NEW ORLEANS — An antithrombotic regimen of apixaban plus a P2Y12 inhibitor such as clopidogrel lowered bleeding events and hospitalizations compared to warfarin plus clopidogrel in a cohort of patients with atrial fibrillation (AFib) and a recent acute coronary syndrome (ACS) or PCI, according to results of the AUGUSTUS trial.
There was an additional reduction in bleeding events when aspirin was avoided as a concurrent therapy.
“We have shown that when it comes to treating this high-risk patient population, less may be more,” said lead author Renato D. Lopes, MD, PhD, with Duke Clinical Research Institute, in a press release. “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. These results should reassure clinicians that it’s OK not to treat most of these patients with aspirin.”
Lopes presented the trial March 17 at the American College of Cardiology’s scientific sessions, and the findings were published simultaneously in the New England Journal of Medicine.
The study used a 2x2 factorial design in an effort to answer two important clinical questions: whether the non-vitamin K oral anticoagulant (NOAC) apixaban is superior to the vitamin K antagonist (VKA) warfarin for reducing bleeding, and also whether patients fare better on double or triple therapy (aspirin, an anticoagulant and a P2Y12 inhibitor).
Lopes et al. randomly assigned 4,614 patients with AFib and a recent ACS or PCI to either warfarin or apixaban in addition to background P2Y12 inhibitor therapy. They also randomly assigned patients in both groups to either receive aspirin or a matching placebo for six months.
At six months, 10.5 percent of the patients receiving apixaban experienced a clinically relevant bleeding episode compared to 14.7 percent of those receiving warfarin—a relative reduction of 31 percent. Also, 16.1 percent of the patients who received aspirin met this bleeding endpoint, versus 9 percent of those receiving a placebo—an 89 percent difference.
Notably, foregoing aspirin therapy didn’t lead to a significant increase in ischemic events, hospitalizations or deaths, although there was a numerical trend toward a higher rate of ischemic events with placebo (7.3 percent) versus aspirin (6.5 percent). Ischemic events included stroke, myocardial infarction, urgent revascularization and definite or probable stent thrombosis. The stroke rate was cut in half with apixaban versus warfarin.
“This is perhaps the last nail in the coffin for aspirin and warfarin going forward” for this patient population, said Dhanunjaya Lakkireddy, MD, executive director of the Kansas City Heart Rhythm Institute and Research Foundation, who wasn’t involved in the study.
“It was very reassuring to see that the ischemic events were not significantly different and that you can actually get away with doing a PCI using a NOAC like apixaban along with a non-aspirin type of antiplatelet therapy. … It clearly shows the point that the shotgun approach of multiple targets for warfarin is not going to be that helpful, and I clearly see that as the cost of these drugs continue to come down, the adaptation and usage of NOACs is significantly going to improve and improve our patient outcomes.”
The death rates in the apixaban and warfarin groups were similar, but those treated with the NOAC were less likely to hospitalized over six months of follow-up (22.5 percent vs. 26.3 percent). Lopes et al. calculated 26 patients would need to be treated with apixaban rather than warfarin to prevent one death or hospitalization.
Study co-author John H. Alexander, MD, MHS, said the trial has the potential to be practice-changing. He agreed with Lakkireddy that warfarin is probably best to avoid in these high-risk patients, but believes more work is needed before ruling out aspirin for all of them.
“I think it has certainly convinced me that there’s not a role to use VKA in patients who need antiplatelet therapy and have AFib, so other than costs—because the NOACs are more expensive—VKA is pretty clearly now associated with worse outcomes,” Alexander said. “I think we still have more work to do to tease out are there some patients who should get aspirin. … That’s going to take some more exploration, so maybe some very high-risk stent thrombosis patients should still be getting aspirin.”
The authors wrote in NEJM that their results are in concordance with North American guidelines, which recommend this population of patients takes a newer NOAC, rather than warfarin, in addition to a P2Y12 inhibitor. However, European guidelines still recommend triple antithrombotic therapy, Lopes et al. noted.