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Apixaban + P2Y12 inhibitor without aspirin safest combo for most AF cases with ACS or PCI

Pearl Toh
26 Mar 2019
Dr Renato Lopes

Use of the NOAC* apixaban led to less bleeding and hospitalizations compared with vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) who had a recent acute coronary syndrome (ACS) or had undergone percutaneous coronary intervention (PCI) and were on treatment with a P2Y12 inhibitor, reveals the AUGUSTUS study. Furthermore, dropping aspirin from the regimen shields these patients against bleeding risk without significant increase in ischaemic events.

“We have shown that when it comes to treating this high-risk patient population, less may be more,” said lead author Dr Renato Lopes of the Duke Clinical Research Institute in Durham, North Carolina, US who presented the findings at the 2019 ACC Annual Scientific Session. “These results should reassure clinicians that it’s okay not to treat most of these patients with aspirin.”

The dilemma

Choosing an optimal antithrombotic therapy for patients with both AF and ACS or had undergone a PCI is challenging, according to Lopes.

Anticoagulants are indicated for AF patients to prevent stroke and blood clots, but have not been shown to guard against stent thrombosis and are generally not recommended for patients with ACS, he explained. On the other hand, DAPT** has been shown to reduce stent thrombosis and heart attacks associated with ACS but not stroke in patients with AF. Combining anticoagulants and DAPT, however, comes with increased risk of bleeding.

Moreover, most studies on AF therapies have excluded patients with ACS and vice versa, with many ACS treatment trials citing AF as an exclusion criterion — thus creating a knowledge gap on how best to treat patients with both conditions, Lopes pointed out.

To address the quandary    

The multinational AUGUSTUS trial was designed with a 2x2 factorial design: patients were randomized 1:1 to receive apixaban 5 mg b.i.d. (2.5 mg for selected patients) or a VKA (INR*** 2–3) as open-label; patients in each arm were subsequently further randomized to receive aspirin or placebo in a double-blind manner for 6 months. [ACC.19, session 405-08; N Engl J Med 2019;doi: 10.1056/NEJMoa1817083]

Subjects were 4,614 patients (median age 70.7 years, 71 percent male) with AF who had a recent ACS or PCI, in whom treatment with a P2Y12 inhibitor was indicated. The most common P2Y12 used was clopidogrel, reported in 92.6 percent of the patients.

When comparing apixaban vs VKA, the primary endpoint of major or clinically relevant nonmajor bleeding occurred in significantly fewer patients treated with apixaban than VKA (10.5 percent vs 14.7 percent, adjusted hazard ratio [HR], 0.69; p<0.001 for both noninferiority and superiority).

For aspirin vs placebo, aspirin led to a higher rate of bleeding than placebo (16.1 percent vs 9.0 percent, HR, 1.89; p<0.001).

Combining the results from both randomizations showed that the cumulative incidence of bleeding was highest with VKA + aspirin (18.7 percent), followed by apixaban + aspirin (13.8 percent), VKA + placebo (10.9 percent), and apixaban + placebo (7.3 percent).

For the secondary outcome of death or hospitalization, the apixaban group saw a significantly lower incidence rate than the VKA group (23.5 percent vs 27.4 percent, HR, 0.83; p=0.002), while there was no significant difference in the aspirin vs placebo comparison (26.2 percent vs 24.7 percent, HR, 1.08; p=0.20).

Ischaemic events were numerically higher without aspirin (placebo) than with aspirin, although the investigators noted that “the event rates were low and the trial was not adequately powered to assess differences in individual ischaemic outcomes.”

They also acknowledged that being insufficiently large to detect small but potentially meaningful differences in ischaemic events as a limitation of the study.  

“This finding suggests that the price for a significantly lower incidence of bleeding events without aspirin may be a modestly higher risk of coronary ischaemic events,” wrote Lopes and co-authors in a paper simultaneously published in NEJM, who advised that the risk of ischaemia be weighed against bleeding when considering aspirin in these patients.  

Is dropping aspirin good for all AF patients with ACS/PCI?

While the trial provides reassurance that the NOAC apixaban should now routinely be recommended over VKA in the setting of AF with ACS or PCI, the investigators cautioned against extrapolating these results to other NOACs.

“The findings from this trial do not necessarily provide reassuring evidence that early discontinuation of aspirin therapy after an ACS or PCI is warranted in all patients,” wrote Dr Shamir Mehta of McMaster University, Hamilton, Canada in an accompanying editorial. [N Engl J Med 2019;doi: 10.1056/NEJMe1902214]

He urged that clinicians continue to base their clinical decision making on balancing three competing risks: coronary ischaemic events, cardioembolic stroke, and bleeding.

“In patients with a low risk of thrombotic events … or a high risk of bleeding, early omission of aspirin therapy and treatment with a direct oral anticoagulant plus clopidogrel is entirely warranted,” advised Mehta. “However, in patients undergoing complex, multivessel, or high-risk PCI or in those presenting with high-risk ACS, aspirin should probably not be routinely omitted for at least several weeks or longer, depending on bleeding risk.”

“Although guideline committees will now have to grapple with incorporating the results of the AUGUSTUS trial into specific recommendations, it is clear that a one-size-fits-all policy is unlikely to apply in these patients,” he added.

 

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Ivermectin confers benefits in the treatment of COVID-19, with a recent study showing that its use helps reduce the risk of death especially in patients with severe pulmonary involvement.
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