AUGUSTUS: Less Bleeding and Fewer Hospitalizations Without Significant Differences in Ischemic Events With Apixaban and No Aspirin in Patients With AFib and ACS ACC 2019: Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation

ACC 2019: 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 the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both, according to results of the AUGUSTUS trial presented at ACC.19 in New Orleans. The results were also published simultaneously in the New England Journal of Medicine.

Appropriate antithrombotic regimens for patients with atrial fibrillation who have acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. Choosing antithrombotic therapy for patients with atrial fibrillation who have acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) is challenging. Oral anticoagulation is in­dicated to prevent stroke and systemic embolism in patients with atrial fibrillation but has not been shown to prevent stent thrombosis and is gener­ally not indicated for secondary prevention after acute coronary syndrome. Dual antiplatelet ther­apy is proven to reduce the incidence of recurrent ischemic events and stent thrombosis but is less effective in reducing the incidence of cardioem­bolic stroke associated with atrial fibrillation. The combination of antithrombotic agents, par­ticularly triple therapy with oral anticoagulation and dual antiplatelet therapy, increases the risk of bleeding. Thus, an oral antithrombotic regimen with an acceptable benefit-risk profile would be useful in the treatment of patients with atrial fi­brillation and concomitant acute coronary syn­drome or PCI. Regimens including non–vitamin K antagonist oral anticoagulants appear to offer a number of advantages over vitamin K antagonists, including the potential for less bleeding. Moreover, the combination of NOACs and thienopyridines also have been found to have a synergistic effect.

In this international trial led by Dr. Renato D. Lopes with an elegant two-by-two factorial design, the investigators randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had under­gone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. Trial enrollment included a total of 4614 patients (median age, 70.7 years; 29 percent women) from 33 countries. The results showed no significant in­teractions between the two randomization factors on the primary or secondary out­comes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspi­rin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Therefore, aspirin was found to increase bleeding by 89% with an absolute increase of over 7%, with an NNH of 14. Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of isch­emic events. Patients in the aspirin group had an incidence of death or hospitaliza­tion and of ischemic events that was similar to that in the placebo group. The investigators, however, acknowledged certain limitations to their trial. The time in the therapeutic range for the patients who received a vitamin K antagonist was modestly lower than in some previous randomized trials of stroke preven­tion involving patients with atrial fibrillation. This finding reflected real-life challenges with vi­tamin K antagonist treatment, especially in an in­ternational setting over a relatively short (6 month) period of time. Second, the trial was not designed to be large enough to detect potentially clinically im­portant differences in less common but impor­tant individual ischemic outcomes. Lopes, however, reiterated that there was compelling evidence supporting the fact that 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 as compared to regimens that included a vitamin K antagonist, aspirin, or both.

Prior to this, the WOEST (What Is the Optimal Antiplate­let and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) tri­al showed a reduction in both bleeding and ischemic events by discontinuing aspirin in patients receiving oral anticoagulation with a vitamin K antagonist and undergoing PCI, although the trial was small and underpowered for such an analysis. In context of this, the investigators stated, “Our results confirm and extend these results in a high-risk population of patients with atrial fibrillation by showing a lower incidence of major or clinically relevant nonmajor bleeding among patients treated without aspirin than among those treated with aspirin, but we found that the inci­dence of ischemic events was not significantly lower among patients who did not receive aspirin. We observed a greater num­ber of coronary ischemic events among patients who did not take aspirin than among those who did, although event rates were low and the trial was not adequately powered to assess differences in individual ischemic outcomes. Although this analysis should be considered exploratory, similar trials have shown a similar pattern of numerically more coronary ischemic events when aspirin was omitted. Thus, when clinicians consider aspirin as a component of antithrombotic therapy after PCI in patients with atrial fibrillation, a potential small absolute decrease in the risk of coronary ischemic events needs to be weighed against a larger absolute increase in the risk of clinically significant bleeding.” Clearly, “We have shown that when it comes to treating this high-risk patient population, less may be more,” said lead author Renato D. Lopes. “Our findings show that the combination of apixaban and a drug such as clopidogrel – without aspirin – is the safest treatment regimen for this difficult-to-treat group of patients, without significantly increasing ischemic events such as heart attacks, strokes and blood clots.” Referring to the numeric increase in ischemic events, in an interview with Dr. C. Michael Gibson, Dr. Lopes acknowledged, “These ischemic events are important, we always want to utilize that. If you look at even the numerically higher rates of ischemic events in placebo even without Aspirin, when you put it into perspective, you have to treat 250 patients to prevent 1 stent thrombosis if that was true. But the price to pay is 15 bleeding events, which may be fatal.” Also bringing up another important point about their discussion, Dr. Gibson emphasized, “These discussions that we are having are very important for the evidence is off label. So we’re not here to promote the use of these drugs in any kind of way. Look at the label in your own country and across the world. Physicians have to be physicians and use their judgment about balancing ischemic risk and bleeding risk and that calculus may be different in different patients. People now have data to support their decision in one way or the other. With all the evidence, we have a higher level of certainty to drive decision making.”

To view the interview with Dr. C. Michael Gibson, click here.

To view the slides, click here.