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

Abstract

Background: 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.

Keywords: Acute coronary syndrome; Antiplatelet therapy; Meta-analysis; Myocardial infarction; Oral anticoagulants.

Figure 1

Flow chart of literature review.

Figure 2

Effect of adding an oral anticoagulant to single (aspirin) or dual (aspirin and clopidogrel) antiplatelet therapy on rate of major adverse cardiovascular events after an acute coronary syndrome. Effect estimates of individual study arms with horizontal lines representing 95% CI; coloured diamonds, subtotal effects and 95% CI from random effects models for direct thrombin inhibitors and factor Xa inhibitors, respectively, and overall effects in addition to single and dual antiplatelet therapy; Open diamonds, subtotal summary effects and 95% CI from random effects models per trial; HR, hazard ratio; CI, confidence interval; ARR, absolute risk reduction (risk difference); b.i.d., twice daily; o.d., once daily; MACE, major adverse cardiovascular events, i.e. a composite of all-cause mortality, myocardial infarction and stroke.

Figure 3

Effect of adding an oral anticoagulant to single (aspirin) or dual (aspirin and clopidogrel) antiplatelet therapy on rate of clinically significant bleeding events after an acute coronary syndrome. Effect estimates of individual study arms with horizontal lines representing 95% CI; coloured diamonds, subtotal effects, and 95% CI from random effects models for direct thrombin inhibitors and factor Xa inhibitors, respectively, and overall effects in addition to single and dual antiplatelet therapy; open diamonds, subtotal summary effects, and 95% CI from random effects models per trial; HR, hazard ratio; CI, confidence interval; ARR, absolute risk reduction (risk difference); b.i.d., twice daily; o.d., once daily.

Figure 4

Effect of adding an oral anticoagulant to single (aspirin) or dual (aspirin and clopidogrel) antiplatelet therapy on rates of major adverse cardiovascular events (A) and TIMI major bleeding events (B) after an acute coronary syndrome in a subgroup of phase III studies. Effect estimates of individual study arms with horizontal lines representing 95% CI; coloured diamonds, subtotal effects, and 95% CI from random effects models for direct thrombin inhibitors and factor Xa inhibitors, respectively, and overall effects in addition to single and dual antiplatelet therapy; open diamonds, subtotal summary effects, and 95% CI from random effects models per trial; HR, hazard ratio; CI, confidence interval; ARR, absolute risk reduction (risk difference); b.i.d., twice daily; o.d., once daily; MACE, major adverse cardiovascular events, i.e. a composite of all-cause mortality, myocardial infarction and stroke.

Figure 5

Association of effects of adding an oral anticoagulant to single (aspirin) or dual (aspirin and clopidogrel) antiplatelet therapy on rate of MACE with effects on rate of clinically significant bleeding events after an acute coronary syndrome. Random-effects meta-regression, stratified on number of antiplatelet drugs. The area of a circle representing a study arm is proportional to its weight in the random-effects model. Shaded areas are 95% confidence intervals. HR, hazard ratio; MACE, major adverse cardiovascular events; Riv, rivaroxaban; Dab, dabigatran, Api, apixaban; Dar, darexaban; Xim, ximelagatran; b.i.d., twice daily; o.d., once daily; number denotes strength in milligram.