagonist, or warfarin specifically) to existing dual antiplatelet therapy, with a target international normalized ratio of 2.0–2.5.221, 222, 545, 546, 549, 550 The use of novel OACs at their lowest tested dose for stroke prevention has been suggested in the most recent European guidelines on myocardial revascularization.551 However, these guideline recommendations are largely based on expert opinion as there are only very limited data available on the optimal antithrombotic management of these patients. Owing to the increased risk of bleeding, patients receiving combined anticoagulant and antiplatelet should be closely observed for signs of bleeding, and ‘triple therapy’ (anticoagulant and dual antiplatelet therapy) should be used for a limited time period only.221, 222, 545, 546, 549-551 Moreover, prasugrel or ticagrelor should not be used as part of triple therapy given the greater risk of major bleeding with these agents compared with clopidogrel.551 A joint consensus document from the European Society of Cardiology (ESC) Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) provides specific recommendations on the duration of combined anticoagulant and single or dual antiplatelet therapy, dependent on a patient’s stroke risk, their bleeding risk, and the clinical setting (elective percutaneous coronary intervention or urgent percutaneous coronary intervention).552

One potential antithrombotic management strategy for patients who have experienced an ACS but have an indication for long-term anticoagulation is dual therapy with anticoagulant plus single antiplatelet therapy. This approach was investigated in the WOEST study, which assessed the safety of traditional triple therapy (dose-adjusted vitamin K antagonist (VKA) plus dual antiplatelet therapy [ASA +clopidogrel]) versus dual therapy (VKA plus single antiplatelet therapy [clopidogrel]). Results showed that patients receiving VKA plus single antiplatelet therapy had similar efficacy outcomes to patients receiving VKA plus dual antiplatelet therapy, but experienced significantly fewer bleeding events and lower mortality rates. The implications of the WOEST trial are limited by the small number of patients enrolled (making it exploratory in nature) and thus, larger studies are needed to confirm the results.247