The results of a randomized controlled trial led by Dr. Renato Lopes presented at TCT 2019 and published in the New England Journal of Medicine showed that in patients with atrial fibrillation and a recent acute coronary syndrome or percutaneous coronary intervention who are treated with a P2Y12 inhibitor, an antithrombotic regimen that consists of apixaban without aspirin led to lower rates of bleeding and fewer hospitalizations without a significant difference in ischemic events as compared to a regimen that consists of two antiplatelet agents or a vitamin K inhibitor or both.
Choosing an antithrombotic therapy in patients with atrial fibrillation and a recent acute coronary syndrome or percutaneous coronary intervention is difficult. Unlike oral anticoagulants, antiplatelet agents are indicated for the secondary prevention of a recurrent ischemic event and have been shown to prevent stent thrombosis. However, antiplatelet agents are not as effective as oral anticoagulants in preventing cardioembolic strokes associated with atrial fibrillation. Therefore, it may be necessary to combine oral anticoagulants with antiplatelet medication to simultaneously reduce the risk of stent thrombosis and the risk of a thromboembolic event. Previous trials have demonstrated a reduced risk of bleeding with the direct oral anticoagulant without aspirin as compared to a vitamin K antagonist with aspirin. However, there were no previous trials that directly compared the use of a vitamin K antagonist with a direct oral anticoagulant in patients who are either on dual antiplatelet therapy or a single antiplatelet therapy.
“In patients with atrial fibrillation and a recent acute coronary syndrome or
PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.” – Dr. Renato Lopes, M.D., Ph.D.
The AUGUSTUS trial was a two factorial, randomized controlled trial that randomized patients with atrial fibrillation who had an acute coronary syndrome or percutaneous coronary intervention to either aspirin or placebo and to either a vitamin K antagonist (VKA) or apixaban, a factor Xa inhibitor. As a result, there were four possible treatment arms: (1) Apixaban + Placebo, (2) Apixaban + aspirin, (3) VKA + placebo, (4) VKA + aspirin. Only patients who were planned to be treated with a P2Y12 inhibitor for at least 6 months were enrolled. Patients who were used anticoagulation for an indication other than atrial fibrillation were excluded from the study. The main outcome consisted of a composite of a major bleed, as defined by the International Society on Thrombosis and Hemostasis (ISTH), or a clinically relevant non-major bleed by 6 months. Secondary outcomes included a composite of hospitalization or death, and a composite of death or ischemic events (stroke, myocardial infarction, stent thrombosis or urgent revascularization).
Of the 4,614 patients enrolled in the trial, 2,306 and 2,308 were randomized to apixaban and a VKA respectively. Also, 50% (2,307) were randomized to aspirin and 50% (2,307) were randomized to placebo. There were no significant interactions between the two groups (Aspirin vs placebo and apixaban vs VKA). When comparing the two anticoagulant regimens, major or clinically relevant nonmajor bleeding occurred in 10.5% and 14.7% of patients randomized to apixaban and VKA respectively (HR 0.69, 95% CI 0.58 to 0.81, p <0.001 for both non-inferiority and superiority). When comparing aspirin with placebo, bleeding occurred in 16.1% of patients on aspirin as compared to 9.0% of patients on placebo (HR 1.89, 95% CI 1.59 to 2.24, p <0.001). Patients in the apixaban group had a lower incidence of hospitalization or death as compared to the VKA group (23.5% vs 27.4%, HR 0.83, 95% CI 0.74 – 0.93, p = 0.02) but similar rates of death or ischemic events (14.3% vs 15.3%, HR 0.93, 95% CI 0.75-1.16). When comparing aspirin with placebo, there was no statistically significant difference in the hospitalization or death outcome (65% vs 60.6%, HR 1.08, 95% CI 1.08, 95% CI 0.96-1.12) or hospitalization or ischemic event outcome (13.9% vs 15.7%, HR 0.89, 95% CI 0.71-1.11).
The study has two main findings: (1) Apixaban was associated with a lower risk of bleeding as compared to a VKA; (2) Dual therapy, with a P2Y12 inhibitor and an oral anticoagulant, was associated with a reduced bleeding risk as compared to triple therapy (aspirin + P2Y12 inhibitor + oral anticoagulant). Unlike previous trials, this study was able to independently assess the effect of both a dual therapy vs triple therapy regimen and a VKA vs apixaban regimen. Additionally, a dual therapy regimen with apixaban was not only associated with lower bleeding risk but no significant difference in ischemic event rates between the two groups.
In an interview with Dr. C. Michael Gibson, Professor of Medicine at Harvard Medical School and an interventional cardiologist at Beth Israel Deaconess Medical Center, Dr. Lopes discussed the applicability of these findings in patients who were medically managed. Dr. Lopes said, “It was interesting to see that the benefits that we found that apixaban being safer than warfarin was pretty much preserved in the medically managed patients, in the ACS treated with PCI and also in the elective PCI. So very consistent results across the board. And also the harm that aspirin caused by increasing bleeding by almost two folds was also preserved very consistently across these three subgroups.”
When discussing the implications of this study in the context of previous trials, Dr. Lopes noted, “I think now with a pretty high level of confidence that by the time of discharge, after a few days, I think it is pretty safe and wise for most patients to be discharged with a NOAC and a P2Y12 inhibitor without aspirin.”
However, the study does have its limitations. The time in the therapeutic range for warfarin was lower than in other trials (59% in this study). Additionally, the study was not powered to detect significant differences in the various ischemic outcomes.
Ultimately, this study adds to the currently growing body of evidence that supports the use of dual therapy in most patients.
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