Apixaban Again Linked to Less Bleeding in AF Patients

Using apixaban (Eliquis; Bristol-Myers Squibb) for the treatment of atrial fibrillation (AF) is associated with significantly less gastrointestinal bleeding when compared with other direct oral anticoagulants (DOACs), even when used in older adults, new research shows.

The observational study, which includes more than 500,000 patients, also showed there was no difference in the comparative efficacy of the different DOACs, with no one drug having an edge when it came to the risks of ischemic stroke or systemic embolism, intracranial hemorrhage (ICH), or mortality.   

“Our results indicated that apixaban might be preferable to other DOACs because of the lower rate of gastrointestinal bleeding and similar rates of stroke, which warrant confirmation by head-to-head randomized controlled trials,” lead investigator Wallis C.Y. Lau, PhD (University College London, England), told TCTMD. “As with all treatment choices, a wide consideration of all potential risks and benefits with respect to the patient’s profile would be needed when choosing an oral anticoagulant.”

The study is the latest suggesting that apixaban might be safer than some of the other available DOACs. One analysis investigating the safety profile of various DOACs showed that apixaban was best when it came to the risk of gastrointestinal bleeding while rivaroxaban  (Xarelto; Bayer/Janssen) had the least favorable safety profile. An observational study from Iceland confirmed those findings, with researchers reporting that gastrointestinal bleeding was nearly 50% more common with rivaroxaban than with apixaban.

Lau said that while there’s emerging evidence showing that apixaban is associated with less gastrointestinal bleeding compared with rivaroxaban and dabigatran (Pradaxa; Boehringer Ingelheim), not much is known about how it fares against edoxaban (Savaysa; Daiichi Sankyo).     

The new study, published October 31, 2022, in the Annals of Internal Medicine, included 527,226 patients with AF from France, Germany, the United Kingdom, and the United States who started a new DOAC prescription between 2010 and 2019. Of these, 281,320 were treated with apixaban, 172,176 with rivaroxaban, 61,008 with dabigatran, and 12,722 with edoxaban.

Overall, the results favored apixaban for reduced gastrointestinal bleeding when compared with the other DOACs:

• Apixaban versus dabigatran (HR 0.81; 95% CI 0.70-0.94)
• Apixaban versus rivaroxaban (HR 0.72; 95% CI 0.66-0.79)
• Apixaban versus edoxaban (HR 0.77; 95% CI 0.66-0.91)

In a subgroup analysis restricted to patients 80 years and older, the results were the same: less gastrointestinal bleeding with apixaban versus the other DOACs, but no difference in the risks of ischemic stroke or systemic embolism, ICH, or death.

Although the study is observational, Lau said there are a number of strengths, noting that they included a large number of patients from four countries, “which allowed us to examine all four DOACs with unprecedented precision and power.” Additionally, the researchers used “publicly available analysis packages to enhance the transparency and reproducibility of the results in observational studies,” she said. The results, said Lau, are robust, adding that they were backed up by several sensitivity analyses. 

There is at least one randomized, controlled trial currently comparing apixaban against another DOAC. In COBRRA AF, which will include more than 3,000 AF patients, Canadian researchers are looking at the relative safety of apixaban and rivaroxaban, with the primary endpoint defined as the risk of clinically adjudicated relevant bleeding at 12 months. A similar study, known as COBRRA, is being conducted by the same researchers in 2,700 patients with VTE.

Lana Castellucci, MD (University of Ottawa, Canada), who is leading the COBRRA trials, said there is evidence from ARISTOTLE, ROCKET-AF, and other large administrative databases suggesting that apixaban is associated with less bleeding, but these are all indirect comparisons. Observational data from administrative databases have limitations, she said, noting they carry risks of indication and misclassification biases that can skew the results. 

“Despite the appearance of improved safety with apixaban in these studies, there are concerns related to medication adherence and its twice-daily prescribing compared to once-daily rivaroxaban,” she told TCTMD in an email. “COBRRA AF is the first trial comparing DOACs in patients with nonvalvular AF and aims to definitively determine the safest anticoagulant for stroke prevention in AF, while minimizing those limitations and biases given its randomized design.”