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). Newer oral anticoagulants have been studied for secondary prevention of ACS and of these, a low-dose regimen of rivaroxaban was the only one to show a positive benefit–risk profile. 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 oral anticoagulant to existing antiplatelet therapy.

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

The use of secondary prevention measures, including dual antiplatelet therapy, has reduced the rate of 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 is 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.

Anticoagulants and antiplatelets target different pathways in clot formation.

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

 

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

Newer oral anticoagulants have been studied for secondary prevention of ACS (dabigatran etexilate, apixaban, rivaroxaban and darexaban). Of these, a low-dose regimen of rivaroxaban was the only one to show a positive benefit–risk profile. In the ATLAS ACS 2 TIMI 51 trial, 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 thienopyridine plus ASA or ASA alone (9.1% vs 10.7%; hazard ratio 0.84; p=0.02), but a significant increase in major bleeding (1.8% vs 0.6%; hazard ratio 3.46; p<0.001).246

In 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) US and European guidelines recommend the addition of an oral anticoagulant (vitamin K antagonist, or warfarin specifically) to existing antiplatelet therapy, with a target international normalized ratio of 2.0–2.5 or 2.0–3.0.221, 239, 240 However, careful monitoring of such patients is recommended because of the increased risk of major bleeding. The WOEST study is the first randomized trial to compare clopidogrel with and without ASA in patients receiving oral anticoagulant therapy and undergoing coronary stent placement. In this study, clopidogrel alone was associated with significantly less bleeding (19.5% vs 44.9%; p<0.001) and mortality (2.5% vs 6.4%; p=0.027) at 1 year than when combined with ASA. The composite incidence of death, MI, stroke, target vessel revascularization or stent thrombosis was similar between the study arms, although it was numerically lower for patients who did not receive ASA (11.3% vs 17.7%; p=0.025.247

It should be noted that, based on current evidence, the newer oral anticoagulant drugs given at approved doses for stroke prevention in atrial fibrillation are not recommended to supplement dual antiplatelet therapy.

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