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The increased risk of hemorrhage was not revealed in 5-mg and 10-mg doses, implying a dose-dependent effect for rivaroxaban.
Meng Lee, MD
The administration of rivaroxaban can substantially increase the risk of intracranial hemorrhage in higher doses—implying a dose-dependent effect for the non-vitamin K antagonist oral anticoagulant (NOAC).
New results of a systematic review of 5 clinical trials that were ≥3 months in length assessed the comparative risk of intracranial hemorrhage with individual NOACs and aspirin and found that doses of 15 mg to 20 mg of rivaroxaban was shown to be associated with an increased risk of hemorrhage (odds ratio [OR], 3.31; 95% CI, 1.42 to 7.72; P for heterogeneity = .36) compared to aspirin in 2 trials. The research team was led by Wen-Yi Huang, MD, PhD, from the Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, in Keelung Branch, Taiwan.
"When compared to aspirin the higher rivaroxaban dose of 15-20 mg once daily greatly increases the risk of intracranial hemorrhage, whereas neither the lower dose of rivaroxaban (10 mg) nor apixaban 5 mg twice-daily confer such comparative risk," Lee told NeurologyLive. "Rivaroxaban 15-20 mg once daily possessed substantial higher risks of intracranial hemorrhage than aspirin, its use in people without atrial fibrillation could not be encouraged."
In total, the final principal analysis included data from 39,398 enrolled participants from the AVERROES, EINSTEIN CHOICE, COMPASS (CVD and PAD), and NAVIGATE ESUS trials. The trials that were analyzed included multiple comparisons. They were a comparison of 5-mg apixaban twice-daily and aspirin in patients with atrial fibrillation, a comparison of 15-mg rivaroxaban once-daily and aspirin in patients with embolic stroke of undetermined source, a comparison of 20-mg or 10-mg rivaroxaban once-daily and aspirin in patients with venous thromboembolism, and 2 comparisons of 5-mg rivaroxaban twice-daily and aspirin in patients with stable cardiovascular disease or stable peripheral or carotid artery disease.
The data showed that a 10-mg once-daily or 5-mg twice-daily dose of rivaroxaban was not associated with an increased risk (OR, 1.43; 95% CI, 0.93 to 2.21; P for heterogeneity = .17) in data from 3 trials. In data from 1 trial, a 5-mg dose of apixaban twice-daily was also not shown to increase the risk of intracranial hemorrhage (OR, 0.84; 95% CI, 0.38 to 1.88).
“A 15-mg to 20-mg dose of rivaroxaban once daily, compared with aspirin, would cause an additional 3 intracranial hemorrhage per 1000 patients who receive it. The quality of a body of evidence was moderate,” Huang and colleagues wrote.
When assessing for fatal bleeding and major bleeding as secondary endpoints, it was revealed that the 15-mg to 20-mg doses of rivaroxaban were shown to be associated with an increased risk of fatal bleeding in 2 trials (OR, 2.37; 95% CI, 1.30 to 4.29; P for heterogeneity = .87). A 10-mg dose once-daily or a 5-mg dose twice-daily was not associated with that risk (OR, 1.47; 95% CI, 0.72 to 2.97; P for heterogeneity = .82), nor was a 5-mg twice-daily dose of apixaban (OR, 0.66; 95% CI, 0.19 to 2.35). The authors noted that according to the data, “a 15-mg to 20-mg dose of rivaroxaban once daily, compared with aspirin, would cause an additional 4 fatal bleeding events in 1000 patients.”
With regard to major bleeding, the risk of increased odds compared to aspirin was found to only come with rivaroxaban. The 15-mg to 20-mg dose of rivaroxaban once-daily (OR, 2.64; 95% CI, 1.68 to 4.16; P for heterogeneity = .70) as well as a 10-mg once-daily or 5-mg twice-daily (OR, 1.56; 95% CI, 1.31 to 1.85; P for heterogeneity = .87) dose of rivaroxaban were shown to carry increased risk in 2 and 3 trials, respectively. This would equal an additional 9 major bleeding events in 100 patients compared to sole aspirin use, according to the authors, with moderate to high evidence quality.
“Although the results were derived from a few (even single) large randomized clinical trials, it might provide evidence to inform the potential design and conduct of future NOAC trials beyond atrial fibrillation,” Huang and colleagues wrote. “Also, indirect comparisons implied that dabigatran in doses of 110 mg to 150 mg twice daily and edoxaban in doses of 30 mg to 60 mg once daily might have comparable risks of intracranial hemorrhage with aspirin, although such results should be interpreted with caution because of the lack of head-to-head comparisons in any randomized clinical trial.”
Subgroup analysis revealed that patients with stroke faced a higher risk of intracranial hemorrhage with 15-mg once-daily rivaroxaban compared to aspirin (OR, 4.01; 95% CI, 1.50 to 10.70), while 5-mg twice-daily apixaban did not show this risk (OR, 0.76; 95% CI, 0.20 to 2.87), nor did it in patients with atrial fibrillation (OR, 0.84; 95% CI, 0.38 to 1.88). In those patients that presented to their respective trial with venous thromboembolism, neither the 20-mg once-daily (OR, 1.53; 95% CI, 0.26 to 9.20) nor the 10-mg once-daily (OR, 0.50; 95% CI, 0.05 to 5.54) rivaroxaban was significantly associated with increased risk of intracranial hemorrhage.
“The novelty of this meta-analysis lies in the comparison across all indications of intracranial hemorrhage with individual NOAC vs aspirin,” the investigators noted. “The efficacy and safety of NOACs as a class in patients with atrial fibrillation has been well established. However, the risk of intracranial hemorrhage possessed by each individual NOAC is crucial when that NOAC is to be considered in a clinical scenario other than treatment of a patient with atrial fibrillation.”
"Although low-dose NOAC may be associated with lower risk of intracranial hemorrhage, it is likely to provide fewer benefits for ischemic event prevention," Lee said. "For example, low-dose rivaroxaban (e.g. 10 mg daily) did not reduce major cardiovascular events or stroke, as compared to aspirin, in patients with vascular disease. Therefore choosing NOAC with proper dosage, rather than low dosage, is essential when certain NOAC is used."
1. Huang WY, Singer DE, Wu YL, et al. Association of Intracranial Hemorrhage Risk With Non-Vitamin K Antagonist Oral Anticoagulant Use vs Aspirin Use: A Systematic Review and Meta-Analysis. JAMA Neurol. Epub August 13, 2018. doi: 10.1001/jamaneurol.2018.2215.