A play for low dose NACOs instead of aspirin in non AF cardioemboli?

https://jamanetwork.com/journals/jamaneurology/fullarticle/2696416?guestAccessKey=c3d1f16d-c420-41af-9f59-581276107692&utm_source=silverchair&utm_campaign=jama_network&utm_content=weekly_highlights&cmp=1&utm_medium=email



"Abstract

Importance  Non–vitamin K antagonist oral anticoagulants (NOACs) might be an attractive choice for stroke prevention in people without atrial fibrillation who may harbor a potential source of cardiac emboli, but not if certain individual NOACs carry risks of intracranial hemorrhage that are heightened relative to aspirin.

Objective  To conduct a systematic review and meta-analysis of randomized clinical trials to assess the risk of intracranial hemorrhage with individual NOACs vs aspirin across all indications.

Data Sources  We searched PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to May 28, 2018, with the terms novel oral anticoagulants, non–vitamin K antagonist oral anticoagulants, direct oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Coumadin, vitamin K antagonist, aspirin, acetylsalicylic acid, or ASA, and major bleeding, fatal bleeding, or intracranial hemorrhage. We restricted our search to clinical trials on humans. There were no language restrictions.

Study Selection  Randomized clinical trials of 3 months or longer that included a comparison of the outcomes of NOAC use vs use of aspirin.

Data Extraction and Synthesis  Two investigators independently abstracted data from eligible studies. We computed a fixed-effect estimate based on the Mantel-Haenszel method.

Main Outcomes and Measures  Odds ratios (ORs) with 95% CI were used as a measure of the association of individual NOAC vs aspirin with the risk of intracranial hemorrhage. The hypothesis that intracranial hemorrhage risk would be higher with NOACs than aspirin was formulated during data collection.

Results  Our principal analysis included 5 randomized clinical trials comparing 1 or more NOACs with aspirin, with 39 398 individuals enrolled. Pooling the results from the fixed-effects model showed that a dose of 15 to 20 mg of rivaroxaban once daily was associated with an increased risk of intracranial hemorrhage (2 trials; OR, 3.31 [95% CI, 1.42 to 7.72]) compared with aspirin, while a 10-mg dose of rivaroxaban once daily or a 5-mg dose twice daily (3 trials; OR, 1.43 [95% CI, 0.93 to 2.21]) and a 5-mg dose of apixaban twice daily (1 trial; OR, 0.84 [95% CI, 0.38 to 1.88]) were not.

Conclusions and Relevance  A 15-mg to 20-mg dose of rivaroxaban once daily is associated with substantially increased risks of intracranial hemorrhage, while smaller daily doses of rivaroxaban and apixaban were not, implying that risk increase is dose dependent. It may be worthwhile to conduct randomized clinical trials comparing specific NOACs in specific doses (eg, apixaban, 5 mg twice daily) and aspirin in patients without atrial fibrillation, but with potential sources of cardiac emboli that could cause stroke.

Introduction

Intracranial hemorrhage is a major concern when an antithrombotic agent is given to a patient, because intracranial hemorrhage is generally associated with a high risk of mortality¹ and poorer health over a lifetime,^2,3 which could offset the benefits of antithrombotic treatment in reducing major ischemic events. Such a concern may lead some physicians to resort to aspirin in certain situations, such as atrial fibrillation, when an oral anticoagulant is indicated. However, in a large clinical trial of patients with atrial fibrillation,⁴ a 5-mg dose of apixaban twice daily was shown to not cause more intracranial hemorrhage than aspirin, and the medication substantially reduced stroke risk, thereby making aspirin, with its much smaller stroke protection benefit, no longer a viable therapeutic option in people with atrial fibrillation, even from a standpoint of safety concern.

Considering the low risks of intracranial hemorrhage with non–vitamin K antagonist oral anticoagulants (NOACs) use, one may wonder whether NOACs could be applied to clinical scenarios beyond atrial fibrillation that traditionally been treated by aspirin. However, NOACs are not all the same. A network meta-analysis comparing one NOAC with another clearly show they are different in terms of effectiveness and safety.⁵ Indeed, another large clinical trial showed that a 15-mg dose of rivaroxaban once daily substantially increased the risk of intracranial hemorrhage in patients with embolic stroke of undetermined source.⁶

Although NOACs and aspirin are in general protective in different vascular beds, NOACs might be an attractive choice for stroke prevention in certain clinical situations, such as in people without recognized atrial fibrillation but with an embolic stroke of undetermined source^7,8 or atrial cardiopathy^9-11 because of their propensity to also cause stroke through cardiac emboli. Nonetheless, the benefit of NOACs compared with aspirin for stroke protection is likely to be less promising in people without atrial fibrillation, compared with people with atrial fibrillation. Therefore it is even more important to clarify whether individual NOACs in various doses harbor comparable risks of intracranial hemorrhage with aspirin based on the evidence currently available before conducting a large clinical trial in such a population. To do this, we conducted a systematic review and meta-analysis of randomized clinical trials for the comparison across all indications of intracranial hemorrhage with individual NOACs vs aspirin."