The AUGUSTUS trial was designed to guide clinicians in treating patients with complex heart problems who are typically left out of other clinical trials. Results were presented Sunday at the 68th Scientific Session of the American College of Cardiology, held in New Orleans, Louisiana.
A trial designed to find the best drug regimen to treat patients with complex heart problems—such as atrial fibrillation (AF) with acute coronary syndrome (ACS)—has found that the novel oral anticoagulant (NOAC) apixaban, in combination with an antiplatelet drug, such as clopidogrel bisulfate, offered the safest choice over combinations that included older anticoagulants, such as warfarin, or aspirin.
The AUGUSTUS trial, presented Sunday at the 68th Scientific Session of the American College of Cardiology, was designed to guide clinicians who face a tough balancing act with these complex patients; individuals who have the combined heart conditions examined in this study are rarely included in randomized clinical trials, simply because they have multiple conditions.
The trial studied 4614 patients with AF from 33 countries, each of whom either had ACS or had undergone an percutaneous coronary intervention (PCI). Patients’ median age was 70, and 71% were men.
As explained by the study’s lead author, Renato D. Lopes, MD, PhD, of the Duke Clinical Research Institute, Duke University School of Medicine, a patient’s AF calls for an anticoagulant like apixaban (Eliquis) to prevent blood clots or strokes. But these drugs have not been shown to prevent blood clots in stents, and they are typically not recommended for patients with ACS. Meanwhile, aspirin and an antiplatelet therapy like clopidogrel (Plavix) has been the standard to prevent heart attacks and stent thrombosis for those with ACS, but this combination has not been shown to reduce stroke for patients with AF.
Worst of all, using a NOAC, aspirin, and an antiplatelet drug together might raise bleeding risks. Because of this, AF patients been excluded from ACS trials. For the first time, AUGUSTUS would study these scenarios, including what happened when patients didn’t take aspirin.
According to a paper simultaneously published in New England Journal of Medicine, the 2-by-2 factorial design worked as follows: patients were randomly assigned to receive apixaban or a vitamin K antagonist, such as warfarin, and to receive either aspirin or a placebo. Researchers said patients knew if they were receiving apixaban or the vitamin K antagonist, but the assignment of aspirin or placebo was double-blind. Dose adjustments of the open-label portion of the drug assignments were made based on patients’ age, weight, and creatinine level.
Patients were treated for 6 months. According to the paper:
Based on these findings, the authors say that AUGUSTUS confirms the safety and efficacy of apixaban compared with vitamin K antagonists. Results show that patients with AF who take a dose recommended for their condition find “that the effect of avoiding aspirin on the incidence of bleeding events seems to be even greater than the benefit of using apixaban instead of (warfarin).”
Overall, the authors concluded, “Our results support the use of a regimen of apixaban with a P2Y12 inhibitor (an antiplatelet therapy), most commonly clopidogrel, without aspirin in a broad population of patients with atrial fibrillation and recent acute coronary syndrome or PCI.”
“We have shown that when it comes to treating this high-risk patient population, less may be more,” lead author Lopes said in a statement. “These results should reassure clinicians that it’s okay not to treat most of these patients with aspirin.”
In an interview with The American Journal of Managed Care, Lopes said trials like AUGUSTUS are important to do once researchers and clinicians have gained a working knowledge of a new drug. The patients in this study had a high risk of bleeding and a high risk of stroke; they could not have been included in a phase 3 study for an FDA approval, because it would have been difficult to learn if the drug was working. But in the real world, patients with AF have multiple comorbidities, and clinicians can't be left to guess. "The timing is critical," he said. "These patients are in front of you, and you need to treat them."
AUGUSTUS is important, Lopes said, because "it fills in those clinical gaps."
Bristol-Myers Squibb and Pfizer provided funding for the study.
Lopes RD, Heizer G, Aronson G, et al, for the AUGUSTUS Investigators. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation [published online March 17, 2019.]. N Engl J Med. DOI: 10.1056/NEJMoa1817083.