New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis.

Oldgren J, Wallentin L, Alexander JH et al.
Eur Heart J. 2013 Mar 6.

Background

Patients with acute coronary syndromes (ACS) remain at risk of recurrent ischaemic events, despite evidence-based care including revascularisation and dual antiplatelet therapy. Oral vitamin K antagonists have been shown to prevent recurrent ischaemic events after ACS, but come with a substantial risk of bleeding and are difficult to use because of the multiple interactions with other drugs and food, and because of the need for laboratory monitoring [1,2].
New oral anticoagulants (NOACs) have been tested as antithrombotic therapy after ACS, in combination with single or dual antiplatelet therapy. All phase II trials showed a definite increase in the incidence of bleeding when oral anticoagulation was combined with antiplatelet therapy, whereas efficacy was less clear [3-6]. Some studies have had to be terminated prematurely, due to the increased risk of bleeding without evidence of efficacy. Thus, the overall benefit of adding NOACs  to antiplatelet treatment after ACS is unknown.
This systematic review and meta-analysis evaluates the efficacy and safety of adding direct thrombin or factor-Xa inhibition by any of the NOACs to single (aspirin) or dual (aspirin and clopidogrel) antiplatelet therapy. Seven double-blind, placebo-controlled phase II and III trials yielded data from 30866 patients with a recent ACS for analysis. Outcome measures are major adverse cardiovascular events (MACE) and clinically significant bleeding events.

Main results

• Additional treatment with an oral anticoagulant In patients receiving single antiplatelet therapy, decreased the rate of MACEs on average by 30%. The rate of bleeding events increased with 79%.
• In patients treated with dual antiplatelet therapy , the addition of an oral anticoagulant decreased the rate of MACEs by 13%. Additional treatment with an anticoagulant led to an increase in clinically significant bleeding rate by 134%.
• The gain in protection against MACEs was larger when adding an anticoagulant to single than to dual antiplatelet therapy (P = 0.03).
• Effects on bleeding were smaller when adding an anticoagulant to single than to dual antiplatelet therapy (P = 0.02).

Conclusion

Addition of a new NOAC to antiplatelet therapy led to a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced in patients receiving dual antiplatelet therapy. Little heterogeneity was seen between different anticoagulant treatments and different trials. The reduction in ischemic events by NOACs was most promising when added to single antiplatelet therapy. However, single antiplatelet treatment is rarely used because many ACS patients are treated with percutaneous coronary interventions and stents, for which guidelines recommend dual antiplatelet treatment. Further studies evaluating NOACs in combination with effective single antiplatelet therapy or shorter duration of triple antithrombotic therapy are warranted.

References

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Oral anticoagulation in addition to antiplatelet treatment after an acute coronary syndrome might reduce ischaemic events but increase bleeding risk. We performed a meta-analysis to evaluate the efficacy and safety of adding direct thrombin or factor-Xa inhibition by any of the novel oral anticoagulants (apixaban, dabigatran, darexaban, rivaroxaban, and ximelagatran) to single (aspirin) or dual (aspirin and clopidogrel) antiplatelet therapy in this setting.

Methods and results
All seven published randomized, placebo-controlled phase II and III studies of novel oral anticoagulants in acute coronary syndromes were included. The database consisted of 30 866 patients, 4135 (13.4%) on single, and 26 731 (86.6%) on dual antiplatelet therapy, with a non-ST- or ST-elevation acute coronary syndrome within the last 7-14 days. We defined major adverse cardiovascular events (MACEs) as the composite of all-cause mortality, myocardial infarction, or stroke; and clinically significant bleeding as the composite of major and non-major bleeding requiring medical attention according to the study definitions. When compared with aspirin alone the combination of an oral anticoagulant and aspirin reduced the incidence of MACE [hazard ratio (HR) and 95% confidence interval 0.70; 0.59-0.84], but increased clinically significant bleeding (HR: 1.79; 1.54-2.09). Compared with dual antiplatelet therapy with aspirin and clopidogrel, adding an oral anticoagulant decreased the incidence of MACE modestly (HR: 0.87; 0.80-0.95), but more than doubled the bleeding (HR: 2.34; 2.06-2.66). Heterogeneity between studies was low, and results were similar when restricting the analysis to phase III studies.

Conclusion
In patients with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy.