Real-world Analysis Suggests Apixaban Is Safest of the NOACs, Even for Patients With A-fib

In a large, real-world study of non-vitamin K antagonist oral anticoagulants (NOACs), apixaban was associated with the lowest risks of bleeding compared with warfarin. But for patients on low doses of apixaban, all-cause mortality was increased in contrast to warfarin, researchers found.

The study included patients both with and without atrial fibrillation. This is important, its authors say, because only about half of anticoagulant users have A-fib and there is a dearth of well-powered observational data on the newer agents versus warfarin in other settings.

“The report provides reassurance in safety of direct oral anticoagulants for patients with atrial fibrillation, and for patients with other indications for prescribing,” lead author Yana Vinogradova, PhD (University of Nottingham, England), told TCTMD in an email.

Published online July 4, 2018, in the BMJ, the study included nearly 200,000 primary care patients from two large databases who were prescribed either warfarin, dabigatran (Pradaxa; Boehringer Ingelheim), rivaroxaban (Xarelto; Bayer/Janssen), or apixaban (Eliquis; Bristol-Myers Squibb).

Among all patients, those taking apixaban had the lowest risks of major, intracranial, and GI bleeding in comparison to warfarin.

In patients with A-fib, apixaban was associated with less major bleeding (adjusted HR 0.66; 95% CI 0.54-0.79) and intracranial bleeding (adjusted HR 0.40; 95% CI 0.25-0.64). Dabigatran also was associated with a decreased risk of intracranial bleeding (adjusted HR 0.45; 95% CI 0.26-0.77).

Similarly, in those without A-fib, apixaban reduced major bleeding (adjusted HR 0.60; 95% CI 0.46-0.79), any GI bleeding (adjusted HR 0.55; 95% CI 0.37-0.83), and upper GI bleeding (adjusted 0.55; 95% CI 0.36 to 0.83) compared with warfarin, and rivaroxaban also was associated with less risk of intracranial bleeds (adjusted HR 0.54; 95% CI 0.35-0.82). Dabigatran and rivaroxaban were associated with higher risks for all GI bleeding compared with apixaban.

There were no differences between any of the groups in occurrence of primary ischemic stroke or primary venous thromboembolism, although among patients without A-fib, rivaroxaban was associated with a higher risk than warfarin (adjusted HR 1.49; 95% CI 1.33-1.68), while dabigatran and apixaban reduced the risk relative to warfarin.

Low-Dose Apixaban Linked to Higher Mortality

Importantly, compared with warfarin, all-cause mortality was higher among patients with A-fib on rivaroxaban (adjusted HR 1.19; 95% CI 1.09-1.29) and among those on reduced doses of apixaban (adjusted HR 1.27; 95% CI 1.12-1.45). Among those without A-fib, there again was greater all-cause mortality with rivaroxaban (adjusted HR 1.51; 95% CI 1.38-1.66) and lower doses of apixaban (adjusted HR 1.34; 95% CI 1.13-1.58).

To TCTMD, Vinogradova said the mortality findings are in line with previous Danish studies on patients with atrial fibrillation, including one in which reduced doses of rivaroxaban and apixaban were associated with an increased risk of death compared warfarin. 

“For patients who were prescribed anticoagulants for other reasons, increased risks for higher and for lower doses of rivaroxaban and for lower doses of apixaban are novel findings,” Vinogradova said.

Patients in the current study who were taking lower doses of an anticoagulant were more likely than those who were taking regular doses to be older and to have more comorbidities, previous events, and more concomitant drug therapy.

“An important limitation for our study and all earlier observational studies is the lack of information on patient adherence to their prescribed drugs, which may lead to possible misclassifications of exposure,” Vinogradova and colleagues write. Another key consideration, they add, is that because of the constant monitoring required in warfarin users, bleeding may be detected and reported more often than in those on NOACs, but may not necessarily be more frequent.