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When used for patients without atrial fibrillation, the risk of intracranial hemorrhage may be dose dependent for some, but not all, non-vitamin K antagonist oral anticoagulants (NOACs) compared with aspirin, according to a systematic review and meta-analysis.

Using five randomized clinical trials that compared aspirin and non-vitamin K antagonist oral anticoagulants in this setting, the researchers found the intracranial hemorrhage risk increased for those taking 15 to 20 mg of rivaroxaban (Xarelto) daily (OR 3.31, 95% CI 1.42-7.72).

However, these increased risks were not found among those taking 10 mg of rivaroxaban daily or 5 mg of apixaban (Eliquis) twice daily, Wen-Yi Huang, MD, PhD, of Chang Gung University College of Medicine in Puzi, Taiwan, and colleagues reported in JAMA Neurology.

Despite the "few (even single) large randomized clinical trials" for these comparisons, the results "might provide evidence to inform the potential design and conduct of future NOAC trials beyond atrial fibrillation," noted the researchers.

Moreover, "although such results should be interpreted with caution," they suggested "[b]ased on these findings, only patients with atrial fibrillation should be considered for administration of 15 to 20 mg of rivaroxaban once daily."

Santosh Murthy, MD, MPH, of New York-Presbyterian Hospital, agreed with that conclusion in commenting to 番茄社区 on the study, in which he was not involved.

"Recent randomized trials have shown that rivaroxaban does not offer any additional thromboembolic benefit compared to aspirin, while apixaban clearly is superior to aspirin in preventing strokes, albeit in different disease settings," he noted.

"Furthermore, an ancillary study of the AVERROES trial comparing brain MRI scans of patients on apixaban versus those on aspirin found no difference in rates of subclinical microhemorrhages," he added. "Taken together, these results favor starting low dose apixaban when strong indications for anticoagulation exist."

Huang and co-authors used research data collected from PubMed, Embase, CENTRAL, and clinicaltrials.gov that compared the endpoints of NOAC use versus aspirin use.

The findings indicate the following risk of intracranial hemorrhage versus aspirin:

• 10 mg of rivaroxaban taken once per day or 5 mg taken two times a day (three trials, OR 1.43, 95% CI 0.93-2.21)
• 5 mg of apixaban twice daily (one trial, OR 0.84, 95% CI 0.38-1.88)

The study also showed that 15 mg to 20 mg of rivaroxaban each day was linked with an increased risk of fatal bleeding (two trials, OR 2.37, 95% CI 1.30-4.29). On the other hand, 10 mg of rivaroxaban each day or 5 mg taken twice a day (three trials, OR 1.47, 95% CI 0.72-2.97) and 5 mg of apixaban taken twice per day (one trial, OR 0.66, 95 % CI 0.19-2.35) were not linked with an increased risk.

Increased risk of major bleeding compared with aspirin was seen with 15 mg to 20 mg dose of rivaroxaban each day (two trials, OR 2.64, 95% CI 1.68-4.16) and a 10 mg dose of rivaroxaban once a day or 5 mg twice per day (three trials, OR 1.56, 95% CI 1.31-1.85).

Murthy pointed out that several aspects of the study stood out. The study is one of the first "to collectively assess published data on bleeding risk between NOACs and aspirin, for indications other than atrial fibrillation," explained Murthy.

The researchers acknowledged the limitations of their work including moderate quality of the evidence and lack of an ethnic subgroup analysis, although intracerebral hemorrhage contributes to a larger number of strokes in Asian than in white populations.

Moreover, the investigators admit that they "were only able to use data on major bleeding provided by the original trials,which used a variety of differing definitions," Huang and co-authors wrote. "Because major bleeding was the secondary endpoint of this study and the differences in definitions was not substantial, this likely made little difference in the overall results of this meta-analysis," they added.

The authors concluded further random clinical trials are need to compare outcomes of select NOACs in specific doses versus aspirin for patients without atrial fibrillation but with potential sources of cardiac emboli that could lead to stroke.

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